5-hydroxytryptamine receptor subtype 2a activators

Abstract

1,1'-Biphenyl-4-yl-(het)arylimino-λ6-sulfanone compounds are 5-HT2A receptor activators, and these compounds and their pharmaceutical compositions are useful for the treatment of neurological or psychiatric disorders.

Description

5-HYDROXYTRYPTAMINE RECEPTOR SUBTYPE 2A ACTIVATORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 717,978 (filed November 8, 2024), which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The present invention relates to the discovery of selective 5-HT2A positive allosteric modulators (PAMs) and agonist-positive allosteric modulators (ago-PAMs) that do not bind to the classical serotonin (5-HT) binding site as non-hallucinogenic psychedelic and / or psychoplastogens.BACKGROUND

[0003] There are fourteen serotonin (5-HT) receptors, and three 5-HT2R subtypes (5-HT2A, 5-HT2B and 5-HT2C), which are family A GPCRs, Pytliak, M, et al,, Physiol. Res. 2011, 60, 15-25. The 5-HT2R subtypes share the same orthosteric ligand (5-HT), have high sequence homology (-80%) and share some conserved signaling, Schmuck, K. et al., FEBS Lett. 1994, 342, 85-90; Felsing, D. E. et al., PLoS One. 2018, 13, e0203137, To date, most small molecules that activate the 5-HT." receptor are classical orthosteric agonists (of varying efficacies) and possess a range of poor to modest selectivity against the 5-HT2B and 5-HT2C receptors (and other biogenic amine receptors). Maroteaux, L. et al., Pharmacol. Ther. 2017, 170, 14-36.

[0004] Psychedelic compounds, such as psilocybin and LSD, exert their effects by primarily activating the 5-HT2A serotonin receptor (with some activity at 5-HT2c). Kim, K. et al., Cell 2020, 182, 1574-1588. Recently, microdosing of psychedelic compounds have shown great promise in the treatment of a wide range of CNS and mental health disorders; however, the hallucinogenic properties of these agents limit their clinical utility. Olson, D. E., ACS Pharm. Transl. Sei. 2021, 4. 563-567; Polito, V. et al., 2019, 14, e0211023. Thus, non-hallucinogenic 5-HT2A activators are in great need.

[0005] One attractive approach to develop non-hallucinogenic 5-HT2A activators is to take advantage of positive allosteric modulation of the 5-HT? A receptor. There are few examples of positive allosteric modulators (PAMs) of the 5-HT2A receptor (Chen, J. et al., J. Med. Chem. 2023, 66, 9992-10009), and this mode of pharmacology could provide greater subtype selectivityto avoid binding to, and activation of 5-HT2B, which could lead to undesired cardiovascular adverse events. Bender, A. M. et al., J. Med. Chem. 2023, 66, 11027-11039.SUMMARY

[0006] One aspect of the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof,wherein:Z1is CR1or N;Z2is CR2or N;Z3is CR3or N;Z4is CR4or N;R1, R2, R3, and R4are independently hydrogen, halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, -OCi- 4alkyl, -OCi-4fluoroalkyl, or C3-4cycloalkyl;R5and R6, at each occurrence, are independently halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, –OC1-4alkyl, –OC1-4fluoroalkyl, or C3-4cycloalkyl;R' is --L-G;L is O, S, NR7a, C(R7b)2, C(O), S(O), or S(O)2;R7ais hydrogen, C1-4alkyl, C3-4cycloalkyl, or –C1-3alkylene–C3-4cycloalkyl;R7b, at each occurrence, is independently hydrogen or C1-6alkyl,G is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, a phenyl, or a C3-8carbocyclyl, the heteroatoms being independently selected from the group consisting of O, N, and S, wherein G is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4alkyl, Ci-4fluoroalkyl, halogen, cyano, -OCi-4alkyl, -OCi-4fluoroalkyl, and C3-4cycloalkyl; R8is C1-6alkyl, C3-4cycloalkyl, or –C1-3alkylene–C3-4cycloalkyl;m is 0, 1, 2, 3, or 4; andn is 0, 1, 2, 3, 4, or 5.

[0007] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0008] In another aspect, the invention provides a method of treating a neurological or psychiatric disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt or composition thereof.

[0009] In another aspect, the invention provides a method for activating the 5-HTZA receptor in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0010] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in a method of treating a neurological or psychiatric disorder.

[0011] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in a method of activating the 5-HT2A receptor in a subject.

[0012] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the treatment of a neurological or psychiatric disorder.

[0013] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for activating the 5-HT2A receptor in a subject.

[0014] In another aspect, the invention provi des a kit compri sing a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.DETAILED DESCRIPTION1, Definitions

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, thepresent document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0016] The terms “comprise(s),” “mclude(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0017] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0,9- 1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0,5 to 1,4.

[0018] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March 's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0019] The term “alkoxy,” as used herein, refers to a group 0 -alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0020] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “Ci -ealkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “Ci-ralkyl” means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, w-propyl, zso-propyl, zz-butyl, sec-butyl, zso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3 -methylhexyl, 2,2-dimethylpentyl, 2,3 -dimethylpentyl, n-heptyl, zz-octyl, w-nonyl, and w-decyl.

[0021] The term “alkenyl,” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond.

[0022] The term “alkoxyalkyl,” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

[0023] The term “alkoxyfluoroalkyl,” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0024] The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon. Representative examples of alkylene include, but are not limited to, -CH2-, -CD2-, -CH2CH2-, -C(CH3)(H)-, -C(CH3)(D)-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0025] The term “alkylamino,” as used herein, means at least one alkyl group, as defined herein, is appended to the parent molecular moiety through an amino group, as defined herein.

[0026] The term “amide,” as used herein, means -C(O)NR- or -NRC(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl,

[0027] The term “aminoalkyl,” as used herein, means at least one amino group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein.

[0028] The term “amino,” as used herein, means -NRxRy, wherein Rx and Ry may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any other moiety where amino appends together two other moieties.amino may be -NRx-, wherein R- may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0029] The term “aryl,” as used herein, refers to a phenyl or a phenyl appended to the parent molecular moiety and fused to a cycloalkane group (e.g., the aryl may be indan-4-yl), fused to a 6-membered arene group (i.e., the aryl is naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl may be benzo[d][l,3]dioxol-5-yl). The term “phenyl” is used when referring to a substituent and the term 6-membered arene is used when referring to a fused ring. The 6-membered arene is monocyclic (e.g., benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system).

[0030] The term “cyanoalkyl,” as used herein, means at least one -CN group, is appended to the parent molecular moiety through an alkylene group, as defined herein.

[0031] The term “cyanofluoroalkyl,” as used herein, means at least one -CN group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0032] The term “cycloalkoxy,” as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety' through an oxygen atom.

[0033] The term “cycloalkyl” or “cycloalkane,” as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term “cycloalkyl” is used herein to refer to a cycloalkane when present as a substituent. A cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g,, decahydronaphthal enyl), or a bridged cycloalkyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g,, bicyclo[2.2.1]heptanyl).Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0034] The term “cycloalkenyl” or “cycloalkene,” as used herein, means a non-aromatic monocyclic or multicyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. The term “cycloalkenyl” is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g.,bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0035] The term “carbocyclyl” means a “cycloalkyl” or a “cycloalkenyl.” The term “carbocycle” means a “cycloalkane” or a “cycloalkene.” The term “carbocyclyl” refers to a “carbocycle” when present as a substituent.

[0036] The term “ 1, 1 -carbocyclylene” means a geminal divalent group derived from acycloalkyl. A representative example is 1,1 -Cs-scycloalkylene (i.e.,A furtherexample is 1,1 -cyclopropylene (i.e.,

[0037] The term “fluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluorom ethyl, pentafluoroethyl, and trifluoropropyl such as 3,3,3 -trifl uor opropy 1,

[0038] The term “difluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which two hydrogen atoms are replaced by fluorine. Representative examples of difluoroalkyl include difluoromethyl and difluoroethyl.

[0039] The term “fluoroalkylene,” as used herein, means an alkylene group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkylene include, but are not limited to -CF2 -, ---CH2CF2-, 1,2-difluoroethylene, 1, 1,2,2-tetrafluoroethylene, 1,3,3,3-tetrafluoropropylene, 1,1,2,3,3-pentafluoropropylene, and perfluoropropylene such as 1,1,2,2,3,3-hexafluoropropylene.

[0040] The term “fluoroalkoxy,” as used herein, means at least one fluoroalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy.

[0041] The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F.

[0042] The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, m which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.

[0043] The term “haloalkoxy,” as used herein, means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.

[0044] The term “halocycloalkyl,” as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms are replaced by a halogen.

[0045] The term “heteroalkyl,” as used herein, means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced by a heteroatom selected from S, O, P and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.

[0046] The term “heteroaryl,” as used herein, refers to an aromatic monocyclic heteroatomcontaining ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). The term “heteroaryl” is used herein to refer to a heteroarene when present as a substituent. The monocyclic heteroaryl are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g. 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). The five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl is an 8- to 12-membered ring system and includes a fused bicyclic heteroaromatic ring system (i.e., 1 Orc electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-l-yl), a monocyclic heteroaryl ring fused to a monocyclic heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic heteroarene (e.g., quinolin-5-yl, indol-4-yl). A bicyclic heteroaryl / heteroarene group includes a 9-membered fused bicyclic heteroaromatic ring system having four double bonds and at least one heteroatom contributing a lone electron pair to a fully aromatic 10K electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or a benzoxadiazolyl. A bicyclic heteroaryl also includes a fused bicyclic ring system composed of one heteroaromatic ring and one non-aromatic ring such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom. Other representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-l-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl),pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2-a]pyridinyl (e.g., imidazo[l,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4- >]pyridin-2-yl, and thiazolo[5,4-d\ pyrimidin-2-y 1.

[0047] The term “heterocycle” or “heterocyclic,” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The term “heterocyclyl” is used herein to refer to a heterocycle when present as a substituent. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane (e.g., 7- to 12-membered fused bicyclic heterocyclyl ring system such as hexahydro-2H-cyclopenta[b]furanyl, octahydro-3aH-cyclohepta[b]furanyl, or 3-oxabicyclo[3.1. Ojhexanyl), or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group (e.g., a 7- to 12-membered spiro heterocyclyl ring system such as 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octanyl, or 5-oxaspiro[2.4]heptanyl), or a bridged heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., a 6- to 10-membered bridged bicyclic heterocyclyl ring system such as 7-oxabicyclo[2.2.1]heptanyl or 2-oxabicyclo[2.1.1]hexanyl), or an alkenylene bridge of two, three, or four carbon atoms. The bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-l-yl). Representative examples of bicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothien-2-yl, l,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1 ]heptyl (including 2-azabicyclo[2.2. l]hept-2-yl), azabicyclo[3.1.0]hexanyi (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-l / / -indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1 jheptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-l-yl, and 3-oxabicyclo[3.1.0]hexan-6-yl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2, 5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane), The monocyclic, bicyclic, and tricyclic heterocyclyls are connected to the parent molecular moiety at a non-aromatic ring atom.

[0048] The term “hydroxyl” or “hydroxy,” as used herein, means an -OH group.

[0049] The term “hydroxyalkyl,” as used herein, means at least one -OH group, is appended to the parent molecular moiety through an alkylene group, as defined herein.

