PHARMACEUTICAL COMPOSITIONS OF 6-(2-(2H-TETRAZOLE-5-YL)ETHYL)-6-FLUORODECAHIDROISOQUINOLINE-3-CARBOXYLIC ACID AND ESTER DERIVATIVES THEREOF

Abstract

6-(2-(2H-tetrazol-5-yl)ethyl)-6-fluorodecahydroisoquinoline-3-carboxylic acid and hydrocarbyl ester derivatives of 6-(2-(2H-tetrazol-5-yl)ethyl)-6-fluorodecahydroisoquinoline-3-carboxylic acid of the formula (see Formula) are disclosed as are pharmaceutical compositions and methods for the treatment of pain, epilepsy, convulsions, and seizures using these compositions.

Description

PHARMACEUTICAL COMPOSITIONS OF 6-(2-(2H-TETRAZOLE-5-YL)ETHYL)-6-FLUORODECAHIDROISOQUINOLINE-3-CARBOXYLIC ACID AND ESTER DERIVATIVES THEREOF FIELD OF INVENTION [1] The present invention relates to pharmaceutical compositions of 6-(2-(2H-tetrazol-5-yl)ethyl)6-fluorodecahydroisoquinoline-3-carboxylic acid and hydrocarbyl ester derivatives of 6-(2-(2H-tetrazol-5-yl)ethyl)-6-fluorodecahydroisoquinoline-3-carboxylic acid for use in the treatment of pain and epilepsy. BACKGROUND OF THE INVENTION [2] The α-amino-3-hydroxy-5-methyl-4-isoxazolazolepropionic acid receptor (also known as the AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic transmembrane receptor known as a glutamate-gated ion channel that mediates rapid synaptic transmission in the central nervous system (CNS). AMPAR has traditionally been classified as a non-NMDA receptor, along with the cyanate receptor. [3] Glutamate is the principal excitatory amino acid neurotransmitter in the central nervous system. AMPA receptors (AMPARs) are large, multi-subunit ion channels composed of combinations of four AMPAR protein subunits: GluA1, GluA2, GluA3, and GluA4 (encoded by four separate genes). AMPARs are found at excitatory synapses of neurons and transduce rapid excitatory neurotransmission. AMPARs transmit a glutamate signal upon depolarization of the postsynaptic neuron. Glutamate released from the excitatory neuron diffuses across the synapse and binds to AMPARs on the postsynaptic neuron. AMPARs physically span the neuronal cell membrane and contain an ion pore or ion channel that is selectively permeable to the interior for the flow of ions mainly sodium (but also potassium and rarely calcium) into the cell from the outside.In the absence of glutamate, the AMPAR ion pore is closed, and ions cannot flow into the neuron. When glutamate binds to the AMPAR, it opens, allowing primarily sodium ions to pass through the pore and across the postsynaptic neuronal cell membrane, resulting in depolarization. Thus, sodium is transported in the depolarization current. AMPARs are critical for neuronal networks and for the physiological function of the brain and central nervous system. In summary, AMPA receptors are neurotransmitter-gated ion channels (activated by glutamate) that open only in response to the chemical signal from glutamate. [4] AMPA receptors play a key role in the generation and propagation of epileptic seizures. Scharfman HE. 2007. Curr Neurol Neurosci Rep. 7:348-354. “The Neurobiology of Epilepsy”; Rogawski MA. 2011. Epilepsy Currents 11:56-63. “Revisiting AMPA receptors as an antiepileptic drug target.” Neurosurgeons and neurologists have observed in clinical samples collected from brain microdialysates (hippocampus) of human epilepsy patients (n=6) that glutamate levels increased before seizures and even more so during seizures in these patients (During MJ and Spencer DD 1993. The Lancet. 341(8861):1607-10). ML / t / ZUZÓ / UIZ lUZ Hippocampal Glutamate and Spontaneous Seizure in the Conscious Human Brain” (Extracellular hippocampal glutamate and spontaneous seizures in the conscious human brain)). [5] Treatment with many different AMPAR antagonists in studies using animal models of seizures, convulsions, and epilepsy has consistently demonstrated the preclinical efficacy of this class of compounds regardless of the non-competitive or competitive mechanism of the AMPAR antagonist molecule. In early clinical trials, neurologists observed that treatment with the experimental therapeutic AMPAR antagonist talampanel showed a reduction in seizures in epilepsy patients (Chappell AS, Sander JW, Brodie MJ, Chadwick D, Lledo A, Zhang D, Bjerke J, Kiesler GM, Arroyo S. 2002. Neurology 58:1680-1682. “A Crossover, Add-On Trial of Talampanel In Patients With Refractory Partial Seizures”).A decade later, the AMPAR antagonist perampanel was approved as the first AMPAR antagonist approved by the EDA and EMEA for the treatment of epilepsy (French JA, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, Kumar D, Laurenza A. 2013. Epilepsia 54:117-125. “Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305”); and Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Squillacote D, Yang H, Gee M, Zhu J, Laurenza A. 2013. Epilepsia 54:126-134.“Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, extension study 307” (Perampanel, a selective, noncompetitive antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, as adjunctive therapy for refractory partial-onset seizures: interim results from the phase III extension study 307)). [6] The permeability of AMPAR to calcium and other cations, such as sodium and potassium, is governed by the GluA2 subunit. If an AMPAR lacks a GluA2 subunit, it is permeable to sodium, potassium, and calcium. The presence of a GluA2 subunit almost always makes the channel impermeable to calcium. This is determined by post-transcriptional modification (RNA editing) of the QaR editing site of the GluA2 mRNA. Here, A—» (Adenosine to Inosine) editing (by adenosine deaminase acting on RNA2) alters the GluA2 RNA coding for the uncharged amino acid glutamine (Q) to instead code for the positively charged arginine (R) in the receptor ion channel. The positively charged amino acid at the critical site makes it energetically unfavorable for calcium to enter the cell through the pore. Sodium is the main ion to which the AMPAR glutamate-activated ion channel is permeable. [7] Failure of RNA-acting adenosine deaminase (ADAR) to edit GluA2 mRNA results in certain neurological disorders due to the resulting altered AMPAR permeability to calcium. Animals lacking ADAR2 die from seizures by day 21 after birth. However, in epilepsy, normal edited AMPAR receptors are present and permeable to sodium. [8] AMPAR antagonists represent a potential target for the treatment of epilepsy because they reduce AMPAR-mediated overexcitation of neuronal networks in epilepsy. Reviewed in Rogawski MA. 2011. ML / t / ZUZÓ / UIZ lUZ Epilepsy Currents 11:56-63. “Revisiting AMPA receptors as an antiepileptic drug target. [9] U.S. Patent No. 5,670,516 discloses that certain decahydroisoquinoline derivatives are AMPA receptor antagonists and, as such, are useful in the treatment of many different neurological conditions, including pain, migraine, seizures, and attacks. Additionally, WO 01 / 02367 A3, published on January 11, 2001, discloses diester prodrug forms of the selective GluR5 antagonist 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.

