WO2012075232A1 - Opioid receptor ligands and methods of using and making the same - Google Patents

Opioid receptor ligands and methods of using and making the same Download PDF

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Publication number
WO2012075232A1
WO2012075232A1 PCT/US2011/062801 US2011062801W WO2012075232A1 WO 2012075232 A1 WO2012075232 A1 WO 2012075232A1 US 2011062801 W US2011062801 W US 2011062801W WO 2012075232 A1 WO2012075232 A1 WO 2012075232A1
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Prior art keywords
dimethyloxan
propyl
amine
methyl
group
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PCT/US2011/062801
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French (fr)
Inventor
Dennis Yamashita
Xiao-Tao Chen
Dimitar Gotchev
Catherine C.K. Yuan
Guodong Liu
Tamara A. Miskowski
Philip Pitis
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Trevena, Inc.
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Publication of WO2012075232A1 publication Critical patent/WO2012075232A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D309/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D309/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14Nitrogen atoms not forming part of a nitro radical
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This application relates to a family of compounds acting as opioid receptor ligands.
  • Such compounds may provide significant therapeutic benefit in the treatment of pain.
  • Opioid receptors mediate the actions of morphine and morphine-like opioids, including most clinical analgesics.
  • Three molecularly and pharmacologically distinct opioid receptor types have been described: ⁇ , ⁇ and ⁇ . Furthermore, each type is believed to have sub-types. All three of these opioid receptor types appear to share the same functional mechanisms at a cellular level. For example, activation of the opioid receptors causes inhibition of adenylate cyclase, and recruits ⁇ -arrestin.
  • OR modulators there is a continuing need for new OR modulators to be used as analgesics. There is a further need for OR agonists as analgesics having reduced side effects. There is a further need for OR agonists as analgesics having reduced side effects for the treatment of pain, immune dysfunction, inflammation, esophageal reflux,
  • ⁇ -opioid agonists are used as analgesics for the treatment of moderate to severe pain.
  • opioid analgesics is often associated with adverse effects on the GI tract, collectively termed opioid-induced bowel dysfunction (OBD).
  • OBD includes symptoms such as constipation, decreased gastric emptying, abdominal pain and discomfort, bloating, nausea, and gastroesophageal reflux
  • ⁇ -opioid antagonists can potentially block undesirable GTrelated side effects without interfering with the beneficial central effects of analgesia or precipitating central nervous system withdrawal symptoms
  • ⁇ -opioid agonists also result in depression of respiratory function
  • ⁇ -opioid antagonists have been shown to reverse such respiratory depression.
  • Postoperative ileus (POI) is a common problem following surgery, especially abdominal surgery. Symptoms of POI are similar to those of OBD.
  • ⁇ - opioid antagonists have been shown to be beneficial in the treatment of POI.
  • the present invention provides for novel ⁇ -opioid receptor (MOR) ligands.
  • the present invention also provides methods of modulating opioid receptor activity using the compositions described in the invention.
  • Certain compositions of the invention act as ⁇ -opioid receptor agonists.
  • Other compositions of the invention act as ⁇ -opioid receptor antagonists.
  • Certain compositions of the invention act as ⁇ -opioid receptor agonists.
  • Other compositions of the invention act as ⁇ -opioid receptor antagonists.
  • Certain compositions of the invention act as ⁇ - opioid receptor agonists.
  • Other compositions of the invention act as ⁇ -opioid receptor antagonists.
  • the invention provides compounds having the structure:
  • variables Aa, Bb and Dd can be selected from the respective groups of chemical or biological moieties later described in the detailed description.
  • MOR ligand derivatives and mimetics are also provided. Also provided are processes for preparing the compounds of the invention.
  • the present invention extends to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the compounds of the present invention can be employed in any form, such as a solid or solution (e.g. , aqueous solution) as is described further below.
  • the compound for example, can be obtained and employed in a lyophilized form alone or with suitable additives.
  • method would comprise administering a therapeutically effective amount of one or more compounds of the present invention to a subject in need thereof.
  • This application describes a family of compounds, OR ligands, with a unique profile.
  • the compounds of the present invention act as agonists or antagonists of opioid receptor (OR)-mediated signal transduction.
  • OR opioid receptor
  • These OR include ⁇ -opioid receptors (MORs), K-opioid receptors (KORs) and ⁇ -opioid receptors (DOR).
  • MORs ⁇ -opioid receptors
  • KORs K-opioid receptors
  • DOR ⁇ -opioid receptors
  • ligands of these receptors are used to treat pathologies associated with ORs including pain and pain related disorders.
  • the compounds of the present invention comprise the following formula:
  • Al is null, CH 2 , CHR1, CR1R2, O, S, SO, S0 2 , NH, NR1, CH, CR1 or N;
  • A2 is null, CH 2 , CHR5, CR5R6, O, S, SO, S0 2 , NH, NR5, CH, CR5 or N;
  • A3 is null, CH 2 , CHR7, CR7R8, O, S, SO, S0 2 , NH, NR7, CH, CR7 or N;
  • A4 is null, CH 2 , CHR9, CR9R10, O, S, SO, S0 2 , NH, NR9, CH, CR9 or N;
  • A5 is null, CH 2 , CHR11, CR11R12, CH 2 CH 2 , CHR11CH 2 , CH 2 CHR11, CHR11CHR12, O, S, NH, NR11, CH, or CR11; and wherein A6 is
  • No more than 2 out of 5 Aa (specifically, Al, A2, A3, A4, A5) can be null at the same time.
  • the number of hetero atoms from Al to A6 cannot exceed 2 at the same time, and S-O; S-S; S-N fragments in the ring structure are excluded from the present invention.
  • the ring consisted of Al, A2, A3, A4, A5 and A6 can be fused with another ring, such as benzene, pyridine, pyrimidine, furan, thiophene, or pyridazine, but not limited to these examples only.
  • the rings could be multiply substituted with cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, formyl, acetyl, amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, and other small substitution groups.
  • the bonds between Aland A2, A2 and A3, A3 and A4, A4 and A5, A5 and A6, A6 and Al and A6 and A7 are independently a single bond or a double bond.
  • the bonds between Aland A2, A2 and A3, A3 and A4, A4 and A5, A5 and A6, and A6 and Al cannot be a double bond at the same time.
  • the ring consisted of Al, A2, A3, A4, A5 and A6 cannot be a benzene ring.
  • A7 is N, CH, CF, COH, CNH 2 , COCH 3 , CCN, or C. Both A6 and A7 cannot be N at the same time.
  • Bl is CH 2 , CHR13, CR13R14, O, S, NH, NR13, CH, CR13, C, CO, or CS.
  • B2 is
  • B3 is H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkylsulfonyl.
  • B4 is null, CH 2 , CHR19, CR19R20, CO, or CS.
  • B5 is alkyl, branched alkyl, halogenated alkyl, carbocycle- substituted alkyl, aryl, carbocycle, or arylalkyl.
  • Aryl, carbocycle (non-aromatic)/ heterocycle (non-aromatic with 1-3 heteroatoms, including O, N, S) are either unsubstituted, or substituted with small substitution groups.
  • Small substitution groups are selected from the following groups consisting of, but not limited to: cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl,
  • the substitution groups are selected from F, CI, Br, CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF3, NH2, NHMe, NMe2,
  • Carbocycle may contain double bonds, but they should not be aromatic.
  • the bond between A7 and Bl is a single bond or a double bond. In other embodiments the bond between B 1 and B2 is a single bond, or a double bond.
  • Dl is an aryl group or a carbocycle.
  • Aryl group is either a monocyclic aromatic group or a bicyclic aromatic group.
  • the following structures are some examples of representive aryl groups, but the aryl groups are not limited to those examples:
  • Carbocycle is either a monocyclic or a bicyclic non-aromatic ring system.
  • the following structures are some examples of representative carbocycle, but the carbocycle is not limited to those examples: Wherein XI, and X2 in the carbocycle examples are independently selected from O, S, N, NH, NR18.
  • the aryl groups are multiply substituted with cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
  • substitution groups are selected from F, CI, Br, CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF3, NH2, NHMe, NMe2,
  • Alkyl is a linear carbon chain having between 1 and 10 carbon atoms.
  • Dl is an aryl, or a carbocycle.
  • Rl, R2, R5, R6, R7, R8, R9, R10, Rl l, R12, R13, R14, R15, R16, R18, R19, and R20 are independently: cyano, halogen, hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl, alkoxycarbonyl.
  • Rl, R2, R5, R6, R7, R8, R9, R10, Rl l, R12, R13, R14, R15, R16, R18, R19, and R20 are independently F, CI, Br, CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , n-Pr, n-Bu, i-Bu, sec- Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-i-Pr, methoxycarbonyl, Ph, benzyl, formyl, and acetyl.
  • Rl and R2 R5 and R6, R7 and R8, R9 and R10, Rl 1 and
  • R12, R13 and R14, R15 and R16, R19 and R20, or R15 and R19 forms a monocyclic carbocycle or heterocycle.
  • R3 is Me, CF 3 , CH 2 OH, CH 2 NH 2 , CH 2 NHBoc, OH, methoxycarbonyl, CN, C0 2 R4, NH, or N-t-butoxycarbonyl.
  • R4 is an alkyl or a branched alkyl group.
  • Me is methyl; Et is ethyl; Boc is t-butoxycarbonyl; i-Pr is i-propyl; t-Bu is t-butyl; Ph is phenyl, Bn is benzyl.
  • the compounds of the present invention comprise the following formula:
  • A2 is CH 2 , CHR5, CR5R6;
  • A4 is CH 2 , CHR9, CR9R10.
  • R5 and R6, and R9 and R10 are independently CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, MeO, EtO, phenyl.
  • R5 and R6, or R9 and R10 forms a monocyclic carbocycle.
  • B3 is selected from the following: H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkylsulfonyl.
  • B3 is H, CH 3 , CH 2 CH 3 , i-Pr, t-Bu, n-Pr, n-Bu, i-Bu, sec-Bu, Bn.
  • R28 is selected from the following: H, alkyl, branched alkyl, halogenated alkyl.
  • R28 is H, CH 3 , CH 2 CH 3 , i-Pr, t-Bu, n-Pr, n-Bu.
  • Dl and D2 are independently: aryl, or carbocycle. Examples of the aryl and carbocyle/heterocycle were shown previously, but the aryl and carbocyle/heterocycle are not limited to those examples.
  • the compounds of the present invention comprise the following formula:
  • A2 is CH 2 , CHR5, CR5R6;
  • A4 is CH 2 , CHR9, CR9R10.
  • R5 and R6, and R9 and R10 are independently CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, MeO, EtO, phenyl.
  • R5 and R6, or R9 and R10 forms a monocyclic carbocycle.
  • B3 is selected from the following: H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkylsulfonyl.
  • B3 is H, CH 3 , CH 2 CH 3 , i-Pr, t-Bu, n-Pr, n-Bu, i-Bu, sec-Bu, Bn.
  • R28 is selected from the following: H, alkyl, branched alkyl, halogenated alkyl.
  • R28 is H, CH 3 , CH 2 CH 3 , i-Pr, t-Bu, n-Pr, n-Bu.
  • Dl and D2 are independently: aryl, or carbocycle. Examples of the aryl and carbocyle/heterocycle were shown previously, but the aryl and carbocyle/heterocycle are not limited to those examples.
  • A2 is CH 2 , CHR5, CR5R6;
  • A4 is CH 2 , CHR9, CR9R10.
  • R5 and R6, and R9 and R10 are independently CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, MeO, EtO, phenyl.
  • R5 and R6, or R9 and R10 forms a monocyclic carbocycle.
  • Dl is: aryl, or carbocycle. Examples of the aryl and carbocyle/heterocycle were shown previously, but the aryl and carbocyle/heterocycle are not limited to those examples.
  • A2 is CH 2 , CHR5, CR5R6;
  • A4 is CH 2 , CHR9, CR9R10.
  • R5 and R6, and R9 and RIO are independently CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, MeO, EtO, phenyl.
  • R5 and R6, or R9 and R10 forms a monocyclic carbocycle.
  • Dl is: aryl, or carbocycle. Examples of the aryl and carbocyle/heterocycle were shown previously, but the aryl and carbocyle/heterocycle are not limited to those examples.
  • A2 is CH 2 , CHR5, CR5R6;
  • A4 is CH 2 , CHR9, CR9R10.
  • R5 and R6, and R9 and R10 are independently CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, MeO, EtO, phenyl.
  • R5 and R6, or R9 and R10 forms a monocyclic carbocycle.
  • Dl and D2 are independently: aryl, or carbocycle. Examples of the aryl and carbocyle/heterocycle were shown previously, but the aryl and carbocyle/heterocycle are not limited to those examples.
  • the following known compounds have the agonist activity in OR mediated signal transduction:
  • the invention provides methods of generating agonist activity in OR mediated signal transduction through administration of the above recited compounds.
  • various atoms in the compositions of the invention are isotopes that occur at lower frequency.
  • hydrogen is replaced at any position in the compositions of the invention with deuterium.
  • hydrogen can also be replaced with tritium.
  • carbon ( C) is replaced at any position in the compositions of the invention with 13 C or 14 C.
  • nitrogen ( 14 N) is replaced with 15 N.
  • oxygen ( 16 0) is replaced at any position in the
  • sulfur ( S) is
  • chlorine ( CI) is replaced at any position in the compositions
  • bromine ( Br) is replaced at any one of the invention.
  • bromine ( Br) is replaced at any one of the invention.
  • the compounds of the preferred embodiments are agonists and antagonists of Opioid Receptors (ORs).
  • ORs Opioid Receptors
  • the ability of the compounds to stimulate OR mediated signaling may be measured using any assay known in the art used to detect OR mediated signaling or OR activity, or the absence of such signaling/activity.
  • OR activity refers to the ability of an OR to transduce a signal. Such activity can be measured, e.g. , in a heterologous cell, by coupling an OR (or a chimeric OR) to a downstream effector such as adenylate cyclase.
  • a "natural ligand-induced activity" as used herein, refers to activation of the OR by a natural ligand of the OR. Activity can be assessed using any number of endpoints to measure OR activity.
  • transduction include the determination of any parameter that is indirectly or directly under the influence of a OR, e.g. , a functional, physical, or chemical effect.
  • inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of inhibition.
  • Control samples without the inhibitor, activator, or modulator to examine the extent of inhibition.
  • Inhibition of an OR is achieved when the OR activity value relative to the control is about 80%, preferably 50%, more preferably 25%.
  • Activation of an OR is achieved when the OR activity value relative to the control (untreated with activators) is 110%, more preferably 150%, more preferably 200-500% (i.e. , two to five fold higher relative to the control), more preferably 1000-3000% or higher.
  • Any suitable physiological change that affects OR activity can be used to assess the influence of a compound on the ORs and natural ligand-mediated OR activity.
  • functional consequences are determined using intact cells or animals, one can also measure a variety of effects such as changes in intracellular second messengers such as cAMP.
  • Modulators of OR activity are tested using OR polypeptides as described above, either recombinant or naturally occurring.
  • the protein can be isolated, expressed in a cell, expressed in a membrane derived from a cell, expressed in tissue or in an animal.
  • neuronal cells, cells of the immune system, transformed cells, or membranes can be used to test the GPCR polypeptides described above. Modulation is tested using one of the in vitro or in vivo assays described herein.
  • Signal transduction can also be examined in vitro with soluble or solid state reactions, using a chimeric molecule such as an extracellular domain of a receptor covalently linked to a heterologous signal transduction domain, or a heterologous extracellular domain covalently linked to the transmembrane and or cytoplasmic domain of a receptor.
  • a chimeric molecule such as an extracellular domain of a receptor covalently linked to a heterologous signal transduction domain, or a heterologous extracellular domain covalently linked to the transmembrane and or cytoplasmic domain of a receptor.
  • ligand-binding domains of the protein of interest can be used in vitro in soluble or solid state reactions to assay for ligand binding.
  • Ligand binding to an OR, a domain, or chimeric protein can be tested in a number of formats. Binding can be performed in solution, in a bilayer membrane, attached to a solid phase, in a lipid monolayer, or in vesicles. Typically, in an assay of the invention, the binding of the natural ligand to its receptor is measured in the presence of a candidate modulator. Alternatively, the binding of the candidate modulator may be measured in the presence of the natural ligand. Often, competitive assays that measure the ability of a compound to compete with binding of the natural ligand to the receptor are used.
  • Binding can be tested by measuring, e.g., changes in spectroscopic characteristics (e.g., fluorescence, absorbance, refractive index), hydrodynamic (e.g., shape) changes, or changes in chromatographic or solubility properties.
  • spectroscopic characteristics e.g., fluorescence, absorbance, refractive index
  • hydrodynamic e.g., shape
  • Modulators may also be identified using assays involving ⁇ -arrestin recruitment, ⁇ - arrestin serves as a regulatory protein that is distributed throughout the cytoplasm in unactivated cells. Ligand binding to an appropriate OR is associated with
  • ⁇ -arrestin redistribution of ⁇ -arrestin from the cytoplasm to the cell surface, where it associates with the OR.
  • receptor activation and the effect of candidate modulators on ligand-induced receptor activation can be assessed by monitoring ⁇ -arrestin recruitment to the cell surface. This is frequently performed by transfecting a labeled ⁇ -arrestin fusion protein (e.g., ⁇ -arrestin-green fluorescent protein (GFP)) into cells and monitoring its distribution using confocal microscopy (see, e.g., Groarke et ah, J. Biol. Chem. 274(33):23263 69 (1999)).
  • GFP ⁇ -arrestin-green fluorescent protein
  • BRET bioluminescence resonance energy transfer
  • Other assays can involve determining the activity of receptors which, when activated by ligand binding, result in a change in the level of intracellular cyclic nucleotides, e.g. , cAMP, by activating or inhibiting downstream effectors such as adenylate cyclase.
  • changes in intracellular cAMP can be measured using immunoassays.
  • the method described in Offermanns & Simon, J. Biol. Chem. 270: 15175 15180 (1995) may be used to determine the level of cAMP.
  • the method described in Felley-Bosco et al. Am. J. Resp. Cell and Mol. Biol. 11 : 159 164 (1994) may be used to determine the level of cGMP.
  • an assay kit for measuring cAMP a is described in U.S. Pat. No. 4, 115,538, herein incorporated by reference.
  • transcription levels can be measured to assess the effects of a test compound on ligand-induced signal transduction.
  • a host cell containing the protein of interest is contacted with a test compound in the presence of the natural ligand for a sufficient time to effect any interactions, and then the level of gene expression is measured.
  • the amount of time to effect such interactions may be empirically determined, such as by running a time course and measuring the level of transcription as a function of time.
  • the amount of transcription may be measured by using any method known to those of skill in the art to be suitable. For example, mRNA expression of the protein of interest may be detected using northern blots or their polypeptide products may be identified using immunoassays.
  • reporter genes may be used as described in U.S. Pat. No. 5,436, 128, herein incorporated by reference.
  • the reporter genes can be, e.g. , chloramphenicol acetyltransferase, firefly luciferase, bacterial luciferase, ⁇ - galactosidase and alkaline phosphatase.
  • the protein of interest can be used as an indirect reporter via attachment to a second reporter such as green fluorescent protein (see, e.g. , Mistili & Spector, Nature Biotechnology 15:961 964 (1997)).
  • the amount of transcription is then compared to the amount of transcription in either the same cell in the absence of the test compound, or it may be compared with the amount of transcription in a substantially identical cell that lacks the protein of interest.
  • a substantially identical cell may be derived from the same cells from which the recombinant cell was prepared but which had not been modified by introduction of heterologous DNA. Any difference in the amount of transcription indicates that the test compound has in some manner altered the activity of the protein of interest.
  • compositions for use in the present invention can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients.
  • the formulations may contain a buffer and/or a preservative.
  • the compounds and their physiologically acceptable salts and solvates can be formulated for administration by any suitable route, including via inhalation, topically, nasally, orally, parenterally ⁇ e.g. , intravenously, intraperitoneally, intravesically or intrathecally) or rectally in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the peptide, chosen route of administration and standard biological practice.
  • compositions are provided.
  • compositions comprising effective amounts of one or more compound(s) of the present invention together with, for example, pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or other carriers.
  • diluents include diluents of various buffer content (e.g., TRIS or other amines, carbonates, phosphates, amino acids, for example, glycinamide hydrochloride (especially in the physiological pH range), N-glycylglycine, sodium or potassium phosphate (dibasic, tribasic), etc. or TRIS-HCl or acetate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g.
  • surfactants such as Pluronics, Tween 20, Tween 80 (Polysorbate 80), Cremophor, polyols such as polyethylene glycol, propylene glycol, etc.
  • anti-oxidants e.g. , ascorbic acid, sodium metabisulfite
  • preservatives e.g. , Thimersol, benzyl alcohol, parabens, etc.
  • bulking substances e.g. , sugars such as sucrose, lactose, mannitol, polymers such as
  • polyvinylpyrrolidones or dextran, etc. are polyvinylpyrrolidones or dextran, etc.); and/or incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid,
  • compositions can be employed to influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of a compound of the present invention. See, e.g. , Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435- 1712 which are herein incorporated by reference.
  • the compositions can, for example, be prepared in liquid form, or can be in dried powder, such as lyophilized form. Particular methods of administering such compositions are described infra.
  • the buffer is selected from the group consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris(hydroxymethyl)- aminomethane, or mixtures thereof.
  • the buffer is glycylglycine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate or mixtures thereof.
  • the preservative is selected from the group consisting of phenol, m-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2- phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof.
  • the preservative is phenol or m-cresol.
  • the preservative is present in a further embodiment of the invention.
  • concentration from about 0.1 mg/ml to about 50 mg/ml more preferably in a concentration from about 0.1 mg/ml to about 25 mg/ml, and most preferably in a concentration from about 0.1 mg/ml to about 10 mg/ml.
  • the formulation may further comprise a chelating agent where the chelating agent may be selected from salts of
  • EDTA ethlenediaminetetraacetic acid
  • citric acid citric acid
  • aspartic acid citric acid
  • mixtures thereof ethlenediaminetetraacetic acid
  • the chelating agent is present in a further embodiment of the invention.
  • the chelating agent is present in a concentration from 0.1 mg/ml to 5 mg/ml. In a further embodiment of the invention the chelating agent is present in a concentration from 0.1 mg/ml to 2 mg/ml. In a further embodiment of the invention the chelating agent is present in a concentration from 2 mg/ml to 5 mg/ml.
  • the formulation may further comprise a stabilizer selected from the group of high molecular weight polymers or low molecular compounds where such stabilizers include, but are not limited to, polyethylene glycol (e.g. PEG 3350), polyvinylalcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, different salts (e.g. sodium chloride), L-glycine, L-histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine and mixtures thereof.
  • PEG 3350 polyethylene glycol
  • PVA polyvinylalcohol
  • polyvinylpyrrolidone polyvinylpyrrolidone
  • carboxymethylcellulose different salts (e.g. sodium chloride)
  • the high molecular weight polymer is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-a further polymer
  • the high molecular weight polymer is present in a concentration from 0.1 mg/ml to 50 mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a concentration from 0.1 mg/ml to 5 mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a concentration from 5 mg/ml to 10 mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a concentration from 10 mg/ml to 20 mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a concentration from 20 mg/ml to 30 mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a concentration from 30 mg/ml to 50 mg/ml.
  • the low molecular weight compound is present in a concentration from 0.1 mg/ml to 50 mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a concentration from 0.1 mg/ml to 5 mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a concentration from 5 mg/ml to 10 mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a concentration from 10 mg/ml to 20 mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a concentration from 20 mg/ml to 30 mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a concentration from 30 mg/ml to 50 mg/ml.
  • the formulation of the invention may further comprise a surfactant where a surfactant may be selected from a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g.
  • a surfactant may be selected from a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g.
  • Tween-20 or Tween-80
  • monoglycerides or ethoxylated derivatives thereof diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids,
  • glycerophospholipids lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium, docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts thereof and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N,N-dimethyl-3-ammonio- 1-propanesulfonate, anionic (alkyl-aryl-sulphonates) monovalent surfactants, palmi
  • dipalmitoylphosphatidylcholine dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g.
  • N-alkyl-N,N- dimethylammonio- 1 -propanesulfonates 3-cholamido- 1 -propyldimethylammonio- 1 - propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases) (e.g.
  • acylcarnitines and derivatives N a -acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N a -acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N a -acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. Each one of these specific surfactants constitutes an alternative embodiment of the invention.
  • Pharmaceutically acceptable sweeteners comprise preferably at least one intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose (4, ,6'-trichloro-4,r,6'-trideoxygalactosucrose), preferably saccharin, sodium or calcium saccharin, and optionally a bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.
  • intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose (4, ,6
  • Intense sweeteners are conveniently employed in low concentrations.
  • concentration may range from 0.04% to 0.1% (w/v) based on the total volume of the final formulation, and preferably is about 0.06% in the low-dosage formulations and about 0.08% in the high-dosage ones.
  • the bulk sweetener can effectively be used in larger quantities ranging from about 10% to about 35%, preferably from about 10% to 15% (w/v).
  • formulations of the invention may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19th edition, 1995, where such conventional techniques of the pharmaceutical industry involve dissolving and mixing the ingredients as appropriate to give the desired end product.
  • phrases "pharmaceutically acceptable” or “therapeutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and preferably do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a State government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia (e.g. , Remington's Pharmaceutical
  • Administration of the compounds of the present invention may be carried out using any method known in the art.
  • administration may be transdermal, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intracerebroventricular, intrathecal, intranasal, aerosol, by suppositories, or oral administration.
  • a pharmaceutical composition of the present invention can be for administration for injection, or for oral, pulmonary, nasal, transdermal, ocular administration.
  • the peptide or a therapeutically acceptable salt thereof can be formulated in unit dosage forms such as capsules or tablets.
  • the tablets or capsules may be prepared by conventional means with pharmaceutically acceptable excipients, including binding agents, for example, pregelatinised maize starch,
  • Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, for example, suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats;
  • emulsifying agents for example, lecithin or acacia
  • non-aqueous vehicles for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils
  • preservatives for example, methyl or propyl-p-hydroxybenzoates or sorbic acid.
  • the preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active compound.
  • the peptide can be formulated in a pharmaceutically
  • Such formulations can be in the form of a cream, lotion, sublingual tablet, aerosols and/or emulsions and can be included in a transdermal or buccal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compounds of the present invention are N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • compositions with pharmaceutically acceptable vehicles or carriers can be administered by either intravenous, subcutaneous, or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers.
  • the compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents, for example, suspending, stabilizing, and/or dispersing agents.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.
  • the pharmaceutical compositions of the present invention may be formulated with a pharmaceutically acceptable carrier to provide sterile solutions or suspensions for injectable administration.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspensions in liquid prior to injection or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, or the like.
  • the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like.
  • absorption enhancing preparations e.g. , liposomes
  • Suitable pharmaceutical carriers are described in "Remington's pharmaceutical Sciences" by E. W. Martin.
  • the compounds may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane,
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, for example, lactose or starch.
  • a suitable powder base for example, lactose or starch.
  • the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the form of drops.
  • the compounds can also be formulated in rectal compositions, for example,
  • suppositories or retention enemas for example, containing conventional suppository bases, for example, cocoa butter or other glycerides.
  • the compounds can be formulated as a depot preparation.
  • Such long- acting formulations can be administered by implantation (for example,
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient.
  • the pack can, for example, comprise metal or plastic foil, for example, a blister pack.
  • the pack or dispenser device can be accompanied by instructions for administration.
  • the compounds of the present invention may be administered to a patient at
  • compositions comprising one or more of compounds of the present invention may be administered to a patient in an amount sufficient to elicit an effective protective or therapeutic response in the patient.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose.”
  • the dose will be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the area to be treated.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular compound or vector in a particular subject.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio, LD50/ED50.
  • Compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue to minimize potential damage to normal cells and, thereby, reduce side effects.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage can vary within this range depending upon the dosage form employed and the route of administration.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC50 the concentration of the test compound that achieves a half-maximal inhibition of symptoms
  • levels in plasma can be measured, for example, by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the dose equivalent of a modulator is from about 1 ng/kg to 10 mg/kg for a typical subject.
  • an effective amount of the drug required to prevent, counter or arrest the progress of the condition In general it is contemplated that an effective amount would be from 0.001 mg/kg to 10 mg/kg body weight, and in particular from 0.01 mg/kg to 1 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.01 to 500 mg, and in particular 0.1 mg to 200 mg of active ingredient per unit dosage form.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g. , an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated.
  • the total dosage may be divided and administered in portions during the day as required.
  • compositions of this invention are useful for treating pain or pain associated disorders.
  • the compositions of this invention are useful for treating immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric conditions, urological and reproductive conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases and cough.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group.
  • 'Vz-alkyl refers to an unbranched alkyl group.
  • C x -C y alkyl refers to an alkyl group having between x and y carbon atoms, inclusively, in the branched or unbranched hydrocarbon group.
  • C 1 -C 4 alkyl refers to a straight chain or branched hydrocarbon moiety having from 1 to 4 carbon atoms, including methyl, ethyl, ⁇ -propyl, isopropyl, rc-butyl, isobutyl, sec-butyl, and ieri-butyl.
  • Ci-C 4 w-alkyl refers to straight chain hydrocarbon moieties having from 1 to 4 carbon atoms including methyl, ethyl, ⁇ -propyl, and /i-butyl.
  • C x -C y x is between 1 and 10 and y is between 2 and 20.
  • C 3 -C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 3 -C7 cycloalkyl also includes cycloheptyl.
  • Cycloalkylalkyl refers to cycloalkyl moieties linked through an alkyl linker chain, as for example, but without limitation,
  • Each alkyl, cycloalkyl, and cycloalkylalkyl group may be optionally substituted as specified herein.
  • alkoxy refers to an alkyl group, phenyl group, benzyl group, or pyrimidinyl group, respectively, each optionally substituted, that is bonded through an oxygen atom.
  • alkylthio refers to an alkyl group, phenyl group, or benzyl group, respectively, each optionally substituted, that is bonded through a sulfur atom.
  • Ci-C 4 acyl refers to a formyl group or a C C 3 alkyl group bonded
  • Ci-C 4 alkoxycarbonyl refers to a C C 4 alkoxy group bonded through a carbonyl moiety.
  • halo refers to fluoro, chloro, bromo, or iodo.
  • Preferred halo groups are fluoro, chloro, and bromo. More preferred halo groups are fluoro and chloro.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,
  • bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).
  • a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
  • Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring.
  • the substituents recited for the ring can also be present on the bridge.
  • Fused e.g., naphthyl and tetrahydronaphthyl
  • spiro rings are also included.
  • heterocycle is taken to mean a saturated or unsaturated 5- or 6-membered ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, said ring optionally being benzofused.
  • exemplary heterocycles include furanyl, thiophenyl (thienyl), pyrrolyl, pyrrolidinyl, pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like.
  • Benzofused heterocyclic rings include isoquinolinyl, benzoxazolyl, benzodioxolyl, benzo
  • heterocycles include pyridinyl, indolyl, furanyl, benzofuranyl, thiophenyl, benzodioxolyl, and thiazolidinyl, all of which may be optionally substituted.
  • aromatic heterocycle or “heteroaryl” is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
  • bicyclic heterocyclic aromatic rings only one of the two rings needs to be aromatic (e.g., 2,3-dihydroindole), though both can be (e.g., quinoline).
  • the second ring can also be fused or bridged as defined above for heterocycles.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined).
  • heterocycles include, but are not limited to, acridinyl, azocinyl,
  • benzimidazolyl benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-
  • tetrahydrofuranyl tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H- 1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
  • Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio means an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkythio group, respectively, substituted one or more times independently with a substituent selected from the group consisting of halo, hydroxy, and C C 3 alkoxy.
  • examples include trifluoromethyl, pentafluoroethyl, 5-fluoro-2-bromopentyl, 3- hydroxypropyloxy, 4-hydroxycyclohexyloxy, 2-bromoethylthio, 3-ethoxypropyloxy, 3-ethoxy-4-chlorocyclohexyl, and the like.
  • substitutions include substitution 1-5 times with halo, each independently selected, or substituted 1-3 times with halo and 1-2 times independently with a group selected from hydroxy and Q-C 3 alkoxy, or substituted 1-3 times independently with a group selected from hydroxy and C C 3 alkoxy, provided that no more than one hydroxy and/or alkoxy substituent may be attached through the same carbon.
  • substituted phenyl and “substituted heterocycle” are taken to mean that the cyclic moiety in either case is substituted with one or more halo substituents, preferably one to five, each independently selected; or substituted with one or more substituents, preferably one to two substituents, independently selected from the group consisting of halo, Q-C 4 alkyl, Q-C 4 alkoxy, and Q-C 4 alkylthio, wherein each alkyl, alkoxy and alkylthio substituent can be further substituted independently with C C 2 alkoxy or with one to five halo groups selected from fluoro and chloro; or substituted with one substituent selected from the group consisting of phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy, wherein the phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimi
  • DMF means N,N-dimethylformamide.
  • the phrase "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • excipients and salt must be compatible with the active ingredient of the formulation (e.g. a compound of formula I). It is understood by those of ordinary skill in this art that the terms “pharmaceutical formulation” and “pharmaceutical composition” are generally interchangeable, and they are so used for the purposes of this application.
  • compositions wherein the parent compound wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).
  • the compounds of the present invention can be delivered in prodrug form.
  • the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same.
  • Prodrugs are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • treating includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
  • Treating or “treatment” of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease-state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease- state, i.e., causing regression of the disease state.
  • preventing means causing the clinical symptoms of the disease state not to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
  • mamal refers to human and non-human patients.
  • the term "therapeutically effective amount” refers to a compound, or a combination of compounds, of the present invention present in or on a recipient in an amount sufficient to elicit biological activity, e.g. pain relief.
  • the combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal
  • Synergy can be in terms of lower cytotoxicity, increased decrease in pain, or some other beneficial effect of the combination compared with the individual components.
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present invention also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • a composition includes a plurality of such compositions, as well as a single composition
  • a reference to “a therapeutic agent” is a reference to one or more therapeutic and/or pharmaceutical agents and equivalents thereof known to those skilled in the art, and so forth.
  • a reference to “a host cell” includes a plurality of such host cells
  • a reference to “an antibody” is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.

Abstract

This application describes a family of compounds acting as opioid receptor ligands. Such compounds may provide significant therapeutic benefit in the treatment of pain and pain related disorders.

Description

Opioid Receptor Ligands and Methods of Using and Making Same
[0001] FIELD OF THE INVENTION
[0002] This application relates to a family of compounds acting as opioid receptor ligands.
Such compounds may provide significant therapeutic benefit in the treatment of pain.
[0003] BACKGROUND
[0004] Opioid receptors (ORs) mediate the actions of morphine and morphine-like opioids, including most clinical analgesics. Three molecularly and pharmacologically distinct opioid receptor types have been described: δ, κ and μ. Furthermore, each type is believed to have sub-types. All three of these opioid receptor types appear to share the same functional mechanisms at a cellular level. For example, activation of the opioid receptors causes inhibition of adenylate cyclase, and recruits β-arrestin.
[0005] When therapeutic doses of morphine are given to patients with pain, they report that the pain is less intense, less discomforting, or entirely gone. In addition to experiencing relief of distress, some patients experience euphoria. However, when morphine in a selected pain-relieving dose is given to a pain-free individual, the experience is not always pleasant; nausea is common, and vomiting may also occur. Drowsiness, inability to concentrate, difficulty in mentation, apathy, lessened physical activity, reduced visual acuity, and lethargy may ensue.
[0006] There is a continuing need for new OR modulators to be used as analgesics. There is a further need for OR agonists as analgesics having reduced side effects. There is a further need for OR agonists as analgesics having reduced side effects for the treatment of pain, immune dysfunction, inflammation, esophageal reflux,
neurological and psychiatric conditions, urological and reproductive conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases and cough. [0007] μ-opioid agonists are used as analgesics for the treatment of moderate to severe pain. The use of opioid analgesics is often associated with adverse effects on the GI tract, collectively termed opioid-induced bowel dysfunction (OBD). OBD includes symptoms such as constipation, decreased gastric emptying, abdominal pain and discomfort, bloating, nausea, and gastroesophageal reflux, μ-opioid antagonists can potentially block undesirable GTrelated side effects without interfering with the beneficial central effects of analgesia or precipitating central nervous system withdrawal symptoms, μ-opioid agonists also result in depression of respiratory function, μ-opioid antagonists have been shown to reverse such respiratory depression. Postoperative ileus (POI) is a common problem following surgery, especially abdominal surgery. Symptoms of POI are similar to those of OBD. μ- opioid antagonists have been shown to be beneficial in the treatment of POI.
[0008] SUMMARY OF THE INVENTION
[0009] According to some embodiments, the present invention provides for novel μ-opioid receptor (MOR) ligands. The present invention also provides methods of modulating opioid receptor activity using the compositions described in the invention. Certain compositions of the invention act as μ-opioid receptor agonists. Other compositions of the invention act as μ-opioid receptor antagonists. Certain compositions of the invention act as δ-opioid receptor agonists. Other compositions of the invention act as δ-opioid receptor antagonists. Certain compositions of the invention act as κ- opioid receptor agonists. Other compositions of the invention act as κ-opioid receptor antagonists.
[0010] The invention provides compounds having the structure:
Figure imgf000004_0001
Figure imgf000004_0002
[0011] In the structure above, variables Aa, Bb and Dd can be selected from the respective groups of chemical or biological moieties later described in the detailed description. MOR ligand derivatives and mimetics are also provided. Also provided are processes for preparing the compounds of the invention.
[0012] According to some embodiments, the present invention extends to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Naturally, the compounds of the present invention can be employed in any form, such as a solid or solution (e.g. , aqueous solution) as is described further below. The compound, for example, can be obtained and employed in a lyophilized form alone or with suitable additives.
[0013] Also provided are methods for treating pain and pain-related disorders. Such a
method would comprise administering a therapeutically effective amount of one or more compounds of the present invention to a subject in need thereof.
[0014] DETAILED DESCRIPTION
[0015] This application describes a family of compounds, OR ligands, with a unique profile.
The compounds of the present invention act as agonists or antagonists of opioid receptor (OR)-mediated signal transduction. These OR include μ-opioid receptors (MORs), K-opioid receptors (KORs) and δ-opioid receptors (DOR). In certain embodiments of the invention, ligands of these receptors are used to treat pathologies associated with ORs including pain and pain related disorders.
[0016] According to some embodiments, the compounds of the present invention comprise the following formula:
Figure imgf000005_0001
wherein Al is null, CH2, CHR1, CR1R2, O, S, SO, S02, NH, NR1, CH, CR1 or N; A2 is null, CH2, CHR5, CR5R6, O, S, SO, S02, NH, NR5, CH, CR5 or N; A3 is null, CH2, CHR7, CR7R8, O, S, SO, S02, NH, NR7, CH, CR7 or N; A4 is null, CH2, CHR9, CR9R10, O, S, SO, S02, NH, NR9, CH, CR9 or N; A5 is null, CH2, CHR11, CR11R12, CH2CH2, CHR11CH2, CH2CHR11, CHR11CHR12, O, S, NH, NR11, CH, or CR11; and wherein A6 is CH, CR3, N, or C.
[0017] No more than 2 out of 5 Aa (specifically, Al, A2, A3, A4, A5) can be null at the same time. The number of hetero atoms from Al to A6 cannot exceed 2 at the same time, and S-O; S-S; S-N fragments in the ring structure are excluded from the present invention. [0018] In some embodiments, the ring consisted of Al, A2, A3, A4, A5 and A6 can be fused with another ring, such as benzene, pyridine, pyrimidine, furan, thiophene, or pyridazine, but not limited to these examples only. It is also understood that the rings could be multiply substituted with cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, formyl, acetyl, amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, and other small substitution groups. In other embodiments, the bonds between Aland A2, A2 and A3, A3 and A4, A4 and A5, A5 and A6, A6 and Al and A6 and A7 are independently a single bond or a double bond. In other embodiments, the bonds between Aland A2, A2 and A3, A3 and A4, A4 and A5, A5 and A6, and A6 and Al cannot be a double bond at the same time. For example, the ring consisted of Al, A2, A3, A4, A5 and A6 cannot be a benzene ring.
[0019] A7 is N, CH, CF, COH, CNH2, COCH3, CCN, or C. Both A6 and A7 cannot be N at the same time.
[0020] Blis CH2, CHR13, CR13R14, O, S, NH, NR13, CH, CR13, C, CO, or CS. B2 is
CH2, CHR15, CR15R16, O, S, NH, NR15, CH, CR15, C, CO, or CS. B3 is H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkylsulfonyl. B4 is null, CH2, CHR19, CR19R20, CO, or CS. B5 is alkyl, branched alkyl, halogenated alkyl, carbocycle- substituted alkyl, aryl, carbocycle, or arylalkyl.
[0021] Aryl, carbocycle (non-aromatic)/ heterocycle (non-aromatic with 1-3 heteroatoms, including O, N, S) are either unsubstituted, or substituted with small substitution groups. Small substitution groups are selected from the following groups consisting of, but not limited to: cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl,
alkylmercaptanyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl. Preferably, the substitution groups are selected from F, CI, Br, CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF3, NH2, NHMe, NMe2,
methoxycarbonyl, Ph, benzyl, MeS02, formyl, and acetyl.
[0022] Carbocycle may contain double bonds, but they should not be aromatic.
[0023] In some embodiments, the bond between A7 and Bl is a single bond or a double bond. In other embodiments the bond between B 1 and B2 is a single bond, or a double bond.
[0024] Dl is an aryl group or a carbocycle.
[0025] Aryl group is either a monocyclic aromatic group or a bicyclic aromatic group. The following structures are some examples of representive aryl groups, but the aryl groups are not limited to those examples:
Figure imgf000008_0001
Figure imgf000009_0001
Carbocycle is either a monocyclic or a bicyclic non-aromatic ring system. The following structures are some examples of representative carbocycle, but the carbocycle is not limited to those examples:
Figure imgf000010_0001
Wherein XI, and X2 in the carbocycle examples are independently selected from O, S, N, NH, NR18.
[0027] In certain embodiments, the aryl groups are multiply substituted with cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, carbocycle, carbocycle- alkyl, and/or other small substitution groups. Preferably, the substitution groups are selected from F, CI, Br, CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF3, NH2, NHMe, NMe2,
methoxycarbonyl, Ph, benzyl, formyl, and acetyl.
[0028] Alkyl is a linear carbon chain having between 1 and 10 carbon atoms.
[0029] Dl is an aryl, or a carbocycle.
[0030] Rl, R2, R5, R6, R7, R8, R9, R10, Rl l, R12, R13, R14, R15, R16, R18, R19, and R20 are independently: cyano, halogen, hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl, alkoxycarbonyl. Preferably, Rl, R2, R5, R6, R7, R8, R9, R10, Rl l, R12, R13, R14, R15, R16, R18, R19, and R20 are independently F, CI, Br, CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec- Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-i-Pr, methoxycarbonyl, Ph, benzyl, formyl, and acetyl.
[0031] In other embodiments, Rl and R2, R5 and R6, R7 and R8, R9 and R10, Rl 1 and
R12, R13 and R14, R15 and R16, R19 and R20, or R15 and R19 forms a monocyclic carbocycle or heterocycle. [0032] R3 is Me, CF3, CH2OH, CH2NH2, CH2NHBoc, OH, methoxycarbonyl, CN, C02R4, NH, or N-t-butoxycarbonyl.
[0033] R4 is an alkyl or a branched alkyl group.
[0034] Me is methyl; Et is ethyl; Boc is t-butoxycarbonyl; i-Pr is i-propyl; t-Bu is t-butyl; Ph is phenyl, Bn is benzyl.
[0035] In certain embodiments, the following compounds are excluded from the genus of compounds of the invention:
1) Benzyl[3-(2,2-dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl]amine
Figure imgf000012_0001
2) [3-(2,2-Dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl](l-phenylethyl)amine
Figure imgf000012_0002
3) 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl]amino}methyl)-N,N- dimethylaniline
Figure imgf000012_0003
Benzyl[3-(2,2-dimethyloxan-4-yl)-3-(4-methoxyphenyl)propyl]amine
Figure imgf000013_0001
4-({ [3-(2,2-Dimethyloxan-4-yl)-3-(4-methoxyphenyl)propyl]amino}methyl)-N,N- dimethylaniline
Figure imgf000013_0002
[3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl](l-phenylethyl)amine
Figure imgf000013_0003
[3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl][(4-methoxyphenyl)methyl]amine
Figure imgf000013_0004
[3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl][(4-methoxyphenyl)methyl]propylamine
Figure imgf000014_0001
9) 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl]amino}methyl)-N,N-dimethylaniline
Figure imgf000014_0002
[(3,4-dimethoxyphenyl)methyl][3-(2,2-dimethyloxan-4-yl)-3-phenylpropyl]amine
Figure imgf000014_0003
[0036] According to some embodiments, the compounds of the present invention comprise the following formula:
Figure imgf000014_0004
wherein A2 is CH2, CHR5, CR5R6; A4 is CH2, CHR9, CR9R10.
[0037] Further R5 and R6, and R9 and R10 are independently CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, MeO, EtO, phenyl. In other enbodiments, R5 and R6, or R9 and R10 forms a monocyclic carbocycle. [0038] Further B3 is selected from the following: H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkylsulfonyl. Preferably, B3 is H, CH3, CH2CH3, i-Pr, t-Bu, n-Pr, n-Bu, i-Bu, sec-Bu, Bn.
[0039] Further R28 is selected from the following: H, alkyl, branched alkyl, halogenated alkyl. Preferably, R28 is H, CH3, CH2CH3, i-Pr, t-Bu, n-Pr, n-Bu.
[0040] Further Dl and D2 are independently: aryl, or carbocycle. Examples of the aryl and carbocyle/heterocycle were shown previously, but the aryl and carbocyle/heterocycle are not limited to those examples.
[0041] According to some embodiments, the compounds of the present invention comprise the following formula:
Figure imgf000015_0001
wherein A2 is CH2, CHR5, CR5R6; A4 is CH2, CHR9, CR9R10.
[0042] Further R5 and R6, and R9 and R10 are independently CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, MeO, EtO, phenyl. In other enbodiments, R5 and R6, or R9 and R10 forms a monocyclic carbocycle.
[0043] Further B3 is selected from the following: H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkylsulfonyl. Preferably, B3 is H, CH3, CH2CH3, i-Pr, t-Bu, n-Pr, n-Bu, i-Bu, sec-Bu, Bn.
[0044] Further R28 is selected from the following: H, alkyl, branched alkyl, halogenated alkyl. Preferably, R28 is H, CH3, CH2CH3, i-Pr, t-Bu, n-Pr, n-Bu.
[0045] Further Dl and D2 are independently: aryl, or carbocycle. Examples of the aryl and carbocyle/heterocycle were shown previously, but the aryl and carbocyle/heterocycle are not limited to those examples.
[0046] According to some embodiments, the compounds of the present invention with
antagonist activity comprise the following formula:
Figure imgf000016_0001
wherein A2 is CH2, CHR5, CR5R6; A4 is CH2, CHR9, CR9R10.
[0047] Further R5 and R6, and R9 and R10 are independently CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, MeO, EtO, phenyl. In other enbodiments, R5 and R6, or R9 and R10 forms a monocyclic carbocycle.
[0048] Further Dl is: aryl, or carbocycle. Examples of the aryl and carbocyle/heterocycle were shown previously, but the aryl and carbocyle/heterocycle are not limited to those examples.
[0049] According to some embodiments, the compounds of the present invention with
antagonist activity comprise the following formula:
Figure imgf000016_0002
wherein A2 is CH2, CHR5, CR5R6; A4 is CH2, CHR9, CR9R10.
[0050] Further R5 and R6, and R9 and RIO are independently CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, MeO, EtO, phenyl. In other enbodiments, R5 and R6, or R9 and R10 forms a monocyclic carbocycle.
[0051] Further Dl is: aryl, or carbocycle. Examples of the aryl and carbocyle/heterocycle were shown previously, but the aryl and carbocyle/heterocycle are not limited to those examples.
[0052] According to some embodiments, the compounds of the present invention with
antagonist activity comprise the following formula:
Figure imgf000017_0001
wherein A2 is CH2, CHR5, CR5R6; A4 is CH2, CHR9, CR9R10.
[0053] Further R5 and R6, and R9 and R10 are independently CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, MeO, EtO, phenyl. In other enbodiments, R5 and R6, or R9 and R10 forms a monocyclic carbocycle.
[0054] Further Dl and D2 are independently: aryl, or carbocycle. Examples of the aryl and carbocyle/heterocycle were shown previously, but the aryl and carbocyle/heterocycle are not limited to those examples.
[0055] According to some embodiments, the following known compounds have the agonist activity in OR mediated signal transduction:
1) Benzyl[3-(2,2-dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl]amine
Figure imgf000018_0001
-Dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl](l-phenylethyl)amine
Figure imgf000018_0002
) 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl]amino}methyl)-N,N- dimethylaniline
Figure imgf000018_0003
) Benzyl[3-(2,2-dimethyloxan-4-yl)-3-(4-methoxyphenyl)propyl]amine
Figure imgf000018_0004
) 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-(4-methoxyphenyl)propyl]amino}methyl)-N,N- dimethylaniline
Figure imgf000019_0001
[3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl](l-phenylethyl)amine
Figure imgf000019_0002
[3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl][(4-methoxyphenyl)methyl]amine
Figure imgf000019_0003
[3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl][(4-methoxyphenyl)methyl]propylamine
Figure imgf000019_0004
4-({ [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl]amino}methyl)-N,N-dimethylaniline
Figure imgf000019_0005
[(3,4-dimethoxyphenyl)methyl] [3-(2,2-dimethyloxan-4-yl)-3-phenylpropyl]amine
Figure imgf000020_0001
[0056] Thus, the invention provides methods of generating agonist activity in OR mediated signal transduction through administration of the above recited compounds.
[0057] According to some embodiments of the invention, various atoms in the compositions of the invention are isotopes that occur at lower frequency. In one preferred embodiment, hydrogen is replaced at any position in the compositions of the invention with deuterium. Optionally, hydrogen can also be replaced with tritium.
12
In another embodiment, carbon ( C) is replaced at any position in the compositions of the invention with 13C or 14C. In another embodiment, nitrogen (14N) is replaced with 15N. In another embodiment, oxygen (160) is replaced at any position in the
17 18 32 compositions of the invention with O or O. In another embodiment, sulfur ( S) is
33 34 36 replaced at any position in the compositions of the invention with S, S or S. In
35
another embodiment, chlorine ( CI) is replaced at any position in the compositions
37 79
of the invention with CI. In another embodiment, bromine ( Br) is replaced at any
81
position in the compositions of the invention with Br.
[0058] The compounds of the preferred embodiments are agonists and antagonists of Opioid Receptors (ORs). The ability of the compounds to stimulate OR mediated signaling may be measured using any assay known in the art used to detect OR mediated signaling or OR activity, or the absence of such signaling/activity. "OR activity" refers to the ability of an OR to transduce a signal. Such activity can be measured, e.g. , in a heterologous cell, by coupling an OR (or a chimeric OR) to a downstream effector such as adenylate cyclase. [0059] A "natural ligand-induced activity" as used herein, refers to activation of the OR by a natural ligand of the OR. Activity can be assessed using any number of endpoints to measure OR activity.
[0060] Generally, assays for testing compounds that modulate OR-mediated signal
transduction include the determination of any parameter that is indirectly or directly under the influence of a OR, e.g. , a functional, physical, or chemical effect.
[0061] Samples or assays comprising ORs that are treated with a potential activator,
inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of inhibition. Control samples
(untreated with inhibitors) are assigned a relative OR activity value of 100%.
Inhibition of an OR is achieved when the OR activity value relative to the control is about 80%, preferably 50%, more preferably 25%. Activation of an OR is achieved when the OR activity value relative to the control (untreated with activators) is 110%, more preferably 150%, more preferably 200-500% (i.e. , two to five fold higher relative to the control), more preferably 1000-3000% or higher.
[0062] The effects of the compounds upon the function of an OR can be measured by
examining any of the parameters described above. Any suitable physiological change that affects OR activity can be used to assess the influence of a compound on the ORs and natural ligand-mediated OR activity. When the functional consequences are determined using intact cells or animals, one can also measure a variety of effects such as changes in intracellular second messengers such as cAMP.
[0063] Modulators of OR activity are tested using OR polypeptides as described above, either recombinant or naturally occurring. The protein can be isolated, expressed in a cell, expressed in a membrane derived from a cell, expressed in tissue or in an animal. For example, neuronal cells, cells of the immune system, transformed cells, or membranes can be used to test the GPCR polypeptides described above. Modulation is tested using one of the in vitro or in vivo assays described herein. Signal transduction can also be examined in vitro with soluble or solid state reactions, using a chimeric molecule such as an extracellular domain of a receptor covalently linked to a heterologous signal transduction domain, or a heterologous extracellular domain covalently linked to the transmembrane and or cytoplasmic domain of a receptor. Furthermore, ligand-binding domains of the protein of interest can be used in vitro in soluble or solid state reactions to assay for ligand binding.
[0064] Ligand binding to an OR, a domain, or chimeric protein can be tested in a number of formats. Binding can be performed in solution, in a bilayer membrane, attached to a solid phase, in a lipid monolayer, or in vesicles. Typically, in an assay of the invention, the binding of the natural ligand to its receptor is measured in the presence of a candidate modulator. Alternatively, the binding of the candidate modulator may be measured in the presence of the natural ligand. Often, competitive assays that measure the ability of a compound to compete with binding of the natural ligand to the receptor are used. Binding can be tested by measuring, e.g., changes in spectroscopic characteristics (e.g., fluorescence, absorbance, refractive index), hydrodynamic (e.g., shape) changes, or changes in chromatographic or solubility properties.
[0065] Modulators may also be identified using assays involving β-arrestin recruitment, β- arrestin serves as a regulatory protein that is distributed throughout the cytoplasm in unactivated cells. Ligand binding to an appropriate OR is associated with
redistribution of β-arrestin from the cytoplasm to the cell surface, where it associates with the OR. Thus, receptor activation and the effect of candidate modulators on ligand-induced receptor activation, can be assessed by monitoring β-arrestin recruitment to the cell surface. This is frequently performed by transfecting a labeled β-arrestin fusion protein (e.g., β-arrestin-green fluorescent protein (GFP)) into cells and monitoring its distribution using confocal microscopy (see, e.g., Groarke et ah, J. Biol. Chem. 274(33):23263 69 (1999)).
[0066] Another technology that can be used to evaluate OR-protein interactions in living cells involves bioluminescence resonance energy transfer (BRET). A detailed discussion regarding BRET can be found in Kroeger et ah , J. Biol. Chem.,
276(16): 12736 43 (2001).
[0067] Other assays can involve determining the activity of receptors which, when activated by ligand binding, result in a change in the level of intracellular cyclic nucleotides, e.g. , cAMP, by activating or inhibiting downstream effectors such as adenylate cyclase. In one embodiment, changes in intracellular cAMP can be measured using immunoassays. The method described in Offermanns & Simon, J. Biol. Chem. 270: 15175 15180 (1995) may be used to determine the level of cAMP. Also, the method described in Felley-Bosco et al. , Am. J. Resp. Cell and Mol. Biol. 11 : 159 164 (1994) may be used to determine the level of cGMP. Further, an assay kit for measuring cAMP a is described in U.S. Pat. No. 4, 115,538, herein incorporated by reference.
[0068] In another embodiment, transcription levels can be measured to assess the effects of a test compound on ligand-induced signal transduction. A host cell containing the protein of interest is contacted with a test compound in the presence of the natural ligand for a sufficient time to effect any interactions, and then the level of gene expression is measured. The amount of time to effect such interactions may be empirically determined, such as by running a time course and measuring the level of transcription as a function of time. The amount of transcription may be measured by using any method known to those of skill in the art to be suitable. For example, mRNA expression of the protein of interest may be detected using northern blots or their polypeptide products may be identified using immunoassays. Alternatively, transcription based assays using reporter genes may be used as described in U.S. Pat. No. 5,436, 128, herein incorporated by reference. The reporter genes can be, e.g. , chloramphenicol acetyltransferase, firefly luciferase, bacterial luciferase, β- galactosidase and alkaline phosphatase. Furthermore, the protein of interest can be used as an indirect reporter via attachment to a second reporter such as green fluorescent protein (see, e.g. , Mistili & Spector, Nature Biotechnology 15:961 964 (1997)).
[0069] The amount of transcription is then compared to the amount of transcription in either the same cell in the absence of the test compound, or it may be compared with the amount of transcription in a substantially identical cell that lacks the protein of interest. A substantially identical cell may be derived from the same cells from which the recombinant cell was prepared but which had not been modified by introduction of heterologous DNA. Any difference in the amount of transcription indicates that the test compound has in some manner altered the activity of the protein of interest.
[0070] Pharmaceutical Compositions/ Formulations
[0071] Pharmaceutical compositions for use in the present invention can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. In a preferred embodiment of the invention, the formulations may contain a buffer and/or a preservative. The compounds and their physiologically acceptable salts and solvates can be formulated for administration by any suitable route, including via inhalation, topically, nasally, orally, parenterally {e.g. , intravenously, intraperitoneally, intravesically or intrathecally) or rectally in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the peptide, chosen route of administration and standard biological practice.
[0072] According to some embodiments, pharmaceutical compositions are provided
comprising effective amounts of one or more compound(s) of the present invention together with, for example, pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or other carriers. Such compositions include diluents of various buffer content (e.g., TRIS or other amines, carbonates, phosphates, amino acids, for example, glycinamide hydrochloride (especially in the physiological pH range), N-glycylglycine, sodium or potassium phosphate (dibasic, tribasic), etc. or TRIS-HCl or acetate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g. , surfactants such as Pluronics, Tween 20, Tween 80 (Polysorbate 80), Cremophor, polyols such as polyethylene glycol, propylene glycol, etc.), anti-oxidants (e.g. , ascorbic acid, sodium metabisulfite), preservatives (e.g. , Thimersol, benzyl alcohol, parabens, etc.) and bulking substances (e.g. , sugars such as sucrose, lactose, mannitol, polymers such as
polyvinylpyrrolidones or dextran, etc.); and/or incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid,
polyglycolic acid, etc. or into liposomes. Hyaluronic acid may also be used. Such compositions can be employed to influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of a compound of the present invention. See, e.g. , Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435- 1712 which are herein incorporated by reference. The compositions can, for example, be prepared in liquid form, or can be in dried powder, such as lyophilized form. Particular methods of administering such compositions are described infra. Where a buffer is to be included in the formulations of the invention, the buffer is selected from the group consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris(hydroxymethyl)- aminomethane, or mixtures thereof. Each one of these specific buffers constitutes an alternative embodiment of the invention. In a preferred embodiment of the invention the buffer is glycylglycine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate or mixtures thereof. [0074] Where a pharmaceutically acceptable preservative is to be included in the formulations of the invention, the preservative is selected from the group consisting of phenol, m-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2- phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof. Each one of these specific preservatives constitutes an alternative embodiment of the invention. In a preferred embodiment of the invention the preservative is phenol or m-cresol.
[0075] In a further embodiment of the invention the preservative is present in a
concentration from about 0.1 mg/ml to about 50 mg/ml, more preferably in a concentration from about 0.1 mg/ml to about 25 mg/ml, and most preferably in a concentration from about 0.1 mg/ml to about 10 mg/ml.
[0076] The use of a preservative in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
[0077] In a further embodiment of the invention the formulation may further comprise a chelating agent where the chelating agent may be selected from salts of
ethlenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof. Each one of these specific chelating agents constitutes an alternative embodiment of the invention.
[0078] In a further embodiment of the invention the chelating agent is present in a
concentration from 0.1 mg/ml to 5 mg/ml. In a further embodiment of the invention the chelating agent is present in a concentration from 0.1 mg/ml to 2 mg/ml. In a further embodiment of the invention the chelating agent is present in a concentration from 2 mg/ml to 5 mg/ml.
[0079] The use of a chelating agent in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
[0080] In a further embodiment of the invention the formulation may further comprise a stabilizer selected from the group of high molecular weight polymers or low molecular compounds where such stabilizers include, but are not limited to, polyethylene glycol (e.g. PEG 3350), polyvinylalcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, different salts (e.g. sodium chloride), L-glycine, L-histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine and mixtures thereof. Each one of these specific stabilizers constitutes an alternative embodiment of the invention. In a preferred embodiment of the invention the stabilizer is selected from the group consisting of L-histidine, imidazole and arginine.
[0081] In a further embodiment of the invention the high molecular weight polymer is
present in a concentration from 0.1 mg/ml to 50 mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a concentration from 0.1 mg/ml to 5 mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a concentration from 5 mg/ml to 10 mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a concentration from 10 mg/ml to 20 mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a concentration from 20 mg/ml to 30 mg/ml. In a further embodiment of the invention the high molecular weight polymer is present in a concentration from 30 mg/ml to 50 mg/ml.
[0082] In a further embodiment of the invention the low molecular weight compound is present in a concentration from 0.1 mg/ml to 50 mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a concentration from 0.1 mg/ml to 5 mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a concentration from 5 mg/ml to 10 mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a concentration from 10 mg/ml to 20 mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a concentration from 20 mg/ml to 30 mg/ml. In a further embodiment of the invention the low molecular weight compound is present in a concentration from 30 mg/ml to 50 mg/ml.
[0083] The use of a stabilizer in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
[0084] In a further embodiment of the invention the formulation of the invention may further comprise a surfactant where a surfactant may be selected from a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g. Tween-20, or Tween-80), monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids,
glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium, docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts thereof and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N,N-dimethyl-3-ammonio- 1-propanesulfonate, anionic (alkyl-aryl-sulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. l-acyl-sn-glycero-3- phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine,
dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N,N- dimethylammonio- 1 -propanesulfonates , 3-cholamido- 1 -propyldimethylammonio- 1 - propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases) (e.g. cetyl- trimethylammonium bromide, cetylpyridinium chloride), non-ionic surfactants, polyethyleneoxide/polypropyleneoxide block copolymers (Pluronics/Tetronics, Triton X- 100, Dodecyl β-D-glucopyranoside) or polymeric surfactants (Tween-40, Tween-80, Brij-35), fusidic acid derivatives— (e.g. sodium tauro-dihydrofusidate etc.), long-chain fatty acids and salts thereof C6-C12 (e.g. oleic acid and caprylic acid), acylcarnitines and derivatives, Na -acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, Na-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, Na-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. Each one of these specific surfactants constitutes an alternative embodiment of the invention.
[0085] The use of a surfactant in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
[0086] Pharmaceutically acceptable sweeteners comprise preferably at least one intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose (4, ,6'-trichloro-4,r,6'-trideoxygalactosucrose), preferably saccharin, sodium or calcium saccharin, and optionally a bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.
[0087] Intense sweeteners are conveniently employed in low concentrations. For example, in the case of sodium saccharin, the concentration may range from 0.04% to 0.1% (w/v) based on the total volume of the final formulation, and preferably is about 0.06% in the low-dosage formulations and about 0.08% in the high-dosage ones. The bulk sweetener can effectively be used in larger quantities ranging from about 10% to about 35%, preferably from about 10% to 15% (w/v).
[0088] The formulations of the invention may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19th edition, 1995, where such conventional techniques of the pharmaceutical industry involve dissolving and mixing the ingredients as appropriate to give the desired end product.
[0089] The phrase "pharmaceutically acceptable" or "therapeutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and preferably do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a State government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia (e.g. , Remington's Pharmaceutical
Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985)) for use in animals, and more particularly in humans.
[0090] Administration of the compounds of the present invention may be carried out using any method known in the art. For example, administration may be transdermal, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intracerebroventricular, intrathecal, intranasal, aerosol, by suppositories, or oral administration. Preferably, a pharmaceutical composition of the present invention can be for administration for injection, or for oral, pulmonary, nasal, transdermal, ocular administration.
[0091] For oral administration, the peptide or a therapeutically acceptable salt thereof can be formulated in unit dosage forms such as capsules or tablets. The tablets or capsules may be prepared by conventional means with pharmaceutically acceptable excipients, including binding agents, for example, pregelatinised maize starch,
polyvinylpyrrolidone, or hydroxypropyl methylcellulose; fillers, for example, lactose, microcrystalline cellulose, or calcium hydrogen phosphate; lubricants, for example, magnesium stearate, talc, or silica; disintegrants, for example, potato starch or sodium starch glycolate; or wetting agents, for example, sodium lauryl sulphate. Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, for example, suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats;
emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl-p-hydroxybenzoates or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active compound.
[0092] For topical administration, the peptide can be formulated in a pharmaceutically
acceptable vehicle containing 0.1 to 10 percent, preferably 0.5 to 5 percent, of the active compound(s). Such formulations can be in the form of a cream, lotion, sublingual tablet, aerosols and/or emulsions and can be included in a transdermal or buccal patch of the matrix or reservoir type as are conventional in the art for this purpose.
[0093] For parenteral administration, the compounds of the present invention are
administered by either intravenous, subcutaneous, or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers. The compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents, for example, suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.
[0094] For administration by injection, it is preferred to use the compound(s) in solution in a sterile aqueous vehicle which may also contain other solutes such as buffers or preservatives as well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make the solution isotonic. In some embodiments, the pharmaceutical compositions of the present invention may be formulated with a pharmaceutically acceptable carrier to provide sterile solutions or suspensions for injectable administration. In particular, injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspensions in liquid prior to injection or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, or the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. If desired, absorption enhancing preparations (e.g. , liposomes) may be utilized. Suitable pharmaceutical carriers are described in "Remington's pharmaceutical Sciences" by E. W. Martin.
[0095] For administration by inhalation, the compounds may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, for example, lactose or starch. For intranasal administration the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the form of drops.
[0096] The compounds can also be formulated in rectal compositions, for example,
suppositories or retention enemas, for example, containing conventional suppository bases, for example, cocoa butter or other glycerides.
[0097] Furthermore, the compounds can be formulated as a depot preparation. Such long- acting formulations can be administered by implantation (for example,
subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0098] The compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient. The pack can, for example, comprise metal or plastic foil, for example, a blister pack. The pack or dispenser device can be accompanied by instructions for administration. [0099] Dosages
[0100] The compounds of the present invention may be administered to a patient at
therapeutically effective doses to prevent, treat, or control diseases and disorders mediated, in whole or in part, by an OR-ligand interaction of the present invention. Pharmaceutical compositions comprising one or more of compounds of the present invention may be administered to a patient in an amount sufficient to elicit an effective protective or therapeutic response in the patient. An amount adequate to accomplish this is defined as "therapeutically effective dose." The dose will be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the area to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular compound or vector in a particular subject.
[0101] Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio, LD50/ED50. Compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue to minimize potential damage to normal cells and, thereby, reduce side effects.
[0102] The data obtained from cell culture assays and animal studies can be used to
formulate a dosage range for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration. For any compound used in the methods of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography (HPLC). In general, the dose equivalent of a modulator is from about 1 ng/kg to 10 mg/kg for a typical subject.
[0103] The amount and frequency of administration of the compounds of the invention
and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. In general it is contemplated that an effective amount would be from 0.001 mg/kg to 10 mg/kg body weight, and in particular from 0.01 mg/kg to 1 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.01 to 500 mg, and in particular 0.1 mg to 200 mg of active ingredient per unit dosage form.
[0104] Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g. , an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated.
Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required.
[0105] Medical Use
[0106] The compositions of this invention are useful for treating pain or pain associated disorders. The compositions of this invention are useful for treating immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric conditions, urological and reproductive conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases and cough.
[0107] Definitions
[0108] 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 to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description and claims.
[0109] The general chemical terms used throughout have their usual meanings. For
example, the term alkyl refers to a branched or unbranched saturated hydrocarbon group. The term 'Vz-alkyl" refers to an unbranched alkyl group. The term "Cx-Cy alkyl" refers to an alkyl group having between x and y carbon atoms, inclusively, in the branched or unbranched hydrocarbon group. By way of illustration, but without limitation, the term "C1-C4 alkyl" refers to a straight chain or branched hydrocarbon moiety having from 1 to 4 carbon atoms, including methyl, ethyl, ^-propyl, isopropyl, rc-butyl, isobutyl, sec-butyl, and ieri-butyl. The term "Ci-C4 w-alkyl" refers to straight chain hydrocarbon moieties having from 1 to 4 carbon atoms including methyl, ethyl, ^-propyl, and /i-butyl. In certain embodiments, Cx-Cy x is between 1 and 10 and y is between 2 and 20. The term "C3-C6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "C3-C7 cycloalkyl" also includes cycloheptyl. Cycloalkylalkyl refers to cycloalkyl moieties linked through an alkyl linker chain, as for example, but without limitation,
cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl. Each alkyl, cycloalkyl, and cycloalkylalkyl group may be optionally substituted as specified herein.
[0110] The terms "alkoxy", "phenyloxy", "benzoxy" and "pyrimidinyloxy" refer to an alkyl group, phenyl group, benzyl group, or pyrimidinyl group, respectively, each optionally substituted, that is bonded through an oxygen atom.
[0111] The terms "alkylthio", "phenylthio", and "benzylthio" refer to an alkyl group, phenyl group, or benzyl group, respectively, each optionally substituted, that is bonded through a sulfur atom.
[0112] The term "Ci-C4 acyl" refers to a formyl group or a C C3 alkyl group bonded
through a carbonyl moiety. The term "Ci-C4 alkoxycarbonyl" refers to a C C4 alkoxy group bonded through a carbonyl moiety.
[0113] The term "halo" refers to fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro, chloro, and bromo. More preferred halo groups are fluoro and chloro.
[0114] As used herein, "carbocycle" or "carbocyclic ring" is intended to mean, unless
otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, any of which can be saturated, unsaturated (including partially and fully unsaturated), or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring can also be present on the bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) and spiro rings are also included.