[0050] The term “hydroxyfluoroalkyl,” as used herein, means at least one -OH group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0051] Terms such as "alkyl," "cycloalkyl," "alkylene," etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance ( e.g., "Ci-4alkyl," "C3-6cycloalkyl," "Ci-4alkylene"). These designations are used as generally understood by those skilled in the art. For example, the representation "C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, "Cbalkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in "Ci-4," the members of the group that follows may have any number of carbon atoms falling within the recited range. A "Ci-4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0052] The term “substituted” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =0 (oxo), =S (tliioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfmylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0053] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc,

[0054] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0055] Abbreviations:AcOH is acetic acidaq is aqueousatm is atmosphere(s)BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthylBoc is tert-butoxy carbonylBOC2O is di-tert-butyl dicarbonateB2pin2 is bis(pinacolato)diboronBrettPhos is 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl BrettPhos Pd G3 is [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1,1'- biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonateBu is butylt-BuOH is tert-butanolCDI is 1,1'-carbonyldiimidazoleCD2O is deuterated formaldehydeCelite® is diatomaceous earthCSA is (1S,4R)-10-camphorsulfonic acidDCE is 1,2-di chloroethaneDCM is dichloromethaneDEA is diethylamineDMAP is 4-dimethylaminopyridineDMF is A’V-dimethylformamide;DMP or Dess-Martin periodinane is l,l,l-tris(acetyloxy)-l,l-dihydro-l,2-benziodoxol-3-(l / / )- oneDIAD is di isopropyl azodi carboxylateDIPEA or DIEA is diisopropylethylamineDMSO is dimethyl sulfoxideDowtherm™ A is a eutectic mixture of 26.5% diphenyl + 73.5% diphenyl oxideDtBAD is di-tert-butyl-azodicarboxylateeq or eq, is equivalent(s)EtOAC is ethyl acetate(4,4'-dtbbpy)NiC12 is 4,4'-bis(l,l-dimethylethyl)-2,2'-bipyndine] nickel (II) dichloride Et2O is diethyl etherEtOH is ethanolh or hr is hour(s)Hex is hexane(s)HATU is hexafluorophosphate azabenzotriazole tetramethyl uroniumHMPA is hexamethylphosphoramideIPA is isopropyl alcoholKOAc is potassium acetateLAH is lithium aluminum hydrideLDA is lithium diisopropylamideLiHMDS / LHMDS is lithium bis(trimethylsilyl)amidemCPBA is meta-chloroperoxy benzoic acidMeCN or ACN is acetonitrileMeI is Iodomethane / methyl iodideMeOD is CD3OD (methanol-dr)MeOH is methanolmin is minute(s)NaBH(OAc)3 is sodium triacetoxyborohydrideNaOAc is sodium acetateNaOtBu is sodium tert-butoxideNaOMe is sodium methoxideNBS is N-bromosuccinimideNCS is N-chlorosuccinimideNH4OAc is ammonium acetateNMO is 4-methylmorpholine N-oxideNMP is / V-methyl-2-pyrrolidone[Pd(allyl)(tBuBrettPhos)]OTf is trifluoromethanesulfonate allyl[(2-Di-tert-butylphosphino-3,6- dimethoxy-2',4',6'-triisopropyl- 1, 1 '-biphenyl)-2-(2'-amino- 1, 1 '-biphenyl)] palladium(II) Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0)Pd(dppf)C12 is [1,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(OAc)2 is palladium(II)acetatePd(PPh3)4 is tetrakis(triphenylphosphine)palladium(0)PIDA is phenyliodine(III) diacetate (i.e., lodobenzene diacetate)PPA is polyphosphoric acidPPh3 is triphenylphosphinePPTS is pyridinium p-toluenesulfonatert or r.t. is room temperaturesat. is saturatedsec is second(s)SCX cartridge or HF SCX cartridge is a strong cation exchanger cartridge (i.e. Agilent part# 14256027)SFC is supercritical fluid chromatographyTBAC or TBACI is tetrabutylammonium chloridetBuXPhos is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenylt-BuXPhos-Pd-G1 is [2-(Di-tert-butylphosphino)-2',4',6'-triisopropyl- 1, 1 '-biphenyl] [2-(2- aminoethyl)phenyl)] palladium(II) chlorideTEA or Et3N is triethylamineTFA is trifluoroacetic acidTHF is tetrahydrofuranTMB is trimethylboroxineTosCl is para-toluenesulfonyl chloridetosyl is para-toluenesulfonylXantphos is 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene2. Compounds

[0056] In one aspect, the invention provides compounds of formula (I), wherein Z1, Z2, Z3, Z4, R5, R6, R7, R8, m, and n are as defined herein,

[0057] Unsubstituted or substituted rings (i.e., optionally substituted) such as aryl, heteroaryl, etc. are composed of both a ring system and the ring system's optional substituents. Accordingly, the ring system may be defined independently of its substituents, such that redefining only the ring system leaves any previous optional substituents present. For example, a 5- to 12-membered heteroaryl with optional substituents may be further defined by specifying the ring system of the 5- to 12-membered heteroaryl is a 5- to 6-membered heteroaryl (i.e., 5- to 6-membered heteroaryl ring system), in which case the optional substituents of the 5- to 12-membered heteroaryl are still present on the 5- to 6-membered heteroaryl, unless otherwise expressly indicated.

[0058] Where heterocyclic and heteroaromatic ring systems are defined as "containing" specified heteroatoms (e.g., 1-3 heteroatoms independently selected from the group consisting of 0, N, and S), any ring atoms of the heterocyclic and heteroaromatic ring systems that are not one of the specified heteroatoms are carbon atoms.

[0059] In the following, numbered embodiments of the invention are disclosed. The first embodiment is denoted El, and subsequent embodiments are denoted El.1, El.2, E2, E2.1, E3, E3.1, etc.

[0060] El. A compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein:Z1is CR1or N;Z2is CR2or N;Z3is CR3or N;Z4is CR4or N;R1, R2, R3, and R4are independently hydrogen, halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, OCi- 4alkyl, ~OCi-4fluoroalkyl, or C3-4cycloalkyl;R5and R6, at each occurrence, are independently halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, - OCi-4alkyl, ~OCi-4fluoroalkyl, or Cb-rcycloalkyl;R7is -L-G;L is O, S, NR7a, C(R7b)2, C(O), S(O), or S(O)2;R7ais hydrogen, Ci-4alkyl, C3-4cycloalkyl, or -Ci-salkylene-Cb-rcycloalkyl;R7b, at each occurrence, is independently hydrogen or Ci -ealkyl,G is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, a phenyl, or a C3-8carbocyclyl, the heteroatoms being independently selected from the group consisting of O, N, and S, wherein G is optionallysubstituted with 1-4 substituents independently selected from the group consisting of Ci- 4alkyl, Ci-4fluoroalkyl, halogen, cyano, -OCi-ialkyl, -OCi- fluoroalkyl, and Cs-icycloalkyl; R8is Ci-ealkyl, C3-4cycloalkyl, or -Ci-salkylene-Cs-icycloalkyl;m is 0, 1, 2, 3, or 4; andn is 0, 1, 2, 3, 4, or 5.

[0061] El l. The compound of El, or a pharmaceutically acceptable salt thereof, wherein the sulfoximine stereochemistry is (S):(I-A).

[0062] El.2. The compound of El, or a pharmaceutically acceptable salt thereof, wherein the sulfoximine stereochemistry is (R):(I-B).

[0063] E2. The compound of any of El -El.2, or a pharmaceutically acceptable salt thereof, wherein Z1is CR1.

[0064] E2.1. The compound of any of E1-E2, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

[0065] E3. The compound of any of El -E2.1, or a pharmaceutically acceptable salt thereof, wherein Z2is CR2.

[0066] E3.1. The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

[0067] E4. The compound of any of El -E3.1, or a pharmaceutically acceptable salt thereof, wherein Z3is CR3.

[0068] E4.1. The compound of any of E1-E4, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

[0069] E5. The compound of any of El -E3.1, or a pharmaceutically acceptable salt thereof, wherein Z3is N.

[0070] E6. The compound of any of E1-E5, or a pharmaceutically acceptable salt thereof, wherein Z4is CR4.

[0071] E6.1. The compound of any of E1-E6, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

[0072] E6.2. The compound of any of E1-E6, or a pharmaceutically acceptable salt thereof, wherein R4is halogen.

[0073] E6.3. The compound of E6.2, or a pharmaceutically acceptable salt thereof, wherein R4is fluoro.

[0074] E7. The compound of any of E1-E5, or a pharmaceutically acceptable salt thereof, wherein Z4is N.

[0075] E8. The compound of any of E1-E7, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0076] E9. The compound of any of E1-E8, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

[0077] E9.1. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0078] E9.2. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0079] E9.3. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0080] E10. The compound of any of El -E9.3, or a pharmaceutically acceptable salt thereof, wherein R5, at each occurrence, is independently a halogen.

[0081] E10.1. The compound of El 0, or a pharmaceutically acceptable salt thereof, wherein R5, at each occurrence, is fluoro.

[0082] El 1. The compound of any of El -El 0.1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-a), (I-b), (I-c), (I-d), or (I-e):

[0083] El 1.1. The compound of El 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-a).

[0084] El 1.2. The compound of El 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-b).

[0085] El 1.3. The compound of El 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-c).

[0086] El 1.4. The compound of El 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-d).

[0087] El 1.5. The compound of El 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-e).

[0088] Ell. 6. The compound of El 1.1, or a pharmaceutically acceptable salt thereof,wherein the compound has formula

[0089] El 1.7. The compound of El 1.1, or a pharmaceutically acceptable salt thereof,wherein the compound has formula

[0090] El 1.8. The compound of El 1.2, or a pharmaceutically acceptable salt thereof,wherein the compound has formula

[0091] El 1.9. The compound of El 1.2, or a pharmaceutically acceptable salt thereof,wherein the compound has formula

[0092] Ell. 10. The compound of El 1.3, or a pharmaceutically acceptable salt thereof,wherein the compound has formula

[0093] Ell. 10, The compound of El 1.3, or a pharmaceutically acceptable salt thereof,

[0094] El 1.12. The compound of El 1.4, or a pharmaceutically acceptable salt thereof,wherein the compound has formula

[0095] El 1.13. The compound of El 1.4, or a pharmaceutically acceptable salt thereof,wherein the compound has formula

[0096] Ell. 14. The compound of El 1.5, or a pharmaceutically acceptable salt thereof,wherein the compound has formula-el).

[0097] Ell. 15. The compound of Ell.5, or a pharmaceutically acceptable salt thereof,wherein the compound has formulael).

[0098] E12. The compound of any of El -El 1.15, or a pharmaceutically acceptable salt thereof, wherein L is O, C(R7b)2, or C(O)

[0099] E12.1. The compound of E12, or a pharmaceutically acceptable salt thereof, wherein L is O.

[0100] E12.2. The compound of E12, or a pharmaceutically acceptable salt thereof, wherein L is C(R7b)2.

[0101] El 2.3. The compound of El 2.2, or a pharmaceutically acceptable salt thereof, wherein R7bis hydrogen.

[0102] El 2.4. The compound of El 2, or a pharmaceutically acceptable salt thereof, wherein L is C(O).

[0103] El 3. The compound of any of E1-E12.4, or a pharmaceutically acceptable salt thereof, wherein G is the optionally substituted 5- to 6-membered heteroaryl containing 1-3 heteroatoms.

[0104] E13.1. The compound of any of E1-E13, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 5- to 6-membered heteroaryl at G is a 6-membered heteroaryl containing one nitrogen atom.

[0105] E13.2. The compound of El 3.1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 6-membered heteroaryl at G is pyridinyl.

[0106] E13.3. The compound of E13.2, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted pyridinyl at G is pyridin-4-yl.

[0107] E13.4. The compound of any of E1-E13.3, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 6-membered heteroaryl at G is independently substituted with one of the optional substituents at each of the positions meta to L.

[0108] E13.5. The compound of E13.4, or a pharmaceutically acceptable salt thereof, wherein the substituents at each of the positions meta to L are Ci-4alkyl.

[0109] E13.6. The compound of E13.5, or a pharmaceutically acceptable salt thereof, wherein the substituents at each of the positions meta to L are methyl.

[0110] E13.7. The compound of E13.5, or a pharmaceutically acceptable salt thereof,wherein

[0111] E13.8. The compound of E13.6 or E13.7, or a pharmaceutically acceptable saltthereof, wherein G

[0112] E14. The compound of any of El -El 2.4, or a pharmaceutically acceptable salt thereof, wherein G is the optionally substituted 4- to 8-membered heterocyclyl containing 1-2 heteroatoms.

[0113] E14.1. The compound of any of E1-E12.4, E13.1-E13.6, or E14, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4-to 8-membered heterocyclyl at G contains a first nitrogen, the first nitrogen being bonded to L,the ring system of the heterocyclyl containing 0 or 1 additional heteroatom selected from the group consisting of 0, N, and S.

[0114] El 4.2. The compound of E14.1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 8-membered heterocyclyl at G is morpholin-4-yl, piperazm-l-yl, l,4-oxazepan-4-yl, 3-azabicyclo[3.2.1]octan-3-yl, pyrrolidin-1-yl, or pipendin-l-yl.

[0115] E14.3. The compound of E14.2, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 8-membered heterocyclyl at G is morpholin-4-yl.

[0116] E14.4. The compound of E14.2 or E14.3, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heterocyclyl at G is independently optionally substituted with 1-2 of the optional substituents at each of the positions 2 ring atoms removed from L.