[10] United States Patent No. 7,247,644 discloses that monoesters of the monoacid, (3S,4aR,6R,8aR)-6-[2-(1 (2)H-tetrazol-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, provide significantly improved bioavailability of the monoacid compared to that provided by administration of the monoacid itself.

[11] However, the bioavailability of these previous methods is not yet high enough to be considered for oral applications. BRIEF DESCRIPTION OF THE INVENTION

[12] In one aspect, the present invention relates to a compound of formula I: And where: R is selected from H and (Ci-C2o)hydrocarbyl.

[13] In a second aspect, the present invention relates to a compound of formula II: II

[14] In a third aspect, it is shown that the compound of formula II, where R = H, selectively inhibits the calcium permeability of AMPAR induced by (S)-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (s-AMPA) in vitro and prevents seizures in vivo in an animal model for epilepsy.

[15] In a fourth aspect, the present invention relates to a method or medicament for treating epilepsy and / or pain by administering compounds of formula II as an orally bioavailable prodrug (R Φ H) of the active pharmaceutical ingredient (R = H).

[16] In a fourth aspect, the present invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound as described herein.

[17] These and other objectives, features, and advantages of the invention will become evident from the following detailed description of the different aspects of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS AND TABLES

[18] Figure 1 illustrates the results of in vitro electrophysiology studies of s-AMPA-induced currents of pyramidal neurons in Sprague Dawley rat cerebral cortex slices with Compound #1 which is 6-(2-(2H-tetrazol-5-yl)ethyl)-6-fluorodecahydroisoquinoline-3-carboxylic acid (R = H).

[19] Figure 2 illustrates the results of in vitro electrophysiology studies of s-AMPA-induced currents of pyramidal neurons in Sprague Dawley rat cerebral cortex slices with Compound #1.

[20] Figure 3 illustrates the results of in vitro electrophysiology studies of NMDA-induced currents of pyramidal neurons in Sprague Dawley rat cerebral cortex slices with Compound #1.

[21] Figure 4 illustrates the results of a single acute administration pharmacokinetic study of treatment with Compound 1 or Compound 2 in Sprague Dawley rats, wherein Compound 1 is measured in plasma samples by LCMS.