[0115] The term "heterocycle" is taken to mean a saturated or unsaturated 5- or 6-membered ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, said ring optionally being benzofused. Exemplary heterocycles, for the purposes of the present invention, include furanyl, thiophenyl (thienyl), pyrrolyl, pyrrolidinyl, pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. Benzofused heterocyclic rings include isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl,
benzofuranyl, benzothiophenyl, indolyl, and the like, all of which may be optionally substituted, which also of course includes optionally substituted on the benzo ring when the heterocycle is benzofused. [0116] Preferred heterocycles include pyridinyl, indolyl, furanyl, benzofuranyl, thiophenyl, benzodioxolyl, and thiazolidinyl, all of which may be optionally substituted.
[0117] As used herein, the term "aromatic heterocycle" or "heteroaryl" is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclic aromatic rings, only one of the two rings needs to be aromatic (e.g., 2,3-dihydroindole), though both can be (e.g., quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→0 and S(0)p, wherein p = 1 or 2). In certain compounds, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
[0118] Examples of heterocycles include, but are not limited to, acridinyl, azocinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4- piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H- 1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
[0119] Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio, means an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkythio group, respectively, substituted one or more times independently with a substituent selected from the group consisting of halo, hydroxy, and C C3 alkoxy. By way of illustration, but without limitation, examples include trifluoromethyl, pentafluoroethyl, 5-fluoro-2-bromopentyl, 3- hydroxypropyloxy, 4-hydroxycyclohexyloxy, 2-bromoethylthio, 3-ethoxypropyloxy, 3-ethoxy-4-chlorocyclohexyl, and the like. Preferred substitutions include substitution 1-5 times with halo, each independently selected, or substituted 1-3 times with halo and 1-2 times independently with a group selected from hydroxy and Q-C3 alkoxy, or substituted 1-3 times independently with a group selected from hydroxy and C C3 alkoxy, provided that no more than one hydroxy and/or alkoxy substituent may be attached through the same carbon.
[0120] The terms "substituted phenyl" and "substituted heterocycle" are taken to mean that the cyclic moiety in either case is substituted with one or more halo substituents, preferably one to five, each independently selected; or substituted with one or more substituents, preferably one to two substituents, independently selected from the group consisting of halo, Q-C4 alkyl, Q-C4 alkoxy, and Q-C4 alkylthio, wherein each alkyl, alkoxy and alkylthio substituent can be further substituted independently with C C2 alkoxy or with one to five halo groups selected from fluoro and chloro; or substituted with one substituent selected from the group consisting of phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy, wherein the phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy moiety can be further substituted with one to two substituents selected from the group consisting of halo, CrC2 alkyl, and CrC2 alkoxy; or substituted with one substituent selected from the group consisting of CrC4 acyl and CrC4 alkoxycarbonyl, and further substituted with zero to one substituent selected from the group consisting of halo, C C4 alkyl, C C4 alkoxy, and C C4 alkylthio. When a substituent is halo, preferred halo groups are fluoro, chloro, and bromo.
[0121] DMF means N,N-dimethylformamide.
[0122] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[0123] By "pharmaceutical formulation" it is further meant that the carrier, solvent,
excipients and salt must be compatible with the active ingredient of the formulation (e.g. a compound of formula I). It is understood by those of ordinary skill in this art that the terms "pharmaceutical formulation" and "pharmaceutical composition" are generally interchangeable, and they are so used for the purposes of this application.
[0124] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the
disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide,
hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic.
[0125] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).
[0126] Since prodrugs are known to enhance numerous desirable qualities of
pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
[0127] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
[0128] As used herein, "treating" or "treatment" includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc. "Treating" or "treatment" of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease-state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease- state, i.e., causing regression of the disease state.
[0129] As used herein, "preventing" means causing the clinical symptoms of the disease state not to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
[0130] As used herein, "mammal" refers to human and non-human patients.
[0131] As used herein, the term "therapeutically effective amount" refers to a compound, or a combination of compounds, of the present invention present in or on a recipient in an amount sufficient to elicit biological activity, e.g. pain relief. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal
concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased decrease in pain, or some other beneficial effect of the combination compared with the individual components.
[0132] All percentages and ratios used herein, unless otherwise indicated, are by weight.
[0133] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present invention also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
[0134] All enantiomers, diastereomers, and mixtures thereof, are included within the scope of the present invention.
[0135] For the purposes of promoting an understanding of the embodiments described
herein, reference will be made to preferred embodiments and specific language will be used to describe the same. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. As used throughout this disclosure, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a composition" includes a plurality of such compositions, as well as a single composition, and a reference to "a therapeutic agent" is a reference to one or more therapeutic and/or pharmaceutical agents and equivalents thereof known to those skilled in the art, and so forth. Thus, for example, a reference to "a host cell" includes a plurality of such host cells, and a reference to "an antibody" is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.
[0136] In addition to those compounds presented in the examples, the following compounds shown in Table 1, further illustrate the scope of the present invention:
Table 1:
Figure imgf000045_0001
[(3,4-dimethoxyphenyl)methyl][(3S)-3-[(4R)-2,2-
13 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(2,3-dimethoxyphenyl)methyl][(3S)-3-[(4R)-2,2-
14 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
15 fluorophenyl)propyl] [(2-fluorophenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
16 fluorophenyl)propyl] [(3-fluorophenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
17 fluorophenyl)propyl] [(3-methylphenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
18 fluorophenyl)propyl] [(2-methylphenyl)methyl] amine
[(2-chlorophenyl)methyl][(3S)-3-[(4R)-2,2-
19 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(3-chlorophenyl)methyl][(3S)-3-[(4R)-2,2-
20 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
21 fluorophenyl)propyl] [(3-methoxyphenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
22 fluorophenyl)propyl] [(2-methoxyphenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
23 fluorophenyl)propyl] [(4-methoxyphenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
24 fluorophenyl)propyl](furan-2-ylmethyl)amine
2-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
25 fluorophenyl)propyl] amino } methyl)phenol
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
26 fluorophenyl)propyl](thian-4-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
27 fluorophenyl)propyl] [(4-fluorophenyl)methyl] amine
[(2-bromophenyl)methyl][(3S)-3-[(4R)-2,2-
28 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(3-bromophenyl)methyl][(3S)-3-[(4R)-2,2-
29 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine [(4-bromophenyl)methyl][(3S)-3-[(4R)-2,2-
30 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl]({ [2-
31 (trifluoromethyl)phenyl] methyl } ) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl]({ [3-
32 (trifluoromethyl)phenyl] methyl } ) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl]({ [4-
33 (trifluoromethyl)phenyl] methyl } ) amine
[(2,3-difluorophenyl)methyl][(3S)-3-[(4R)-2,2-
34 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(2,4-difluorophenyl)methyl][(3S)-3-[(4R)-2,2-
35 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(2,5-difluorophenyl)methyl][(3S)-3-[(4R)-2,2-
36 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(3,4-difluorophenyl)methyl][(3S)-3-[(4R)-2,2-
37 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(3,5-difluorophenyl)methyl][(3S)-3-[(4R)-2,2-
38 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl] [(2,3,4-
39 trifluorophenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl] [(2,3,5-
40 trifluorophenyl)methyl] amine
benzyl[(3S)-3-(3-bromo-2,6-difluorophenyl)-3-[(4R)-
41 2,2-dimethyloxan-4-yl]propyl]amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
42 fluorophenyl)propyl] methylamine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
43 fluorophenyl)propyl]propan-2-ylamine
benzyl(butyl)[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-
44 (4-fluorophenyl)propyl] amine benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
45 fluorophenyl)propyl](2-methylpropyl)amine benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
46 fluorophenyl)propyl](3-methylbutyl)amine
2-{benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
47 fluorophenyl)propyl] amino } acetonitrile
( 1 R) - 1 - [(4R)-2,2-dimethyloxan-4-yl] - 1 - (4- fluorophenyl)-3- ( { [6- (trifluoromethyl)pyridin-3 -
48 yl] methyl } amino)propan- 1 -ol
benzyl[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4S)-
49 2,2-dimethyloxan-4-yl]propyl]amine
2-({ [(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4S)-2,2-
50 dimethyloxan-4-yl]propyl]amino}methyl)phenol
3-({ [(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4S)-2,2-
51 dimethyloxan-4-yl]propyl]amino}methyl)phenol
[(3-bromophenyl)methyl][(3S)-3-(4-chloro-2- methoxyphenyl)-3-[(4S)-2,2-dimethyloxan-4-
52 yl]propyl] amine
[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(3-
53 chlorophenyl)methyl] amine
[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(3-
54 methylphenyl)methyl] amine
[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl]({ [3-
55 (trifluoromethyl)phenyl] methyl } ) amine
[(4-bromophenyl)methyl][(3S)-3-(4-chloro-2- methoxyphenyl)-3-[(4S)-2,2-dimethyloxan-4-
56 yl]propyl] amine
[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl]({ [4-
57 (trifluoromethyl)phenyl] methyl } ) amine
[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl]({ [2-
58 (trifluoromethyl)phenyl] methyl } ) amine benzyl[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4R)-
59 2,2-dimethyloxan-4-yl]propyl]amine
2-({ [(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4R)-2,2-
60 dimethyloxan-4-yl]propyl]amino}methyl)phenol
3-({ [(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4R)-2,2-
61 dimethyloxan-4-yl]propyl]amino}methyl)phenol
[(3-bromophenyl)methyl][(3S)-3-(4-chloro-2- methoxyphenyl)-3-[(4R)-2,2-dimethyloxan-4-
62 yl]propyl] amine
[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl] [(3-
63 chlorophenyl)methyl] amine
[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl] [(3-
64 methylphenyl)methyl] amine
[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl]({ [3-
65 (trifluoromethyl)phenyl] methyl } ) amine
[(4-bromophenyl)methyl][(3S)-3-(4-chloro-2- methoxyphenyl)-3-[(4R)-2,2-dimethyloxan-4-
66 yl]propyl] amine
[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl]({ [4-
67 (trifluoromethyl)phenyl] methyl } ) amine
[(3S)-3-(4-chloro-2-methoxyphenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl]({ [2-
68 (trifluoromethyl)phenyl] methyl } ) amine
benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-
69 (3,4,5-trifluorophenyl)propyl]amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3,4,5-
70 trifluorophenyl)propyl](pyridin-3-ylmethyl)amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3,4,5- trifluorophenyl)propyl]({ [6-
71 (trifluoromethyl)pyridin- 3 -yl] methyl } ) amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3,4,5-
72 trifluorophenyl)propyl](thiophen-2-ylmethyl)amine [(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3,4,5-
73 trifluorophenyl)propyl](thiophen-3-ylmethyl)amine benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-
74 (3,4,5-trifluorophenyl)propyl]amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3,4,5-
75 trifluorophenyl)propyl](pyridin-3-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3,4,5- trifluorophenyl)propyl]({ [6-
76 (trifluoromethyl)pyridin- 3 -yl] methyl } ) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3,4,5-
77 trifluorophenyl)propyl](thiophen-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3,4,5-
78 trifluorophenyl)propyl](thiophen-3-ylmethyl)amine
2-({ [(3R)-3-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]-3- (4-fluoro-2-
79 methoxyphenyl)propyl] amino } methyl )phenol
[(3R)-3-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-(4- fluoro-2-methoxyphenyl)propyl][(3-
80 methylphenyl)methyl] amine
2-({ [(3S)-3-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]-3- (4-fluoro-2-
81 methoxyphenyl)propyl] amino } methyl )phenol
[(3S)-3-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-(4- fluoro-2-methoxyphenyl)propyl][(3-
82 methylphenyl)methyl] amine
3-({ [(3R)-3-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]-3- (4-fluoro-2-
83 methoxyphenyl)propyl] amino } methyl )phenol
[(3-bromophenyl)methyl][(3R)-3-[(4S)-2,2-dimethyl- l,3-dioxolan-4-yl]-3-(4-fluoro-2-
84 methoxyphenyl)propyl] amine
[(3-chlorophenyl)methyl][(3R)-3-[(4S)-2,2-dimethyl- l,3-dioxolan-4-yl]-3-(4-fluoro-2-
85 methoxyphenyl)propyl] amine
[(3R)-3-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-(4-
86
fluoro-2-methoxyphenyl)propyl] ({ [3- (trifluoromethyl)phenyl] methyl } ) amine
[(4-bromophenyl)methyl][(3R)-3-[(4S)-2,2-dimethyl- l,3-dioxolan-4-yl]-3-(4-fluoro-2-
87 methoxyphenyl)propyl] amine
3-({ [(3S)-3-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]-3- (4-fluoro-2-
88 methoxyphenyl)propyl] amino } methyl )phenol
[(3-bromophenyl)methyl][(3S)-3-[(4S)-2,2-dimethyl- l,3-dioxolan-4-yl]-3-(4-fluoro-2-
89 methoxyphenyl)propyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4S)-2,2-dimethyl- l,3-dioxolan-4-yl]-3-(4-fluoro-2-
90 methoxyphenyl)propyl] amine
[(3S)-3-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-(4- fluoro-2-methoxyphenyl)propyl] ({ [3-
91 (trifluoromethyl)phenyl] methyl } ) amine
[(4-bromophenyl)methyl][(3S)-3-[(4S)-2,2-dimethyl- l,3-dioxolan-4-yl]-3-(4-fluoro-2-
92 methoxyphenyl)propyl] amine
benzyl[(3S)-3-[(4R)-2,2-dimethyl-l,3-dioxolan-4-
93 yl]-3-(4-fluoro-2-methoxyphenyl)propyl]amine
[(3-bromophenyl)methyl][(3S)-3-[(4R)-2,2-dimethyl- l,3-dioxolan-4-yl]-3-(4-fluoro-2-
94 methoxyphenyl)propyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4R)-2,2-dimethyl- l,3-dioxolan-4-yl]-3-(4-fluoro-2-
95 methoxyphenyl)propyl] amine
benzyl[(3R)-3-[(4R)-2,2-dimethyl-l,3-dioxolan-4-
96 yl]-3-(4-fluoro-2-methoxyphenyl)propyl]amine
2-({ [(3R)-3-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-3- (4-fluoro-2-
97 methoxyphenyl)propyl] amino } methyl )phenol
[(3-bromophenyl)methyl][(3R)-3-[(4R)-2,2-dimethyl- l,3-dioxolan-4-yl]-3-(4-fluoro-2-
98 methoxyphenyl)propyl] amine
99
[(3-chlorophenyl)methyl][(3R)-3-[(4R)-2,2-dimethyl- l,3-dioxolan-4-yl]-3-(4-fluoro-2- methoxyphenyl)propyl] amine
[(3S)-3-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-(4- fluoro-2-methoxyphenyl)propyl][(3-
100 methylphenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-(4- fluoro-2-methoxyphenyl)propyl] ({ [3-
101 (trifluoromethyl)phenyl] methyl } ) amine
[(3R)-3-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-(4- fluoro-2-methoxyphenyl)propyl][(3-
102 methylphenyl)methyl] amine
[(3R)-3-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-(4- fluoro-2-methoxyphenyl)propyl] ({ [3-
103 (trifluoromethyl)phenyl] methyl } ) amine
[(3R)-3-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-(4- fluoro-2-methoxyphenyl)propyl](pyridin-3-
104 ylmethyl) amine
benzyl[(3S)-3-(2,5-difluorophenyl)-3-[(4R)-2,2-
105 dimethyloxan-4-yl]propyl] amine
benzyl[(3S)-3-(3,5-difluoro-2-methoxyphenyl)-3-
106 [(4R)-2,2-dimethyloxan-4-yl]propyl]amine benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
107 fluoro-2-methoxyphenyl)propyl]amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-
108 phenylpropyl] amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-[4-
109 (trifluoromethyl)phenyl]propyl]amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-[4- (trifluoromethyl)phenyl] propyl] [ (3 -
110 methylphenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-[4- (trifluoromethyl)phenyl] propyl] [ (3 -
111 fluorophenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4R)-2,2- dimethyloxan-4- yl] - 3 - [4-
112 (trifluoromethyl)phenyl]propyl]amine 2-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-[4-
113 (trifluoromethyl)phenyl]propyl]amino}methyl)phenol benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
114 fluoro-2-methoxyphenyl)propyl]amine
2-({ [(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
115 fluoro-2-methoxyphenyl)propyl] amino } methyl)phenol
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-fluoro-2-
116 methoxyphenyl)propyl] [(3-methylphenyl)methyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-fluoro-2-
117 methoxyphenyl)propyl] [(3-fluorophenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4S)-2,2- dimethyloxan-4-yl]-3-(4-fhioro-2-
118 methoxyphenyl)propyl] amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
119 methoxyphenyl)propyl] amine
benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-
120 phenylpropyl] amine
[(3,4-difluorophenyl)methyl][(3S)-3-[(4R)-2,2-
121 dimethyloxan-4-yl] -3-phenylpropyl] amine
[(3,5-difluorophenyl)methyl][(3S)-3-[(4R)-2,2-
122 dimethyloxan-4-yl] -3-phenylpropyl] amine
4-[(lS)-3-(benzylamino)-l-[(4R)-2,2-dimethyloxan-4-
123 yl]propyl]phenol
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
124 methoxyphenyl)propyl] amine
3-[(lS)-3-(benzylamino)-l-[(4R)-2,2-dimethyloxan-4-
125 yl]propyl]phenol
2-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-
126 phenylpropyl] amino } methyl)phenol
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-
127 phenylpropyl] [(3-methylphenyl)methyl] amine
[(3-bromophenyl)methyl][(3S)-3-[(4R)-2,2-
128 dimethyloxan-4-yl] -3-phenylpropyl] amine
129
[(3-chlorophenyl)methyl][(3S)-3-[(4R)-2,2- dimethyloxan-4-yl] -3-phenylpropyl] amine
2-({ [(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-
130 phenylpropyl] amino } methyl)phenol
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-
131 phenylpropyl] [(3-methylphenyl)methyl] amine
[(3-bromophenyl)methyl][(3S)-3-[(4S)-2,2-
132 dimethyloxan-4-yl] -3-phenylpropyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4S)-2,2-
133 dimethyloxan-4-yl] -3-phenylpropyl] amine
2-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
134 methoxyphenyl)propyl] amino } methyl )phenol
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
135 methoxyphenyl)propyl] [(3-methylphenyl)methyl] amine
[(3-bromophenyl)methyl][(3S)-3-[(4R)-2,2-
136 dimethyloxan-4-yl]-3-(4-methoxyphenyl)propyl]amine
[(3-chlorophenyl)methyl][(3S)-3-[(4R)-2,2-
137 dimethyloxan-4-yl]-3-(4-methoxyphenyl)propyl]amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
138 methoxyphenyl)propyl] [(3-methylphenyl)methyl] amine
2-({ [(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
139 methoxyphenyl)propyl] amino } methyl )phenol
[(3-bromophenyl)methyl][(3S)-3-[(4S)-2,2-
140 dimethyloxan-4-yl]-3-(4-methoxyphenyl)propyl]amine
[(3-chlorophenyl)methyl][(3S)-3-[(4S)-2,2-
141 dimethyloxan-4-yl]-3-(4-methoxyphenyl)propyl]amine benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
142 methoxyphenyl)propyl] amine
benzyl[(3S)-3-(4-bromophenyl)-3-[(4R)-2,2-
143 dimethyloxan-4-yl]propyl] amine
2-[(lS)-3-(benzylamino)-l-[(4R)-2,2-dimethyloxan-4-
144 yl] propyl] - 5 -fluorophenol
benzyl[(3S)-3-(3-bromophenyl)-3-[(4R)-2,2-
145 dimethyloxan-4-yl]propyl] amine
146
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-[4- fluoro-2-(propan-2-yloxy)phenyl]propyl]amine benzyl[(3S)-3-(4-bromophenyl)-3-[(4S)-2,2-
147 dimethyloxan-4-yl]propyl] amine
benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-[4-
148 fluoro-2-(propan-2-yloxy)phenyl]propyl]amine benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(2-
149 ethoxy-4-fluorophenyl)propyl]amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(2-
150 ethoxy-4-fluorophenyl)propyl]amine
benzyl[(3S)-3-(2,4-dimethoxyphenyl)-3-[(4S)-2,2-
151 dimethyloxan-4-yl]propyl] amine
[(3S)-3-(2,4-dimethoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(3-
152 methylphenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-(2,4- dimethoxyphenyl)-3-[(4S)-2,2-dimethyloxan-4-
153 yl]propyl] amine
[(3-bromophenyl)methyl][(3S)-3-(2,4- dimethoxyphenyl)-3-[(4S)-2,2-dimethyloxan-4-
154 yl]propyl] amine
[(3S)-3-(2,4-dimethoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(3-
155 fluorophenyl)methyl] amine
benzyl[(3S)-3-(2,4-dimethoxyphenyl)-3-[(4R)-2,2-
156 dimethyloxan-4-yl]propyl] amine
[(3S)-3-(2,4-dimethoxyphenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl] [(3-
157 methylphenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-(2,4- dimethoxyphenyl) - 3 - [ (4R) -2,2-dimethyloxan-4-
158 yl]propyl] amine
[(3-bromophenyl)methyl][(3S)-3-(2,4- dimethoxyphenyl) - 3 - [ (4R) -2,2-dimethyloxan-4-
159 yl]propyl] amine
[(3S)-3-(2,4-dimethoxyphenyl)-3-[(4R)-2,2-
160
dimethyloxan-4-yl]propyl] [(3- fluorophenyl)methyl] amine
benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-[2-
161 methoxy-4-(trifluoromethyl)phenyl]propyl]amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-[2-methoxy-4- (trifluoromethyl)phenyl] propyl] [ (3 -
162 methylphenyl)methyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-[2-methoxy-4- (trifluoromethyl)phenyl] propyl] [ (3 -
163 fluorophenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4S)-2,2- dimethyloxan-4-yl] -3- [2-methoxy-4-
164 (trifluoromethyl)phenyl]propyl]amine
[(3-bromophenyl)methyl][(3S)-3-[(4S)-2,2- dimethyloxan-4-yl] -3- [2-methoxy-4-
165 (trifluoromethyl)phenyl]propyl]amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-[2-
166 methoxy-4-(trifluoromethyl)phenyl]propyl]amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-[2-methoxy-4- (trifluoromethyl)phenyl] propyl] [ (3 -
167 methylphenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4R)-2,2- dimethyloxan-4-yl] -3- [2-methoxy-4-
168 (trifluoromethyl)phenyl]propyl]amine
[(3-bromophenyl)methyl][(3S)-3-[(4R)-2,2- dimethyloxan-4-yl] -3- [2-methoxy-4-
169 (trifluoromethyl)phenyl]propyl]amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-[2-methoxy-4- (trifluoromethyl)phenyl] propyl] [ (3 -
170 fluorophenyl)methyl] amine
benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(2-
171 methoxy-4-methylphenyl)propyl]amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(2-methoxy-4-
172 methylphenyl)propyl] [(3-methylphenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4S)-2,2- dimethyloxan-4-yl]-3-(2-methoxy-4-
173 methylphenyl)propyl] amine [(3-bromophenyl)methyl][(3S)-3-[(4S)-2,2- dimethyloxan-4-yl]-3-(2-methoxy-4-
174 methylphenyl)propyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(2-methoxy-4- methylphenyl)propyl]({ [3-
175 (trifluoromethyl)phenyl] methyl } ) amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(2-
176 methoxy-4-methylphenyl)propyl]amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(2-methoxy-4-
177 methylphenyl)propyl] [(3-methylphenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4R)-2,2- dimethyloxan-4-yl]-3-(2-methoxy-4-
178 methylphenyl)propyl] amine
[(3-bromophenyl)methyl][(3S)-3-[(4R)-2,2- dimethyloxan-4-yl]-3-(2-methoxy-4-
179 methylphenyl)propyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(2-methoxy-4- methylphenyl)propyl]({ [3-
180 (trifluoromethyl)phenyl] methyl } ) amine
benzyl[(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4S)-
181 2,2-dimethyloxan-4-yl]propyl]amine
[(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(3-
182 methylphenyl)methyl] amine
[(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(3-
183 chlorophenyl)methyl] amine
[(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(3-
184 bromophenyl)methyl] amine
[(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl]({ [3-
185 (trifluoromethyl)phenyl] methyl } ) amine
3-({ [(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4S)-2,2-
186 dimethyloxan-4-yl]propyl]amino}methyl)phenol
187
benzyl[(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4R)- 2,2-dimethyloxan-4-yl]propyl]amine
[(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl] [(3-
188 methylphenyl)methyl] amine
[(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl] [(3-
189 chlorophenyl)methyl] amine
[(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl] [(3-
190 bromophenyl)methyl] amine
[(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl]({ [3-
191 (trifluoromethyl)phenyl] methyl } ) amine
3-({ [(3S)-3-(4-bromo-2-methoxyphenyl)-3-[(4R)-2,2-
192 dimethyloxan-4-yl]propyl]amino}methyl)phenol
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl][(6-methoxypyridin-3-
193 yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl]({ [6-(trifluoromethyl)pyridin-3-
194 yl] methyl } ) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
195 fluorophenyl)propyl] (1,3- oxazol-4-ylmethyl) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
196 fluorophenyl)propyl] ( lH-imidazol-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
197 fluorophenyl)propyl] ( 1 ,3-thiazol-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
198 fluorophenyl)propyl] ( 1 ,3-thiazol-5-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
199 fluorophenyl)propyl](thiophen-3-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl][(5-methylthiophen-2-
200 yl)methyl] amine
201
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl](thiophen-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
202 fluorophenyl)propyl] (furan- 3 -ylmethyl) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl][(5-methylfuran-2-
203 yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
204 fluorophenyl)propyl]dipropylamine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
205 fluorophenyl)propyl]bis(prop-2-en-l-yl))amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
206 fluorophenyl)propyl]bis(propan-2-yl))amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
207 fluorophenyl)propyl] bis (2-methoxyethyl) amine
3-[(2-cyanoethyl)[(3S)-3-[(4R)-2,2-dimethyloxan-4-
208 yl]-3-(4-fluorophenyl)propyl]amino]propanenitrile
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
209 fluorophenyl)propyl](2-methoxyethyl)amine
3-{ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
210 fluorophenyl)propyl] amino Jpropanenitrile butyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
211 fluorophenyl)propyl] methylamine
l-[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
212 fluorophenyl)propyl]pyrrolidine
l-[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
213 fluorophenyl)propyl]piperidine
4-[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
214 fluorophenyl)propyl] morpholine
4-[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
215 fluorophenyl)propyl]thiomorpholine
l-[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
216 fluorophenyl)propyl]-4-methylpiperazine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
217 fluorophenyl)propyl]dimethylamine benzyl[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-
218 2,2-dimethyloxan-4-yl]propyl]amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2-
219 dimethyloxan-4-yl]propyl](pyridin-3-ylmethyl)amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl]({ [6-
220 (trifluoromethyl)pyridin- 3 -yl] methyl } ) amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl][(6-methoxypyridin-3-
221 yl)methyl] amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl](pyrimidin-5-
222 ylmethyl) amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2-
223 dimethyloxan-4-yl]propyl](pyrazin-2-ylmethyl)amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl](thiophen-3-
224 ylmethyl) amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl][(5-methylthiophen-2-
225 yl)methyl] amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl](thiophen-2-
226 ylmethyl) amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl](l,3-thiazol-2-
227 ylmethyl) amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl](l,3-thiazol-5-
228 ylmethyl) amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2-
229 dimethyloxan-4-yl]propyl](furan-3-ylmethyl)amine
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl][(5-methylfuran-2-
230 yl)methyl] amine
231
[(3S)-3-(3-chloro-5-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl] ( lH-imidazol-2- ylmethyl) amine
benzyl[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-
232 2,2-dimethyloxan-4-yl]propyl]amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl]({ [6-
233 (trifluoromethyl)pyridin- 3 -yl] methyl } ) amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl][(6-methoxypyridin-3-
234 yl)methyl] amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2-
235 dimethyloxan-4-yl]propyl](pyrazin-2-ylmethyl)amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl](thiophen-3-
236 ylmethyl) amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl][(5-methylthiophen-2-
237 yl)methyl] amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl](thiophen-2-
238 ylmethyl) amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl](l,3-thiazol-2-
239 ylmethyl) amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl](l,3-thiazol-5-
240 ylmethyl) amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2-
241 dimethyloxan-4-yl]propyl](furan-3-ylmethyl)amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl][(5-methylfuran-2-
242 yl)methyl] amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
243 fluorophenyl)propyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
244 fluorophenyl)propyl](pyridin-3-ylmethyl)amine [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3- fluorophenyl)propyl]({ [6-(trifluoromethyl)pyridin-3-
245 yl] methyl } ) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3- fluorophenyl)propyl][(6-methoxypyridin-3-
246 yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3- fluorophenyl)propyl][(6-methoxypyridin-3-
246 yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
247 fluorophenyl)propyl](pyrazin-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3- fluorophenyl)propyl][(6-methylpyridin-3-
248 yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
249 fluorophenyl)propyl](thiophen-3-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3- fluorophenyl)propyl][(5-methylthiophen-2-
250 yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
251 fluorophenyl)propyl](thiophen-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
252 fluorophenyl)propyl] ( 1 ,3-thiazol-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
253 fluorophenyl)propyl] ( 1 ,3-thiazol-5-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
254 fluorophenyl)propyl] (furan- 3 -ylmethyl) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3- fluorophenyl)propyl][(5-methylfuran-2-
255 yl)methyl] amine
[(3S)-3-(4-chloro-3-fluorophenyl)-3-[(4R)-2,2-
256 dimethyloxan-4-yl]propyl](pyridin-3-ylmethyl)amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
257 fluorophenyl)propyl](pyridin-3-ylmethyl)amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
258
fluorophenyl)propyl] ( { [6-(trifluoromethyl)pyridin-3- yl] methyl } ) amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl][(6-methoxypyridin-3-
259 yl)methyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
260 fluorophenyl)propyl](thiophen-3-ylmethyl)amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl][(5-methylthiophen-2-
261 yl)methyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
262 fluorophenyl)propyl](thiophen-2-ylmethyl)amine
3-bromo-5-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3- (4-fluorophenyl)propyl] amino } methyl)- 1 ,2-
263 dihydropyridin-2-one
3-chloro-5-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3- (4-fluorophenyl)propyl] amino } methyl)- 1 ,2-
264 dihydropyridin-2-one
5-chloro-3-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3- (4-fluorophenyl)propyl] amino } methyl)- 1 ,2-
265 dihydropyridin-2-one
(cyclopentylmethyl)[(3S)-3-[(4R)-2,2-dimethyloxan-4-
266 yl] -3-(4-fluorophenyl)propyl] amine
[(5-bromo-2-fluoropyridin-3-yl)methyl][(3S)-3- [(4R)-2,2-dimethyloxan-4-yl]-3-(4-
267 fluorophenyl)propyl] amine
[(6-bromopyridin-3-yl)methyl][(3S)-3-[(4R)-2,2-
268 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(2-bromopyridin-3-yl)methyl][(3S)-3-[(4R)-2,2-
269 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(5-bromopyridin-3-yl)methyl][(3S)-3-[(4R)-2,2-
270 dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine
[(5-chloro-2-fluoropyridin-3-yl)methyl][(3S)-3- [(4R)-2,2-dimethyloxan-4-yl]-3-(4-
271 fluorophenyl)propyl] amine
272
methyl 5-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl] amino } methyl)thiophene-2-carboxylate methyl 5-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
273 fluorophenyl)propyl]amino}methyl)thiophene-3-carboxylate methyl 3-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
274 fluorophenyl)propyl] amino } methyl)benzoate
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
275 fluorophenyl)propyl](naphthalen-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
276 fluorophenyl)propyl] (naphthalen- 1 -ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
277 fluorophenyl)propyl](quinolin-3-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
278 fluorophenyl)propyl](quinolin-4-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
279 fluorophenyl)propyl](2-phenylethyl)amine
5-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
280 fluorophenyl)propyl] amino }methyl)pyridine-2-carbonitrile l',l'-dideutriumbenzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
281 fluorophenyl)propyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl] (methyl) (thiophen-2-
282 ylmethyl) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl](ethyl)(thiophen-2-
283 ylmethyl) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
284 fluorophenyl)propyl](propyl)(thiophen-2-ylmethyl)amine butyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
285 fluorophenyl)propyl](thiophen-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- fluorophenyl)propyl](2-methylpropyl)(thiophen-2-
286 ylmethyl) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
287 fluorophenyl)propyl](propan-2-yl)(thiophen-2-ylmethyl)amine benzyl[(3S)-3-[4-chloro-3-(trifluoromethyl)phenyl]-3-
288 [(4R)-2,2-dimethyloxan-4yl]propyl]amine
[(3S)-3-[4-chloro-3-(trifluoromethyl)phenyl]-3-
289 [(4R)-2,2-dimethyloxan-4-yl]propyl](pyridin-3-ylmethyl)amine
[(3S)-3-[4-chloro-3-(trifluoromethyl)phenyl]-3-
290 [(4R)-2,2-dimethyloxan-4-yl]propyl](pyridin-3-ylmethyl)amine
[(3S)-3-[4-chloro-3-(trifluoromethyl)phenyl]-3-
291 [(4R)-2,2-dimethyloxan-4-yl]propyl](thiophen-3-ylmethyl)amine
[(3S)-3-[4-chloro-3-(trifluoromethyl)phenyl]-3- [(4R)-2,2-dimethyloxan-4-yl]propyl](thiophen-2-
292 ylmethyl) amine
benzyl[(3S)-3-[4-chloro-3-(trifluoromethyl)phenyl]-3-
293 [(4S)-2,2-dimethyloxan-4-yl]propyl]amine
[(3S)-3-[4-chloro-3-(trifluoromethyl)phenyl]-3-
294 [(4S)-2,2-dimethyloxan-4-yl]propyl](pyridin-3-ylmethyl)amine
[(3S)-3-[4-chloro-3-(trifluoromethyl)phenyl]-3-
295 [(4S)-2,2-dimethyloxan-4-yl]propyl](pyridin-3-ylmethyl)amine
[(3S)-3-[4-chloro-3-(trifluoromethyl)phenyl]-3- [(4S)-2,2-dimethyloxan-4-yl]propyl](thiophen-3-
296 ylmethyl) amine
[(3S)-3-[4-chloro-3-(trifluoromethyl)phenyl]-3- [(4S)-2,2-dimethyloxan-4-yl]propyl](thiophen-2-
297 ylmethyl) amine
(cyclohexylmethyl)[(3S)-3-[(4R)-2,2-dimethyloxan-4-
298 yl]-3-(3-fluoro-4-methylphenyl)propyl]amine
(cyclopentylmethyl)[(3S)-3-[(4R)-2,2-dimethyloxan-4-
299 yl]-3-(3-fluoro-4-methylphenyl)propyl]amine
(3,3-dimethylbutyl)[(3S)-3-[(4R)-2,2-dimethyloxan-4-
300 yl]-3-(3-fluoro-4-methylphenyl)propyl]amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-
301 (pyridin-2-yl)propyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(pyridin-2-
302 yl)propyl](thiophen-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(pyridin-2-
303
yl)propyl] ({ [6-(trifluoromethyl)pyridin-3- yl] methyl } ) amine
(cyclohexylmethyl)[(3S)-3-[(4R)-2,2-dimethyloxan-4-
304 yl] -3-(pyridin-2-yl)propyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(pyridin-2-
305 yl)propyl] (thiophen- 3 -ylmethyl) amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-
306
(thiophen-2-yl)propyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(thiophen-2-
307
yl)propyl](pyridin-3-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(thiophen-2-
308 yl)propyl] ({ [6-(trifluoromethyl)pyridin-3- yl] methyl } ) amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(thiophen-2-
309
yl)propyl] [(6-methylpyridin-3-yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(thiophen-2-
310
yl)propyl] [(6-methoxypyridin-3-yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(thiophen-2-
311
yl)propyl](thiophen-2-ylmethyl)amine benzyl[(3S)-3-(4-chlorophenyl)-3-[(9S)-6-
312
oxaspiro [4.5] decan- 9 -yl] propyl] amine
[(3S)-3-(4-chlorophenyl)-3-[(9S)-6-
313 oxaspiro[4.5]decan-9-yl]propyl][(6-methylpyridin-3- yl)methyl] amine
[(3S)-3-(4-chlorophenyl)-3-[(9S)-6-
314 oxaspiro[4.5]decan-9-yl]propyl]({ [6- (trifluoromethyl)pyridin- 3 -yl] methyl } ) amine
[(3S)-3-(4-chlorophenyl)-3-[(9S)-6-
315 oxaspiro [4.5 ] decan-9 - yl] propyl] (thiophen- 3 - ylmethyl) amine
[(3S)-3-(4-chlorophenyl)-3-[(9S)-6-
316 oxaspiro[4.5]decan-9-yl]propyl][(5-methylthiophen-2- yl)methyl] amine
benzyl[(3S)-3-(4-fluorophenyl)-3-(2,2,6,6-
317 tetramethyloxan-4-yl)propyl]amine
318
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4- methylphenyl)propyl] amine
2-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-
319 methylphenyl)propyl] amino } methyl)phenol benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
320 methylphenyl)propyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
321 methylphenyl)propyl] [(3-methylphenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4S)-2,2-
322 dimethyloxan-4-yl]-3-(4-methylphenyl)propyl]amine
2-({ [(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
323 methylphenyl)propyl] amino } methyl)phenol
3-({ [(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
324 methylphenyl)propyl] amino } methyl)phenol benzyl[(3S)-3-(4-chlorophenyl)-3-[(4R)-2,2-
325 dimethyloxan-4-yl]propyl] amine
[(3S)-3-(4-chlorophenyl)-3-[(4R)-2,2-dimethyloxan-4-
326 yl]propyl] [(3-methylphenyl)methyl] amine
[(3S)-3-(4-chlorophenyl)-3-[(4R)-2,2-dimethyloxan-4-
327 yl]propyl] [(3-chlorophenyl)methyl] amine
2-({ [(3S)-3-(4-chlorophenyl)-3-[(4R)-2,2-
328 dimethyloxan-4-yl]propyl]amino}methyl)phenol benzyl[(3S)-3-(4-chlorophenyl)-3-[(4S)-2,2-
329 dimethyloxan-4-yl]propyl] amine
[(3S)-3-(4-chlorophenyl)-3-[(4S)-2,2-dimethyloxan-4-
330 yl]propyl] [(3-methylphenyl)methyl] amine
[(3S)-3-(4-chlorophenyl)-3-[(4S)-2,2-dimethyloxan-4-
331 yl]propyl] [(3-chlorophenyl)methyl] amine
2-({ [(3S)-3-(4-chlorophenyl)-3-[(4S)-2,2-
332 dimethyloxan-4-yl]propyl]amino}methyl)phenol
3-({ [(3S)-3-(4-chlorophenyl)-3-[(4S)-2,2-
333 dimethyloxan-4-yl]propyl]amino}methyl)phenol benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
334 fluoro-4-methylphenyl)propyl]amine
335
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4- methylphenyl)propyl] [(3-methylphenyl)methyl] amine benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-
336 fluoro-4-methylphenyl)propyl]amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
337 methylphenyl)propyl] [(3-methylphenyl)methyl] amine benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
338 ethoxyphenyl)propyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
339 ethoxyphenyl)propyl] [(2-fluorophenyl)methyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
340 ethoxyphenyl)propyl] [(3-fluorophenyl)methyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(4-
341 ethoxyphenyl)propyl] [(3-methylphenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-[(4S)-2,2-
342 dimethyloxan-4-yl]-3-(4-ethoxyphenyl)propyl]amine benzyl[(3S)-3-(4-chlorophenyl)-3-[(9R)-6-
343 oxaspiro [4.5] decan- 9 -yl] propyl] amine
[(3S)-3-(4-chlorophenyl)-3-[(9R)-6- oxaspiro [4.5 ] decan-9 - yl] propyl] [ (2-
344 fluorophenyl)methyl] amine
[(3S)-3-(4-chlorophenyl)-3-[(9R)-6- oxaspiro [4.5 ] decan-9 - yl] propyl] [ (3 -
345 fluorophenyl)methyl] amine
[(3S)-3-(4-chlorophenyl)-3-[(9R)-6- oxaspiro [4.5 ] decan-9 - yl] propyl] [ (3 -
346 methylphenyl)methyl] amine
[(3S)-3-(4-chlorophenyl)-3-[(9R)-6- oxaspiro [4.5 ] decan-9 - yl] propyl] [ (3 -
347 chlorophenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
348 methylphenyl)propyl] [( 1R) - 1 -phenylethyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
349 methylphenyl)propyl] [ ( 1 S ) - 1 -phenylethyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
350
methylphenyl)propyl][(5-methylfuran-2- yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4- methylphenyl)propyl][(5-methylthiophen-2-
351 yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4- methylphenyl)propyl][(6-methoxypyridin-3-
352 yl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
353 methylphenyl)propyl] ( 1 H-imidazol-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
354 methylphenyl)propyl](pyrazin-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
355 methylphenyl)propyl](pyrimidin-5-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
356 methylphenyl)propyl] ( 1 ,3-thiazol-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
357 methylphenyl)propyl](thiophen-3-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
358 methylphenyl)propyl](thiophen-2-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
359 methylphenyl)propyl] ( 1 ,3-oxazol-4-ylmethyl)amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
360 methylphenyl)propyl] ( 1 ,3-thiazol-5-ylmethyl)amine benzyl[(3S)-3-(3,4-difluorophenyl)-3-[(4R)-2,2-
361 dimethyloxan-4-yl]propyl] amine
dibenzyl[(3S)-3-(3,4-difluorophenyl)-3-[(4R)-2,2-
362 dimethyloxan-4-yl]propyl] amine
benzyl[(3S)-3-(3,4-difluorophenyl)-3-[(4S)-2,2-
363 dimethyloxan-4-yl]propyl] amine
benzyl[(3S)-3-(3,5-difluorophenyl)-3-[(4R)-2,2-
364 dimethyloxan-4-yl]propyl] amine
[(3S)-3-(3,5-difluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl] [(3-
365 methylphenyl)methyl] amine 2-({ [(3S)-3-(3,5-difluorophenyl)-3-[(4R)-2,2-
366 dimethyloxan-4-yl]propyl]amino}methyl)phenol benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
367 methylphenyl)propyl] amine
[(3-bromophenyl)methyl][(3S)-3-[(4R)-2,2-
368 dimethyloxan-4-yl]-3-(3-methylphenyl)propyl]amine
[(3-chlorophenyl)methyl][(3S)-3-[(4R)-2,2-
369 dimethyloxan-4-yl]-3-(3-methylphenyl)propyl]amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
370 methylphenyl)propyl] [(3-fluorophenyl)methyl] amine
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
371 methylphenyl)propyl] [(3-methylphenyl)methyl] amine
3-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
372 methylphenyl)propyl] amino } methyl)phenol
[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
373 methylphenyl)propyl] [(2-fluorophenyl)methyl] amine benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-
374 methylphenyl)propyl] amine
[(3-bromophenyl)methyl][(3S)-3-[(4S)-2,2-
375 dimethyloxan-4-yl]-3-(3-methylphenyl)propyl]amine
[(3-chlorophenyl)methyl][(3S)-3-[(4S)-2,2-
376 dimethyloxan-4-yl]-3-(3-methylphenyl)propyl]amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-
377 methylphenyl)propyl] [(3-fluorophenyl)methyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-
378 methylphenyl)propyl] [(3-methylphenyl)methyl] amine
3-({ [(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-
379 methylphenyl)propyl] amino } methyl)phenol
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-
380 methylphenyl)propyl] [(2-fluorophenyl)methyl] amine
2-({ [(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-
381 methylphenyl)propyl] amino } methyl)phenol
2-({ [(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(3-
382 methylphenyl)propyl] amino } methyl)phenol benzyl[(3S)-3-(4-bromo-2,6-difluorophenyl)-3-[(4S)-
383 2,2-dimethyloxan-4-yl]propyl]amine
[(3S)-3-(4-bromo-2,6-difluorophenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(3-
384 methylphenyl)methyl] amine
benzyl[(3S)-3-(4-bromo-2,6-difluorophenyl)-3-[(4R)-
385 2,2-dimethyloxan-4-yl]propyl]amine
[(3S)-3-(4-bromo-2,6-difluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl] [(3-
386 methylphenyl)methyl] amine
benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(2-
387 methylphenyl)propyl] amine
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(2-
388 methylphenyl)propyl] amine
benzyl[(3S)-3-(3,5-difluorophenyl)-3-[(4S)-2,2-
389 dimethyloxan-4-yl]propyl] amine
[(3S)-3-(3,5-difluorophenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(3-
390 methylphenyl)methyl] amine
3-({ [(3S)-3-(3,5-difluorophenyl)-3-[(4S)-2,2-
391 dimethyloxan-4-yl]propyl]amino}methyl)phenol
[(3S)-3-(3,5-difluorophenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(2-
392 fluorophenyl)methyl] amine
2-({ [(3S)-3-(3,5-difluorophenyl)-3-[(4S)-2,2-
393 dimethyloxan-4-yl]propyl]amino}methyl)phenol
[(3-bromophenyl)methyl][(3S)-3-(3,5- difluorophenyl)-3-[(4S)-2,2-dimethyloxan-4-
394 yl]propyl] amine
[(3-chlorophenyl)methyl][(3S)-3-(3,5- difluorophenyl)-3-[(4S)-2,2-dimethyloxan-4-
395 yl]propyl] amine
[(3S)-3-(3,5-difluorophenyl)-3-[(4S)-2,2- dimethyloxan-4-yl]propyl] [(3-
396 fluorophenyl)methyl] amine [(3S)-3-(3,5-difluorophenyl)-3-[(4R)-2,2- dimethyloxan-4-yl]propyl] [(3-
397 fluorophenyl)methyl] amine
[(3-chlorophenyl)methyl][(3S)-3-(3,5- difluorophenyl)-3-[(4R)-2,2-dimethyloxan-4-
398 yl]propyl] amine
[(3-bromophenyl)methyl][(3S)-3-(3,5- difluorophenyl)-3-[(4R)-2,2-dimethyloxan-4-
399 yl]propyl] amine
3-({ [(3S)-3-(3,5-difluorophenyl)-3-[(4R)-2,2-
400 dimethyloxan-4-yl]propyl]amino}methyl)phenol benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-
402 fluoro-4-methylphenyl)propyl]amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
403 methylphenyl)propyl](thiophen-2-ylmethyl)amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
404 methylphenyl)propyl](thiophen-3-ylmethyl)amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4- methylphenyl)propyl][(5-methylthiophen-2-
405 yl)methyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
406 methylphenyl)propyl](pyridin-3-ylmethyl)amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4- methylphenyl)propyl] ({ [6-(trifluoromethyl)pyridin-3-
407 yl] methyl } ) amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4- methylphenyl)propyl][(6-methoxypyridin-3-
408 yl)methyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4- methylphenyl)propyl][(6-methylpyridin-3-
409 yl)methyl] amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
410 methylphenyl)propyl] ( 1 ,3-thiazol-2-ylmethyl)amine
[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-(3-fluoro-4-
411 methylphenyl)propyl] ( 1 ,3-thiazol-5-ylmethyl)amine benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-
412 (pyridin- 3 - yl)propyl] amine
benzyl[(3S)-3-[(4S)-2,2-dimethyloxan-4-yl]-3-
413 (pyridin- 3 - yl)propyl] amine
414 benzyl({2-[(2,2-dimethyloxan-4-yl)(4-fluorophenyl)amino]ethyl})amine
415 2-(benzylamino)-N-(2,2-dimethyloxan-4-yl)-N-(4-fluorophenyl)acetamide benzyl[3-(2,2-dimethylmorpholin-4-yl)-3-(4-
416 fluorophenyl)propyl] amine
[(3-bromophenyl)methyl][3-(2,2-dimethylmorpholin-4-
417 yl)-3-(4-fluorophenyl)propyl]amine
[(3-chlorophenyl)methyl][3-(2,2-dimethylmorpholin-4-
418 yl)-3-(4-fluorophenyl)propyl]amine
[3-(2,2-dimethylmorpholin-4-yl)-3-(4-
419 fluorophenyl)propyl] [(3-methylphenyl)methyl] amine
[3-(2,2-dimethylmorpholin-4-yl)-3-(4- fluorophenyl)propyl]({ [3-
420 (trifluoromethyl)phenyl] methyl } ) amine
benzyl[3-(4-fluorophenyl)-3-(morpholin-4-
421 yl)propyl] amine
[3-(4-fluorophenyl)-3-(morpholin-4-yl)propyl]({ [6-
422 (trifluoromethyl)pyridin- 3 -yl] methyl } ) amine
[3-(4-fluorophenyl)-3-(morpholin-4-
423 yl)propyl](thiophen-3-ylmethyl)amine
[3-(4-fluorophenyl)-3-(morpholin-4-
424 yl)propyl](thiophen-2-ylmethyl)amine
benzyl({2-[(R)-[(4R)-2,2-dimethyloxan-4-yl](4-
425 fluorophenyl)methyl]propyl } )amine
(diastereomer 1)
benzyl({2-[(R)-[(4R)-2,2-dimethyloxan-4-yl](4-
426 fluorophenyl)methyl]propyl } )amine
(diastereomer 2)
benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-2,2-difluoro-3-(4-
427 fluorophenyl)propyl] amine
428 4-[(lS)-l-[(4S)-2,2-dimethyloxan-4-yl]-3-[(pyridin-3- ylmethyl)amino]propyl]benzonitrile
4-[(lS)-3-(benzylamino)-l-[(4R)-2,2-dimethyloxan-4-
429
yl]propyl]benzonitrile
4-[(lS)-3-(benzylamino)-l-[(4S)-2,2-dimethyloxan-4-
430
yl]propyl]benzonitrile
4-[(lS)-l-[(4S)-2,2-dimethyloxan-4-yl]-3-{ [(6-
431 methoxypyridin- 3 - yl)methyl]amino}propyl]benzonitrile
4-[(lS)-l-[(4S)-2,2-dimethyloxan-4-yl]-3-{ [(5-
432 methylthiophen-2- yl)methyl]amino}propyl]benzonitrile
4-[(lS)-l-[(4S)-2,2-dimethyloxan-4-yl]-3-{ [(5-
433
methylfuran-2-yl)methyl] amino } propyl] benzonitrile
4-[(lS)-l-[(4S)-2,2-dimethyloxan-4-yl]-3-{ [(6-
434 methylpyridin- 3 - yl)methyl]amino}propyl]benzonitrile
4-[(lS)-l-[(4S)-2,2-dimethyloxan-4-yl]-3-({ [6-
435 (trifluoromethyl)pyridin-3- yl] methyl } amino)propyl] benzonitrile
4- [( 1 S)- 1 - [(4R)-2,2-dimethyloxan-4-yl] -3- { [(6-
436 methylpyridin- 3 - yl)methyl]amino}propyl]benzonitrile
4- [( 1 S )- 1 - [(4R)-2,2-dimethyloxan-4-yl] -3- ( { [6-
437 (trifluoromethyl)pyridin-3- yl] methyl } amino)propyl] benzonitrile
4-[(lS)-l-[(4R)-2,2-dimethyloxan-4-yl]-3-
438
[ (thiophen-3 -ylmethyl) amino] propyl] benzonitrile
4-[(lS)-l-[(4R)-2,2-dimethyloxan-4-yl]-3-{ [(5-
439 methylthiophen-2- yl)methyl]amino}propyl]benzonitrile
4-[(lS)-3-amino-l-[(4S)-2,2-dimethyloxan-4-
440
yl]propyl]benzonitrile
4-[(lS)-3-{ [ (6-bromopyridin- 3 -yl)methyl] amino } - 1 -
441
[(4R)-2,2-dimethyloxan-4-yl]propyl]benzonitrile
442 4-[(lS)-l-[(4R)-2,2-dimethyloxan-4-yl]-3-{ [(3- methylthiophen-2- yl)methyl]amino}propyl]benzonitrile
4- [( 1 S)- 1 - [(4R)-2,2-dimethyloxan-4-yl] -3- { [(4-
443 methylthiophen-2- yl)methyl]amino}propyl]benzonitrile
4-[(lS)-l-[(4R)-2,2-dimethyloxan-4-yl]-3-{ [(4,5-
444 dimethylthiophen-2- yl)methyl]amino}propyl]benzonitrile
4-[( 1 S)-3- { [(4-bromothiophen-2-yl)methyl] amino } - 1 -
445
[(4R)-2,2-dimethyloxan-4-yl]propyl]benzonitrile
4-[(lS)-3-{ [ (5 -bromothiophen-2- yl)methyl] amino } - 1 -
446
[(4R)-2,2-dimethyloxan-4-yl]propyl]benzonitrile
4-[(lS)-3-({ [5-chloro-6-(trifluoromethyl)pyridin-3-
447 yl]methyl}amino)-l-[(4R)-2,2-dimethyloxan-4- yl]propyl]benzonitrile
4-[(lS)-3-[benzyl(methyl)amino]-l-[(4R)-2,2-
448
dimethyloxan-4-yl]propyl]benzonitrile
4-[(lS)-3-[benzyl(butyl)amino]-l-[(4R)-2,2-
449
dimethyloxan-4-yl]propyl]benzonitrile
4-[(lS)-3-[benzyl(2-methylpropyl)amino]-l-[(4R)-
450
2,2-dimethyloxan-4-yl]propyl]benzonitrile
4-[(lS)-3-[benzyl(propan-2-yl)amino]-l-[(4R)-2,2-
451
dimethyloxan-4-yl]propyl]benzonitrile
4-[(lS)-l-[(4S)-2,2-dimethyloxan-4-yl]-3-{ [(3-
452 methylthiophen-2- yl)methyl]amino}propyl]benzonitrile
4-[(lS)-l-[(4S)-2,2-dimethyloxan-4-yl]-3-{ [(4-
453 methylthiophen-2- yl)methyl]amino}propyl]benzonitrile
4-[(lS)-l-[(4S)-2,2-dimethyloxan-4-yl]-3-{ [(4,5-
454 dimethylthiophen-2- yl)methyl]amino}propyl]benzonitrile
4-[( 1 S)-3- { [(4-bromothiophen-2-yl)methyl] amino } - 1 -
455
[(4S)-2,2-dimethyloxan-4-yl]propyl]benzonitrile
4-[(lS)-3-{ [ (5 -bromothiophen-2- yl)methyl] amino } - 1 -
456
[(4S)-2,2-dimethyloxan-4-yl]propyl]benzonitrile 4-[(lS)-3-({ [5-chloro-6-(trifluoromethyl)pyridin-3-
457 yl] methyl } amino)- 1 - [(4S )-2,2-dimethyloxan-4- yl]propyl]benzonitrile
4-[(lS)-3-(2,3-dihydro-lH-isoindol-2-yl)-l-[(4R)-
458
2,2-dimethyloxan-4-yl]propyl]benzonitrile
4-[(lS)-3-[(cyclohex-l-en-l-ylmethyl)amino]-l-
459
[(4R)-2,2-dimethyloxan-4-yl]propyl]benzonitrile
4-[(lS)-3-(2,3-dihydro-lH-isoindol-2-yl)-l-[(4R)-2,2-dimethyloxan-4-
460 yl]propyl]benzonitrile
3-(benzylamino)-l-(2,2-dimethyloxan-4-yl)-l-(4-fluorophenyl)propan-l-ol
461 (diastereomer 1)
3-(benzylamino)-l-(2,2-dimethyloxan-4-yl)-l-(4-fluorophenyl)propan-l-ol
462 (diastereomer 2)
500 Benzyl[3-(2,2-dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl]amine
501 [3-(2,2-Dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl](l-phenylethyl)amine
502 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl]amino}methyl)-N,N- dimethylaniline
503 Benzyl[3-(2,2-dimethyloxan-4-yl)-3-(4-methoxyphenyl)propyl]amine
504 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-(4-methoxyphenyl)propyl]amino}methyl)-N,N- dimethylaniline
505 [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl](l-phenylethyl)amine
506 [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl][(4-methoxyphenyl)methyl]amine
507 [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl][(4- methoxyphenyl)methyl]propylamine
508 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl]amino}methyl)-N,N- dimethylaniline
509 [(3,4-dimethoxyphenyl)methyl][3-(2,2-dimethyloxan-4-yl)-3-phenylpropyl]amine
[0137] Examples
[0138] The following examples are illustrative, but not limiting, of the methods and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in therapy and that are obvious to those skilled in the art are within the spirit and scope of the embodiments.
Scheme 3
Figure imgf000077_0001
3-10
4-bromo-l-fluorobenzene was treated with 1.0 equivalent of n-BuLi at -78 °C in anhydrous THF to generate the corresponding lithium reagent (3-2), which subsequently reacted with the aldehyde 3-3 at -78°C to afford the corresponding carbinol, which was a mixture of two diatereoisomers and was not separated and used as crude for next step. Ley oxidation of the crude carbinol led to the formation of the ketone 3-4 in 93% yield in two steps. Treatment of 3-4 with diethyl cyanomethylphosphate uinder basic conditions gave rise to two unsaturated nitriles (3-5 and 3-6). The geometry of the C=C double bond was determined by NMR spectral methods. DIBAL reduction of 3-6 led to the unsaturated aldehyde (3-7) in 51% yield. Reductive amination of 3-7 was accomplished through a two stage process, in which 3-7 first reacted with benzylamine in DCM to form the resulting imine, which was detectable by HPLC method, then DCM was removed under reduced pressure, followed by reduction with NaBH4 in Methanol. Thus, 3-8 was obtained from 3-7 in 81% yield after purification. Attempt to reduce the C=C double bond with 10% Pd/C under the atmosphere of hydrogen surprising led to the formation of 3-9 in quantitative yield. Following the same reductive amination procedure as for 3-7, 3-9 was converted to the desired product 3-10 in 63% yield.
Scheme 4
Figure imgf000079_0001
4-4 In order to synthesize enantiomerically enriched products (4-1 and 4-2), we followed a procedure described in Angew. Chem. Int.Ed. 2006, 45, 2785. Treatment of 3-5 with CuH, generated in situ from Cu(OAc)2 and PHMS, in the presence of (R)-(Sp)- Josi-Phos, led to the formation of 4-1 and 4-2. The enatiomeric excess of 4-1 was around 75%, and the enatiomeric excess of 4-2 was around 60%. It was later found that by switching the solvent to toluene and lowering the reaction temperature to - 40°C the ee value of 4-1 and 4-2 can be improved upto 98%. LAH reduction of 4-2 was performed in diethyl ether and the desired amine 4-3 was obtained greater than 95% yield, and it was pure enough for the next reaction. Following the same procedure described in Scheme 3 for reductive amination, enantiomerically enriched product 4-4 was isolated in 95% yield after HPLC prurification. Scheme 5
Figure imgf000080_0001
5-1 3-4
The oxidation of 5-1 was also accomplished by Dess-Martin periodinane in DCM and the desired product 3-4 was isolated in 94% yield.
Scheme 7
Figure imgf000081_0001
Reduction amination of 3-3 with 4-fluoroaniline 7-1 was performed under
Na(OAc)3BH and DCE and the desired product 7-2 was isolated in 90% yield. The second reductive amination was performed on 7-2 with the aldehyde 7-3 to afford 7-4 in 87% yield. After removing the Boc group in presence of TFA in DCM, 7-4 was subject to another reductive amination and the final product 7-6 was isolated in 29% yield. Scheme 8
Figure imgf000082_0001
8-3
[0143] The aniline analogue (7-2) obtained from scheme 7 reacted with 2- bromoacetylbromide in DCM and TEA to afford the amide 8-2 in 73% yield. Benzylamine displacement of the bromide in 8-2 under basic conditions gave the product 8-3 in 32% yield after purification.
Scheme 9
>95% yield
Figure imgf000082_0002
9-1 9-2 9-3
[0144] The aldehyde 9-3, which was used as a starting material in this invention, was prepared from a known compound 9-1. Treatment of 9-1 with
(methoxymethyl)triphenylphosphanium chloride and sodium
bis (trimethylsilyl) amide . Scheme 10
Figure imgf000083_0001
10-1 10-2
24% yield 26% yield
The relative stereochemistry of 10-1 and 10-2 were not determined.
A methyl group can be introduced at the alpha position of the nitrile (4-2). Under LiHMDS and iodomethane condition, two distereoisomers (10-1 and 10-2) can be isolated. However, the relative stereochemistry of 10-1 and 10-2 were not determined.
Scheme 11
Figure imgf000083_0002
60% yield
Fluoronation of the intermediate (4-2) was accomplished under LiHMDS and N- fluorobenzenesulfonimide to provide intermediate 11-1 in 60% yield (ref: Differding, E.; Duthaler, R.O.; Krieger, A.; Ruegg, G.M.; Schmit, C. SynLett, 1991, 395). Scheme 12
Figure imgf000084_0001
Introduction of a cyano group on the final product (12-6) was accomplished via Ullmann coupling reaction. Intermediate 12-1 can be synthesized, following the reaction sequence in Scheme 3. To reduce the nitrile group in 12-1, cobalt-mediated reduction gave a better result than LAH. The primary amine was protected with a Cbz group. The resulting intermediate was transformed to a cyano analog under the Ullman conditions. Further chemical elaboration on intermediate 12-4 led to the final analog (12-6) in two steps.
Scheme 13
Figure imgf000085_0001
13-2 13-4
51% yield 70% yield
Intermediate 3-4 was converted to 13-1 and 13-2 when it reacted with allyl magnesium chloride. Two diastereomers can be separated by Si02 column chromatography, but the relative and absolute stereochemistry of both 13-1 and 13-2 was not determined. After ozonolysis of 13-1, the intermediate was then transformed to 13-3 under the reductive amination conditions outlined in Scheme 3.
Scheme 14
Figure imgf000085_0002
Intermediate 14-3 was prepared from 3-(4-fluorophenyl)acrylnitrile and 2,2- dimethylmorpholine at 100 oC for 30h [Arkivoc, 2001, (vii), 76], although in low yield.
[0145] Example 3
Figure imgf000086_0001
Ex 3
[0146] Benzyl[(2Z)-3-(2,2-dimethyloxan-4-yl)-3-(4-fluorophenyl)prop-2-en-l-yl]amine
Figure imgf000086_0002
3A
[0147] 3.1 Preparationof 3A.
[0148] To a solution of 4-F-bromobenzene (922 mg, 5.27 mmol) in 10 mL of THF was added n-BuLi (1.6 M in hexane, 3.0 mL, 4.93 mmol) at -78 °C. The solution was stirred for 30 mins at -78 °C and 2,2-dimethyloxane-4-carbaldehyde (500 mg, 3.52 mmol) in 5 mL of THF was added dropwise. The reaction was allowed to stir for 15 min and was quenched with methanol. THF was removed under reduced pressure. The residue was diluted with 100 mL of ethyl acetate and was washed with sat. NH4C1, brine, and dried over MgS04. After filtration and concentration, the residue was purified on 50 g snap column (Biotage), eluted with 0-40% ethyl acetate in Hex over 14 CV(column volume). The desired products (3 A as a mixture of two isomers) (930 mg, 99% yield) were isolated.
[0149] LC-MS (ESI) m/z: 221.1 [M+l- H20] observed.
Figure imgf000087_0001
3B
[0150] 3.2 Preparation of 3B.
[0151] To a solution of 3A (16.75 g, 70.3 mmol) in 300 mL of DCM were added NMO
(16.4 g, 140 mmol) and 4A MS (35 g) . The solution was stirred for 30 mins and then TPAP (0.74 g, 2.1 mmol, 0.03 eq.) was added in two portions. The reaction was allowed to stir for 2 h. After checking the TLC, the alcohol was almost gone. It was filtered through a short pad of Si02, washed with 5% ethyl acetate in DCM. The filtrate was concentrated and the residue was purified on 340 g Snap column (Biotage), 0-40% ethyl acetate in Hex 10 CV (column volume) to give 3B (15.4 g, 93% yield).
[0152] LC-MS (ESI) m/z: 237.1 [M+l] observed. [0153] 3.3 Alternative preparation of 3B.
[0154] To a solution of 2A (830 mg, 3.5mmol) in 15 mL of DCM was added Dess-Martin periodinane (1.60 g, 3.83 mmol) at room temperature. The reaction was stirred for 3 h. The solvent was removed and the residue was directly loaded on 50 g snap column(Biotage), eluted with 0-40% ethyl acetate in Hex 12 CV(column volume) to give 3B (770 mg, 94% yield).
Figure imgf000088_0001
3C 3D [0155] 3.4 Preparation of 3C and 3D.
[0156] To a suspension of NaH (1.11 g, 46.3 mmol) in 70 mL of anhydrous THF at 0 °C was added a solution of NCCH2P(0)(OCH2CH3)2 (8.20 g, 46.3 mmol) in 20 mL of THF over 5 min. The solution was stirred at room temperature for 1/2 h. Then it was cooled to 0 °C again and a solution of 3B (7.30 g, 30.9 mmol) in 30 mL of THF was added in one portion. The reaction mixture was stirred at room temperature overnight. After removal of THF, it was diluted with 200 mL of ethyl acetate, washed with H20, brine, dried over MgS04. After filtration and concentration, the residue was purified on 340g snap column (Biotage), eluted with 10-25% ethyl acetate in Hex 10 CV(column volume) to give 3C as the first fraction (4.60 g, 57% yield) and 3D as the second fraction (2.94 g, 37% yield).
[0157] LC-MS (ESI) m/z: 260.2 [M+l] observed for 3C.
[0158] LC-MS (ESI) m/z: 260.1 [M+l] observed for 3D.
Figure imgf000089_0001
3E
[0159] 3.5 Preparation of 3E.
[0160] To a solution of 3D (305 mg, 1.17 mmol) in 5 mL of DCM at room temperature was added DIBAL-H (1.0 M in THF, 2.92 mL, 2.92 mmol) at -78°C. The mixture was stirred from -78°C to room temperature overnight. The reaction mixture was quenched with 1 mL of methanol and 1 mL of H20. To a gel-like suspension was added 10 mL of ethyl acetate, followed by 10 g of Na2S04. After stirring the mixture for lh, it was filtered and concentrated. The residue was purified by 10 g snap column (Biotage), eluted with 0-45% ethyl acetate in Hex, 14 CV (column volume) to give 3E (157 mg, 51% yield).
[0161] LC-MS (ESI) m/z: 263.2 [M+l] observed for 3E.
[0162] 3.6 Preparation of Ex3.
[0163] To a solution of 3E (157 mg, 0.60 mmol) in 5 mL of DCM at room temperature was Na2S04 (43 mg) and benzyl NH2 (71 mg, 0.66 mmol). The solution was stirred overnight. After filtration and concentration, the residue was dissolved in 5 mL of methanol at 0°C. Then NaBH4 (27 mg, 0.72 mmol) was added in one portion. After stirring at 0 °C for lh, the reaction was quenched with 2 mL of H20. The solution was then diluted with DCM (60 mL). After separation of the DCM layer, the aq. layer was extracted with DCM (10 mL x2). The combined organic layers were washed with brine, dried over MgS04. After filtration and concentration, the residue was purified by 25 g snap column, eluted with 0-10% methanol in DCM, 15 CV to give Ex3 (172 mg, 81% yield).
[0164] Examples 4-5 were prepared in an analogous manner as described in Ex 3. The list of these examples was shown in Table 2 with the MS and 1H NMR data.
Table 2:
Figure imgf000090_0001
[0165] Example 6
Figure imgf000091_0001
Ex6
[0166] Benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-3-(4-fluorophenyl)propyl]amine,
trifluoroacetic acid
Figure imgf000091_0002
6A 6B
[0167] 6.1 Preparation of 6A and 6B.
[0168] Cu(OAc)2 (97 mg, 0.53 mmol)and (R)-(S)-Josiphos*ethanol (340 mg, 0.53
mmol)were placed in an oven-dried flask. The flask was evacuated and backfilled with N2. PHMS( 5.28 mL) and benzene (50.0 mL) were added via syringe and the mixture was stirred for 15 min. The reaction flask was placed in 0°C iced- water bath. A solution of 3C in 20.0 mL of benzene was added, followed by t-BuOH. The mixture was stirred from 0°C to room temperature until the completion of the reaction (overnight). It was quenched with 10 mL of H20 and then 5 mL of 2.5N NaOH. It was then diluted with 400 mL of ethyl acetate and the organic layer was washed with brine (10 mL x 2). The organic layer was separated and dried over MgS04. After filtration and concentration, the residue was purified on 2 xlOO g snap column (Biotage), eluted with 0-40% ethyl acetate in Hex over 30 CV (column volume) to give 6A as the first fraction (2.10g, 45%yield) and 6B as the second fraction (2.50 g, 54% yield).
[0169] LC-MS (ESI) m/z: 262.2 [M+l] observed for 6A.
[0170] LC-MS (ESI) m/z: 262.2 [M+l] observed for 6B.
Figure imgf000092_0001
6C
[0171] 6.2 Preparation of 6C.
[0172] To a solution of 6B (2.50 g, 9.57 mmol) in 50 mL of diethyl ether at 0 °C was added LAH (1.0M in THF, 9.57 mL, 9.57 mmol). The mixture was stirred at 0 °C for 2h. The reaction was quenched with 5 mL of methanol and 10.0 mL of IN NaOH. It was then extracted with 300 mL of ethyl acetate and washed with brine. After dried over MgS04, it was filtered and concentrated to provide 6C (2.66 g, quantitative yield), which was pure enough for the next step.
[0173] LC-MS (ESI) m/z: 266.2 [M+l] observed for 6C.