[0117] E14.5. The compound of E14.4, or a pharmaceutically acceptable salt thereof, wherein the optional substituents at each of the positions 2 ring atoms removed from L are Ci-

[0118] E14.6. The compound of E14.5, or a pharmaceutically acceptable salt thereof, wherein the optional substituents at each of the positions 2 ring atoms removed from L are methyl.

[0119] E14.7. The compound of E14.6, or a pharmaceutically acceptable salt thereof,wherein

[0121] E14.9. The compound of E14.7, or a pharmaceutically acceptable salt thereof,wherein

[0122] E14.10. The compound of E14.8 or E14.9, or a pharmaceutically acceptable saltthereof, wherein G is 'Y • °

[0123] El 5. The compound of any of E1-E12.4, or a pharmaceutically acceptable salt thereof, wherein G is the optionally substituted phenyl.

[0124] El 5.1. The compound of any of El -E12.4 or El 5, or a pharmaceutically acceptable salt thereof, wherein the phenyl at G is independently substituted with one of the optional substituents at each of the positions meta to L.

[0125] E15.2. The compound of E15.1, or a pharmaceutically acceptable salt thereof, wherein the substituents at each of the positions meta to L are Ci-4alkyl.

[0126] El 5.3. The compound of El 5.2, or a pharmaceutically acceptable salt thereof, wherein the substituents at each of the positions meta to L are methyl.

[0127] El 6. The compound of any of El -El 4.10, or a pharmaceutically acceptable salt

[0128] E l 6.1. The compound of El 6, or a pharmaceutically acceptable salt thereof,wherein

[0129] El 6.2. The compound of El 6, or a pharmaceutically acceptable salt thereof.wherein

[0130] El 7. The compound of any of El -El 6.2, or a pharmaceutically acceptable salt thereof, wherein R8is Ci -ealkyl.

[0131] El 7.1. The compound of El 7, or a pharmaceutically acceptable salt thereof, wherein R8is methyl.

[0132] El 7.2. The compound of El 7, or a pharmaceutically acceptable salt thereof, wherein R8is ethyl.

[0133] El 8. The compound of E l selected from the group consisting of:((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[l,r-biphenyl]-4- yI)(methyl)-6-suIfanone;((4-(((cis)-2,6-dimethylmorpholino)methyl)phenyl)imino)(4'-fluoro-[l,r-biphenyl]-4-yl)(methyl)-A,6-sulfanone;((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)-3-fluorophenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone;((2-((2,6-dimethylpyridin-4-yl)oxy)pyrimidin-5-yl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-A,6-sulfanone;((4-((2,6-dimethylpyridin-4-yl)oxy)-3-fluorophenyl)imino)(4'-fluoro-[l,l'-biphenyl]-4- yl)(methyl)-k6-sulfanone;((4-(((cis)-2,6-dimethylmorpholino)methyl)phenyl)imino)(ethyl)(4'-fluoro-[l,r-biplienyl]-4- yl)-X6-sulfanone;((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)-3-fluorophenyl)imino)(ethyl)(4'-fluoro-[l,r- biphenyl] -4-yl)-X6-sulfanone;((2-((2,6-dimethylpyridin-4-yl)oxy)pyrimidin-5-yl)imino)(ethyl)(4'-fluoro-[l,r-biphenyl]-4- yl)-X6-sulfanone;((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(ethyl)(4'-fluoro-[l,r-biphenyl]- 4-yl)-λ6-sulfanone;(S)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-A6-sulfanone;(R)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-A6-sulfanone;((4-((trans)-3,4-dimethylpyrrolidine-1-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-X6-sulfanone;(4'-fluoro-[ 1, 1 '-biphenyl]-4-yl)(methyl)((4-(morpholine-4-carbonyl)phenyl)imino)-6- sulfanone;((4-((trans)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-X6-sulfanone;(4'-fluoro-[ 1, 1 '-biphenyl]-4-yl)(methyl)((4-(2,2,6,6-tetramethylmorpholine-4- carbonyl)phenyl)imino)-λ6-sulfanone;((4-((cis)-3,5-dimethylpiperidine-1-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-7 -sulfanone;(4'-fluoro-[l,r-biphenyl]-4-yl)(methyl)((4-((cis)-3,4,5-trimethylpipera ine-l- carbonyl)phenyl)imino)-λ6-sulfanone;((4-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)phenyl)imino)(4'-fluoro-[l,l'-biphenyl]-4- yl)(methyl)-7 -sulfanone;((4-(2,2-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[l,r-biphenyl]-4- yl)(methyl)-7 -sulfanone;((4-(l,4-oxazepane-4-carbonyl)phenyl)imino)(4'-fluoro-[l,l'-biphenyl]-4-yl)(methyl)-X6- sulfanone;(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)((4-(piperidine-1-carbonyl)phenyl)imino)-λ6-sulfanone; (S)-[ 1, 1 '-biphenyl]-4-yl((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)immo)(methyl)- A6-sulfanone;(S)-((4-((cis)-2,6-dimetliylmorpholine-4-carbonyl)phenyl)immo)(2'-fluoro-[l,r-biphenyl]-4- yl)(methyl)-6-sulfanone;(S)-((4-((cis)-2,6-dimetliylmorpholine-4-carbonyl)phenyl)immo)(3'-fluoro-[l,r-biphenyl]-4- yl)(methyl)-6-sulfanone;(S)-(3',4'-difluoro-[l,r-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4- carbonyl)phenyl) imino) (methyl) -A6- SU Ifanone;(S)-(2',4'-difluoro-[l,r-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4- carbonyl)phenyl)imino)(methyl)-A6-sulfanone;(R)-[l,l'-biphenyl]-4-yl((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)- A6-sulfanone;(R)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(2'-fluoro-[l,l'-biphenyl]-4- yl)(methyl)-A6-sulfanone;(R)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(3'-fluoro-[l,l'-biphenyl]-4- yl)(methyl)-A6-sulfanone;(R)-(3',4'-difluoro-[l,r-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4- carbonyI)phenyl)imino)(methyl)-6-sulfanone;(R)-(2',4'-difluoro-[l,r-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4- carbony 1 ) ph eny 1) im ino)(methy 1) -X6- sulfanone;or a pharmaceutically acceptable salt thereof,

[0134] E19. A pharmaceutical composition comprising the compound of any of E1-E18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0135] E20. A method of activating the 5-HT2A receptor in a subject in need thereof, comprising administering to the subject, a therapeutically effective amount of the compound of any of El -El 8, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of El 9.

[0136] E21. The method of E20, wherein the subject suffers from a neurological or psychiatric disorder.

[0137] E22. A method of treating a neurological or psychiatric disorder comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any of El -El 8, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition ofE19.

[0138] E23. A compound of any of E1-E18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of El 9, for use in a method of treating a neurological or psychiatric disorder.

[0139] E24. Use of a compound of any of El -El 8, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of El 9, in the manufacture of a medicament for treating a neurological or psychiatric disorder.

[0140] E25. The method, compound or pharmaceutically acceptable salt thereof, pharmaceutical composition, or use of any of E21-E24, wherein the neurological or psychiatric disorder is selected from the group consisting of depression, cognitive dysfunction, psychomotor retardation, migraine, cluster headaches, social and emotional withdrawal, sleep disorders, bipolar disorder, negative thinking, panic disorder, anxiety7, chronic pain, eating disorders, body dysmorphic disorder (BDD), substance use disorder (SLID), dementia in Parkinson’s disease, and obsessive compulsive disorder.

[0141] Throughout the embodiments and description of the compounds of the invention, all instances of haloalkyl may be fluoroalkyl (e.g., any Ci-rhaloalkyl may be Ci-4fluoroalkyl).

[0142] Compound names and / or structures can be assigned / determined by using the Struct:::Name naming algorithm as part of CHEMDRAW® ULTRA.

[0143] The compound may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “5” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in 1UPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl.Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. In the compounds disclosed herein, a chiral atom depicted or described without a specific stereochemical configuration (e.g., a straight bond, not wedged or dashed bond, HC(OH)(CH3)(CH2CH3)) encompasses any stereochemical configuration at the chiral atom.

[0144] Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furmss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods.

[0145] It should be understood that the compound may possess tautomeric forms, as well as geometric isomers, and that these also constitute embodiments of the disclosure.

[0146] In the compounds of formula (I), and any subformulas, any "hydrogen" or "H," whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes1H (protium) and2H (deuterium).

[0147] The present disclosure also includes isotopically-labeled compounds (e g., deuterium labeled), where an atom in the isotopically-labeled compound is specified as a particular isotope of the atom. Exampl es of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,ljC,14C,15N,18O,17O,J1P,32P,35S,i8F, andj6Cl, respectively. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positronemitting isotopes that can be incorporated in compounds of formula (I) arenC,1JN,15O, and18F.

[0148] Isotopically-enriched forms of compounds of formula (I), or any subformulas, may generally be prepared by conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples using an appropriate isotopically-enriched reagent in place of a non-isotopically-enriched reagent. The extent of isotopic enrichment can be characterized as a percent incorporation of a particular isotope at an isotopically -labeled atom (e.g., % deuterium incorporation at a deuterium label).

[0149] The disclosed compounds may form pharmaceutically acceptable salts of the compounds. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, tri chloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0150] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, ApV-dimethylaniline, A-methylpiperidme, A-methylmorpholme, dicyclohexylamme, procaine, dibenzylamine, N, N-dibenzylphenethylamine, 1-ephenamine and N. N ’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.3. Pharmaceutical Compositions and Formulations

[0151] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The disclosed compounds may also be provided as formulations, such as spray-dried dispersion formulations.

[0152] The pharmaceutical compositions and formulations may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention (e.g., a compound of formula (1) or any of its subformulas) are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0153] For example, a therapeutically effective amount of a compound of formula (I) or any of its subformulas, may be about 1 mg / kg to about 1000 mg / kg, about 5 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 20 mg / kg to about 800 mg / kg, about 25 mg / kg to about 750 mg / kg, about 30 mg / kg to about 700 mg / kg, about 35 mg / kg to about 650 mg / kg, about 40 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0154] The pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0155] Thus, the compounds and their physiologically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington's Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.), Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0156] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[0157] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives,glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.

[0158] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.

[0159] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.

[0160] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.

[0161] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0,1 to about 10%.

[0162] Suitable colorants include a colorant such as an FD& C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0163] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1,0%.

[0164] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.

[0165] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxy toluene (“BUT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%.

[0166] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative's) in a systemic or topical composition is typically about 0.01 to about 5%.

[0167] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.

[0168] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

[0169] Suitable suspending agents include AVICEL RC-591 (from EMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.

[0170] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C. T. F. A. Cosmetic Ingredient Handbook, 1992, pp.587-592;Remington’s Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5%.

[0171] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of an active compound (e.g., a compound of formula (I) or any of its subformulas) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.

[0172] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.

[0173] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricantsinclude magnesium stearate, stearic acid, and talc. Specific colorants are the FD& C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0174] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I) or any of its subformulas), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0175] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.

[0176] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0177] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0178] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropylmethylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0179] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be m any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I) or any of its subformulas), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0180] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0181] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0182] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0183] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane- 1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropylmyristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%.

[0184] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%.

[0185] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.

[0186] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.

[0187] The amount of thickener(s) in a topical composition is typically about 0% to about 95%.

[0188] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organ! cal ly-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxy vinyl polymer, sodium carboxy methyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[0189] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.

[0190] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.4. Methods of Use

[0191] The disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treatment of disorders, such as neurological or psychiatric disorders. The disclosed compounds and pharmaceutical compositions may also be used in methods for increasing 5-HT2A receptor activity in a subject. The methods further include cotherapeutic methods for improving treatment outcomes. In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions.a. Treating disorders

[0192] The disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treating, preventing, ameliorating, controlling, reducing, or reducing the risk of a variety of disorders, or symptoms of the disorders, in which a patient may benefit from increasing activity of the 5-HT2A receptor. Disorders include neurological or psychiatric disorders such as depression, cognitive dysfunction, psychomotor retardation, migraine, cluster headaches, social and emotional withdrawal, sleep disorders, bipolar disorder, negative thinking, panic disorder, anxiety, chronic pain, eating disorders, body dysmorphic disorder (BDD), substance use disorder (SUD), dementia m Parkinson’s disease, and obsessive compulsive disorder. The methods may comprise administering to a subject in need of such treatment a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effecti ve amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof.