[22] Figure 5 illustrates the results of a single acute administration pharmacokinetic study of treatment with Compound 1 or Compound 2 in Sprague Dawley rats, wherein Compound 1 is measured in brain samples by LCMS.

[23] Figure 6 illustrates the results of a single acute administration pharmacokinetic study of treatment with Compound 1 or Compound 2 in Sprague Dawley rats, wherein Compound 1 is measured in cerebrospinal fluid (CSF) samples by LCMS.

[24] Figure 7A-7C illustrates the results of single ascending dose (SAD) studies of acute oral administration of Compound 2 with 1 day treatment in vivo in Sprague Dawley rats, wherein Compound 1 is measured in plasma (Fig. 7A), CSF (Fig. 7B), and brain (Fig. 7C) samples by LCMS at 75 minutes and 300 minutes.

[25] Figure 8A-8B illustrates the results of an open field assay (OFA) on the same animals as in the SAD studies of Figure 7A-7C, where the total distance traveled (Fig. 8A) and vertical time exploration (Fig. 8B) were measured.

[26] Figure 9A-9C illustrates additional OFA results in Figure 8A-8B, where ambulatory movement (Fig.9A) and stereotypical movement (Fig.9B) were counted and resting time was measured (Fig.9C).

[27] Figure 10A-10D illustrates the results of a battery of Irwin neurological tests on the same animals as in the SAD studies in Figure 7A-7C, in which cage observations (Fig.1OA), autonomic responses (Fig.1OB), and suspended tests (Fig.1OC) were scored, and fecal pellets were counted (Fig.1OD).

[28] Figure 11 illustrates the results of body weight measurements of Sprague Dawley rats participating in a 5-day multiple ascending dose (MAD) study with once-daily dosing;

[29] Figure 12 illustrates the results of an OFA in the same Sprague Dawley rats as in Figure 11, in which total distance traveled and vertical time exploration were measured and ambulatory movement and stereotypical movement were counted.

[30] Figure 13A-13D illustrates the results of an Irwin neurological test battery on the same Sprague Dawley rats as in Figure 11, in which cage observations (Fig.13A), anatomical responses (Fig.13B), and suspended tests (Fig.13C) were scored, and fecal pellets were counted (Fig.13D); performed on day three (3) of the MAD study.

[31] Figure 14A-14D illustrates the results of an Irwin neurological test battery on the same Sprague Dawley rats as in Figure 13A-13D; performed on day five (5) of the MAD study.

[32] Figure 15A-15B illustrates the results of once-daily oral MAD studies in Sprague Dawley rats for five days, where the plasma level of Compound 1 was measured by LCMS on days 1, 3, and 5; the concentration of Compound 1 is plotted against time (Fig. 15A) and dose (Fig. 15B).

[33] Figure 16 illustrates the results of the same MAD studies in Figure 15A-15B, where the level of Compound 1 is measured in CSF and by means of LCMS on day 5.

[34] Figure 17 illustrates the results of the same MAD studies in Figure 15A-15B, where the level of Compound 1 in the brain is measured on day 5.

[35] Table 1 illustrates some compounds.

[36] Table 2 illustrates the comparative results of s-AMPA versus NMDA in in vitro electrophysiology studies of pyramidal neurons with 6-(2-(2H-tetrazol-5-yl)ethyl)-6-fluorodecahydroisoquinoline-3-carboxylic acid (R = H).

[37] Table 3 presents the results of an in vivo efficacy study of 6-(2-(2H-tetrazol-5I)ethyl)-6-fluorodehydroisoquinoline-3-carboxylic acid (R = H). DETAILED DESCRIPTION OF THE INVENTION

[38] This disclosure generally relates to 6-(2-(2H-tetrazol-5-yl)ethyl)-6-fluorodecahydroisoquinoline-3-carboxylic acid and hydrocarbyl ester derivatives of 6-(2-(2H-tetrazol-5-yl)ethyl)-6-fluorodecahydroisoquinoline-3-carboxylic acid, pharmaceutical compositions thereof, and methods for treating certain disorders.

[39] Throughout this specification, terms and substituents retain their definitions.

[40] For convenience and clarity, certain terms used in the specification, examples, and claims are described in this document.

[41] The terms “hydrocarbyl”, “aliphatic hydrocarbyl”, “aromatic hydrocarbyl”, and “alkyl”, as used herein and described below, include all possible structural features that are so for the defined group, such as linear, branched, cyclic, polycyclic, gated, etc.

[42] “Hydrocarbyl” (or “hydrocarbon”) refers to any group comprising hydrogen and carbon as the only elemental constituents.