[0174] 6.3 Preparation of Ex6. [0175] To a solution of 6C (1.90g, 7.15 mmol) in DCM(50 mL) was added PhCHO (0.68 g, 6.44 mmol). The solution was stirred at room temperature overnight. The solvent was removed and redissolved in 40 mL of methanol. It was then cooled to 0°C and NaBH4 (270 mg, 7.15 mmol) was added in one portion. After 10 min, the mixture was quenched with 5 mL of H20 and 5 mL of 2.5N NaOH. methanol was removed under reduced pressure and the residue was dissolved in 200 mL of ethyl acetate. The aq. layer separated and then was extracted with 25 mL of ethyl acetate. The combined organic layer was dried over MgS04. After it was filtered and
concentrated, the residue was purified by 50 g snap column(Biotage), eluted with 0- 80% ethyl acetate in Hex 8 CV(column volume), followed by 0- 10% methanol in DCM 25 CV to Ex 6 (2.05 g, 90% yield).
Or Ex 6 can be purified by reverse-phase HPLC as a TFA salt.
[0176] LC-MS (ESI) m/z: 356.3 [M+l] observed.
[0177] 1H NMR (400 MHz, CDC13) ) δ 9.22 (s, 2H), 7.43 - 7.15 (m, 6H), 7.06 - 6.86 (m, 4H), 3.95 - 3.67 (m, 3H), 3.64 - 3.35 (m, 4H), 2.53 (d, / = 35.9, 2H), 2.15 (q, / = 8.8, 2H), 1.91 - 1.52 (m, 3H), 1.26 - 0.96 (m, 7H), 0.85 (t, / = 12.7, 1H).
The absolute configuration of Ex 6 was determined by X-ray crystallography method on another salt form of Ex 6 (namely with L-(+)-tartaric acid).
[0178] Examples 7-400 and 402-413 were prepared in an analogous manner as described in
Ex 6. The list of these examples was shown in Table 3 with the MS and 1H NMR data.
Table 3
Ex # Chemical Name (free base) MS m/z 1H NMR [M+l]
IH NMR (400 MHz, CDC13) 59.22 (s, 2H), 7.43 - 7.15 (m, 6H), 7.06 - 6.86 (m, 4H), 3.95 - 3.67 (m, 3H), 3.64 - 3.35 (m, benzyl[(3S)-3-[(4R)-2,2- 4H), 2.53 (d, J = 35.9, 2H), 2.15 (q, J = 8.8, dimethyloxan-4-yl]-3-(4- 2H), 1.91 - 1.52 (m, 3H), 1.26 - 0.96 (m, fluorophenyl)propyl] amine 356.3 7H), 0.85 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) 5 9.83 (d, J = 23.2, 2H), 7.46 (t, J = 11.6, 2H), 7.33 (d, J = 2.9, 3H), 7.24 (s, 2H), 7.05 - 6.81 (m, 4H), 3.91 (dd, J = 52.9, 12.9, 2H), 3.64 - benzyl[(3S)-3-[(4S)-2,2- 3.33 (m, 2H), 2.63 - 2.15 (m, 4H), 1.98 (t, dimethyloxan-4-yl]-3-(4- J = 7.5, IH), 1.82 - 1.49 (m, 8H), 1.20 - fluorophenyl)propyl] amine 356.3 0.79 (m, 8H).
IH NMR (400 MHz, CDC13) 57.37 - 7.12 (m, 5H), 7.11 - 7.00 (m, 2H), 7.00 - 6.87 (m, 2H), 3.96 (dd, J = 11.4, 3.8, IH), 3.89 - 3.75 (m, IH), 3.64 (q, J = 13.1, 2H), 3.33 (td, J = 12.0, 2.2, IH), 3.21 (td, J = 11.3, 3.4, IH), 2.42 - 2.26 (m, 3H), 2.00 (dtd, J benzyl[(3R)-3-(4-fluorophenyl)- = 11.8, 7.7, 3.9, IH), 1.82 - 1.46 (m, 4H),
3-(oxan-4- 1.29 (ddd, J = 24.6, 12.1, 4.4, IH), 1.19 - yl)propyl] amine 328.2 1.04 (m, 2H).
IH NMR (400 MHz, CDC13) 59.11 (s, 2H), 7.06 - 6.86 (m, 4H), 6.80 (dd, J = 14.1, 4.8, 2H), 6.67 (dd, J = 8.1, 1.6, IH), 4.10 (s, 4H), 3.85 - 3.64 (m, 6H), 3.57 (dd,
4-({ [(3S)-3-[(4R)-2,2- J = 12.3, 10.5, IH), 2.50 (d, J = 29.7, 2H), dimethyloxan-4-yl]-3-(4- 2.15 (t, J = 9.3, 2H), 1.70 (ddd, J = 40.3, fluorophenyl)propyl] amino } met 21.0, 10.0, 3H), 1.21 - 0.95 (m, 7H), 0.85 hyl)-2-methoxyphenol 402.3 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) 58.64 (s, 2H), 7.98 (d, J = 3.5, 2H), 7.24 (s, IH),
[(3S)-3-[(4R)-2,2-dimethyloxan- 6.98 (dt, J = 33.8, 8.5, 5H), 4.26 (s, 2H),
4-yl]-3-(4- 3.80 - 3.40 (m, 2H), 3.01 - 2.56 (m, 2H), fluorophenyl)propyl] (pyridin-4- 2.25 (d, J = 7.7, 2H), 2.08 - 1.56 (m, 3H), ylmethyl) amine 357.3 1.26 - 0.97 (m, 7H), 0.87 (t, J = 12.8, IH).
[(3S)-3-[(4R)-2,2-dimethyloxan- IH NMR (400 MHz, CDC13) 58.99 (s,
4-yl]-3-(4- IH), 8.61 (s, IH), 8.44 (d, J = 7.7, IH),
357.3
fluorophenyl)propyl] (pyridin-3- 7.90 - 7.66 (m, IH), 7.09 - 6.83 (m, 4H), ylmethyl) amine 6.12 (s, 6H), 4.39 - 4.10 (m, 2H), 3.79 - 3.45 (m, 2H), 2.85 (dd, J = 10.9, 7.2, IH), 2.68 (dd, J = 11.0, 6.9, IH), 2.24 (t, J = 8.7, 2H), 1.99 - 1.87 (m, IH), 1.84 - 1.58 (m, 2H), 1.25 - 0.96 (m, 7H), 0.87 (t, J = 12.8,
IH).
IH NMR (400 MHz, CDC13) 58.59 - 8.44 (m, IH), 7.90 (td, J = 7.8, 1.7, IH), 7.55 - 7.35 (m, 2H), 7.11 - 6.83 (m, 4H), 4.24 (s,
2H), 3.88 - 3.66 (m, IH), 3.59 (td, J = 12.3, 2.2, IH), 2.93 - 2.77 (m, IH), 2.77 - 2.62 (m, IH), 2.28 (ddd, J = 12.2, 9.8, 2.6,
[(3S)-3-[(4R)-2,2-dimethyloxan- 2H), 2.04 - 1.90 (m, IH), 1.76 (ddd, J =
4-yl]-3-(4- 33.2, 16.2, 8.2, 2H), 1.16 (tt, J = 12.4, 6.2, fluorophenyl)propyl] (pyridin-2- IH), 1.08 - 1.00 (m, 6H), 0.89 (t, J = 12.7, ylmethyl) amine 357.2 IH).
IH NMR (400 MHz, CDC13) 59.15 (s, 2H), 6.93 (d, J = 6.9, 4H), 6.81 (d, J = 1.6,
[(3,4- IH), 6.76 - 6.59 (m, 2H), 4.42 (s, 2H), dimethoxyphenyl)methyl] [(3S)- 3.85 - 3.63 (m, 9H), 3.57 (td, J = 12.3, 2.1,
3-[(4R)-2,2- IH), 2.50 (d, J = 33.5, 2H), 2.21 - 2.02 (m, dimethyloxan-4-yl]-3-(4- 2H), 1.87 - 1.56 (m, 3H), 1.24 - 0.94 (m, fluorophenyl)propyl] amine 416.3 7H), 0.85 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) 59.20 (s, IH), 8.79 (s, IH), 7.12 - 6.83 (m, 6H), 6.76 (dd, J = 7.6, 1.2, IH), 4.33 (s, 2H),
[(2,3- 4.11 - 3.88 (m, 2H), 3.80 (t, J = 9.9, 5H), dimethoxyphenyl)methyl] [(3S)- 3.71 (dd, J = 12.0, 3.9, IH), 3.64 - 3.47 (m,
3-[(4R)-2,2- IH), 2.54 (d, J = 22.6, 2H), 2.18 (t, J = 8.7, dimethyloxan-4-yl]-3-(4- 2H), 1.92 - 1.51 (m, 3H), 1.25 - 0.92 (m, fluorophenyl)propyl] amine 416.3 7H), 0.84 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) 59.36 (s, 2H), 7.39 - 7.18 (m, 2H), 7.16 - 6.84 (m, 5H), 4.21 (s, 2H), 4.03 - 3.82 (m, 2H),
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.72 (dd, J = 12.0, 3.9, IH), 3.57 (td, J =
4-yl]-3-(4- 12.3, 2.1, IH), 2.57 (d, J = 40.5, 2H), 2.29 fluorophenyl)propyl] [(2- - 2.05 (m, 2H), 1.93 - 1.55 (m, 3H), 1.26 - fluorophenyl)methyl] amine 374.3 0.96 (m, 7H), 0.86 (t, J = 12.7, IH).
[(3S)-3-[(4R)-2,2-dimethyloxan- IH NMR (400 MHz, CDC13) 59.57 (s,
374.2
4-yl]-3-(4- 2H), 7.35 - 7.17 (m, IH), 7.10 - 6.83 (m, fluorophenyl)propyl] [(3- 6H), 3.75 (ddd, J = 20.5, 16.2, 8.6, 3H), fluorophenyl)methyl] amine 3.56 (td, J = 12.2, 2.0, IH), 2.81 (d, J =
89.1, 2H), 2.51 (d, J = 41.6, 2H), 2.16 (q, J = 9.0, 2H), 1.90 - 1.51 (m, 3H), 1.25 - 0.93 (m, 7H), 0.92 - 0.76 (m, IH).
IH NMR (400 MHz, CDC13) 59.22 (s, 2H), 7.24 (s, OH), 7.16 (t, J = 7.5, IH), 7.08 (d, J = 7.6, IH), 7.00 (d, J = 11.3, 2H), 6.94 (d, J = 7.0, 4H), 4.45 (s, 2H), 3.83 - 3.62 (m, 3H), 3.56 (td, J = 12.3, 2.1, IH), 2.51
[(3S)-3-[(4R)-2,2-dimethyloxan- (d, J = 35.8, 2H), 2.24 (s, 3H), 2.21 - 2.06
4-yl]-3-(4- (m, 2H), 1.86 - 1.66 (m, 2H), 1.63 (d, J = fluorophenyl)propyl] [(3- 12.9, IH), 1.18 - 0.96 (m, 7H), 0.85 (t, J = methylphenyl)methyl] amine 370.3 12.7, IH).
IH NMR (400 MHz, CDC13) 59.26 (s, 2H), 7.17 (dt, J = 7.7, 4.0, 2H), 7.13 - 7.06 (m, 2H), 6.97 (dd, J = 18.2, 8.1, 4H), 3.89
[(3S)-3-[(4R)-2,2-dimethyloxan- - 3.66 (m, 3H), 3.57 (td, J = 12.3, 2.2, IH),
4-yl]-3-(4- 3.33 (s, 2H), 2.53 (d, J = 39.9, 2H), 2.34 - fluorophenyl)propyl] [(2- 2.04 (m, 5H), 1.91 - 1.52 (m, 3H), 1.26 - methylphenyl)methyl] amine 370.3 0.93 (m, 7H), 0.86 (dd, J = 16.1, 9.4, IH).
IH NMR (400 MHz, CDC13) 59.27 (s, 2H), 7.39 - 7.31 (m, 2H), 7.30 - 7.17 (m, 2H), 7.01 - 6.90 (m, 4H), 4.47 (s, 2H), 4.04 (s, 2H), 3.72 (dd, J = 12.0, 3.7, IH), 3.58 (td, J = 12.3, 2.2, IH), 2.73 - 2.61 (m,
[(2-chlorophenyl)methyl] [(3S)- IH), 2.58 (d, J = 10.0, IH), 2.20 (dt, J =
3-[(4R)-2,2- 8.5, 6.4, 2H), 1.93 - 1.89 (m, OH), 1.91 - dimethyloxan-4-yl]-3-(4- 1.69 (m, 2H), 1.65 (d, J = 12.8, IH), 1.21 - fluorophenyl)propyl] amine 390.2 0.97 (m, 7H), 0.86 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) 59.49 (s, 2H), 7.31 - 7.18 (m, 3H), 7.13 (d, J = 7.4,
IH), 7.05 - 6.90 (m, 4H), 4.15 (s, IH), 3.91 - 3.65 (m, 3H), 3.56 (td, J = 12.2, 2.0,
[(3-chlorophenyl)methyl] [(3S)- IH), 2.57 (s, IH), 2.47 (s, IH), 2.27 - 2.04
3-[(4R)-2,2- (m, 2H), 1.85 - 1.66 (m, 2H), 1.62 (d, J = dimethyloxan-4-yl]-3-(4- 12.6, IH), 1.23 - 0.93 (m, 7H), 0.92 - 0.79 fluorophenyl)propyl] amine 390.2 (m, IH).
[(3S)-3-[(4R)-2,2-dimethyloxan- IH NMR (400 MHz, CDC13) 59.27 (s,
386.3
4-yl]-3-(4- 2H), 7.18 (t, J = 7.9, IH), 6.95 (t, J = 9.7, fluorophenyl)propyl] [(3- 4H), 6.85 - 6.73 (m, 3H), 4.25 (s, 2H), methoxyphenyl)methyl] amine 3.84 - 3.65 (m, 6H), 3.57 (td, J = 12.3, 2.1,
IH), 2.57 (s, IH), 2.47 (s, IH), 2.24 - 2.05 (m, 2H), 1.88 - 1.67 (m, 2H), 1.63 (d, J = 12.9, IH), 1.19 - 0.95 (m, 7H), 0.86 (dd, J
= 15.9, 9.6, IH).
IH NMR (400 MHz, CDC13) 58.82 (s, IH), 8.62 (s, IH), 7.32 (td, J = 8.2, 1.6, 1H), 7.11 (dd, J = 7.5, 1.6, IH), 6.97 (dd, J = 16.0, 7.2, 4H), 6.88 (td, J = 7.5, 0.8, IH), 6.83 (d, J = 8.2, IH), 5.18 (s, 2H), 3.94 (dd, J = 28.3, 12.8, 2H), 3.81 - 3.66 (m, 4H),
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.58 (td, J = 12.3, 2.2, IH), 2.62 (s, IH),
4-yl]-3-(4- 2.52 (s, IH), 2.28 - 2.09 (m, 2H), 1.91 - fluorophenyl)propyl] [(2- 1.68 (m, 2H), 1.66 (d, J = 12.8, IH), 1.26 - methoxyphenyl)methyl] amine 386.3 0.93 (m, 7H), 0.93 - 0.75 (m, IH).
IH NMR (400 MHz, CDC13) 59.07 (s, 2H), 7.12 (d, J = 8.7, 2H), 6.96 (dd, J = 17.1, 7.8, 4H), 6.78 (t, J = 5.8, 2H), 4.54 (s, 2H), 3.83 - 3.63 (m, 5H), 3.57 (td, J =
[(3S)-3-[(4R)-2,2-dimethyloxan- 12.3, 2.1, IH), 2.55 (d, J = 4.4, IH), 2.46
4-yl]-3-(4- (s, IH), 2.27 - 2.03 (m, 2H), 1.86 - 1.68 fluorophenyl)propyl] [(4- (m, 2H), 1.64 (d, J = 12.8, IH), 1.20 - 0.95 methoxyphenyl)methyl] amine 386.3 (m, 7H), 0.86 (dd, J = 16.0, 9.5, IH).
IH NMR (400 MHz, CDC13) 59.49 (s, 2H), 7.33 (dd, J = 1.8, 0.6, IH), 7.06 - 6.92 (m, 4H), 6.36 (d, J = 3.2, IH), 6.29 (dd, J = 3.3, 1.9, IH), 3.95 (q, J = 14.4, 2H), 3.78 - 3.64 (m, 2H), 3.57 (td, J = 12.3, 2.1, 2H),
[(3S)-3-[(4R)-2,2-dimethyloxan- 2.71 - 2.57 (m, IH), 2.52 (dd, J = 14.4, 8.1,
4-yl]-3-(4- IH), 2.30 - 2.10 (m, 2H), 1.94 - 1.71 (m, fluorophenyl)propyl] (furan-2- 2H), 1.66 (d, J = 12.8, IH), 1.23 - 0.96 (m, ylmethyl) amine 346.3 7H), 0.87 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) 58.53 (s, IH), 8.32 (s, IH), 7.17 (td, J = 8.1, 1.5, IH), 7.00 - 6.90 (m, 5H), 6.87 (d, J = 7.8, IH), 6.78 (t, J = 7.4, IH), 5.90 (s, 4H), 3.94
2-({ [(3S)-3-[(4R)-2,2- (dd, J = 41.8, 13.2, 2H), 3.71 (dd, J = 12.1, dimethyloxan-4-yl]-3-(4- 3.9, IH), 3.56 (td, J = 12.2, 2.0, IH), 2.63 fluorophenyl)propyl] amino } met
(s, IH), 2.54 (s, IH), 2.25 - 2.07 (m, 2H), hyl)phenol 372.3
1.90 - 1.66 (m, 2H), 1.61 (d, J = 12.8, IH), 1.22 - 0.94 (m, 7H), 0.86 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) 59.12 (s, IH), 8.99 (s, IH), 7.01 (d, J = 6.9, 4H), 3.75 (dd, J = 12.0, 3.8, IH), 3.60 (td, J = 12.3, 2.1, IH), 2.82 - 2.41 (m, 10H), 2.21
[(3S)-3-[(4R)-2,2-dimethyloxan- (t, J = 8.7, 2H), 1.98 (d, J = 13.2, 2H), 1.90
4-yl]-3-(4- - 1.72 (m, 2H), 1.67 (d, J = 14.2, 2H), 1.43 fluorophenyl)propyl] (thian-4- - 1.26 (m, 2H), 1.21 - 1.11 (m, IH), 1.05 ylmethyl) amine 380.3 (m, 6H), 0.88 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) 59.34 (s, 2H), 7.27 - 7.19 (m, 3H), 7.02 - 6.91 (m,
6H), 3.90 - 3.67 (m, 3H), 3.58 (td, J =
[(3S)-3-[(4R)-2,2-dimethyloxan- 12.2, 2.1, IH), 2.77 - 2.37 (m, 6H), 2.23 - 4-yl]-3-(4- 2.05 (m, 2H), 1.86 - 1.67 (m, 2H), 1.63 (d, fluorophenyl)propyl] [(4- J = 12.6, IH), 1.20 - 0.94 (m, 7H), 0.86 (t, fluorophenyl)methyl] amine 374.3 J = 12.8, IH).
IH NMR (400 MHz, CDC13) 59.25 (s, 2H), 7.52 (dt, J = 8.3, 4.2, IH), 7.37 (dd, J = 7.6, 1.3, IH), 7.31 - 7.13 (m, 3H), 7.08 - 6.88 (m, 4H), 4.17 - 3.96 (m, 2H), 3.73 (dd, J = 12.1, 4.0, IH), 3.65 - 3.51 (m,
[(2-bromophenyl)methyl] [(3S)- IH), 3.02 (s, 4H), 2.77 - 2.52 (m, 2H),
3-[(4R)-2,2- 2.31 - 2.14 (m, 2H), 1.93 - 1.70 (m, 2H), dimethyloxan-4-yl]-3-(4- 1.66 (d, J = 13.0, IH), 1.22 - 0.96 (m, 7H), fluorophenyl)propyl] amine 434.2 0.87 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) 59.35 (s, 2H), 7.48 - 7.42 (m, IH), 7.41 (s, IH), 7.21 - 7.14 (m, IH), 7.07 - 6.91 (m, 3H), 3.91 - 3.68 (m, 2H), 3.58 (td, J = 12.2, 2.1,
[(3-bromophenyl)methyl] [(3S)- IH), 2.89 (s, 5H), 2.59 (s, IH), 2.50 (s,
3-[(4R)-2,2- IH), 2.27 - 2.08 (m, 2H), 1.87 - 1.68 (m, dimethyloxan-4-yl]-3-(4- 2H), 1.63 (d, J = 12.7, IH), 1.23 - 0.95 (m, fluorophenyl)propyl] amine 434.2 7H), 0.92 - 0.78 (m, IH).
IH NMR (400 MHz, CDC13) 59.25 (s, 2H), 7.43 (d, J = 8.4, 2H), 7.11 (d, J = 8.4,
2H), 7.08 - 6.89 (m, 4H), 3.76 (dt, J =
[(4-bromophenyl)methyl] [(3S)- 10.5, 9.0, 3H), 3.58 (td, J = 12.3, 2.1, IH), 3-[(4R)-2,2-
3.31 (s, 4H), 2.57 (s, IH), 2.48 (s, IH), dimethyloxan-4-yl]-3-(4- 2.15 (ddd, J = 16.2, 11.5, 3.8, 2H), 1.84 - fluorophenyl)propyl] amine 434.2
1.68 (m, 2H), 1.63 (d, J = 13.0, IH), 1.24 - 0.96 (m, 7H), 0.93 - 0.79 (m, IH).
IH NMR (400 MHz, CDC13) 59.48 (s, 2H), 7.77 - 7.29 (m, 5H), 7.09 - 6.87 (m,
[(3S)-3-[(4R)-2,2-dimethyloxan- 5H), 4.86 (s, OH), 4.21 - 3.98 (m, 2H),
4-yl]-3-(4- 3.82 - 3.65 (m, IH), 3.65 - 3.47 (m, IH), fluorophenyl)propyl]({ [2- 3.13 - 2.87 (m, IH), 2.60 (ddd, J = 22.1, (trifluoromethyl)phenyl] methyl } 13.9, 8.8, 6H), 2.32 - 2.10 (m, 2H), 2.03
)amine 424.2 (dd, J = 12.4, 5.4, OH), 1.96 - 1
IH NMR (400 MHz, CDC13) 59.44 (s, IH), 7.71 - 7.48 (m, 2H), 7.49 - 7.37 (m, 2H), 7.09 - 6.89 (m, 4H), 3.88 (q, J = 13.3,
2H), 3.80 - 3.67 (m, IH), 3.58 (ddd, J =
[(3S)-3-[(4R)-2,2-dimethyloxan- 14.1, 10.7, 2.0, IH), 3.40 (s, 3H), 2.59 (d, J
4-yl]-3-(4- = 5.4, IH), 2.50 (s, IH), 2.25 - 2.08 (m, fluorophenyl)propyl]({ [3- 2H), 1.88 - 1.68 (m, 2H), 1.68 - 1.54 (m, (trifluoromethyl)phenyl] methyl } IH), 1.20 - 0.97 (m, 7H), 0.87 (dd, J =
)amine 424.2 23.4, 10.7, IH).
IH NMR (400 MHz, CDC13) 59.41 (s, IH), 7.69 - 7.42 (m, 2H), 7.38 (d, J = 8.0,
[(3S)-3-[(4R)-2,2-dimethyloxan- 2H), 7.09 - 6.87 (m, 4H), 4.01 - 3.50 (m,
4-yl]-3-(4- 7H), 2.59 (s, IH), 2.50 (s, IH), 2.18 (t, J = fluorophenyl)propyl]({ [4- 8.6, 2H), 1.86 - 1.69 (m, 2H), 1.63 (d, J = (trifluoromethyl)phenyl] methyl } 12.6, IH), 1.23 - 0.94 (m, 7H), 0.92 - 0.79
)amine 424.3 (m, IH).
IH NMR (400 MHz, CDC13) 59.49 (s, 2H), 7.22 - 7.12 (m, IH), 7.12 - 7.02 (m, 2H), 7.01 - 6.90 (m, 4H), 4.09 - 3.90 (m, 2H), 3.73 (dd, J = 12.1, 3.9, IH), 3.59 (td, J
[(2,3- = 12.3, 2.0, IH), 3.01 (s, 4H), 2.74 - 2.61 difluorophenyl)methyl] [(3S)-3- (m, IH), 2.53 (dd, J = 14.9, 7.3, IH), 2.21
[(4R)-2,2- (t, J = 8.8, 2H), 1.93 - 1.72 (m, 2H), 1.67 dimethyloxan-4-yl]-3-(4- (d, J = 13.0, IH), 1.23 - 0.97 (m, 7H), 0.87 fluorophenyl)propyl] amine 392.2 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) 59.48 (s, 2H), 7.31 (dd, J = 14.6, 8.3, IH), 7.04 -
[(2,4- 6.90 (m, 4H), 6.91 - 6.71 (m, 2H), 4.01 - difluorophenyl)methyl] [(3S)-3- 3.83 (m, 2H), 3.72 (dd, J = 11.9, 4.5, IH), [(4R)-2,2- 3.58 (dd, J = 12.2, 10.8, IH), 2.69 - 2.36 dimethyloxan-4-yl]-3-(4- (m, 5H), 2.20 (t, J = 8.8, 2H), 1.92 - 1.70 fluorophenyl)propyl] amine 392.2
(m, 2H), 1.65 (d, J = 12.9, IH), 1.27 - 0.94 (m, 7H), 0.87 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) 59.44 (s, IH), 7.12 - 6.89 (m, 6H), 4.06 - 3.86 (m,
[(2,5- 2H), 3.82 - 3.48 (m, 4H), 2.66 (td, J = difluorophenyl)methyl] [(3S)-3- 11.9, 5.5, IH), 2.60 - 2.47 (m, IH), 2.28 - [(4R)-2,2- 2.14 (m, 2H), 1.91 - 1.71 (m, 2H), 1.66 (d, dimethyloxan-4-yl]-3-(4- J = 13.0, IH), 1.21 - 0.97 (m, 7H), 0.87 (t, fluorophenyl)propyl] amine 392.3 J = 12.8, IH).
IH NMR (400 MHz, CDC13) 59.54 (s, 2H), 7.21 - 7.05 (m, 2H), 7.04 - 6.92 (m,
[(3,4- 4H), 3.90 - 3.67 (m, 3H), 3.58 (td, J = difluorophenyl)methyl] [(3S)-3- 12.2, 1.9, IH), 2.76 - 2.37 (m, 4H), 2.25 - [(4R)-2,2- 2.04 (m, 2H), 1.75 (td, J = 12.0, 6.0, 2H), dimethyloxan-4-yl]-3-(4- 1.63 (d, J = 12.9, IH), 1.20 - 0.95 (m, 7H), fluorophenyl)propyl] amine 392.3 0.86 (dd, J =
IH NMR (400 MHz, CDC13) 59.65 (s, IH), 7.09 - 6.93 (m, 4H), 6.91 - 6.82 (m, 2H), 6.77 (tt, J = 8.7, 2.1, IH), 3.84 (dd, J = 33.0, 13.3, 2H), 3.72 (dd, J = 12.0, 4.0,
[(3,5- IH), 3.57 (td, J = 12.2, 2.0, IH), 2.82 (s, difluorophenyl)methyl] [(3S)-3- 2H), 2.60 (td, J = 11.4, 5.3, IH), 2.49 (t, J
[(4R)-2,2- = 9.0, IH), 2.18 (dd, J = 17.1, 8.4, 2H), dimethyloxan-4-yl]-3-(4- 1.86 - 1.69 (m, 2H), 1.64 (d, J = 12.9, IH), fluorophenyl)propyl] amine 392.2 1.23 - 0.94 (m, 7H), 0.86 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) 59.53 (s, 2H), 7.15 - 6.87 (m, 6H), 4.05 - 3.87 (m, 2H), 3.81 - 3.68 (m, IH), 3.66 - 3.22 (m,
[(3S)-3-[(4R)-2,2-dimethyloxan- 3H), 2.72 - 2.59 (m, IH), 2.59 - 2.43 (m,
4-yl]-3-(4- IH), 2.20 (t, J = 8.8, 2H), 1.88 - 1.71 (m, fluorophenyl)propyl] [(2,3,4- 2H), 1.66 (d, J = 12.6, IH), 1.22 - 0.98 (m, trifluorophenyl)methyl] amine 410.2 7H), 0.87 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) 59.66 (s, 2H), 7.13 - 6.80 (m, 5H), 4.14 - 3.92 (m, 2H), 3.73 (dd, J = 12.0, 4.0, IH), 3.67 -
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.52 (m, IH), 3.10 - 2.42 (m, 5H), 2.22 (t,
4-yl]-3-(4- J = 8.8, 2H), 1.92 - 1.72 (m, 2H), 1.67 (d, J fluorophenyl)propyl] [(2,3,5- = 12.5, IH), 1.26 - 0.97 (m, 7H), 0.95 - trifluorophenyl)methyl] amine 410.2 0.81 (m, IH).
benzyl[(3S)-3-(3-bromo-2,6- IH NMR (400 MHz, CDC13) 5 9.60 (s,
452.2
difluorophenyl)-3-[(4R)- 2H), 7.34 (ddd, J = 8.8, 7.8, 5.7, IH), 7.23 2,2-dimethyloxan-4- (dtt, J = 9.8, 6.3, 3.1, 5H), 6.70 (td, J = 9.5, yl]propyl] amine 1.4, IH), 3.90 - 3.35 (m, 4H), 2.72 - 2.31
(m, 3H), 2.19 - 1.82 (m, 3H), 1.78 - 1.39 (m, 4H), 1.18 - 0.70 (m, 9H).
IH NMR (400 MHz, CDC13) δ 11.87 (s, IH), 7.53 - 7.09 (m, 5H), 6.98 (t, J = 8.0,
4H), 4.89 (s, 2H), 4.21 (t, J = 13.2, IH), benzyl[(3S)-3-[(4R)-2,2- 4.06 - 3.85 (m, IH), 3.82 - 3.70 (m, IH), dimethyloxan-4-yl]-3-(4- 3.67 - 3.50 (m, IH), 3.01 (t, J = 10.4, OH), fluorophenyl)propyl] methylamin 2.82 - 2.50 (m, 4H), 2.41 - 2.06 (m, 2H), e 370.3 2.04 - 1.60 (m, 3H), 1.32 - 0.64 (m, 9H).
IH NMR (400 MHz, CDC13) δ 10.66 (s, benzyl[(3S)-3-[(4R)-2,2- IH), 7.59 - 7.28 (m, 5H), 7.07 - 6.72 (m, dimethyloxan-4-yl]-3-(4- 4H), 4.57 - 4.24 (m, 4H), 4.20 - 3.43 (m, fluorophenyl)propyl]propan-2- 5H), 2.51 (ddt, J = 95.7, 49.1, 12.4, 2H), ylamine 398.3 2.17 - 1.45 (m, 4H), 1.38 - 0.68 (m, 15H).
IH NMR (400 MHz, CDC13) δ 10.72 (s, IH), 8.23 (s, 2H), 7.61 - 7.09 (m, 5H), 6.98 (dd, J = 6.9, 3.4, 4H), 4.13 (s, 2H), 3.87 - 3.52 (m, 2H), 3.10 - 2.69 (m, 3H), benzyl(butyl)[(3S)-3-[(4R)-2,2- 2.53 (dt, J = 47.9, 12.5, IH), 2.36 - 2.06 dimethyloxan-4-yl]-3- (m, 2H), 2.01 - 1.36 (m, 5H), 1.32 - 0.95 (4-fluorophenyl)propyl] amine 412.3 (m, 10H), 0.93 - 0.71 (m, 4H).
IH NMR (400 MHz, CDC13) δ 10.45 (s, IH), 7.72 - 7.11 (m, 7H), 6.98 (dd, J = 9.1, benzyl[(3S)-3-[(4R)-2,2- 7.3, 4H), 4.21 (dt, J = 26.6, 13.4, 2H), 3.70 dimethyloxan-4-yl]-3-(4- (dt, J = 24.5, 9.9, 2H), 3.00 - 2.73 (m, 2H), fluorophenyl)propyl] (2- 2.69 - 2.23 (m, 3H), 2.19 - 2.04 (m, IH), methylpropyl)amine 412.3 2.04 - 1.62 (m, 4H), 1.25 - 0.77 (m, 15H).
IH NMR (400 MHz, CDC13) δ 11.06 (s, IH), 7.55 - 7.18 (m, 5H), 7.11 - 6.85 (m, 6H), 4.26 - 4.02 (m, 2H), 3.89 - 3.52 (m, benzyl[(3S)-3-[(4R)-2,2- 2H), 3.12 - 2.67 (m, 3H), 2.52 (dt, J = dimethyloxan-4-yl]-3-(4- 24.2, 11.5, IH), 2.34 - 2.06 (m, 2H), 2.01 - fluorophenyl)propyl] (3- 1.65 (m, 3H), 1.60 - 1.26 (m, 3H), 1.23 - methylbutyl) amine 426.4 0.71 (m, 16H).
IH NMR (400 MHz, CDC13) δ 7.40 - 7.13
2-{benzyl[(3S)-3-[(4R)-2,2- (m, 6H), 7.09 - 6.83 (m, 4H), 3.75 (ddd, J dimethyloxan-4-yl]-3-(4- = 11.8, 5.0, 1.3, IH), 3.64 (dd, J = 12.4,
395.2
fluorophenyl)propyl] amino } acet 2.2, IH), 3.58 (d, J = 13.2, IH), 3.45 (d, J = onitrile 13.2, IH), 3.31 (q, J = 17.3, 2H), 2.49 - 2.23 (m, 3H), 2.17 - 1.95 (m, IH), 1.88 - 1.71 (m, 2H), 1.71 - 1.45 (m, 2H), 1.32 - 1.01 (m, 8H), 0.91 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 8.65 (s, IH), 7.91 (d, J = 7.2, IH), 7.69 (d, J = 8.1, IH), 7.18 - 7.09 (m, IH), 7.03 (dt, J = 28.1, 8.6, 2H), 4.83 (s, 2H), 4.14 (d, J = 13.5, IH), 3.97 (d, J = 13.5, IH), 3.75 (dd,
(lR)-l-[(4R)-2,2-dimethyloxan- J = 12.0, 4.1, IH), 3.59 (dd, J = 12.1, 10.2,
4-yl]-l-(4- IH), 3.00 (d, J = 12.2, IH), 2.71 (t, J = 9.6, fluorophenyl)-3-({ [6- IH), 2.60 - 2.30 (m, IH), 2.15 - 1.88 (m, (trifluoromethyl)pyridin- 3 - 2H), 1.63 (d, J = 12.5, IH), 1.38 - 1.21 (m, yl] methyl } amino)propan- 1 -ol 441.2 IH), 1.16 - 0.84 (m, 9H).
IH NMR (400 MHz, CDC13) δ 10.12 (s, benzyl[(3S)-3-(4-chloro-2- IH), 9.01 (s, IH), 8.62 (s, IH), 7.46 - 7.00 methoxyphenyl) -3 - [ (4S ) - (m, 5H), 6.78 (dt, J = 32.4, 4.8, 3H), 4.01 - 2,2-dimethyloxan-4- 3.25 (m, 7H), 2.51 (s, 3H), 2.04 (s, IH), yl]propyl] amine 402.3 1.90 - 1.40 (m, 3H), 1.22 - 0.74 (m, 9H).
IH NMR (400 MHz, CDC13) δ 9.06 (s, 2H), 8.55 (s, IH), 8.18 (s, IH), 7.40 - 7.07 (m, IH), 7.05 - 6.66 (m, 6H), 3.93 (dt, J = 18.0, 8.9, 2H), 3.69 (s, 3H), 3.65 - 3.30 (m,
2-({ [(3S)-3-(4-chloro-2- 2H), 2.60 (d, J = 31.4, 3H), 2.23 - 2.01 (m, methoxyphenyl)-3-[(4S)-2,2- IH), 1.83 (d, J = 8.7, 2H), 1.61 (d, J = 12.8, dimethyloxan-4- IH), 1.16 (d, J = 10.3, 6H), 1.10 - 0.77 (m, yl]propyl]amino}methyl)phenol 418.3 3H).
IH NMR (400 MHz, CDC13) δ 8.82 (s, IH), 8.29 (s, OH), 7.11 (t, J = 7.8, OH), 7.02
3-({ [(3S)-3-(4-chloro-2- - 6.72 (m, 2H), 6.65 (d, J = 7.5, OH), 4.04 methoxyphenyl)-3-[(4S)-2,2- - 3.38 (m, 2H), 2.67 (s, IH), 2.14 (d, J = dimethyloxan-4- 6.5, OH), 1.86 (s, IH), 1.65 (d, J = 12.6, yl]propyl]amino}methyl)phenol 418.2 OH), 1.29 - 0.83 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.53 (s, IH), 9.33 (s, IH), 7.51 - 7.31 (m, 2H),
[(3-bromophenyl)methyl] [(3S)- 7.26 - 7.07 (m, 2H), 6.86 (ddd, J = 30.5,
3-(4-chloro-2- 19.4, 4.9, 3H), 6.23 (s, IH), 3.97 - 3.65 (m, methoxyphenyl)-3-[(4S)-2,2- 5H), 3.65 - 3.33 (m, 2H), 2.82 - 2.34 (m, dimethyloxan-4- 3H), 2.08 (t, J = 11.4, IH), 1.83 (d, J = 9.0, yl]propyl] amine 480.2
2H), 1.63 (d, J = 12.9, IH), 1.32 - 0.77 (m, 9H).
IH NMR (400 MHz, CDC13) δ 9.43 (s, IH), 9.15 (s, IH), 8.13 (s, IH), 7.38 - 7.05
(m, 4H), 6.86 (ddd, J = 30.2, 19.3, 4.9,
[(3S)-3-(4-chloro-2- 3H), 3.97 - 3.65 (m, 5H), 3.62 - 3.33 (m, methoxyphenyl)-3-[(4S)-2,2- 2H), 2.55 (d, J = 37.0, 3H), 2.09 (dd, J = dimethyloxan-4-yl]propyl] [(3- 14.1, 8.0, IH), 1.82 (s, 2H), 1.64 (d, J = chlorophenyl)methyl] amine 436.2 12.8, IH), 1.25 - 0.79 (m, 9H).
IH NMR (400 MHz, CDC13) δ 9.24 (s, IH), 8.98 (s, IH), 8.16 (s, IH), 7.17 (t, J = 7.5, IH), 7.10 (d, J = 7.6, IH), 7.04 - 6.96 (m, 2H), 6.92 - 6.83 (m, 2H), 6.77 (d, J = 1.7, IH), 3.85 - 3.65 (m, 5H), 3.62 - 3.53 (m, IH), 3.52 - 3.40 (m, IH), 2.76 - 2.43
[(3S)-3-(4-chloro-2- (m, 3H), 2.26 (s, 3H), 2.08 (d, J = 12.2, methoxyphenyl)-3-[(4S)-2,2- IH), 1.82 (d, J = 9.1, 2H), 1.64 (d, J = 12.9, dimethyloxan-4-yl]propyl] [(3- IH), 1.15 (d, J = 13.2, 6H), 1.10 - 0.87 (m, methylphenyl)methyl] amine 416.3 3H).
IH NMR (400 MHz, CDC13) δ 9.58 (s, IH), 9.42 (s, IH), 7.61 - 7.51 (m, 2H), 7.44 (p, J = 7.7, 2H), 6.94 - 6.82 (m, 3H), 6.78 (d, J = 1.7, IH), 4.00 - 3.78 (m, 2H),
[(3S)-3-(4-chloro-2- 3.70 (s, 3H), 3.60 - 3.53 (m, IH), 3.46 (td, methoxyphenyl)-3-[(4S)-2,2- J = 12.1, 2.4, IH), 2.59 (dd, J = 41.2, 27.3, dimethyloxan-4-yl]propyl]({ [3- 3H), 2.09 (t, J = 11.3, IH), 1.82 (d, J = 9.5, (trifluoromethyl)phenyl] methyl } 2H), 1.62 (d, J = 12.9, IH), 1.14 (d, J =
)amine 470.2 12.3, 7H), 1.10 - 0.86 (m, 4H).
IH NMR (400 MHz, CDC13) δ 9.41 (s, IH), 9.30 (s, IH), 7.42 (d, J = 8.4, 2H), 7.12 (d, J = 8.4, 2H), 6.93 - 6.84 (m, 2H),
[(4-bromophenyl)methyl] [(3S)- 6.79 (s, IH), 3.84 - 3.64 (m, 5H), 3.62 -
3-(4-chloro-2- 3.53 (m, IH), 3.46 (td, J = 12.1, 2.4, IH), methoxyphenyl)-3-[(4S)-2,2- 2.73 - 2.38 (m, 3H), 2.05 (t, J = 11.3, IH), dimethyloxan-4- 1.81 (s, 2H), 1.62 (d, J = 12.8, IH), 1.23 - yl]propyl] amine 480.2 1.10 (m, 6H), 1.11 - 0.92 (m, 3H).
[(3S)-3-(4-chloro-2-
IH NMR (400 MHz, CDC13) δ 9.42 (s, methoxyphenyl)-3-[(4S)-2,2- IH), 9.24 (s, IH), 8.50 (s, IH), 7.56 (d, J = dimethyloxan-4-yl]propyl]({ [4- 8.1, 2H), 7.38 (d, J = 8.1, 2H), 6.94 - 6.82 (trifluoromethyl)phenyl] methyl }
(m, 2H), 6.78 (d, J = 1.5, IH), 3.88 (dd, J = )amine 470.2
33.3, 12.7, 2H), 3.69 (s, 3H), 3.63 - 3.53 (m, IH), 3.52 - 3.40 (m, IH), 2.57 (d, J =
44.2, 3H), 2.10 (t, J = 11.1, IH), 1.83 (d, J = 9.0, 2H), 1.63 (d, J = 12.8, IH), 1.23 - 1.11 (m, 6H), 1.10 - 0.86 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.61 - 8.61 (m, 3H), 7.67 (d, J = 7.6, IH), 7.52 (ddd, J = 21.8, 17.9, 7.3, 3H), 6.89 (dt, J = 8.2, 4.9,
2H), 6.79 (d, J = 1.7, IH), 4.14 (dd, J =
[(3S)-3-(4-chloro-2- 39.6, 13.3, 2H), 3.67 (d, J = 11.6, 3H), 3.63 methoxyphenyl)-3-[(4S)-2,2- - 3.54 (m, IH), 3.47 (td, J = 12.1, 2.2, IH), dimethyloxan-4-yl]propyl]({ [2- 2.69 (s, 3H), 2.17 (s, IH), 1.83 (s, 2H), (trifluoromethyl)phenyl] methyl } 1.65 (d, J = 12.7, IH), 1.16 (d, J = 11.3,
)amine 470.3 6H), 1.11 - 0.83 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.39 (s, IH), 9.22 (s, IH), 7.28 (dd, J = 5.0, 1.6, 3H), 7.25 - 7.18 (m, 2H), 6.84 (d, J = 7.5,
2H), 6.78 (d, J = 8.5, IH), 6.20 (s, OH), 3.80 (d, J = 12.9, IH), 3.76 - 3.65 (m, 5H), benzyl[(3S)-3-(4-chloro-2- 3.55 (tt, J = 7.8, 3.8, IH), 2.52 (d, J = 39.4, methoxyphenyl) -3 - [ (4R)- 3H), 2.08 (t, J = 11.4, IH), 1.86 (d, J = 9.4, 2,2-dimethyloxan-4- 2H), 1.63 (d, J = 12.6, IH), 1.19 - 0.94 (m, yl]propyl] amine 402.2 8H), 0.85 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 8.68 (s, IH), 8.37 (s, IH), 7.83 (s, 2H), 7.21 - 7.11 (m, IH), 6.99 - 6.88 (m, 2H), 6.87 - 6.80 (m, 2H), 6.80 - 6.72 (m, 2H), 3.92 (dd, J = 34.6, 12.7, 2H), 3.73 - 3.62 (m, 4H), 3.60 -
2-({ [(3S)-3-(4-chloro-2- 3.46 (m, IH), 2.56 (d, J = 34.8, 3H), 2.16 - methoxyphenyl)-3-[(4R)-2,2- 2.01 (m, IH), 1.84 (s, 2H), 1.58 (d, J = dimethyloxan-4- 12.2, IH), 1.13 - 0.92 (m, 8H), 0.83 (t, J = yl]propyl]amino}methyl)phenol 418.2 12.8, IH).
IH NMR (400 MHz, CDC13) δ 8.72 (d, J = 46.3, 3H), 8.43 (s, IH), 7.08 (t, J = 7.8, IH), 6.94 - 6.83 (m, 2H), 6.80 (s, 2H),
6.74 (d, J = 8.1, IH), 6.63 (d, J = 7.5, IH),
3-({ [(3S)-3-(4-chloro-2- 3.92 - 3.65 (m, 6H), 3.57 (t, J = 11.5, IH), methoxyphenyl)-3-[(4R)-2,2- 2.64 (s, 3H), 2.11 (s, IH), 1.89 (s, 2H), dimethyloxan-4- 1.63 (d, J = 12.3, IH), 1.19 - 0.95 (m, 8H), yl]propyl]amino}methyl)phenol 418.2 0.86 (t, J = 12.8, IH).
482.2
[(3-bromophenyl)methyl] [(3S)- IH NMR (400 MHz, CDC13) δ 10.64 (s, 3-(4-chloro-2- IH), 9.18 (s, IH), 8.79 (s, IH), 7.52 - 7.42 methoxyphenyl)-3-[(4R)-2,2- (m, IH), 7.39 (s, IH), 7.22 - 7.10 (m, 2H), dimethyloxan-4- 6.93 - 6.83 (m, 2H), 6.81 (d, J = 1.6, IH), yl]propyl] amine 3.89 (d, J = 10.6, IH), 3.84 - 3.68 (m, 5H),
3.59 (td, J = 12.2, 1.9, IH), 2.61 (s, 3H), 2.12 (d, J = 3.2, IH), 1.99 - 1.74 (m, 2H), 1.66 (d, J = 12.6, IH), 1.21 - 0.96 (m, 8H),
0.87 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) δ 9.42 (s, IH), 9.17 (s, IH), 8.10 (s, IH), 7.38 - 7.18 (m, 3H), 7.13 (d, J = 7.6, IH), 6.91 - 6.83 (m, 2H), 6.81 (d, J = 8.7, IH), 3.85 (d, J = 12.6, IH), 3.79 - 3.68 (m, 5H), 3.58 (td, J
[(3S)-3-(4-chloro-2- = 12.3, 2.0, IH), 2.55 (d, J = 40.6, 3H), methoxyphenyl)-3-[(4R)-2,2- 2.10 (t, J = 11.2, IH), 1.88 (d, J = 12.3, dimethyloxan-4-yl]propyl] [(3- 2H), 1.65 (d, J = 12.7, IH), 1.20 - 0.96 (m, chlorophenyl)methyl] amine 436.2 8H), 0.87 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 9.43 (s, IH), 9.31 (s, IH), 7.15 (t, J = 7.5, IH), 7.07 (d, J = 7.6, IH), 7.04 - 6.95 (m, 2H), 6.83 (dd, J = 11.5, 3.0, 2H), 6.78 (d, J = 8.2, IH), 4.52 (s, OH), 3.78 - 3.61 (m, 6H), 3.55 (td, J = 12.2, 2.1, IH), 2.56 (s, 2H),
[(3S)-3-(4-chloro-2- 2.42 (d, J = 14.5, IH), 2.30 - 2.17 (m, 3H), methoxyphenyl)-3-[(4R)-2,2- 2.08 (t, J = 11.6, IH), 1.86 (s, 2H), 1.63 (d, dimethyloxan-4-yl]propyl] [(3- J = 12.7, IH), 1.19 - 0.93 (m, 8H), 0.85 (t, methylphenyl)methyl] amine 416.3 J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 11.27 (s, IH), 9.14 (s, IH), 8.75 (s, IH), 7.61 (d, J = 6.6, IH), 7.52 (s, IH), 7.49 - 7.39 (m, 2H),
6.93 - 6.84 (m, 2H), 6.80 (d, J = 0.9, IH), 4.02 (d, J = 12.8, IH), 3.97 - 3.87 (m, IH),
[(3S)-3-(4-chloro-2- 3.78 (dd, J = 12.1, 4.1, IH), 3.71 (s, 3H), methoxyphenyl)-3-[(4R)-2,2- 3.65 - 3.54 (m, IH), 2.63 (s, 3H), 2.13 (d, J dimethyloxan-4-yl]propyl]({ [3- = 3.5, IH), 1.92 (dd, J = 32.3, 20.3, 2H), (trifluoromethyl)phenyl] methyl } 1.67 (d, J = 12.7, IH), 1.20 - 0.97 (m, 8H),
)amine 470.2 0.88 (t, J = 12.8, IH).
[(4-bromophenyl)methyl] [(3S)- IH NMR (400 MHz, CDC13) δ 9.35 (s,
3-(4-chloro-2- IH), 9.23 (s, IH), 7.84 (s, IH), 7.42 (d, J = methoxyphenyl)-3-[(4R)-2,2- 8.4, 2H), 7.11 (d, J = 8.4, 2H), 6.94 - 6.82
482.1
dimethyloxan-4- (m, 2H), 6.79 (d, J = 1.4, IH), 3.85 - 3.64 yl]propyl] amine (m, 6H), 3.56 (tt, J = 8.6, 4.3, IH), 2.57 (s,
2H), 2.46 (s, IH), 2.06 (t, J = 11.4, IH), 1.87 (d, J = 17.0, 2H), 1.63 (d, J = 12.6,
IH), 1.18 - 0.93 (m, 8H), 0.86 (t, J = 12.7,
IH).
IH NMR (400 MHz, CDC13) δ 9.39 (s, IH), 9.23 (s, IH), 9.02 (s, IH), 7.55 (d, J = 8.1, 2H), 7.37 (d, J = 8.1, 2H), 6.84 (d, J = 7.9, 2H), 6.78 (s, IH), 3.87 (dd, J = 29.3,
[(3S)-3-(4-chloro-2- 12.8, 2H), 3.78 - 3.66 (m, 4H), 3.57 (td, J methoxyphenyl)-3-[(4R)-2,2- = 12.2, 1.9, IH), 2.56 (d, J = 41.6, 3H), dimethyloxan-4-yl]propyl]({ [4- 2.10 (t, J = 11.0, IH), 1.91 (d, J = 7.8, 2H), (trifluoromethyl)phenyl] methyl } 1.64 (d, J = 12.6, IH), 1.20 - 0.95 (m, 8H),
)amine 470.2 0.86 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 9.49 (s, IH), 9.01 (s, IH), 7.91 (s, IH), 7.66 (d, J = 7.5, IH), 7.59 (d, J = 7.5, IH), 7.49 (dt, J = 15.0, 7.1, 2H), 6.97 - 6.83 (m, 2H), 6.79 (s,
[(3S)-3-(4-chloro-2- IH), 4.13 (dd, J = 34.7, 13.9, 2H), 3.79 - methoxyphenyl)-3-[(4R)-2,2- 3.64 (m, 4H), 3.56 (tt, J = 13.8, 6.9, IH), dimethyloxan-4-yl]propyl]({ [2- 2.67 (d, J = 6.8, 3H), 2.29 - 2.10 (m, IH), (trifluoromethyl)phenyl] methyl } 1.89 (s, 2H), 1.66 (d, J = 12.8, IH), 1.22 - )amine 470.3 0.95 (m, 8H), 0.85 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) δ 9.04 (s, 2H), 8.38 (s, 2H), 7.38 - 7.28 (m, 3H), 7.27 - 7.19 (m, 3H), 6.62 (dd, J = 8.0, 6.5, 2H), 3.86 (dd, J = 35.0, 13.0, 2H), 3.69 - benzyl[(3S)-3-[(4S)-2,2- 3.58 (m, IH), 3.48 (td, J = 12.1, 2.5, IH), dimethyloxan-4-yl]-3- 2.58 (d, J = 32.0, 2H), 2.14 (t, J = 8.7, 2H), (3,4,5- 1.82 - 1.62 (m, 2H), 1.58 (d, J = 12.9, IH), trifluorophenyl)propyl] amine 392.2 1.16 (d, J = 11.3, 6H), 1.09 - 0.88 (m, 3H).
IH NMR (400 MHz, CDC13) δ 11.76 (s, 3H), 10.11 (s, 2H), 9.15 (s, IH), 8.60 (d, J = 5.4, IH), 8.51 (d, J = 8.0, IH), 7.86 (dd, J = 7.9, 5.8, IH), 6.72 (dd, J = 7.9, 6.5, 2H), 4.40 - 4.22 (m, 2H), 3.61 (dd, J = 12.0, 3.5, IH), 3.48 (td, J = 12.1, 2.2, IH), 2.92 (td, J
[(3S)-3-[(4S)-2,2-dimethyloxan- = 11.6, 5.2, IH), 2.86 - 2.70 (m, IH), 2.22
4-yl]-3-(3,4,5- (t, J = 8.4, 2H), 1.99 - 1.94 (m, IH), 1.87 trifluorophenyl)propyl] (pyridin- (td, J = 12.5, 6.0, IH), 1.78 - 1.66 (m, IH), 3 -ylmethyl) amine 393.2
1.61 (d, J = 12.9, IH), 1.14 (d, J = 4.1, 6H), 1.11 - 0.90 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.33 (s, 2H), 8.72 (s, 3H), 8.01 - 7.85 (m, IH), 7.70 (d, J = 8.1, IH), 6.70 (dd, J = 7.7, 6.5, 2H), 4.11 (q, J = 13.4, 2H), 3.67 (dd, J = 12.1, 3.5, IH), 3.52 (td, J = 12.1, 2.3, IH),
[(3S)-3-[(4S)-2,2-dimethyloxan- 2.80 (td, J = 11.9, 5.3, IH), 2.67 (dd, J = 4-yl]-3-(3,4,5- 11.1, 7.3, IH), 2.21 (t, J = 8.5, 2H), 1.90 - trifluorophenyl)propyl]({ [6- 1.70 (m, 2H), 1.63 (d, J = 12.9, IH), 1.18 (trifluoromethyl)pyridin- 3 - (d, J = 10.6, 6H), 1.03 (tt, J = 12.7, 10.0,
71 yl] methyl } ) amine 461.2 3H).
IH NMR (400 MHz, CDC13) δ 9.19 (s, 2H), 8.76 (s, IH), 7.32 (dd, J = 5.1, 1.1, IH), 7.06 (d, J = 2.7, IH), 6.97 (dd, J = 5.1, 3.6, IH), 6.67 (dd, J = 7.9, 6.5, 2H), 4.25 - 3.98 (m, 2H), 3.72 - 3.57 (m, IH), 3.49 (td,
[(3S)-3-[(4S)-2,2-dimethyloxan- J = 12.1, 2.4, IH), 2.64 (d, J = 36.6, 2H),
4-yl]-3-(3,4,5- 2.17 (dd, J = 18.0, 9.2, 2H), 1.87 - 1.65 (m, trifluorophenyl)propyl] (thiophen 2H), 1.60 (d, J = 12.9, IH), 1.17 (d, J =
72 -2- ylmethyl) amine 398.2 10.1, 6H), 1.13 - 0.87 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.18 (s, 2H), 7.70 (s, IH), 7.31 (dd, J = 4.6, 2.6, 2H), 7.02 (dd, J = 4.2, 2.1, IH), 6.65 (dd, J = 8.0, 6.5, 2H), 3.95 (q, J = 13.5, 2H), 3.70
[(3S)-3-[(4S)-2,2-dimethyloxan- - 3.58 (m, IH), 3.48 (td, J = 12.1, 2.4, IH),
4-yl]-3-(3,4,5- 2.58 (d, J = 31.3, 2H), 2.24 - 2.06 (m, 2H), trifluorophenyl)propyl] (thiophen 1.83 - 1.64 (m, 2H), 1.59 (d, J = 12.9, IH),
73 - 3 - ylmethyl) amine 398.2 1.16 (d, J = 10.3, 6H), 1.12 - 0.89 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.21 (s, 2H), 7.55 (s, IH), 7.36 - 7.28 (m, 3H), 7.23 (dd, J = 6.5, 3.1, 3H), 6.61 (dd, J = 8.0, 6.4, 2H), 3.77 (ddd, J = 20.9, 16.0, 8.4, benzyl[(3S)-3-[(4R)-2,2- 3H), 3.57 (td, J = 12.3, 2.1, IH), 2.65 - dimethyloxan-4-yl]-3- 2.43 (m, 2H), 2.15 (t, J = 8.8, 2H), 1.82 - (3,4,5- 1.54 (m, 3H), 1.17 - 0.96 (m, 8H), 0.87 (t,
74 trifluorophenyl)propyl] amine 392.3 J = 12.7, IH).
[(3S)-3-[(4R)-2,2-dimethyloxan-
IH NMR (400 MHz, CDC13) δ 11.56 (s,
4-yl]-3-(3,4,5- 4H), 9.13 (s, IH), 8.61 (d, J = 5.2, IH), trifluorophenyl)propyl] (pyridin- 8.48 (d, J = 8.1, IH), 7.83 (dd, J = 7.9, 5.7,
75 3 -ylmethyl) amine 393.2
IH), 6.73 (dd, J = 7.9, 6.5, 2H), 4.44 - 4.17 (m, 2H), 3.71 (dd, J = 11.9, 4.1, IH), 3.58
(dd, J = 12.2, 10.3, IH), 2.91 (dt, J = 11.4, 5.9, IH), 2.83 - 2.68 (m, IH), 2.42 - 2.11 (m, 2H), 2.00 - 1.54 (m, 3H), 1.28 - 0.98 (m, 8H), 0.90 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 9.75 (s, IH), 8.69 (d, J = 1.8, IH), 7.91 (dd, J = 8.1,
I.9, IH), 7.67 (d, J = 8.1, IH), 6.69 (dd, J = 7.9, 6.4, 2H), 4.96 (s, IH), 4.17 - 3.94 (m, 2H), 3.71 (dd, J = 12.1, 3.8, IH), 3.58 (td, J
[(3S)-3-[(4R)-2,2-dimethyloxan- = 12.2, 2.1, 2H), 3.44 (s, 3H), 2.73 (td, J =
4-yl]-3-(3,4,5- I I.8, 5.3, IH), 2.62 (td, J = 11.4, 4.7, IH), trifluorophenyl)propyl]({ [6- 2.30 - 2.12 (m, 2H), 1.91 - 1.71 (m, 2H), (trifluoromethyl)pyridin- 3 - 1.66 (d, J = 12.8, IH), 1.21 - 0.97 (m, 8H),
76 yl] methyl } ) amine 461.2 0.89 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 9.26 (s, 2H), 7.65 (s, IH), 7.31 (dd, J = 5.1, 1.1, IH), 7.06 (dd, J = 3.5, 0.8, IH), 6.96 (dd, J = 5.1, 3.6, IH), 6.65 (dd, J = 8.0, 6.4, 2H), 4.11 (q, J = 14.0, 2H), 3.75 (dd, J = 12.1,
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.7, IH), 3.58 (td, J = 12.3, 2.1, IH), 2.63
4-yl]-3-(3,4,5- (d, J = 32.8, 2H), 2.27 - 2.09 (m, 2H), 1.87 trifluorophenyl)propyl] (thiophen - 1.57 (m, 3H), 1.23 - 0.97 (m, 8H), 0.89
77 -2- ylmethyl) amine 398.1 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 9.10 (s, 2H), 8.34 (s, IH), 7.36 - 7.27 (m, 2H), 7.06 - 6.94 (m, IH), 6.64 (dd, J = 8.0, 6.4, 2H), 3.95 (q, J = 13.4, 2H), 3.75 (dd, J =
[(3S)-3-[(4R)-2,2-dimethyloxan- 12.1, 3.7, IH), 3.58 (td, J = 12.3, 2.1, IH),
4-yl]-3-(3,4,5- 2.58 (d, J = 31.3, 2H), 2.27 - 2.07 (m, 2H), trifluorophenyl)propyl] (thiophen 1.82 - 1.54 (m, 3H), 1.20 - 0.97 (m, 8H),
78 - 3 - ylmethyl) amine 398.1 0.89 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 7.12 (td, J = 7.9, 1.6, IH), 7.05 (dd, J = 8.3, 6.7, IH),
6.91 (dd, J = 7.4, 1.3, IH), 6.79 (dd, J =
8.1, 1.0, IH), 6.72 (td, J = 7.4, 1.1, IH),
2-({ [(3R)-3-[(4S)-2,2-dimethyl- 6.65 - 6.50 (m, 2H), 4.25 (dd, J = 15.5, 6.7, l,3-dioxolan-4-yl]-3-
IH), 3.92 - 3.79 (m, 2H), 3.79 - 3.73 (m, (4-fluoro-2- 3H), 3.67 (dd, J = 8.3, 6.1, IH), 3.41 (dd, J methoxyphenyl)propyl] amino } m
= 8.2, 7.1, IH), 3.13 (d, J = 6.1, IH), 2.58 -
79 ethyl)phenol 390.2
2.39 (m, 2H), 2.30 - 2.15 (m, IH), 1.83 (dd, J = 11.2, 5.8, IH), 1.41 (d, J = 5.7,
3H), 1.34 (s, 3H).
IH NMR (400 MHz, CDC13) δ 7.15 (t, J = 7.5, IH), 7.09 - 6.96 (m, 4H), 6.57 (ddd, J = 13.4, 9.8, 2.5, 2H), 4.26 (dd, J = 15.4, 6.7, IH), 3.80 - 3.71 (m, 3H), 3.70 - 3.64
[(3R)-3-[(4S)-2,2-dimethyl-l,3- (m, 2H), 3.64 - 3.55 (m, IH), 3.43 (dd, J = dioxolan-4-yl]-3-(4- 8.2, 7.1, IH), 3.16 (t, J = 7.6, IH), 2.53 - fluoro-2- 2.42 (m, 2H), 2.30 (s, 3H), 2.20 (dtd, J = methoxyphenyl)propyl] [(3- 12.1, 7.8, 4.3, IH), 1.90 - 1.76 (m, IH),
80 methylphenyl)methyl] amine 388.3 1.40 (d, J = 6.4, 3H), 1.34 (s, 3H).
IH NMR (400 MHz, CDC13) δ 7.22 - 7.07 (m, 2H), 6.91 (d, J = 7.4, IH), 6.79 (dd, J = 8.1, 0.9, IH), 6.72 (td, J = 7.4, 1.1, IH), 6.67 - 6.52 (m, 2H), 4.28 (dt, J = 7.3, 6.1,
2-({ [(3S)-3-[(4S)-2,2-dimethyl- IH), 3.93 (dd, J = 8.2, 6.2, IH), 3.87 (d, J = l,3-dioxolan-4-yl]-3- 6.4, 2H), 3.80 - 3.69 (m, 3H), 3.53 - 3.43 (4-fluoro-2- (m, IH), 3.35 (dt, J = 8.8, 5.9, IH), 2.60 - methoxyphenyl)propyl] amino } m 2.39 (m, 2H), 1.99 - 1.81 (m, 2H), 1.29 (s,
81 ethyl)phenol 390.2 3H), 1.25 (d, J = 7.1, 3H).
IH NMR (400 MHz, CDC13) δ 7.22 - 7.11 (m, 2H), 7.06 - 6.95 (m, 3H), 6.67 - 6.50 (m, 2H), 4.29 (dt, J = 7.2, 6.0, IH), 3.93
[(3S)-3-[(4S)-2,2-dimethyl-l,3- (dd, J = 8.1, 6.2, IH), 3.78 - 3.70 (m, 3H), dioxolan-4-yl]-3-(4- 3.63 (q, J = 13.0, 2H), 3.53 - 3.46 (m, IH), fluoro-2- 3.34 (d, J = 6.2, IH), 2.46 (t, J = 7.1, 2H), methoxyphenyl)propyl] [(3- 2.30 (s, 3H), 1.88 (dd, J = 14.6, 7.4, 2H),
82 methylphenyl)methyl] amine 388.3 1.28 (s, 3H), 1.24 (s, 3H).
IH NMR (400 MHz, CDC13) δ 7.13 - 6.95 (m, 2H), 6.71 - 6.43 (m, 5H), 5.30 (d, J = 19.8, 2H), 4.71 (s, 2H), 4.24 (dd, J = 15.3, 6.7, IH), 3.78 - 3.68 (m, 3H), 3.65 (dd, J = 8.3, 6.1, IH), 3.53 (dd, J = 25.7, 12.6, 2H),
3-({ [(3R)-3-[(4S)-2,2-dimethyl- 3.40 (dd, J = 8.2, 7.2, IH), 3.11 (s, IH), l,3-dioxolan-4-yl]-3- 2.59 - 2.36 (m, 2H), 2.29 - 2.13 (m, IH), (4-fluoro-2- 2.06 - 1.95 (m, IH), 1.87 (dd, J = 14.4, 9.1, methoxyphenyl)propyl] amino } m IH), 1.38 (d, J = 4.9, 3H), 1.30 (d, J = 15.3,
83 ethyl)phenol 390.2 3H).
[(3-bromophenyl)methyl] [(3R)- IH NMR (400 MHz, CDC13) δ 7.56 - 7.29
84 452.1
3-[(4S)-2,2-dimethyl- (m, 3H), 7.30 - 7.15 (m, IH), 7.16 - 6.99 l,3-dioxolan-4-yl]-3-(4-fluoro-2- (m, 3H), 6.58 (ddd, J = 13.2, 9.4, 2.5, 2H), methoxyphenyl)propyl] amine 4.64 (s, IH), 4.25 (dd, J = 15.2, 6.8, IH),
3.80 - 3.73 (m, 3H), 3.67 (dd, J = 7.7, 5.6, 2H), 3.59 (d, J = 13.5, IH), 3.42 (dd, J = 8.2, 7.1, IH), 3.16 (s, IH), 2.44 (dd, J = 12.5, 6.2, 2H), 2.26 - 2.11 (m, IH), 1.89 - 1.74 (m, IH), 1.74 - 1.51 (m, IH), 1.41 (d, J = 5.6, 3H), 1.33 (s, 3H).
IH NMR (400 MHz, CDC13) δ 7.30 - 7.13 (m, 3H), 7.12 - 6.99 (m, 2H), 6.57 (ddd, J
= 13.3, 9.5, 2.5, 2H), 4.25 (dd, J = 15.5, 6.8, IH), 3.76 (d, J = 3.9, 3H), 3.71 - 3.55
[(3-chlorophenyl)methyl] [(3R)- (m, 3H), 3.42 (dd, J = 8.2, 7.1, IH), 3.16 (t,
3-[(4S)-2,2-dimethyl- J = 7.5, IH), 2.50 - 2.37 (m, 2H), 2.27 - l,3-dioxolan-4-yl]-3-(4-fluoro-2- 2.08 (m, IH), 1.93 - 1.73 (m, IH), 1.41 (d,
85 methoxyphenyl)propyl] amine 408.2 J = 5.4, 4H), 1.34 (s, 3H).
IH NMR (400 MHz, CDC13) δ 7.67 - 7.31 (m, 7H), 7.05 (dd, J = 8.3, 6.7, IH), 6.57 (ddd, J = 13.3, 9.4, 2.5, 2H), 4.72 (s, IH),
[(3R)-3-[(4S)-2,2-dimethyl-l,3- 4.26 (dd, J = 15.4, 6.7, IH), 3.81 - 3.72 (m, dioxolan-4-yl]-3-(4- 4H), 3.72 - 3.60 (m, 2H), 3.42 (dd, J = 8.2, fluoro-2- 7.1, IH), 3.16 (t, J = 7.7, IH), 2.53 - 2.39 methoxyphenyl)propyl]({ [3- (m, 2H), 2.20 (dtd, J = 12.1, 7.8, 4.3, IH), (trifluoromethyl)phenyl] methyl } 1.92 - 1.65 (m, 2H), 1.40 (d, J = 5.3, 3H),
86 )amine 442.3 1.33 (s, 3H).
IH NMR (400 MHz, CDC13) δ 7.52 - 7.32 (m, 2H), 7.25 - 6.94 (m, 4H), 6.57 (ddd, J = 13.4, 9.6, 2.5, 2H), 4.62 (s, OH), 4.25 (dd, J = 15.4, 6.8, IH), 3.82 - 3.71 (m, 3H), 3.71 - 3.51 (m, 3H), 3.42 (dd, J = 8.2,
[(4-bromophenyl)methyl] [(3R)- 7.1, IH), 3.15 (d, J = 9.0, IH), 2.51 - 2.37
3-[(4S)-2,2-dimethyl- (m, 2H), 2.18 (dtd, J = 12.1, 7.8, 4.3, IH), l,3-dioxolan-4-yl]-3-(4-fluoro-2- 1.91 - 1.72 (m, IH), 1.70 - 1.47 (m, IH),
87 methoxyphenyl)propyl] amine 452.2 1.40 (d, J = 6.0, 3H), 1.33 (s, 3H).
IH NMR (400 MHz, CDC13) δ 7.16 (dd, J
3-({ [(3S)-3-[(4S)-2,2-dimethyl- = 8.4, 6.8, IH), 7.07 (t, J = 7.8, IH), 6.74 - l,3-dioxolan-4-yl]-3- 6.43 (m, 5H), 4.26 (dd, J = 13.2, 6.1, 2H), (4-fluoro-2- 3.90 (dd, J = 8.1, 6.2, IH), 3.78 - 3.69 (m, methoxyphenyl)propyl] amino } m
3H), 3.64 - 3.38 (m, 3H), 3.30 (d, J = 6.1,
88 ethyl)phenol 390.2
IH), 2.48 (t, J = 7.2, 2H), 1.92 (dt, J = 14.6, 6.9, 2H), 1.40 - 1.13 (m, 7H).
IH NMR (400 MHz, CDC13) δ 7.56 - 7.29 (m, 3H), 7.29 - 7.03 (m, 5H), 6.70 - 6.47 (m, 2H), 4.65 (s, IH), 4.28 (dt, J = 7.3, 6.0, IH), 3.93 (dd, J = 8.1, 6.2, IH), 3.76 (d, J = 5.2, 3H), 3.62 (dd, J = 30.4, 13.5, 2H), 3.54
[(3-bromophenyl)methyl] [(3S)- - 3.45 (m, IH), 3.39 - 3.26 (m, IH), 2.51 -
3-[(4S)-2,2-dimethyl- 2.33 (m, 2H), 1.87 (dt, J = 13.8, 4.2, 2H), l,3-dioxolan-4-yl]-3-(4-fluoro-2- 1.49 (d, J = 39.4, 2H), 1.28 (s, 3H), 1.24 (s,
89 methoxyphenyl)propyl] amine 452.2 3H).