[0193] The compounds and compositions may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The compounds and compositions may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions, in combination with other agents.

[0194] In the treatment of conditions such as those that would benefit from increasing activity of the 5-HT2A receptor, an appropriate dosage level may be about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. The dosage level may be about 0.1 to about 250 mg / kg per day, or about 0.5 to about 100 mg / kg per day. Asuitable dosage level can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. b. Increasing Activity of the 5-HTIA Receptor

[0195] Compounds may augment activity of the 5-HT2A receptor by positive allosteric modulation and / or by direct agonism. Positive allosteric modulation may occur through compound binding to the 5-HT2A receptor (e.g., at an allosteric site) and augmentation of receptor activity elicited by serotonin or other 5-HT2A receptor agonist. Direct agonism may occur through compound binding to the 5-HT2A receptor (e.g., at an allosteric site) and augmentation of receptor activity independent of serotonin or other 5-HT2A receptor agonist ligand. Without wishing to be bound by theory, the compounds are believed to bind to a site on the 5-HT2A receptor distinct from the classical serotonin binding site, including when augmentating 5-HT2A receptor activity by direct agonism (i.e., allosteric agonism). Thus, compounds may function as positive allosteric modulators or as Ago-PAMs, the latter referring to compounds having both positive allosteric modulator and allosteric agonist activity.

[0196] Compounds possessing positive allosteric modulatory activity offer numerous advantages in terms of opportunities for ligand or receptor signal bias, both pure PAM and Ago-PAM pharmacological profiles, varying degrees of PAM efficacy, and receptor activation only when 5-HT is present, and hence, less internalization / desensitization. Conn, P. J. et al., Nat. Rev. DrugDiscov. 2014, 13, 692-708. Thus, the discovery and development of highly selective 5-HT2A PAMs and ago-PAMs represent key small molecule therapeutics with the potential to treata wide-range of neurological or psychiatric disorders without dose-limiting hallucinogenic limitations. The neurological or psychiatric disorders include, but are not limited to: depression, cognitive dysfunction, psychomotor retardation, migraine, cluster headaches, social and emotional withdrawal, sleep disorders, bipolar disorder, negative thinking, panic disorder, anxiety, chronic pain, eating disorders, body dysmorphic disorder (BDD), substance use disorder (SUD), dementia in Parkinson’s disease, and obsessive compulsive disorder. Maroteaux, L. et al., Pharmacol. Ther. 2017, 170, 14-36; Kozlowska, U. et al., J. Neurochem. 2021, 162, 89-108.

[0197] In some embodiments, the disclosure relates to a method for increasing activity of the 5-HT 2A receptor receptor in at least one cell, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one product of a disclosed method in an amount effective to increase activity of the 5-HT2A receptor in the at least one cell. In some embodiments, the cell is mammalian, for example, human. In some embodiments, the cell has been isolated from a subject prior to the contacting step. In some embodiments, contacting is via administration to a subject.

[0198] In some embodiments, the invention relates to a method for increasing activity of the 5-HT2A receptor in a subject, comprising the step of administering to the subject at least one disclosed compound or at least one product of a disclosed method in a dosage and amount effective to increase activity of the 5-HT2A receptor in the subject. In some embodiments, the subject is mammalian, for example, human. In some embodiments, the mammal has been diagnosed with a need for 5-HT2A receptor activation / potentiation prior to the administering step. In some embodiments, the mammal has been diagnosed with a need for 5-HT2A receptor activation / potentiation prior to the administering step. In some embodiments, the method further comprises the step of identifying a subject in need of 5-HT2A receptor activation / potentiation,

[0199] In some embodiments, the disclosure relates to a method for increasing acti vity of the 5-HT2A receptor in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the compound administered increases activity of the 5-HT2A receptor with an EC50 of less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, or less than about 100 nM. In some embodiments, the compoundadministered increases activity of the 5-HT2A receptor with an EC50 of between about 10 μM and about 1 nM, about 1 pM and about 1 nM, about 100 nM and about 1 nM, or about 10 nM and about 1 nM.

[0201] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed with a need for increase of 5-HT2A receptor activity prior to the administering step. In some embodiments, the method further comprises the step of identifying a mammal in need of increasing 5-HT2A receptor activity. In some embodiments, the increased activity of the 5-HT2A receptor treats a disorder associated with 5-HT2A receptor activity in the mammal.

[0202] In some embodiments, increasing activity of the 5-HT2A receptor in a mammal is associated with the treatment of a disorder associated with the 5-HT2A receptor, such as a disorder disclosed herein. The disorders that may be treated by compounds disclosed herein include neurological or psychiatric disorders such as depression, cognitive dysfunction, psychomotor retardation, migraine, cluster headaches, social and emotional withdrawal, sleep disorders, bipolar disorder, negative thinking, panic disorder, anxiety, chronic pain, eating disorders, body dysmorphic disorder (BDD), substance use disorder (SUB), dementia in Parkinson’s disease, and obsessive compulsive disorder.c. Combination Therapies

[0203] In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be an interval of time between administration of the additional therapeuti c agent and the disclosed compounds. In some embodiments, administration of an additional therapeutic agent with a disclosed compound may allow lower doses of the other therapeutic agents and / or administration at less frequent intervals. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients maybe used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula (I) or any of its subformulas. The abovecombinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.

[0204] The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound may be used. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent. Thus, when used in combination with one or more other active ingredients, the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly.

[0205] The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.

[0206] The above combinations include combinations of a disclosed compound not only with one other active compound, but also with two or more other active compounds. Likewise, disclosed compounds can be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which disclosed compounds are useful. Such other drugs can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to a disclosed compound is preferred. Accordingly, the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

[0207] The weight ratio of a disclosed compound to the second active ingredient can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose ofeach will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of a disclosed compound to the other agent will generally range from about 1000: 1 to about 1: 1000, preferably about 200: 1 to about 1: 200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0208] In such combinations a disclosed compound and other active agents can be administered separately or in conjunction. In addition, the administration of one element can be prior to, concurrent to, or subsequent to the administration of other agent(s).

[0209] Accordingly, the disclosed compounds can be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compounds. The subject compound and the other agent can be coadministered, either in concomitant therapy or in a fixed combination.

[0210] In some embodiments, the compound can be employed in combination with any other agent that is used to treat a disorder described herein, such as a standard of care therapy for a disorder that would benefit from 5-HT2A receptor activity, such as a disorder described herein.

[0211] In some embodiments, the compound can be employed in combination with selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, or other standard of care agents.d. Modes of Administration

[0212] Methods of treatment may include any number of modes of administering a discl osed composition. Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the agent may be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e.g., mannitol, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or nonaqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g. Gelucire™). In the pharmaceuticalcomposition, the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition.

[0213] For parenteral administration, the agent can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration, the agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.

[0214] The term “parenterally,” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.5. Kits

[0215] In one aspect, the disclosure provides a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof and instructions for use thereof.

[0216] The kits may comprise information, instructions, or both that use of the kit will provide treatment for medical conditions in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. In addition or in the alternative, the kit may include the compound, a composition, or both; and information, instructions, or both, regarding methods of application of compound, or of composition, preferably with the benefit of treating or preventing medical conditions in mammals (e.g., humans).6. Chemical Synthesis

[0217] Compounds of formula (I) or any of its subformulas may be synthesized as shown in the following schemes and examples.

[0218] The compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, byrecrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel’s Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0219] A disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like.

[0220] Reaction conditions and reaction times for each individual step can vary’ depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to described herein.

[0221] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found inPGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic processes described herein.

[0222] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[0223] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0224] It can be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

[0225] All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer.1H chemical shifts are reported in 5 values in ppm downfield with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, integration, Reversed-phase LCMS analysis was performed using an Agilent 1200 system comprised of a binary pump with degasser, high-performance autosampler, thermostatted column compartment, C18 column, diode-array detector (DAD) and an Agilent 6150 MSD with the following parameters. The gradient conditions were 5% to 95% acetonitrile with the aqueous phase 0.1% TFA in water over 1.4 minutes. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 pm, 1.0 x 50 mm) at 0.5 mL / min, with column and solvent temperatures maintained at 55 °C. The DAD was set to scan from 190 to 300 nm, and the signals used were 220 nm and 254 nm (both with a band width of 4nm). The MS detector was configured with an electrospray ionization source, and the low- resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13cycles / second, and peak width of 0.008 minutes. The drying gas flow was set to 13 liters per minute at 300 °C and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set at 3000 V, and the fragmentor voltage was set at 100V. Data acquisition was performed with Agilent Chemstation and Analytical Studio Reviewer software.EXAMPLE 1. Preparation of ([1,1'-biphenyl]-4-yl)(imino)-λ6-sulfanonesGeneral Scheme 1Example compounds according to General Scheme 1:

[0226] (4-Bromophenyl)(imino)(methyl)-λ6-sulfanone. To a solution of (4-bromophenyl)(methyl)sulfane (1.50 g, 7.39 mmol, 1 eq) in MeOH (37 mL) was added ammonium carbonate (3.26 g, 34.0 mmol, 4.6 eq) and Iodobenzene diacetate (7.14 g, 22.2 mmol, 3 eq). The resulting reaction mixture was stirred at r.t. for 1 h, after which time sat. NaHCO3 solution was slowly added. The aqueous layer was extracted with DCM, and combined organic extracts were dried over MgSO4. Solvents were filtered and concentrated, and the crude residue was purified by normal-phase column chromatography (3-100% EtOAc in hexanes, then 10% MeOH in EtOAc) to give the title compound. (1.34 g, 78%).1H NMR (400 MHz, CDCl3) δ7.89 - 7.85 (m, 2H), 7.70 - 7.67 (m, 2H), 3.09 (s, 3H). ES-MS [M+1]+ = 233.9, 235.9.

[0227] (4'-Fluoro-[1,1'-biphenyl]-4-yl)(imino)(methyl)-λ6-sulfanone. (4-Bromophenyl)(imino)(methyl)-λ6-sulfanone (500 mg, 2.14 mmol, 1 eq), 4-fluorophenylboronic acid (359 mg, 2.56 mmol, 1.2 eq), cesium carbonate (2.10 g, 6.41 mmol, 3 eq), and Pd(dppf)Cb. (235 mg, 0.32 mmol, 0.15 eq) were combined in a flask, which was sealed and placed under an inert atmosphere. 1,4-Dioxane (10 mL), and H2O (2 mL) were then added, and solvents were degassed under N2. The resulting reaction mixture was then stirred at 110 °C overnight, after which time the reaction mixture was cooled to r.t. and diluted with DCM and H2O. The aqueous layer was extracted with DCM, and the combined organic extracts were dried over MgSO4 Solvents were filtered and concentrated, and crude residue was purified by normal-phase column chromatography (3-100% EtOAc in hexanes, then 0-5% MeOH in DCM) to give the title compound (521 mg, 98%).1H NMR (400 MHz, CDCl3) δ8.08 - 8.05 (m, 2H), 7.72 - 7.69 (m, 2H), 7.60 - 7.55 (m, 2H), 7.20 - 7.14 (m, 2H), 3.15 (s, 3H), 2.60 (br s, 1H). ES-MS [M+1]+ = 250.1.

[0228] Ethyl(4'-fluoro-[1,1'-biphenyl]-4-yl)(imino)-λ6-sulfanone. The title compound was prepared in a similar manner to (4'-fluoro-[1,1'-biphenyl]-4-yl)(imino)(methyl)-λ6-sulfanone. ES-MS [M+l] = 264.0.EXAMPLE 2. Preparation of (4-bromophenyl)methanone amidesGeneral Scheme 2Example compounds according to General Scheme 2:

[0229] (4-Bromophenyl)((cis)-2,6-dimethylmorpholino)methanone, 4-Bromobenzoic acid (50 mg, 0.25 mmol, 1 eq), (cis)-2,6-dimethylmorpholine (34 mg, 0.30 mmol, 1.2 eq), DIPEA (0.13 mL, 0.75 mmol, 3 eq), and HATU (189 mg, 0.50 mmol, 2 eq) were combined in DMF (1 mL). The resulting solution was stirred at r.t. overnight, after which time the reaction mixture was purified by RP-HPLC (5-55% MeCN in 0.1% aqueous TFA solution over 10 min). The fractions containing product were basified with sat. NaHCO3solution, and extracted with DCM The combined organic extracts were filtered through a hydrophobic phase separator and concentrated to give the title compound (56.4 mg, 76%).1H NMR (400 MHz, CDCl3) δ7.57 -7.54 (m, 2H), 7.29 - 7.26 (m, 2H), 4.62- 4.44 (m, 1H), 3.71 – 3.39 (m, 3H), 2.90 – 2.67 (m, 1H), 2.66 – 2.41 (m, 1H), 1.24 (s, 3H), 1.10 (s, 3H). ES-MS [M+l]+= 298.0, 300.0.