[43] A first subset of hydrocarbyl is “aliphatic hydrocarbyl,” which refers to hydrocarbyl groups that are not aromatic. These include any variety of sp3, sp2, and sp hybridized carbons that are not arranged to be aromatic, as is readily understood by someone with a background in chemistry. Aliphatic hydrocarbyl groups encompass one or more alkane (sp3), alkene (sp2), alkyne (sp), and allenoid (sp2 and sp) functional groups. Two or more alkene, alkyne, and / or allenoid functional groups may be conjugated in a hydrocarbyl group, and the group is still defined as an aliphatic hydrocarbyl group as long as the conjugation does not constitute aromaticity.

[44] Examples of aliphatic hydrocarbyl groups include methyl, ethyl, isopropyl, isobutyl, cyclopropyl, t-butyl, neopentyl, 3-methylbutyl, 3,3-dimethylbutyl, 2-propylpentyl, 2-butylhexyl, 2-pentylheptyl, 2-hexiloctyl, n-hexyl, noctyl, 2-ethylbutyl, 1-methyl-2-ethylbutyl, decyl, dodecyl, tetradecyl, 9-hexadecen-yl, 9-octadeccen-yl, 9,12-octadec-dienyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, dicyclohexylmethyl, 2-butenyl, 2-butynyl, cyclopentyl, norbornyl, etc.

[45] A second subset of hydrocarbyl is “aromatic hydrocarbyl” and “aryl,” which refers to hydrocarbyl groups that are aromatic. Aromatic hydrocarbyl groups include, for example, phenyl (CeHs), naphthyl (C10H7), anthracene (C14H9), etc.

[46] A third subset of hydrocarbyl is “alkyl” (or alkane) which refers to hydrocarbyl groups consisting exclusively of sp3 hybridized carbon atoms. Alkyl groups are also a subset of aliphatic hydrocarbyl groups, except that they are fully saturated hydrocarbyl groups that exclude the presence of sp2 and sp hybridized carbon atoms. Examples of alkyl groups from the examples described above for aliphatic hydrocarbyl groups include methyl, ethyl, isopropyl, isobutyl, cyclopropyl, t-butyl, neopentyl, 3-methylbutyl, 3,3-dimethylbutyl, 2-propylpentyl, 2-butylhexyl, 2-pentylheptyl, 2-hexiloctyl, n-hexyl, n-octyl, 2-ethylbutyl, 1-methyl-2-ethylbutyl, decyl, dodecyl, tetradecyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, dicyclohexylmethyl, cyclopentyl, norbornyl, etc. Alkyl groups do not include, for example, 9-hexadec-en-yl, 9-octadec-en-yl, 9,12-octadec-dien-yl, 2-butenyl, 2-butynyl, etc.which are also examples of aliphatic hydrocarbyl groups described above.

[47] Hydrocarbyl groups may be exclusively aliphatic hydrocarbyl, aromatic hydrocarbyl, or alkyl in nature. Alternatively, the term hydrocarbyl encompasses combinations of one or more of these subset groups, usually as substituents. Thus, an aliphatic hydrocarbyl optionally substituted with, for example, a phenyl group may be encompassed by the term “hydrocarbyl” or “aliphatic hydrocarbyl optionally substituted with phenyl.” “Alkyl optionally substituted with phenyl” indicates that, apart from the phenyl group, all other carbon atoms are sp3 hybridized.

[48] ​​As defined above, aliphatic hydrocarbyl, aromatic (i.e., aryl) hydrocarbyl, and alkyl, alone or in combination, are appropriate limitations of hydrocarbyl provided the carbon atom count is equal to or less than the carbon atom count of the hydrocarbyl on which it is relied. Likewise, alkyl is an additional limitation of aliphatic hydrocarbyl provided the carbon atom count provided is equal to or less than the carbon atom count of the hydrocarbyl on which it is relied.

[49] As used herein, the term “optionally substituted” may be used interchangeably with “unsubstituted or substituted.” The term “substituted” refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical. For example, substituted alkyl, aryl, cycloalkyl, etc., refers to alkyl, aryl, or cycloalkyl where one or more H atoms in each residue are replaced with the specified substituent.

[50] As indicated above, the definitions of R for hydrocarbyl, aliphatic hydrocarbyl, aromatic hydrocarbyl, and alkyl groups further include the number of carbons, designated as (Cx-Cy), where x is the minimum number of carbon atoms and y is the maximum number of carbon atoms. For example, “(CrC2O)hydrocarbyl” indicates a hydrocarbyl group of one to twenty carbons and “(C5-C14)aliphatic hydrocarbyl” indicates an aliphatic hydrocarbyl group of five to fourteen carbons. The carbon count of optional carbon-containing substituents, e.g., phenyl, is separate from the (Cx-Cy) designation.