IH NMR (400 MHz, CDC13) δ 7.39 - 7.01 (m, 7H), 6.69 - 6.49 (m, 2H), 4.65 (s, IH), 4.28 (dt, J = 7.3, 6.0, IH), 3.93 (dd, J = 8.1, 6.2, IH), 3.75 (d, J = 5.4, 3H), 3.63 (dd, J =
[(3-chlorophenyl)methyl] [(3S)- 31.0, 13.5, 2H), 3.53 - 3.44 (m, IH), 3.41 -
3-[(4S)-2,2-dimethyl- 3.28 (m, IH), 2.50 - 2.35 (m, 2H), 1.87 (dt, l,3-dioxolan-4-yl]-3-(4-fluoro-2- J = 13.8, 4.3, 2H), 1.49 (s, 2H), 1.29 (d, J =
90 methoxyphenyl)propyl] amine 408.2 8.1, 3H), 1.24 (s, 3H).
IH NMR (400 MHz, CDC13) δ 7.42 (ddd, J = 17.1, 15.8, 8.6, 4H), 7.18 (dd, J = 8.5, 6.8, IH), 6.68 - 6.51 (m, 2H), 4.29 (dt, J =
[(3S)-3-[(4S)-2,2-dimethyl-l,3- 7.3, 6.0, IH), 3.93 (dd, J = 8.1, 6.2, IH), dioxolan-4-yl]-3-(4- 3.83 - 3.62 (m, 5H), 3.57 - 3.45 (m, IH), fluoro-2- 3.44 _ 3.24 (m, IH), 2.54 - 2.37 (m, 2H), methoxyphenyl)propyl]({ [3- 1.88 (dt, J = 13.8, 7.0, 2H), 1.42 (d, J = (trifluoromethyl)phenyl] methyl } 16.3, IH), 1.29 (d, J = 6.1, 3H), 1.24 (s,
91 )amine 442.2 3H).
IH NMR (400 MHz, CDC13) δ 7.53 - 7.33 (m, 3H), 7.27 - 7.13 (m, 2H), 7.13 - 7.03 (m, 2H), 6.68 - 6.51 (m, 2H), 4.62 (s, IH), 4.28 (dt, J = 7.2, 6.0, IH), 3.92 (dd, J = 8.1, 6.2, IH), 3.79 - 3.69 (m, 3H), 3.69 - 3.54
[(4-bromophenyl)methyl] [(3S)- (m, 2H), 3.53 - 3.44 (m, IH), 3.38 - 3.26
3-[(4S)-2,2-dimethyl- (m, IH), 2.43 (dd, J = 10.3, 4.3, 2H), 1.94 l,3-dioxolan-4-yl]-3-(4-fluoro-2- - 1.81 (m, 2H), 1.52 (s, 2H), 1.28 (s, 3H),
92 methoxyphenyl)propyl] amine 452.2 1.25 (d, J = 7.7, 3H).
benzyl[(3S)-3-[(4R)-2,2-
IH NMR (400 MHz, CDC13) δ 7.38 - 7.14 dimethyl- 1 ,3-dioxolan-4- (m, 4H), 7.06 (dd, J = 8.3, 6.8, IH), 6.57 yl]-3-(4-fluoro-2- (ddd, J = 13.4, 9.8, 2.4, 2H), 4.26 (dd, J =
93 methoxyphenyl)propyl] amine 374.3
15.2, 6.8, IH), 3.85 - 3.58 (m, 6H), 3.50 - 3.36 (m, IH), 3.16 (s, IH), 2.48 (dd, J =
10.5, 4.4, 2H), 2.30 - 2.11 (m, IH), 1.82 (ddd, J = 32.9, 17.5, 10.8, 3H), 1.41 (s, 3H), 1.33 (s, 3H), 0.93 - 0.70 (m, IH).
IH NMR (400 MHz, CDC13) δ 7.44 - 7.28 (m, 2H), 7.17 - 6.96 (m, 3H), 6.58 (ddd, J
= 13.2, 9.4, 2.5, 2H), 4.25 (dd, J = 15.4, 6.7, IH), 3.83 - 3.73 (m, 3H), 3.65 (ddd, J
= 33.0, 19.1, 8.3, 3H), 3.42 (dd, J = 8.2,
[(3-bromophenyl)methyl] [(3S)- 7.1, IH), 3.16 (s, IH), 2.52 - 2.35 (m, 2H),
3-[(4R)-2,2-dimethyl- 2.27 - 2.12 (m, IH), 1.92 - 1.72 (m, IH), l,3-dioxolan-4-yl]-3-(4-fluoro-2- 1.52 (t, J = 9.4, 2H), 1.41 (s, 3H), 1.34 (s,
94 methoxyphenyl)propyl] amine 452.2 3H).
IH NMR (400 MHz, CDC13) δ 7.29 - 7.14 (m, 4H), 7.13 - 6.97 (m, 2H), 6.58 (ddd, J = 13.3, 9.4, 2.5, 2H), 4.25 (dd, J = 15.4, 6.8, IH), 3.82 - 3.73 (m, 3H), 3.72 - 3.53
[(3-chlorophenyl)methyl] [(3S)- (m, 3H), 3.42 (dd, J = 8.2, 7.1, IH), 3.16
3-[(4R)-2,2-dimethyl- (s, IH), 2.44 (dd, J = 7.6, 6.7, 2H), 2.19 l,3-dioxolan-4-yl]-3-(4-fluoro-2- (dtd, J = 12.1, 7.8, 4.3, IH), 1.92 - 1.73
95 methoxyphenyl)propyl] amine 408.2 (m, IH), 1.60 - 1.13 (m, 9H).
IH NMR (400 MHz, CDC13) δ 7.35 - 7.06 (m, 6H), 6.68 - 6.40 (m, 2H), 4.28 (dd, J = 13.3, 6.0, IH), 3.92 (dd, J = 8.1, 6.2, IH), 3.81 - 3.70 (m, 3H), 3.70 - 3.58 (m, 2H), benzyl[(3R)-3-[(4R)-2,2- 3.49 (t, J = 7.8, IH), 3.34 (dd, J = 13.8, 7.4, dimethyl- 1 ,3-dioxolan-4- IH), 2.45 (t, J = 7.2, 2H), 1.86 (dd, J = yl]-3-(4-fluoro-2- 14.4, 7.5, 2H), 1.33 (s, IH), 1.25 (d, J =
96 methoxyphenyl)propyl] amine 374.2 16.8, 6H).
IH NMR (400 MHz, CDC13) δ 7.23 - 7.07 (m, 2H), 6.91 (d, J = 7.4, IH), 6.82 - 6.67 (m, 2H), 6.66 - 6.47 (m, 2H), 4.28 (dt, J =
2-({ [(3R)-3-[(4R)-2,2-dimethyl- 7.2, 6.0, IH), 3.93 (dd, J = 8.1, 6.2, IH), l,3-dioxolan-4-yl]-3- 3.86 (s, 2H), 3.77 (d, J = 6.1, 3H), 3.53 - (4-fluoro-2- 3.43 (m, IH), 3.35 (dd, J = 6.2, 2.7, IH), methoxyphenyl)propyl] amino } m 2.61 - 2.37 (m, 2H), 1.95 - 1.84 (m, 2H),
97 ethyl)phenol 390.2 1.29 (s, 3H), 1.25 (d, J = 6.8, 3H).
[(3-bromophenyl)methyl] [(3R)- IH NMR (400 MHz, CDC13) δ 7.38 (s,
3-[(4R)-2,2-dimethyl- IH), 7.33 (td, J = 4.7, 2.0, IH), 7.21 - 7.05
98 452.2
l,3-dioxolan-4-yl]-3-(4-fluoro-2- (m, 3H), 6.67 - 6.50 (m, 2H), 4.29 (dt, J = methoxyphenyl)propyl] amine 7.3, 6.0, IH), 3.93 (dd, J = 8.1, 6.2, IH),
3.76 (d, J = 4.6, 3H), 3.63 (dd, J = 30.0, 13.5, 2H), 3.53 - 3.44 (m, IH), 3.40 - 3.28 (m, IH), 2.51 - 2.38 (m, 2H), 1.87 (dt, J = 13.8, 4.2, 2H), 1.28 (s, 4H), 1.25 (d, J =
8.2, 4H).
IH NMR (400 MHz, CDC13) δ 7.28 - 7.12 (m, 4H), 7.12 - 7.01 (m, IH), 6.68 - 6.50 (m, 2H), 4.29 (dt, J = 7.2, 6.0, IH), 3.93
(dd, J = 8.1, 6.2, IH), 3.81 - 3.73 (m, 3H),
[(3-chlorophenyl)methyl] [(3R)- 3.63 (dd, J = 30.6, 13.5, 2H), 3.50 (t, J =
3-[(4R)-2,2-dimethyl- 7.8, IH), 3.40 - 3.27 (m, IH), 2.51 - 2.36 l,3-dioxolan-4-yl]-3-(4-fluoro-2- (m, 2H), 1.87 (dt, J = 13.8, 4.2, 2H), 1.40 -
99 methoxyphenyl)propyl] amine 408.2 1.27 (m, 4H), 1.27 - 1.20 (m, 3H).
IH NMR (400 MHz, CDC13) δ 7.15 (t, J =
7.4, IH), 7.12 - 6.94 (m, 4H), 6.57 (ddd, J = 13.4, 9.9, 2.4, 2H), 4.26 (dd, J = 15.2,
6.7, IH), 3.75 (d, J = 6.2, 3H), 3.71 - 3.52
[(3S)-3-[(4R)-2,2-dimethyl-l,3- (m, 3H), 3.42 (dd, J = 8.2, 7.1, IH), 3.16 dioxolan-4-yl]-3-(4- (s, IH), 2.57 - 2.39 (m, 2H), 2.35 - 2.08 fluoro-2- (m, 4H), 2.00 (s, IH), 1.83 (dd, J = 10.8, methoxyphenyl)propyl] [(3- 5.7, IH), 1.60 (s, 2H), 1.41 (s, 3H), 1.35 (d,
100 methylphenyl)methyl] amine 388.3 J = 11.0, 3H).
IH NMR (400 MHz, CDC13) δ 7.42 (ddd, J = 19.6, 15.8, 8.4, 4H), 7.05 (dd, J = 8.3,
[(3S)-3-[(4R)-2,2-dimethyl-l,3- 6.8, IH), 6.57 (ddd, J = 13.2, 9.5, 2.4, 2H), dioxolan-4-yl]-3-(4- 4.26 (dd, J = 15.1, 6.8, IH), 3.82 - 3.57 (m, fluoro-2- 6H), 3.50 - 3.31 (m, IH), 3.16 (s, IH), methoxyphenyl)propyl]({ [3- 2.46 (t, J = 7.3, 2H), 2.31 - 2.11 (m, IH), (trifluoromethyl)phenyl] methyl } 2.00 (s, IH), 1.93 - 1.72 (m, IH), 1.47 (s,
101 )amine 442.2 IH), 1.41 (s, 3H), 1.33 (s, 3H).
IH NMR (400 MHz, CDC13) δ 7.23 - 7.10 (m, 2H), 7.08 - 6.90 (m, 3H), 6.70 - 6.45
(m, 2H), 4.29 (dd, J = 13.0, 6.2, IH), 3.93
(dd, J = 8.0, 6.2, IH), 3.75 (d, J = 9.7, 3H),
[(3R)-3-[(4R)-2,2-dimethyl- 1,3- 3.63 (dd, J = 28.3, 13.0, 2H), 3.50 (t, J = dioxolan-4-yl]-3-(4- 7.8, IH), 3.34 (dd, J = 13.8, 7.2, IH), 2.46 fluoro-2- (t, J = 7.1, 2H), 2.30 (s, 3H), 2.00 - 1.73 methoxyphenyl)propyl] [(3- (m, 2H), 1.46 (s, IH), 1.28 (s, 3H), 1.24 (s,
102 methylphenyl)methyl] amine 388.3 4H). IH NMR (400 MHz, CDC13) δ 7.59 - 7.31
(m, 5H), 7.18 (dd, J = 8.4, 6.8, IH), 6.67 -
[(3R)-3-[(4R)-2,2-dimethyl- 1,3- 6.44 (m, 2H), 4.39 - 4.19 (m, IH), 3.93 dioxolan-4-yl]-3-(4- (dd, J = 8.1, 6.2, IH), 3.79 - 3.61 (m, 5H), fluoro-2- 3.50 (t, J = 7.8, IH), 3.36 (dd, J = 14.7, 6.2, methoxyphenyl)propyl]({ [3- IH), 2.53 - 2.38 (m, 2H), 1.88 (dd, J = (trifluoromethyl)phenyl] methyl } 14.4, 7.8, 2H), 1.45 (s, IH), 1.28 (s, 3H),
103 )amine 442.2 1.24 (s, 4H).
IH NMR (400 MHz, CDC13) δ 8.45 (dd, J = 4.7, 1.5, 2H), 7.55 (d, J = 7.7, IH), 7.30 -
[(3R)-3-[(4R)-2,2-dimethyl- 1,3- 7.06 (m, 2H), 6.72 - 6.47 (m, 2H), 4.40 - dioxolan-4-yl]-3-(4- 4.19 (m, IH), 3.92 (dd, J = 8.1, 6.2, IH), fluoro-2- 3.83 - 3.53 (m, 5H), 3.49 (t, J = 7.8, IH), methoxyphenyl)propyl] (pyridin- 3.43 - 3.27 (m, IH), 2.56 - 2.35 (m, 2H),
3- 2.00 - 1.78 (m, 2H), 1.43 (s, IH), 1.28 (s,
104 ylmethyl) amine 375.2 3H), 1.23 (s, 4H).
9.34 (s, 2H), 7.30 - 7.22 (m, 3H), 7.22 - 7.16 (m, 2H), 6.89 (td, J = 9.2, 4.6, IH), 6.84 - 6.75 (m, IH), 6.64 (ddd, J = 8.6, 5.4, 3.1, IH), 3.88 - 3.61 (m, 3H), 3.52 (td, J = 12.3, 2.2, IH), 3.16 (s, 2H), 2.58 (d, J = 9.7, IH), 2.46 (t, J = 8.2, 2H), 2.08 (t, J = benzyl[(3S)-3-(2,5- 11.9, IH), 1.88 - 1.68 (m, 2H), 1.59 (d, J = difluorophenyl)-3-[(4R)-2,2- 12.7, IH), 1.22 - 0.95 (m, 7H), 0.86 (t, J =
105 dimethyloxan-4-yl]propyl] amine 374.3 12.7, IH).
9.40 (s, 2H), 7.22 (tt, J = 7.0, 3.5, 5H), 6.77 - 6.64 (m, 2H), 3.86 - 3.75 (m, 4H), 3.74 - benzyl[(3S)-3-(3,5-difluoro-2- 3.65 (m, 2H), 3.55 (dd, J = 12.2, 10.2, IH), methoxyphenyl) -3 - 2.57 (dd, J = 36.5, 30.1, 3H), 2.06-1.94 [(4R)-2,2-dimethyloxan-4- (m,4H), 1.67 (d, J = 12.1, IH), 1.19 - 0.94
106 yl]propyl] amine 404.3 (m, 7H), 0.86 (t, J = 12.7, IH).
8.98 (d, J = 142.7, 2H), 7.30 - 7.22 (m, 3H), 7.17 (dd, J = 6.5, 3.0, 2H), 6.83 (dd, J = 8.3, 6.8, IH), 6.58 - 6.44 (m, 2H), 4.25 benzyl[(3S)-3-[(4R)-2,2- (s, 2H), 3.89 - 3.65 (m, 3H), 3.64 (s, 3H), dimethyloxan-4-yl]-3-(4- 3.53 (td, J = 12.3, 2.1, IH), 2.53 (s, 2H), fluoro-2- 2.13 - 2.00 (m, IH), 1.93 - 1.55 (m, 3H),
107 methoxyphenyl)propyl] amine 386.3 1.14 - 0.92 (m, 7H), 0.80 (t, J = 12.8, IH).
benzyl[(3S)-3-[(4R)-2,2- 9.37 (d, J = 30.2, 2H), 7.26 - 7.09 (m, 8H),
108 338.3
dimethyloxan-4-yl]-3- 6.95 - 6.88 (m, 2H), 3.77 - 3.58 (m, 3H), phenylpropyl] amine 3.51 (td, J = 12.3, 2.1, IH), 2.73 - 2.30 (m,
3H), 2.16 - 2.02 (m, 2H), 1.84 - 1.63 (m, 2H), 1.58 (d, J = 12.8, IH), 1.13 - 1.01 (m, IH), 0.97 (d, J = 10.5, 7H), 0.81 (t, J =
12.8, IH).
9.33 (s, 2H), 7.46 (d, J = 7.9, 2H), 7.23 (d, J = 3.5, 3H), 7.16 (d, J = 3.6, 2H), 7.05 (d, J = 8.0, 2H), 3.85 - 3.61 (m, 3H), 3.52 (t, J benzyl[(3S)-3-[(4R)-2,2- = 11.7, IH), 2.97 (s, 2H), 2.40-2.20 dimethyloxan-4-yl] -3- [4- (m,4H), 1.90 - 1.51 (m, 3H), 1.20 - 1.04 (trifluoromethyl)phenyl]propyl] a (m, IH), 1.01 (s, 3H), 0.98 (s, 3H), 0.85
109 mine 406.3 (dd, J = 32.2, 19.7, 2H).
9.14 (s, 2H), 7.46 (d, J = 7.9, 2H), 7.07 (dt,
J = 23.9, 7.2, 4H), 6.99 - 6.88 (m, 2H),
[(3S)-3-[(4R)-2,2-dimethyloxan- 4.45 (s, 2H), 3.81 - 3.58 (m, 3H), 3.53 (t, J
4-yl]-3-[4- = 11.8, IH), 2.64 - 2.21 (m, 3H), 2.19 (s, (trifluoromethyl)phenyl]propyl] [ 3H), 1.95 - 1.52 (m, 3H), 1.23 - 1.04 (m,
(3- 2H), 1.00 (d, J = 12.8, 6H), 0.83 (t, J =
110 methylphenyl)methyl] amine 420.3 12.7, IH).
9.34 (s, 2H), 7.48 (d, J = 8.0, 2H), 7.27 - 7.19 (m, IH), 7.07 (d, J = 8.0, 2H), 6.95 (t,
[(3S)-3-[(4R)-2,2-dimethyloxan- J = 7.9, 3H), 3.74 (ddd, J = 21.9, 16.1, 8.6,
4-yl]-3-[4- 3H), 3.54 (dd, J = 12.2, 10.5, 3H), 2.48 (d, (trifluoromethyl)phenyl]propyl] [ J = 50.7, 2H), 2.22 (dd, J = 26.3, 14.6, 2H),
(3- 1.90 - 1.68 (m, 2H), 1.60 (d, J = 12.5, IH),
111 fluorophenyl)methyl] amine 424.2 1.16 - 0.91 (m, 7H), 0.84 (t, J = 12.7, IH).
9.33 - 8.81 (m, 2H), 7.49 (d, J = 8.0, 2H), 7.30 - 7.23 (m, IH), 7.19 (s, 2H), 7.07 (d, J
[(3-chlorophenyl)methyl] [(3S)- = 7.8, 3H), 4.95 - 4.41 (m, 4H), 3.92 - 3-[(4R)-2,2- 3.65 (m, 3H), 3.63 - 3.50 (m, IH), 2.68 - dimethyloxan-4-yl] -3- [4- 2.37 (m, 2H), 2.37 - 2.09 (m, 2H), 1.91 - (trifluoromethyl)phenyl]propyl] a 1.55 (m, 3H), 1.02 (d, J = 11.6, 7H), 0.91 -
112 mine 440.2 0.82 (m, IH).
8.42 (d, J = 103.4, 2H), 7.45 (d, J = 8.0, 2H), 7.15 - 7.01 (m, 3H), 6.90 (d, J = 7.2,
IH), 6.85 - 6.68 (m, 2H), 5.53 (s, 3H),
2-({ [(3S)-3-[(4R)-2,2- 3.90 (dd, J = 45.3, 11.9, 2H), 3.67 (dd, J = dimethyloxan-4-yl] -3- [4- 11.9, 4.3, IH), 3.52 (t, J = 11.7, IH), 2.52 (trifluoromethyl)phenyl]propyl] a
(d, J = 48.4, 2H), 2.28 - 2.04 (m, 2H), 1.78
113 mino } methyl)phenol 422.3
(dd, J = 32.8, 8.7, 2H), 1.57 (d, J = 12.3, IH), 1.14 - 0.89 (m, 7H), 0.84 (t, J = 12.7,
IH).
9.21 (d, J = 107.6, 2H), 7.28 - 7.21 (m, 3H), 7.21 - 7.15 (m, 2H), 6.84 (dd, J = 8.3, 6.8, IH), 6.52 (td, J = 8.2, 2.4, IH), 6.46
(dd, J = 10.8, 2.4, IH), 3.86 - 3.66 (m, benzyl[(3S)-3-[(4S)-2,2- 2H), 3.62 (s, 3H), 3.57 - 3.34 (m, 3H), dimethyloxan-4-yl]-3-(4- 2.48 (d, J = 28.1, 3H), 2.03 (s, IH), 1.76 (d, fluoro-2- J = 9.3, 2H), 1.58 (d, J = 13.0, IH), 1.11 (s,
114 methoxyphenyl)propyl] amine 386.3 3H), 1.08 (s, 3H), 1.03 - 0.82 (m, 3H).
8.28 (d, J = 132.0, 2H), 7.11 (t, J = 7.4, IH), 6.92 (d, J = 6.9, IH), 6.88 - 6.79 (m, 2H), 6.72 (t, J = 7.4, IH), 6.56 - 6.43 (m, 2H), 6.07 (s, 3H), 3.90 (dd, J = 34.5, 12.5,
2H), 3.63 (d, J = 4.3, 3H), 3.53 (dd, J =
2-({ [(3S)-3-[(4S)-2,2- 11.9, 3.6, IH), 3.41 (td, J = 12.1, 2.2, IH), dimethyloxan-4-yl]-3-(4- 2.58 (s, 3H), 2.05 (s, IH), 1.77 (d, J = 8.4, fluoro-2- 2H), 1.56 (d, J = 12.4, IH), 1.12 (s, 3H), methoxyphenyl)propyl] amino } m 1.09 (s, 3H), 0.92 (tdd, J = 17.6, 12.1, 6.2,
115 ethyl)phenol 402.3 3H).
9.04 (d, J = 164.7, 2H), 7.88 - 7.80 (m, IH), 7.12 (t, J = 7.5, IH), 7.05 (d, J = 7.6, IH), 6.96 (d, J = 11.8, 2H), 6.89 - 6.84 (m, IH), 6.57 - 6.44 (m, 2H), 3.78 - 3.68 (m, 2H), 3.63 (d, J = 4.0, 3H), 3.54 (ddd, J = 15.9, 10.1, 4.1, 2H), 3.41 (td, J = 12.1, 2.3,
[(3S)-3-[(4S)-2,2-dimethyloxan- IH), 2.51 (s, 3H), 2.21 (s, 3H), 2.07 (d, J = 4-yl]-3-(4-fluoro-2- 18.6, IH), 1.84 - 1.53 (m, 4H), 1.27 (s, methoxyphenyl)propyl] [(3- IH), 1.18 (s, IH), 1.11 (s, 3H), 1.08 (s,
116 methylphenyl)methyl] amine 400.3 2H), 0.92 (tdd, J = 17.6, 12.2, 6.0, 3H).
9.31 (d, J = 117.2, 2H), 7.89 - 7.83 (m, IH), 7.23 (dd, J = 13.8, 7.6, IH), 6.93 (dt, J = 5.0, 4.5, 3H), 6.54 (td, J = 8.2, 2.4, IH),
6.49 (dd, J = 10.8, 2.4, IH), 3.87 (d, J = 11.9, 2H), 3.79 - 3.69 (m, 2H), 3.66 (d, J = 4.0, 3H), 3.53 (dd, J = 11.1, 3.8, IH), 3.43
[(3S)-3-[(4S)-2,2-dimethyloxan- (dd, J = 12.2, 2.3, IH), 2.52 (d, J = 35.9, 4-yl]-3-(4-fluoro-2- 2H), 2.06 (s, IH), 1.84 - 1.72 (m, 2H), methoxyphenyl)propyl] [(3- 1.66 - 1.56 (m, IH), 1.12 (s, 3H), 1.09 (s,
117 fluorophenyl)methyl] amine 404.3 3H), 1.01 - 0.85 (m, 3H). 9.04 (d, J = 190.8, 2H), 7.25 (d, J = 8.0,
IH), 7.22 - 7.16 (m, 2H), 7.09 (d, J = 7.5, IH), 6.87 (dd, J = 8.3, 6.9, IH), 6.59 - 6.46 (m, 2H), 5.18 (s, 2H), 3.93 - 3.69 (m, 2H),
[(3-chlorophenyl)methyl] [(3S)- 3.66 (d, J = 5.0, 3H), 3.54 (dd, J = 11.9,
3-[(4S)-2,2- 3.5, IH), 3.42 (td, J = 12.1, 2.3, IH), 2.54 dimethyloxan-4-yl]-3-(4-fluoro- (s, 2H), 2.08 (d, J = 16.0, IH), 1.77 (s, 2H),
2- 1.60 (d, J = 11.9, IH), 1.13 (s, 3H), 1.10 (s,
118 methoxyphenyl)propyl] amine 420.2 3H), 1.04 - 0.84 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.36 (d, J = 57.5, 2H), 7.28 - 7.13 (m, 5H), 6.82 (d, J = 8.7, 2H), 6.72 (d, J = 8.6, 2H), 3.77 - 3.58
(m, 5H), 3.51 (d, J = 10.5, IH), 2.50 (s, benzyl[(3S)-3-[(4R)-2,2- 2H), 2.19 - 1.95 (m, 4H), 1.83 - 1.59 (m, dimethyloxan-4-yl]-3-(4- 2H), 1.56 (d, J = 12.6, IH), 1.16 - 0.88 (m,
119 methoxyphenyl)propyl] amine 368.3 8H), 0.79 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 7.33 - 7.08 (m, 8H), 7.03 (dd, J = 5.1, 3.2, 2H), 3.69 - 3.50 (m, 3H), 3.43 (td, J = 12.2, 2.5, IH), 2.33 (t, J = 7.3, 2H), 2.28 - 2.12 (m, IH), benzyl[(3S)-3-[(4S)-2,2- 1.94 (dtd, J = 15.8, 7.8, 3.8, IH), 1.81 - dimethyloxan-4-yl]-3- 1.56 (m, 3H), 1.40 (d, J = 36.5, 3H), 1.25 -
120 phenylpropyl] amine 338.3 0.84 (m, 10H).
IH NMR (400 MHz, CDC13) δ 7.30 - 7.08
[(3,4- (m, 3H), 7.08 - 6.89 (m, 4H), 6.88 - 6.74 difluorophenyl)methyl] [(3S)-3- (m, IH), 3.81 - 3.63 (m, IH), 3.63 - 3.45
[(4R)-2,2- (m, 3H), 2.35 - 2.13 (m, 3H), 2.03 - 1.88 dimethyloxan-4-yl]-3- (m, IH), 1.87 - 1.52 (m, 3H), 1.35 (s, 2H),
121 phenylpropyl] amine 374.3 1.23 - 0.96 (m, 8H), 0.88 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 7.33 - 7.10 (m, 4H), 7.03 - 6.88 (m, 2H), 6.73 (ddd, J = 10.7, 8.0, 3.7, 3H), 3.75 (ddd, J = 22.2,
[(3,5- 16.1, 8.7, 3H), 3.61 - 3.28 (m, 4H), 2.54 difluorophenyl)methyl] [(3S)-3- (d, J = 55.6, 2H), 2.13 (dd, J = 15.3, 6.5,
[(4R)-2,2- 2H), 1.89 - 1.69 (m, 2H), 1.62 (d, J = 12.6, dimethyloxan-4-yl]-3- IH), 1.24 - 0.92 (m, 8H), 0.85 (t, J = 12.8,
122 phenylpropyl] amine 374.3 IH).
4-[(lS)-3-(benzylamino)-l- IH NMR (400 MHz, CDC13) δ 7.24 (d, J = [(4R)-2,2-dimethyloxan-4- 4.1, 5H), 6.80 (s, IH), 6.69 (dd, J = 4.4,
123 yl]propyl]phenol 354.3 2.7, IH), 6.52 (d, J = 8.4, IH), 4.34 (dd, J = 11.4, 6.1, IH), 3.78 (s, 3H), 2.89 - 2.35 (m,
4H), 2.03 - 1.38 (m, 6H), 1.30 (dd, J = 23.8, 12.6, IH), 1.18 (d, J = 7.7, 3H), 1.02
(d, J = 15.3, 3H).
IH NMR (400 MHz, CDC13) δ 7.31 - 7.04 (m, 7H), 6.76 - 6.49 (m, 3H), 3.86 - 3.63
(m, 4H), 3.63 - 3.47 (m, 3H), 2.19 (dd, J = benzyl[(3S)-3-[(4R)-2,2- 7.1, 4.0, IH), 2.02 - 1.88 (m, IH), 1.84 - dimethyloxan-4-yl]-3-(3- 1.55 (m, 4H), 1.47 (s, 3H), 1.25 - 0.95 (m,
124 methoxyphenyl)propyl] amine 368.3 9H), 0.88 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 7.37 - 7.21 (m, 5H), 7.10 (d, J = 8.5, IH), 6.73 - 6.52
(m, 2H), 4.36 (d, J = 6.0, IH), 3.83 (s, 3H),
3-[(lS)-3-(benzylamino)-l- 2.93 - 2.39 (m, 4H), 2.05 - 1.79 (m, 4H), [(4R)-2,2-dimethyloxan-4- 1.79 - 1.52 (m, 3H), 1.48 - 1.22 (m, 3H),
125 yl]propyl]phenol 354.3 1.22 - 1.13 (m, 3H), 1.01 (d, J = 7.1, 3H).
IH NMR (400 MHz, CDC13) δ 7.37 - 7.21 (m, 5H), 7.10 (d, J = 8.5, IH), 6.73 - 6.52
2-({ [(3S)-3-[(4R)-2,2- (m, 2H), 4.36 (d, J = 6.0, IH), 3.83 (s, 3H), dimethyloxan-4-yl]-3- 2.93 - 2.39 (m, 4H), 2.05 - 1.79 (m, 4H), phenylpropyl] amino } methyl)phe 1.79 - 1.52 (m, 3H), 1.48 - 1.22 (m, 3H),
126 nol 354.3 1.22 - 1.13 (m, 3H), 1.01 (d, J = 7.1, 3H).
IH NMR (400 MHz, CDC13) δ 7.27 - 7.04 (m, 5H), 7.02 (d, J = 7.6, IH), 6.99 - 6.85 (m, 4H), 3.77 - 3.43 (m, 4H), 2.47 (d, J =
[(3S)-3-[(4R)-2,2-dimethyloxan- 42.1, 2H), 2.19 (s, 3H), 2.10 (dd, J = 10.3,
4-yl]-3- 6.9, 2H), 1.86 - 1.65 (m, 2H), 1.59 (d, J = phenylpropyl] [(3- 12.8, IH), 1.18 - 0.88 (m, 8H), 0.82 (t, J =
127 methylphenyl)methyl] amine 352.2 12.8, IH).
IH NMR (400 MHz, CDC13) δ 7.36 (dd, J = 8.3, 3.2, 2H), 7.29 - 7.05 (m, 5H), 6.93 (d, J = 7.0, 2H), 3.86 - 3.60 (m, 3H), 3.54
[(3-bromophenyl)methyl] [(3S)- (dd, J = 22.3, 11.7, 2H), 2.48 (d, J = 48.7,
3-[(4R)-2,2- 2H), 2.20 - 2.00 (m, 2H), 1.89 - 1.63 (m, dimethyloxan-4-yl]-3- 2H), 1.59 (d, J = 12.3, IH), 1.22 - 0.91 (m,
128 phenylpropyl] amine 416.2 8H), 0.83 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 7.29 - 7.08
[(3-chlorophenyl)methyl] [(3S)- (m, 6H), 7.06 (d, J = 7.4, IH), 6.97 - 6.86
3-[(4R)-2,2- (m, 2H), 3.69 (dt, J = 12.2, 8.5, 3H), 3.52
129 372.2
dimethyloxan-4-yl]-3- (td, J = 12.2, 2.0, IH), 3.04 (s, 2H), 2.48 phenylpropyl] amine (d, J = 49.2, 2H), 2.11 (t, J = 7.9, IH), 1.85
- 1.70 (m, 2H), 1.59 (d, J = 12.6, IH), 1.19 - 0.90 (m, 8H), 0.83 (dd, J = 15.5, 10.0,
IH).
IH NMR (400 MHz, CDC13) δ 7.25 - 7.05 (m, 5H), 6.99 - 6.78 (m, 4H), 6.70 (t, J = 7.3, IH), 3.86 (dd, J = 47.4, 12.4, 2H), 3.50 (d, J = 11.6, IH), 3.39 (t, J = 11.9, IH),
2-({ [(3S)-3-[(4S)-2,2- 3.10 (br, IH), 2.52 (d, J = 36.4, 2H), 2.08 dimethyloxan-4-yl]-3- (d, J = 8.3, 2H), 1.73 (d, J = 46.9, 2H), 1.55 phenylpropyl] amino } methyl)phe (d, J = 13.0, IH), 1.09 (d, J = 8.7, 6H), 0.93
130 nol 354.3 (ddd, J = 17.1, 16.6, 7.1, 3H).
IH NMR (400 MHz, CDC13) δ 9.04 (d, J = 34.9, 2H), 7.30 - 7.08 (m, 4H), 7.03 (d, J = 7.6, IH), 7.00 - 6.90 (m, 4H), 4.06 (s, 2H), 3.72 (dd, J = 19.6, 10.8, 2H), 3.53 (dd, J = 12.0, 3.6, IH), 3.40 (td, J = 12.1, 2.3, IH),
[(3S)-3-[(4S)-2,2-dimethyloxan- 2.51 (d, J = 43.2, 2H), 2.20 (s, 3H), 2.10
4-yl]-3- (dd, J = 9.2, 7.9, 2H), 1.91 - 1.61 (m, 2H), phenylpropyl] [(3- 1.58 (d, J = 12.8, IH), 1.10 (d, J = 9.4, 6H),
131 methylphenyl)methyl] amine 352.3 1.06 - 0.85 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.46 (d, J = 61.8, 2H), 7.46 - 7.28 (m, 2H), 7.28 - 7.07 (m, 6H), 6.95 (d, J = 1.4, IH), 3.70 (dd, J = 29.3, 13.0, 2H), 3.61 - 3.45 (m, IH), 3.40
[(3-bromophenyl)methyl] [(3S)- (td, J = 12.1, 2.4, IH), 2.49 (dd, J = 33.0,
3-[(4S)-2,2- 10.6, 4H), 2.20 - 2.05 (m, 2H), 1.89 - 1.64 dimethyloxan-4-yl]-3- (m, 2H), 1.58 (d, J = 12.9, IH), 1.11 (t, J =
132 phenylpropyl] amine 416.2 10.6, 6H), 1.06 - 0.82 (m, 3H).
1H NMR (400 MHz, CDC13) δ 9.26 (d, / = 56.1, 2H), 7.31 - 7.10 (m, 7H), 7.07 (d, / = 7.5, IH), 7.01 - 6.86 (m, 2H), 3.88 (s, 2H), 3.75 (dd, / = 31.5, 13.0, 2H), 3.59 - 3.46
[(3-chlorophenyl)methyl] [(3S)- (m, IH), 3.41 (td, / = 12.1, 2.4, IH), 2.51
3-[(4S)-2,2- (d, / = 49.2, 2H), 2.21 - 1.99 (m, 2H), 1.92 dimethyloxan-4-yl]-3- - 1.65 (m, 2H), 1.58 (d, / = 12.9, IH), 1.11
133 phenylpropyl] amine 372.2 (d, / = 8.9, 6H), 1.07 - 0.83 (m, 3H).
2-({ [(3S)-3-[(4R)-2,2- 1H NMR (400 MHz, CDC13) δ 8.32 (d, / = dimethyloxan-4-yl]-3-(4- 52.6, 2H), 7.13 (dd, / = 11.1, 4.3, IH), 6.92
134 384.3
methoxyphenyl)propyl] amino } m (d, / = 7.3, IH), 6.88 - 6.78 (m, 3H), 6.74 ethyl)phenol (t, / = 7.8, 3H), 4.04 - 3.80 (m, 2H), 3.71
(s, 3H), 3.72 - 3.61 (m, 8H), 3.55 - 3.47 (m, 2H), 2.56 (d, / = 25.5, 2H), 2.21 - 2.06 (m, IH), 1.67 (d, / = 8.6, 2H), 1.55 (d, / = 12.2, IH), 1.14 - 0.92 (m, 8H), 0.81 (t, / =
12.8, IH).
1H NMR (400 MHz, CDC13) δ 9.07 (d, / = 30.2, 2H), 7.11 (t, 7 = 7.5, IH), 7.03 (d, / = 7.6, IH), 7.00 - 6.88 (m, 2H), 6.84 (d, / = 8.7, 2H), 6.73 (d, / = 8.7, 2H), 4.25 (br, IH), 3.75 - 3.59 (m, 6H), 3.52 (dd, / =
[(3S)-3-[(4R)-2,2-dimethyloxan- 12.1, 10.4, IH), 2.50 (d, / = 32.8, 2H), 2.20
4-yl]-3-(4- (s, 3H), 2.07 (dd, / = 16.6, 8.3, 2H), 1.84 - methoxyphenyl)propyl] [(3- 1.63 (m, 2H), 1.58 (d, / = 12.9, IH), 1.21 -
135 methylphenyl)methyl] amine 382.3 0.92 (m, 9H), 0.80 (t, / = 12.8, IH).
1H NMR (400 MHz, CDC13) δ 9.32 (d, / = 48.2, 2H), 7.44 - 7.30 (m, 2H), 7.16 - 7.03 (m, 2H), 6.84 (d, / = 8.7, 2H), 6.74 (d, / = 8.7, 2H), 3.90 - 3.61 (m, 6H), 3.52 (dd, / =
[(3-bromophenyl)methyl] [(3S)- 12.2, 10.3, IH), 2.62 - 2.28 (m, 2H), 2.07
3-[(4R)-2,2- (dd, / = 14.7, 5.8, 2H), 1.81 - 1.60 (m, dimethyloxan-4-yl]-3-(4- 2H), 1.57 (d, / = 13.2, IH), 1.12 - 0.91 (m,
136 methoxyphenyl)propyl] amine 446.2 8H), 0.80 (t, 7 = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 9.34 (s, IH), 7.32 - 7.12 (m, 4H), 7.08 (d, J = 7.4, IH), 6.83 (t, J = 5.7, 2H), 6.74 (d, J = 8.7, 2H), 3.81 - 3.59 (m, 6H), 3.59 - 3.42 (m,
[(3-chlorophenyl)methyl] [(3S)- IH), 2.48 (d, J = 40.3, 3H), 2.07 (dd, J =
3-[(4R)-2,2- 15.1, 6.3, 2H), 1.81 - 1.61 (m, 2H), 1.57 dimethyloxan-4-yl]-3-(4- (d, J = 12.9, IH), 1.13 - 0.91 (m, 8H), 0.80
137 methoxyphenyl)propyl] amine 402.3 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) δ 9.02 (d, J = 50.5, 2H), 7.12 (t, J = 7.5, IH), 7.04 (d, J = 7.6, IH), 6.95 (d, J = 10.7, 2H), 6.86 (d, J = 8.7, 2H), 6.74 (t, J = 5.7, 2H), 3.73 (d, J =
15.9, 7 H), 3.54 (dd, J = 11.9, 3.6, IH),
[(3S)-3-[(4S)-2,2-dimethyloxan- 3.47 - 3.32 (m, IH), 2.52 (d, J = 33.8, 2H),
4-yl]-3-(4- 2.21 (s, 3H), 2.14 - 2.04 (m, IH), 1.66 (d, J methoxyphenyl)propyl] [(3- = 8.4, 2H), 1.56 (d, J = 12.9, IH), 1.08 (t, J
138 methylphenyl)methyl] amine 382.3 = 11.7, 6H), 1.04 - 0.81 (m, 3H). 1H NMR (400 MHz, CDC13) δ 8.35 (d, J =
94.6, 2H), 7.11 (t, J = 7.3, 1H), 6.99 - 6.87 (m, 1H), 6.84 (d, J = 8.6, 3H), 6.72 (t, J = 8.4, 3H), 3.93 (d, J = 13.0, 3H), 3.82 (d, J =
12.8, 2H), 3.69 (s, 3H), 3.52 (dd, J = 11.9, 3.7, 1H), 3.46 - 3.30 (m, 1H), 2.55 (d, J =
2-({ [(3S)-3-[(4S)-2,2- 21.6, 2H), 2.06 (dd, J = 18.5, 9.8, 2H), 1.76 dimethyloxan-4-yl]-3-(4- (s, 1H), 1.71 - 1.59 (m, 1H), 1.53 (d, J = methoxyphenyl)propyl] amino } m 12.9, 1H), 1.09 (d, J = 8.7, 6H), 1.04 - 0.76
139 ethyl)phenol 384.3 (m, 3H).
1H NMR (400 MHz, CDC13) δ 9.28 (d, / = 59.6, 2H), 7.46 - 7.28 (m, 2H), 7.16 - 7.06 (m, 2H), 6.85 (t, J = 5.7, 2H), 6.74 (d, / = 8.7, 2H), 3.85 - 3.62 (m, 5H), 3.53 (dd, / = 11.8, 3.8, 1H), 3.41 (dd, / = 17.8, 6.4, 1H),
[(3-bromophenyl)methyl] [(3S)- 3.23 (br, 1H), 2.51 (d, / = 37.9, 2H), 2.07
3-[(4S)-2,2- (dd, / = 14.9, 5.8, 2H), 1.65 (d, / = 8.5, dimethyloxan-4-yl]-3-(4- 2H), 1.55 (d, / = 12.9, 1H), 1.17 - 0.84 (m,
140 methoxyphenyl)propyl] amine 446.2 9H).
1H NMR (400 MHz, CDC13) δ 9.31 (d, / = 58.0, 2H), 7.31 - 7.13 (m, 4H), 7.08 (d, / = 7.4, 1H), 6.85 (d, / = 8.7, 2H), 6.74 (t, / = 5.7, 2H), 3.82 - 3.62 (m, 5H), 3.53 (dd, / = 11.5, 4.0, 1H), 3.41 (dd, / = 17.4, 6.8, 1H),
[(3-chlorophenyl)methyl] [(3S)- 3.17 (br, 1H), 2.51 (d, / = 38.8, 2H), 2.07
3-[(4S)-2,2- (dd, / = 15.2, 6.7, 2H), 1.65 (d, / = 8.4, dimethyloxan-4-yl]-3-(4- 2H), 1.55 (d, 7 = 13.0, 1H), 1.16 - 0.80 (m,
141 methoxyphenyl)propyl] amine 402.2 9H).
1H NMR (400 MHz, CDC13) δ 9.06 (d, / = 63.2, 2H), 7.30 - 7.20 (m, 3H), 7.20 - 7.13
(m, 3H), 6.84 (t, J = 5.7, 2H), 6.73 (t, / = 5.7, 2H), 3.85 - 3.65 (m, 5H), 3.53 (dd, / =
11.8, 3.7, 1H), 3.46 - 3.32 (m, 1H), 3.07 benzyl[(3S)-3-[(4S)-2,2- (br, 1H), 2.52 (d, / = 36.0, 2H), 2.05 (t, / = dimethyloxan-4-yl]-3-(4- 8.7, 2H), 1.84 - 1.59 (m, 2H), 1.55 (d, / =
142 methoxyphenyl)propyl] amine 368.3 13.0, 1H), 1.15 - 0.82 (m, 9H).
1H NMR (400 MHz, CDC13) δ 9.45 (s, 2H), 7.31 (d, / = 8.3, 2H), 7.26 - 7.11 (m, 5H), benzyl [ (3 S ) -3 - (4-bromophenyl) - 6.80 (d, / = 8.3, 2H), 3.76 - 3.57 (m, 3H),
3-[(4R)-2,2- 3.51 (d, / = 10.7, 1H), 2.44 (d, / = 33.3,
143 dimethyloxan-4-yl]propyl] amine 416.2
2H), 2.14 - 1.92 (m, 4H), 1.80 - 1.61 (m, 2H), 1.54 (s, IH), 0.96 (t, / = 13.2, 8H),
0.80 (d, / = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.32 (s, IH), 8.54 (s, IH), 7.30 - 7.12 (m, 7H), 6.51 (dd, / = 10.5, 2.4, IH), 6.42 (dd, / = 9.6, 2.4, IH), 4.03 - 3.81 (m, 2H), 3.49 (s, 3H),
2-[(lS)-3-(benzylamino)-l- 3.01 (s, 1H), 2.79 (d, / = 41.8, 2H), 1.84 - [(4R)-2,2-dimethyloxan-4- 1.64 (m, 3H), 1.31 (dd, / = 19.7, 15.0, 3H),
144 yl]propyl]-5-fluorophenol 372.3 1.14 (t, / = 15.9, 7H).
IH NMR (400 MHz, CDC13) δ 7.41 - 7.21 (m, 6H), 7.11 (d, J = 13.3, 2H), 6.92 (s, IH), 3.96 (s, 2H), 3.64 (d, J = 10.3, IH), benzyl [(3S)-3-(3 -bromophenyl) - 3.50 (s, IH), 2.63 (s, 3H), 2.25 (s, 2H),
3-[(4R)-2,2- 1.67 (d, J = 53.4, 2H), 1.01 (t, J = 13.7,
145 dimethyloxan-4-yl]propyl] amine 416.2 9H), 0.85 (s, IH)
IH NMR (400 MHz, CDC13) δ 9.45 (d, J = 192.2, 2H), 7.41 - 7.19 (m, 6H), 6.52 (dd, J = 10.4, 2.4, IH), 6.30 (dd, J = 10.8, 2.3, IH), 4.36 (dt, J = 12.1, 6.1, IH), 3.90 (s, 2H), 3.66 - 3.46 (m, 2H), 2.77 (dd, J = 17.4, 13.6, 4H), 1.90 - 1.81 (m, 2H), 1.68 benzyl[(3S)-3-[(4R)-2,2- (dd, J = 14.0, 4.4, IH), 1.43 (dt, J = 12.6, dimethyloxan-4-yl] -3- [4- 6.6, 2H), 1.33 - 1.23 (m, IH), 1.21 - 1.11 fluoro-2-(propan-2- (m, 10H), 1.11 - 1.00 (m, 3H), 0.98 (d, J =
146 yloxy)phenyl]propyl] amine 414.3 6.6, IH).
IH NMR (400 MHz, CDC13) δ 7.39 - 7.29 (m, 2H), 7.29 - 7.09 (m, 6H), 6.96 - 6.84 (m, 2H), 3.69 - 3.48 (m, 3H), 3.43 (td, J = 12.2, 2.4, IH), 2.39 - 2.24 (m, 2H), 2.26 - 2.14 (m, IH), 2.00 - 1.83 (m, IH), 1.66 benzyl [ (3 S ) -3 - (4-bromophenyl) - (qdd, J = 11.6, 9.0, 4.7, 3H), 1.28 (d, J =
3-[(4S)-2,2- 7.5, 2H), 1.12 (d, J = 7.6, 5H), 1.09 - 0.84
147 dimethyloxan-4-yl]propyl] amine 418.2 (m, 3H).
IH NMR (400 MHz, CDC13) δ 7.32 - 7.12 (m, 6H), 6.50 (dd, J = 10.6, 2.4, IH), 6.27 (dd, J = 11.0, 2.4, IH), 4.35 (dt, J = 12.1, benzyl[(3S)-3-[(4S)-2,2-
6.0, IH), 3.79 - 3.59 (m, 4H), 2.98 (dd, J = dimethyloxan-4-yl] -3- [4- 9.3, 4.6, IH), 2.66 (t, J = 7.8, 2H), 1.91 - fluoro-2-(propan-2- 1.54 (m, 6H), 1.50 (dd, J = 13.6, 7.3, IH),
148 yloxy)phenyl]propyl] amine 414.3
1.22 (ddd, J = 14.8, 7.5, 4.2, 10H), 1.13 (s, 3H).
1H NMR (400 MHz, CDC13) δ 7.31 - 7.14 (m, 6H), 6.53 (dd, J = 10.6, 2.4, 1H), 6.26
(dd, J = 10.7, 2.4, 1H), 3.93 - 3.76 (m, benzyl[(3S)-3-[(4S)-2,2- 3H), 3.77 - 3.61 (m, 4H), 3.09 - 2.98 (m, dimethyloxan-4-yl]-3-(2- 1H), 2.72 - 2.57 (m, 2H), 1.89 - 1.63 (m, ethoxy-4- 6H), 1.50 (dt, J = 13.5, 6.4, 2H), 1.27 -
149 fluorophenyl)propyl] amine 400.3 1.20 (m, 7H), 1.13 (s, 3H).
1H NMR (400 MHz, CDC13) δ 7.33 - 7.19 (m, 5H), 7.22 - 7.15 (m, 2H), 6.55 (dd, / = 10.7, 2.4, 1H), 6.31 (dd, / = 10.7, 2.4, 1H), 3.88 - 3.69 (m, 4H), 3.14 (d, / = 9.7, 1H), 2.71 (ddd, / = 21.7, 14.6, 8.7, 2H), 2.85 - 2.61 (m, 2H), 2.11 - 2.05 (m, 1H), 1.89 benzyl[(3S)-3-[(4R)-2,2- (dd, / = 14.1, 5.0, 2H), 1.82 - 1.71 (m, dimethyloxan-4-yl]-3-(2- 1H), 1.65 (dd, / = 7.7, 3.3, 1H), 1.51 - 1.40 ethoxy-4- (m, 3H), 1.29 (d, 7 = 7.0, 2H), 1.25 - 1.13
150 fluorophenyl)propyl] amine 400.3 (m, 8H).
1H NMR (400 MHz, CDC13) δ 7.26 - 7.11 (m, 5H), 6.90 (d, / = 8.3, 1H), 6.43 - 6.33 (m, 2H), 3.73 (s, 3H), 3.68 - 3.58 (m, 4H), 3.57 - 3.49 (m, 2H), 3.49 - 3.38 (m, 1H), 2.70 (s, 1H), 2.40 - 2.25 (m, 2H), 1.91 (d, / benzyl[(3S)-3-(2,4- = 8.2, 1H), 1.83 - 1.52 (m, 3H), 1.42 (s, dimethoxyphenyl)-3-[(4S)-2,2- 1H), 1.22 - 1.07 (m, 7H), 1.07 - 0.98 (m,
151 dimethyloxan-4-yl]propyl] amine 398.3 2H).
1H NMR (400 MHz, CDC13) δ 7.09 (t, / = 7.6, 1H), 6.93 (dd, / = 19.1, 8.9, 4H), 6.44 - 6.30 (m, 2H), 3.73 (s, 3H), 3.66 (s, 3H),
[(3S)-3-(2,4-dimethoxyphenyl)- 3.63 - 3.40 (m, 4H), 2.70 (s, 1H), 2.39 -
3-[(4S)-2,2- 2.28 (m, 2H), 2.25 (s, 3H), 1.91 (d, / = 8.1, dimethyloxan-4-yl]propyl] [(3- 1H), 1.82 - 1.55 (m, 3H), 1.19 - 0.91 (m,
152 methylphenyl)methyl] amine 412.3 10H).
1H NMR (400 MHz, CDC13) δ 7.16 - 7.08 (m, 3H), 7.04 - 6.98 (m, 1H), 6.90 (d, / =
[(3-chlorophenyl)methyl] [(3S)- 8.3, 1H), 6.38 (dt, / = 6.5, 2.4, 2H), 3.72
3-(2,4- (d, / = 3.2, 3H), 3.67 (s, 3H), 3.63 - 3.38 dimethoxyphenyl)-3-[(4S)-2,2- (m, 4H), 2.70 (s, 1H), 2.40 - 2.23 (m, 2H), dimethyloxan-4- 1.96 - 1.84 (m, 1H), 1.84 - 1.54 (m, 3H),
153 yl]propyl] amine 432.3 1.20 - 0.92 (m, 9H). 1H NMR (400 MHz, CDC13) δ 7.34 - 7.23
(m, 2H), 7.12 - 7.05 (m, 2H), 6.90 (d, / =
[(3-bromophenyl)methyl] [(3S)- 8.3, IH), 6.46 - 6.32 (m, 2H), 3.73 (d, / =
3-(2,4- 3.5, 3H), 3.67 (s, 3H), 3.64 - 3.39 (m, 4H), dimethoxyphenyl)-3-[(4S)-2,2- 2.70 (s, IH), 2.38 - 2.21 (m, 2H), 1.90 (d, / dimethyloxan-4- = 8.7, IH), 1.70 (dd, / = 12.7, 1.8, 4H),
154 yl]propyl] amine 476.2 1.21 - 0.91 (m, 10H).
IH NMR (400 MHz, CDC13) δ 7.19 - 7.14 (m, IH), 6.97 - 6.83 (m, 3H), 6.37 (dt, J =
[(3S)-3-(2,4-dimethoxyphenyl)- 6.3, 2.4, 2H), 3.73 (s, 3H), 3.67 (s, 3H),
3-[(4S)-2,2- 3.64 - 3.40 (m, 4H), 2.70 (s, IH), 2.36 - dimethyloxan-4-yl]propyl] [(3- 2.25 (m, 2H), 1.90 (s, IH), 1.84 - 1.53 (m,
155 fluorophenyl)methyl] amine 416.3 3H), 1.19 - 0.91 (m, 9H).
IH NMR (400 MHz, CDC13) δ 7.24 - 7.18 (m, 3H), 7.16 - 7.09 (m, 3H), 6.87 (d, J = 8.2, IH), 6.37 (dt, J = 7.1, 2.4, 2H), 3.73 (s,
3H), 3.71 - 3.46 (m, 7H), 2.67 (s, IH), benzyl[(3S)-3-(2,4- 2.38 - 2.26 (m, 2H), 1.93 (d, J = 8.2, 2H), dimethoxyphenyl)-3-[(4R)-2,2- 1.72 (d, J = 12.9, IH), 1.59 (br, IH), 1.20 -
156 dimethyloxan-4-yl]propyl] amine 398.3 0.95 (m, 9H), 0.87 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) δ 7.10 (t, J = 7.7, IH), 7.00 - 6.90 (m, 3H), 6.87 (d, J =
8.2, IH), 6.37 (dt, J = 3.9, 2.4, 2H), 3.73 (d, J = 3.7, 3H), 3.73 - 3.62 (m, 4H), 3.62
[(3S)-3-(2,4-dimethoxyphenyl)- - 3.47 (m, 3H), 2.67 (s, IH), 2.43 - 2.28
3-[(4R)-2,2- (m, 2H), 2.25 (s, 3H), 2.01 - 1.77 (m, 2H), dimethyloxan-4-yl]propyl] [(3- 1.72 (d, J = 13.0, 2H), 1.46 (s, IH), 1.22 -
157 methylphenyl)methyl] amine 412.3 0.95 (m, 9H), 0.87 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) δ 7.17 - 7.06 (m, 3H), 7.06 - 6.97 (m, IH), 6.86 (d, J = 8.1, IH), 6.43 - 6.35 (m, 2H), 3.73 (d, J =
[(3-chlorophenyl)methyl] [(3S)- 4.0, 3H), 3.72 - 3.62 (m, 4H), 3.62 - 3.47
3-(2,4- (m, 3H), 2.67 (s, IH), 2.40 - 2.25 (m, 2H), dimethoxyphenyl)-3-[(4R)-2,2- 1.91 (dd, J = 8.2, 4.5, 2H), 1.72 (d, J = dimethyloxan-4- 12.9, 2H), 1.42 (s, IH), 1.19 - 0.95 (m,
158 yl]propyl] amine 432.3 9H), 0.87 (t, J = 12.8, IH).
[(3-bromophenyl)methyl] [(3S)- 1H NMR (400 MHz, CDC13) δ 7.33 - 7.26
3-(2,4- (m, 2H), 7.11 - 7.04 (m, 2H), 6.86 (d, / = dimethoxyphenyl)-3-[(4R)-2,2- 8.1, IH), 6.45 - 6.35 (m, 2H), 3.74 (s, 3H),
159 476.2
dimethyloxan-4- 3.73 - 3.64 (m, 4H), 3.62 - 3.46 (m, 3H), yl]propyl] amine 2.66 (s, 1H), 2.38 - 2.23 (m, 2H), 1.99 - 1.77 (m, 2H), 1.72 (d, / = 12.9, 2H), 1.41 (s, 1H), 1.22 - 0.98 (m, 9H), 0.87 (t, / =
12.8, 1H).
1H NMR (400 MHz, CDC13) δ 7.15 (td, / = 7.9, 6.0, 1H), 6.85 (ddd, / = 14.5, 11.8, 6.7, 4H), 6.37 (dd, / = 11.5, 2.4, 2H), 3.72 (d, / = 8.3, 3H), 3.71 - 3.65 (m, 4H), 3.55 (ddd,
[(3S)-3-(2,4-dimethoxyphenyl)- / = 17.2, 13.5, 10.9, 3H), 2.74 - 2.59 (m,
3-[(4R)-2,2- 1H), 2.37 - 2.26 (m, 2H), 1.99 - 1.76 (m, dimethyloxan-4-yl]propyl] [(3- 2H), 1.72 (d, / = 12.9, 3H), 1.14 - 0.94 (m,
160 fluorophenyl)methyl] amine 416.3 9H), 0.89 (d, 7 = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 7.21 (ddd, / = 7.3, 4.4, 1.5, 3H), 7.17 - 7.08 (m, 5H), 6.96 (s, 1H), 3.73 (s, 3H), 3.62 (d, / = 13.1, 1H), 3.58 - 3.47 (m, 2H), 3.47 - 3.38 (m, benzyl[(3S)-3-[(4S)-2,2- 1H), 2.87 (s, 1H), 2.35 - 2.22 (m, 2H), dimethyloxan-4-yl] -3- [2- 2.04 - 1.87 (m, 1H), 1.81 (s, 1H), 1.75 - methoxy-4- 1.66 (m, 1H), 1.67 - 1.60 (m, 1H), 1.46 (s, (trifluoromethyl)phenyl]propyl] a 1H), 1.13 (d, / = 9.9, 7H), 1.01 (ddd, / =
161 mine 436.3 16.4, 14.5, 8.7, 3H).
1H NMR (400 MHz, CDC13) 5 7.11 (dq, / = 15.8, 8.1, 3H), 6.96 (s, 3H), 6.91 (d, / =
[(3S)-3-[(4S)-2,2-dimethyloxan- 7.7, 1H), 3.74 (s, 3H), 3.60 - 3.36 (m, 4H),
4-yl] -3- [2-methoxy-4- 2.86 (s, 1H), 2.36 - 2.26 (m, 2H), 2.24 (s, (trifluoromethyl)phenyl]propyl] [ 3H), 2.03 - 1.89 (m, 1H), 1.81 (s, 1H),
(3- 1.77 - 1.56 (m, 3H), 1.13 (d, / = 9.8, 7H),
162 methylphenyl)methyl] amine 450.3 1.02 (dt, 7 = 9.8, 8.8, 3H).
1H NMR (400 MHz, CDC13) δ 7.19 - 7.09 (m, 3H), 6.97 (s, 1H), 6.93 - 6.81 (m, 3H), 3.75 (s, 3H), 3.62 (d, / = 13.5, 1H), 3.56 -
[(3S)-3-[(4S)-2,2-dimethyloxan- 3.39 (m, 3H), 2.88 (s, 1H), 2.35 - 2.18 (m,
4-yl] -3- [2-methoxy-4- 2H), 2.05 - 1.90 (m, 1H), 1.81 (s, 1H), (trifluoromethyl)phenyl]propyl] [ 1.71 (dd, / = 13.0, 2.6, 1H), 1.68 - 1.59
(3- (m, 1H), 1.11 (t, / = 15.7, 7H), 1.06 - 0.97
163 fluorophenyl)methyl] amine 454.3 (m, 3H).
[(3-chlorophenyl)methyl] [(3S)- 1H NMR (400 MHz, CDC13) δ 7.25 - 7.07
3-[(4S)-2,2- (m, 5H), 7.04 - 6.92 (m, 2H), 3.75 (s, 3H), dimethyloxan-4-yl] -3- [2- 3.65 - 3.37 (m, 4H), 2.87 (s, 1H), 2.33 -
164 470.3
methoxy-4- 2.19 (m, 2H), 1.94 (dd, J = 8.2, 4.2, 1H), (trifluoromethyl)phenyl]propyl] a 1.78 (d, J = 25.8, IH), 1.71 (dd, J = 13.0, mine 2.7, IH), 1.65 (d, J = 6.0, IH), 1.13 (d, J =
10.4, 7H), 1.01 (tt, J = 11.3, 8.7, 3H).
IH NMR (400 MHz, CDC13) δ 7.37 - 7.24 (m, 2H), 7.12 (s, 2H), 7.10 - 7.01 (m, 2H),
[(3-bromophenyl)methyl] [(3S)- 6.97 (s, IH), 3.75 (s, 3H), 3.63 - 3.38 (m,
3-[(4S)-2,2- 4H), 2.87 (s, IH), 2.32 - 2.19 (m, 2H), dimethyloxan-4-yl] -3- [2- 2.04 - 1.89 (m, IH), 1.81 (s, IH), 1.71 (dd, methoxy-4- J = 13.0, 2.7, IH), 1.64 (s, IH), 1.14 (d, J = (trifluoromethyl)phenyl]propyl] a 10.5, 7H), 1.01 (ddd, J = 15.0, 12.7, 9.6,
165 mine 514.2 3H).
IH NMR (400 MHz, CDC13) δ 7.21 (ddd, J = 7.4, 4.4, 1.4, 2H), 7.17 - 7.06 (m, 5H), 6.96 (s, IH), 3.79 - 3.71 (m, 3H), 3.71 - benzyl[(3S)-3-[(4R)-2,2- 3.66 (m, IH), 3.65 - 3.49 (m, 3H), 2.83 (s, dimethyloxan-4-yl] -3- [2- IH), 2.29 (dd, J = 8.2, 6.2, 2H), 1.96 (dd, J methoxy-4- = 8.1, 4.2, 2H), 1.73 (dd, J = 13.0, 1.4, 2H), (trifluoromethyl)phenyl]propyl] a 1.13 (dd, J = 12.4, 5.0, IH), 1.00 (t, J = 8.6,
166 mine 436.3 7H), 0.89 (t, J = 12.6, IH).
IH NMR (400 MHz, CDC13) δ 7.09 (t, J = 7.8, 3H), 6.96 (s, 3H), 6.91 (d, J = 7.6, IH),
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.81 - 3.64 (m, 4H), 3.62 - 3.45 (m, 3H),
4-yl] -3- [2-methoxy-4- 2.83 (s, IH), 2.36 - 2.17 (m, 5H), 2.05 - (trifluoromethyl)phenyl]propyl] [ 1.79 (m, 2H), 1.71 (t, J = 16.8, 2H), 1.22 - (3- 1.05 (m, 2H), 1.00 (t, J = 8.4, 7H), 0.89 (t,
167 methylphenyl)methyl] amine 450.3 J = 12.6, IH).
IH NMR (400 MHz, CDC13) δ 7.15 (s, IH), 7.10 (ddd, J = 18.2, 8.1, 4.9, 4H), 7.03
[(3-chlorophenyl)methyl] [(3S)- - 6.95 (m, 2H), 3.75 (s, 3H), 3.70 (ddd, J =
3-[(4R)-2,2- 11.8, 4.9, 1.4, IH), 3.64 - 3.46 (m, 3H), dimethyloxan-4-yl] -3- [2- 2.84 (s, IH), 2.26 (dd, J = 9.5, 5.1, 2H), methoxy-4- 1.95 (dd, J = 8.1, 4.3, 2H), 1.77 - 1.68 (m, (trifluoromethyl)phenyl]propyl] a IH), 1.59 (s, IH), 1.24 - 0.93 (m, 9H),
168 mine 470.2 0.89 (t, J = 12.6, IH).
[(3-bromophenyl)methyl] [(3S)-
IH NMR (400 MHz, CDC13) δ 7.36 - 7.25 3-[(4R)-2,2- (m, 2H), 7.12 - 7.01 (m, 4H), 6.97 (s, IH), dimethyloxan-4-yl] -3- [2- 3.74 (d, J = 11.7, 3H), 3.72 - 3.64 (m, IH), methoxy-4-
3.64 - 3.45 (m, 3H), 2.84 (s, IH), 2.37 - (trifluoromethyl)phenyl]propyl] a
2.19 (m, 2H), 1.95 (t, J = 6.2, 2H), 1.73 (d,
169 mine 514.2
J = 12.8, 2H), 1.22 - 0.95 (m, 9H), 0.89 (t, J = 12.6, IH).
IH NMR (400 MHz, CDC13) δ 7.18 - 7.06 (m, 3H), 6.97 (s, IH), 6.91 - 6.78 (m, 3H),
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.75 (s, 3H), 3.70 (ddd, J = 11.8, 4.9, 1.4,
4-yl] -3- [2-methoxy-4- IH), 3.57 (ddd, J = 21.1, 14.9, 11.3, 3H), (trifluoromethyl)phenyl]propyl] [ 2.85 (s, IH), 2.35 - 2.16 (m, 2H), 2.02 - (3- 1.79 (m, 2H), 1.73 (d, J = 12.9, 2H), 1.24 -
170 fluorophenyl)methyl] amine 454.3 0.94 (m, 9H), 0.89 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 7.26 - 7.19 (m, 2H), 7.17 - 7.10 (m, 3H), 6.89 (d, J = 7.7, IH), 6.66 (d, J = 7.6, IH), 6.58 (s, IH), 3.67 (s, 3H), 3.61 (d, J = 13.1, IH), 3.57 - 3.37 (m, 3H), 2.75 (s, IH), 2.44 - 2.27 (m, benzyl[(3S)-3-[(4S)-2,2- 2H), 2.26 (s, 3H), 2.01 - 1.87 (m, IH), dimethyloxan-4-yl]-3-(2- 1.84 - 1.67 (m, 2H), 1.63 (dd, J = 15.1, 9.3, methoxy-4- IH), 1.11 (t, J = 10.0, 7H), 1.07 - 0.92 (m,
171 methylphenyl)propyl] amine 382.3 3H).
IH NMR (400 MHz, CDC13) δ 7.09 (t, J =
7.5, IH), 7.00 - 6.86 (m, 4H), 6.66 (d, J =
7.6, IH), 6.59 (s, IH), 3.67 (s, 3H), 3.61 - 3.38 (m, 4H), 2.75 (s, IH), 2.41 - 2.28 (m,
[(3S)-3-[(4S)-2,2-dimethyloxan- 2H), 2.25 (d, J = 6.5, 6H), 1.92 (d, J = 9.0, 4-yl]-3-(2-methoxy-4- IH), 1.85 - 1.67 (m, 2H), 1.67 - 1.55 (m, methylphenyl)propyl] [(3- IH), 1.11 (t, J = 10.0, 7H), 1.06 - 0.93 (m,
172 methylphenyl)methyl] amine 396.3 3H).
IH NMR (400 MHz, CDC13) δ 7.12 (ddd, J = 5.6, 4.9, 2.4, 3H), 7.07 - 6.96 (m, IH), 6.89 (d, J = 7.7, IH), 6.66 (d, J = 7.6, IH), 6.59 (s, IH), 3.68 (s, 3H), 3.61 - 3.39 (m,
[(3-chlorophenyl)methyl] [(3S)- 4H), 2.75 (s, IH), 2.31 (dd, J = 8.0, 6.1,
3-[(4S)-2,2- 2H), 2.27 (d, J = 5.3, 3H), 2.00 - 1.86 (m, dimethyloxan-4-yl]-3-(2- IH), 1.86 - 1.67 (m, 2H), 1.67 - 1.56 (m, methoxy-4- IH), 1.11 (t, J = 11.6, 7H), 1.10 - 0.89 (m,
173 methylphenyl)propyl] amine 416.3 3H).
IH NMR (400 MHz, CDC13) δ 9.75 (s,
[(3-bromophenyl)methyl] [(3S)- IH), 9.14 (s, IH), 7.45 - 7.30 (m, 2H), 3-[(4S)-2,2-
7.13 (dd, J = 16.6, 8.9, 2H), 6.81 (d, J = dimethyloxan-4-yl]-3-(2- 7.7, IH), 6.67 (d, J = 7.6, IH), 6.58 (s, IH), methoxy-4-
3.81 (d, J = 10.7, IH), 3.67 (d, J = 20.0,
174 methylphenyl)propyl] amine 460.2
4H), 3.56 - 3.37 (m, 2H), 2.57 (d, J = 33.1, 3H), 2.25 (s, 3H), 2.09 (s, IH), 1.80 (d, J =
13.0, 2H), 1.62 (d, J = 12.8, IH), 1.16 (dd, J = 35.6, 13.2, 7H), 0.95 (ddd, J = 17.6,
17.1, 7.2, 3H).