[0230] (4-Bromo-2-fluorophenyl)((cis)-2,6-dimethylmorpholino)methanone. The title compound was prepared in a similar manner to (4-bromophenyl)((cis)-2,6-dimethylmorpholino)methanone. ES-MS [M+l]+= 316.0, 318.0.EXAMPLE 3. Preparation of 5-bromo-2-(aryloxy)pyrimidinesGeneral Scheme 3H(XGExample compounds according to General Scheme 3:

[0231] 5-Bromo-2-((2,6-dimethylpyridin-4-yl)oxy)pyrimidine. 5-Bromo-2-fluoropyrimidine (35 mg, 0.20 mmol, 1 eq), 2,6-dimethylpyridin-4-ol (26 mg 0.21 mmol, 1.05 eq), and potassium carbonate (83 mg, 0.59 mmol, 3 eq) were combined in MeCN (1 mL) and stirred at 60 °C overnight, after which time the reaction mixture was cooled to r.t. and diluted with sat. NaHCO3 solution and DCM. The aqueous layer was extracted with DCM, and the combined organic extracts were concentrated to give the title compound, which was carried forward without additional purification (55 mg, 99%). ES-MS [M+1]+= 279.9, 281.9.EXAMPLE 4. Preparation of (4-bromobenzyl)-aminesGeneral Scheme 4Example compounds according to General Scheme 4:

[0232] (cis)-4-(4-Bromobenzyl)-2,6-dimethylmorpholine hydrochloride. 4- Bromobenzaldehyde (35 mg, 0.19 mmol, 1 eq), and (cis)-2,6-dimethylmorpholine (33 mg, 0.28 mmol, 1.5 eq) were combined in 1,4-dioxane (1 mL), and AcOH (0.022 mL, 0.38 mmol, 2 eq) was added. The resulting solution was stirred at r.t. After 15 min, sodium triacetoxyborohydride (40 mg, 0.19 mmol, 1.5 eq) was added. The resulting reaction mixture was stirred at r.t. overnight, after which time sat. NaHCO3solution was added. The aqueous layer was extracted with DCM. The combined organic extracts were concentrated, re-suspended in 4M HCI in 1,4-dioxane solution, and concentrated. The residue was taken up in H2O and DCM, and the organic layer was removed. The aqueous layer was concentrated to give the title compound as the hydrochloride salt (61 mg, 100%).(400 MHz, MeOD) 87.69 - 7.65 (m, 2H), 7.53 -7.49 (m, 2H), 4.33 (s, 2H), 3.94 - 3.84 (m, 2H), 3.35 - 3.29 (m, 2H), 2.78 - 2.71 (m, 2H), 1.22 (s, 3H), 1.20 (s, 3H). ES-MS [M+l]+= 284.1, 286.1.EXAMPLE 5. Preparation of (4-bromo-phenoxy)-ethersGeneral Scheme 5Example compounds according to General Scheme 5:

[0233] 4-(4-Bromo-2-fluorophenoxy)-2,6-dimethylpyridine. 4-Chloro-2,6-dimethylpyridine (50 mg, 0.35 mmol, 1 eq), 4-bromo-2-fluorophenol (74 mg, 0.39 mmol, 1,1eq), and potassium carbonate (149 mg, 1.06 mmol, 3 eq) were combined in NMP (1.5 mL), and stirred under microwave irradiation at 190 °C for 1 h, after which time the reaction mixture was cooled to r.t. and purified by RP-HPLC (5-35% MeCN in 0.1 % aqueous TFA solution over 10 min). Fractions containing product were concentrated to give the title compound (23 mg, 22%).1H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 9.3, 1.8 Hz, 1H), 7.45 (d, J = 6.9 Hz, 1H), 7.18 – 7.09 (m, 1H), 6.78 (s, 2H), 2.90 (s, 6H). ES-MS [M+1]+= 296.0, 298.0.EXAMPLE 6. Preparation of 1,1'-Biphenyl-4-yl-(het)arylimino-λ6-sulfanones General Scheme 6Example compounds according to General Scheme 6:

[0234] ((4-(((cis)-2,6-Dimethylmorpholino)methyl)phenyl)imino)(ethyl)(4'-fluoro-[1,1'-biphenyl]-4-yl)-λ6-sulfanone. Ethyl(4'-fluoro-[1,1'-biphenyl]-4-yl)(imino)-λ6-sulfanone (16 mg, 0.062 mmol, 1 eq), (czs)-4-(4-bromobenzyl)-2,6-dimethylmorpholine hydrochloride (24 mg, 0.074 mmol, 1.2 eq), cesium carbonate (81 mg, 0.25 mmol, 4 eq), rac-BINAP (2.9 mg, 0.005 mmol, 0.075 eq), and palladium(II) acetate (0.70 mg, 0.003 mmol, 0.05 eq) were combined in toluene (0.6 mL), which was degassed under N2. The reaction mixture was then stirred at 110 °C under an inert atmosphere overnight, after which time the reaction was cooled to r.t., diluted with EtOAc, and filtered through Celite®. The filtrate was concentrated, andpurified by RP-HPLC (5-60% MeCN in 0.1% aqueous TFA solution over 10 min). The fractions containing product were basified with sat. NaHCCh solution and extracted with DCM. The combined organic extracts were filtered through a hydrophobic phase separator and concentrated to give the title compound (7.1 mg. 25%).NMR (400 MHz, CDCh) 57.98 - 7.95 (m, 2H), 7.68 - 7.66 (m, 2H), 7.57 - 7.53 (m, 2H), 7.18 - 7.13 (m, 2H), 7.07 - 7.05 (m, 2H), 7.01 - 6.98 (m, 2H), 3.71 - 3.59 (m, 2H), 3.44 - 3.28 (m, 4H), 2.67 (d, J = 9.7 Hz, 2H), 1.78 - 1.62 (m, 2H), 1.35 (t, J = 7.4 Hz, 3H), 1.10 (d, J = 6.3 Hz, 6H). ES-MS [M+1]+= 467.3.

[0235] ((4-(((czs)-2,6-Dimethylmorpholino)methyl)phenyl)imino)(4'-fluoro-[l,l'-biphenyI]-4-yl)(methyl)-X6-sulfanone. The title compound was prepared in a similar manner to ((4-(((c’Z5)-2,6-dimethylmorpholino)methyl)phenyl)imino)(ethyl)(4'-fluoro-[l,r-biphenyl]-4-yl)-X.6-sulfanone using (4'-fluoro-[1,1'-biphenyl]-4-yl)(imino)(methyl)-λ6-sulfanone, ES-MS [M+l]’ = 453,3.

[0236] ((2-((2,6-Dimethylpyridin-4-yl)oxy)pyrimidin-5-yl)imino)(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone. The title compound was prepared in a similar manner to ((4-(((cis)-2,6-dimethylmorpholino)methyl)phenyl)imino)(ethyl)(4'-fluoro-[1,1'-biphenyl]-4-yl)-λ6-sulfanone using (4'-fluoro-[1,1'-biphenyl]-4-yl)(imino)(methyl)-λ6-sulfanone and 5-bromo-2-((2,6-dimethylpyridin-4-yl)oxy)pyrimidine. ES-MS [M+1]+= 449.3.

[0237] ((4-((2,6-Dimethylpyridin-4-yl)oxy)-3-fluorophenyI)imino)(4'-fluoro-[l,l'-biphenyI]-4-yI)(methyl)-k6-sulfanone, The title compound was prepared in a similar manner to ((4-(((czs)-2,6-dimethylmorpholino)methyl)phenyl)imino)(ethyl)(4'-fluoro-[l,l '-biphenyl]-4-yl)~6-sulfanone using (4'-fluoro-[l,1’-biphenyl]-4-yl)(imino)(methyl)-A.6-sulfanone and 4-(4-bromo-2-fluorophenoxy)-2,6-dimethylpyridine. ES-MS [M+l]+= 465,2.

[0238] ((4-((czs)-2,6-DimethyIinorpholine-4-carbonyI)phenyl)iniino)(ethyl)(4'-fluoro- [1,1 ’-biphenyl] -4-yl) -k6-sulfanone. The title compound was prepared in a similar manner to ((4-(((czs)-2,6-dimethylmorpholino)methyl)phenyl)imino)(ethyl)(4’-fluoro-[ 1, 1 '-biphenyl]-4-yl)-X6-sulfanone using (4-broniophenyl)((c / s)-2,6-dimethylmorpholino)methanone. ES-MS [M-H]+= 481.2.EXAMPLE 7. Preparation of ((aminocarbonyl)phenyl)imino)([1,1'-biphenyl]-4-yl)-λ6-sulfanonesGeneral Scheme 7Example compounds according to General Scheme 7:

[0239] Ethyl 4-(((4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)(oxo)-λ6-sulfaneylidene)amino)benzoate. (4'-Fluoro-[1,1'-biphenyl]-4-yl)(imino)(methyl)-λ6-sulfanone (200 mg, 0.80 mmol, 1 eq), ethyl 4-bromobenzoate (202 mg, 0.88 mmol, 1.1 eq), cesium carbonate (526 mg, 1.60 mmol, 2 eq), palladium(II) acetate (9.1 mg, 0.040 mmol, 0.05 eq) and rac-BINAP (37 mg, 0.060 mmol, 0.075 eq) were combined in toluene (5 mL), and degassed under N2. The resulting reaction mixture was stirred under an inert atmosphere at 110 °C overnight, after which time the reaction mixture was cooled to r.t, and filtered through Celite® with DCM and EtOAc, The filtrate was concentrated, and crude residue was purified by normalphase column chromatography (3-90% EtOAc in hexanes) to give the title compound (263 mg, 82%). (400 MHz, CDCh) 58.01 - 7.98 (m, 2H), 7.84 - 7.80 (m, 2H), 7.69 - 7.66 (m,2H), 7.57 - 7.52 (m, 2H), 7.19 - 7.13 (m, 2H), 7.05 - 7.02 (m, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.31 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). ES-MS [M+1]+= 398.3.

[0240] 4-(((4'-Fluoro-[1,1'-biphenyl]-4-yl)(methyl)(oxo)-λ6-sulfaneylidene)amino)benzoic acid. To a solution of ethyl 4-(((4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)(oxo)-λ6-sulfaneylidene)amino)benzoate (257 mg, 0.646 mmol, 1 eq) in THF (2 mL), H2O (2 mL), and MeOH (1 mL) was added 4M aqueous NaOH solution (0.49 mL, 1.94 mmol, 3 eq). The resulting reaction mixture was stirred at 80 °C overnight, after which time the reaction was cooled to r.t. and brought to pH 2 with 2M aqueous HC1 solution. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a hydrophobic phase separator and concentrated to give the title compound (221 mg, 92%).1H NMR (400 MHz, MeOD) δ 8.05 - 8.02 (m, 2H), 7.84 - 7.81 (m, 2H), 7.78 - 7.75 (m, 2H), 7.72 - 7.67 (m, 2H), 7.23 - 7.17 (m, 2H), 7.03 - 7.00 (m, 2H), 3.40 (s, 3H). ES-MS [M+1]+= 370.1.

[0241] ((4-((7'raMs)-3,4-dimethyIpyrroIidine-l-carbonyI)phenyI)imino)(4'-fluoro-[14 ’-biphenyl] -4-yl)(methyl)-k6-sulfanone. 4-(((4'-Fluoro-[l,l'-biphenyl]-4-yl)(methyl)(oxo)- A6-sulfaneylidene)amino)benzoic acid (16 mg, 0.043 mmol, 1 eq), (rram)-3,4-dimethylpyrrolidine hydrochloride (8.8 mg, 0.065 mmol, 1.5 eq), DIPEA (0.023 mL, 0.13 mmol, 3 eq) and IIATU (25 mg, 0.065 mmol, 1.5 eq) were combined in DMF (1 mL). The resulting reaction mixture was stirred at r.t. for 2 h, after which time the reaction mixture was purified byRP-HPLC (28-58% MeCN in 0.1% aqueous TFA solution over 5 min). The fractions containing product were basified with sat. NaHCO3solution, and extracted with DCM. The combined organic extracts were filtered through a hydrophobic phase separator and concentrated to give the title compound (14.0 mg, 72%).NMR (400 MHz, CDCh) δ 8.00 - 7.97 (m, 2H), 7.68 - 7.65 (m, 2H), 7.57 - 7.52 (m, 2H), 7.34 - 7.31 (m, 2H), 7.19 - 7.13 (m, 2H), 7.03 - 7.00 (m, 2H), 3.82 - 3.77 (m, 1H), 3.59 (ddd, J = 10.1, 6.9, 2.9 Hz, 1H), 3.29 (s, 3H), 3.19 - 3.03 (m, 2H), 1.80 - 1.62 (m, 2H), 1.05 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.3 Hz, 3H). ES-MS [M+1]+= 451.2.

