- TYK2 INHIBITORS AND USES THEREOF
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Described herein are compounds that are useful in treating a TYK2-mediated disorder. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
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Paragraph 00334
(2020/09/27)
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- Equilibrium Constants for the Interconversion of Substituted 1-Phenylethyl Alcohols and Ethers. A Measurement of Intramolecular Electrostatic Interactions
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Equilibrium constants for the reactions of ring-substituted 1-phenylethyl alcohols with a series of aliphatic alcohols of pKa 12.4-16 to form the corresponding ethers, and for interconversion of the ethers, have been determined in 50:45:5 HOH/CF3CH2OH/ROH (v/v/v), μ = 0.5 (NaCIO4), at 25 deg C.Formation of ethers from the alcohols is favorable, with values of K = 3-74; replacement of water by methanol is favored by factors of 50-74.Equilibrium constants increase with increasing pKa of the alcohol with values of βeq = δlog K/δpKROH in the range 0.17-0.27.This is attributed to hydrogen bonding of the alcohol to the solvent and to an electrostatic interaction between substituents on the alcohol and the aryl group.The contribution from hydrogen bonding to the solvent is estimated to be β = 0.17; for 90percent HOH it is 0.25.An increase in βeq with electron-withdrawing substituents on the benzene ring and a complementary increase in ρeq with electron-donating substituents on ROH are described by an electrostatic interaction coefficient τ = δβeq/δ? = δρeq/δpKROH = 0.10 +/- 0.01.No change in τ for dipole-dipole interactions was observed with increasing water concentration in the range 50-90percent (v/v).The electrostatic interactions that are described by τ can cause changes in structure-reactivity parameters, such as ρ or β, in the absence of changes in transition-state structure.
- Rothenberg, Marc E.,Richard, John P.,Jencks, William P.
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p. 1340 - 1346
(2007/10/02)
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- Reactions of Substituted 1-Phenylethyl Carbocations with Alcohols and Other Nucleophilic Reagents
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Selectivities of a series of substituted 1-phenylethyl carbocations toward alcohols and other nucleophiles have been determined by product analysis.The 1-(4-dimethylamino)phenyl)ethyl carbocation exhibits a high selectivity in its reactions with alcohols , with KEtOH/KTFE = 140 and βnuc = 0.5.The selectivity for activation-limited reactions with alcohols decreases progressively with increasing reactivity of the carbocation, in contrast to the behavior expected from the N+ scale of reactivity.A sharper drop in selectivity for carbocations that react faster than ca. 109 S-1 is attributed to an approach to limiting rate constants for the more reactive alcohol.The limiting selectivity of kEtOH/kTFE = 2 for carbocations with ks ca. 1011 S-1 may represent reaction from a pool of solvent molecules in which there is a modest charge-dipole interaction between the alcohol and carbocation.The relatively low reactivity of water corresponds to that expected for an alcohol of pKa ca. 13.This is ascribed to an imbalance between charge development and solvation of the transition state compared with H3O+.Substituted acetate anions react with the 1-(4-methoxyphenyl)ethyl carbocation with βnuc = 0.13.The selectivity decreases with increasing cation reactivity as the carboxylate ions approach limiting rate constants of ca. 5 * 108 M-1 s-1.This relatively low limit is attributed to a requirement for desolvation of basic oxygen anions before reaction.A dependence of solvent selectivity on the leaving group shows that the 1-(4-methylphenyl)ethyl carbocation reacts with solvent, in part, through an ion pair.Azide ion reacts from a pool that can be described by an equilibrium constant of Kas = 0.3 M-1.Styrene formation from this carbocation is catalyzed by a leaving carboxylate ion and by added buffers, wih β = 0.14.The equilibrium constant for the formation of a reactive base-cation pair is ca. 0.04 M-1.Rate constants for collapse of the ion pair, to form ester, and for proton removal, to form 4-methylstyrene, were estimated to be approximately 1.6 * 1010 s-1 and 6 * 107 s-1, respectively.The rate constants for deprotonation and for hydration of the styrene give the acid dissociation constant of the carbocation to form 4-methylstyrene, pKA = -11.2.
- Richard, John P.,Jencks, William P.