IH NMR (400 MHz, CDC13) δ 7.60 - 7.33 (m, 4H), 6.80 (d, J = 7.6, IH), 6.66 (d, J =
[(3S)-3-[(4S)-2,2-dimethyloxan- 7.5, IH), 6.57 (s, IH), 3.81 (dd, J = 41.5, 4-yl]-3-(2-methoxy-4- 30.1, 2H), 3.63 (s, 3H), 3.57 - 3.39 (m, methylphenyl)propyl]({ [3- 2H), 2.56 (s, 3H), 2.23 (s, 3H), 2.10 (s, (trifluoromethyl)phenyl] methyl } IH), 1.79 (s, 2H), 1.62 (d, J = 12.6, IH),
175 )amine 450.3 1.23 - 0.80 (m, 10H).
IH NMR (400 MHz, CDC13) δ 7.26 (s, 5H), 6.79 (d, J = 7.1, IH), 6.67 (d, J = 6.6,
IH), 6.58 (s, IH), 3.88 (d, J = 56.0, 2H), benzyl[(3S)-3-[(4R)-2,2- 3.76 - 3.59 (m, 4H), 3.55 (d, J = 11.3, IH), dimethyloxan-4-yl]-3-(2- 2.63 (s, 3H), 2.26 (s, 3H), 1.88 (s, 2H), methoxy-4- 1.64 (s, IH), 1.02 (d, J = 13.2, 8H), 0.83 (d,
176 methylphenyl)propyl] amine 382.3 J = 12.5, IH).
IH NMR (400 MHz, CDC13) δ 9.17 (s, IH), 8.62 (s, IH), 7.16 - 7.02 (m, 2H), 7.02 - 6.89 (m, 2H), 6.78 (d, J = 7.6, IH), 6.57 (s, IH), 3.86 - 3.58 (m, 6H), 3.55 (d, J
[(3S)-3-[(4R)-2,2-dimethyloxan- = 11.4, IH), 2.56 (s, 3H), 2.24 (d, J = 12.8, 4-yl]-3-(2-methoxy-4- 6H), 2.09 (s, IH), 1.87 (s, IH), 1.74 (s, methylphenyl)propyl] [(3- IH), 1.64 (d, J = 13.0, IH), 1.23 - 0.89 (m,
177 methylphenyl)methyl] amine 396.3 8H), 0.80 (t, J = 12.7, IH)
IH NMR (400 MHz, CDC13) δ 9.07 (d, J = 282.9, 2H), 7.35 - 7.17 (m, 4H), 7.10 (d, J = 7.3, IH), 6.79 (d, J = 7.6, IH), 6.68 (d, J = 7.4, IH), 6.60 (s, IH), 3.87 (s, IH), 3.81
[(3-chlorophenyl)methyl] [(3S)- - 3.59 (m, 5H), 3.55 (t, J = 11.6, IH), 2.58
3-[(4R)-2,2- (d, J = 19.7, 3H), 2.26 (s, 3H), 2.14 (s, IH), dimethyloxan-4-yl]-3-(2- 1.88 (s, IH), 1.73 (s, IH), 1.65 (d, J = 12.1, methoxy-4- IH), 1.20 - 0.90 (m, 8H), 0.80 (t, J = 12.7,
178 methylphenyl)propyl] amine 416.3 IH).
[(3-bromophenyl)methyl] [(3S)-
IH NMR (400 MHz, CDC13) δ 8.91 (d, J = 3-[(4R)-2,2- 333.1, 2H), 7.47 - 7.37 (m, IH), 7.31 (s, dimethyloxan-4-yl]-3-(2- IH), 7.14 (d, J = 5.2, 2H), 6.78 (d, J = 7.7, methoxy-4-
IH), 6.68 (d, J = 7.6, IH), 6.60 (s, IH),
179 methylphenyl)propyl] amine 460.2
5.04 (br, IH), 3.88 (d, J = 12.6, IH), 3.76 - 3.59 (m, 5H), 3.55 (dd, J = 12.2, 10.3, IH),
2.59 (d, J = 38.7, 3H), 2.25 (s, 3H), 2.13 (s, IH), 1.87 (s, IH), 1.65 (d, J = 12.3, 2H), 1.24 - 0.90 (m, 8H), 0.79 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) δ 9.21 (d, J =
294.5, 2H), 7.53 (d, J = 7.2, IH), 7.49 - 7.36 (m, 3H), 6.77 (d, J = 7.7, IH), 6.66 (d, J = 7.6, IH), 6.58 (s, IH), 3.93 (d, J = 12.5,
[(3S)-3-[(4R)-2,2-dimethyloxan- 2H), 3.79 (d, J = 12.2, IH), 3.73 - 3.46 (m, 4-yl]-3-(2-methoxy-4- 5H), 2.57 (d, J = 19.4, 3H), 2.24 (s, 3H), methylphenyl)propyl]({ [3- 2.10 (s, IH), 1.86 (s, IH), 1.72 (s, IH), (trifluoromethyl)phenyl] methyl } 1.62 (d, J = 12.5, IH), 1.20 - 0.92 (m, 8H),
180 )amine 450.3 0.79 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) δ 9.21 (d, J = 183.6, IH), 7.33 - 7.23 (m, 2H), 7.23 - 7.16 (m, 3H), 6.98 (dd, J = 8.1, 1.8, IH), 6.87 (d, J = 1.8, IH), 6.79 (d, J = 8.1, IH), 3.78 (d, J = 32.0, 2H), 3.64 (s, 3H), 3.60 - benzyl[(3S)-3-(4-bromo-2- 3.34 (m, 2H), 2.96 (s, IH), 2.51 (s, 3H), methoxyphenyl) -3 - [ (4S ) - 2.08 (s, IH), 1.76 (s, 2H), 1.59 (d, J = 12.5, 2,2-dimethyloxan-4- IH), 1.10 (d, J = 13.8, 6H), 1.04 - 0.80 (m,
181 yl]propyl] amine 448.2 3H).
IH NMR (400 MHz, CDC13) δ 9.10 (d, J =
217.6, 2H), 7.19 (s, 2H), 7.14 (t, J = 7.5, IH), 7.07 (d, J = 7.5, IH), 6.97 (dd, J = 8.5,
7.0, 3H), 6.87 (d, J = 1.8, IH), 6.80 (d, J =
8.1, IH), 3.78 (d, J = 12.8, IH), 3.67 (d, J = 20.2, 4H), 3.52 (dd, J = 11.9, 3.6, IH), 3.41
[(3S)-3-(4-bromo-2- (td, J = 12.1, 2.3, IH), 3.28 (s, IH), 2.51 (s, methoxyphenyl)-3-[(4S)-2,2- 3H), 2.22 (s, 3H), 2.06 (s, IH), 1.76 (s, dimethyloxan-4-yl]propyl] [(3- 2H), 1.59 (d, J = 12.8, IH), 1.10 (d, J =
182 methylphenyl)methyl] amine 460.2 13.3, 6H), 1.03 - 0.80 (m, 3H).
IH NMR (400 MHz, CDC13) δ 7.33 - 7.17 (m, 5H), 7.09 (d, J = 7.6, IH), 6.99 (dd, J = 8.1, 1.8, IH), 6.90 (d, J = 1.8, IH), 6.81 (d,
J = 8.1, IH), 3.83 (s, IH), 3.79 - 3.63 (m,
[(3S)-3-(4-bromo-2- 4H), 3.61 - 3.46 (m, IH), 3.43 (dd, J = methoxyphenyl)-3-[(4S)-2,2-
12.2, 2.4, IH), 3.23 (s, IH), 2.53 (s, 3H), dimethyloxan-4-yl]propyl] [(3- 2.09 (s, IH), 1.77 (s, 2H), 1.60 (d, J = 13.0,
183 chlorophenyl)methyl] amine 482.2
IH), 1.11 (d, J = 13.0, 6H), 1.04 - 0.84 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.14 (d, J = 287.9, 2H), 7.42 (dd, J = 6.4, 2.5, IH), 7.35 (s, IH), 7.19 - 7.08 (m, 2H), 7.00 (dd, J = 8.1, 1.7, IH), 6.90 (d, J = 1.8, IH), 6.81 (d, J = 8.1, IH), 3.80 (d, J = 41.1, 3H), 3.68 (s,
[(3S)-3-(4-bromo-2- 3H), 3.54 (dd, J = 12.0, 3.6, IH), 3.47 - methoxyphenyl)-3-[(4S)-2,2- 3.35 (m, IH), 2.54 (s, 3H), 2.11 (s, IH), dimethyloxan-4-yl]propyl] [(3- 1.78 (s, 2H), 1.60 (d, J = 13.1, IH), 1.12 (d,
184 bromophenyl)methyl] amine 526.1 J = 12.8, 6H), 1.05 - 0.88 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.21 (d, J =
294.5, 2H), 7.53 (d, J = 7.2, IH), 7.48 - 7.36 (m, 3H), 6.77 (d, J = 7.7, IH), 6.66 (d, J = 7.6, IH), 6.58 (s, IH), 3.93 (d, J = 12.5, 2H), 3.79 (d, J = 12.2, IH), 3.68 (dd, J =
[(3S)-3-(4-bromo-2- 12.0, 3.9, IH), 3.62 (s, 3H), 3.53 (dd, J = methoxyphenyl)-3-[(4S)-2,2- 12.2, 10.3, IH), 2.57 (d, J = 19.4, 3H), 2.10 dimethyloxan-4-yl]propyl]({ [3- (s, IH), 1.86 (s, IH), 1.72 (s, IH), 1.62 (d, (trifluoromethyl)phenyl] methyl } J = 12.5, IH), 1.19 - 0.90 (m, 8H), 0.79 (t,
185 )amine 514.2 J = 12.8, IH).
1H NMR (400 MHz, CDC13) δ 8.64 (d, / = 282.9, 2H), 7.09 (t, J = 7.8, IH), 7.00 (dd, / = 8.1, 1.7, IH), 6.91 (d, / = 1.8, IH), 6.86 - 6.72 (m, 3H), 6.60 (d, / = 7.4, IH), 3.84 (d, / = 9.9, 3H), 3.74 (s, IH), 3.66 (s, 3H),
3-({ [(3S)-3-(4-bromo-2- 3.48 (dd, / = 39.9, 3.0, 2H), 2.60 (s, 3H), methoxyphenyl)-3-[(4S)-2,2- 2.11 (s, IH), 1.79 (s, 2H), 1.59 (d, / = 12.5, dimethyloxan-4- IH), 1.12 (d, / = 11.3, 6H), 1.01 (d, / =
186 yl]propyl]amino}methyl)phenol 462.2 12.5, 3H).
1H NMR (400 MHz, CDC13) δ 9.28 (d, / = 173.7, 2H), 7.32 - 7.22 (m, 3H), 7.22 - 7.13 (m, 6H), 6.97 (dd, / = 8.0, 1.6, IH), 6.87 (d, / = 1.8, IH), 6.76 (d, / = 8.1, IH), 3.79 (d, / = 13.0, IH), 3.74 - 3.60 (m, 5H), benzyl[(3S)-3-(4-bromo-2- 3.51 (s, IH), 2.48 (s, 3H), 2.17 - 2.09 (m, methoxyphenyl) -3 - [ (4R)- 2H), 1.82 (s, 2H), 1.60 (d, / = 12.3, IH), 2,2-dimethyloxan-4- 0.97 (t, / = 13.0, 8H), 0.81 (d, / = 12.7,
187 yl]propyl] amine 446.2 IH).
[(3S)-3-(4-bromo-2- IH NMR (400 MHz, CDC13) δ 8.79 (d, J =
188 460.2
methoxyphenyl)-3-[(4R)-2,2- 252.2, 2H), 7.18 - 7.08 (m, 2H), 6.96 (dd, J dimethyloxan-4-yl]propyl] [(3- = 17.1, 9.6, 3H), 6.88 (d, J = 1.7, IH), 6.77 methylphenyl)methyl] amine (d, J = 8.1, IH), 3.81 (s, IH), 3.70 (dd, J =
12.1, 4.1, 2H), 3.65 (s, 3H), 3.53 (dd, J =
12.2, 10.3, IH), 2.55 (s, 2H), 2.23 (s, 3H), 2.11 (s, IH), 1.80 (d, J = 34.0, 2H), 1.62 (d, J = 12.7, IH), 1.15 - 0.88 (m, 8H), 0.80 (t,
J = 12.8, IH).
IH NMR (400 MHz, CDC13) δ 7.23 (d, J =
11.1, 3H), 7.10 (s, IH), 6.98 (s, IH), 6.89 (d, J = 1.8, IH), 6.77 (d, J = 8.1, IH), 3.81
[(3S)-3-(4-bromo-2- (d, J = 13.2, IH), 3.67 (s, 5H), 3.52 (t, J = methoxyphenyl)-3-[(4R)-2,2- 11.2, IH), 2.51 (s, 3H), 2.10 (s, IH), 1.90 dimethyloxan-4-yl]propyl] [(3- (s, 3H), 1.61 (d, J = 12.0, IH), 1.00 (d, J =
189 chlorophenyl)methyl] amine 482.2 5.3, 8H), 0.80 (t, J = 12.6, IH).
IH NMR (400 MHz, CDC13) δ 9.35 (d, J = 156.8, 2H), 7.48 - 7.29 (m, 2H), 7.13 (dd, J = 4.1, 1.6, 2H), 6.98 (dd, J = 8.1, 1.7, IH), 6.90 (s, IH), 6.76 (d, J = 8.1, IH), 3.78 (d, J = 13.2, IH), 3.72 - 3.62 (m, 5H), 3.52
[(3S)-3-(4-bromo-2- (dd, J = 12.2, 10.2, IH), 3.25 (s, IH), 2.49 methoxyphenyl)-3-[(4R)-2,2- (d, J = 31.8, 3H), 2.06 (s, IH), 1.83 (s, 2H), dimethyloxan-4-yl]propyl] [(3- 1.60 (d, J = 12.7, IH), 1.16 - 0.88 (m, 8H),
190 bromophenyl)methyl] amine 526.1 0.80 (t, J = 12.8, IH).
IH NMR (400 MHz, CDC13) δ 9.83 - 8.88 (m, 2H), 7.55 (s, IH), 7.48 (s, IH), 7.41 (d, J = 5.0, 2H), 7.08 - 6.93 (m, IH), 6.89 (d, J
[(3S)-3-(4-bromo-2- = 1.8, IH), 6.76 (d, J = 8.1, IH), 3.85 (d, J methoxyphenyl)-3-[(4R)-2,2- = 27.3, 2H), 3.73 - 3.64 (m, 4H), 3.54 (d, J dimethyloxan-4-yl]propyl]({ [3- = 10.3, IH), 2.91 (s, 3H), 2.54 (s, 2H), 2.10 (trifluoromethyl)phenyl] methyl } (s, IH), 1.84 (s, 2H), 1.58 (s, IH), 0.98 (t, J
191 )amine 514.2 = 13.8, 8H), 0.81 (d, J = 13.0, IH)
IH NMR (400 MHz, CDC13) δ 8.67 (d, J = 201.7, 2H), 7.07 (s, IH), 6.99 (s, IH), 6.90 (d, J = 1.5, IH), 6.76 (dd, J = 19.0, 8.1, 3H), 6.58 (d, J = 7.3, IH), 3.78 (s, 2H),
3-({ [(3S)-3-(4-bromo-2- 3.73 - 3.64 (m, 5H), 3.52 (s, IH), 2.58 (s, methoxyphenyl)-3-[(4R)-2,2- 3H), 2.10 (s, IH), 1.83 (s, 2H), 1.59 (d, J = dimethyloxan-4- 12.9, IH), 0.98 (t, J = 11.4, 8H), 0.82 (d, J
192 yl]propyl]amino}methyl)phenol 462.2 = 12.7, IH).
193 387.3
[(3S)-3-[(4R)-2,2-dimethyloxan- IH NMR (400 MHz, CDC13) δ 9.14 (s, 4-yl]-3-(4- 2H), 8.02 (s, IH), 7.56 (dd, J = 8.6, 2.0, fluorophenyl)propyl] [(6- IH), 6.91 (d, J = 6.8, 4H), 6.69 (d, J = 8.6, methoxypyridin- 3 - IH), 6.66 - 6.37 (m, 2H), 3.93 - 3.64 (m, yl)methyl] amine 6H), 3.54 (t, J = 11.4, IH), 2.62 (d, J =
18.2, IH), 2.49 (s, IH), 2.20 - 2.05 (m, 2H), 1.73 (dd, J = 21.4, 9.7, 2H), 1.60 (d, J = 13.3, IH), 1.16 - 0.90 (m, 8H), 0.82 (t, J
= 12.8, IH).
IH NMR (400 MHz, CDC13) δ 9.83 (s, 2H), 8.60 (s, IH), 7.80 (d, J = 8.1, IH), 7.58 (d, J = 8.1, IH), 6.91 (d, J = 6.9, 4H), 3.88 (q, J = 13.5, 2H), 3.66 (dd, J = 11.4,
[(3S)-3-[(4R)-2,2-dimethyloxan- 4.4, IH), 3.53 (dd, J = 12.2, 10.2, IH), 2.57
4-yl]-3-(4- (s, IH), 2.46 (s, IH), 2.25 - 2.00 (m, 2H), fluorophenyl)propyl]({ [6- 1.75 (dd, J = 24.2, 11.8, 2H), 1.60 (d, J = (trifluoromethyl)pyridin- 3 - 13.0, IH), 1.12 - 0.89 (m, 9H), 0.79 (d, J =
194 yl] methyl } ) amine 425.3 12.8, IH).
IH NMR (400 MHz, CDC13) δ 9.49 (s, IH), 7.77 (s, IH), 7.67 (s, IH), 6.93 (dd, J = 15.7, 7.1, 4H), 3.92 (q, J = 14.1, 2H), 3.67 (dd, J = 11.8, 4.7, IH), 3.53 (t, J = 12.2, IH), 2.85 - 2.63 (m, IH), 2.58 (s,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 2.19 (t, J = 8.8, 2H), 1.84 (d, J = 9.8,
4-yl]-3-(4- IH), 1.70 (dd, J = 12.0, 8.7, IH), 1.62 (d, J fluorophenyl)propyl] (1,3- = 12.3, IH), 1.24 - 0.89 (m, 9H), 0.83 (t, J
195 oxazol-4-ylmethyl)amine 347.3 = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 7.24 (s, 2H), 6.97 (dt, J = 29.1, 8.5, 4H), 4.27 (d, J = 15.2, 2H), 3.81 - 3.66 (m, IH), 3.58 (d, J
[(3S)-3-[(4R)-2,2-dimethyloxan- = 11.7, IH), 2.72 (s, IH), 2.57 (s, IH), 2.25
4-yl]-3-(4- (d, J = 9.6, 2H), 1.94 (d, J = 7.5, IH), 1.67 fluorophenyl)propyl] ( 1 H- (d, J = 13.0, 2H), 1.02 (d, J = 11.6, 9H),
196 imidazol-2-ylmethyl)amine 346.3 0.88 (d, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 7.67 (d, J = 3.2, IH), 7.32 (d, J = 3.2, IH), 7.03 - 6.85 (m, 4H), 4.31 (q, J = 14.7, 2H), 3.67 (dd, J = 12.0, 3.8, IH), 3.53 (td, J = 12.3, 2.2,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 2.86 - 2.72 (m, IH), 2.72 - 2.59 (m, 4-yl]-3-(4- IH), 2.28 - 2.12 (m, 2H), 1.89 (d, J = 10.8, fluorophenyl)propyl] (1,3- IH), 1.82 - 1.67 (m, IH), 1.63 (d, J = 12.7,
197 thiazol-2-ylmethyl)amine 363.2
IH), 1.20 - 0.92 (m, 8H), 0.83 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 8.80 (s, IH), 7.81 (s, IH), 6.93 (d, J = 6.9, 4H), 4.14 (q, J = 14.3, 2H), 3.69 (dd, J = 12.0, 3.8, IH), 3.59 - 3.44 (m, IH), 2.74 - 2.56
[(3S)-3-[(4R)-2,2-dimethyloxan- (m, IH), 2.51 (t, J = 8.8, IH), 2.24 - 2.02
4-yl]-3-(4- (m, 2H), 1.74 (tt, J = 12.1, 9.9, 2H), 1.60 fluorophenyl)propyl] (1,3- (d, J = 12.9, IH), 1.16 - 0.92 (m, 9H), 0.83
198 thiazol-5-ylmethyl)amine 363.2 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 9.47 (d, J =
26.6, 2H), 7.28 - 7.16 (m, 2H), 6.93 (dd, J = 24.1, 5.9, 5H), 3.78 (s, 2H), 3.65 (dd, J =
11.9, 4.7, IH), 3.50 (t, J = 12.1, IH), 2.70
[(3S)-3-[(4R)-2,2-dimethyloxan- (s, IH), 2.45 (d, J = 33.9, 2H), 2.22 - 2.00
4-yl]-3-(4- (m, 2H), 1.84 - 1.63 (m, 2H), 1.57 (d, J = fluorophenyl)propyl] (thiophen- 12.7, IH), 1.24 - 0.87 (m, 8H), 0.80 (t, J =
199 3 -ylmethyl) amine 362.2 12.7, IH).
IH NMR (400 MHz, CDC13) δ 6.97 - 6.85 (m, 4H), 6.73 (d, J = 3.4, IH), 6.58 - 6.44 (m, IH), 3.87 (t, J = 11.4, 2H), 3.66 (dd, J
[(3S)-3-[(4R)-2,2-dimethyloxan- = 12.1, 3.6, IH), 3.51 (dd, J = 12.2, 10.2,
4-yl]-3-(4- IH), 2.56 (s, IH), 2.45 (s, IH), 2.30 (s, fluorophenyl)propyl] [(5- 3H), 2.22 - 2.06 (m, 2H), 1.82 - 1.53 (m, methylthiophen-2- 4H), 1.12 - 0.92 (m, 9H), 0.80 (t, J = 12.8,
200 yl)methyl] amine 376.3 IH).
1H NMR (400 MHz, CDC13) δ 9.57 (d, / = 25.5, 2H), 7.25 - 7.15 (m, IH), 6.98 (d, / = 2.9, IH), 6.95 - 6.76 (m, 5H), 4.05 - 3.85 (m, 2H), 3.65 (dd, / = 12.0, 3.8, IH), 3.51
[(3S)-3-[(4R)-2,2-dimethyloxan- (td, / = 12.2, 2.1, IH), 2.50 (d, / = 37.9,
4-yl]-3-(4- 2H), 2.23 - 1.97 (m, 2H), 1.88 - 1.63 (m, fluorophenyl)propyl] (thiophen- 2H), 1.59 (d, 7 = 12.8, IH), 1.20 - 0.90 (m,
201 2-ylmethyl)amine 362.2 8H), 0.80 (t, 7 = 12.8, IH).
1H NMR (400 MHz, CDC13) δ 9.41 (d, / = 20.6, 2H), 7.34 (s, IH), 7.18 (s, IH), 6.92 (d, / = 6.9, 4H), 6.34 (d, / = 1.0, IH), 3.79
[(3S)-3-[(4R)-2,2-dimethyloxan- - 3.57 (m, 3H), 3.52 (td, / = 12.3, 2.2, IH),
4-yl]-3-(4- 2.48 (d, 7 = 37.6, 2H), 2.30 - 1.98 (m, 2H), fluorophenyl)propyl] (furan-3- 1.90 - 1.63 (m, 2H), 1.58 (d, / = 12.9, IH),
202 ylmethyl) amine 346.3 1.23 - 0.90 (m, 8H), 0.81 (t, / = 12.7, IH). 1H NMR (400 MHz, CDC13) δ 9.38 (s, 2H),
7.07 - 6.82 (m, 4H), 6.16 (d, / = 3.1, IH),
[(3S)-3-[(4R)-2,2-dimethyloxan- 5.81 (d, / = 2.2, IH), 3.82 (q, / = 15.5,
4-yl]-3-(4- 2H), 3.66 (dd, / = 12.0, 3.9, IH), 3.52 (td, fluorophenyl)propyl] [(5- / = 12.2, 2.0, IH), 2.52 (d, / = 36.7, 2H), methylfuran-2- 2.31 - 2.06 (m, 5H), 1.89 - 1.54 (m, 3H),
203 yl)methyl] amine 360.3 1.16 - 0.92 (m, 9H), 0.82 (t, / = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 11.87 (s, IH), 7.10 - 6.90 (m, 4H), 4.65 (s, IH), 3.77 - 3.63 (m, IH), 3.56 (td, J = 12.3, 2.3, IH), 2.96 - 2.67 (m, 5H), 2.50 - 2.34 (m,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 2.30 - 2.06 (m, 2H), 1.95 - 1.62 (m,
4-yl]-3-(4- 3H), 1.62 - 1.35 (m, 4H), 1.27 - 1.05 (m, fluorophenyl)propyl] dipropylami IH), 1.05 - 0.92 (m, 7H), 0.92 - 0.77 (m,
204 ne 350.2 7H).
IH NMR (400 MHz, CDC13) δ 12.69 (s, IH), 7.01 - 6.83 (m, 4H), 5.80 (dd, J = 17.1, 10.0, IH), 5.69 (dd, J = 17.1, 10.0, IH), 5.42 (t, J = 9.3, 2H), 5.32 (dd, J = 17.0, 7.2, 2H), 3.77 - 3.65 (m, IH), 3.62 -
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.38 (m, 5H), 2.77 (td, J = 12.4, 4.3, IH),
4-yl]-3-(4- 2.43 (td, J = 12.4, 4.4, IH), 2.31 - 2.08 (m, fluorophenyl)propyl]bis(prop-2- 2H), 1.96 - 1.61 (m, 3H), 1.22 - 0.90 (m,
205 en-l-yl))amine 346.1 8H), 0.82 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 10.50 (s, IH), 7.09 - 6.83 (m, 4H), 3.70 (dd, J = 12.0, 3.9, IH), 3.62 - 3.48 (m, 2H), 3.48 - 3.29 (m, IH), 2.76 - 2.52 (m, IH), 2.51 -
[(3S)-3-[(4R)-2,2-dimethyloxan- 2.24 (m, 2H), 2.24 - 1.89 (m, 2H), 1.89 -
4-yl]-3-(4- 1.66 (m, 2H), 1.31 (d, J = 6.6, 3H), 1.25 - fluorophenyl)propyl]bis(propan- 1.04 (m, 10H), 0.99 (dd, J = 14.9, 5.2, 7H),
206 2-yl))amine 350.2 0.80 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 6.96 (p, J = 8.8, 4H), 3.70 (dd, J = 12.0, 4.0, IH), 3.56 (t, J = 11.1, 5H), 3.17 (s, 10H), 2.94 (dd, J
[(3S)-3-[(4R)-2,2-dimethyloxan- = 12.3, 8.4, IH), 2.73 (td, J = 12.2, 4.5,
4-yl]-3-(4- IH), 2.17 (dt, J = 19.9, 10.4, 2H), 2.03 - fluorophenyl)propyl]bis(2- 1.62 (m, 3H), 1.27 - 0.89 (m, 8H), 0.83 (t,
207 methoxyethyl) amine 382.1 J = 12.7, IH).
208 372.1
3-[(2-cyanoethyl)[(3S)-3-[(4R)- IH NMR (400 MHz, CDC13) δ 9.77 (s, 2,2-dimethyloxan-4- 2H), 7.08 - 6.88 (m, 4H), 3.81 (dd, J = yl]-3-(4- 12.1, 3.9, IH), 3.61 (dd, J = 12.3, 10.3, fluorophenyl)propyl] amino]prop IH), 3.30 - 3.01 (m, 4H), 2.79 (s, IH), anenitrile 2.70 - 2.45 (m, 5H), 2.34 - 2.05 (m, 2H),
1.87 - 1.65 (m, 3H), 1.20 (tt, J = 12.5, 6.2, IH), 1.04 (t, J = 12.0, 7H), 0.92 (t, J =
12.8, IH).
1H NMR (400 MHz, CDC13) δ 8.98 (d, / = 90.2, 2H), 6.97 (p, / = 8.8, 4H), 3.68 (dd, /
= 12.0, 3.8, IH), 3.54 (t, / = 11.3, IH), 3.48 - 3.32 (m, 3H), 3.19 (s, 3H), 2.95 (s,
[(3S)-3-[(4R)-2,2-dimethyloxan- 2H), 2.73 (s, IH), 2.57 (s, IH), 2.20 (t, / =
4-yl]-3-(4- 8.5, 2H), 1.84 (d, / = 9.3, IH), 1.73 (d, / = fluorophenyl)propyl] (2- 8.5, IH), 1.64 (d, / = 12.7, IH), 1.23 - 0.90
209 methoxyethyl) amine 324.1 (m, 8H), 0.83 (t, 7 = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.83 - 9.00 (m, IH), 6.96 (d, / = 6.9, 4H), 3.72 (dd, / = 11.9, 4.2, IH), 3.56 (t, / = 11.4, IH), 3.10 (d, J = 3.1, 2H), 2.75 (d, / = 6.4, 3H), 2.56
3-{ [(3S)-3-[(4R)-2,2- (d, / = 11.3, IH), 2.28 - 2.06 (m, 2H), 1.78 dimethyloxan-4-yl]-3-(4- (dd, J = 212, 10.5, 2H), 1.63 (d, / = 12.4, fluorophenyl)propyl] amino }prop IH), 1.24 - 0.92 (m, 8H), 0.85 (t, / = 12.7,
210 anenitrile 319.1 IH).
1H NMR (400 MHz, CDC13) δ 11.93 (s, IH), 7.10 - 6.89 (m, 4H), 5.19 (s, IH), 3.71 (dd, / = 12.1, 3.8, IH), 3.65 - 3.44
(m, IH), 3.01 - 2.86 (m, IH), 2.81 - 2.44 butyl[(3S)-3-[(4R)-2,2- (m, 5H), 2.21 (ddd, / = 36.7, 30.6, 20.4, dimethyloxan-4-yl]-3-(4- 2H), 1.99 - 1.60 (m, 3H), 1.60 - 1.37 (m, fluorophenyl)propyl] methylamin 2H), 1.26 (dt, / = 15.4, 7.7, 2H), 1.17 -
211 e 336.1 0.91 (m, 8H), 0.84 (dd, / = 16.5, 9.2, 4H).
1H NMR (400 MHz, CDC13) δ 11.93 (s, IH), 7.10 - 6.89 (m, 4H), 5.19 (s, IH), 3.71 (dd, / = 12.1, 3.8, IH), 3.65 - 3.44
(m, IH), 3.01 - 2.86 (m, IH), 2.81 - 2.44 (m, 5H), 2.21 (ddd, / = 36.7, 30.6, 20.4, l-[(3S)-3-[(4R)-2,2- 2H), 1.99 - 1.60 (m, 3H), 1.60 - 1.37 (m, dimethyloxan-4-yl]-3-(4- 2H), 1.26 (dt, / = 15.4, 7.7, 2H), 1.17 -
212 fluorophenyl)propyl]pyrrolidine 320.1 0.91 (m, 8H), 0.84 (dd, / = 16.5, 9.2, 4H).
213 334.1
l-[(3S)-3-[(4R)-2,2- 1H NMR (400 MHz, CDC13) δ 11.88 (s, dimethyloxan-4-yl]-3-(4- 1H), 6.96 (dd, / = 8.8, 7.6, 4H), 5.35 (s, fluorophenyl)propyl]piperidine 1H), 3.71 (dd, / = 12.4, 4.3, 3H), 3.64 - 3.49 (m, 1H), 2.85 (s, 1H), 2.56 (d, / = 41.1, 3H), 2.19 (dd, / = 25.2, 13.7, 2H), 1.94 (dd, / = 39.8, 27.0, 5H), 1.81 - 1.53 (m, 2H), 1.26 - 0.89 (m, 8H), 0.83 (t, / =
12.7, 1H).
1H NMR (400 MHz, CDC13) δ 12.15 (s, 1H), 6.96 (d, / = 6.9, 4H), 3.99 - 3.77 (m,
4H), 3.72 (dd, / = 12.0, 4.1, 1H), 3.66 - 3.39 (m, 3H), 2.87 - 2.42 (m, 4H), 2.31 - 2.09 (m, 2H), 1.90 (td, / = 12.0, 4.6, 1H),
4-[(3S)-3-[(4R)-2,2- 1.75 (dt, / = 16.5, 6.0, 1H), 1.65 (d, / = dimethyloxan-4-yl]-3-(4- 13.0, 1H), 1.25 - 0.91 (m, 8H), 0.84 (t, / =
214 fluorophenyl)propyl] morpholine 336.1 12.8, 1H).
1H NMR (400 MHz, CDC13) δ 11.65 (s, 1H), 7.24 (s, 1H), 6.96 (d, / = 6.9, 4H), 3.81 - 3.63 (m, 3H), 3.56 (td, / = 12.3, 2.2, 1H), 3.18 (t, / = 12.6, 2H), 2.90 - 2.64 (m,
4-[(3S)-3-[(4R)-2,2- 3H), 2.64 - 2.42 (m, 3H), 2.31 - 2.05 (m, dimethyloxan-4-yl]-3-(4- 2H), 1.99 - 1.70 (m, 2H), 1.65 (d, / = 12.8, fluorophenyl)propyl] thiomorpho 1H), 1.27 - 0.91 (m, 8H), 0.84 (t, / = 12.7,
215 line 352.1 1H).
1H NMR (400 MHz, CDC13) δ 6.96 (d, / = 6.9, 4H), 3.70 (dd, / = 12.1, 3.6, 1H), 3.55
(d, 7 = 2.2, 1H), 3.43 (d, / = 25.1, 8H), 2.75 (s, 4H), 2.58 - 2.49 (m, 1H), 2.16 (s, l-[(3S)-3-[(4R)-2,2- 2H), 1.85 (dd, / = 12.0, 4.2, 1H), 1.74 (dd, dimethyloxan-4-yl]-3-(4- / = 12.1, 3.6, 1H), 1.64 (d, / = 12.6, 1H), fluorophenyl)propyl] -4- 1.10 (dd, / = 12.4, 5.0, 1H), 1.00 (t, / =
216 methylpiperazine 349.1 10.6, 7H), 0.83 (s, 1H).
1H NMR (400 MHz, CDC13) δ 7.34 - 7.13 (m, 5H), 7.04 - 6.84 (m, 4H), 4.28 (q, J =
11.9, 2H), 3.70 (dd, J = 12.0, 3.9, 1H), 3.56 (td, J = 12.3, 2.0, 1H), 3.19 (ddd, J = 9.1,
[(3S)-3-[(4R)-2,2-dimethyloxan- 7.3, 4.4, 1H), 3.05 (td, J = 8.6, 6.6, 1H),
4-yl]-3-(4- 2.47 - 2.28 (m, 1H), 2.11 (ddd, J = 15.5, fluorophenyl)propyl] dimethylam 8.1, 4.0, 1H), 1.88 - 1.56 (m, 3H), 1.17 -
217 ine 357.1 0.92 (m, 9H), 0.86 (t, J = 12.7, 1H).
218 390
benzyl[(3S)-3-(3-chloro-5- 1H NMR (400 MHz, CDC13) δ 9.38 (s, fluorophenyl)-3-[(4R)- 2H), 7.36 - 7.15 (m, 5H), 6.87 (d, J = 8.3, 2,2-dimethyloxan-4- IH), 6.72 (s, IH), 6.55 (d, J = 9.0, IH), yl]propyl] amine 3.87 - 3.56 (m, 3H), 3.50 (t, J = 11.4, IH),
2.47 (d, J = 27.9, 2H), 2.11 (d, J = 9.9, 2H), 1.81 - 1.61 (m, 2H), 1.55 (d, J = 12.6, IH), 1.14 - 0.88 (m, 8H), 0.82 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 9.13 (s, IH), 8.56 (s, IH), 8.38 (s, IH), 7.77 (s, IH), 6.94 (d, J = 9.0, IH), 6.83 (s, IH), 6.68 (d, J = 9.0, IH), 4.24 (s, 2H), 3.70 (dd,
[(3S)-3-(3-chloro-5- J = 12.3, 4.1, IH), 3.55 (s, IH), 2.87 (s, fluorophenyl)-3-[(4R)-2,2- IH), 2.73 (s, IH), 2.23 (s, 2H), 1.88 (d, J = dimethyloxan-4- 7.4, IH), 1.76 (d, J = 8.7, IH), 1.64 (d, J = yl]propyl] (pyridin-3- 12.4, IH), 1.03 (t, J = 9.9, 8H), 0.88 (s,
219 ylmethyl) amine 391 IH).
IH NMR (400 MHz, CDC13) δ 9.69 (s,
2H), 8.62 (s, IH), 7.84 (d, J = 8.2, IH), 7.62 (d, J = 8.1, IH), 6.91 (dt, J = 8.3, 2.0,
IH), 6.77 (s, IH), 6.60 (d, J = 9.0, IH),
[(3S)-3-(3-chloro-5- 3.94 (q, J = 13.5, 2H), 3.68 (dd, J = 12.0, fluorophenyl)-3-[(4R)-2,2- 3.9, IH), 3.54 (dd, J = 12.3, 10.3, IH), 2.58 dimethyloxan-4-yl]propyl]({ [6- (d, J = 35.5, 2H), 2.17 (t, J = 9.0, 2H), 1.90 (trifluoromethyl)pyridin- 3 - - 1.68 (m, 2H), 1.61 (d, J = 12.2, IH), 1.22
220 yl] methyl } ) amine 459 - 0.91 (m, 7H), 0.85 (t, J = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.40 (s, 2H), 8.02 (s, IH), 7.54 (dd, / = 8.6, 2.0, IH), 6.90 (dt, / = 8.3, 2.0, IH), 6.76 (s, IH),
6.68 (d, / = 8.6, IH), 6.59 (d, J = 9.1, IH),
[(3S)-3-(3-chloro-5- 3.92 - 3.63 (m, 6H), 3.53 (dd, / = 12.2, fluorophenyl)-3-[(4R)-2,2- 10.2, IH), 2.53 (d, / = 33.2, 2H), 2.14 (dd, dimethyloxan-4-yl]propyl] [(6- 7 = 20.2, 11.0, 2H), 1.84 - 1.64 (m, 2H), methoxypyridin-3- 1.58 (d, / = 12.7, IH), 1.23 - 0.91 (m, 9H),
221 yl)methyl] amine 421 0.84 (t, / = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.14 (s, IH), 8.74 (s, 2H), 6.94 (dt, / = 8.3, 2.0, IH),
[(3S)-3-(3-chloro-5-
6.81 (s, IH), 6.75 - 6.59 (m, IH), 3.96 (d, / fluorophenyl)-3-[(4R)-2,2- = 15.3, 2H), 3.72 (dd, / = 12.1, 3.9, IH), dimethyloxan-4- 3.57 (d, J = 2.1, IH), 2.76 - 2.52 (m, 2H), yl]propyl] (pyrimidin-5-
2.18 (s, 2H), 1.86 - 1.69 (m, 2H), 1.62 (d, /
222 ylmethyl) amine 392.1
= 12.6, IH), 1.21 - 0.96 (m, 8H), 0.89 (d, / = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.77 - 9.30 (m, 1H), 8.63 - 8.51 (m, 2H), 8.49 - 8.41 (m, 1H), 6.91 (dt, / = 8.3, 2.0, 1H), 6.81 (s, 1H), 6.66 (d, / = 9.0, 1H), 4.23 (t, / = 12.0, 2H), 3.75 - 3.63 (m, 1H), 3.56 (dd, / =
[(3S)-3-(3-chloro-5- 12.3, 2.2, 1H), 2.89 - 2.77 (m, 1H), 2.70 (s, fluorophenyl)-3-[(4R)-2,2- 1H), 2.26 (d, / = 9.6, 2H), 1.91 (dd, / = dimethyloxan-4- 13.4, 9.5, 1H), 1.74 (dd, / = 12.1, 8.7, 1H), yl]propyl] (pyrazin-2- 1.63 (d, / = 12.4, 1H), 1.23 - 0.94 (m, 8H),
223 ylmethyl) amine 392 0.88 (t, / = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.30 (s, 2H), 7.30 - 7.22 (m, 2H), 6.97 (dd, / = 4.7, 1.4,
1H), 6.89 (dt, / = 8.3, 1.9, 1H), 6.75 (s, 1H), 6.58 (d, / = 9.0, 1H), 3.85 (d, / = 9.4,
[(3S)-3-(3-chloro-5- 2H), 3.67 (dd, / = 12.0, 3.9, 1H), 3.52 (dd, fluorophenyl)-3-[(4R)-2,2- / = 12.2, 10.3, 1H), 2.50 (d, / = 29.3, 2H), dimethyloxan-4- 2.23 - 2.04 (m, 2H), 1.81 - 1.63 (m, 2H), yl]propyl] (thiophen-3- 1.57 (d, / = 12.3, 1H), 1.16 - 0.89 (m, 8H),
224 ylmethyl) amine 396 0.83 (t, / = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.42 (s, 2H), 6.89 (dt, J = 8.3, 2.0, 1H), 6.82 - 6.70 (m, 2H), 6.60 (d, J = 9.1, 1H), 6.57 - 6.47
[(3S)-3-(3-chloro-5- (m, 1H), 3.90 (d, J = 11.4, 2H), 3.78 - 3.58 fluorophenyl)-3-[(4R)-2,2- (m, 1H), 3.58 - 3.47 (m, 1H), 2.54 (d, J = dimethyloxan-4-yl]propyl] [(5- 32.2, 2H), 2.31 (s, 3H), 2.16 (d, J = 9.4, methylthiophen-2- 2H), 1.71 (s, 2H), 1.59 (d, J = 12.9, 1H),
225 yl)methyl] amine 410 1.17 - 0.90 (m, 8H), 0.84 (t, J = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.33 (s, 2H), 7.24 (d, / = 5.1, 1H), 7.00 (d, / = 3.3, 1H), 6.95 - 6.82 (m, 2H), 6.76 (s, 1H), 6.59 (d, / = 9.1, 1H), 4.04 (d, / = 11.2,
[(3S)-3-(3-chloro-5- 2H), 3.68 (dd, J = 12.1, 3.7, 1H), 3.62-3.46 fluorophenyl)-3-[(4R)-2,2- (m, 1H),2.57 (d,J = 30.0, 2H), 2.15 (d,J = dimethyloxan-4- 9.1, 2H), 1.72 (d, J = 4.1, 2H), 1.58 (d, J = yl]propyl] (thiophen-2- 12.7,1H), 1.15-0.91 ( m, 8H), 0.84 (t , J =
226 ylmethyl) amine 396 12.7,1H)
[(3S)-3-(3-chloro-5- 1H NMR (400 MHz, CDC13) δ 9.79 (s, 2H), fluorophenyl)-3-[(4R)-2,2- 7.72 (d, / = 3.2, 1H), 7.37 (d, / = 3.2, 1H),
227 397
dimethyloxan-4-yl]propyl] (1,3- 6.90 (dt, / = 8.3, 2.1, 1H), 6.80 (s, 1H), thiazol-2- 6.72 - 6.58 (m, 1H), 4.37 (q, / = 14.8, 2H), ylmethyl) amine 3.70 (dd, / = 12.1, 3.8, 1H), 3.54 (td, / =
12.3, 2.2, 1H), 2.82 (dd, / = 11.3, 5.2, 1H), 2.76 - 2.62 (m, 1H), 2.23 (t, / = 8.4, 2H), 1.96 - 1.79 (m, 1H), 1.79 - 1.68 (m, 1H),
1.62 (d, / = 12.8, 1H), 1.23 - 0.94 (m, 8H),
0.87 (t, / = 12.8, 1H).
1H NMR (400 MHz, CDC13) δ 9.40 (s, 1H), 8.94 (s, 1H), 7.93 (s, 1H), 6.93 (dt, / = 8.2, 2.0, 1H), 6.79 (s, 1H), 6.62 (d, / = 8.9, 1H), 4.26 (q, / = 14.3, 2H), 3.74 (dd, / =
[(3S)-3-(3-chloro-5- 12.0, 3.9, 1H), 3.57 (dd, / = 12.3, 10.2, fluorophenyl)-3-[(4R)-2,2- 1H), 2.82 - 2.53 (m, 2H), 2.34 - 2.02 (m, dimethyloxan-4-yl]propyl] (1,3- 2H), 1.76 (dd, / = 15.9, 8.0, 2H), 1.61 (d, / thiazol-5- = 12.5, 1H), 1.23 - 0.97 (m, 8H), 0.89 (t, /
228 ylmethyl) amine 397 = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 10.79 (s, 1H), 8.97 (s, 2H), 7.40 - 7.27 (m, 2H), 6.91 (dt, / = 8.2, 2.1, 1H), 6.77 (s, 1H), 6.66 - 6.56 (m, 1H), 6.33 (d, / = 1.0, 1H),
[(3S)-3-(3-chloro-5- 4.02 - 3.86 (m, 1H), 3.75 (ddd, / = 20.5, fluorophenyl)-3-[(4R)-2,2- 17.2, 8.7, 3H), 3.54 (td, / = 12.3, 2.2, 1H), dimethyloxan-4- 2.56 (d, / = 32.8, 2H), 2.26 - 2.05 (m, 2H), yl]propyl] (furan-3- 1.84 - 1.65 (m, 2H), 1.59 (d, / = 12.3, 1H),
229 ylmethyl) amine 380 1.11 - 0.93 (m, 8H), 0.86 (t, / = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.25 (s, 2H),
6.90 (dt, / = 8.3, 1.9, 1H), 6.78 (s, 1H), 6.62 (d, / = 9.0, 1H), 6.19 (d, / = 3.1, 1H), 5.83 (d, / = 2.2, 1H), 3.87 (d, / = 8.4, 2H),
[(3S)-3-(3-chloro-5- 3.68 (dd, / = 12.0, 4.1, 1H), 3.53 (dd, / = fluorophenyl)-3-[(4R)-2,2- 12.2, 10.4, 1H), 2.57 (d, J = 29.1, 2H), 2.26 dimethyloxan-4-yl]propyl] [(5- - 2.05 (m, 5H), 1.88 - 1.64 (m, 2H), 1.60 methylfuran-2- (d, / = 12.8, 1H), 1.15 - 0.92 (m, 8H), 0.85
230 yl)methyl] amine 394 (t, / = 12.7, 1H).
lH NMR (400 MHz, CDC13) δ 10.35 (s,
1H), 7.27 (s, 2H), 6.93 (d, / = 8.0, 1H),
[(3S)-3-(3-chloro-5- 6.83 (s, 1H), 6.69 (d, / = 9.1, 1H), 4.33 (d, fluorophenyl)-3-[(4R)-2,2- / = 11.7, 2H), 3.72 (d, 7 = 4.3, 1H), 3.57 (s, dimethyloxan-4-yl]propyl] ( 1H-
1H), 2.69 (d, / = 45.3, 2H), 2.26 (d, / = imidazol-2- 9.3, 2H), 2.05 - 1.72 (m, 2H), 1.65 (s, 1H),
231 ylmethyl) amine 380
1.04 (t, / = 10.6, 8H), 0.92 (d, / = 12.6, 1H).
1H NMR (400 MHz, CDC13) δ 9.01 (s, 2H), 7.23 (dd, / = 17.1, 9.2, 4H), 7.18 (s, 2H), 6.70 (dd, / = 20.0, 8.9, 2H), 3.81 (d, / = 20.3, 2H), 3.69 (dd, / = 1 1.8, 4.0, 1H), 3.52 benzyl[(3S)-3-(4-chloro-3- (t, / = 11.9, 1H), 2.54 (d, / = 34.5, 2H), fluorophenyl)-3-[(4R)- 2.14 (s, 2H), 1.69 (s, 2H), 1.57 (d, / = 12.4, 2,2-dimethyloxan-4- 1H), 1.15 - 0.89 (m, 8H), 0.82 (t, / = 12.7,
232 yl]propyl] amine 390.2 1H).
1H NMR (400 MHz, CDC13) δ 9.50 (s, 2H), 8.63 (s, 1H), 7.81 (d, / = 7.2, 1H), 7.62 (d, / = 8.1, 1H), 7.26 (t, J= 7.9, 1H), 6.85 - 6.65 (m, 2H), 3.96 (q, / = 13.5, 2H), 3.70
[(3S)-3-(4-chloro-3- (dd, / = 12.0, 4.0, 1H), 3.55 (dd, / = 12.2, fluorophenyl)-3-[(4R)-2,2- 10.4, 1H), 2.59 (d, / = 43.5, 2H), 2.26 - dimethyloxan-4-yl]propyl]({ [6- 2.07 (m, 2H), 1.94 - 1.69 (m, 2H), 1.62 (d, (trifluoromethyl)pyridin- 3 - / = 12.7, 1H), 1.19 - 0.91 (m, 8H), 0.84 (t,
233 yl] methyl } ) amine 459.2 / = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 13.28 (s, 1H), 9.17 (s, 2H), 8.16 (s, 1H), 7.75 (d, / = 8.5, 1H), 7.27 (t, J= 7.9, 1H), 6.92 - 6.58 (m, 3H), 3.91 (d, / = 11.7, 5H), 3.72 (dd, /
[(3S)-3-(4-chloro-3- = 12.1, 3.9, 1H), 3.56 (dd, / = 12.3, 10.4, fluorophenyl)-3-[(4R)-2,2- 1H), 2.62 (d, / = 49.2, 2H), 2.32 - 2.05 (m, dimethyloxan-4-yl]propyl] [(6- 2H), 1.93 - 1.66 (m, 2H), 1.62 (d, / = 12.6, methoxypyridin-3- 1H), 1.20 - 0.92 (m, 8H), 0.86 (t, / = 12.7,
234 yl)methyl] amine 421.2 1H).
1H NMR (400 MHz, CDC13) δ 9.51 (s, 1H), 8.53 (s, 2H), 8.43 (s, 1H), 7.26 (t, / = 7.9, 1H), 6.87 - 6.70 (m, 2H), 4.29 - 4.06 (m, 2H), 3.69 (dd, / = 11.8, 4.0, 1H), 3.54 (t, /
[(3S)-3-(4-chloro-3- = 11.4, 1H), 2.80 (d, / = 10.9, 1H), 2.69 (d, fluorophenyl)-3-[(4R)-2,2- / = 10.2, 1H), 2.35 - 2.15 (m, 2H), 1.90 (d, dimethyloxan-4- / = 10.9, 1H), 1.74 (d, / = 8.6, 1H), 1.63 yl]propyl] (pyrazin-2- (d, / = 12.9, 1H), 1.20 - 0.92 (m, 8H), 0.85
235 ylmethyl) amine 392.2 (t, / = 12.7, 1H).
[(3S)-3-(4-chloro-3- 1H NMR (400 MHz, CDC13) δ 9.43 (s, 2H), fluorophenyl)-3-[(4R)-2,2- 7.34 - 7.13 (m, 3H), 6.96 (dd, / = 4.9, 1.2, dimethyloxan-4- 1H), 6.71 (ddd, / = 9.8, 9.0, 1.7, 2H), 3.80
236 396.2
yl]propyl] (thiophen-3- (s, 2H), 3.65 (dd, / = 12.1, 3.8, 1H), 3.50 ylmethyl) amine (t,/= 11.2, 1H),2.47 (d,/ = 29.1,2H),
2.26 - 2.01 (m, 2H), 1.79-1.61 (m, 2H), 1.56 (d,/= 12.5, IH), 1.16-0.87 (m, 8H),
0.81 (t,/= 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.27 (s, 2H), 7.23 (t, /= 7.9, IH), 6.81 - 6.67 (m, 3H),
6.52 (d, /= 2.3, IH), 3.91 (d, /= 12.6, 2H), 3.67 (dd, / = 11.9, 4.4, IH), 3.52 (t, /
[(3S)-3-(4-chloro-3- = 11.5, IH), 2.55 (d, /= 38.5, 2H), 2.31 (d, fluorophenyl)-3-[(4R)-2,2- /= 0.6, 3H), 2.16 (d, /= 9.0, 2H), 1.73 dimethyloxan-4-yl]propyl] [(5- (dd, /= 25.8, 10.3, 2H), 1.60 (d, /= 12.8, methylthiophen-2- IH), 1.16 - 0.90 (m, 8H), 0.82 (t, /= 12.7,
237 yl)methyl] amine 410.2 IH).
1H NMR (400 MHz, CDC13) δ 9.42 (s, 2H), 7.32-7.19 (m, 2H), 6.99 (d, 7=2.7, IH), 6.89 (dd, /= 5.1, 3.5, IH), 6.73 (ddd, / = 9.9, 9.0, 1.8, 2H), 3.99 (q, /= 13.9, 2H),
[(3S)-3-(4-chloro-3- 3.67 (dd, /= 12.1, 3.8, IH), 3.51 (td, / = fluorophenyl)-3-[(4R)-2,2- 12.2, 2.1, IH), 2.54 (d, /= 33.9, 2H), 2.13 dimethyloxan-4- (dt, /= 12.9, 6.5, 2H), 1.84 - 1.63 (m, 2H), yl]propyl] (thiophen-2- 1.58 (d,/ = 12.8, IH), 1.16-0.91 (m, 8H),
238 ylmethyl) amine 396.2 0.82 (t,/= 12.7, IH).
lH NMR (400 MHz, CDC13) δ 9.63 (s, 2H), 7.68 (d, /= 3.2, IH), 7.35 (d, /= 3.2, IH), 7.24 (t, /= 7.9, IH), 6.77 (ddd, /= 9.8, 9.0, 1.7, 2H), 4.33 (q, /= 14.7, 2H), 3.67 (dd, /= 12.0, 3.9, IH), 3.53 (td, /= 12.2,
[(3S)-3-(4-chloro-3- 2.0, IH), 2.91-2.74 (m, IH), 2.64 (dd, / = fluorophenyl)-3-[(4R)-2,2- 14.9, 7.5, IH), 2.22 (t, /= 8.4, 2H), 1.88 dimethyloxan-4-yl]propyl] (1,3- (d, /= 10.1, IH), 1.82 - 1.67 (m, IH), 1.62 thiazol-2- (d, /= 12.7, IH), 1.17 - 0.90 (m, 8H), 0.84
239 ylmethyl) amine 397.2 (t,/= 12.7, IH).
IH NMR (400 MHz, CDC13) δ 12.83 (s, IH), 9.50 (s, 2H), 7.94 (s, IH), 7.27 (t, J = 7.9, IH), 6.79 (dd, J = 9.8, 1.8, IH), 6.73
[(3S)-3-(4-chloro-3- (dd, J = 8.2, 1.6, IH), 4.22 (q, J = 14.3, fluorophenyl)-3-[(4R)-2,2- 2H), 3.71 (dd, J = 12.1, 3.9, IH), 3.62 - dimethyloxan-4-yl]propyl] (1,3- 3.45 (m, IH), 2.79 - 2.47 (m, 2H), 2.26 - thiazol-5- 2.02 (m, 2H), 1.74 (ddd, J = 12.0, 9.5, 5.5,
240 ylmethyl) amine 397.2
2H), 1.60 (d, J = 12.6, IH), 1.20 - 0.92 (m, 8H), 0.86 (t, J = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.42 (s, 2H), 7.36 (s, 1H), 7.27 (dt, / = 15.8, 4.7, 2H), 6.74 (ddd, / = 9.9, 9.0, 1.8, 2H), 6.34 (d, /
[(3S)-3-(4-chloro-3- = 1.1, 1H), 3.86 - 3.58 (m, 3H), 3.52 (td, / fluorophenyl)-3-[(4R)-2,2- = 12.3, 2.2, 1H), 2.49 (d, / = 30.0, 2H), dimethyloxan-4- 2.22 - 2.01 (m, 2H), 1.82 - 1.64 (m, 2H), yl]propyl] (furan-3- 1.57 (d, / = 12.8, 1H), 1.17 - 0.89 (m, 8H),
241 ylmethyl) amine 380.2 0.82 (t, / = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.15 (s, 2H),
7.25 (t, J = 1.9, 1H), 6.76 (ddd, J = 9.1, 9.0, 1.6, 2H), 6.18 (d, / = 3.1, 1H), 5.82 (d, / = 2.2, 1H), 3.86 (q, / = 14.5, 2H), 3.68
[(3S)-3-(4-chloro-3- (dd, / = 12.0, 4.0, 1H), 3.53 (dd, / = 12.2, fluorophenyl)-3-[(4R)-2,2- 10.4, 1H), 2.56 (d, / = 34.4, 2H), 2.32 - dimethyloxan-4-yl]propyl] [(5- 2.06 (m, 5H), 1.89 - 1.64 (m, 2H), 1.60 (d, methylfuran-2- / = 12.7, 1H), 1.17 - 0.90 (m, 8H), 0.84 (t,
242 yl)methyl] amine 394.2 / = 12.7, 1H).
lH NMR (400 MHz, CDC13) δ 9.30 (s, 2H), 7.29 - 7.10 (m, 6H), 6.83 (td, / = 8.4, 2.1, 1H), 6.70 (d, / = 7.7, 1H), 6.63 (dd, / = 9.7, 1.8, 1H), 3.83 - 3.57 (m, 3H), 3.51 (td, / = 12.3, 2.0, 1H), 2.46 (d, / = 33.6, 2H), benzyl[(3S)-3-[(4R)-2,2- 2.17 - 1.96 (m, 2H), 1.87 - 1.62 (m, 2H), dimethyloxan-4-yl]-3-(3- 1.57 (d, / = 12.8, 1H), 1.14 - 0.91 (m, 8H),
243 fluorophenyl)propyl] amine 356.3 0.82 (t, / = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.10 (s, 1H),
8.55 (s, 1H), 8.40 (d, J = 1.6, 1H), 7.77 (s, 1H), 7.22 (dd, / = 14.0, 7.7, 1H), 6.97 - 6.70 (m, 3H), 4.32 - 4.16 (m, 2H), 3.69 (dd, / = 11.7, 4.5, 1H), 3.55 (t, / = 11.4,
1H), 2.86 (dd, / = 10.8, 6.8, 1H), 2.70 (dd,
[(3S)-3-[(4R)-2,2-dimethyloxan- / = 11.2, 6.9, 1H), 2.22 (t, / = 8.6, 2H),
4-yl]-3-(3- 1.97 - 1.83 (m, 1H), 1.77 (d, / = 8.5, 1H), fluorophenyl)propyl] (pyridin-3- 1.64 (d, / = 12.5, 1H), 1.22 - 0.93 (m, 8H),
244 ylmethyl) amine 357.2 0.87 (t, / = 12.8, 1H).
[(3S)-3-[(4R)-2,2-dimethyloxan- 1H NMR (400 MHz, CDC13) δ 9.41 (s, 2H),
4-yl]-3-(3- 8.61 (s, 1H), 7.82 (d, / = 8.1, 1H), 7.62 (d, fluorophenyl)propyl]({ [6- 7 = 8.1, 1H), 7.23 - 7.17 (m, 1H), 6.87 (td,
245 425.2
(trifluoromethyl)pyridin- 3 - / = 8.4, 2.0, 1H), 6.80 - 6.59 (m, 2H), 3.97 yl] methyl } ) amine (d, / = 13.7, 2H), 3.72 (dd, / = 12.1, 3.9,
1H), 3.64 - 3.49 (m, 1H), 2.60 (d, / = 48.7,
2H), 2.17 (d, / = 8.7, 2H), 1.78 (dd, / = 9.8, 6.1, 2H), 1.64 (d, / = 13.0, 1H), 1.22 - 0.95 (m, 8H), 0.87 (t, / = 12.7, 1H). lH NMR (400 MHz, CDC13) δ 9.05 (s, 2H), 8.14 (s, 1H), 7.70 (d, / = 8.7, 1H), 7.26 - 7.20 (m, 1H), 6.88 (td, / = 8.3, 2.1, 1H), 6.77 (t, / = 7.1, 2H), 6.70 - 6.62 (m, 1H), 3.90 (d, / = 11.1, 5H), 3.73 (dd, / = 12.0,
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.9, 1H), 3.57 (dd, / = 12.3, 10.2, 1H), 2.69
4-yl]-3-(3- (s, 1H), 2.56 (s, 1H), 2.16 (d, / = 10.0, 2H), fluorophenyl)propyl] [(6- 1.77 (dd, / = 10.5, 6.5, 2H), 1.63 (d, / = methoxypyridin-3- 13.0, 1H), 1.21 - 0.94 (m, 8H), 0.87 (t, / =
246 yl)methyl] amine 387.3 12.8, 1H).
lH NMR (400 MHz, CDC13) δ 9.05 (s, 2H), 8.14 (s, 1H), 7.70 (d, / = 8.7, 1H), 7.26 - 7.20 (m, 1H), 6.88 (td, / = 8.3, 2.1, 1H), 6.77 (t, / = 7.1, 2H), 6.70 - 6.62 (m, 1H), 3.90 (d, / = 11.1, 5H), 3.73 (dd, / = 12.0,
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.9, 1H), 3.57 (dd, / = 12.3, 10.2, 1H), 2.69
4-yl]-3-(3- (s, 1H), 2.56 (s, 1H), 2.16 (d, / = 10.0, 2H), fluorophenyl)propyl] [(6- 1.77 (dd, / = 10.5, 6.5, 2H), 1.63 (d, / = methoxypyridin-3- 13.0, 1H), 1.21 - 0.94 (m, 8H), 0.87 (t, / =
246 yl)methyl] amine 387.3 12.8, 1H).
lH NMR (400 MHz, CDC13) δ 9.47 (s, 2H),
8.52 (s, 2H), 8.48 - 8.38 (m, 1H), 7.26 - 7.14 (m, 2H), 6.95 - 6.65 (m, 3H), 4.18 (q, / = 15.0, 2H), 3.70 (dd, / = 12.0, 3.8, 1H), 3.62 - 3.47 (m, 1H), 2.82 (td, / = 11.8, 5.4,
[(3S)-3-[(4R)-2,2-dimethyloxan- 1H), 2.73 - 2.56 (m, 1H), 2.36 - 2.11 (m,
4-yl]-3-(3- 2H), 1.92 (dd, / = 16.7, 6.4, 1H), 1.84 - fluorophenyl)propyl] (pyrazin-2- 1.66 (m, 1H), 1.65 (d, / = 12.9, 1H), 1.25 -
247 ylmethyl) amine 358.3 0.94 (m, 8H), 0.87 (t, / = 12.7, 1H).
lH NMR (400 MHz, CDC13) δ 10.00 (s, 1H), 8.95 (s, 1H), 8.34 (d, / = 8.2, 1H),
[(3S)-3-[(4R)-2,2-dimethyloxan- 7.59 (d, 7 = 8.3, 1H), 7.28 - 7.18 (m, 1H), 4-yl]-3-(3- 6.94 - 6.62 (m, 3H), 4.27 - 4.09 (m, 2H), fluorophenyl)propyl] [(6- 3.67 (dd, / = 12.0, 3.9, 1H), 3.55 (dd, / = methylpyridin-3- 12.2, 10.2, 1H), 2.91 - 2.77 (m, 1H), 2.77 -
248 yl)methyl] amine 371.3
2.55 (m, 4H), 2.36 - 2.08 (m, 2H), 1.98 - 1.81 (m, 1H), 1.76 (dd, / = 8.3, 3.6, 1H),
1.64 (d, / = 12.8, 1H), 1.17 - 0.95 (m, 8H),
0.86 (t, / = 12.8, 1H).
1H NMR (400 MHz, CDC13) δ 9.23 (d, / = 20.9, 2H), 7.31 - 7.09 (m, 3H), 6.95 (dd, / = 4.8, 1.1, 1H), 6.85 (td, / = 8.4, 2.1, 1H), 6.73 (d, / = 7.7, 1H), 6.65 (dd, / = 9.7, 1.9,
1H), 3.84 (d, / = 9.1, 2H), 3.68 (dd, / = 12.0, 3.9, 1H), 3.53 (td, / = 12.2, 2.0, 1H),
[(3S)-3-[(4R)-2,2-dimethyloxan- 2.49 (d, / = 41.7, 2H), 2.13 (dd, / = 18.1,
4-yl]-3-(3- 9.0, 2H), 1.83 - 1.65 (m, 2H), 1.59 (d, / = fluorophenyl)propyl] (thiophen- 12.6, 1H), 1.19 - 0.91 (m, 8H), 0.84 (t, / =
249 3 -ylmethyl) amine 362.2 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.22 (s, 2H), 7.72 (br, 1H), 7.27 - 7.12 (m, 1H), 6.86 (td, / = 8.4, 2.3, 1H), 6.77 - 6.71 (m, 2H), 6.67 (d, / = 9.7, 1H), 6.52 (d, / = 2.5, 1H), 3.90 (q, / = 13.5, 2H), 3.69 (dd, / = 11.9,
[(3S)-3-[(4R)-2,2-dimethyloxan- 4.1, 1H), 3.54 (dd, / = 12.2, 10.4, 1H), 2.56
4-yl]-3-(3- (d, / = 45.2, 2H), 2.31 (s, 3H), 2.24 - 2.05 fluorophenyl)propyl] [(5- (m, 2H), 1.90 - 1.66 (m, 2H), 1.62 (d, / = methylthiophen-2- 12.8, 1H), 1.26 - 0.92 (m, 8H), 0.85 (t, / =
250 yl)methyl] amine 376.2 12.7, 1H).
lH NMR (400 MHz, CDC13) δ 9.27 (s, 2H), 8.51 (br, 1H), 7.29 - 7.12 (m, 2H), 6.98 (d,
/ = 2.8, 1H), 6.86 (ddd, / = 10.3, 6.7, 2.7, 2H), 6.74 (d, / = 7.7, 1H), 6.66 (dd, / =
9.7, 1.8, 1H), 4.01 (q, / = 13.8, 2H), 3.69
(dd, / = 12.0, 3.8, 1H), 3.53 (td, / = 12.3,
[(3S)-3-[(4R)-2,2-dimethyloxan- 2.1, 1H), 2.56 (d, / = 43.6, 2H), 2.26 - 2.03
4-yl]-3-(3- (m, 2H), 1.91 - 1.64 (m, 2H), 1.60 (d, / = fluorophenyl)propyl] (thiophen- 12.7, 1H), 1.24 - 0.92 (m, 8H), 0.85 (t, / =
251 2-ylmethyl)amine 362.2 12.7, 1H).
lH NMR (400 MHz, CDC13) δ 7.69 (d, / = 3.3, 1H), 7.34 (d, J = 3.2, 1H), 7.27 - 7.11
(m, 1H), 6.85 (td, / = 8.3, 2.2, 1H), 6.78 (d, / = 7.7, 1H), 6.73 - 6.66 (m, 1H), 4.34 (q,
[(3S)-3-[(4R)-2,2-dimethyloxan- / = 14.7, 2H), 3.69 (dd, / = 12.0, 3.6, 1H), 4-yl]-3-(3- 3.54 (td, / = 12.2, 2.2, 1H), 2.82 (td, / = fluorophenyl)propyl] (1,3- 12.0, 5.5, 1H), 2.73 - 2.58 (m, 1H), 2.31 -
252 thiazol-2-ylmethyl)amine 363.2
2.09 (m, 2H), 1.99 - 1.81 (m, 1H), 1.75 (dt, /= 16.6, 6.0, IH), 1.64 (d, /= 12.9, IH),
1.21 - 0.94 (m, 8H), 0.86 (t, /= 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.42 (s, 3H), 8.85 (s, IH), 7.85 (s, IH), 7.28 - 7.14 (m, 2H), 6.88 (td, /= 8.4, 2.2, IH), 6.77 (d, / = 7.7, IH), 6.73 - 6.64 (m, IH), 4.19 (q, / = 14.2, 2H), 3.72 (dd, /= 12.1, 3.7, IH), 3.56 (td, /= 12.3, 2.2, IH), 2.78 - 2.61 (m, IH),
[(3S)-3-[(4R)-2,2-dimethyloxan- 2.61-2.50 (m, IH), 2.17 (qd, 7=12.4,
4-yl]-3-(3- 4.6, 2H), 1.89 - 1.68 (m, 2H), 1.62 (d, / = fluorophenyl)propyl] (1,3- 12.9, IH), 1.22 - 0.93 (m, 8H), 0.87 (t, / =
253 thiazol-5-ylmethyl)amine 363.2 12.8, IH).
lH NMR (400 MHz, CDC13) δ 9.09 (s, 3H), 7.34 (s, IH), 7.29 (s, IH), 7.27 - 7.13 (m, IH), 6.87 (td, /= 8.4, 2.1, IH), 6.75 (d, / =
7.6, IH), 6.67 (d, /= 9.6, IH), 6.32 (s, IH), 3.86 - 3.63 (m, 3H), 3.55 (t, /= 11.4,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 2.59 (s, IH), 2.48 (s, IH), 2.15 (dd, /
4-yl]-3-(3- = 20.1, 9.9, 2H), 1.81 - 1.65 (m, 2H), 1.60 fluorophenyl)propyl] (furan-3- (d, /= 12.6, IH), 1.21 - 0.91 (m, 8H), 0.85
254 ylmethyl) amine 346.2 (t,/= 12.8, IH).
1H NMR (400 MHz, CDC13) δ 9.18 (s, 2H), 7.92 (s, IH), 7.25 - 7.12 (m, IH), 6.86 (td, /= 8.4, 2.2, IH), 6.77 (d, /= 7.7, IH), 6.73 - 6.66 (m, IH), 6.17 (d, /= 3.1, IH), 5.81
(dd, /= 3.1, 0.9, IH), 3.85 (q, /= 14.4,
[(3S)-3-[(4R)-2,2-dimethyloxan- 2H), 3.68 (dd, /= 12.0, 3.8, IH), 3.54 (td,
4-yl]-3-(3- /= 12.3, 2.2, IH), 2.60 (s, IH), 2.51 (s, fluorophenyl)propyl] [(5- IH), 2.32 - 2.07 (m, 5H), 1.91-1.68 (m, methylfuran-2- 2H), 1.62 (d,/ = 12.8, IH), 1.20-0.93 (m,
255 yl)methyl] amine 360.3 8H), 0.85 (t,/= 12.8, IH).