[0242] ((4-((cis)-3,5-Dimethylpiperidine-1-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone. The title compound was prepared in a similar manner to ((4-((trans)-3,4-dimethylpyrrolidine-1-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone using (cis)-3,5-dimethylpiperidine. ES-MS [M+1]+= 465.2.

[0243] (4'-FIuoro-[l,l'_b>phenyl]-4-yI)(methyl)((4-(2,2,6,6-tetramethylmorpholine-4-carbonyl)phenyl)imino) X6-sulfanone. The title compound was prepared in a similar manner to ((4-((tra / iy)-3,4-dimethylpyrrolidine-l-carbonyl)phenyl)immo)(4'-fluoro-[l,r-biphenyl]-4-yl)(methyl)-A,6-sulfanone using 2,2,6,6-tetramethylmorpholine. ES-MS [M+l]+::::495.2.EXAMPLE 8. Preparation of (S)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone and (R)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone

[0244] (S)-((4-((cis)-2,6-Dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone and (R)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone. (4'-Fluoro-[1,1'-biphenyl]-4-yl)(imino)(methyl)-λ6-sulfanone (200 mg, 0.80 mmol, 1 eq), (4-bromophenyl)((czs)-2,6-dimethylmorpholino)methanone (263 mg, 0.88 mmol, 1.1 eq), cesium carbonate (526 mg, 1.60 mmol, 2 eq), rac-BINAP (37 mg, 0.060 mmol, 0.075 eq), and palladium(II) acetate (9.1 mg, 0.040 mmol, 0.05 eq) were combined in toluene (5 mL), which was degassed under N2. The reaction mixture was then stirred at 110 °C under an inert atmosphere overnight, after which time the reaction was cooled to r.t., diluted with DCM, and filtered through Celite®. The filtrate was concentrated, and purified by normal-phase column chromatography (0-5% MeOH in DCM) to give the racemic title compound (315 mg, 84%). The racemic material was separated by chiral supercritical fluid chromatography (4.6 x 250 mm Chiralcel OX-H column, methanol co-solvent with 0.1% diethylamine modifier, 30% isocratic gradient at 40 °C) to afford 114.6 mg of an early eluting enantiomer (7.87 min elution, 36% yield) (enantiomer 1 ), and 113.2 mg of a late eluting enantiomer (8.57 min elution, 36% yield) (enantiomer 2). Enantiomer 1 was assigned as the (R) enantiomer based on its independent synthesis in Example 12. Enantiomer 2 was assigned as the (S) enantiomer based on itsindependent synthesis in Example 12. NMR (400 MHz, CDCl3) δ 8.01 - 7.97 (m, 2H), 7.69 - 7.66 (m, 2H), 7.57 - 7.52 (m, 2H), 7.21 - 7.13 (m, 4H), 7.05 - 7.02 (m, 2H), 4.65 - 4.28 (m, 1H), 3.75 - 3.43 (m, 3H), 3.30 (s, 3H), 2.90 - 2.30 (m, 2H), 1.25 - 1.00 (m, 6H). ES-MS [M+1]+= 467.2.EXAMPLE 9. Preparation of (5’)-(4-bromophenyl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-k6-sulfanone and (7?)-(4-bromophenyl)((4-((civ)-2,6-dimethyImorpholine-4-carbonyI)phenyl)imino)(methyI)-k6-suIfanone

[0245] tert-Butyl 4-(((4-bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)benzoate. (4-Bromophenyl)(imino)(methyl)-λ6-sulfanone (250 mg, 1.07 mmol, 1 eq), 4-dimethylaminopyridine (130 mg, 1.07 mmol, 1 eq) and copper(I) iodide (20 mg,0.11 mmol, 0.1 eq) were combined in MeOH (4 mL) and stirred at r.t. for 5 min. (4-( / ez7-Butoxycarbonyl)phenyl)boronic acid (356 mg, 1.60 mmol, 1.5 eq) was then added, and the resulting reaction mixture was stirred at r.t. under ambient atmosphere overnight, after which time the reaction mixture was diluted with DCM and sat. NaHCO3solution. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a hydrophobic phase separator and concentrated. The crude residue was purified by normal-phase column chromatography (3-50% EtOAc in hexanes) to give the title compound (193 mg, 44%).1H NMR (400 MHz, CDCl3) δ 7.81 - 7.74 (m, 4H), 7.68 - 7.65 (m, 2H), 6.99 - 6.96 (m, 2H), 3.27 (s, 3H), 1.53 (s, 9H). ES-MS [M+1]+= 410.1, 412.2.

[0246] (S)-(4-Bromophenyl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-λ6-sulfanone and (R)-(4-bromophenyl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-λ6-sulfanone. To a solution of tert-butyl 4-(((4-bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)benzoate (188 mg, 0.46 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL). The resulting solution was stirred at r.t. for 2 h, after which time solvents were concentrated, and the resulting residue was dried under vacuum and used directly without further purification (163 mg, 100%). ES-MS [M+1]+= 354.1, 356.0. The crude residue was combined with (cis)-2,6-dimethylmorpholine (79 mg, 0.69 mmol, 1.5 eq) in DCM (3 mL), and DIPEA (0.40 mL, 2.29 mmol, 5 eq) was added, followed by HATU (209 mg, 0.55 mmol, 1.2 eq). The resulting reaction mixture was stirred at r.t. overnight, after which time sat. NaHCO3solution was added. The aqueous layer was extracted with DCM, and combined organic extracts were filtered through a hydrophobic phase separator and concentrated. The crude residue was purified by normal-phase column chromatography (3-100% EtOAc in hexanes) to give the racemic title compound (205 mg, 99%). The racemic material was separated by chiral supercritical fluid chromatography (4.6 x 250 mm Chiralcel OX-H column, methanol co-solvent with 0.1% diethylamine modifier, 30% isocratic gradient at 40 °C) to afford 62.6 mg of an early eluting (5) enantiomer (6.42 min elution, 31% yield), and 65.7 mg of a late eluting( / ?)- enantiomer (6.96 mm elution, 32% yield). The earlier eluting enantiomer was assigned as the (5)- enantiomer based on its independent synthesis in Example 12. The later eluting enantiomer was assigned as the (R) enantiomer based on its independent synthesis in Example 12.1H NMR (400 MHz, CDCh) 57.82 - 7.79 (m, 2H), 7.69 - 7.66 (m, 2H), 7.21 - 7.17 (m, 2H), 7.00 - 6.97 (m, 2H), 4.70 - 4.26 (m, 1H), 3.78 - 3.41 (m, 3H), 3.26 (s, 3H), 2.82 - 2.37 (m, 2H), 1.27 - 1.00 (m, 6H). ES-MS [M+1]+= 451.1, 453.1.EXAMPLE 10. Preparation of ([l,l'-biphenyI]-4-yl)((4-((cis)-2,6-dimethylmorphoIine-4-carbonyl)phenyl)imino)(methyl)-k6-sulfanone enantiomers

[0247] (7?)-(3',4'-Difluoro-[Ll'-biphenyI]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-k6-sulfanone (enantiomer 2). (7?)-(4-Bromophenyl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-X6-sulfanone (late eluting enantiomer from Example 9) (13.1 mg, 0.029 mmol, 1 eq), 3,4-difluorophenylboronic acid (6.9 mg, 0.044 mmol, 1.5 eq), cesium carbonate (29 mg, 0.087 mmol, 3 eq), and Pd(dppf)C12 (3.2 mg, 0.004 mmol, 0.15 eq) were combined in a vial, which was sealed and placed under an inert atmosphere. 10:1 1,4-dioxane / H2O solution (0.6 mL total, degassed under vacuum) was then added via syringe. The resulting reaction mixture was stirred at 110 °C for 2 h, after which time the reaction mixture was cooled to r.t. and diluted with DCM and H2O. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a hydrophobic phase separator and concentrated. The crude residue was purified by RP-HPLC (25-55% MeCN in 0.1% aqueous TFA solution over 5 min). The fractions containing product were basified with sat. NaHCO3solution and extracted with DCM. The combined organic extracts were filtered through a hydrophobic phase separator and concentrated to give the title compound (2.9 mg, 21%). ’H NMR (400 MHz, CDCh) 58.02 - 7.99 (m, 2H), 7.67 - 7.64 (m, 2H), 7.42 - 7.36 (m, 1H), 7.33 - 7.25 (m, 2H), 7.21 - 7.17 (m, 2H), 7.04 - 7.01 (m, 2H), 4.62 - 4.31 (m, 1H), 3.77 -3.41 (m, 3H), 3.30 (s, 3H), 2.88 - 2.35 (m, 2H), 1.29 - 0.99 (m, 6H). ES-MS [M+1]+= 485.2.

[0248] (7?)-((4-(( )-2,6-DimethyImorpholine-4-carbonyl)phenyl)imino)(3'-fliioro-[1,1 '-biphenyl] -4-yl)(methyl)-k6-sulfanone (enantiomer 2). The title compound was prepared in a similar manner to (R)-(3',4'-difluoro-[l,r-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-X6-sulfanone (enantiomer 2), using the late eluting enantiomer from Example 9. ES-MS [M+1]+= 467.2.

[0249] (7?)-(2',4'-Difluoro-[l,l'-biphenyl]-4-yl)((4-((cM)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-k6-sulfanone (enantiomer 2). The title compound was prepared in a similar manner to (7?)-(3',4'-difluoro-[l,r-biphenyl]-4-yl)((4-((c7T)-2.6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-X6-sulfanone (enantiomer 2), using the late eluting enantiomer from Example 9. ES-MS [M+1]+= 485.2.

[0250] (iS)-((4-((c»)-2,6-DimethyImorpholine-4-carbonyI)phenyI)imino)(3'-fluoro-[l,l'-biphenyI]-4-yl)(methyl)-k6-sulfanone (enantiomer 1). The title compound was prepared in a similar manner to (7Q-(3(4'-difluoro-[l J '-biphenyl]-4-yl)((4-((c / s)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-X6-sulfanone (enantiomer 2), using the early eluting enantiomer from Example 9. ES-MS [M+1]+= 467.2.

[0251] (1S’)-(3',4'-Difluoro-[l,l’-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorphoIine-4-carbonyl)phenyl)imino)(methyl)-k6-sulfanone (enantiomer 1). The title compound was prepared in a similar manner to (7?)-(3',4'-difluoro-[l,r-biphenyl]-4-yl)((4-((c7T)-2.6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-X6-sulfanone (enantiomer 2), using the early eluting enantiomer from Example 9. ES-MS [M+1]+= 485.2.EXAMPLE 11. Preparation of (5)-(4-bromophenyl)((4-((c7s)-2,6-dimethylmorphoIine-4-carbonyl)phenyl)imino)(methyl)-k6-sulfanone and ( / ?)-(4-bromophenyl)((4-((c«)-2,6-dimethyImorpholine-4-carbonyl)phenyI)imino)(methyI)-k6-suIfanonelate eluting enantiomer (R)

[0252] / erf-Butyl (57)-4-(((4-bromophenyI)(methyI)(oxo)-k6-sulfaneylidene)amino)benzoate and / er / -butyl (jR)-4-(((4-bromophenyl)(methyl)(oxo)-X6-sidfaneylidene)amino)benzoate. (4-Bromophenyl)(imino)(methyl)-λ6-sulfanone (500 mg, 2.14 mmol, 1 eq), 4-dimethylaminopyridine (261 mg, 2,14 mmol, 1 eq) and copper(I) iodide (81 mg, 0.43 mmol, 0.2 eq) were combined in MeOH (9 mL) and stirred at r.t. for 5 min. (4-(7ert-butoxycarbonyl)phenyl)boronic acid (711 mg, 3.20 mmol, 1.5 eq) was then added, and the resulting reaction mixture was stirred at r.t. under ambient atmosphere overnight (or until consumption of starting material), after which time the reaction mixture was diluted with DCM and sat. NaHCCh solution. The aqueous layer was extracted with DCM, and the combinedorganic extracts were filtered through a hydrophobic phase separator and concentrated. The crude residue was purified by normal-phase column chromatography (3-50% EtOAc in hexanes) to give the title compound (193 mg, 44%).NMR (400 MHz, CDCl3) δ 7.81 – 7.74 (m, 4H), 7.68 – 7.65 (m, 2H), 6.99 – 6.96 (m, 2H), 3.27 (s, 3H), 1.53 (s, 9H). ES-MS [M+1]+= 410.1, 412.2. The racemic material was separated by chiral supercritical fluid chromatography (4.6 x 250 mm Chiralcel OX-H column, ethanol co-solvent, 35% isocratic gradient at 40 °C) to afford 131.8 mg of the early eluting (5) enantiomer (3.48 min elution, 15% yield), and 121 mg of the late eluting (R) enantiomer (4.17 min elution, 14% yield) as white solids. Absolute stereochemistry determined by X-ray analysis of crystals grown after ester hydrolysis of early eluting enantiomer (see next step).