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p. 1373 - 1383
(2007/10/02)
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- Concerted Bimolecular Substitution Reactions of 1-Phenylethyl Derivatives
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Substituted 1-phenylethyl derivatives with ?+ > -0.08 exhibit bimolecular substitution reactions with azide ion in 20percent acetonitrile in water.The reactions with 1-phenylethyl chlorides follow a Hammett correlation with ρ = -2.9, compared with ρ = -5.6 (r+ = 1.15) for solvolysis.Swain-Scott correlations give values of s = 0.46 and 0.22 for 1-(4-nitrophenyl)ethyl chloride and tosylate, respectively; there are large positive deviations for azide ion and water and negative deviations for cyanide ion.The value of βnuc is 0.09 for reactions of substituted acetates with the chloride.The reactions exhibit ''synergism'' between the nucleophile and leaving group that favors the bimolecular reaction with Me2S, Br- > Cl- > OTs- leaving groups.The bimolecular reaction with azide follows the Grunwald-Winstein Y correlation with m = 0.8 in methanol-water mixtures.Bimolecular reactions with less reactive nucleophiles in the series N3-, CN-, AcO-, and ROH appear at progressively larger ? values, as the carbocation becomes less stable.It is concluded that these reactions are SN2 displacements that proceed through an open, ''exploded'' transition state that closely resembles a carbocation.Specific salt effects are small in water but are significant in acetonitrile-water mixtures and could be mistaken for normal or induced common ion rate depressions.No evidence was obtained for nucleophilic assistance to the formation of a carbocation intermediate.Concurrent SN1 and SN2 pathways occur in the reactions with solvent and azide of dimethylsulfonium ion, 1-(4-fluorophenyl)ethyl chloride, 1-(3-methoxyphenyl)ethyl chloride, and, probably, 1-(3-nitro-4-methoxyphenyl)ethyl chloride.Crude estimates of the lifetime of the carbocation intermediate in the presence of the nucleophile are consistent with the hypothesis that the concerted reactions are enforced by the absence of a significant lifetime of the carbocation in the presence of the nucleophile and that stepwise mechanisms are followed when the intermediate has a significant lifetime; the change from a stepwise to a concerted mechanism occurs when the intermediate ceases to have a lifetime in the presence of a nucleophile.
- Richard, John P.,Jencks, William P.
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p. 1383 - 1396
(2007/10/02)
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- Formation and Stability of Ring-Substituted 1-Phenylethyl Carbocations
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The solvolysis of 1-phenylethyl derivatives with electron-donating 4-substituents in 50:50 trifluoroethanol:water(v:v) occurs at a rate that is independent of azide concentration but gives yields of the corresponding azide adducts of up to 98percent by trapping a carbocation intermediate.Rate constants for reactions of the cations with solvent range from 2 x 103 s-1 (4-Me2N) to 4 x 109 s-1 (4-Me), assuming a diffusion-controlled rate constant of 5 x 109 M-1 s-1 for their reactions with azide and thiol anions.Correlation of the rate constants following the Yukawa-Tsuno treatment gives ρn = 2.5, ρr = 5.2, and r+ = 2.1 for the reaction with trifluoroethanol, and ρn = 2.7, ρr = 4.9, and r+ = 1.8 for the reaction with water.The reverse reaction, acid-catalyzed cleavage of substituted 1-phenylethyl alcohols to give the corresponding carbocation, follows ρn = -4.9, ρr = -4.4, and r+ = 0.9.This gives values of ρn = -7.6, ρr = -9.3, and r+ = 1.2 for formation of the cations at equilibrium.There is an imbalance in the development of resonance delocalization, analogous to the "nitroalkane anomaly", that is consistent with a dependence of the fraction of maximal resonance delocalization on the fraction of rehybridization or C-X bond cleavage.Solvent effects on carbocation stability in aqueous-organic mixtures are relatively small.They depend mainly on the nucleophilicity of the solvent components and a specific solvent effect of trifluoroethanol on the reactivity of hydroxylic nucleophiles, including trifluoroethanol itself.The "ionizing power" of the solvent has only a small effect on cation stability, and there is little effect of the concentration or nature of added salts.
- Richard, John P.,Rothenberg, Marc E.,Jencks, William P.
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p. 1361 - 1372
(2007/10/02)
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- GENERAL BASE CATALYSIS OF THE ADDITION OF HYDROXYLIC REAGENTS TO UNSTABLE CARBOCATIONS AND ITS DISAPPEARANCE.
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General base catalysis of the addition of ROH is significant for 1-phenylethyl carbocations of moderate stability and is most important for weakly basic alcohols. The Bronsted slope for catalysis of the addition of trifluoroethanol to the 1-(4-methoxyphenyl)ethyl carbocation is beta equals 0. 08. The development of positive charge on the attacking alcohol decreases with decreasing stability of the carbocation. It is concluded that the observed catalysis involves hydrogen bonding and represents the transition region between fully concerted, coupled general acid-base catalysis and specific acid catalysis with solvation of the proton in the transition state.
- Richard,Jencks
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p. 1396 - 1401
(2007/10/02)
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