H NMR (400 MHz, CDC13) δ 9.11 (s, IH),
8.54 (s, IH), 8.40 (d, /= 7.9, IH), 7.78 (s, IH), 7.28 (t, J= 7.9, IH), 6.98 - 6.68 (m, 2H), 4.24 (s, 2H), 3.69 (dd, /= 12.0, 4.0,
[(3S)-3-(4-chloro-3- IH), 3.54 (t, /= 11.4, IH), 2.86 (s, IH), fluorophenyl)-3-[(4R)-2,2- 2.71 (s, IH), 2.21 (t, /= 8.9, 2H), 1.90 (dd, dimethyloxan-4- /= 19.3, 7.6, IH), 1.74 (d, /= 8.6, IH), yl]propyl] (pyridin-3- 1.63 (d,/= 12.5, IH), 1.16-0.92 (m, 9H),
256 ylmethyl) amine 391.2 0.86 (t,/= 12.7, IH). 1H NMR (400 MHz, CDC13) δ 10.18 (s,
2H), 9.08 (s, IH), 8.54 (s, IH), 8.37 (d, / = 7.6, IH), 7.74 (s, IH), 7.08 - 6.79 (m, 4H), 4.21 (s, 2H), 3.56 (dd, / = 11.9, 3.8, IH), 3.50 - 3.33 (m, IH), 2.85 (dd, / = 11.3,
[(3S)-3-[(4S)-2,2-dimethyloxan- 7.4, IH), 2.70 (t, / = 9.2, IH), 2.29 - 2.09
4-yl]-3-(4- (m, 2H), 2.05 - 1.80 (m, IH), 1.72 (dd, / = fluorophenyl)propyl] (pyridin-3- 8.1, 3.8, IH), 1.60 (d, / = 13.0, IH), 1.26 -
257 ylmethyl) amine 357.2 0.86 (m, 9H).
1H NMR (400 MHz, CDC13) δ 9.99 - 9.24 (m, 2H), 8.62 (s, IH), 7.82 (d, / = 7.5, IH), 7.60 (d, / = 7.7, IH), 6.99 - 6.89 (m, 4H), 4.53 - 4.08 (m, IH), 3.95 (d, / = 13.1, 2H),
[(3S)-3-[(4S)-2,2-dimethyloxan- 3.54 (d, / = 3.7, IH), 3.48 - 3.35 (m, IH),
4-yl]-3-(4- 2.64 (s, IH), 2.51 (s, IH), 2.15 (d, / = 8.4, fluorophenyl)propyl]({ [6- 2H), 1.77 (d, / = 33.4, 2H), 1.58 (d, / = (trifluoromethyl)pyridin- 3 - 13.2, IH), 1.11 (d, 7 = 8.6, 6H), 1.07 - 0.79
258 yl] methyl } ) amine 425.2 (m, 3H).
IH NMR (400 MHz, CDC13) δ 9.01 (s, 2H), 8.13 (s, IH), 7.70 (d, / = 7.7, IH), 6.93 (dd, / = 10.3, 7.0, 4H), 6.77 (d, / =
8.6, IH), 3.90 (d, / = 10.8, 5H), 3.59 (dd, / = 12.0, 3.6, IH), 3.45 (dt, / = 12.1, 5.9,
[(3S)-3-[(4S)-2,2-dimethyloxan-
IH), 2.68 (s, IH), 2.56 (s, IH), 2.25 - 2.04 4-yl]-3-(4- (m, 2H), 1.70 (d, / = 8.5, 2H), 1.59 fluorophenyl)propyl] [(6- methoxypyridin- 3 - (d, / = 13.2, IH), 1.13 (d, / = 8.1, 6H),
259 yl)methyl] amine 387.2 0.97 (ddd, / = 17.5,16.8,6.8,3H).
1H NMR (400 MHz, CDC13) δ 9.25 (d, / = 31.7, 2H), 7.21 (dd, / = 5.1, 2.0, 2H), 6.95 (dd, 7 = 4.8, 1.1, IH), 6.92 - 6.77 (m, 4H), 5.92 (br, IH), 3.83 (d, / = 9.3, 2H), 3.54 (dd, / = 12.0, 3.5, IH), 3.40 (td, / = 12.2,
[(3S)-3-[(4S)-2,2-dimethyloxan- 2.3, IH), 2.48 (d, 7 = 41.0, 2H), 2.11 (dt, /
4-yl]-3-(4- = 16.8, 8.5, 2H), 1.69 (ddd, / = 14.5, 12.0, fluorophenyl)propyl] (thiophen- 5.8, 2H), 1.55 (d, / = 13.0, IH), 1.09 (d, /
260 3 -ylmethyl) amine 362.2 = 9.4, 6H), 1.04 - 0.79 (m, 3H).
[(3S)-3-[(4S)-2,2-dimethyloxan- 1H NMR (400 MHz, CDC13) δ 9.16 (d, / =
4-yl]-3-(4- 25.4, 2H), 8.13 (s, IH), 7.00 - 6.84 (m, fluorophenyl)propyl] [(5- 4H), 6.73 (d, / = 3.4, IH), 6.51 (dd, / =
261 376.2
methylthiophen-2- 3.4, 1.0, IH), 3.90 (q, / = 14.0, 2H), 3.64 - yl)methyl] amine 3.49 (m, 1H), 3.41 (td, / = 12.2, 2.3, 1H),
2.60 (s, 1H), 2.49 (s, 1H), 2.30 (d, / = 0.7, 3H), 2.22 - 2.01 (m, 2H), 1.91 - 1.61 (m, 2H), 1.57 (d, / = 12.9, 1H), 1.10 (d, J =
9.1, 6H), 1.06 - 0.81 (m, 3H).
1H NMR (400 MHz, CDC13) δ 9.18 (s, 2H), 7.23 (dd, / = 5.1, 1.0, 1H), 6.97 (t, J = 5.3, 2H), 6.90 (tt, = 5.1, 3.4, 5H), 4.03 (q, / = 13.8, 2H), 3.55 (dd, / = 12.0, 3.5, 1H), 3.41
[(3S)-3-[(4S)-2,2-dimethyloxan- (td, / = 12.2, 2.4, 1H), 2.62 (s, 1H), 2.51 (s,
4-yl]-3-(4- 1H), 2.13 (dd, / = 17.8, 7.6, 2H), 1.91 - fluorophenyl)propyl] (thiophen- 1.63 (m, 2H), 1.57 (d, / = 12.7, 1H), 1.10
262 2-ylmethyl)amine 362.2 (d, / = 9.4, 6H), 1.05 - 0.81 (m, 3H).
1H NMR (400 MHz, CDC13) δ 9.64 (s, 2H), 7.89 (s, 1H), 7.18 (s, 1H), 7.05 (dd, / = 8.5, 5.4, 2H), 6.97 (t, J = 8.5, 2H), 3.69 (dd, / =
3-bromo-5-({ [(3S)-3-[(4R)-2,2- 12.1, 3.9, 3H), 3.55 (t, / = 11.4, 1H), 2.72 dimethyloxan-4-yl]-3- (d, / = 29.1, 2H), 2.41 - 2.19 (m, 2H), 1.91
(4- (s, 1H), 1.75 (d, / = 8.6, 1H), 1.67 (d, / = fluorophenyl)propyl] amino } met 13.2, 1H), 1.11 (dd, / = 12.2, 4.9, 1H), 1.02 hyl)-l,2- (s, 3H), 1.00 (t, / = 9.2, 7H), 0.85 (t, / =
263 dihydropyridin-2-one 451.2 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.71 (s, 2H), 7.67 (s, 1H), 7.12 (s, 1H), 7.08 - 6.90 (m,
3-chloro-5-({ [(3S)-3-[(4R)-2,2- 4H), 3.79 - 3.60 (m, 3H), 3.54 (s, 1H), dimethyloxan-4-yl]-3- 2.72 (d, / = 28.3, 2H), 2.29 (d, / = 9.3,
(4- 2H), 1.90 (d, / = 12.3, 1H), 1.74 (d, / = fluorophenyl)propyl] amino } met 8.5, 1H), 1.67 (d, / = 12.9, 1H), 1.11 (dt, / hyl)-l,2- = 12.6, 7.4, 1H), 0.99 (t, / = 9.2, 7H), 0.86
264 dihydropyridin-2-one 407.2 (d, / = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.41 (s, 1H), 9.15 (s, 1H), 7.43 (d, / = 2.7, 1H), 7.24 (d, J = 2.1, 1H), 7.09 - 6.89 (m, 4H), 3.76 (s,
5-chloro-3-({ [(3S)-3-[(4R)-2,2- 2H), 3.69 (dd, / = 12.1, 3.9, 1H), 3.62 - dimethyloxan-4-yl]-3- 3.45 (m, 1H), 2.69 (d, / = 45.0, 2H), 2.24
(4- (dd, / = 15.6, 6.2, 2H), 1.88 (d, / = 10.4, fluorophenyl)propyl] amino } met 1H), 1.82 - 1.68 (m, 1H), 1.64 (d, / = 12.8, hyl)-l,2- 1H), 1.10 (dd, / = 12.4, 4.9, 1H), 1.00 (t, /
265 dihydropyridin-2-one 407.2 = 10.4, 7H), 0.83 (t, 7 = 12.7, 1H).
266 348.3
(cyclopentylmethyl) [ (3 S ) -3 - 1H NMR (400 MHz, CDC13) δ 11.28 (s, [(4R)-2,2-dimethyloxan-4- 2H), 8.20 (s, 2H), 7.05 (d, / = 6.9, 4H), yl]-3-(4- 3.86 (dd, / = 11.8, 4.2, IH), 3.68 (t, / = fluorophenyl)propyl] amine 11.4, IH), 3.27 - 2.94 (m, OH), 2.85 (d, / =
5.4, 3H), 2.65 (s, IH), 2.25 (dd, / = 17.1, 8.9, 2H), 2.09 (dt, / = 15.2, 7.6, IH), 1.98 - 1.69 (m, 5H), 1.69 - 1.41 (m, 4H), 1.29 - 1.02 (m, 10H), 0.97 (t, / = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.61 (s, IH), 8.20 (d, 7 = 1.1, IH), 7.89 (dd, / = 8.3, 2.3, IH), 6.93 (d, / = 6.9, 4H), 3.91 (d, J = 22, 2H), 3.69 (dd, / = 12.0, 3.8, IH), 3.55 (td,
[(5-bromo-2-fluoropyridin-3- / = 12.2, 2.1, IH), 2.63 (dd, / = 10.9, 5.1, yl)methyl][(3S)-3- IH), 2.58 - 2.42 (m, IH), 2.17 (t, / = 8.6, [(4R)-2,2-dimethyloxan-4-yl]-3- 2H), 1.89 - 1.65 (m, 2H), 1.62 (d, / = 12.5,
(4- IH), 1.09 (dd, / = 12.4, 4.9, IH), 0.99 (t, /
267 fluorophenyl)propyl] amine 455.2 = 10.9, 7H), 0.83 (t, / = 12.7, IH).
lH NMR (400 MHz, CDC13) δ 9.53 (s, 2H), 8.24 (d, / = 1.9, IH), 7.48 (dd, / = 8.3, 2.4, IH), 7.41 (d, / = 8.2, IH), 6.92 (d, / = 7.2, 4H), 3.79 (d, / = 10.1, 2H), 3.69 (dd, / = 12.1, 3.9, IH), 3.55 (dd, / = 12.2, 10.2,
[(6-bromopyridin-3- IH), 2.57 (s, IH), 2.46 (s, IH), 2.22 - 2.02 yl)methyl][(3S)-3-[(4R)-2,2- (m, 2H), 1.84 - 1.67 (m, 2H), 1.60 (d, / = dimethyloxan-4-yl]-3-(4- 13.0, IH), 1.08 (dd, / = 12.4, 4.9, IH), 0.99
268 fluorophenyl)propyl] amine 435.2 (t, / = 12.5, 7H), 0.82 (t, / = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.51 - 8.93 (m, IH), 8.32 (dd, / = 4.7, 1.6, IH), 7.70 (dd, / = 7.6, 1.6, IH), 7.23 (dd, / = 7.6, 4.8, IH), 7.04 - 6.89 (m, 4H), 4.91 (s, 2H), 4.08 (d, / = 2.2, 2H), 3.70 (d, / = 3.9, IH), 3.66 - 3.49 (m, IH), 2.84 - 2.56 (m, 2H),
[ (2-bromopyridin- 3 - 2.19 (t, / = 8.8, 2H), 1.80 (dd, 7 = 28.0, yl)methyl][(3S)-3-[(4R)-2,2- 11.0, IH), 1.62 (s, IH), 1.11 (tt, / = 12.6, dimethyloxan-4-yl]-3-(4- 6.4, IH), 1.08 - 0.91 (m, 7H), 0.86 (d, / =
269 fluorophenyl)propyl] amine 437.2 12.7, IH).
lH NMR (400 MHz, CDC13) δ 9.66 (s, IH), 8.54 (d, / = 38.6, 2H), 7.92 (s, IH), 6.93
[ (5 -bromopyridin- 3 -
(d, / = 6.9, 4H), 3.89 (q, / = 13.4, 2H), yl)methyl][(3S)-3-[(4R)-2,2- 3.69 (dd, / = 12.0, 4.0, IH), 3.54 (dd, / = dimethyloxan-4-yl]-3-(4-
12.2, 10.2, IH), 2.63 (dd, / = 11.5, 6.1,
270 fluorophenyl)propyl] amine 435.2
IH), 2.57 - 2.44 (m, IH), 2.24 - 2.03 (m, 2H), 1.74 (dd, / = 17.1, 9.9, 2H), 1.60 (d, /
= 12.7, 1H), 1.23 - 1.03 (m, 1H), 0.99 (t, / = 12.1, 7H), 0.82 (t, / = 12.8, 1H).
1H NMR (400 MHz, CDC13) δ 9.73 (s, 1H), 8.21 (d, / = 2.8, 1H), 7.62 (dd, / = 7.8, 2.8, 1H), 6.94 (d, / = 7.2, 4H), 4.05 (s, 2H), 3.69 (dd, / = 12.1, 3.8, 1H), 3.55 (td, / =
[(5-chloro-2-fluoropyridin-3- 12.2, 2.1, 1H), 2.73 - 2.63 (m, 1H), 2.58 yl)methyl][(3S)-3- (d, / = 10.6, 1H), 2.18 (t, J = 8.6, 2H), 1.76 [(4R)-2,2-dimethyloxan-4-yl]-3- (ddd, / = 12.0, 11.6, 6.9, 2H), 1.62 (d, / =
(4- 12.6, 1H), 1.10 (dd, / = 12.4, 5.0, 1H), 1.00
271 fluorophenyl)propyl] amine 409.2 (t, / = 10.8, 7H), 0.83 (t, / = 12.8, 1H).
1H NMR (400 MHz, CDC13) δ 9.26 (s, 2H), 7.55 (d, / = 3.8, 1H), 6.98 (d, / = 3.8, 1H),
6.91 (d, / = 6.9, 4H), 6.03 (s, 1H), 4.04 (dd, / = 30.7, 14.2, 2H), 3.78 (s, 3H), 3.70 (dd, / = 12.0, 3.8, 1H), 3.55 (dt, / = 12.2,
6.1, 1H), 2.65 (d, / = 5.0, 1H), 2.53 (s, methyl 5-({ [(3S)-3-[(4R)-2,2- 1H), 2.27 - 2.05 (m, 2H), 1.88 - 1.63 (m, dimethyloxan-4-yl]-3-(4- 2H), 1.61 (d, / = 12.7, 1H), 1.20 - 1.05 (m, fluorophenyl)propyl] amino } met 1H), 0.99 (t, / = 12.9, 7H), 0.83 (t, / =
272 hyl)thiophene-2-carboxylate 420.2 12.8, 1H).
1H NMR (400 MHz, CDC13) δ 9.25 (s, 2H), 7.97 (d, / = 1.0, 1H), 7.37 (s, 1H), 6.91 (d, / = 7.0, 4H), 6.17 (s, 1H), 4.04 (q, / = 14.2, 2H), 3.76 (s, 3H), 3.70 (dd, / = 12.1, 3.9, 1H), 3.54 (dd, / = 12.3, 10.3, 1H), 2.64 (s, methyl 5-({ [(3S)-3-[(4R)-2,2- 1H), 2.53 (s, 1H), 2.24 - 2.06 (m, 2H), dimethyloxan-4-yl]-3-(4- 1.86 - 1.65 (m, 2H), 1.61 (d, / = 12.5, 1H), fluorophenyl)propyl] amino } met 1.08 (dd, / = 12.4, 4.9, 1H), 1.05 - 0.91
273 hyl)thiophene-3-carboxylate 420.2 (m, 7H), 0.83 (t, 7 = 12.7, 1H
1H NMR (400 MHz, CDC13) δ 9.19 (s, 2H), 7.91 (d, / = 7.5, 1H), 7.85 (s, 1H), 7.34 (dt, / = 15.2, 7.6, 2H), 6.88 (d, / = 6.9, 4H), 6.70 (s, 1H), 3.83 (d, / = 11.5, 5H), 3.67 (dd, / = 11.8, 4.4, 1H), 3.52 (t, / = 12.1, methyl 3-({ [(3S)-3-[(4R)-2,2- 1H), 2.56 (s, 1H), 2.46 (s, 1H), 2.20 - 1.89 dimethyloxan-4-yl]-3-(4- (m, 2H), 1.71 (dd, 7 = 20.9, 9.3, 2H), 1.58 fluorophenyl)propyl] amino } met (d, / = 13.0, 1H), 1.17 - 0.86 (m, 8H), 0.80
274 hyl)benzoate 414.2 (t, / = 12.8, 1H). IH NMR (400 MHz, CDC13) δ 9.44 (s,
2H), 7.74 - 7.57 (m, 3H), 7.54 (s, IH),
[(3S)-3-[(4R)-2,2-dimethyloxan- 7.42 - 7.29 (m, 2H), 7.16 (dd, J = 8.5, 1.6,
4-yl]-3-(4- IH), 6.89 - 6.67 (m, 4H), 1.51 (d, J = 13.0, fluorophenyl)propyl] (naphthalen IH), 1.09 - 0.80 (m, 8H), 0.74 (t, J = 12.7,
275 -2- ylmethyl) amine 406.2 IH).
1H NMR (400 MHz, CDC13) δ 9.24 (d, / = 33.2, 2H), 7.67 (d, / = 7.9, 3H), 7.43 (dt, / = 15.0, 7.0, 2H), 7.36 - 7.19 (m, 2H), 6.87 - 6.74 (m, 4H), 3.98 (s, 2H), 3.62 (dd, / = 12.0, 3.8, IH), 3.46 (dd, / = 12.2, 10.3,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 2.48 (s, 2H), 2.16 - 1.94 (m, 2H),
4-yl]-3-(4- 1.60 (d, / = 8.5, 2H), 1.50 (d, / = 12.6, fluorophenyl)propyl] (naphthalen IH), 1.13 - 0.82 (m, 8H), 0.74 (t, / = 12.8,
276 - 1 - ylmethyl) amine 406.3 IH).
1H NMR (400 MHz, CDC13) δ 10.20 (s, 2H), 9.17 (s, IH), 8.86 (s, IH), 7.94 (dd, /
= 10.8, 9.0, 2H), 7.79 (dd, / = 11.4, 4.1,
IH), 7.67 (t, / = 7.6, IH), 6.97 (ddd, / = 25.2, 13.0, 7.1, 4H), 4.29 (s, 2H), 3.66 (dd,
/ = 12.1, 3.9, IH), 3.59 - 3.46 (m, IH), 2.88 (d, / = 4.1, IH), 2.72 (d, / = 4.5, IH),
[(3S)-3-[(4R)-2,2-dimethyloxan- 2.23 (t, J = 8.6, 2H), 1.93 (d, / = 7.7, IH),
4-yl]-3-(4- 1.82 - 1.70 (m, IH), 1.64 (d, / = 12.7, IH), fluorophenyl)propyl] (quinolin-3- 1.10 (dd, / = 12.4, 4.9, IH), 1.00 (d, / =
277 ylmethyl) amine 407.3 11.9, 7H), 0.84 (t, / = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.31 (d, / = 58.0, 2H), 7.26 - 7.12 (m, 4H), 7.08 (d, / = 7.4, 2H), 6.85 (d, / = 8.7, 2H), 6.74 (t, / = 5.7, 2H), 3.83 - 3.64 (m, 5H), 3.53 (dd, / = 11.5, 4.0, IH), 3.41 (dd, / = 17.4, 6.8, IH),
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.17 (s, 2H), 2.56 (s, IH), 2.46 (s, IH),
4-yl]-3-(4- 2.07 (dd, / = 15.2, 6.7, 2H), 1.82 - 1.69 fluorophenyl)propyl] (quinolin-4- (m, IH), 1.70 - 1.59 (m, IH), 1.55 (d, / =
278 ylmethyl) amine 407.3 13.0, IH), 1.22 - 0.79 (m, 9H).
1H NMR (400 MHz, CDC13) δ 9.34 (d, / = 37.1, 2H), 7.26 - 7.09 (m, 3H), 7.09 - 6.98
[(3S)-3-[(4R)-2,2-dimethyloxan- (m, 2H), 6.96 - 6.82 (m, 4H), 4.02 (s, IH), 4-yl]-3-(4- 3.46 (dd, / = 12.0, 3.9, IH), 3.29 (td, / = fluorophenyl)propyl] (2- 12.2, 2.0, IH), 2.94 (s, 2H), 2.85 (dd, / =
279 phenylethyl) amine 370.2
10.5, 5.1, 2H), 2.61 (s, IH), 2.48 (s, IH), 2.20 - 2.03 (m, 2H), 1.79 (dd, 7 = 11.4,
3.9, IH), 1.71 - 1.54 (m, IH), 1.49 (d, / = 12.7, IH), 0.75 (t, / = 12.8, IH)
1H NMR (400 MHz, CDC13) δ 10.01 - 9.36 (m, IH), 8.61 (d, / = 1.5, IH), 7.76 (dd, / = 8.0, 2.1, IH), 7.60 (d, / = 8.0, IH), 6.94 (d, / = 6.9, 4H), 3.92 (d, / = 4.7, 2H), 3.69 (dd, / = 12.1, 3.8, IH), 3.56 (dd, / = 12.2, 10.2, IH), 3.03 (s, 2H), 2.61 (d, / = 5.3,
5-({ [(3S)-3-[(4R)-2,2- IH), 2.49 (s, IH), 2.15 (d, / = 11.3, 2H), dimethyloxan-4-yl]-3-(4- 1.77 (dd, / = 10.1, 5.6, 2H), 1.63 (d, / = fluorophenyl)propyl] amino } met 12.5, IH), 1.19 - 0.92 (m, 8H), 0.83 (t, / = hyl)pyridine-2-carbonitrile 382.3 12.8, IH).
1H NMR (400 MHz, CDC13) δ 9.27 (s, 2H), 7.41 - 7.31 (m, 3H), 7.26 (dd, / = 6.5, 2.9,
2H), 7.11 - 6.93 (m, 4H), 4.49 (s, IH), 3.76 (dd, / = 12.0, 4.0, IH), 3.61 (dd, / =
1 ' , 1 '-dideutriumbenzyl[(3S)-3- 12.2, 10.4, IH), 2.57 (d, / = 36.5, 2H), 2.33 [(4R)-2,2-dimethyloxan-4-yl]-3- - 2.06 (m, 2H), 1.95 - 1.73 (m, 2H), 1.67
(4- (d, / = 12.7, IH), 1.29 - 0.97 (m, 8H), 0.90 fluorophenyl)propyl] amine 358.3 (t, / = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 12.27 (s, IH), 7.45 (d, J = 5.6, IH), 7.23 - 6.93 (m, 6H), 4.44 (d, J = 9.6, IH), 4.35 (s, IH), 3.82 (dd, J = 12.0, 4.1, IH), 3.66 (t, J =
12.0, IH), 3.02 (s, OH), 2.70 (d, J = 19.9,
[(3S)-3-[(4R)-2,2-dimethyloxan- 4H), 2.46 (d, J = 10.2, IH), 2.36 (s, IH),
4-yl]-3-(4- 2.25 (d, J = 9.8, IH), 2.03 (s, IH), 1.87 (s, fluorophenyl)propyl] (methyl) (thi IH), 1.79 (d, J = 13.4, IH), 1.22 (dd, J = ophen-2- 12.1, 4.6, IH), 1.10 (t, J = 10.5, 7H), 0.93 ylmethyl) amine 376.2 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 7.44 (dd, J = 11.9, 4.9, IH), 7.16 - 6.97 (m, 6H), 4.45 (br, IH), 3.82 (dd, J = 11.9, 4.4, IH), 3.67 (t, J = 12.0, IH), 3.06 (d, J = 9.7, 2H), 2.86
[(3S)-3-[(4R)-2,2-dimethyloxan- (d, J = 32.8, IH), 2.72 - 2.46 (m, IH), 2.35
4-yl]-3-(4- (d, J = 10.5, IH), 2.23 (d, J = 8.1, IH), 2.08 fluorophenyl)propyl] (ethyl) (thio
- 1.96 (m, IH), 1.87 (s, IH), 1.80 (d, J = phen-2- 13.2, IH), 1.34 (t, J = 6.9, 2H), 1.24 (dd, J ylmethyl) amine 390.3
= 14.5, 7.7, 2H), 1.19 - 1.01 (m, 7H), 0.93 (t, J = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 12.61 (s, IH), 7.50 - 7.35 (m, IH), 7.21 - 6.89 (m, 6H), 4.44 (br, IH), 3.81 (dd, / = 12.0, 4.3,
IH), 3.20 (s, 2H), 2.99 - 2.68 (m, 3H),
[(3S)-3-[(4R)-2,2-dimethyloxan- 2.68 - 2.44 (m, IH), 2.39 (s, IH), 2.23 (s,
4-yl]-3-(4- IH), 2.16 - 1.93 (m, IH), 1.92 - 1.71 (m, fluorophenyl)propyl] (propyl) (thi 3H), 1.68 (s, IH), 1.32 - 1.00 (m, 8H),
284 ophen-2-ylmethyl)amine 404.3 1.00 - 0.82 (m, 4H).
1H NMR (400 MHz, CDC13) δ 12.24 (s, IH), 7.44 (dd, / = 10.9, 4.9, IH), 7.17 - 6.96 (m, 6H), 4.45 (br, IH), 3.81 (dd, / = 11.8, 4.4, 2H), 3.66 (t, / = 11.4, IH), 3.05 - 2.70 (m, 3H), 2.60 (s, IH), 2.37 (d, / = butyl[(3S)-3-[(4R)-2,2- 11.0, IH), 2.22 (s, IH), 1.99 (d, / = 6.4, dimethyloxan-4-yl]-3-(4- IH), 1.93 - 1.73 (m, 2H), 1.73 - 1.51 (m, fluorophenyl)propyl] (thiophen- 2H), 1.47 - 1.16 (m, 3H), 1.16 - 0.99 (m,
285 2-ylmethyl)amine 418.3 7H), 0.99 - 0.85 (m, 4H).
1H NMR (400 MHz, CDC13) δ 11.30 (s, IH), 7.45 (s, IH), 7.21 - 6.94 (m, 6H), 6.17 (br, 1H), 4.51 (d, / = 21.3, 2H), 3.82 (dd, / = 12.0, 4.2, IH), 3.67 (t, / = 11.6,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 2.82 (d, / = 12.9, 2H), 2.71 (s, IH),
4-yl]-3-(4- 2.56 (d, / = 11.9, IH), 2.43 (s, IH), 2.21 (s, fluorophenyl)propyl] (2- IH), 2.04 (d, / = 9.5, 2H), 1.95 - 1.70 (m, methylpropyl)(thiophen-2- 2H), 1.23 (dd, / = 12.4, 4.5, IH), 1.17 -
286 ylmethyl) amine 418.3 0.83 (m, 14H).
1H NMR (400 MHz, CDC13) δ 11.32 (s,
IH), 7.43 (dd, / = 17.3, 4.9, IH), 7.22 - 6.87 (m, 6H), 5.04 (s, 2H), 4.66 - 4.27 (m, 2H), 3.79 (d, / = 4.2, IH), 3.75 - 3.50 (m,
[(3S)-3-[(4R)-2,2-dimethyloxan- 2H), 3.13 - 2.12 (m, 3H), 1.93 (dd, / =
4-yl]-3-(4- 105.8, 10.9, 4H), 1.40 (d, / = 6.4, IH), 1.31 fluorophenyl)propyl] (propan-2- - 1.14 (m, 5H), 1.07 (dd, / = 17.6, 14.4,
287 yl) (thiophen-2- ylmethyl) amine 404.3 8H), 0.88 (d, 7 = 12.3, IH).
1H NMR (400 MHz, CDC13) δ 9.51 (s, 2H), benzyl[(3S)-3-[4-chloro-3- 7.33 (d, / = 8.2, IH), 7.19 (ddt, / = 9.5, (trifluoromethyl)phenyl] -3- 6.7, 3.2, 6H), 7.05 (dd, / = 8.2, 1.8, IH), [(4R)-2,2-dimethyloxan- 3.83 - 3.58 (m, 3H), 3.45 (ddd, / = 21.1,
288 4yl]propyl] amine 440.2
13.1, 8.7, IH), 2.86 (s, IH), 2.48 (s, IH), 2.37 (s, IH), 2.29 - 2.03 (m, 2H), 1.71
(ddd, / = 20.5, 17.4, 9.8, 2H), 1.55 (d, / = 12.6, IH), 1.10 - 0.86 (m, 8H), 0.80 (t, / =
12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.11 (s, IH), 8.56 (s, IH), 8.43 (d, / = 6.3, IH), 7.81 (s, IH), 7.42 (d, / = 8.2, IH), 7.33 (s, IH), 7.17 (s, IH), 4.25 (s, 2H), 3.70 (dd, / =
[(3S)-3-[4-chloro-3- 11.8, 4.0, IH), 3.56 (t, / = 11.6, IH), 2.88 (trifluoromethyl)phenyl] -3- (s, IH), 2.70 (s, IH), 2.44 - 2.16 (m, 2H), [(4R)-2,2-dimethyloxan-4- 1.94 (s, IH), 1.79 (d, / = 8.7, IH), 1.64 (d, yl]propyl] (pyridin-3- 7 = 12.2, IH), 1.12 - 0.94 (m, 8H), 0.87 (t,
289 ylmethyl) amine 441.2 / = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.81 (s, IH), 8.62 (s, IH), 7.80 (d, / = 7.9, IH), 7.60 (d, / = 8.0, IH), 7.39 (d, / = 8.2, IH), 7.29 (s, IH), 7.14 - 7.06 (m, IH), 3.93 (q, / = 13.9, 2H), 3.67 (dd, / = 11.9, 4.3, IH), 3.54 (t, /
[(3S)-3-[4-chloro-3- = 11.3, IH), 3.05 (s, IH), 2.61 (d, / = 6.3, (trifluoromethyl)phenyl] -3- IH), 2.48 (t, / = 9.1, IH), 2.24 (dd, / = [(4R)-2,2-dimethyloxan-4- 25.3, 13.5, 2H), 1.96 - 1.72 (m, 2H), 1.62 yl]propyl] (pyridin-3- (d, / = 12.5, IH), 1.21 - 0.89 (m, 8H), 0.84
290 ylmethyl) amine 509.2 (t, / = 12.6, IH).
IH NMR (400 MHz, CDC13) δ 9.44 (d, J = 26.4, 2H), 7.36 (d, J = 8.2, IH), 7.31 - 7.18 (m, 3H), 7.08 (dd, J = 8.2, 1.8, IH), 6.95 (dd, J = 4.9, 1.3, IH), 3.82 (s, 2H), 3.66 (dd, J = 12.0, 3.8, IH), 3.51 (td, J = 12.2,
[(3S)-3-[4-chloro-3- 2.0, IH), 3.10 (s, IH), 2.51 (s, IH), 2.40 (s, (trifluoromethyl)phenyl] -3- IH), 2.22 (dd, J = 14.2, 5.8, IH), 2.15 (d, J [(4R)-2,2-dimethyloxan-4- = 11.1, IH), 1.87 - 1.65 (m, 2H), 1.57 (d, J yl]propyl] (thiophen-3- = 12.7, IH), 1.13 - 0.88 (m, 8H), 0.82 (t, J
291 ylmethyl) amine 446.2 = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.33 (s, 2H), 7.36 (d, / = 8.2, IH), 7.31 - 7.20 (m, 2H), 7.09 (dd, / = 8.2, 1.9, IH), 6.97 (d, / = 2.7,
[(3S)-3-[4-chloro-3- IH), 6.88 (dd, / = 5.1, 3.5, IH), 4.97 (s, (trifluoromethyl)phenyl] -3- IH), 4.02 (q, / = 14.2, 2H), 3.68 (dd, / = [(4R)-2,2-dimethyloxan-4-
12.1, 3.9, IH), 3.52 (td, / = 12.2, 2.0, IH), yl]propyl] (thiophen-2- 2.59 (s, IH), 2.47 (s, IH), 2.24 (dd, / =
292 ylmethyl) amine 446.2
14.2, 5.8, IH), 2.15 (d, / = 6.4, IH), 1.75 (ddd, / = 13.6, 12.1, 7.5, 2H), 1.59 (d, / =
12.5, IH), 1.18 - 0.88 (m, 8H), 0.83 (t, / =
12.7, IH).
1H NMR (400 MHz, CDC13) δ 7.43 (d, / = 8.2, IH), 7.38 - 7.25 (m, 7H), 7.17 (d, / = 8.2, IH), 3.83 (dd, / = 26.4, 12.8, 2H), 3.63 (dd, / = 12.0, 3.5, IH), 3.49 (dt, / = 12.1, 6.1, IH), 2.61 (s, 3H), 2.49 (s, IH), 2.28 benzyl[(3S)-3-[4-chloro-3- (dd, / = 25.5, 14.3, 2H), 1.88 (d, / = 8.9, (trifluoromethyl)phenyl] -3- IH), 1.83 - 1.70 (m, IH), 1.65 (d, / = 12.6, [(4S)-2,2-dimethyloxan-4- IH), 1.21 (t, / = 14.0, 6H), 1.02 (dt, / =
293 yl]propyl] amine 440.2 15.6, 7.2, 3H).
1H NMR (400 MHz, CDC13) δ 9.20 (s, IH),
8.64 (s, IH), 8.50 (d, J = 1.3, IH), 7.88 (s, IH), 7.51 (d, / = 8.2, IH), 7.44 (d, / = 1.8,
IH), 7.34 - 7.28 (m, 2H), 4.34 (s, 2H),
3.65 (d, / = 3.4, IH), 3.61 - 3.42 (m, IH),
[(3S)-3-[4-chloro-3- 2.97 (dt, / = 11.3, 5.5, IH), 2.81 (dd, / = (trifluoromethyl)phenyl] -3- 11.3, 7.0, IH), 2.40 (d, / = 11.4, 2H), 2.14 [(4S)-2,2-dimethyloxan-4- - 1.93 (m, IH), 1.85 (dd, / = 8.0, 3.9, IH), yl]propyl] (pyridin-3- 1.70 (d, / = 12.7, IH), 1.21 (d, / = 3.1,
294 ylmethyl) amine 441.2 6H), 1.08 (dd, 7 = 20.4, 8.0, 3H).
IH NMR (400 MHz, CDC13) δ 8.63 (s, IH), 7.82 (d, J = 7.8, IH), 7.60 (d, J = 8.0, IH), 7.38 (d, J = 8.2, IH), 7.30 (d, J = 1.6, IH), 7.13 (dd, J = 8.2, 1.7, IH), 3.96 (q, J = 13.7, 2H), 3.55 (dd, J = 12.0, 3.5, IH), 3.44 (dd, J = 12.1, 2.4, IH), 2.89 (br, IH), 2.73
[(3S)-3-[4-chloro-3- - 2.58 (m, IH), 2.51 (dd, J = 11.2, 7.6, (trifluoromethyl)phenyl] -3- IH), 2.37 - 2.08 (m, 2H), 1.86 (d, J = 8.5, [(4S)-2,2-dimethyloxan-4- IH), 1.81 - 1.69 (m, IH), 1.59 (d, J = 12.7, yl]propyl] (pyridin-3- IH), 1.10 (d, J = 8.3, 6H), 0.95 (ddd, J =
295 ylmethyl) amine 509.2 17.7, 12.5, 6.0, 3H).
1H NMR (400 MHz, CDC13) δ 9.39 (d, / = 26.9, 2H), 7.36 (d, / = 8.2, IH), 7.33 - 7.20 (m, 3H), 7.09 (dd, / = 8.2, 1.9, IH), 6.95
[(3S)-3-[4-chloro-3- (dd, / = 4.9, 1.3, IH), 3.85 (d, / = 10.1, (trifluoromethyl)phenyl] -3- 2H), 3.54 (dd, / = 12.0, 3.3, IH), 3.41 (td, [(4S)-2,2-dimethyloxan-4- / = 12.0, 2.6, IH), 2.58 (s, 2H), 2.41 (s, yl]propyl] (thiophen-3- IH), 2.22 (dd, / = 14.1, 5.7, IH), 2.12 (s,
296 ylmethyl) amine 446.2
IH), 1.78 (d, 7 = 8.9, IH), 1.74 - 1.62 (m, IH), 1.56 (d, / = 12.8, IH), 1.10 (d, / =
8.6, 6H), 1.03 - 0.80 (m, 3H).
1H NMR (400 MHz, CDC13) δ 9.57 (s, 2H),
7.35 (d, / = 8.2, IH), 7.27 (d, / = 1.7, IH), 7.22 (dd, / = 5.1, 0.9, IH), 7.11 (dd, / = 8.2, 1.8, IH), 6.99 (d, / = 2.7, IH), 6.88 (dd, / = 5.1, 3.5, IH), 4.00 (q, / = 14.2,
2H), 3.54 (dd, / = 12.0, 3.4, IH), 3.41 (td, / = 12.0, 2.5, IH), 2.58 (d, / = 4.8, 2H),
[(3S)-3-[4-chloro-3- 2.46 (t, / = 9.0, IH), 2.23 (dd, / = 14.1, (trifluoromethyl)phenyl] -3- 5.7, IH), 2.15 (s, IH), 1.81 (d, 7 = 7.8, [(4S)-2,2-dimethyloxan-4- IH), 1.76 - 1.64 (m, IH), 1.57 (d, / = 12.9, yl]propyl] (thiophen-2- IH), 1.10 (d, / = 8.2, 6H), 1.03 - 0.79 (m,
297 ylmethyl) amine 446.2 3H).
(cyclohexylmethyl) [ (3 S ) - 3 - 7.15 (t, J = 7.9, IH), 6.76 (dd, J = 11.7, 9.2, [(4R)-2,2-dimethyloxan-4- 2H), 3.77 (d, J = 3.9, IH), 3.64 (s, IH), yl]-3-(3-fluoro-4- 2.67 (s, 4H), 2.16 - 1.46 (m, 18H), 1.38 -
298 methylphenyl)propyl] amine 376.3 1.02 (m, 5H), 0.94 (dd, J = 15.1, 10.7, 2H).
7.05 (t, J = 7.6, IH), 6.73 - 6.50 (m, IH), 3.77 - 3.63 (m, IH), 3.63 - 3.42 (m, IH), 3.09 - 2.81 (m, IH), 2.81 - 2.27 (m, 6H),
(cyclopentylmethyl) [ (3 S ) -3 - 2.15 (dd, J = 17.3, 5.2, 3H), 1.95 (dddd, J = [(4R)-2,2-dimethyloxan-4- 29.6, 27.5, 18.8, 6.4, IH), 1.87 - 1.26 (m, yl]-3-(3-fluoro-4- 12H), 1.19 - 0.92 (m, 7H), 0.92 - 0.66 (m,
299 methylphenyl)propyl] amine 362.3 IH).
7.16 (s, IH), 6.77 (dd, J = 11.3, 9.1, 2H), 3.78 (dd, J = 12.1, 3.7, IH), 3.65 (dd, J =
(3,3-dimethylbutyl)[(3S)-3- 24.0, 11.8, IH), 3.02 - 2.48 (m, 3H), 2.27 [(4R)-2,2-dimethyloxan-4- (t, J = 9.1, 5H), 1.76 (s, 16H), 1.62 - 1.40 yl]-3-(3-fluoro-4- (m, 2H), 1.20 (dd, J = 12.3, 5.0, IH), 1.11
300 methylphenyl)propyl] amine 364.3 (d, J = 11.9, 7H), 0.92 (d, J = 16.0, 9H).
8.66 (dt, J = 6.2, 3.1, IH), 8.32 (ddd, J = 7.9, 4.8, 1.6, IH), 7.85 - 7.61 (m, 2H), 7.36 (d,5H), 4.04 (td, 2H), 3.74 (dd, J = 12.2, 3.7, IH), 3.59 (ddd, J = 25.6, 17.9, 2.2, IH), 3.32 - 3.10 (m, IH), 2.96 (dd, J = benzyl[(3S)-3-[(4R)-2,2- 13.4, 6.1, IH), 2.83 (m, IH), 2.53 - 2.21 dimethyloxan-4-yl]-3- (m, 2H), 2.10 (ddd, IH), 1.70 (d, J = 12.9,
301 (pyridin-2-yl)propyl] amine 339.3 IH), 1.41-0.85 (m, 9H). 8.62 (s, IH), 8.26 (dd, J = 7.8, 6.3, IH),
7.78 - 7.67 (m, IH), 7.63 (d, J = 8.0, IH), 7.35 (dd, J = 5.1, 1.1, IH), 7.01 (dd, J =
[(3S)-3-[(4R)-2,2-dimethyloxan- 5.1, 3.5, 2H), 4.30 (d, J = 17.3, 3H), 3.22 4-yl]-3-(pyridin-2- (s, IH), 2.97 (s, 2H), 2.37 (dd, J = 26.8, yl)propyl] (thiophen-2- 7.0, 2H), 2.07 (s, IH), 1.71 (d, J = 12.3,
302 ylmethyl) amine 345.2 IH), 1.34 - 0.86 (m, 10H).
8.77 (s, IH), 8.65 (d, J = 5.3, IH), 8.39 (t, J = 7.9, IH), 8.11 (d, J = 8.1, 1H), 7.91 - 7.61 (m, 3H), 4.21 (t, J = 8.0, 2H), 3.77
[(3S)-3-[(4R)-2,2-dimethyloxan- (dd, J = 12.1, 4.0, IH), 3.64 (t, J = 11.3, 4-yl]-3-(pyridin-2- IH), 3.27 (d, J = 7.2, IH), 3.16 - 2.86 (m, yl)propyl]({ [6- 2H), 2.42 (d, J = 44.7, 2H), 2.24 - 2.00 (m, (trifluoromethyl)pyridin- 3 - IH), 1.76 (d, J = 11.5, IH), 1.33 - 0.78 (m,
303 yl] methyl } ) amine 408.3 9H).
8.90 (s, 2H), 8.68 (d, J = 5.4, IH), 8.35 (t, J
= 7.8, IH), 7.91 - 7.65 (m, 2H), 3.83 - 3.71 (m, IH), 3.71 - 3.55 (m, IH), 3.32 (s, IH), 2.99 (s, IH), 2.76 (s, 3H), 2.40 (d, J =
(cyclohexylmethyl) [ (3 S ) - 3 - 37.1, 2H), 2.21 - 2.05 (m, IH), 1.70 (d, J = [(4R)-2,2-dimethyloxan-4- 35.4, 7H), 1.22 (dt, J = 12.3, 10.9, 3H),
304 yl]-3-(pyridin-2-yl)propyl]amine 345.3 1.17 - 1.10 (m, 7H), 1.09 - 0.87 (m, 4H).
8.66 (t, J = 5.5, IH), 8.28 (tdd, J = 7.8, 3.6,
1.5, IH), 7.85 - 7.61 (m, 2H), 7.53 - 7.37 (m, IH), 7.37 - 7.21 (m, IH), 7.21 - 7.02 (m, IH), 4.27 - 3.91 (m, 2H), 3.75 (dd, J =
12.1, 3.8, IH), 3.59 (ddd, J = 25.7, 17.0, 4.0, IH), 3.23 - 3.06 (m, IH), 2.90 (t, J =
9.6, IH), 2.79 (d, J = 4.6, IH), 2.48 - 2.21
[(3S)-3-[(4R)-2,2-dimethyloxan- (m, 2H), 2.20 - 1.97 (m, IH), 1.70 (d, J = 4-yl]-3-(pyridin-2- 12.4, IH), 1.18 (dd, J = 11.9, 7.4, 2H), 1.15 yl)propyl] (thiophen-3- - 1.06 (m, 5H), 1.00 (dd, J = 23.8, 11.5,
305 ylmethyl) amine 345.2 2H).
1H NMR (400 MHz, CDC13) δ 9.29 (brs, IH), 7.37 - 7.23 (m, 5H), 7.17 (d, / = 5.1, benzyl[(3S)-3-[(4R)-2,2- H), 6.89 (dd, / = 5.1, 3.4, IH), 6.74 - 6.66
306 dimethyloxan-4-yl]-3- 344.2 (m, IH), 3.94 - 3.78 (m, 2H), 3.74 (dd, / =
(thiophen-2-yl)propyl] amine 12.0, 3.9, IH), 3.60 (dd, / = 12.2, 10.2,
IH), 2.69 (m, 2H), 2.58 (t, / = 8.4, IH), 2.17 (m, IH), 1.78 (dd, / = 8.0, 3.9, 2H), 1.64 (d, / = 12.9, IH), 1.20 (dt, / = 12.5, 6.7, 2H), 1.13 (s, 3H), 1.09 (s, 3H), 0.98 (t,
/ = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.12 (s, IH), 8.63 (s, IH), 8.43 (d, / = 7.6, IH), 7.79 (s, IH), 7.21 (d, / = 4.7, IH), 6.95 (dd, / = 5.1, 3.4, IH), 6.79 (d, / = 2.6, IH), 4.29
[(3S)-3-[(4R)-2,2-dimethyloxan- (dd, / = 27.8, 13.2, 2H), 3.75 (dd, / = 11.9, 4-yl]-3-(thiophen-2-
307 345.2 4.1, IH), 3.62 (dd, / = 12.2, 10.5, IH), 3.05 yl)propyl] (pyridin-3- - 2.80 (m, 2H), 2.68 (t, / = 8.6, IH), 2.31 ylmethyl) amine
(m, IH), 1.86 (ddd, / = 17.8, 16.3, 8.1, 2H), 1.71 (d, / = 11.9, IH), 1.26 (d, / = 12.4, IH), 1.19 (dd, / = 10.7, 6.8, IH), 1.13 (s, 3H), 1.11 (s, 3H), 1.02 (t, / = 12.8, IH). lH NMR (400 MHz, CDC13) δ 9.72 (s, 2H), 8.68 (s, IH), 7.91 (d, / = 8.0, IH), 7.74 - 7.72 (m, IH), 7.68 (d, / = 8.0, IH), 7.18 (d, / = 4.8, IH), 6.90 (dd, / = 5.1, 3.4, IH),
[(3S)-3-[(4R)-2,2-dimethyloxan- 6.72 (dd, / = 3.4, 0.8, IH), 4.20 (brs, IH), 4-yl]-3-(thiophen-2- 4.04 (dd, / = 34.6, 13.3, 2H), 3.77 (dd, / =
308 yl)propyl]({ [6- 413.2
12.0, 4.0, IH), 3.63 (dd, / = 12.1, 10.4, (trifluoromethyl)pyridin- 3 - IH), 2.75 (dd, / = 23.1, 10.3, 2H), 2.62 (t, yl] methyl } ) amine
/ = 8.6, IH), 2.24 (m, IH), 1.81 (dd, / = 11.9, 8.7, 2H), 1.69 (d, / = 12.9, IH), 1.31 - 1.15 (m, 2H), 1.13 (s, 3H), 1.11 (s, 3H), 1.00 (t, / = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.04 (s, IH), 8.38 (d, / = 7.9, IH), 7.63 (d, / = 8.1, IH), 7.20 (d, / = 4.7, IH), 6.94 (dd, / = 5.1, 3.4, IH), 6.78 (d, / = 2.6, IH), 6.02 (brs, IH),
[(3S)-3-[(4R)-2,2-dimethyloxan- 4.28 (dd, / = 27.5, 12.8, 2H), 3.78 - 3.52
4-yl]-3-(thiophen-2-
309 359.2 (m, 2H), 2.97 - 2.79 (m, 2H), 2.78 (s, 3H), yl)propyl] [(6-methylpyridin-3- 2.66 (t, / = 8.5, IH), 2.28 (m, IH), 1.87 yl)methyl] amine
(dd, / = 34.3, 7.9, 2H), 1.70 (d, / = 12.4, IH), 1.25 (d, / = 12.9, IH), 1.18 (dd, / = 12.4, 4.9, IH), 1.13 (s, 3H), 1.11 (s, 3H), 1.01 (t, / = 12.8, IH).
[(3S)-3-[(4R)-2,2-dimethyloxan- lH NMR (400 MHz, CDC13) δ 9.03 (brs,
4-yl]-3-(thiophen-2- IH), 8.16 (s, IH), 7.69 (d, / = 8.2, IH),
310 375.2
yl)propyl] [(6-methoxypyridin-3- 7.20 (d, / = 4.8, IH), 6.92 (dd, / = 5.1, 3.4, yl)methyl] amine IH), 6.80 (d, / = 8.3, IH), 6.75 (d, / = 2.6,
IH), 4.14 (brs, IH), 4.02 - 3.85 (m, 6H), 3.78 (dd, / = 11.8, 4.2, 1H), 3.63 (t, / =
11.3, 1H), 2.79 (d, / = 24.1, 2H), 2.62 (t, / = 8.4, 1H), 2.23 (m, 1H), 1.82 (d, / = 8.2, 2H), 1.69 (d, / = 12.5, 1H), 1.28 - 1.15 (m, 2H), 1.14 (s, 3H), 1.11 (s, 3H), 1.01 (t, / = 12.8, 1H).
1H NMR (400 MHz, CDC13) δ 9.45 (brs, 1H), 7.31 (dd, / = 5.1, 0.7, 1H), 7.18 (d, / = 4.9, 1H), 7.08 (d, / = 3.0, 1H), 7.01 - 6.94 (m, 1H), 6.91 (dd, / = 5.1, 3.4, 1H),
[(3S)-3-[(4R)-2,2-dimethyloxan- 6.78 - 6.68 (m, 1H), 4.11 (q, / = 14.2, 2H), 4-yl]-3-(thiophen-2- 3.75 (dd, / = 12.0, 4.0, 1H), 3.61 (dd, / =
311 350.2
yl)propyl] (thiophen-2- 12.2, 10.3, 2H), 2.76 (m, 2H), 2.61 (t, / = ylmethyl) amine 8.4, 1H), 2.22 (m, 1H), 1.80 (dt, / = 12.1,
8.6, 2H), 1.67 (d, / = 12.9, 1H), 1.24 (d, / = 13.3, 1H), 1.17 (dd, / = 12.3, 4.9, 1H), 1.13 (s, 3H), 1.10 (s, 3H), 1.00 (t, / = 12.8, 1H).
lH NMR (400 MHz, MeOD) δ 7.46 - 7.37 (m, 5H), 7.37 - 7.32 (m, 2H), 7.21 - 7.15 (m, 2H), 4.17 - 4.06 (m, 2H), 3.62 (ddd, / benzyl [ (3 S ) -3 - (4-chlorophenyl) - = 11.8, 4.8, 1.6, 1H), 3.49 (td, / = 12.1,
3-[(9S)-6- 2.5, 1H), 2.88 (td, / = 12.0, 4.9, 1H), 2.63
312 398.2
oxaspiro[4.5]decan-9- (td, / = 11.7, 4.4, 1H), 2.39 (ddd, / = 11.9, yl]propyl] amine 8.5, 3.7, 1H), 2.28 - 2.14 (m, 1H), 2.08 - 1.53 (m, 10H), 1.51 - 1.42 (m, 1H), 1.30 (t, / = 12.5, 1H), 1.18 (d, / = 11.6, 1H), 1.06 (ddd, 7 = 25.2, 12.4, 4.9, 1H).
1H NMR (400 MHz, CDC13) δ 9.04 (s, 1H), 8.36 (d, / = 8.0, 1H), 7.62 (d, / = 8.3, 1H),
[(3S)-3-(4-chlorophenyl)-3- 7.33 - 7.21 (m, 2H), 7.04 (d, / = 8.3, 2H), [(9S)-6- 4.25 (s, 2H), 3.64 (d, / = 8.4, 1H), 3.40 (t,
313 oxaspiro[4.5]decan-9- 413.2
/ = 10.9, 1H), 2.89 (m, 1H), 2.76 (m, 4H), yl]propyl] [(6-methylpyridin-3- 2.27 (m, 2H), 1.94 (d, / = 34.1, 2H), 1.80 - yl)methyl] amine
1.42 (m, 9H), 1.35 (m, 1H), 1.25 (t, / = 12.3, 1H), 1.15 - 0.97 (m, 2H).
[(3S)-3-(4-chlorophenyl)-3- lH NMR (400 MHz, CDC13) δ 9.62 (brs,
[(9S)-6- 1H), 8.70 (s, 1H), 7.88 (d, / = 8.1, 1H),
314 oxaspiro[4.5]decan-9- 467.2 7.68 (d, / = 8.1, 1H), 7.27 (d, / = 8.6, 2H), yl]propyl]({ [6- 6.98 (t, / = 5.6, 2H), 4.61 (brs, 1H), 4.02 (trifluoromethyl)pyridin- 3 - (q, / = 13.5, 2H), 3.65 (dd, / = 12.0, 3.1, yl] methyl } ) amine 1H), 3.40 (td, / = 11.9, 2.6, 1H), 2.80 - 2.65 (m, 1H), 2.59 (t, / = 9.2, 1H), 2.33 - 2.13 (m, 2H), 1.96 - 1.78 (m, 2H), 1.78 - 1.39 (m, 8H), 1.39 - 1.30 (m, 1H), 1.27 (d, / = 12.5, 1H), 1.15 - 0.93 (m, 2H).
1H NMR (400 MHz, MeOD) δ 7.58 - 7.48 (m, 2H), 7.40 - 7.30 (m, 2H), 7.22 - 7.16 (m, 2H), 7.14 (dd, / = 4.4, 1.9, 1H), 4.17
[(3S)-3-(4-chlorophenyl)-3- (d, / = 13.6, 2H), 3.67 - 3.57 (m, 1H), 3.49 [(9S)-6- (td, / = 12.1, 2.4, 1H), 2.86 (td, / = 12.0,
315 oxaspiro[4.5]decan-9- 404.2
5.0, 1H), 2.61 (td, / = 12.0, 4.8, 1H), 2.38 yl]propyl] (thiophen-3- (ddd, / = 11.8, 8.5, 3.7, 1H), 2.27 - 2.12 ylmethyl) amine
(m, 1H), 2.08 - 1.40 (m, 11H), 1.30 (t, / = 12.5, 1H), 1.18 (d, / = 11.6, 1H), 1.06 (ddd, 7 = 25.2, 12.3, 4.9, 1H).
1H NMR (400 MHz, MeOD) δ 7.37 - 7.28 (m, 2H), 7.20 - 7.09 (m, 2H), 6.94 (d, / = 3.5, 1H), 6.75 - 6.67 (m, 1H), 4.24 (s, 2H),
[(3S)-3-(4-chlorophenyl)-3- 3.65 - 3.54 (m, 1H), 3.47 (td, / = 12.1, 2.4, [(9S)-6- 1H), 2.83 (td, / = 11.9, 5.1, 1H), 2.67 -
316 oxaspiro[4.5]decan-9- 418.2
2.52 (m, 1H), 2.46 (d, / = 0.9, 3H), 2.36 yl]propyl] [(5-methylthiophen-2- (ddd, / = 11.9, 8.5, 3.7, 1H), 2.25 - 2.08 yl)methyl] amine
(m, 1H), 2.07 - 1.38 (m, 12H), 1.28 (t, / = 12.4, 1H), 1.16 (d, J = 11.5, 1H), 1.06 (td, / = 12.5, 4.8, 1H).
7.30 - 7.09 (m, 5H), 7.07 - 6.81 (m, 4H), 3.62 (dd, J = 30.2, 13.1, 2H), 3.41 (s, OH), 2.33 (t, J = 7.4, 2H), 2.29 - 2.18 (m, 1H), 2.09 - 1.77 (m, 5H), 1.75 - 1.55 (m, 2H), benzyl[(3S)-3-(4-fluorophenyl)- 1.16 (s, 3H), 1.10 (d, J = 5.4, 3H), 1.07 - 3-(2,2,6,6- 1.05 (m, 1H), 1.04 (s, 3H), 1.00 (s, 3H), tetramethyloxan-4- 0.88 (t, J = 12.6, 1H), 0.72 (t, J = 12.7,
317 yl)propyl] amine 384.3 1H).
7.24 - 7.17 (m, 2H), 7.16 - 7.09 (m, 3H), 7.01 (d, J = 7.8, 2H), 6.89 (d, J = 8.0, 2H), 3.68 (ddd, j = 11.8, 5.0, 1.3, 1H), 3.62 - 3.49 (m, 3H), 2.32 (t, J = 7.3, 2H), 2.25 (s, 3H), 2.22 - 2.13 (m, 1H), 1.93 (dtd, J = benzyl[(3S)-3-[(4R)-2,2- 15.7, 7.7, 3.8, 1H), 1.81 - 1.66 (m, 2H), dimethyloxan-4-yl]-3-(4- 1.65 - 1.56 (m, 1H), 1.37 (d, J = 20.2, 1H),
318 methylphenyl)propyl] amine 352.3
1.20 - 1.05 (m, 2H), 1.02 (s, 3H), 1.01 (s, 3H), 0.86 (t, J = 12.7, IH).