[0253] (S)-4-(((4-Bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)benzoic acid.To a solution of tert-butyl (S)-4-(((4-bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)benzoate (132 mg, 0.32 mmol, 1 eq; early eluting enantiomer from previous step) in DCM (2 mL) was added TFA (1 mL). The resulting reaction mixture was stirred at r.t. for 1 h, after which time solvents were concentrated. DCM and MeOH were then added, and solvents were further concentrated to give the title compound as a white solid (100 mg, 88%). Absolute stereochemistry was determined by X-ray analysis of crystals grown from hexanes / diethyl ether.

[0254] (R)-4-(((4-Bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)benzoic acid.The (7?) enantiomer was prepared in a similar fashion from tert-butyl (R)-4-(((4-bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)benzoate (121 mg, 0.29 mmol, 1 eq; lateeluting enantiomer from previous step) to give the title compound as a white solid (104 mg, 100%).

[0255] (S)-(4-Bromophenyl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-λ6-sulfanone. To a solution of (5)-4-(((4-bromophenyl)(methyl)(oxo)-A6-sulfaneylidene)amino)benzoic acid (77 mg, 0.22 mmol, 1 eq) and cA-2,6-dimethylmorpholine (30 mg, 0.26 mmol, 1.2 eq) in DCM (2 mL) was added DIPEA (0.11 mL, 0.65 mmol, 3 eq), followed by HATU (99 mg, 0.26 mmol, 1.2 eq). The resulting reaction mixture was stirred at r.t. overnight, after which time sat. NaHCO3solution was added. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a hydrophobic phase separator and concentrated. The crude residue was purified by normalphase column chromatography (3-100% EtOAc in hexanes) to give the title compound as a white solid (95.5 mg, 97%).1H NMR (400 MHz, CDCl3) δ 7.82 – 7.79 (m, 2H), 7.69 – 7.66 (m, 2H), 7.21 – 7.17 (m, 2H), 7.00 – 6.97 (m, 2H), 4.70 – 4.26 (m, 1H), 3.78 – 3.41 (m, 3H), 3.26 (s, 3H), 2.82 – 2.37 (m, 2H), 1.27 – 1.00 (m, 6H). Peak broadening is observed in the aliphatic region. ES-MS [M+1]+= 451.1, 453.1. When the (S) enantiomer was assayed for biological activity by the procedure described below, its EC50 was 46 nM, with ECmaxof 42.

[0256] (R)-(4-Bromophenyl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-λ6-sulfanone. The (7?) enantiomer was prepared in a similar fashion from (R)-4-(((4-bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)benzoic acid (112 mg, 0.32 mmol, 1 eq) to give the title compound as a white solid (116 mg, 81%). When the (R)enantiomer was assayed for biological activity by the procedure described below, it was inactive (EC50 >10,000).EXAMPLE 12. Preparation of (S)-(3',4'-difluoro-[1,1'-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-λ6-sulfanone

[0257] (S)-(3',4'-Difluoro-[1,1'-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-λ6-sulfanone. (S)-(4-Bromophenyl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-λ6-sulfanone (13.1 mg, 0.029 mmol, 1 eq), 3,4-difluorophenylboronic acid (6.9 mg, 0.044 mmol, 1.5 eq), cesium carbonate (29 mg, 0,087 mmol, 3 eq), and Pd(dppf)C12 (3,2 mg, 0.004 mmol, 0.15 eq) were combined in a vial, which was sealed and placed under an inert atmosphere. 10:1 1,4-dioxane / H2O solution (0.6 mL, total, degassed under vacuum) was then added via syringe. The resulting reaction mixture was stirred at 110 °C for 2 h, after which time the reaction mixture was cooled to r.t. and diluted with DCM and H2O. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a hydrophobic phase separator and concentrated. The crude residue was purified by RP-HPLC (25-55% MeCN in 0,1% aqueous TFA solution over 5 min). The tractions containing product were basified with sat. NaHCO3solution and extracted with DCM. The combined organic extracts were filtered through a hydrophobic phase separator and concentrated to give the title compound (2.9 mg, 21%).NMR (400 MHz, CDCl3) δ 8.02 – 7.99 (m, 2H), 7.67 – 7.64 (m, 2H), 7.42 – 7.36 (m, 1H), 7.33 – 7.25 (m, 2H), 7.21 – 7.17 (m, 2H), 7.04 – 7.01 (m, 2H), 4.62 – 4.31 (m, 1H), 3.77 – 3.41 (m, 3H), 3.30 (s, 3H), 2.88 – 2.35 (m, 2H), 1.29 – 0.99 (m, 6H). Peak broadening is observed in the aliphatic region. ES-MS [M+1]+= 485.2.

[0258] The compounds shown in Table 1 may be prepared similarly to the compounds described above, with appropriate starting materials.Table 1aEarlier eluting enantiomer of Example 8 and independently synthesized according to Example 12 from ( / ?)-(4-bromophenyl)((4-((cz )-2,6-dimethylmorpholine-4- carbonyl)phenyl)imino)(methyl)-X6-sulfanone.bLater eluting enantiomer of Example 8 and independently synthesized according to Example 12 from (S)-(4-bromophenyl)((4-((cis)-2,6-dimethylmorpholine-4- carbonyl)phenyl)imino)(methyl)-λ6-sulfanone.cPrepared from the later eluting enantiomer of (4-bromophenyl)((4-((cz's)-2,6- dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-X6-sulfanone in Example 9 and independently synthesized according to Example 12 from (R)-(4-bromophenyl)((4-((czs)-2,6- dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-X6-sulfanone.dPrepared from the earlier eluting enantiomer of (4-bromophenyl)((4-((cz'5)-2,6- dimethylniorpholine-4-carbonyl)phenyl)imino)(methyl)-X6-sulfanone in Example 9 and independently synthesized according to Example 12 from (5’)-(4-Bromophenyl)((4-((czs)-2,6- dimethylniorpholine-4-carbonyl)phenyl)imino)(methyl)-X6-sulfanone.Biological ActivityA. 5-HTIA Receptor Activity

[0259] Calcium Mobilization Assay. To determine the functional activity of 5-HT2A positive allosteric modulators in a cellular assay, receptor- induced mobilization of intracellular calcium was measured in Chinese Hamster Ovary (CHO) stably expressing human 5-HT2A. The stable 5-HT2A-CHO cells were cultured in F12 medium containing 10% fetal bovine serum, 20 mMHEPES, 100 units / mL antibiotics / antimycotic, 0.5 mg / ml G418. All reagents used were from Life Technologies (Carlsbad, CA) unless otherwise noted.

[0260] Briefly, the day before the assay, stable 5-HT2A-CHO cells (15,000 cells / 20 µL / well) were plated in black- walled, clear-bottomed, 384 well plates (Greiner Bio-One, Monroe, NC) in F12 medium containing 10% dialyzed fetal bovine serum, 20 mM HEPES, and 100 units / mL antibiotics / antimycotic and then incubated overnight at 37 °C in the presence of 5% CO2. The next day, calcium assay buffer (Hank’s balanced salt solution (HBSS), 20 mM HEPES, 2.5 mM Probenecid, 4.16 mM sodium bicarbonate (Sigma-Aldrich, St. Louis, MO)) was prepared to dilute compounds, agonists, and Fluo-4-acetomethoxy ester (Fluo-4-AM, Ion Biosciences), fluorescent calcium indicator dye. Compounds (10 mM stock in DMSO) were serially diluted 1:3 into 10 point concentration response curves in DMSO using the Bravo Liquid Handler (Agilent, Santa Clara, CA). The diluted compounds were transferred to a 384 well daughter plates using an Echo acoustic liquid handler (Beckman Coulter, Indianapolis, Indiana), and diluted in assay buffer to a 2X final concentration. The agonist plates were prepared using 5-HT (Tocris, Minneapolis, MN) concentrations to elicit the EC40 and ECmax responses by diluting inassay buffer to a 5X final concentration. The 2X dye solution (2.3 µM) was prepared by mixing a 2.3 mM Fluo-4-AM stock in DMSO with 10% (w / v) pluronic acid F-I27 in a 1: 1 ratio in assay buffer. Using a microplate washer (BioTek, Winooski, VT), cells were washed with assay buffer for 4 times to remove medium. After the final wash, 20 pL of assay buffer remained in the cell plates. Immediately, 20 pL of the 2X dye solution (final 1.15 pM) was added to each well of the cell plate using a Multidrop Combi dispenser (Thermo Fisher, Waltham, MA). After cells were incubated with the dye solutions for 50 min at 37 °C in the presence of 5% CO2, the dye solutions were removed and replaced with assay buffer using a microplate washer, leaving 20 pL of assay buffer in the cell plate. The compound, agonist, and cell plates were placed inside the Functional Drug Screening System uCell (FDSS uCell, Hamamatsu, Japan) to measure the Calcium flux. The triple add protocol was used to measure Ca kinetics; Compound, 5-HT for EC40, and 5-HT for ECmax adds in an order. Briefly, after establishment of a fluorescence baseline for 2 seconds (excitation, 480 nm; emission, 530 nm), first add occurred by adding 20 pL of test compound to the cells, and the response was measured for 140 seconds. This is followed by second add; 10 pL (5X) of an EC40 concentration of 5-HT agonist was added to the cells, and the response of the cells was measured for 125 seconds. Immediately, the third add occurred by adding 12 µL assay buffer or 5X of an ECmax concentration of 5-HT and the response of the cells was measured for 90 seconds. DMSO vehicle in the first add was added to the control wells to ensure EC40 and ECmax responses. Calcium fluorescence was recorded as fold over basal fluorescence and raw data were normalized to the maximal response to 5-HT agonist.Compound-evoked increase in calcium response in the absence of 5-HT agonist was determined as agonist activity of positive allosteric modulators (Ago-PAM). Compound-evoked increase in calcium response in the presence of 5-HT EC10 agonist was determined as potentiator activity of positive allosteric modulator. Potency (EC50) and maximum response (% 5-HT Max) for compounds were determined using a four-parameter logistical equation using GraphPad Prism (La Jolla, CA) or the Dotmatics software platform (Woburn, MA).where A is the molar concentration of the compound; bottom and top denote the lower and upper plateaus of the concentration-response curve; HillSlope is the Hill coefficient that describes the steepness of the curve; and EC50 is the molar concentration of compound required to generate aresponse halfway between the top and bottom.

[0261] Human 5-HT2A agonist and positive allosteric modulatory activities are shown in Table 2.Table 2.B. Functional assessment of 5-HT2A activator compounds in cellular IP-One assay 1. EXPERIMENTAL PRINCIPLE

[0262] Activation of 5-HT2A receptor leads to a Gαq-coupled signaling cascade. This involves the activation of phospholipase C (PLC) hydrolyzing phosphatidyl inositol-4,5 bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (IP3). The resulting IP3 is then further metabolized to inositol 1 phosphate (IP1). By treating cells with lithium chloride (LiCl), inositol monophosphatase inhibitor, to block degradation of I Pl to myoinositol, IPl accumulation can be used as a direct measurement of 5-HT2A receptor activation.

[0263] Homogeneous Time-Resolved Fluorescence (HTRF®) IP-One assay was employed using CHO cells stably expressing human 5-HT2A receptor. HTRF IP-One assay is a Time-Resolved Resonance Energy Transfer (TR-FRET) competitive immunoassay. Intracellular IP1 generated by cells competes with IP1 labeled with d2 (emission 620 nm) for the binding to IP1 antibody labeled with terbium cryptate (emission 665 nm). Compound-mediated 5-HT2A activation induces accumulation of IP1 production which then blocks the energy transfer, resulting decrease in HTRF ratio (665 nm / 620 nm). Thus, the fluorescence emission ratio (665 nm / 620 nm) is inversely proportional to the IP1 amount produced in the cells.

[0264] To monitor agonist activity, compounds were added to the 5-HT2A cells. To assess potentiator activity, compounds were added to the cells in the presence of 5-HT (EC20) concentration. This functional assay allows us to determine the potency and efficacy of compounds activating Gq-coupled 5-HT2A receptor.2. MATERIALS AND EQUIPMENT3. METHODS

[0265] Functional agonist and potentiator activities of compounds were determined by measuring IPl amount in Chinese Hamster Ovary (CHO) cells stably expressing human 5-HT2A receptor using HTRF IP-One Gq kit. The 5-HT2A-CHO cells were cultured in F12 medium containing 10% fetal bovine serum, 20 mM HEPES, 100 units / mL antibiotics / antimycotic, and 0.5 mg / mL G418.

[0266] On the day of assay, testing compounds (10 mM stocks) were serially diluted 1:3 into 10 point concentration response curves in DMSO using the Bravo Liquid Handler. Using an Echo acoustic liquid handler, 0.315 pL of the serial diluted compounds was transferred to each well in a 384 well daughter plate. DMSO vehicle was added to the control wells to monitor basal responses (no agonist). 5-HT agonist was also serially diluted in the same way and added to the positive control wells to generate 5-HT CRC for determining 5-HT maximum response, and also for determining 5-HT concentration needed for eliciting EC2.0 response for subsequent potentiator mode assay set up. The daughter plate was further diluted to a 3.5 X final concentration by adding 30 pL IP-One IX stimulation buffer to each well.

[0267] Agonist mode assay was set up to assess the abilities of compounds directly to activate 5-HT2A receptor in the absence of 5-HT agonist. The 5-HT2A-CHO cells were trypsinized and seeded at the density of 30,000 cells / 10 pL stimulation buffer / well into a white, solid-flat bottom 384 well plate. Immediately after plating, 4 pL of the compounds and controls prepared in the daughter were added to the cell plate using the 384 well tips of Bravo Liquid Handler. The cell plate was spun at lOOxg for 30 seconds and incubated at 25 °C for 1 hour with gentle shaking at 50 rpm.

[0268] During incubation, each IPl-d2 and IPl antibody terbium cryptate was diluted to 1:20 in lysis and detection buffer, separately. The detection mixture was prepared by mixing equal volume of each diluted reagent. Immediately after the incubation, 6 pL of detection mixture containing 3 pL of each IPl -d2 and IPl antibody terbium cryptate was added to eachwell. The cell plate was spun at 1 OOxg for 30 seconds and incubated at 25 °C for 1 hour with gentle shaking at 50 rpm. Immediately after the detection incubation, TR-FRET signals were measured at two channels, 665 and 620 nm using EnVision Plate reader. All emission ratio (665 / 620) was normalized to % 5-HT max. Individual concentration response curves were generated using a four-parameter logistical equation using GraphPad Prism (La Jolla, CA), EC50 was extracted from the fitting, and maximal response was presented as % 5-HT Max);where A is the molar concentration of the compound; bottom and top denote the lower and upper plateaus of the concentration-response curve; HillSlope is the Hill coefficient that describes the steepness of the curve; and EC50 is the molar concentration of compound required to generate a response halfway between the top and bottom..

[0269] Immediately after the agonist mode assay, potentiator mode assay was set up to assess the abilities of compounds to potentiate the submaximal response of 5-HT agonist (EC20). The 5-HT agonist concentration for EC20 response was determined from the 5-HT CRC performed in the agonist mode above. Compounds were diluted in a same way as described in the agonist mode assay and DMSO vehicle was added to all the control wells including basal, 5-HT Max and 5-HT EC 20. After transferring 0.315 pL of the serial diluted compounds to a 384 well daughter plate, the daughter plate was further diluted to a 3.5 X final concentration by adding 30 |1L stimulation buffer containing 5-HT agonist (0.12 pM) for EC20 response. The following buffers were added to the control wells containing DMSO vehicle; buffer alone to basal controls, buffer containing 350 pM 5-HT to 5-HT Max controls, and buffer containing 0.12 pM 5-HT to 5-HT EC20 controls.

[0270] Once the potentiator mode assay daughter plate was prepared, new 5-HT2A cell plate was made as described above. The subsequent procedures including compound addition, incubation, detection, and data analysis were performed exactly same as described above in the agonist mode assay.

[0271] The potency for compound 11 was measured in the IPl assay as described above, and the observed potency values were as follows. Agonist mode: EC50 = 400 nM, 239% 5-HTxiax. Potentiator mode: EC50 = 14611M, 344% 5-HTMax. Additionally, compound 11 does notdisplace agonist radioligand binding ([125I](±)DOI) to 5-HT2A in radioligand competition binding experiments (% inhibition < 50% across multiple concentrations up to 10 pM). Radioligand binding experiments were conducted by Eurofins Cerep using their standard assay methodology (https: / / www.eurofinsdiscovery.com / catalog / 5-ht2a-human-serotonin-gpcr-bmding-agonist-radioligand-leadhunter-assay-fr / 471).

[0272] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0273] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

CLAIMS1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein:Z1is CR1or N;Z2is CR2or N;Z3is CR3or N;Z4is CR4or N;R1, R2, R3, and R4are independently hydrogen, halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, -OCi- 4alkyl, -OCi-4fluoroalkyl, or C3-4cycloalkyl;R5and R6, at each occurrence, are independently halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, - OCi-4alkyl, -OCi-4fluoroalkyl, or C3-4cycloalkyl;R7is 1 G.L is O, S, NR7a, C(R7b)2, C(O), S(O), or S(O)2;R7ais hydrogen, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl;R7b, at each occurrence, is independently hydrogen or Ci-6alkyl,G is a 5- to 6-membered heteroaryl containing 1-3 heteroatonis, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, a phenyl, or a C3-8carbocyclyl, the heteroatonis being independently selected from the group consisting of O, N, and S, wherein G is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4alkyl, Ci-4fluoroalkyl, halogen, cyano, -OCi-4alkyl, -OCi-4fluoroalkyl, and C3-4cycloalkyl; R8is Ci-6alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl;m is 0, 1, 2, 3, or 4; andn is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z1is CR'3. The compound of claim I or 2, or a pharmaceutically acceptable salt thereof, wherein Z2is CR24. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Z3is CR35. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Z3is N.

6. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein Z4is CR47. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein Z4is N.

8. The compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein m is 0.

9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2,10. The compound of any of claims 1 -9, or a pharmaceutically acceptable salt thereof, wherein R5, at each occurrence, is independently a halogen.

11. The compound of any of claims 1 - 10, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (l-a), (I-b), (l-c), (I-d), or (I-e):

12. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L is 0, C(R7b)2, or C(O).

13. The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein G is the optionally substituted 5- to 6-membered heteroaryl containing 1 -3 heteroatoms.

14. The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein G is the optionally substituted 4- to 8-membered heterocyclyl containing 1-2 heteroatoms.

15. The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein G is the optionally substituted phenyl.

16. The compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof,17. The compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R8is Ci-salkyl.

18. The compound of claim 1 selected from the group consisting of:((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[l,r-biphenyl]-4- yl)(methyl)-6-sulfanone;((4-(((cis)-2,6-dimethylmorpholino)methyl)phenyl)imino)(4'-fluoro-[l,r-biphenyl]-4-yl)(methyl)-A,6-sulfanone;((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)-3-fluorophenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone;((2-((2,6-dimethylpyridin-4-yl)oxy)pyrimidin-5-yl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-A,6-sulfanone;((4-((2,6-dimethylpyridin-4-yl)oxy)-3-fluorophenyl)imino)(4'-fluoro-[l,l'-biphenyl]-4- yl)(methyl)-k6-sulfanone;((4-(((cis)-2,6-dimethylmorpholino)methyl)phenyl)imino)(ethyl)(4'-fluoro-[l,r-biplienyl]-4- yl)-X6-sulfanone;((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)-3-fluorophenyl)imino)(ethyl)(4'-fluoro-[l,r- biphenyl] -4-yl)-X6-sulfanone;((2-((2,6-dimethylpyridin-4-yl)oxy)pyrimidin-5-yl)imino)(ethyl)(4'-fluoro-[l,r-biphenyl]-4- yl)-X6-sulfanone;((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(ethyl)(4'-fluoro-[l,r-biphenyl]- 4-yl)-λ6-sulfanone;(S)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-A6-sulfanone;(R)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-A6-sulfanone;((4-((trans)-3,4-dimethylpyrrolidine-1-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-X6-sulfanone;(4'-fluoro-[ 1, 1 '-biphenyl]-4-yl)(methyl)((4-(morpholine-4-carbonyl)phenyl)imino)-6- sulfanone;((4-((trans)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-X6-sulfanone;(4'-fluoro-[ 1, 1 '-biphenyl]-4-yl)(methyl)((4-(2,2,6,6-tetramethylmorpholine-4- carbonyl)phenyl)imino)-λ6-sulfanone;((4-((cis)-3,5-dimethylpiperidine-1-carbonyl)phenyl)imino)(4'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-7 -sulfanone;(4'-fluoro-[l,r-biphenyl]-4-yl)(methyl)((4-((cis)-3,4,5-trimethylpipera ine-l- carbonyl)phenyl)imino)-λ6-sulfanone;((4-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)phenyl)imino)(4'-fluoro-[l,l'-biphenyl]-4- yl)(methyl)-7 -sulfanone;((4-(2,2-dimethylmorpholine-4-carbonyl)phenyl)imino)(4'-fluoro-[l,r-biphenyl]-4- yl)(methyl)-7 -sulfanone;((4-(l,4-oxazepane-4-carbonyl)phenyl)imino)(4'-fluoro-[l,l'-biphenyl]-4-yl)(methyl)-X6- sulfanone;(4'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)((4-(piperidine-1-carbonyl)phenyl)imino)-λ6-sulfanone; (S)-[1,1'-biphenyl]-4-yl((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)- A6-sulfanone;(S)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(2'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-k6-sulfanone;(S)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(3'-fluoro-[1,1'-biphenyl]-4- yl)(methyl)-k6-sulfanone;(S)-(3',4'-difluoro-[1,1'-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4- carbonyl)phenyl)imino)(methyl)-A6-sulfanone;(S)-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4- carbonyl)phenyl)imino)(methyl)-A6-sulfanone;(R)-[1,1'-biphenyl]-4-yl((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-λ6-sulfanone;(R)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(2'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone;(R)-((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(3'-fluoro-[1,1'-biphenyl]-4-yl)(methyl)-λ6-sulfanone;(R)-(3',4'-difluoro-[1,1'-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-λ6-sulfanone;(R)-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)-λ6-sulfanone;(S)-(4-Bromophenyl)((4-((cis)-2,6-dimethylmorpholine-4-carbonyl)phenyl)imino)(methyl)- A,6-sulfanoneor a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound of any of claims 1-18, or apharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

20. A method of activating the 5-HT2A receptor in a subject in need thereof comprising administering to the subject, a therapeutically effective amount of the compound of any of claims 1 -18, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 19.

21. The method of claim 20, wherein the subject suffers from a neurological or psychiatric disorder.

22. A method of treating a neurological or psychiatric disorder comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19.

23. A compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 19, for use in a method of treating a neurological or psychiatric disorder.

24. Use of a compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19, in the manufacture of a medicament for treating a neurological or psychiatric disorder25. The method, compound or pharmaceutically acceptable salt thereof pharmaceutical composition, or use of any of claims 21-24, wherein the neurological or psychiatric disorder is selected from the group consisting of depression, cognitive dysfunction, psychomotor retardation, migraine, cluster headaches, social and emotional withdrawal, sleep disorders, bipolar disorder, negative thinking, panic disorder, anxiety, chronic pain, eating disorders, body dysmorphic disorder (BDD), substance use disorder (SUD), dementia in Parkinson’s disease, and obsessive compulsive disorder.

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