IH NMR (400 MHz, CDC13) δ 8.49 (bs, 2H), 7.19 (t, J = 7.0, IH), 7.08 (d, J = 7.8, 2H), 6.96 (dd, J = 7.0, 4.0, 2H), 6.87 (d, J = 8.0, 2H), 6.78 (t, J = 7.5, IH), 3.94 (dd, J = 40.4, 12.9, 2H), 3.71 (dd, J = 11.9, 3.8,
2-({ [(3S)-3-[(4R)-2,2- IH), 3.57 (t, J = 11.1, IH), 2.59 (d, J = dimethyloxan-4-yl]-3-(4- 30.7, 2H), 2.31 (s, 3H), 2.24 - 2.08 (m, methylphenyl)propyl] amino } met 4H), 1.76 (m, IH), 1.60 (d, J = 14.0, 2H),
319 hyl)phenol 368.3 1.16 - 0.97 (m, 8H), 0.87 (t, J = 12.8, IH)
1H NMR (400 MHz, CDC13) δ 9.75 (bs, 2H), 7.45 (s, 2H), 7.33 (s, 3H), 7.02 (t, / = 8.2, 2H), 6.91 (d, / = 7.6, 2H), 3.90 (d, / = 38.7, 2H), 3.57 (dd, / = 11.7, 4.0, IH), 3.45 (t, / = 11.3, IH), 2.58 (s, IH), 2.48 (s, IH),
2.32 (s, IH), 2.27 (s, 3H), 2.21 (s, IH), benzyl[(3S)-3-[(4S)-2,2- 2.01 (s, IH), 1.76 (s, IH), 1.66 (t, / = 13.0, dimethyloxan-4-yl]-3-(4- IH), 1.14 (d, / = 7.6, 6H), 1.11 - 0.88 (m,
320 methylphenyl)propyl] amine 352.3 3H)
IH NMR (400 MHz, CDC13) δ 9.71 (bs, 2H), 7.26 - 7.19 (m, 4H), 7.13 (d, J = 7.3, IH), 7.03 (d, J = 7.8, 2H), 6.90 (d, J = 8.0, 2H), 3.86 (dd, J = 54.4, 13.6, 2H), 3.57 (dd, J = 11.9, 3.6, IH), 3.45 (td, J = 12.2, 2.2, IH), 2.52 (d, J = 37.4, 2H), 2.29 (d, J =
[(3S)-3-[(4S)-2,2-dimethyloxan- 16.7, 6H), 2.21 (t, J = 9.7, IH), 2.00 (d, J =
4-yl]-3-(4- 10.3, IH), 1.76 (dd, J = 8.1, 3.7, IH), 1.67 methylphenyl)propyl] [(3- (d, J = 13.1, IH), 1.13 (d, J = 7.3, 7H), 1.01
321 methylphenyl)methyl] amine 366.3 (ddd, J = 17.6, 16.6, 6.4, 3H)
IH NMR (400 MHz, CDC13) δ 9.86 (s, 2H), 7.50 - 7.37 (m, 2H), 7.31 (dd, J = 12.0, 7.6, 2H), 7.05 (d, J = 7.6, 2H), 6.92 (d, J = 7.8, 2H), 4.04 - 3.76 (m, 2H), 3.58 (dd, J = 11.9, 3.8, IH), 3.46 (t, J = 11.1,
[(3-chlorophenyl)methyl] [(3S)- IH), 2.53 (d, J = 49.9, 2H), 2.33 (s, IH),
3-[(4S)-2,2- 2.26 (d, J = 13.5, 4H), 2.01 (s, IH), 1.77 (s, dimethyloxan-4-yl]-3-(4- IH), 1.68 (d, J = 12.7, IH), 1.15 (d, J = 5.5,
322 methylphenyl)propyl] amine 386.2 6H), 1.12 - 0.90 (m, 3H)
2-({ [(3S)-3-[(4S)-2,2- IH NMR (400 MHz, CDC13) δ 8.41 (bd, J
323 368.3
dimethyloxan-4-yl]-3-(4- = 125.9, 2H), 7.19 (m, IH), 7.07 (s, 2H), methylphenyl)propyl] amino } met 6.97 (s, IH), 6.89 (d, J = 6.2, 3H), 6.79 (s, hyl)phenol IH), 3.95 (d, J = 36.0, 2H), 3.52 (d, J =
41.6, 2H), 2.30 (s, 3H), 2.12 (s, 3H), 1.77 (d, J = 36.3, 2H), 1.60 (s, IH), 1.17 (d, J = 8.2, 6H), 1.11 - 0.73 (m, 4H)
IH NMR (400 MHz, CDC13) δ 8.96 (bd, J = 73.9, 2H), 7.11 (dd, J = 17.1, 7.9, 3H), 6.93 (d, J = 8.0, 2H), 6.87 (s, IH), 6.82 (d, J = 8.2, IH), 6.63 (d, J = 7.6, IH), 3.80 (s,
3-({ [(3S)-3-[(4S)-2,2- 2H), 3.66 - 3.53 (m, IH), 3.47 (t, J = 11.0, dimethyloxan-4-yl]-3-(4- IH), 2.69 (s, IH), 2.60 (s, IH), 2.31 (s, methylphenyl)propyl] amino } met 3H), 2.16 (d, J = 7.8, 3H), 1.62 (m, IH),
324 hyl)phenol 368.3 1.17 (d, J = 10.1, 6H), 1.13 - 0.87 (m, 4H)
IH NMR (400 MHz, CDC13) δ 9.81 (bd, J = 28.9, 2H), 7.44 (d, J = 2.9, 2H), 7.38 - 7.29 (m, 3H), 7.20 (d, J = 8.3, 2H), 6.98 (t, J = 8.0, 2H), 4.00 - 3.77 (m, 2H), 3.71 (dd, J = 11.9, 4.5, IH), 3.56 (t, J = 11.5, IH), 2.47 (d, J = 35.7, 3H), 2.29 (t, J benzyl [ (3 S ) -3 - (4-chlorophenyl) - = 9.1, IH), 2.05 - 1.86 (m, IH), 1.75 (t, J =
3-[(4R)-2,2- 11.7, 2H), 1.23 - 1.10 (m, IH), 1.04 (d, J =
325 dimethyloxan-4-yl]propyl] amine 372.2 14.4, 7H), 0.88 (t, J = 12.6, IH)
IH NMR (400 MHz, CDC13) δ 9.77 (d, J = 31.3, 2H), 7.22 (dd, J = 12.9, 7.7, 5H), 7.14 (d, J = 6.8, IH), 6.98 (t, J = 8.0, 2H), 3.90 (d, J = 13.6, IH), 3.78 (d, J = 13.6, IH), 3.71 (dd, J = 11.9, 4.3, IH), 3.56 (t, J =
[(3S)-3-(4-chlorophenyl)-3- 11.3, IH), 2.48 (d, J = 33.9, 3H), 2.30 (d, J [(4R)-2,2-dimethyloxan-4- = 10.9, 4H), 2.05 - 1.86 (m, IH), 1.75 (t, J yl]propyl][(3- = 10.7, 2H), 1.24 - 1.10 (m, IH), 1.04 (d, J
326 methylphenyl)methyl] amine 386.2 = 14.5, 7H), 0.88 (t, J = 12.8, IH)
IH NMR (400 MHz, CDC13) δ 9.93 (d, J = 47.9, 2H), 7.43 (dd, J = 13.1, 4.5, 2H), 7.31 (dt, J = 15.4, 7.3, 2H), 7.23 (d, J = 8.4, 2H),
6.99 (d, J = 8.4, 2H), 3.88 (dd, J = 51.3, 13.4, 2H), 3.72 (dd, J = 12.1, 4.1, IH), 3.58
[(3S)-3-(4-chlorophenyl)-3- (t, J = 11.3, IH), 2.61 - 2.23 (m, 4H), 2.04 [(4R)-2,2-dimethyloxan-4- - 1.87 (m, IH), 1.76 (t, J = 13.1, 2H), 1.30 yl]propyl][(3- - 1.12 (m, IH), 1.05 (d, J = 13.3, 7H), 0.89
327 chlorophenyl)methyl] amine 406.2 (t, J = 12.6, IH) IH NMR (400 MHz, CDC13) δ 8.52 (bs,
2H), 7.31 - 7.17 (m, 3H), 6.99 (d, J = 5.0, IH), 6.96 - 6.89 (m, 3H), 6.82 (t, J = 7.5, IH), 3.97 (dd, J = 42.9, 12.9, 2H), 3.71 (dd, J = 11.9, 3.9, IH), 3.57 (t, J = 11.1,
2-({ [(3S)-3-(4-chlorophenyl)-3- IH), 2.59 (d, J = 31.8, 2H), 2.17 (d, J = 9.2,
[(4R)-2,2- 3H), 1.61 (d, J = 12.6, 2H), 1.17 - 1.10 (m, dimethyloxan-4- IH), 1.06 (d, J = 13.9, 6H), 1.00 (s, IH),
328 yl]propyl]amino}methyl)phenol 388.2 0.87 (t, J = 12.7, IH)
IH NMR (400 MHz, CDC13) δ 9.82 (bd, J = 26.8, 2H), 7.50 - 7.41 (m, 2H), 7.40 - 7.29 (m, 3H), 7.20 (d, J = 8.3, 2H), 6.98 (d, J = 8.4, 2H), 3.99 (d, J = 12.7, IH), 3.87 (s, IH), 3.58 (dd, J = 11.9, 3.6, IH), 3.45 (dd, J = 12.1, 10.0, IH), 2.49 (d, J = 30.5, 2H), benzyl [ (3 S ) -3 - (4-chlorophenyl) - 2.40 - 2.21 (m, 2H), 2.09 - 1.88 (m, IH),
3-[(4S)-2,2- 1.76 (d, J = 8.3, IH), 1.66 (d, J = 13.3, IH),
329 dimethyloxan-4-yl]propyl] amine 372.2 1.12 (d, J = 7.4, 6H), 1.10 - 0.88 (m, 3H)
IH NMR (400 MHz, CDC13) δ 9.76 (bs, 2H), 7.25 - 7.11 (m, 6H), 6.98 (d, J = 8.4, 2H), 3.88 (dd, J = 55.0, 13.5, 2H), 3.58 (dd, J = 12.0, 3.6, IH), 3.51 - 3.36 (m,
[(3S)-3-(4-chlorophenyl)-3- IH), 2.49 (d, J = 34.2, 2H), 2.30 (d, J = [(4S)-2,2-dimethyloxan-4- 12.3, 5H), 2.06 - 1.90 (m, IH), 1.86 - 1.69 yl]propyl][(3- (m, IH), 1.66 (d, J = 13.7, IH), 1.12 (d, J =
330 methylphenyl)methyl] amine 386.2 6.7, 6H), 1.09 - 0.83 (m, 3H)
IH NMR (400 MHz, CDC13) δ 9.94 (d, J = 44.2, 2H), 7.48 - 7.38 (m, 2H), 7.38 - 7.27 (m, 2H), 7.23 (d, J = 8.4, 2H), 7.00 (d, J = 8.4, 2H), 4.11 - 3.75 (m, 2H), 3.59 (dd, J = 12.0, 3.7, IH), 3.46 (dd, J = 12.1, 9.9, IH),
[(3S)-3-(4-chlorophenyl)-3- 2.50 (d, J = 37.8, 2H), 2.40 - 2.24 (m, 2H), [(4S)-2,2-dimethyloxan-4- 2.00 (dd, J = 13.0, 7.6, IH), 1.77 (d, J = yl]propyl][(3- 7.8, IH), 1.71 - 1.62 (m, IH), 1.14 (d, J =
331 chlorophenyl)methyl] amine 406.2 5.8, 6H), 1.11 - 0.88 (m, 3H)
IH NMR (400 MHz, CDC13) δ 8.62 (bd, J = 131.7, 2H), 7.25 - 7.18 (m, 3H), 7.03 -
2-({ [(3S)-3-(4-chlorophenyl)-3- 6.97 (m, IH), 6.94 (t, J = 9.1, 3H), 6.82 (t,
[(4S)-2,2- J = 7.4, IH), 3.98 (dd, J = 48.3, 13.0, 2H), dimethyloxan-4- 3.60 (dd, J = 12.0, 3.6, IH), 3.47 (dd, J =
332 yl]propyl]amino}methyl)phenol 388.2
12.2, 9.8, IH), 2.60 (d, J = 28.6, 2H), 1.86 (m, 4H), 1.73 (d, J = 8.7, IH), 1.61 (d, J =
12.7, IH), 1.17 (d, J = 10.3, 6H), 0.99 (ddd, J = 20.3, 19.2, 8.9, 3H)
IH NMR (400 MHz, CDC13) δ 8.80 (bs, 2H), 7.31 - 7.24 (m, 2H), 7.15 (t, J = 7.8, IH), 6.98 (d, J = 8.4, 2H), 6.86 - 6.77 (m, 2H), 6.67 (d, J = 7.5, IH), 3.95 - 3.72 (m, 2H), 3.62 (dd, J = 11.7, 4.1, IH), 3.49 (dd,
3-({ [(3S)-3-(4-chlorophenyl)-3- J = 12.2, 9.9, IH), 2.64 (d, J = 35.1, IH),
[(4S)-2,2- 2.21 (dd, J = 10.8, 7.9, 2H), 1.93 - 1.68 (m, dimethyloxan-4- 2H), 1.61 (d, J = 12.5, IH), 1.18 (d, J = 9.7,
333 yl]propyl]amino}methyl)phenol 388.2 6H), 1.14 - 0.85 (m, 4H)
IH NMR (400 MHz, CDC13) δ 9.75 (bs, 2H), 7.59 - 7.41 (m, 2H), 7.33 (s, 3H), 7.01 (d, J = 7.2, IH), 6.68 (d, J = 11.1, 2H), 3.94 (d, J = 55.2, 2H), 3.67 - 3.53 (m, IH), benzyl[(3S)-3-[(4R)-2,2- 3.46 (t, J = 11.6, IH), 2.52 (d, J = 36.8, dimethyloxan-4-yl]-3-(3- 2H), 2.31 (d, J = 32.0, 2H), 2.19 (s, 3H), fluoro-4- 1.99 (d, J = 10.3, IH), 1.36 - 1.25 (m, IH),
334 methylphenyl)propyl] amine 370.3 1.13 (d, J = 6.1, 7H), 1.08 - 0.84 (m, 3H)
IH NMR (400 MHz, CDC13) δ 9.76 (bs, 2H), 7.29 - 7.18 (m, 3H), 7.13 (d, J = 7.2, IH), 7.02 (t, J = 7.6, IH), 6.69 (dd, J = 15.4, 9.1, 2H), 4.06 - 3.71 (m, 2H), 3.58 (dd, J = 11.8, 4.1, IH), 3.46 (t, J = 11.5,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 2.52 (d, J = 36.6, 2H), 2.31 (s, 4H), 4-yl]-3-(3-fluoro-4- 2.26 (d, J = 7.6, IH), 2.19 (d, J = 1.2, 3H), methylphenyl)propyl] [(3- 2.08 - 1.87 (m, IH), 1.74 (s, IH), 1.13 (d, J
335 methylphenyl)methyl] amine 384.3 = 6.5, 6H), 1.11 - 0.77 (m, 4H)
IH NMR (400 MHz, CDC13) δ 9.69 (bs, 2H), 7.57 - 7.41 (m, 2H), 7.33 (s, 3H), 7.01 (d, J = 10.0, IH), 6.67 (d, J = 10.7, 2H), 3.91 (d, J = 46.5, 2H), 3.71 (d, J = 10.0, IH), 3.58 (s, IH), 2.51 (d, J = 42.8, benzyl[(3S)-3-[(4S)-2,2- 3H), 2.28 (s, IH), 2.20 (s, 4H), 2.02 (dd, J dimethyloxan-4-yl]-3-(3- = 22.7, 16.0, IH), 1.77 (s, IH), 1.30 - 1.12 fluoro-4- (m, 2H), 1.05 (d, J = 11.7, 6H), 0.98 - 0.76
336 methylphenyl)propyl] amine 370.3 (m, IH)
[(3S)-3-[(4S)-2,2-dimethyloxan- IH NMR (400 MHz, CDC13) δ 9.76 (bs,
337 384.3
4-yl]-3-(3-fluoro-4- 2H), 7.28 - 7.15 (m, 3H), 7.12 (d, J = 7.2, methylphenyl)propyl] [(3- IH), 7.02 (t, J = 7.5, IH), 6.68 (dd, J = methylphenyl)methyl] amine 16.6, 9.0, 2H), 3.85 (d, J = 38.9, 2H), 3.70
(dd, J = 11.7, 3.8, IH), 3.56 (t, J = 11.9, IH), 2.44 (dd, J = 45.2, 30.1, 3H), 2.30 (s, 3H), 2.26 (d, J = 8.0, IH), 2.19 (d, J = 1.0, 3H), 1.98 (d, J = 22.2, IH), 1.24 - 1.11 (m, IH), 1.04 (d, J = 12.3, 8H), 0.96 - 0.78 (m,
2H)
IH NMR (400 MHz, CDC13) δ 9.74 (bd, J = 37.4, 2H), 7.45 (dd, J = 6.4, 3.0, 2H),
7.34 (dd, J = 4.9, 1.6, 3H), 6.92 (d, J = 8.6,
2H), 6.75 (d, J = 8.6, 2H), 3.96 (q, J = 7.0, 3H), 3.84 (d, J = 13.8, IH), 3.58 (dd, J = 11.9, 3.7, IH), 3.46 (dd, J = 12.2, 10.0, IH), 2.52 (d, J = 35.2, 2H), 2.31 (s, IH),
2.19 (d, J = 8.5, IH), 2.00 (t, J = 9.4, IH), benzyl[(3S)-3-[(4S)-2,2- 1.70 (dd, J = 33.7, 10.3, 2H), 1.40 (t, J = dimethyloxan-4-yl]-3-(4- 7.0, 3H), 1.13 (d, J = 7.3, 6H), 1.10 - 0.87
338 ethoxyphenyl)propyl] amine 382.3 (m, 3H)
IH NMR (400 MHz, CDC13) δ 9.79 (bs, 2H), 7.75 (m, IH), 7.33 (d, J = 4.3, IH), 7.16 (m, IH), 7.05 (t, J = 8.7, IH), 6.94 (d, J = 7.4, 2H), 6.74 (d, J = 7.1, 2H), 4.06 (s, 2H), 3.95 (q, J = 6.9, 2H), 3.63 - 3.40 (m,
[(3S)-3-[(4S)-2,2-dimethyloxan- 2H), 2.56 (d, J = 25.0, 2H), 2.29 (d, J =
4-yl]-3-(4- 47.2, 2H), 2.00 (s, IH), 1.76 (m, 2H), 1.38 ethoxyphenyl)propyl] [(2- (t, J = 6.9, 3H), 1.14 (d, J = 5.2, 6H), 1.12 -
339 fluorophenyl)methyl] amine 400.3 0.83 (m, 3H)
IH NMR (400 MHz, CDC13) δ 9.88 (bs, 2H), 7.36 - 7.27 (m, 2H), 7.25 - 7.17 (m, IH), 7.04 (t, J = 7.9, IH), 6.94 (d, J = 8.4,
2H), 6.76 (d, J = 8.2, 2H), 3.97 (m,3H), 3.88 (s, IH), 3.58 (dd, J = 11.9, 3.8, IH),
3.46 (t, J = 11.2, IH), 2.54 (d, J = 40.8,
[(3S)-3-[(4S)-2,2-dimethyloxan- 2H), 2.29 (d, J = 39.2, 2H), 2.00 (d, J = 9.1,
4-yl]-3-(4- IH), 1.83 - 1.63 (m, 2H), 1.40 (t, J = 7.0, ethoxyphenyl)propyl] [(3- 3H), 1.14 (d, J = 4.9, IH), 1.11 - 0.84 (m,
340 fluorophenyl)methyl] amine 400.3 3H)
[(3S)-3-[(4S)-2,2-dimethyloxan- IH NMR (400 MHz, CDC13) δ 9.69 (bs,
4-yl]-3-(4- IH), 7.24 (d, J = 13.8, 2H), 7.13 (m, IH),
341 396.3
ethoxyphenyl)propyl] [(3- 6.96 (m, J = 25.7, 2H), 6.75 (m, 2H), 3.91 methylphenyl)methyl] amine (m,4H), 3.52 (dd, J = 41.9, 9.4, 2H), 2.50
(s, 2H), 2.28 (d, J = 31.3, 4H), 2.00 (s, IH), 1.71 (d, J = 27.4, 2H), 1.49 - 1.34 (m, 3H),
1.33 - 1.22 (m, IH), 1.13 (s, 6H), 1.09 - 0.79 (m, 3H)
IH NMR (400 MHz, CDC13) δ 9.84 (bs, 2H), 7.43 (s, 2H), 7.29 (d, J = 8.1, 2H), 6.93 (d, J = 7.6, 2H), 6.76 (d, J = 7.4, 2H), 4.08 - 3.89 (m, 3H), 3.83 (d, J = 13.2, IH), 3.49 (dd, J = 32.5, 20.8, 2H), 2.52 (d, J =
[(3-chlorophenyl)methyl] [(3S)- 41.9, 2H), 2.39 - 2.10 (m, 2H), 1.99 (d, J =
3-[(4S)-2,2- 13.9, IH), 1.86 - 1.51 (m, 2H), 1.28 (d, J = dimethyloxan-4-yl]-3-(4- 23.9, 3H), 1.13 (s, 6H), 1.08 - 0.73 (m,
342 ethoxyphenyl)propyl] amine 416.2 3H)
IH NMR (400 MHz, CDC13) δ 9.82 (bs, 2H), 7.45 (m, 2H), 7.33 (m, 3H), 7.20 (m, 2H), 6.98 (m, 2H), 3.88 (d, J = 32.8, 2H), benzyl [ (3 S ) -3 - (4-chlorophenyl) - 3.72 (d, J = 8.1, IH), 3.47 (t, J = 12.2, IH),
3-[(9R)-6- 2.43 (m,3H), 2.00 (m,lH), 1.84 (m, IH), oxaspiro[4.5]decan-9- 1.63 (m, 5H), 1.49 - 1.16 (m, 5H), 1.05
343 yl]propyl] amine 398.3 (dd, J = 30.6, 12.6, 3H)
IH NMR (400 MHz, CDC13) δ 9.84 (bs, 2H), 7.74 (m,lH), 7.36 (m, IH), 7.20
[(3S)-3-(4-chlorophenyl)-3- (m,3H), 7.04 (m,3H), 4.05 (m, 2H), 3.74
[(9R)-6- (bd, J = 11.7, IH), 3.50 (m, IH), 2.44 oxaspiro[4.5]decan-9- (m,3H), 2.02 (m, IH), 1.85 (m, IH), 1.73 yl]propyl][(2- (m, 2H), 1.62 (m, 3H), 1.49 - 1.18 (m,
344 fluorophenyl)methyl] amine 416.2 5H), 1.18 - 0.96 (m, 3H)
IH NMR (400 MHz, CDC13) δ 9.96 (bd, J = 45.2, 2H), 7.33 (dd, J = 13.4, 7.7, IH), 7.25 - 7.18 (m, 4H), 7.12 - 6.91 (m, 3H),
[(3S)-3-(4-chlorophenyl)-3- 3.91 (bd, J = 37.6, 2H), 3.73 (dd, J = 11.9,
[(9R)-6- 4.3, IH), 3.48 (t, J = 11.7, IH), 2.44 (t, J = oxaspiro[4.5]decan-9- 37.0, 3H), 1.95 (s, IH), 1.85 (s, IH), 1.66 yl]propyl][(3- (m,5H), 1.49 - 1.17 (m, 5H), 1.17 - 0.96
345 fluorophenyl)methyl] amine 416.2 (m, 3H)
[(3S)-3-(4-chlorophenyl)-3- IH NMR (400 MHz, CDC13) δ 9.76 (bs,
[(9R)-6- 2H), 7.22 (m, 5H), 7.14 (d, J = 7.0, IH), oxaspiro[4.5]decan-9- 6.98 (t, J = 7.1, 2H), 3.84 (d, J = 32.5, 2H),
346 412.3
yl]propyl][(3- 3.72 (d, J = 8.7, IH), 3.47 (t, J = 11.8, IH), methylphenyl)methyl] amine 2.48 (d, J = 38.9, 3H), 2.32 (s, 4H), 1.99 (s,
IH), 1.84 (s, IH), 1.70 (s, 2H), 1.59 (m,3H), 1.48 - 1.17 (m, 5H), 1.05 (m,3H)
IH NMR (400 MHz, CDC13) δ 9.84 (bs,
[(3S)-3-(4-chlorophenyl)-3- 2H), 7.52 (m, 2H), 7.49 - 7.12 (m, 3H),
[(9R)-6- 7.00 (s, 3H), 3.97 (m, 2H), 3.50 (m, 2H), oxaspiro[4.5]decan-9- 2.40 (m, 3H), 2.03 (s, IH), 1.84 (s, IH), yl]propyl][(3- 1.73 (s, 2H), 1.62 (m, 3H), 1.42-1.25 (m,
347 chlorophenyl)methyl] amine 432.2 5H), 1.12 (s, 3H)
IH NMR (400 MHz, CDC13) δ 9.93 (bs,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 7.44 (m, 5H), 6.98 (s, IH), 6.61 (bs,
4-yl]-3-(3-fluoro-4- 2H), 4.22 (m, IH), 3.63 (m, 2H), 2.45 (m, methylphenyl)propyl] [(1R)- 1- 2H), 2.17 (m, 5H), 1.72 (m,4H), 1.04 (d, J
348 phenylethyl] amine 384.1 = 15.0, 6H), 0.91 (m,2H)
IH NMR (400 MHz, CDC13) δ 9.65 (bs, IH), 7.65 - 7.31 (m, 5H), 7.00 (s, IH),
[(3S)-3-[(4R)-2,2-dimethyloxan- 6.61 (bs, 2H), 4.22 (m, IH), 3.64 (m,2H), 4-yl]-3-(3-fluoro-4- 2.36 (m, 2H), 2.20 (m, 3H), 1.84 (d, J = methylphenyl)propyl] [(IS)- 1- 58.5, 4H), 1.17 (m, 2H), 1.05 (d, J = 12.8,
349 phenylethyl] amine 384.1 6H), 0.91 (m,2H)
IH NMR (400 MHz, CDC13) δ 9.16 (s, 2H), 7.10 (t, J = 7.9, IH), 6.79 - 6.63 (m, 2H), 6.25 (d, J = 3.1, IH), 5.89 (dd, J = 3.1, 0.9, IH), 3.93 (q, J = 14.3, 2H), 3.76 (dd, J
= 12.0, 3.8, IH), 3.61 (td, J = 12.2, 2.1,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 2.66 (d, J = 37.2, 2H), 2.24 (d, J = 1.3, 4-yl]-3-(3-fluoro-4- 3H), 2.22 - 2.13 (m, 5H), 1.95 - 1.72 (m, methylphenyl)propyl] [(5- 2H), 1.69 (d, J = 12.8, IH), 1.17 (td, J = methylfuran-2- 12.5, 5.0, IH), 1.08 (d, J = 10.0, 7H), 0.91
350 yl)methyl] amine 374.1 (t, J = 12.8, IH)
IH NMR (400 MHz, CDC13) δ 8.91 (s, 2H), 7.10 (t, J = 7.9, IH), 6.81 (d, J = 3.5, IH), 6.70 (dd, J = 14.2, 9.1, 2H), 6.61 (d, J = 3.3, IH), 4.03 (q, J = 14.3, 2H), 3.77 (dd, J = 11.9, 3.9, IH), 3.61 (dd, J = 12.3, 10.1,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 2.74 (s, IH), 2.64 (s, IH), 2.41 (s, 4-yl]-3-(3-fluoro-4- 3H), 2.25 (d, J = 1.3, 3H), 2.19 (t, J = 8.9, methylphenyl)propyl] [(5- 2H), 1.93 - 1.73 (m, 2H), 1.69 (d, J = 12.7, methylthiophen-2- IH), 1.17 (td, J = 12.4, 5.0, IH), 1.08 (d, J
351 yl)methyl] amine 390.1 = 10.5, 7H), 0.91 (t, J = 12.7, IH) IH NMR (400 MHz, CDC13) δ 9.01 (s,
2H), 8.11 (s, IH), 7.63 (d, J = 8.6, IH), 7.10 (t, J = 7.9, IH), 6.78 (d, J = 8.7, IH), 6.69 (dd, J = 11.3, 9.1, 2H), 4.02 - 3.82 (m, 5H), 3.78 (dd, J = 12.0, 3.7, IH), 3.62 (dd,
[(3S)-3-[(4R)-2,2-dimethyloxan- J = 12.3, 10.1, IH), 2.73 (s, IH), 2.63 (s, 4-yl]-3-(3-fluoro-4- IH), 2.25 (d, J = 1.3, 3H), 2.18 (t, J = 8.7, methylphenyl)propyl] [(6- 2H), 1.80 (d, J = 12.0, 2H), 1.68 (d, J = methoxypyridin- 3 - 12.4, IH), 1.23 - 1.12 (m, IH), 1.09 (d, J =
352 yl)methyl] amine 401.1 10.5, 7H), 0.92 (t, J = 12.7, IH)
IH NMR (400 MHz, CDC13) δ 7.68 (s, 2H), 7.12 (t, J = 8.0, IH), 6.74 (t, J = 7.8, 2H), 3.85 - 3.69 (m, 2H), 3.63 (t, J = 11.1,
[(3S)-3-[(4R)-2,2-dimethyloxan- 2H), 2.65 (s, 2H), 2.33 - 2.18 (m, 4H), 4-yl]-3-(3-fluoro-4- 2.12 (s, IH), 1.75 (m, 3H), 1.17 (dd, J = methylphenyl)propyl] ( 1 H- 12.7, 4.8, IH), 1.09 (d, J = 8.6, 7H), 0.93
353 imidazol-2-ylmethyl)amine 360.3 (t, J = 12.7, IH)
IH NMR (400 MHz, CDC13) δ 10.28 - 9.21 (m, IH), 8.60 (dd, J = 10.1, 1.9, 2H), 8.51 (dd, J = 2.4, 1.6, IH), 7.10 (d, J = 8.1, IH), 6.86 - 6.65 (m, 2H), 4.26 (d, J = 6.8, 2H), 3.77 (dd, J = 12.1, 3.6, IH), 3.62 (d, J
= 2.2, IH), 2.99 - 2.83 (m, IH), 2.85 - 2.71 (m, IH), 2.32 (ddd, J = 12.5, 9.3, 5.7,
IH), 2.24 (d, J = 1.4, 4H), 1.98 (dt, J =
[(3S)-3-[(4R)-2,2-dimethyloxan- 21.5, 8.8, IH), 1.90 - 1.75 (m, IH), 1.72
4-yl]-3-(3-fluoro-4- (d, J = 12.6, IH), 1.19 (tt, J = 12.4, 6.3, methylphenyl)propyl] (pyrazin-2- IH), 1.09 (d, J = 9.6, 7H), 0.95 (d, J = 12.7,
354 ylmethyl) amine 372.1 IH)
IH NMR (400 MHz, CDC13) δ 9.19 (s, IH), 8.78 (s, IH), 7.63 (s, IH), 7.13 (d, J = 4.6, IH), 6.81 - 6.65 (m, 2H), 3.98 (dd, J = 27.4, 13.7, 2H), 3.77 (s, IH), 3.63 (d, J =
[(3S)-3-[(4R)-2,2-dimethyloxan- 4.8, IH), 2.67 (s, 2H), 2.24 (d, J = 15.7, 4-yl]-3-(3-fluoro-4- 5H), 1.72 (d, J = 13.8, 2H), 1.17 (s, IH), methylphenyl)propyl] (pyrimidin 1.09 (dd, J = 7.7, 4.5, 7H), 1.00 - 0.83 (m,
355 - 5 - ylmethyl) amine 372.1 IH)
IH NMR (400 MHz, CDC13) δ 7.77 (d, J =
[(3S)-3-[(4R)-2,2-dimethyloxan- 3.3, IH), 7.42 (d, J = 3.3, IH), 7.11 (t, J = 4-yl]-3-(3-fluoro-4- 7.8, IH), 6.74 (dd, J = 13.2, 9.1, 2H), 4.54
356 377.1
methylphenyl)propyl] (1,3- - 4.28 (m, 2H), 3.83 - 3.69 (m, IH), 3.62 thiazol-2-ylmethyl)amine (t, J = 11.1, IH), 2.90 (m,lH), 2.79 (m,
IH), 2.25 (t, J = 7.9, 4H), 2.12 - 1.62 (m, 5H), 1.18 (dd, J = 12.4, 5.1, IH), 1.09 (d, J = 10.0, 6H), 0.92 (t, J = 12.9, IH)
IH NMR (400 MHz, CDC13) δ 8.97 (bd, J = 27.8, 2H), 7.36 - 7.28 (m, 2H), 7.10 (t, J = 7.8, IH), 7.01 (dd, J = 4.8, 1.4, IH), 6.75 - 6.60 (m, 2H), 4.07 - 3.85 (m, 2H), 3.77 (dd, J = 12.0, 3.7, IH), 3.61 (dd, J = 12.3,
10.1, IH), 2.75 - 2.42 (m, 2H), 2.24 (s,
[(3S)-3-[(4R)-2,2-dimethyloxan- 3H), 2.17 (t, J = 8.9, 2H), 1.89 - 1.71 (m,
4-yl]-3-(3-fluoro-4- 2H), 1.67 (d, J = 12.6, IH), 1.25 - 1.12 (m, methylphenyl)propyl] (thiophen- IH), 1.09 (d, J = 10.8, 7H), 0.91 (t, J =
357 3 -ylmethyl) amine 376 12.8, IH)
IH NMR (400 MHz, CDC13) δ 9.01 (bd, J = 33.6, 2H), 7.32 (d, J = 5.0, IH), 7.17 - 7.02 (m, 2H), 7.02 - 6.93 (m, IH), 6.76 - 6.62 (m, 2H), 4.13 (q, J = 14.1, 2H), 3.78 (dd, J = 12.1, 3.7, IH), 3.62 (td, J = 12.3, 2.2, IH), 2.69 (d, J = 36.7, 2H), 2.25 (d, J =
[(3S)-3-[(4R)-2,2-dimethyloxan- 1.3, 3H), 2.18 (dd, J = 14.4, 6.0, 2H), 1.81
4-yl]-3-(3-fluoro-4- (tt, J = 12.3, 8.8, 2H), 1.68 (d, J = 12.7, methylphenyl)propyl] (thiophen- IH), 1.25 - 1.12 (m, IH), 1.09 (d, J = 10.7,
358 2-ylmethyl)amine 376 7H), 0.92 (t, J = 12.8, IH)
IH NMR (400 MHz, CDC13) δ 9.26 (bs, 2H), 7.86 (s, IH), 7.76 (s, IH), 7.10 (t, J = 7.9, IH), 6.81 - 6.64 (m, 2H), 4.03 (q, J = 14.0, 2H), 3.77 (dd, J = 12.0, 3.7, IH), 3.62 (td, J = 12.3, 2.1, IH), 2.89 - 2.76 (m, IH), 2.70 (dd, J = 14.4, 7.6, IH), 2.31 - 2.15 (m,
[(3S)-3-[(4R)-2,2-dimethyloxan- 5H), 1.86 (dddd, J = 20.5, 16.5, 12.4, 6.2, 4-yl]-3-(3-fluoro-4- 2H), 1.70 (d, J = 12.8, IH), 1.18 (td, J = methylphenyl)propyl] (1,3- 12.5, 5.0, IH), 1.09 (d, J = 9.8, 7H), 0.93
359 oxazol-4-ylmethyl)amine 361.1 (dd, J = 16.0, 9.5, IH)
IH NMR (400 MHz, CDC13) δ 9.74 - 9.10 (m, IH), 8.89 (s, IH), 7.88 (s, IH), 7.12 (t,
[(3S)-3-[(4R)-2,2- J = 7.8, IH), 6.71 (s, 2H), 4.25 (d, J = 8.2, dimethyloxan-4- yl] - 3 - (3 - fluoro- 2H), 3.78 (dd, J = 12.1, 3.8, IH), 3.63 (dd, 4- J = 12.2, 10.1, IH), 2.74 (dd, J = 9.4, 4.4, methylphenyl)propyl] (1,3- IH), 2.66 (d, J = 5.3, IH), 2.25 (d, J = 1.3,
360 thiazol-5-ylmethyl)amine 377
5H), 1.93 - 1.74 (m, 2H), 1.68 (d, J = 14.3, IH), 1.16 (dd, J = 12.2, 5.0, IH), 1.09 (d, J
= 9.7, 7H), 0.92 (t, J = 12.7, IH)
9.47 (s, 2H), 7.38 - 7.10 (m, 5H), 7.02 - 6.88 (m, 2H), 6.70 (dd, J = 8.3, 4.6, IH), 3.69 (dt, J = 12.2, 8.5, 3H), 3.52 (td, J = 12.2, 2.1, IH), 2.53 (t, J = 8.3, 2H), 2.42 (s, benzyl[(3S)-3-(3,4- IH), 2.10 (d, J = 23.7, 2H), 1.89 - 1.72 (m, difluorophenyl)-3-[(4R)-2,2- 2H), 1.59 (d, J = 12.0, IH), 1.15 - 0.93 (m,
361 dimethyloxan-4-yl]propyl] amine 374.2 7H), 0.87 (t, J = 12.7, IH).
12.05 - 10.75 (m, IH), 7.32 (d, J = 20.8, 10H), 7.02 - 6.77 (m, 2H), 6.69 - 6.51 (m, IH), 4.69 - 3.82 (m, 3H), 3.76 - 3.65 (m, IH), 3.61 - 3.43 (m, IH), 2.79 - 2.59 (m, dibenzyl[(3S)-3-(3,4- IH), 2.50 - 2.28 (m, 2H), 2.24 - 2.08 (m, difluorophenyl)-3-[(4R)-2,2- IH), 2.02 - 1.75 (m, 2H), 1.65 - 1.52 (m,
362 dimethyloxan-4-yl]propyl] amine 464.3 IH), 1.00 (m, 7H), 0.87 - 0.70 (m, IH).
9.37 (s, 2H), 7.36 - 7.11 (m, 6H), 7.03 - 6.84 (m, 2H), 6.73 (dd, J = 8.3, 4.7, IH), 4.26 (s, IH), 3.75 (dd, J = 29.5, 12.6, 2H), 3.59 - 3.52 (m, IH), 3.43 (td, J = 12.0, 2.6, benzyl[(3S)-3-(3,4- IH), 2.67 - 2.35 (m, 3H), 2.09 (t, J = 11.7, difluorophenyl)-3-[(4S)-2,2- IH), 1.93 - 1.69 (m, 2H), 1.60 (d, J = 12.9,
363 dimethyloxan-4-yl]propyl] amine 374.3 IH), 1.22 - 0.84 (m, 8H).
1H NMR (400 MHz, CDC13) δ 9.50 (s, 2H), 7.29 - 7.20 (m, 5H), 7.12 (dd, / = 8.5, 6.0, IH), 6.76 (t, / = 9.4, 2H), 3.78 (d, / = 6.6, IH), 3.75 - 3.64 (m, IH), 3.56 (t, / = 8.8, IH), 3.46 (d, / = 2.5, IH), 2.67 - 2.52 (m, benzyl[(3S)-3-(3,5-
2H), 2.46 (s, IH), 2.15 - 1.91 (m, 3H), difluorophenyl)-3-[(4R)-2,2- 1.86 (s, 4H), 1.67 (d, / = 12.9, IH), 1.20 -
364 dimethyloxan-4-yl]propyl] amine 374.3
0.91 (m, 8H), 0.86 (s, IH).
1H NMR (400 MHz, CDC13) δ 9.44 (s, 2H), 7.16 - 7.05 (m, 2H), 7.05 - 6.94 (m, 3H), 6.76 (dd, / = 13.7, 5.0, 2H), 3.78 - 3.60 (m, 2H), 3.60 - 3.50 (m, IH), 3.46 (dt, / =
[(3S)-3-(3,5-difluorophenyl)-3- 11.9, 5.9, IH), 2.62 (td, / = 10.4, 4.1, 2H),
[(4R)-2,2- 2.45 (s, IH), 2.19 (d, / = 10.0, 5H), 2.13 - dimethyloxan-4-yl]propyl] [(3- 1.91 (m, 3H), 1.67 (d, / = 12.8, IH), 1.20 -
365 methylphenyl)methyl] amine 388.3
0.91 (m, 8H), 0.87 (d, / = 12.6, IH).
366 390.2
2-({ [(3S)-3-(3,5- 1H NMR (400 MHz, CDC13) δ 9.17 - 8.75 difluorophenyl)-3-[(4R)-2,2- (m, IH), 8.47 - 8.06 (m, IH), 7.11 (t, J = dimethyloxan-4- 8.3, 2H), 6.94 (d, / = 7.5, IH), 6.86 (d, / = yl]propyl]amino}methyl)phenol 8.1, IH), 6.74 (dt, / = 15.1, 8.2, 3H), 4.02
(d, / = 11.9, IH), 3.85 (s, IH), 3.66 (dd, /
= 12.1, 3.9, IH), 3.53 (s, 2H), 2.93 (bs, 5H), 2.65 (s, 2H), 2.50 (s, IH), 2.00 (d, / = 5.7, 3H), 1.63 (d, 7 = 10.6, IH), 1.16 - 0.89 (m, 8H), 0.84 (t, / = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.18 (d, / = 54.2, 2H), 7.25 - 7.19 (m, 3H), 7.15 (dd, / = 6.6, 3.0, 2H), 7.07 (t, J = 7.8, IH), 6.94 (d, 7 = 7.5, IH), 6.71 (d, 7 = 7.0, 2H), 3.79 - 3.62 (m, 3H), 3.51 (td, / = 12.3, 2.1, 3H),
2.52 (s, IH), 2.42 (s, IH), 2.23 (s, 3H), benzyl[(3S)-3-[(4R)-2,2- 2.14 - 1.97 (m, 2H), 1.81 - 1.63 (m, 2H), dimethyloxan-4-yl]-3-(3- 1.58 (d, / = 12.8, IH), 1.18 - 0.92 (m, 8H),
367 methylphenyl)propyl] amine 352.3
0.81 (t, / = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 9.40 (d, / = 69.3, 2H), 7.39 - 7.29 (m, 2H), 7.25 - 7.05 (m, 3H), 6.95 (d, / = 7.5, IH), 6.72 (d, / = 7.3, 2H), 3.80 - 3.59 (m, 3H), 3.52 (td, / = 12.3, 2.1, IH), 2.58 (d, / = 32.7, 3H), 2.40
[(3-bromophenyl)methyl] [(3S)- (d, / = 8.9, IH), 2.23 (s, 3H), 2.07 (dd, / = 3-[(4R)-2,2- 15.1, 6.3, 2H), 1.83 - 1.65 (m, 2H), 1.58 dimethyloxan-4-yl]-3-(3- (d, / = 12.8, IH), 1.19 - 0.89 (m, 8H), 0.82
368 methylphenyl)propyl] amine 432.3
(t, / = 12.8, IH).
lH NMR (400 MHz, CDC13) δ 9.27 (s, 2H), 7.24 - 7.13 (m, 3H), 7.07 (dd, / = 7.4, 5.6, 2H), 6.95 (d, / = 7.5, IH), 6.72 (d, / = 7.2, 2H), 3.76 - 3.61 (m, 3H), 3.52 (d, / = 2.1,
[(3-chlorophenyl)methyl] [(3S)-
IH), 2.55 (s, IH), 2.42 (s, IH), 2.23 (s, 3-[(4R)-2,2- 3H), 2.07 (d, / = 8.4, 2H), 1.77 (bs, 11H), dimethyloxan-4-yl]-3-(3-
1.58 (d, / = 12.5, IH), 0.99 (d, / = 10.2,
369 methylphenyl)propyl] amine 386.3
8H), 0.82 (s, IH).
1H NMR (400 MHz, CDC13) δ 9.33 (d, / = 60.9, 2H), 7.25 - 7.15 (m, IH), 7.08 (t, / = 7.8, IH), 6.99 - 6.88 (m, 4H), 6.72 (d, / = 7.2, 2H), 3.84 - 3.59 (m, 3H), 3.59 - 3.31
[(3S)-3-[(4R)-2,2-dimethyloxan- (m, 3H), 2.55 (s, IH), 2.43 (s, IH), 2.23 (s, 4-yl]-3-(3- 3H), 2.15 - 1.98 (m, 2H), 1.82 - 1.63 (m, methylphenyl)propyl] [(3- 2H), 1.59 (d, / = 12.8, IH), 1.21 - 0.89 (m,
370 fluorophenyl)methyl] amine 370.3
8H), 0.82 (t, / = 12.7, IH). 1H NMR (400 MHz, CDC13) δ 9.17 (dd, /
= 105.8, 59.7, 2H), 7.24 - 7.13 (m, 2H), 7.13 - 6.99 (m, 2H), 6.98 - 6.88 (m, 2H), 6.72 (d, / = 7.2, 2H), 3.60 (m, 6H), 2.54 (s,
[(3S)-3-[(4R)-2,2-dimethyloxan- IH), 2.43 (s, IH), 2.23 (s, 3H), 2.19 (s, 4-yl]-3-(3- 3H), 2.07 (dd, / = 15.8, 8.3, 2H), 1.84 - methylphenyl)propyl] [(3- 1.64 (m, 2H), 1.58 (d, / = 12.6, IH), 1.18 -
371 methylphenyl)methyl] amine 366.3
0.90 (m, 8H), 0.82 (t, / = 12.7, IH). lH NMR (400 MHz, CDC13) δ 8.67 (d, / =
44.3, 2H), 7.10 (t, J = 7.9, IH), 7.04 (t, / = 7.8, IH), 6.96 (d, / = 7.7, IH), 6.79 - 6.69 (m, 4H), 6.56 (d, / = 7.5, IH), 3.81 - 3.62 (m, 3H), 3.52 (d, / = 1.9, IH), 3.26 (s, 8H),
3-({ [(3S)-3-[(4R)-2,2-
2.63 (s, IH), 2.52 (s, IH), 2.24 (s, 3H), dimethyloxan-4-yl]-3-(3- 2.08 (t, / = 8.8, 2H), 1.75 (dd, / = 22.0, methylphenyl)propyl] amino } met
10.4, 2H), 1.58 (d, / = 12.2, IH), 1.00 (d, /
372 hyl)phenol 368.3
= 8.7, 8H), 0.83 (t, 7 = 12.8, IH).
1H NMR (400 MHz, CDC13) δ 9.17 (d, / = 41.1, 2H), 7.29 - 7.16 (m, 2H), 7.08 (t, / = 7.6, IH), 7.02 (td, / = 7.6, 0.8, IH), 6.99 - 6.90 (m, 2H), 6.73 (d, / = 7.6, 2H), 4.77 (bs, 2H), 3.88 (s, 2H), 3.68 (dd, / = 12.0, 3.8, IH), 3.53 (td, / = 12.3, 2.1, IH), 2.60
[(3S)-3-[(4R)-2,2-dimethyloxan- (s, IH), 2.49 (s, IH), 2.23 (s, 3H), 2.19 - 4-yl]-3-(3- 2.01 (m, 2H), 1.88 - 1.66 (m, 2H), 1.62 (d, methylphenyl)propyl] [(2- / = 12.9, IH), 1.19 - 0.91 (m, 7H), 0.83 (t,
373 fluorophenyl)methyl] amine 370.3
/ = 12.8, IH).
1H NMR (400 MHz, CDC13) δ 9.24 (s, IH),
9.07 (s, IH), 7.22 (dd, / = 6.3, 2.7, 3H), 7.16 (dd, / = 6.6, 2.9, 2H), 7.07 (t, 7 = 7.5, IH), 6.94 (d, / = 7.5, IH), 6.72 (d, / = 7.8, 2H), 3.73 (dd, / = 28.6, 12.9, 2H), 3.59 - 3.29 (m, 5H), 2.55 (s, IH), 2.44 (s, IH), benzyl[(3S)-3-[(4S)-2,2- 2.23 (s, 3H), 2.12 - 1.97 (m, 2H), 1.84 - dimethyloxan-4-yl]-3-(3- 1.61 (m, 2H), 1.57 (d, / = 12.9, IH), 1.10
374 methylphenyl)propyl] amine 352.2
(d, J = 9.0, 6H), 1.04 - 0.80 (m, 3H).
1H NMR (400 MHz, CDC13) δ 9.61 (bs, IH), 9.30 (bs, IH), 7.40 - 7.29 (m, 2H),
[(3-bromophenyl)methyl] [(3S)- 7.15 - 7.05 (m, 3H), 7.00 - 6.88 (m, IH), 3-[(4S)-2,2- 6.74 (t, / = 3.8, 2H), 3.79 - 3.62 (m, 2H), dimethyloxan-4-yl]-3-(3- 3.52 (dd, / = 11.9, 3.5, IH), 3.41 (dt, / =
375 methylphenyl)propyl] amine 432.3
12.1, 6.0, IH), 2.56 (s, IH), 2.44 (s, IH), 2.24 (s, 3H), 2.12-1.98 (m, 2H), 1.84- 1.50 (m, 16H), 1.04 (bs, 10.7, 12H).
1H NMR (400 MHz, CDC13) δ 9.60 (bs,
IH), 9.34 (bs, IH), 7.30 - 7.12 (m, 3H), 7.08 (t, /= 7.5, 2H), 6.94 (d, /= 7.6, IH),
6.73 (d, /= 7.6, 2H), 3.71 (q, /= 13.4, 2H), 3.52 (dd, /= 12.0, 3.5, IH), 3.40 (td,
/= 12.1, 2.3, IH), 2.55 (s, IH), 2.43 (s,
[(3-chlorophenyl)methyl] [(3S)- IH), 2.23 (s, 3H), 2.13 - 2.00 (m, 2H), 3-[(4S)-2,2-
1.79 (d, /= 19.7, 9H), 1.58 (d, /= 12.9, dimethyloxan-4-yl]-3-(3- IH), 1.10 (d, /= 8.5, 7H), 1.05 - 0.80 (m,
376 methylphenyl)propyl] amine 386.2
4H).
1H NMR (400 MHz, CDC13) δ 9.54 (bs, IH), 9.33 (bs, IH), 7.28 - 7.14 (m, IH), 7.08 (t, /= 7.5, IH), 7.03 - 6.88 (m, 4H), 6.73 (d, J =1.9, 2H), 3.75 (dd, /= 29.5, 13.3, 2H), 3.52 (dd, /= 12.0, 3.5, IH), 3.40
[(3S)-3-[(4S)-2,2-dimethyloxan- (td, /= 12.1, 2.3, IH), 2.55 (s, IH), 2.43 (s, 4-yl]-3-(3- IH), 2.23 (s, 3H), 2.19-1.91 (m, 7H), methylphenyl)propyl] [(3- 1.72 (ddd, /= 12.0, 11.5, 7.2, 2H), 1.58 (d,
377 fluorophenyl)methyl] amine 370.2
/= 13.0, IH), 1.16-0.79 (m, 10H).
1H NMR (400 MHz, CDC13) δ 9.34 (bs, IH), 9.07 (bs, IH), 7.16 - 6.99 (m, 4H), 6.99 - 6.90 (m, 3H), 6.77 - 6.67 (m, 2H), 3.76 - 3.60 (m, J =93, 2H), 3.51 (dd, / =
[(3S)-3-[(4S)-2,2-dimethyloxan- 12.4, 4.2, 2H), 3.45 - 3.34 (m, IH), 2.56 (s, 4-yl]-3-(3- IH), 2.44 (s, IH), 2.33 - 2.15 (m, /= 12.4, methylphenyl)propyl] [(3- 7H), 2.15 - 1.99 (m, 2H), 1.73 (d, /= 24.4,
378 methylphenyl)methyl] amine 366.3
8H), 1.11 (dd,/= 14.8,7.3, 9H).
1H NMR (400 MHz, CDC13) δ 8.70 (s, 2H), 7.09 (t, /= 7.5, IH), 7.01 (t, J =1.9, IH), 6.95 (d, /= 7.6, IH), 6.74 (d, /= 8.1, 3H), 6.69 (d, /= 8.2, IH), 6.55 (d, /= 7.5, IH), 3.68 (d, /= 10.1, 2H), 3.52 (dd, /= 11.9, 3.7, IH), 3.47 - 3.32 (m, IH), 2.62 (s, IH),
2.52 (s, IH), 2.28 (s, IH), 2.23 (s, 3H),
3-({[(3S)-3-[(4S)-2,2- 2.06 (t, /= 8.5, 2H), 1.79 (d, /= 6.3, IH), dimethyloxan-4-yl]-3-(3-
1.68 (dd, /= 8.1, 3.7, IH), 1.55 (d, / = methylphenyl)propyl] amino } met
12.7, IH), 1.09 (d,/=6.8,6H), 1.06-0.81
379 hyl)phenol 368.3
(m, 3H).
[(3S)-3-[(4S)-2,2-dimethyloxan- 1H NMR (400 MHz, CDC13) δ 9.13 (d, / =
380 370.3
4-yl]-3-(3- 45.4, 2H), 7.31 - 7.20 (m, 2H), 7.12 - 6.91 methylphenyl)propyl] [(2- (m, 4H), 6.75 (d, / = 8.5, 2H), 4.43 (bs, fluorophenyl)methyl] amine 3H), 3.91 (q, / = 13.6, 2H), 3.59 - 3.49 (m,
IH), 3.42 (td, / = 12.2, 2.3, IH), 2.63 (s, IH), 2.52 (s, IH), 2.24 (s, 3H), 2.20 - 2.01 (m, 2H), 1.88 - 1.64 (m, 2H), 1.59 (d, IH), 1.12 (d, / = 6.9, 6H), 1.08 - 0.84 (m, 3H).
1H NMR (400 MHz, CDC13) δ 8.65 - 8.41 (m, IH), 8.41 - 8.17 (m, IH), 7.07 (d, / = 7.5, 2H), 6.99 - 6.82 (m, 3H), 6.71 (d, / = 9.2, 3H), 3.87 (dd, / = 41.0, 12.7, 2H), 3.51 (dd, / = 12.0, 3.5, IH), 3.40 (dd, / = 12.1,
2-({ [(3S)-3-[(4S)-2,2- 9.8, IH), 2.53 (d, / = 33.6, 2H), 2.23 (s, dimethyloxan-4-yl]-3-(3- 3H), 2.03 (s, 2H), 1.82 - 1.60 (m, 2H), methylphenyl)propyl] amino } met
1.55 (d, / = 13.1, IH), 1.10 (d, 7 = 7.9,
381 hyl)phenol 368.3
6H), 0.96 (d, / = 12.8, 4H).
1H NMR (400 MHz, CDC13) δ 8.64 - 8.44 (m, IH), 8.44 - 8.27 (m, IH), 7.08 (s, 2H), 6.95 (s, IH), 6.89 (d, / = 7.3, 2H), 6.76 - 6.58 (m, 3H), 4.61 (s, IH), 3.86 (dd, / = 35.3, 12.9, 2H), 3.63 (dd, / = 12.0, 3.8,
2-({ [(3S)-3-[(4R)-2,2- 2H), 3.49 (t, / = 11.2, 2H), 2.50 (d, / = dimethyloxan-4-yl]-3-(3- 38.7, 2H), 2.22 (s, 3H), 2.03 (m, 2H), 1.71 methylphenyl)propyl] amino } met
(m, 2H), 1.52 (d, / = 12.9, IH), 0.98 (d, / =
382 hyl)phenol 368.3
10.9, 9H), 0.80 (m, IH).
1H NMR (400 MHz, CDC13) δ 7.27 - 7.11 (m, 5H), 6.95 (q, / = 2.5, 2H), 3.65 (d, / = 13.1, IH), 3.61 - 3.53 (m, 2H), 3.48 (td, / benzyl[(3S)-3-(4-bromo-2,6- = 12.1, 2.6, IH), 2.75 (td, / = 11.0, 4.4, difluorophenyl)-3-[(4S)- IH), 2.43 - 2.28 (m, 2H), 2.06 - 1.77 (m, 2,2-dimethyloxan-4- 3H), 1.77 - 1.70 (m, IH), 1.21 - 0.89 (m,
383 yl]propyl] amine 454.2
9H).
1H NMR (400 MHz, CDC13) δ 7.15 - 7.07 (m, IH), 7.02 - 6.89 (m, 5H), 3.64 - 3.39
[(3S)-3-(4-bromo-2,6- (m, 5H), 2.74 (td, J = 11.0, 4.4, IH), 2.43 - difluorophenyl)-3-[(4S)-2,2- 2.28 (m, 2H), 2.26 (s, 3H), 2.06 - 1.77 (m, dimethyloxan-4-yl]propyl] [(3- 3H), 1.74 (d, / = 12.9, IH), 1.22 - 0.90 (m,
384 methylphenyl)methyl] amine 468.2
11H).
1H NMR (400 MHz, CDC13) δ 7.34 - 7.27 benzyl[(3S)-3-(4-bromo-2,6- (m, 4H), 7.27 - 7.21 (m, IH), 7.05 (q, / = difluorophenyl)-3-[(4R)- 2.5, 2H), 3.84 - 3.61 (m, 4H), 2.90 - 2.77 2,2-dimethyloxan-4- (m, IH), 2.52 - 2.38 (m, 2H), 2.19 - 1.98
385 yl]propyl] amine 454.2
(m, 2H), 1.89 (dd, / = 16.3, 9.4, 2H), 1.31 - 1.12 (m, 9H), 1.10 (s, 1H), 0.98 (t, / =
12.7, 1H).
1H NMR (400 MHz, CDC13) δ 7.10 (t, J = 7.8, 1H), 7.03 - 6.88 (m, 5H), 3.70 (dd, / = 6.7, 5.2, 1H), 3.58 (ddd, / = 26.7, 16.5, 9.6,
[(3S)-3-(4-bromo-2,6-
3H), 2.74 (d, / = 3.2, 1H), 2.42 - 2.30 (m, difluorophenyl)-3-[(4R)-2,2- 2H), 2.25 (s, 3H), 1.94 (s, 2H), 1.78 (d, / = dimethyloxan-4-yl]propyl] [(3-
13.0, 2H), 1.23 - 0.96 (m, 11H), 0.89 (t, /
386 methylphenyl)methyl] amine 468.2
= 12.8, 1H).
1H NMR (400 MHz, CDC13) δ 7.23 - 6.84 (m, 9H), 5.24 - 5.09 (m, 1H), 4.00 (q, / = 7.2, 1H), 3.50 (m, 3H), 3.36 (td, / = 12.0, 2.1, 1H), 2.54 (bs, 1H), 2.37 - 2.20 (m, benzyl[(3S)-3-[(4S)-2,2- 2H), 2.15 (s, 3H), 2.00 - 1.82 (m, 2H), dimethyloxan-4-yl]-3-(2- 1.70 (d, / = 11.8, 2H), 1.64 - 1.50 (m, 1H),
387 methylphenyl)propyl] amine 352.3
1.19 - 0.83 (m, 10H).
1H NMR (400 MHz, CDC13) δ 7.43 - 6.92 (m, 9H), 5.32 (s, 1H), 3.89 - 3.73 (m, 1H), 3.73 - 3.58 (m, 3H), 2.70 (Bs, 1H), 2.50 - 2.36 (m, 2H), 2.30 (s, 3H), 2.17 - 2.02 (m, benzyl[(3S)-3-[(4R)-2,2- 1H), 1.85 (d, / = 12.0, 3H), 1.80 - 1.62 (m, dimethyloxan-4-yl]-3-(2- 1H), 1.37 - 1.19 (m, 2H), 1.13 (m, 7H),
388 methylphenyl)propyl] amine 352.3
1.01 (t, / = 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.40 (bs, 2H), 7.37 - 7.05 (m, 5H), 6.59 (tt, / = 8.8, 2.2, 1H), 6.54 - 6.43 (m, 2H), 3.75 (dd, / = 31.3, 13.1, 2H), 3.60 - 3.48 (m, 1H), 3.41 (td, / = 12.1, 2.4, 1H), 2.85 (bs, 2H), 2.49 benzyl[(3S)-3-(3,5- (d, / = 26.4, 2H), 2.10 (dt, / = 10.9, 7.2, difluorophenyl)-3-[(4S)-2,2- 2H), 1.80 - 1.59 (m, 2H), 1.55 (d, / = 12.8,
389 dimethyloxan-4-yl]propyl] amine 374.2
1H), 1.10 (d, / = 10.8, 6H), 0.95 (m, 4H).
1H NMR (400 MHz, CDC13) δ 7.04 (dd, / = 10.6, 5.0, 1H), 6.94 - 6.82 (m, 3H), 6.56
[(3S)-3-(3,5-difluorophenyl)-3-
- 6.45 (m, 3H), 3.58 - 3.43 (m, 3H), 3.38
[(4S)-2,2- (td, / = 12.2, 2.5, 1H), 2.35 - 2.12 (m, 6H), dimethyloxan-4-yl]propyl] [(3-
1.92 - 1.78 (m, 1H), 1.71 - 1.42 (m, 3H),
390 methylphenyl)methyl] amine 388.3
1.13 - 0.79 (m, 10H).
1H NMR (400 MHz, CDC13) δ 7.08 (m,
3-({ [(3S)-3-(3,5- 1H), 6.70 (d, / = 7.7, 1H), 6.58 (dd, / = difluorophenyl)-3-[(4S)-2,2- 18.1, 16.0, 5H), 3.54 (d, / = 14.9, 3H), 3.44 dimethyloxan-4- (td, / = 12.2, 2.5, 1H), 2.30 (m, 3H), 1.91
391 yl]propyl]amino}methyl)phenol 390.2
(m, 1H), 1.77 - 1.32 (m, 5H), 1.12 (m, 10H).
1H NMR (400 MHz, CDC13) δ 7.09 (m,
[(3S)-3-(3,5-difluorophenyl)-3- 2H), 6.92 (m, 2H), 6.49 (m, 3H), 3.59 (m,
[(4S)-2,2- 2H), 3.52 - 3.46 (m, 1H), 3.38 (m, 1H), dimethyloxan-4-yl]propyl] [(2- 2.21 (m, 3H), 1.93 - 1.79 (m, 1H), 1.51 (m,
392 fluorophenyl)methyl] amine 392.3
4H), 0.99 (m, 10H).
1H NMR (400 MHz, CDC13) δ 7.09 (td, / =
8.0, 1.7, 1H), 6.89 - 6.81 (m, 1H), 6.76 (dd, 7 = 8.1, 1.0, 1H), 6.68 (td, 7 = 7.4, 1.2, 1H), 6.64 - 6.50 (m, 3H), 3.92 - 3.71 (m, 2H), 3.56 (ddd, / = 11.9, 5.0, 1.6, 1H), 3.44
2-({ [(3S)-3-(3,5- (td, / = 12.1, 2.5, 1H), 2.48 - 2.29 (m, 2H), difluorophenyl)-3-[(4S)-2,2- 2.22 (ddd, / = 11.7, 8.6, 3.5, 1H), 2.04 - dimethyloxan-4- 1.87 (m, 1H), 1.80 - 1.47 (m, 3H), 1.19 -
393 yl]propyl]amino}methyl)phenol 390.3
0.85 (m, 10H).
1H NMR (400 MHz, CDC13) δ 9.86 - 9.44 (m, 1H), 7.42 - 7.31 (m, 2H), 7.29 - 7.05 (m, 3H), 6.61 (m, 1H), 6.56 - 6.44 (m,
[(3-bromophenyl)methyl] [(3S)- 1H), 4.62 (s, 1H), 3.86 - 3.63 (m, 1H), 3-(3,5- 3.55 (dd, / = 12.0, 3.6, 1H), 3.42 (dd, / = difluorophenyl)-3-[(4S)-2,2- 12.1, 9.7, 1H), 2.65 - 2.37 (m, 1H), 2.23 - dimethyloxan-4- 1.99 (m, / = 10.9, 1H), 1.83 - 1.40 (m,
394 yl]propyl] amine 454.2
7H), 1.20 - 0.83 (m, 7H).
1H NMR (400 MHz, CDC13) δ 9.46 (s, 2H), 7.34 - 7.19 (m, 3H), 7.12 (d, / = 7.1, 1H), 6.61 (tt, / = 8.8, 2.2, 1H), 6.56 - 6.46 (m,
[(3-chlorophenyl)methyl] [(3S)- 2H), 3.77 (dd, / = 33.3, 13.2, 3H), 3.63 - 3-(3,5- 3.48 (m, 1H), 3.43 (td, / = 12.1, 2.4, 1H), difluorophenyl)-3-[(4S)-2,2- 2.53 (d, / = 31.6, 2H), 2.22 - 2.00 (m, 2H), dimethyloxan-4- 1.85 - 1.61 (m, 2H), 1.55 (d, / = 12.9, 1H),
395 yl]propyl] amine 408.2
1.12 (d, / = 9.2, 6H), 1.07 - 0.84 (m, 3H).
1H NMR (400 MHz, CDC13) δ 9.58 (s, 2H), 7.29 - 7.21 (m, 1H), 7.06 - 6.89 (m, 3H), 6.61 (tt, / = 8.8, 2.2, 1H), 6.55 - 6.44 (m, 2H), 3.80 (dd, / = 34.6, 13.1, 2H), 3.62 -
[(3S)-3-(3,5-difluorophenyl)-3- 3.50 (m, 1H), 3.42 (td, / = 12.1, 2.4, 1H),
[(4S)-2,2- 2.52 (d, / = 31.2, 2H), 2.12 (dt, / = 11.1, dimethyloxan-4-yl]propyl] [(3- 7.4, 2H), 1.81 - 1.59 (m, 2H), 1.56 (d, / =
396 fluorophenyl)methyl] amine 392.3
13.0, 1H), 1.17 - 0.82 (m, 10H).
[(3S)-3-(3,5-difluorophenyl)-3- 1H NMR (400 MHz, CDC13) δ 9.43 (s, 2H),
[(4R)-2,2- 7.25 (dt, / = 7.6, 6.7, 1H), 6.99 (m, / =
397 392.3
dimethyloxan-4-yl]propyl] [(3- 14.6, 8.2, 3H), 6.62 (ddd, / = 8.8, 5.5, 2.2, fluorophenyl)methyl] amine 1H), 6.49 (dd, /= 8.0, 2.1, 2H), 3.81 (dd, /
= 33.5, 12.9, 2H), 3.68 (dd, /= 12.1, 3.8,
2H), 3.64 - 3.47 (m, 3H), 2.52 (d, /= 31.6,
2H), 2.14 (dd, /= 19.0, 9.6, 2H), 1.70 (dd, /= 15.4, 6.7, 2H), 1.58 (d, /= 12.7, 1H),
1.21 - 0.91 (m, 9H), 0.84 (t, /= 12.8, 1H).
1H NMR (400 MHz, CDC13) δ 9.55 (bs, 2H), 7.27-7.17 (m, 3H), 7.12 (d, /= 7.0, 1H), 6.61 (dd, /= 6.6, 4.4, 1H), 6.50 (dd, /
[(3-chlorophenyl)methyl] [(3S)- = 8.0, 2.1, 2H), 3.85 - 3.63 (m, 3H), 3.52 3-(3,5-
(d, /= 2.0, 1H), 2.51 (d, J =21.%, 2H), difluorophenyl)-3-[(4R)-2,2- 2.34 (s, 2H), 2.15 (d, /= 8.8, 2H), 1.70 (s, dimethyloxan-4- 2H), 1.57 (d,/= 13.0, 1H), 1.20-0.93 (m,
398 yl]propyl] amine 408.3
9H), 0.85 (t,/= 12.7, 1H).
1H NMR (400 MHz, CDC13) δ 9.41 (bs, 2H), 7.46 (d, J =1.1, 1H), 7.41 - 7.31 (m, 2H), 7.28 - 7.08 (m, 3H), 6.61 (tt, /= 8.8, 2.2, 1H), 6.55 - 6.42 (m, 2H), 3.82 - 3.62
[(3-bromophenyl)methyl] [(3S)- (m, 3H), 3.52 (td, /= 12.3, 2.1, 1H), 2.51 3-(3,5- (d,/ = 29.9, 2H), 2.12 (ddd,/= 13.8, 11.1, difluorophenyl)-3-[(4R)-2,2- 6.4, 2H), 1.79 - 1.62 (m, 2H), 1.56 (d, / = dimethyloxan-4- 12.9, 1H), 1.17 - 0.92 (m, 9H), 0.84 (t, / =
399 yl]propyl] amine 454.2
12.8, 1H).
1H NMR (400 MHz, CDC13) δ 8.91 (bs, 2H), 7.07 (t, J= 7.9, 1H), 6.78 (s, 1H), 6.73 (d, /= 8.2, 1H), 6.67 - 6.56 (m, 2H), 6.50 (d, /= 5.9, 2H), 3.99 - 3.61 (m, 3H), 3.58 - 3.44 (m, /= 12.3, 1H), 2.57 (d, / =
3-({[(3S)-3-(3,5- 36.9, 2H), 2.13 (d, /= 9.2, 2H), 1.71 (dd, / difluorophenyl)-3-[(4R)-2,2- = 20.2, 8.2, 2H), 1.54 (d, /= 12.1, 1H), dimethyloxan-4- 0.99 (t, /= 12.6, 9H), 0.84 (t, /= 12.7,
400 yl]propyl]amino}methyl)phenol 390.3
1H).
1H NMR (400 MHz, CDC13) δ 9.14 (bd, / = 31.9, 2H), 7.30 - 7.22 (m, 3H), 7.22 - 7.13 (m, 3H), 7.00 (t, J= 7.8, 1H), 6.61
(dd, /= 13.8, 6.1, 2H), 5.60 (s, 1H), 3.76 (dd, J= 31.3, 12.8, 2H), 3.54 (dd, /= 12.0,
3.5, 1H), 3.41 (td, /= 12.2, 2.3, 1H), 2.52 benzyl[(3S)-3-[(4S)-2,2- (d, /= 33.4, 2H), 2.16 (d, /= 1.3, 3H), dimethyloxan-4-yl]-3-(3-
2.07 (t, /= 8.8, 2H), 1.68 (ddd, /= 13.7, fluoro-4-
12.0, 7.5, 2H), 1.55 (d, /= 13.0, 1H), 1.19
402 methylphenyl)propyl] amine 370.3
-0.80 (m, 10H). 1H NMR (400 MHz, CDC13) δ 9.36 (d, / =
45.6, 2H), 7.23 (dd, /= 5.1, 1.1, IH), 7.01 (dd,/= 11.5,5.0, 2H), 6.89 (dd, 7=5.1, 3.5, IH), 6.64 (dd, /= 14.3, 6.3, 2H), 4.02 (d, /= 12.2, 2H), 3.61 - 3.34 (m, 4H), 2.58
[(3S)-3-[(4S)-2,2-dimethyloxan-
(d, /= 32.2, 2H), 2.16 (d, /= 1.3, 3H),
4-yl]-3-(3-fluoro-4- 2.11 (t,/=8.3,2H), 1.84- 1.62 (m, 2H), methylphenyl)propyl] (thiophen- 1.58 (d, /= 13.0, IH), 1.17 - 0.81 (m,
403 2-ylmethyl)amine 376.2
10H).
1H NMR (400 MHz, CDC13) δ 9.03 (d, / = 28.9, 2H), 7.98 (bs, IH), 7.22 (dd, / = 4.5, 2.6, 2H), 7.02 (t, / = 7.8, IH), 6.95 (dd, / = 4.1, 2.2, IH), 6.62 (dd, /= 13.1, 5.7, 2H), 3.87 (q, /= 13.4, 2H), 3.56 (dd, /= 12.0,
[(3S)-3-[(4S)-2,2-dimethyloxan- 3.6, IH), 3.42 (td, /= 12.2, 2.3, IH), 2.54
4-yl]-3-(3-fluoro-4- (d, /= 38.6, 2H), 2.16 (d, /= 1.2, 3H), methylphenyl)propyl] (thiophen- 2.13 - 1.97 (m, 2H), 1.69 (m, 2H), 1.56 (d,
404 3 -ylmethyl) amine 376.2
/= 12.9, IH), 1.19 - 0.83 (m, 10H).
1H NMR (400 MHz, CDC13) δ 9.41 (s, IH), 8.94 (d, /= 22.1, 2H), 7.02 (t, /= 7.8, IH), 6.74 (d, /= 3.4, IH), 6.69 - 6.59 (m, 2H), 6.52 (dd, /= 3.4, 1.0, IH), 3.95 (dd, / =
[(3S)-3-[(4S)-2,2-dimethyloxan- 32.9, 13.8, 2H), 3.62 - 3.51 (m, IH), 3.43 4-yl]-3-(3-fluoro-4- (td, /= 12.2, 2.3, IH), 2.60 (d, /= 43.7, methylphenyl)propyl] [(5- 2H), 2.32 (d, /= 0.7, 3H), 2.21 - 1.98 (m, methylthiophen-2- 5H), 1.85 - 1.63 (m, 2H), 1.58 (d, /= 12.9,
405 yl)methyl] amine 390.2
IH), 1.23-0.81 (m, 10H).
1H NMR (400 MHz, CDC13) δ 10.24 (bs, 4H), 9.09 (bs, IH), 8.56 (bs, IH), 8.40 (d, / = 7.5, IH), 7.77 (bs, IH), 7.06 (t, /= 7.8, IH), 6.70 (t, /= 9.8, 2H), 4.23 (q, /= 13.4, 2H), 3.56 (dd, /= 12.0, 3.7, IH), 3.51 - 3.36 (m, IH), 2.86 (t, /= 8.9, IH), 2.73
[(3S)-3-[(4S)-2,2-dimethyloxan- (dd, 7=11.2, 6.6, IH), 2.27 - 2.06 (m,
4-yl]-3-(3-fluoro-4- 5H), 1.88 (d, 7 = 7.5, IH), 1.72 (dd,/ = methylphenyl)propyl] (pyridin-3- 8.1, 3.8, IH), 1.60 (d, /= 12.6, IH), 1.21 -
406 ylmethyl) amine 371.3
0.83 (m, 10H).
[(3S)-3-[(4S)-2,2-dimethyloxan-
1H NMR (400 MHz, CDC13) δ 9.91 - 9.38 4-yl]-3-(3-fluoro-4- (bs, 2H), 8.60 (s, IH), 7.84 (d, /= 7.8, IH), methylphenyl)propyl]({ [6- 7.60 (d, /= 8.0, IH), 7.01 (bs, J =1.9, IH), (trifluoromethyl)pyridin- 3 - 6.67 - 6.54 (m, 2H), 3.93 (dd, /= 20.0,
407 yl] methyl } ) amine 439.3
2H), 3.53 (d, /= 3.5, IH), 3.48 - 3.37 (m, IH), 2.62 (s, IH), 2.52 (s, IH), 2.13 (dd, /
= 15.8, 5.0, 5H), 1.72 (s, 2H), 1.58 (d, / = 12.6, IH), 1.17 - 0.82 (m, 10H).
1H NMR (400 MHz, CDC13) δ 9.33 (d, / = 42.7, 2H), 7.98 (s, IH), 7.50 (d, / = 8.6,
IH), 7.00 (d, / = 7.9, IH), 6.73 - 6.52 (m,
[(3S)-3-[(4S)-2,2-dimethyloxan- 3H), 3.79 (d, / = 11.4, 5H), 3.53 (d, / = 4-yl]-3-(3-fluoro-4- 3.6, IH), 3.42 (m, IH), 2.53 (d, / = 30.8, methylphenyl)propyl] [(6-
2H), 2.16 (d, / = 1.3, 3H), 2.08 (d, / = 8.5, methoxypyridin- 3 -
2H), 1.71 (dd, 7 = 25.4, 10.0, 2H), 1.57 (d,
408 yl)methyl] amine 401.3
/ = 12.8, IH), 1.20 - 0.75 (m, 10H).
1H NMR (400 MHz, CDC13) δ 10.08 (bs,
4H), 8.97 (s, IH), 8.36 (d, / = 7.4, IH), 7.58 (d, / = 7.4, IH), 7.05 (t, 7 = 7.9, IH),
6.68 (dd, / = 13.1, 9.2, 2H), 4.20 (q, / =
[(3S)-3-[(4S)-2,2-dimethyloxan- 13.5, 2H), 3.55 (dd, / = 12.0, 3.7, IH), 3.50 4-yl]-3-(3-fluoro-4- - 3.35 (m, IH), 2.83 (s, IH), 2.70 (s, 4H), methylphenyl)propyl] [(6- 2.17 (d, / = 1.0, 5H), 1.98 - 1.78 (m, IH), methylpyridin- 3 -
1.71 (dd, / = 8.0, 3.7, IH), 1.59 (d, / =
409 yl)methyl] amine 385.3
12.9, IH), 1.23 - 0.66 (m, 10H). lH NMR (400 MHz, CDC13) δ 7.69 (d, / = 3.3, IH), 7.34 (d, / = 3.2, IH), 7.02 (t, / = 7.9, IH), 6.73 - 6.57 (m, 2H), 4.34 (q, / = 14.7, 2H), 3.60 - 3.49 (m, IH), 3.43 (td, /
[(3S)-3-[(4S)-2,2-dimethyloxan- = 12.1, 2.3, IH), 2.89 - 2.76 (m, IH), 2.73 4-yl]-3-(3-fluoro-4- - 2.62 (m, IH), 2.18 (m, 5H), 1.97 - 1.82 methylphenyl)propyl] (1,3- (m, IH), 1.78 - 1.64 (m, IH), 1.60 (d, / =
410 thiazol-2-ylmethyl)amine 377.2
12.8, IH), 1.18 - 0.82 (m, 10H).
1H NMR (400 MHz, CDC13) δ 9.53 (bs, 2H), 8.12 - 7.72 (bs, IH), 7.03 (t, 7 = 7.9, IH), 6.64 (t, / = 7.4, 3H), 4.18 (q, / = 14.0, 2H), 3.56 (dd, / = 12.0, 3.6, IH), 3.43 (td,
[(3S)-3-[(4S)-2,2-dimethyloxan- / = 12.2, 2.2, IH), 2.74 - 2.60 (m, IH), 4-yl]-3-(3-fluoro-4- 2.56 (t, / = 9.1, IH), 2.14 (dd, / = 20.8, methylphenyl)propyl] (1,3- 5.5, 5H), 1.86 - 1.61 (m, 2H), 1.57 (d, / =
411 thiazol-5-ylmethyl)amine 377.2
12.9, IH), 1.22 - 0.84 (m, 10H).
1H NMR (400 MHz, CDC13) δ 9.50 (bs, 2H), 8.69 - 8.41 (m, 2H), 8.00 (d, J = 1.9, IH), 7.70 (dd, / = 7.8, 5.5, IH), 7.25 (s, benzyl[(3S)-3-[(4R)-2,2- 5H), 3.86 (s, 2H), 3.68 - 3.60 (m, IH), dimethyloxan-4-yl]-3- 3.52 (d, / = 10.5, IH), 2.71 (bs, IH), 2.66 -
412 (pyridin- 3 - yl)propyl] amine 339.2
2.48 (m, 2H), 2.30 (bs, IH), 1.99 (d, / = 9.4, IH), 1.84 (d, / = 8.2, IH), 1.56 (d, / =
12.2, IH), 1.20 - 0.90 (m, 9H), 0.85 (d, / =
12.6, IH).
1H NMR (400 MHz, CDC13) δ 9.52 (bs, 2H), 8.60 (s, IH), 8.53 (d, / = 5.1, IH), 8.01 (d, / = 7.8, IH), 7.76 - 7.63 (m, IH), 7.25 (s, 5H), 3.88 (m, 2H), 3.54 (d, / = 3.7, IH), 3.43 (m, IH), 2.73 (s, IH), 2.56 (m, benzyl[(3S)-3-[(4S)-2,2- 2H), 2.27 (bs, IH), 2.02 (bs, IH), 1.85 (bs, dimethyloxan-4-yl]-3- IH), 1.55 (d, / = 12.3, IH), 1.15 - 0.81 (m,
413 (pyridin- 3 - yl)propyl] amine 339
10H).
[0124] Example 414
Figure imgf000179_0001
[0125] Ex414
[0126] Benzyl({2-[(2,2-dimethyloxan-4-yl)(4-fluorophenyl)amino]ethyl})amine
Figure imgf000179_0002
[0127] 414A [0128] 414.1 Preparation of 414A.
[0129] A solution of 2,2-dimethytetrahydropyran-4-one (3B, 200 mg, 1.56 mmol), 4- fluoroaniline (164 uL, 1.56 mmol), sodium triacetoxyborohydride (496 mg, 2.34 mmol, 1.5 eq), and acetic acid (107 uL, 1.87 mmol, 1.2 eq) in DCE (20 mL), was allowed to stir at room temperature for 2h. LCMS of the mixture indicated product. Mixture was quenched with 2N NaOH, diluted with DCM and filtered through a hydrophobic frit. The filtrate was concentrated to give 414A (267 mg, 77% yield).
[0130] LC-MS (ESI) m/z: 224.1 [M+l] observed.
Figure imgf000180_0001
[0131] 414B
[0132] 414.2 Preparation of 414B.
[0133] A solution of 414A (167 mg, 0.75 mmol), N-boc-2-aminoacetaldehyde (143 mg, 0.90 mmol, 1.2 eq), sodium triacetoxyborohydride (238 mg, 1.13 mmol, 1.5 eq) in DCE (10 mL) was stirred overnight. Additional amounts of N-boc-2-aminoacetaldehyde (143 mg, 0.90 mmol, 1.2 eq), sodium triacetoxyborohydride (238 mg, 1.13 mmol, 1.5 eq) in addition to acetic acid (129 uL, 2.25 mmol, 3eq) were added. The resulting mixture was allowed to stir overnight. The mixture was treated with NaHC03 solution and allowed to stir for several minutes. DCM (10 mL) was added and the mixture was filtered through a hydrophobic frit. The filtrate was concentrated to a yellow oil, which was purified on silica gel (50 g, Biotage system), eluting with 10- 50% ethyl acetate in Hexane to provide 414B (187 mg, 68% yield). [0134] LC-MS (ESI) m/z: 367.3 [M+l] observed.
Figure imgf000181_0001
[0135] 414C
[0136] 414.3 Preparation of 414C.
[0137] To a solution of 414B (187 mg, 0.51 mmol) in DCM (2 mL) was added TFA (1.3 mL). After stirring for 20 min, LCMS indicated the reaction was complete. The mixture was concentrated and the residue was dissolved in DCM and washed with NaHCC"3 solution. The mixture was filtered through a hydrophobic frit and the organic layer concentrated to provide 414C (123 mg, 91% yield).
[0138] LC-MS (ESI) m/z: 267.2 [M+l] observed.
[0139] 414.4 Preparation of Ex414.
[0140] A solution of 414C (60 mg, 0.23 mmol), benzaldehyde (11 uL, 0.11 mmol), sodium triacetoxyborohydride (73 mg, 0.35 mmol, 1.5 eq) and acetic acid (16 uL, 0.28 mmol, 1.2 eq) in DCE (2 mL) was allowed to stir at room temperature for 3d. The mixture was quenched with saturated NaHCC solution, diluted with DCM and filtered through a hydrophobic frit. The filtrate was concentrated to a clear orange oil , which was purified by preparative HPLC to provide the fraction containing the desired product, which was neutralized with sat. NaHC03 to afford Ex414 (24.2 mg, 29% yield).
[0141] LC-MS (ESI) m/z: 357.3 [M+l] observed. [0142] 1H NMR (400 MHz, CDC13) ) ) δ 7.37 - 7.31 (m, 4H), 7.31 - 7.24 (m, 4H), 7.21 (dt, / = 4.9, 2.0, 2H), 6.72 - 6.62 (m, 2H), 6.29 (ddd, 7 = 6.8, 5.4, 3.2, 2H), 3.74 - 3.49 (m, 7H), 3.03 (qt, / = 14.7, 7.2, 2H), 2.52 - 2.28 (m, 2H), 1.45 - 1.26 (m, 3H), 1.20 - 1.17 (m, 1H), 1.15 (d, / = 5.2, 3H), 1.12 (s, 3H).
[0143] Example 415
Figure imgf000182_0001
[0144] tx41 b
[0145] 2-(Benzylamino)-N-(2,2-dimethyloxan-4-yl)-N-(4-fluorophenyl)acetamide
Figure imgf000182_0002
[0146] 41 bA
[0147] 415.1 Preparation of 415A.
[0148] A solution of 414A (80 mg, 0.36 mmol), bromoacetyl chloride (30 uL, 0.36 mmol), triethylamine (60 uL, 0.43 mmol) in DCM (4 mL) was allowed to stir at room temperature for 2 h. Additional bromoacetyl chloride (15 uL, 0.5 eq) and triethylamine (30 uL, 0.6 eq) were added and the solution was allowed to stir over 3d. The mixture was washed with NaHC03 solution and brine. The organic extract was filtered through a hydrophobic frit to remove water and concentrated. The residue was purified on silica gel column (lOg, Biotage) eluting with 10-50% ethyl acetate in hexane to afford 415A as a white solid (90.7 mg, 0.26 mmol, 73% yield).
[0149] LC-MS (ESI) m/z: 344.1/346.1 [M+l] observed.
[0150] 415.2 Preparation of Ex415.
[0151] A solution of 415A (90 mg, 0.26 mmol), benzylamine (28.4 uL, 0.26 mmol), and cesium carbonate (186 mg, 0.57 mmol) in 3 mL of DMF was allowed to stir at room temperature under nitrogen for 2 h. The mixture was filter through a syringe filter and purified by HPLC. The desired fractions were combined and concentrated to about 50% of the original volume. The resulting solution was treated with saturated NaHC03 and extracted with ether (20 ml X3). The combined organic layers were dried over MgS04 and concentrated to provide Ex415 (30.9 mg, 32% yield).
[0152] LC-MS (ESI) m/z: 371.2 [M+l] observed.
[0153] 1H NMR (400 MHz, CDC13) ) δ 7.28 - 7.11 (m, 5H), 7.01 (dd, / = 9.0, 8.1, 2H), 6.95 - 6.88 (m, 2H), 5.04 - 4.92 (m, 1H), 3.75 - 3.64 (m, 2H), 3.62 (s, 2H), 2.88 (s, 2H), 1.64 - 1.53 (m, 2H), 1.28 - 1.15 (m, 4H), 1.12 - 1.02 (m, 4H).
Example 416
Figure imgf000183_0001
Ex416 benzyl[3-(2,2-dimethylmorpholin-4-yl)-3-(4-fluorophenyl)propyl]amine
Figure imgf000184_0001
416A
416.1 Preparation of 416A
3-(4-Fluorophenyl)acrylonitrile (486 mg, 3.3 mmol) and 2,2-dimethylmorpholine (345 mg, 3.0 mmol) were mixed and stirred for 2h. No reaction was observed. It was then heated at 100 oC for 30h. The reaction was stopped and the material was purified on BioTage 25g snap column, eluted with 0-50% EtOAc in Hex to give the desired product (416A, 74 mg).
[0154] LC-MS (ESI) m/z: 263.2 [M+l] observed.
Figure imgf000184_0002
[0155] 416B
[0156] 416.2 Preparation of 416B
[0157] Following an analogous procedure for 6C, 415A (74 mg) was converted to 416B (75 mg).
[0158] LC-MS (ESI) m/z: 267.2 [M+l] observed. [0159] 416.3 Preparation of Ex416 [0160] Following an analogous procedure for 6D, 416B (11 mg, 0.04 mmol) was transformed to Ex416 (8.3 mg, 35% yield) after HPLC purification.
[0161] LC-MS (ESI) m/z: 357.1 [M+l] observed.
[0162] 1H NMR (400 MHz, CDC13) δ 9.70 (s, 2H), 7.46 - 7.26 (m, 7H), 7.13 (t, J = 8.4, 2H), 4.38 (d, J = 9.9, 1H), 3.89 (m, 4H), 3.00 - 2.37 (m, 7H), 1.43 - 1.01 (m, 6H).
[0163] Example 417-424 were prepared in an analogous manner as described in Ex416. The characterization of these examples was shown in Table 4.
Table 4:
Figure imgf000185_0001
[3-(2,2-dimethylmorpholin- IH NMR (400 MHz, CDC13) δ 9.86 (s,
4-yl)-3-(4- 4H), 7.66 - 7.30 (m, 7H), 7.14 (t, J = 8.4, fluorophenyl)propyl]({ [3- 2H), 4.36 (dd, J = 25.4, 10.5, IH), 4.14 - (trifluoromethyl)phenyl] met 3.37 (m, 5H), 3.15 - 2.17 (m, 8H), 1.48 -
420 hyl}) amine 425.1 0.97 (m, 6H).
IH NMR (400 MHz, CDC13) δ 9.92 (s, IH), 7.38 - 7.21 (m, 7H), 7.06 (t, J = 8.4, benzyl [3 - (4-fluorophenyl) - 2H), 4.23 (d, J = 10.1, IH), 3.85 (q, J = 3-(morpholin-4- 13.0, 2H), 3.67 (s, 4H), 2.82 (s, 2H), 2.76
421 yl)propyl] amine 329.1 - 2.56 (m, 4H), 2.49 (d, J = 8.4, 2H).
[3 - (4-fluorophenyl) -3 - IH NMR (400 MHz, CDC13) δ 9.93 (s, (morpholin-4- IH), 7.30 (dd, J = 8.3, 5.0, 2H), 7.24 (s, yl)propyl]({ [6- 5H), 7.06 (t, J = 8.4, 2H), 4.23 (d, J = 9.8, (trifluoromethyl)pyridin- 3 - IH), 3.85 (q, J = 13.0, 2H), 3.67 (s, 4H),
422 yl] methyl } ) amine 398.2 2.96 - 2.55 (m, 6H), 2.49 (d, J = 8.5, IH).
IH NMR (400 MHz, CDC13) δ 7.51 - 7.36 (m, 3H), 7.33 (dd, J = 4.9, 2.9, IH),
[3-(4-fluorophenyl)-3- 7.20 (t, J = 8.3, 2H), 7.09 (d, J = 4.4, IH),
(morpholin-4- 4.38 (d, J = 9.1, IH), 3.83 (d, J = 31.0, yl)propyl] (thiophen-3- 5H), 3.60 (s, IH), 3.08 (s, IH), 2.81 (s,
423 ylmethyl) amine 335.1 5H), 2.59 (d, J = 9.4, 2H).
IH NMR (400 MHz, CDC13) δ 7.34 (dd, J = 8.3, 5.0, 2H), 7.22 (dd, J = 5.1, 1.0, IH), 7.15 - 6.97 (m, 3H), 6.88 (dd, J = 5.1, 3.6,
[3-(4-fluorophenyl)-3- IH), 4.28 (d, J = 10.2, IH), 4.17 - 4.05
(morpholin-4- (m, 2H), 3.73 (s, 4H), 3.45 (d, J = 40.3, yl)propyl] (thiophen-2- IH), 2.83 (s, IH), 2.84 - 2.58 (m, 5H),
424 ylmethyl) amine 335.2 2.58 - 2.39 (m, IH).
Example 425
Figure imgf000187_0001
Ex425 benzyl({2-[(R)-[(4R)-2,2-dimethyloxan-4-yl](4-fluorophenyl)methyl]propyl})amine
Figure imgf000187_0002
425A 425B
Fast moving Slow moving
isomer on isomer on
BioTage column BioTage column
425.1 Preparation of 425 A and 425B
To a solution of 6B (100 mg, 0.38 mmol) in anhydrous THF (3.83 ml) at -78 °C under nitrogen, LiHMDS (1.0 M in THF, 0.42 mL, 0.42 mmol, 1.1 eq.) was added dropwise. The mixture was stirred at -78 °C for 1.5 h and it turned to be a yellowish solution. Mel was added to it at -78 °C and the mixture was stirred from -78 °C to RT for 2 h. LC-MS identified a mass corresponding to the desired product. The residue was purified on 10 g Snap column (Biotage), 0-40% EtOAc in Hex 15 CV to give the first fraction 425 A (25 mg, 24%) and the second fraction 425B (30 mg, 26%).
[0124] LC-MS (ESI) m/z: 276.2 [M+l] observed for 425A
[0125] LC-MS (ESI) m/z: 276.2 [M+l] observed for 425B [0126] 425.2 Preparation of Ex425 and 426
[0127] Following an analogous manner described in Ex6, 425A and 425B were transformed to Ex425 and Ex426. The characterization of these examples was shown in Table 5.
[0128] Table 5:
Figure imgf000188_0001
Example 427
Figure imgf000189_0001
EX427 benzyl[(3S)-3-[(4R)-2,2-dimethyloxan-4-yl]-2,2-difluoro-3-(4-fluorophenyl)propyl]amine
Figure imgf000189_0002
427A
427.1 Preparation of 427 A
[0164] To a solution of 6B (100 mg, 0.38 mmol) in anhydrous THF (3.83 ml) at -78 °C
under nitrogen, LiHMDS (1.0 M in THF, 0.42 mL, 0.42 mmol, 1.1 eq.) was added dropwise. The mixture was stirred at -78 °C for 1.5 h and it turned to be a yellowish solution. N- Fluorobenzenesulfonimide (265 mg, 0.84mmol) was added to it at -78 °C and the mixture was stirred from -78 °C to RT for 2 h. LC-MS identified a mass corresponding to the desired product. The residue was purified on 10 g Snap column (Biotage), 0-40% EtOAc in Hex 15 CV to give the first fraction 427A (68 mg, 60%).
[0165] LC-MS (ESI) m/z: 298.3 [M+l] observed for 427A
[0166] 427-2 Preparation of Ex427
[0167] Following an analogous manner as described in Ex6, 427 A was transformed to
Ex427. [0168] LC-MS (ESI) m/z: 392.3 [M+l] observed for Ex427
1H NMR (400 MHz, CDC13) δ 7.45 - 7.24 (m, 5H), 7.13 - 7.07 (m, 2H), 7.03 (t, / = 8.6, 2H), 4.07 (dd, 7 = 34.2, 13.1, 2H), 3.71 (ddd, 7 = 22.4, 12.1, 6.9, 2H), 3.13 - 2.95 (m, 1H), 2.91 - 2.73 (m, 2H), 2.40 (d, 7 = 8.8, 1H), 1.89 (d, / = 12.4, 1H), 1.44 - 1.28 (m, 1H), 1.18 - 1.04 (m, 8H), 0.95 (t, / = 12.8, 1H).
Example 428
Figure imgf000190_0001
Ex428
4-[(lS)-l-[(4S)-2,2-dimethyloxan-4-yl]-3-[(pyridin-3- ylmethyl)amino]propyl]benzonitrile, trifluoroacetic acid
Figure imgf000190_0002
428A
428.1 Preparation of 428 A
[0169] The preparation of 428A was started from (3S)-3-(4-bromophenyl)-3-[(4R)-2,2- diemthyloxan-4-yl]propanenitrile, which can be prepared from 1,4-dibromobenzene via a reaction sequence outlined in Ex6.
[0170] To a solution of (3S)-3-(4-bromophenyl)-3-[(4R)-2,2-diemthyloxan-4- yl]propanenitrile (1.0 g, 3.1 mmol) in methanol (10 ml) at 0 °C, Cobalt chloride hexahydrate (2.953 g, 12.41 mmol) was added. After 15 min, NaBH4 (470 mg, 12.41 mmol) was added at 0 °C and the reaction mixture was stirred for another 40 min, and quenched by HCl (IN, 20 ml), basified with ammonium hydroxide (50 ml), and then extracted with Et20 (50 ml x 3). The organic layer was combined washed with brine, dried over Na2S04 and concentrated to give 428A as brownish oil (0.8 g, 79%).
[0171] LC-MS (ESI) m/z: 326.1 [M+l] observed.
Figure imgf000191_0001
428B
428.2 Preparation of 428B
[0172] Benzyl chlorofomate (2.5 mL, 10.67 mmol) was added to a mixture of amine 428A (2.9 g, 8.89 mmol) and Et3N (2.48 mL 17.68 mmol) in CH2C12 (30 mL). The resulting mixture was stirred at RT. After 2h, the reaction was diluted with CH2C12 (5 ml) and washed with water, brine, dried and concentrated, the residual was purified on 340 g Snap column (Biotage), 0-40% EtOAc in Hex 15 CV to give 428B (1.49 g, 36% yield).
[0173] LC-MS (ESI) m/z: 482.1 [M+Na] observed.
NHCbz
Figure imgf000191_0002
428C
428.3 Preparation of 428C
[0174] A mixture of bromide 428B (300 mg, 0.65 mmol), copper cyanide (300 mg, 0.65 mmol) and copper iodide (70 mg, 0.78 mmol) in DMF (3.26 ml). The suspension was degassed three times and heated with microwave to 200 °C for 2 h. Then, the mixture was diluted with 10 mL water and extracted with diethyl ether (10 mL x3). The organic solution was dried with Na2S04 and concentrated. The residue was purified on 10 g Snap column (Biotage), 0-40% EtOAc in Hex 15 CV to give 428C (180 mg, 68 % yield) as a clear oil.
[0175] LC-MS (ESI) m/z: 407.3 [M+l] observed.
Figure imgf000192_0001
428D
428.4 Preparation of 428D
[0176] A mixture of 428C (220 mg, 0.54 mmol) and palladium on activated charcoal (40 mg) in MeOH (40 ml) was bubbled with H2 balloon. After lh, the catalyst was removed by filtration and the filter pad was washed by MeOH (10 ml), the combined material was concentrated on rotavep left 428D (150 mg, 100%).
[0177] LC-MS (ESI) m/z: 273.2 [M+l] observed.
[0178] 428.5 Preparation of Ex428
[0179] Following an analogous procedure described in 6.3, 428D (10 mg, 0.04 mmol) was converted to Ex428 (12.6 mg, 72% yield) after HPLC purification.
[0180] LC-MS (ESI) m/z: 364.2 [M+l] observed.
[0181] 1H NMR (400 MHz, CDC13) δ 9.24 (s, 1H), 8.65 (d, / = 5.3, 1H), 8.52 (d, J = 1.9,
1H), 7.89 (dd, / = 7.8, 5.8, 1H), 7.66 (d, / = 8.2, 2H), 7.34 - 7.23 (m, 2H), 6.22 (brs, IH), 4.34 (s, 2H), 3.66 (dd, / = 12.0, 3.0, IH), 3.53 (td, / = 11.9, 3.0, IH), 2.98 (dd, / = 11.2, 6.2, IH), 2.79 (dd, / = 11.6, 7.2, IH), 2.41 (dd, 7 = 26.4, 14.9, 2H), 2.13 - 2.00 (m, IH), 1.88 (d, / = 8.2, IH), 1.71 (d, / = 12.7, IH), 1.26 (d, / = 6.9, IH), 1.22 (s, 3H), 1.21 (s, 3H), 1.12 (d, / = 12.8, 2H).
[0182] Examples 429-459 were prepared in an analogous manner as described in Ex428.
The list of these examples was shown in Table 6 with the MS and IH NMR data.
Table 6:
Figure imgf000193_0001
= 11.7, IH), 1.18 (s, 3H), 1.15 (s, 3H),
1.02 (t, / = 12.4, 2H).
1H NMR (400 MHz, CDC13) δ 9.31 (s, IH), 8.21 (s, IH), 7.78 (d, / = 8.4, IH), 7.65 (t, J = 7.8, 2H), 7.24 (d, / = 8.2, 2H),
4-[(lS)-l-[(4S)-2,2- 6.86 (d, / = 8.6, IH), 4.05 - 3.91 (m, 5H), dimethyloxan-4-yl]-3-{ [(6- 3.68 (d, / = 11.5, IH), 3.54 (d, / = 3.4,
431 methoxypyridin- 3 - 394.3
2H), 2.76 (m, IH), 2.62 (m, IH), 2.38 (t, / yl)methyl] amino }propyl]be
= 10.1, IH), 2.28 (m, IH), 1.98 (d, / = nzonitrile
8.3, IH), 1.86 (m, IH), 1.70 (d, / = 13.0, IH), , 1.25 (s, 3H), 1.22 (s, 3H), 1.15 - 1.03 (m, 3H).
1H NMR (400 MHz, CDC13) δ 9.24 (s, IH), 7.60 (d, / = 8.2, 2H), 7.19 (d, / = 8.3, 2H), 6.82 (d, / = 3.4, IH), 6.60 (dt, / =
4-[(lS)-l-[(4S)-2,2- 15.2, 7.6, IH), 4.01 (dd, / = 30.7, 13.9, dimethyloxan-4-yl]-3-{ [(5- 2H), 3.62 (dd, / = 11.3, 3.8, IH), 3.57 -
432 methylthiophen-2- 383.2
3.31 (m, 2H), 2.67 (m, IH), 2.55 (m, IH), yl)methyl] amino }propyl]be
2.40 (m, 3H), 2.35 (t, / = 8.4, IH), 2.24 nzonitrile
(m, IH), 1.87 (dd, / = 42.1, 8.4, 2H), 1.66 (d, / = 11.6, IH), 1.19 (s, 3H), 1.17 (s, 3H), 1.02 (dt, 7 = 12.1, 8.7, 3H).
1H NMR (400 MHz, CDC13) δ 9.26 (s, IH), 7.61 (d, / = 8.1, 2H), 7.21 (t, J = 8.6, 2H), 6.27 (d, / = 3.0, IH), 5.92 (d, / = 2.2,
4-[(lS)-l-[(4S)-2,2- IH), 3.96 (q, / = 14.3, 2H), 3.63 (dd, / = dimethyloxan-4-yl]-3-{ [(5- 11.1, 3.7, IH), 3.48 (dt, / = 11.9, 6.1, IH),
433 methylfuran-2- 367.3
2.74 (m, 2H), 2.57 (m, IH), 2.38 (m, IH), yl)methyl] amino }propyl]be
2.25 (d, / = 3.7, IH), 2.21 (m, 3H), 1.96 nzonitrile
(s, IH), 1.81 (m, IH), 1.67 (d, / = 12.6, IH), 1.19 (s, 3H), 1.17 (s, 3H), 1.10 - 0.96 (m, 3H).
1H NMR (400 MHz, CDC13) δ 9.11 (s, IH), 8.43 (d, / = 8.2, IH), 7.68 (d, / = 8.3,
4-[(lS)-l-[(4S)-2,2- IH), 7.63 (d, / = 8.1, 2H), 7.25 (d, / = 8.1, dimethyloxan-4-yl]-3-{ [(6- 2H), 4.28 (s, 2H), 3.63 (dd, J = 11.6, 4.0,
434 methylpyridin- 3 - 378.3 IH), 3.49 (dt, / = 12.2, 6.1, IH), 2.98 - yl)methyl] amino }propyl]be 2.86 (m, IH), 2.79 (s, 3H), 2.72 (d, / = nzonitrile 11.2, IH), 2.37 (dd, / = 27.3, 15.9, 2H),
2.02 (d, / = 13.1, IH), 1.85 (d, / = 8.5, IH), 1.67 (d, / = 12.7, IH), 1.23 (d, / = 7.1, 1H), 1.19 (s, 3H), 1.18 (s, 3H), 1.06
(t, / = 12.3, 3H).
1H NMR (400 MHz, CDC13) δ 7.66 (d, / = 19.8, 2H), 7.36 (dd, / = 5.6, 3.1, 2H), 7.24-7.23 (m, 5H), 5.16 - 4.94 (m, 2H),
4-[(lS)-l-[(4S)-2,2- 4.09 (dd, / = 40.0, 13.6, 2H), 3.90 - 3.57 dimethyloxan-4-yl]-3-({ [6- (m, 2H), 3.25 - 3.06 (m, 1H), 2.97 - 2.76
435 (trifluoromethyl)pyridin- 3 - 432.2 (m, 1H), 2.66 (brs, 1H), 2.41 (ddd, / = yl] methyl } amino)propyl]be 21.0, 13.4, 3.7, 2H), 2.24 - 2.00 (m, 1H), nzonitrile 1.90 (dt, / = 15.9, 5.9, 1H), 1.78 (d, / =
12.5, 1H), 1.22 (qd, / = 12.3, 5.0, 1H),
1.10 (s, 3H), 1.08 (s, 3H), 1.05 - 0.88 (m, 2H).
1H NMR (400 MHz, MeOD) δ 8.44 (d, / = 2.0, 1H), 7.88 (dd, / = 8.2, 2.2, 1H), 7.66 - 7.59 (m, 2H), 7.45 (d, 7 = 8.1, 1H),
4-[(lS)-l-[(4R)-2,2- 7.30 (d, / = 8.4, 2H), 4.15 - 4.03 (m, 2H), dimethyloxan-4-yl]-3-{ [(6- 3.85 - 3.54 (m, 2H), 2.83 (td, / = 12.0,
436 methylpyridin- 3 - 378.3
4.9, 1H), 2.60 - 2.45 (m, 4H), 2.45 - 2.31 yl)methyl] amino }propyl]be
(m, 1H), 2.27 - 2.12 (m, 1H), 1.93 (ddd, / nzonitrile
= 17.6, 12.5, 7.1, 2H), 1.76 (d, / = 12.8, 1H), 1.11 (dt, / = 18.4, 6.0, 1H), 1.00 - 0.97 (m, 7H), 0.86 (t, / = 12.7, 1H).
1H NMR (400 MHz, MeOD) δ 8.77 (d, / = 1.9, 1H), 8.10 (dd, / = 8.2, 1.9, 1H), 7.90 (d, 7 = 8.1, 1H), 7.77 - 7.70 (m, 2H),
4-[(lS)-l-[(4R)-2,2- 7.46 - 7.39 (m, 2H), 4.34 - 4.22 (m, 2H), dimethyloxan-4-yl]-3-({ [6- 3.81 - 3.65 (m, 2H), 2.98 (td, / = 12.1,
437 (trifluoromethyl)pyridin- 3 - 432.2
4.8, 1H), 2.66 (td, / = 11.9, 4.8, 1H), 2.58 yl] methyl } amino)propyl]be
- 2.44 (m, 1H), 2.37 - 2.22 (m, 1H), 2.21 nzonitrile
- 1.93 (m, 2H), 1.87 (d, / = 12.8, 1H), 1.23 (qd, / = 11.8, 6.0, 1H), 1.10 (d, / = 13.6, 7H), 0.98 (t, / = 12.8, 1H).
1H NMR (400 MHz, MeOD) δ 7.76 - 7.69
4-[(lS)-l-[(4R)-2,2- (m, 2H), 7.56 - 7.49 (m, 2H), 7.43 - 7.36 dimethyloxan-4-yl]-3- (m, 2H), 7.16 - 7.10 (m, 1H), 4.15 (s,
438 [(thiophen-3- 369.2 2H), 3.81 - 3.65 (m, 2H), 2.86 (td, / = ylmethyl)amino]propyl]ben 12.1, 4.9, 1H), 2.62 - 2.40 (m, 2H), 2.32 - zonitrile 2.18 (m, 1H), 2.18 - 1.78 (m, 3H), 1.22
(qd, / = 12.0, 6.0, 1H), 1.10 (d, / = 13.2, 7H), 0.97 (t, / = 12.7, IH).
1H NMR (400 MHz, MeOD) δ 7.76 - 7.68 (m, 2H), 7.42 - 7.35 (m, 2H), 6.96 (d, / =
4-[(lS)-l-[(4R)-2,2- 3.5, IH), 6.77 - 6.69 (m, IH), 4.35 - 4.16 dimethyloxan-4-yl]-3-{ [(5- (m, 2H), 3.81 - 3.65 (m, 2H), 2.85 (td, / =
439 methylthiophen-2- 383.2
12.0, 5.0, IH), 2.63 - 2.38 (m, 5H), 2.32 - yl)methyl] amino }propyl]be
2.18 (m, IH), 2.18 - 1.77 (m, 3H), 1.21 nzonitrile
(ddd, / = 24.7, 12.0, 6.1, IH), 1.08 (m, 7H), 0.96 (t, 7 = 12.7, IH).
1H NMR (400 MHz, CDC13) δ 7.64 (d, / = 8.3, 2H), 7.25 - 7.21 (m, 2H), 3.64 (d, / =
4-[(lS)-3-amino-l-[(4S)- 11.5, IH), 3.52 (dd, / = 13.3, 10.2, IH),
440 2,2-dimethyloxan-4- 378.3
2.64 (m, 2H), 2.38 (m, IH), 2.18 (m, IH), yl] propyl] benzonitrile
1.96 (m, 4H), 1.69 (d, / = 12.8, IH), 1.22 (s, 3H), 1.20 (s, 3H), 1.13 - 1.00 (m, 3H).
1H NMR (400 MHz, CDC13) δ 8.33 (dd, / = 4.7, 1.9, IH), 7.72 (dd, / = 7.6, 1.9, IH), 7.56 (d, / = 8.3, 2H), 7.28 - 7.21 (m, IH),
4-[(lS)-3-{ [(6- 7.13 (d, 7 = 8.3, 2H), 4.14 - 3.98 (m, 2H), bromopyridin-3- 3.70 (dd, / = 12.1, 3.6, IH), 3.56 (td, / =
441 yl)methyl] amino } - 1 - 442.2
12.2, 2.1, IH), 2.74 - 2.64 (m, IH), 2.64 - [(4R)-2,2-dimethyloxan-4- 2.53 (m, IH), 2.36 - 2.18 (m, 2H), 2.16 - yl] propyl] benzonitrile
1.73 (m, 3H), 1.64 (d, / = 14.1, IH), 1.16 - 1.06 (m, IH), 1.03 (s, 3H), 1.00 (s, 3H), 0.97 - 0.80 (m, 3H).
1H NMR (400 MHz, CDC13) δ 7.65 - 7.60 (m, 2H), 7.31 - 7.22 (m, IH), 7.20 (d, / =
4-[(lS)-l-[(4R)-2,2- 8.3, 2H), 6.82 (d, / = 5.1, IH), 4.03 (q, / = dimethyloxan-4-yl]-3-{ [(3- 14.4, 2H), 3.77 (dd, / = 12.2, 3.7, IH),
442 methylthiophen-2- 383.3 3.62 (t, / = 11.2, IH), 2.72 - 2.51 (m, 2H), yl)methyl] amino }propyl]be 2.34 (dd, / = 28.1, 15.9, 2H), 2.14 (m, nzonitrile 3H), 2.00 - 1.65 (m, 3H), 1.24 - 1.15 (m,
IH), 1.10 (s, 3H), 1.07 (s, 3H), 1.03 - 0.86 (m, 3H).
4-[(lS)-l-[(4R)-2,2- lH NMR (400 MHz, CDC13) δ 7.61 (d, / = dimethyloxan-4-yl]-3-{ [(4- 8.3, 2H), 7.20 (d, / = 8.3, 2H), 6.90 - 6.84
443 methylthiophen-2- 383.3 (m, 2H), 4.00 (q, / = 14.1, 2H), 3.75 (dd, / yl)methyl] amino }propyl]be = 11.7, 4.1, IH), 3.61 (dd, / = 12.2, 10.1, nzonitrile IH), 2.60 (dd, / = 50.2, 6.0, 2H), 2.35 (dd,
/ = 26.5, 14.6, 2H), 2.19 (d, / = 0.8, 3H), 1.89 (dd, / = 34.2, 10.4, 2H), 1.66 (brs,
IH), 1.24 - 1.14 (m, IH), 1.10 (s, 3H), 1.07 (s, 3H), 1.04 - 0.86 (m, 3H).
lH NMR (400 MHz, CDC13) δ 7.59 (d, / = 8.3, 2H), 7.18 (d, / = 8.3, 2H), 6.69 (s,
4-[(lS)-l-[(4R)-2,2- IH), 3.89 (q, / = 14.2, 2H), 3.74 (dd, / = dimethyloxan-4-yl]-3- 11.9, 3.8, IH), 3.59 (t, / = 11.2, IH), 2.58
{ [(4,5-
444 397.3 (d, / = 45.0, 2H), 2.34 (dd, / = 27.5, 15.6, dimethylthiophen-2- 2H), 2.24 (s, 3H), 2.02 (s, 3H), 1.97 - yl)methyl] amino }propyl]be
1.77 (m, 2H), 1.66 (brs, IH), 1.22 - 1.09 nzonitrile
(m, IH), 1.08 (s, 3H), 1.05 (s, 3H), 1.02 - 0.84 (m, 3H).
lH NMR (400 MHz, CDC13) δ 7.62 (d, / = 8.3, 2H), 7.23 (s, IH), 7.20 - 7.15 (m,
4-[(lS)-3-{ [(4- 2H), 7.00 (d, / = 1.3, IH), 4.10 - 3.96 (m, bromothiophen-2- 2H), 3.80 - 3.70 (m, IH), 3.65 - 3.55 (m,
445 yl)methyl] amino } - 1 - 447.1
IH), 2.72 - 2.48 (m, 2H), 2.41 - 2.20 (m, [(4R)-2,2-dimethyloxan-4- 2H), 1.97 - 1.74 (m, 2H), 1.73 - 1.43 (brs, yl] propyl] benzonitrile
IH), 1.21 - 1.14 (m, IH), 1.09 (s, 3H), 1.07 (s, 3H), 1.03 - 0.86 (m, 3H).
lH NMR (400 MHz, CDC13) δ 7.62 (d, / = 8.3, 2H), 7.18 (d, / = 8.3, 2H), 6.93 (d, / =
4-[(lS)-3-{ [(5- 3.8, IH), 6.83 (d, / = 3.8, IH), 3.98 (q, / = bromothiophen-2- 14.2, 2H), 3.75 (dd, / = 12.0, 3.9, IH),
446 yl)methyl] amino } - 1 - 447.1 3.60 (t, / = 11.2, IH), 2.71 - 2.47 (m, 2H), [(4R)-2,2-dimethyloxan-4- 2.33 (dd, / = 31.5, 23.1, 2H), 1.95 - 1.79 yl] propyl] benzonitrile (m, 2H), 1.67 (brs, IH), 1.22 - 1.10 (m,
IH), 1.09 (s, 3H), 1.05 (s, 3H), 1.02 - 0.85 (m, 3H).
lH NMR (400 MHz, CDC13) δ 7.62 - 7.58 (m, 2H), 7.50 - 7.45 (m, IH), 7.41 (dd, /
4-[(lS)-3-({ [5-chloro-6- = 8.3, 2.0, IH), 7.18 - 7.13 (m, 2H), 3.88 (trifluoromethyl)pyridin- 3 - - 3.77 (m, 2H), 3.77 - 3.69 (m, IH), 3.64
447 yl]methyl}amino)-l-[(4R)- 465.2 - 3.54 (m, IH), 2.64 - 2.40 (m, 2H), 2.38
2,2-dimethyloxan-4- - 2.16 (m, 2H), 1.93 - 1.77 (m, 2H), 1.75 yl] propyl] benzonitrile - 1.60 (brs, IH), 1.19 - 1.11 (m, IH), 1.10
- 1.06 (m, 3H), 1.06 - 1.02 (m, 3H), 1.02
- 0.84 (m, 3H).
448 4-[(lS)-3- 377.3 lH NMR (400 MHz, CDC13) δ 7.61 (d, / = [benzyl(methyl)amino] - 1 - 7.6, 2H), 7.48 - 7.21 (m, 5H), 7.18 (d, / = [(4R)-2,2- 8.3, 2H), 4.21 (dd, / = 29.4, 12.9, IH), dimethyloxan-4- 4.02 - 3.92 (m, IH), 3.78 (dd, / = 12.1, yl] propyl] benzonitrile 3.8, IH), 3.62 (t, / = 12.2, IH), 3.00 (brs,
IH), 2.64 (d, / = 23.7, 3H), 2.33 (m, 3H), 2.14 - 1.67 (m, 3H), 1.19 (qd, / = 12.5, 5.1, IH), 1.09 (s, 3H), 1.06 (s, 3H), 1.02 - 0.84 (m, 2H).
1H NMR (400 MHz, CDC13) δ 7.64 (t, / = 7.7, 2H), 7.52 - 7.33 (m, 4H), 7.28 - 7.24
4-[(lS)-3- (m, IH), 7.20 (t, / = 7.4, 2H), 4.22 - 4.11 [benzyl(butyl)amino] - 1 - (m, 2H), 3.81 (d, / = 12.0, IH), 3.66 (td, /
449 [(4R)-2,2- 419.3 = 12.2, 5.5, IH), 2.90 (m, 3H), 2.44 (m, dimethyloxan-4- 3H), 2.12 - 1.42 (m, 5H), 1.33 (td, / = yl] propyl] benzonitrile 14.4, 7.3, 2H), 1.26 - 1.15 (m, IH), 1.12
(s, 3H), 1.10 (s, 3H), 1.01 (d, / = 11.5, IH), 0.98 - 0.88 (m, 4H).
1H NMR (400 MHz, CDC13) δ 7.60 (d, / = 8.2, 2H), 7.48 - 7.20 (m, 5H), 7.17 (d, / =
4-[(lS)-3-[benzyl(2- 8.2, 2H), 4.23 (m, 2H), 3.78 (dd, / = 12.2, methylpropyl)amino] - 1 - 3.8, IH), 3.63 (t, / = 11.1, IH), 2.72 (d, /
450 [(4R)- 419.3 = 40.4, 2H), 2.42 (m, 2H), 2.25 (d, / =
2,2-dimethyloxan-4- 10.4, IH), 1.97 (m, 3H), 1.63 (brs, IH), yl] propyl] benzonitrile 1.21 - 1.10 (m, IH), 1.09 (s, 3H), 1.07 (s,
3H), 1.03 - 0.92 (m, 2H), 0.92 - 0.81 (m, 7H).
1H NMR (400 MHz, CDC13) δ 7.62 (d, / = 7.9, IH), 7.51 - 7.32 (m, 6H), 7.18 (d, / = 8.0, IH), 7.03 (d, / = 8.0, IH), 4.25 (dd, / = 44.2, 12.9, IH), 3.96 - 3.79 (m, IH),
4-[(lS)-3-[benzyl(propan-2- 3.71 (dd, / = 18.4, 10.4, 2H), 3.58 (dd, / = yl)amino]-l-[(4R)-2,2-
451 405.3 24.9, 12.2, IH), 2.70 (dd, / = 33.0, 9.0, dimethyloxan-4- IH), 2.26 - 2.15 (m, IH), 2.12 - 1.94 (m, yl] propyl] benzonitrile
2H), 1.91 - 1.48 (m, 3H), 1.40 - 1.23 (m, 5H), 1.16 (d, J = 6.6, 2H), 1.06 (s, 3H), 1.03 (s, 3H), 0.90 (m, IH), 0.88 - 0.77 (m, IH).
1H NMR (400 MHz, CDC13) δ 7.60 (d, / =
4-[(lS)-l-[(4S)-2,2- 8.3, 2H), 7.23 (d, / = 5.1, IH), 7.19 (d, / =
452 dimethyloxan-4-yl]-3-{ [(3- 383.2 8.3, 2H), 6.80 (d, / = 5.1, IH), 4.01 (q, / = methylthiophen-2- 14.3, 2H), 3.61 (d, / = 11.8, IH), 3.48 (dd, yl)methyl] amino }propyl]be
/ = 11.8, 8.7, IH), 2.65 (m, IH), 2.54 (m, nzonitrile IH), 2.29 (d, / = 38.7, 2H), 2.13 (m, 3H),
1.86 (m, 2H), 1.82 (brs, IH), 1.66 (d, / = 13.1, IH), 1.19 (s, 3H), 1.16 (s, 3H), 1.03 (m, 3H).
lH NMR (400 MHz, CDC13) δ 7.59 (d, / = 8.3, 2H), 7.19 (d, / = 8.3, 2H), 6.86 (d, / =
4-[(lS)-l-[(4S)-2,2- 9.3, 2H), 4.01 (q, / = 14.1, 2H), 3.61 (dd, dimethyloxan-4-yl]-3-{ [(4- / = 11.9, 2.9, IH), 3.47 (dt, / = 11.9, 6.1,
453 methylthiophen-2- 383.3 IH), 2.60 (d, / = 46.4, 2H), 2.35 (t, / = yl)methyl] amino }propyl]be 8.4, IH), 2.17 (m, 5H), 1.87 (dd, / = 45.2, nzonitrile 8.4, 2H), 1.65 (d, / = 12.7, IH), 1.19 (s,
3H), 1.16 (s, 3H), 1.01 (dt, / = 12.3, 8.6, 3H).
lH NMR (400 MHz, CDC13) δ 7.59 (d, / =
4-[(lS)-l-[(4S)-2,2- 8.3, 2H), 7.20 (d, / = 8.3, 2H), 6.69 (s, dimethyloxan-4-yl]-3- IH), 3.92 (dd, / = 31.0, 14.0, 2H), 3.60 (d,
{ [(4,5- / = 11.7, IH), 3.48 (dd, / = 11.9, 8.9, IH),
454 397.3
dimethylthiophen-2- 2.59 (d, / = 48.4, 2H), 2.35 (t, / = 8.4, yl)methyl] amino }propyl]be IH), 2.24 (m, 4H), 2.02 (s, 3H), 1.90 (m, nzonitrile 3H), 1.66 (d, / = 13.1, IH), 1.19 (s, 3H),
1.16 (s, 3H), 1.01 (dt, / = 12.5, 8.7, 3H). lH NMR (400 MHz, CDC13) δ 7.62 (d, / = 8.3, 2H), 7.23 (d, / = 1.4, IH), 7.19 (d, / =
4-[(lS)-3-{ [(4- 8.3, 2H), 7.00 (d, / = 1.4, IH), 4.06 (dd, / bromothiophen-2- = 29.7, 14.3, 2H), 3.62 (d, / = 11.7, IH),
455 yl)methyl] amino } - 1 - 447.1
3.49 (dd, / = 13.3, 10.1, IH), 2.73 - 2.50 [(4S)-2,2-dimethyloxan-4- (m, 2H), 2.41 - 2.17 (m, 2H), 1.98 (m, yl] propyl] benzonitrile
3H), 1.65 (d, / = 12.6, IH), 1.20 (s, 3H), 1.17 (s, 3H), 1.10 - 0.96 (m, 3H).
lH NMR (400 MHz, CDC13) δ 7.62 (d, / = 8.3, 2H), 7.19 (d, / = 8.3, 2H), 6.94 (d, / =
4-[(lS)-3-{ [(5- 3.8, IH), 6.84 (d, / = 3.8, IH), 4.01 (dd, / bromothiophen-2- = 32.6, 14.3, 2H), 3.61 (d, / = 11.7, IH),
456 yl)methyl] amino } - 1 - 447.1
3.48 (dd, / = 11.9, 8.7, IH), 2.60 (d, / = [(4S)-2,2-dimethyloxan-4- 48.3, 2H), 2.38 - 2.16 (m, 2H), 1.96 (m, yl] propyl] benzonitrile
3H), 1.65 (d, / = 11.9, IH), 1.20 (s, 3H), 1.17 (s, 3H), 1.01 (dd, / = 14.9, 10.1, 3H).
4-[(lS)-3-({ [5-chloro-6- lH NMR (400 MHz, CDC13) δ 7.60 (d, / =
457 (trifluoromethyl)pyridin- 3 - 465.2 8.3, 2H), 7.48 (d, / = 8.2, IH), 7.44 - 7.40 yl] methyl } amino)- 1 - [(4S )- (m, IH), 7.16 (d, / = 8.3, 2H), 3.86 (dd, / 2,2-dimethyloxan-4- = 29.2, 13.3, 2H), 3.64 - 3.57 (m, 1H), yl] propyl] benzonitrile 3.52 - 3.43 (m, 1H), 2.54 (d, / = 46.3,
2H), 2.29 (m, 3H), 1.96 - 1.71 (m, 2H), 1.63 (d, / = 11.1, 1H), 1.19 (s, 3H), 1.16 (s, 3H), 1.08 - 0.95 (m, 3H).
lH NMR (400 MHz, CDC13) δ 7.65 (d, / = 8.3, 2H), 7.39 - 7.33 (m, 2H), 7.30 - 7.21 (m, 4H), 5.10 - 4.98 (m, 2H), 4.09 (dd, / = 39.6, 14.3, 2H), 3.79 (dd, / = 12.1, 3.7,
4-[(lS)-3-(2,3-dihydro-lH- 1H), 3.65 (td, / = 12.3, 2.2, 1H), 3.12 (dt, isoindol-2-yl)-l-[(4R)-
458 375.3 / = 12.0, 6.1, 1H), 2.87 - 2.73 (m, 1H),
2,2-dimethyloxan-4- 2.49 - 2.33 (m, 2H), 2.19 - 2.03 (m, 1H), yl] propyl] benzonitrile
1.90 (dd, / = 8.1, 4.0, 1H), 1.78 (d, / = 12.5, 1H), 1.22 (qd, / = 12.5, 5.2, 1H),
I.10 (s, 3H), 1.08 (s, 3H), 1.02 (d, / =
I I.4, 1H), 0.93 (t, / = 12.6, 1H).
lH NMR (400 MHz, CDC13) δ 7.64 (d, / = 8.3, 2H), 7.23 (d, / = 8.3, 2H), 3.81 - 3.72 (m, 1H), 3.61 (t, / = 11.2, 1H), 3.31 (m,
4-[(lS)-3-[(cyclohex-l-en- 2H), 2.55 (d, / = 60.7, 2H), 2.42 - 2.14 1 -ylmethyl)amino] - 1 -
459 367.3 (m, 4H), 1.90 (t, / = 28.6, 6H), 1.70 (d, /
[(4R)-2,2-dimethyloxan-4- = 12.1, 1H), 1.53 (dd, / = 22.8, 6.0, 4H), yl] propyl] benzonitrile
1.18 (dd, / = 12.4, 5.1, 1H), 1.09 (s, 3H), 1.07 (s, 3H), 1.01 (d, / = 12.9, 1H), 0.92 (t, / = 12.6, 1H).
Example 460
Figure imgf000200_0001
Ex460 -[(lS)-3-(2,3-dihydro-lH-isoindol-2-yl)-l-[(4R)-2,2-dimethyloxan-4-yl]propyl]benzonitrile, trifluoroacetic acid 0.1 Preparation of Ex460
[0124] To a stirred solution of 428D (10 mg, 0.037 mmol) and molecular sieves (68.5 mg) in dried methanol (0.92 mL) was added phthaldialdehyde (5.92 mg, 0.044 mmol) followed by 0.18 drop of glacial acetic acid. The reaction was followed by LCMS until the imine was formed (after 4 h) and then sodium cyanoborohydride (9.24 mg, 0.147 mmol) was added. After overnight, the mixture was then subjected to HPLC purification to give Ex460 (3.0 mg, 14% yield). (HPLC purification method: Luna acid medium column, 10-60% acetonitrile in H20 over 10 min, followed by flashing with 100% acetonitrile, 0.1% TFA modifier was employed).
[0125] MS and 1H NMR data
[0126] Example 461
Figure imgf000201_0001
[0127] Ex461
[0128] 3-(benzylamino)-l-(2,2-dimethyloxan-4-yl)-l-(4-fluorophenyl)propan-l-ol ( one diastereoisomer, the relative stereochemistry of Ex461 not determined)
Figure imgf000202_0001
461A 461 B
The first fraction Thesecond fraction
461.1 Preparation of 461 A and 46 IB
To a solution of 3B (0.50 g, 2.11 mmol) in 10 mL of Et20 at -78 oC was added C3H5MgCl (1.0M, 4.0 mmol, 4.0 mL). The mixture was stirred at -78 oC for 2h. The reaction was quenched with 0.5 mL of MeOH. The solution was acidified with IN HCl and extracted with EtOAc and washed with Brine. After dried over MgS04 and filtered, the residue was taken directly to on 50 g snap column, eluted with 10-25% EtOAc in Hex, 12 CV (twice) to give 461 A (170 mg, 27% yield) and 46 IB (300 mg, 51% yield).
[0124] LC-MS (ESI) m/z: 261.0 [M+1-H20] observed for 461 A.
[0125] LC-MS (ESI) m/z: 261.0 [M+1-H20] observed for 46 IB.
Figure imgf000202_0002
461 C
461.2 Preparation of 461 C
To a solution of 461A (170 mg, 0.61 mmol) in 10 mL of DCM at -78 oC was bubbled a stream of 03 for 10 min until the solution turned to light blue. After blowing off excess of 03 with 02, it was quenched with 0.8 g of polymer-bound PPh3. The suspension was stirred overnight. Filtered and concentrated to give 461C.
LC-MS (ESI) m/z: 237.0 [M+1-C2H30] observed for 461C.
461.3 Preparation of Ex461
To a solution of 461C (15 mg, 0.054 mmol) and benzylamine (20 mg, 0.19 mmol) in 0.5 mL of DCM was stirred at rt. After 10 min, 22 mg of NaBH(OAc)3 was added and the solution was agitated under sonication for 2 mins. LC-MS indicated completion of reaction. The mixture was purified under HPLC to provide EX461 as a TFA salt (12.4 mg, 47% yield).
LC-MS (ESI) m/z: 372.1 [M+l] observed.
1H NMR (400 MHz, CDC13) δ 10.85 (s, 1H), 7.94 (s, 1H), 7.41 - 7.27 (m, 3H), 7.21 - 7.10 (m, 4H), 7.01 - 6.87 (m, 2H), 4.12 - 3.83 (m, 4H), 3.74 (d, J = 13.2, 1H), 3.66 - 3.55 (m, 1H), 3.47 (td, J = 12.1, 2.4, 1H), 2.96 (s, 1H), 2.67 (d, J = 6.3, 1H), 2.45 (ddd, J = 14.9, 10.9, 3.8, 1H), 2.15 - 2.03 (m, 1H), 1.94 (tt, J = 12.4, 3.3, 1H), 1.59 (d, J = 12.7, 1H), 1.27 - 0.94 (m, 9H).
[0129] Example 462
Figure imgf000203_0001
Ex462
[0130] 3-(benzylamino)-l-(2,2-dimethyloxan-4-yl)-l-(4-fluorophenyl)propan-l-ol ( the other diastereoisomer, the relative stereochemistry of Ex462 not determined)
462.1 Preparation of Ex462
Following an analogous procedure described in Ex461, Ex462 was prepared from 461B. LC-MS (ESI) m/z: 372.1 [M+l] observed.
1H NMR (400 MHz, CDC13) δ 10.81 (s, 1H), 8.00 (s, 1H), 7.43 - 7.26 (m, 3H), 7.21 - 7.09 (m, 4H), 6.95 (q, J = 8.7, 2H), 4.25 - 3.88 (m, 4H), 3.72 (dd, J = 12.0, 3.5, 2H), 3.56 (td, J = 12.2, 2.3, 1H), 2.91 (s, 1H), 2.63 (d, J = 33.6, 1H), 2.46 (ddd, J = 14.9, 10.5, 4.3, 1H), 2.06 (dt, J = 15.1, 4.2, 1H), 1.93 (ddd, J = 12.5, 7.9, 3.3, 1H), 1.63 (d, J = 12.7, 1H), 1.22 (qd, J = 12.6, 5.0, 1H), 1.12 - 0.98 (m, 7H), 0.97 - 0.87 (m, 1H).
Intermediate A
Figure imgf000204_0001
Intermediate A Preparation of intermediate A
A DIBAL solution (0.81 ml, 1M in toluene, 0.81 mmol) was added dropwise to a solution of nitrile 6B (201 mg, 0.77 mmol) in toluene (7 ml) at -78°C under N2. The resulting mixture was stirred at-78°C for 1.5 h and TLC (EtOAc:Hexane / 3:7) showed the reaction had completed. The reaction was quenched by adding saturated NH4C1 (5 ml), then warm to room temperaturand diluted with water(5 ml). The product was extracted by Et20 (3 x 20 ml), the combined extracts were washed by brine, dried (MgS04) and concentrated, the residual was purified by flash chromatography (25 g silica gel column, eluted by EtOAc in hexane: 7%, 1CV; 7- 40%,10CV; 40-60%, 6CV; 60%, 2CV) gave 159 mg (78%) as a clear oil.
LC-MS (ESI) m/z: 265.2 [M+l] observed.
Intermediate A was used in some cases to prepare the examples listed in Table 3. [0129] Examples 500-509
[0130] Examples 500-509 were known compounds, and can hypothetically be prepared following an analogous reaction sequence outlined in Ex6.
[0179] Example 517.
[0180] The ability of compounds to act as agonists at human μ-opioid receptor (MOR), κ- opioid receptor (KOR), and δ-opioid receptor (DOR) (hMOR, hKOR, hDOR respectively) was determined by measuring changes in intracellular cAMP levels. Their ability to recruit β-arrestin 2 was determined by the PathHunter™ β-arrestin assay from DiscoveRx Corporation (Freemont, CA). Plasmids encoding the hMOR (Assession NP_000905), hKOR (Assession NP_000903) and hDOR (Assession NP_000902) were generated in the pCMV-Prolink backbone and transfected into an EA-arrestin parental Human Embryonic Kidney (HEK-293) cell line from
DiscoveRx Corporation. Clonal stable lines were subsequently selected under G418.
[0181] Cell Culture and plating
[0182] Cell lines were grown adherently in Minimum Essential Media (Cellgro cat # 10- 010-CM) containing 10% fetal bovine serum (Hyclone cat # SH30071.03), 4 mM glutamine (Cellgro cat # 25-005-CI), 150 ug/ml hygromycin B (Cellgro cat # 30-240- CR), 150 ug/ml G418 (Cellgro cat # 30-234-CR), and 100 u/ 100 μg
penicillin/streptomycin (Lonza cat # 17-603E). Prior to the assay cells were removed from the flasks with CellStripper (Cellgro cat # 25-056-CI), repeatedly pipetted to disperse cells, and spun at low speed for 5 min at room temperature. Cells were then resuspended at 300,000 cells/ml in growth media and plated at 4000 cells/well in 384 well plates (Greiner part # 784080). Plates were incubated overnight at 37°C in a humidified incubator.
[0183] cAMP assay
[0184] Receptor G-protein mediated responses were determined by measuring changes in intracellular cAMP using CisBio HTRF cAMP HiRange kit (cat # 62AM6PEJ) based on time-resolved fluorescence resonance energy transfer (TR-FRET). Growth media was removed and replaced with Ham's F12 containing IB MX (500 μΜ), NKH-477 (3 uM, a water soluble forskolin derivative, catalog # 1603, Tocris, Ellis ville, MO) and test or control compounds at the desired concentrations. For agonist assays compounds were added at desired final concentration and for antagonist assays compounds were added at twice the desired final concentration. For antagonist assays DAMGO was subsequently added to all wells at twice desired final concentration 15 minutes after addition of test compounds. Following a 30 minute incubation at 37 °C the components of the cAMP HiRange kit were added as directed and the plates were read after 1 hour on a BMG PheraStar plate reader. [0185] β-arrestin assay
[0186] Receptor mediated b-arrestin recruitment was determined using the DiscoveRx b- arrestin PathHunter Detection kit (cat # 93-0001). In this system, β-Arrestin is fused to an N-terminal deletion mutant of β-gal (termed the enzyme acceptor of EA) and the GPCR of interest is fused to a smaller (42 amino acids), weakly complementing fragment termed ProLink™. In cells that stably express these fusion proteins, ligand stimulation results in the interaction of β-Arrestin and the Prolink-tagged GPCR, forcing the complementation of the two β-gal fragments and resulting in the formation of a functional enzyme that converts substrate to detectable signal. Growth media was removed and replaced with Ham's F12 containing lOmM HEPES, IB MX (500 μΜ), NKH-477 (3 μΜ, a water soluble forskolin derivative, catalog # 1603, Tocris, Ellisville, MO) and test or control compounds at the desired concentrations. Following an 60 minute incubation at 37 °C the components of the DiscoveRx β- arrestin PathHunter Detection kit (cat # 93-0001) were added as directed and the plates were read after 1 hour on a BMG PheraStar plate reader.
[0187] Data handling
[0188] Each plate contained 16 wells of basal (forskolin stimulated cells) and 16 maximally stimulated wells (forskolin plus 1 μΜ DAMGO-treated cells). (DAMGO is [D-Ala2, N-Me-Phe4, Gly5-ol] -Enkephalin acetate salt, SigmaAdrich, St. Louis MO, cat # E7384) The % maximal response was calculated as the (unknown well counts - average basal well counts) / (average DAMGO max well counts - average basal well counts)* 100.
For antagonist assays, each plate contained 16 wells of agonist control (NKH-477-forskolin plus 1 uM DAMGO-treated cells) and 16 maximally antagonized wells (agonist control plus 10 uM naloxone). The % maximal response was calculated as the (unknown well counts - average agonist control well counts) / (average agonist well counts - average naloxone max well counts)* 100.
Concentration-response data including EC50 (the concentration of compound producing
50% of the maximal response) and intrinsic activity (the percent maximal activation compared to full activation by DAMGO) were determined using a four-parameter non-linear regression algorithm (Xlfit equation 203, IDBS, Hill slope fixed at 1).
[0189] While the invention has been described with reference to particularly preferred embodiments and examples, those skilled in the art recognize that various modifications may be made to the invention without departing from the spirit and scope thereof.
[0190] All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety.

Claims

CLAIMS What is claimed is:
1. A compound having the structure:
B3
Figure imgf000209_0001
wherein Al is selected from the group consisting of null, CH2, CHRl, CR1R2, O, S, SO, S02, NH, NR1, CH, CR1 and N;
A2 is selected from the group consisting of null, CH2, CHR5, CR5R6, O, S, SO, S02, NH, NR5, CH, CR5 and N;
A3 is selected from the group consisting of null, CH2, CHR7, CR7R8, O, S, SO, S02, NH, NR7, CH, CR7 and N;
A4 selected from the group consisting of is null, CH2, CHR9, CR9R10, O, S, SO, S02, NH, NR9, CH, CR9 and N;
A5 is selected from the group consisting of null, CH2, CHRl 1, CR11R12, CH2CH2, CHR11CH2, CH2CHR11, CHR11CHR12, O, S, NH, NRl l, CH, or CRl l;
A6 is selected from the group consisting of CH, CR3, N, or C;
A7 is selected from the group consisting of N, CH, CF, COH, CNH2, COCH3, CCN, or C and wherein A6 and A7 cannot be N at the same time;
Bl is selected from the group consisting of CH2, CHR13, CR13R14, O, S, NH, NR13, CH, CR13, C, CO, and CS;
B2 is selected from the group consisting of CH2, CHR15, CR15R16, O, S, NH, NR15, CH, CR15, C, CO, and CS;
B3 is selected from the group consisting of H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, alkylsulfonyl;
B4 is selected from the group consisting of null, CH2, CHR19, CR19R20, CO, and CS;
B5 is selected from the group consisting of alkyl, branched alkyl, halogenated alkyl, carbocycle-substituted alkyl, aryl, carbocycle, or arylalkyl;
Dl is selected from the group consisting of an aryl group or a carbocycle;
Rl, R2, R5, R6, R7, R8, R9, RIO, Rl l, R12, R13, R14, R15, R16, R18, R19, and R20 are independently selected from the group consisting of cyano, halogen, hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, aryl)alkyl, carbocycle, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl, alkoxycarbonyl.
Or Rl and R2, R5 and R6, R7 and R8, R9 and RIO, Rl 1 and R12, R13 and R14, R15 and R16, R19 and R20, or R15 and R19 forms a monocyclic carbocycle or heterocycle.
R3 is selected from the group consisting of CH3, CF3, CH2OH, CH2NH2, CH2NH-butoxycarbonyl, OH, methoxycarbonyl, CN, C02R4, NH, or N-t- butoxycarbonyl; and
R4 is selected from the group consisting of an alkyl and a branched alkyl group;
wherein the aryl is selected from the group consisting of:
Figure imgf000211_0001
Figure imgf000211_0002
210
Figure imgf000212_0001
wherein the carbocycle is selected from the group consisting of:
Figure imgf000213_0001
wherein XI, and X2 in the heterocycle are independently selected from the group consisting of O, S, N, NH, and NR18; wherein the aryl, carbocycles/ heterocycle with 1-3 heteroatoms, wherein the heteroatoms are selected from the group consisting of O, N and S, are unsubstituted, or substituted with substitution groups selected from the group consisting of F, CI, Br, CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF3, methoxycarbonyl, Ph, benzyl , formyl, and acetyl; wherein no more than 2 out of 5 of Al, A2, A3, A4, and A5 can be null at the same time, wherein the number of heteroatoms in Al, A2, A3, A4, A5 and A6 cannot exceed 2 at the same time;
wherein the bonds between Al, A2, A3, A4, A5 and A6 cannot be S-O, S-S, or S-N; and wherein alkyl is a linear carbon chain having between 1 and 10 carbon atoms.
2. The following known compounds are excluded from claim 1:
1) Benzyl[3-(2,2-dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl]amine
Figure imgf000214_0001
2) [3-(2,2-Dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl](l- phenylethyl) amine
Figure imgf000214_0002
3) 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl]amino}methyl)- N,N-dimethylaniline
Figure imgf000215_0001
4) Benzyl[3-(2,2-dimethyloxan-4-yl)-3-(4-methoxyphenyl)propyl]amine
Figure imgf000215_0002
5) 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-(4-methoxyphenyl)propyl]amino}methyl)- N,N-dimethylaniline
Figure imgf000215_0003
6) [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl] ( 1 -phenylethyl)amine
Figure imgf000215_0004
7) [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl] [(4- methoxyphenyl)methyl] amine
Figure imgf000216_0001
8) [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl] [(4- methoxyphenyl)methyl]propylamine
Figure imgf000216_0002
9) 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl]amino}methyl)-N,N- dimethylaniline
Figure imgf000216_0003
10) [(3,4-dimethoxyphenyl)methyl] [3-(2,2-dimethyloxan-4-yl)-3- phenylpropyl] amine
Figure imgf000216_0004
3. The compound of claim 1, wherein Rl, R2, R5, R6, R7, R8, R9, RIO, Rl l, R12, R13, R14, R15, R16, R18, R19, and R20 are independently F, CI, Br, CH3, CH2CH3, CH2F, CHF2, CF3, n-propyl, n-butyl, isobutyl, sec-buytyl, isopropyl, tert- butyl, CN, OH, O CH3 O CH2CH3, O-i-prolyl, methoxycarbonyl, phenyl, benzyl, CHO, and COCH3.
4. The compound of claim 1, wherein Rl and R2, R5 and R6, R7 and R8, R9 and RIO, Rl 1 and R12, R13 and R14, R15 and R16, R19 and R20, or R15 and R19 forms a monocyclic carbocycle or heterocycle.
5. The compound of claim 1, wherein the aryl is multiply substituted with groups selected from cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl,
alkylmercaptanyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl.
6. The compound of claim 1, wherein the carbocycle is multiply substituted with groups selected from cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl,
alkylmercaptanyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl.
7. The compound of claim 1, wherein the ring formed by Al, A2, A3, A4, A5 an A6 is fused with another ring.
8. The compound of claim 7, wherein the other ring is selected from the group consisting of a benzene ring, a pyridine ring, a pyrimidine ring, a furan ring, a thiophene ring, and a pyridazine ring.
9. The compound of claim 7, wherein the fused ring is substituted at one or multiple positions with a moiety selected from the group consisting of cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, formyl, acetyl, amino, alkylamino, mercaptanyl, and alkylmercaptanyl.
10. The compound of claim 1, wherein the bond between Aland A2, A2 and A3, A3 and A4, A4 and A5, A5 and A6, A6 and Al and A6 and A7 are independently a single bond or a double bond.
11. The compound of claim 1, wherein the bond between Aland A2, A2 and A3, A3 and A4, A4 and A5, A5 and A6, A6 and Al and A6 and A7 are not
simulataneously be double bonds.
12. The compound of claim 1, wherein the ring formed by Al, A2, A3, A4, A5 and A6 is not a benzene ring, or a pyridine ring.
13. The compound of claim 1, wherein the bond between A6 and A7 is a single bond.
14. The compound of claim 1, wherein the bond between A6 and A7 is a double bond.
15. The compound of claim 1, wherein the bond between A7 and Bl is a single bond.
16. The compound of claim 1, wherein the bond between A7 and Bl is a double bond.
17. The compound of claim 1, wherein the bond between Bl and B2 is a single bond.
18. The compound of claim 1, wherein the bond between Bl and B2 is a double bond.
19. The compound of claim 1, wherein Rl, R2, R5, R6, R7, R8, R9, RIO, Rl l, R12, R13, R14, R15, R16, R18, R19, and R20 are independently selected from the group consisting of F, CI, Br, CH3, CH2CH3, CH2F, CHF2, CF3, n-propyl, n-butyl, isobutyl, sec-butyl, i-propyl, t-butyl, CN, OH, OCH3, OCH2CH3, O-i-propyl, methoxycarbonyl, phenyl, benzyl, formyl, and acetyl.
20. The compound of claim 1, wherein Rl and R2, R5 and R6, R7 and R8, R9 and RIO, Rl 1 and R12, R13 and R14, R15 and R16, R19 and R20, or R15 and R19 forms a monocyclic carbocycle or heterocycle.
21. A compound having the structure:
Figure imgf000219_0001
wherein A2 is CH2, CHR5, CR5R6;
A4 is CH2, CHR9, CR9R10;
R5 and R6, and R9 and RIO are independently selected from the group consisting of CH3, CH2CH3, CH2F, CHF2, CF3, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-i-Pr, phenyl, benzyl, formyl, and acetyl. In other enbodiments, R5 and R6, or R9 and RIO forms a monocyclic carbocycle.
B3 is selected from the group consisting of H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkylsulfonyl.
R28 is selected from the group consisting of H, alkyl, branched alkyl, halogenated alkyl. and
Dl and D2 are independently selected from the group consisting of aryl/ heteroaryl, or carbocycle/ heterocycle, as defined in claim 1.
22. The compound of claim 21, wherein B3 is selected from the consisting of H, CH3, CH2CH3, i-prolyl, t-butyl, n-prolyl, n-butyl, i- butyl, sec- butyl, and benzene.
23. The compound of claim 21, wherein R28 is selected from the consisting of H, CH3, CH2CH3, i-prolyl, t-butyl, n-prolyl and n-butyl.
24. The compound of claim 21, wherein R5 and R6, or R9 and RIO forms a ring.
25. The compound of claim 24, wherein the ring system is a carbocycle or a heterocycle as defined in claim 1.
26. A com ound having the structure:
Figure imgf000220_0001
wherein A2 is CH2, CHR5, CR5R6;
A4 is CH2, CHR9, CR9R10;
R5 and R6, and R9 and RIO are independently selected from the group consisting of CH3, CH2CH3, CH2F, CHF2, CF3, n-prolyl, n-butyl, i- butyl, sec-butyl, i-prolyl, t-butyl, CN, OH, O CH3, OCH2CH3, O-i-prolyl, phenyl, benzyl, formyl, and acetyl;
B3 is selected from the group consisting of H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkylsulfonyl;
R28 is selected from the group consisting of H, CH3, CH2CH3, i- prolyl, t-butyl, n-prolyl and n-butyl; and
Dl and D2 are independently selected from the group consisting of aryl or carbocycle, as defined in claim 1.
27. The compound of claim 26, wherein B3 is selected from the consisting of H, CH3, CH2CH3, i-propyl, t-butyl, n-propyl, n-butyl, i-butyl, sec-butyl, benzyl.
28. The compound of claim 26, wherein R5 and R6, or R9 and RIO forms a ring.
29. The compound of claim 28, wherein the ring system is a carbocycle as defined in claim 1.
30. The compound of claim 26, wherein R28 is selected from the consisting of H, CH3, CH2CH3, i-prolyl, t-butyl, n-prolyl and n-butyl.
31. A compound with antagonist activity having the structure:
Figure imgf000221_0001
wherein A2 is CH2, CHR5, CR5R6;
A4 is CH2, CHR9, CR9R10;
R5 and R6, and R9 and RIO are independently selected from the group consisting of CH3, CH2CH3, CH2F, CHF2, CF3, n-prolyl, n-butyl, i-butyl, sec-butyl, i-prolyl, t-butyl, CN, CH30, CH2CH30, phenyl;
and
Dl is selected from the group consisting of aryl, or carbocycle, as defined in claim 1.
32. The compound of claim 31, wherein R5 and R6, or R9 and RIO form a ring.
33. The compound of claim 32, wherein the ring system is a carbocycle as defined in claim 1.
34. A compound with antagonist activity having the structure:
Figure imgf000222_0001
wherein A2 is CH2, CHR5, CR5R6;
A4 is CH2, CHR9, CR9R10;
R5 and R6, and R9 and RIO are independently selected from the group consisting of CH3, CH2CH3, CH2F, CHF2, CF3, n-prolyl, n-butyl, i-Bu, sec-butyl, i- prolyl, t-butyl, CN, CH30, CH2CH30, phenyl; and
Dl is selected from the group consisting of aryl/ heteroaryl, or carbocycle, as defined in claim 1.
35. The compound of claim 34, wherein R5 and R6, or R9 and RIO form a ring.
36. The compound of claim 35, wherein the ring system is a carbocycle as defined in claim 1.
37. A compound with antagonist activity having the structure:
Figure imgf000222_0002
wherein A2 is CH2, CHR5, CR5R6;
CH2, CHR9, CR9R10;
R5 and R6, and R9 and RIO are independently selected from the group consisting of CH3, CH2CH3, CH2F, CHF2, CF3, n-prolyl, n-butyl, i-butyl, sec-butyl, i- prolyl, t-butyl, CN, CH30, CH2CH30, and phenyl; and
Dl and D2 are independently selected from the group consisting of aryl or carbocycle, as defined in claim 1.
38. The compound of claim 37, wherein R5 and R6, or R9 and RIO form a ring.
39. The compound of claim 38, wherein the ring system is a carbocycle as defined in claim 1.
40. A method of treating pain comprising: administering to a subject in need thereof a therapeutically effective amount of one or more compounds of claim 1.
41. A method of treating pain comprising: administering to a subject in need thereof a therapeutically effective amount of one or more compounds of claim 21.
42. A method of treating pain comprising: administering to a subject in need thereof a therapeutically effective amount of one or more compounds of claim 26.
43. A method of treating opioid- induced bowel dysfunction, opioid- induced repiratory depression, and post-operative ileus comprising: administering to a subject in need thereof a therapeutically effective amount of one or more compounds of claim 31.
44. A method of treating opioid-induced bowel dysfunction, opioid-induced repiratory depression, and post-operative ileus comprising: administering to a subject in need thereof a therapeutically effective amount of one or more compounds of claim 34.
45. A method of treating opioid-induced bowel dysfunction, opioid-induced repiratory depression, and post-operative ileus comprising: administering to a subject in need thereof a therapeutically effective amount of one or more compounds of claim 37.
46. A process of preparing compounds in claim 1.
47. A method of treating pain comprising: administering to a subject in need thereof a therapeutically effective amount of the following known compounds:
1) Benzyl[3-(2,2-dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl]amine
Figure imgf000224_0001
2) [3-(2,2-Dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl](l- phenylethyl) amine
Figure imgf000224_0002
3) 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-(2-methoxyphenyl)propyl]amino}methyl)- N,N-dimethylaniline
Figure imgf000224_0003
4) Benzyl[3-(2,2-dimethyloxan-4-yl)-3-(4-methoxyphenyl)propyl]amine
Figure imgf000225_0001
5) 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-(4-methoxyphenyl)propyl]amino}methyl)- N,N-dimethylaniline
Figure imgf000225_0002
6) [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl](l-phenylethyl)amine
Figure imgf000225_0003
7) [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl] [(4- methoxyphenyl)methyl] amine
Figure imgf000225_0004
8) [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl] [(4- methoxyphenyl)methyl]propylamine
Figure imgf000226_0001
9) 4-({ [3-(2,2-Dimethyloxan-4-yl)-3-phenylpropyl]amino}methyl)-N,N- dimethylaniline
Figure imgf000226_0002
10) [(3,4-dimethoxyphenyl)methyl] [3-(2,2-dimethyloxan-4-yl)-3- phenylpropyl] amine
Figure imgf000226_0003
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