[51] Unless otherwise specified, the term “carbocycle” is intended to include ring systems in which all the ring atoms are carbons, but of any oxidation state. Thus, carbocycle (C3-C10) refers to both non-aromatic and aromatic systems, including systems such as cyclopropane, benzene, and cyclohexene; carbopolycycle (C8-C12) refers to systems such as norbornane, decalin, indane, and naphthalene. Carbocycle, if not otherwise limited, refers to monocycles, bicycles, and polycycles.

[52] The compounds described herein may contain, at a substituent R, double bonds and may also contain other centers of geometric asymmetry; unless otherwise specified, the compounds are intended to include both the E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included, e.g., tetrazole tautomers: H NN N' NH N —N

[53] Compounds may also contain, at a substituent R, one or more asymmetric centers and thus may also give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S). The present invention is intended to include all possible isomers, as well as their racemic and optically pure forms. The optically active (R) and (S) isomers can be prepared using chiral-free or chiral reagents, or resolved using conventional techniques.

[54] For clarity, the atom numbering convention for the decahydroisoquinoline ring system and its appendages is shown below:

[55] In different embodiments of the present invention, R is selected from: (Ci-C2c)hydrocarbyl, (Cr Ci8)hydrocarbyl, (Ci-Ci9)hydrocarbyl, (Ci-Ci8)hydrocarbyl, (Ci-Ci7)hydrocarbyl, (Ci-Ci6)hydrocarbyl, (Ci-Ci5)hydrocarbyl, (Ci-Ci4)hydrocarbyl, (Ci-Ci3)hydrocarbyl, (Ci-Ci2)hydrocarbyl, (Ci-Cn)hydrocarbyl, (Ci-Cio)hydrocarbyl, (Cr Cg)hydrocarbyl, (Ci-Cs)hydrocarbyl, (Ci-C7)hydrocarbyl, (Ci-Cj)hydrocarbyl, (Ci-Cs)hydrocarbyl, (Ci-C4)hydrocarbyl, and (CrC4)hydrocarbyl.

[56] In different embodiments of the present invention, R is selected from: (C2-C2c)hydrocarbyl, (C2Cig)hydrocarbyl, (C2-Ci8)hydrocarbyl, (C2-Ci7)hydrocarbyl, (C2-Ci6)hydrocarbyl, (C2-Ci5)hydrocarbyl, (C2-Ci4)hydrocarbyl, (C2-Ci3)hydrocarbyl, (C2-Ci2)hydrocarbyl, (C2-Cn)hydrocarbyl, (C2-Cio)hydrocarbyl, (C2-C9)hydrocarbyl, (C2Cs)hydrocarbyl, (C2-C7)hydrocarbyl, (Cg-Cejhydrocarbyl, (C2-C5)hydrocarbyl, (C2-C4)hydrocarbyl, and (C2-C3)hydrocarbyl.

[57] In different embodiments of the present invention, R is selected from: (Cs-Cscihydrocarbyl, (C3Cig)hydrocarbyl, (C3-Cis)hydrocarbyl, (C3-Ci7)hydrocarbyl, (Cs-Ciejhydrocarbyl, (C3-Ci5)hydrocarbyl, (C3-Ci4)hydrocarbyl, (C3-Ci3)hydrocarbyl, (C3-Ci2)hydrocarbyl, (C3-Cn)hydrocarbyl, (C3-Cio)hydrocarbyl, (C3-Cg)hydrocarbyl, (C3Csjhydrocarbyl, (C3-C7)hydrocarbyl, (Cs-Cejhydrocarbyl, (Cs-Csjhydrocarbyl, and (C3-C4)hydrocarbyl.

[58] In different embodiments of the present invention, R is selected from: (C4-C2o)hydrocarbyl, (C4Cig)hydrocarbyl, (C4-Ci8)hydrocarbyl, (C4-Ci7)hydrocarbyl, (C4-Ci6)hydrocarbyl, (C4-Ci5)hydrocarbyl, (C4-Ci4)hydrocarbyl, (C4-Ci3)hydrocarbyl, (C4-Ci2)hydrocarbyl, (C4-Cn)hydrocarbyl, (C4-Ci0)hydrocarbyl, (C4-C9)hydrocarbyl, (C4Cej)hydrocarbyl, (C4-C7)hydrocarbyl, (C4-Ce)hydrocarbyl, and (C4-C5)hydrocarbyl.

[59] In different embodiments of the present invention, R is selected from: (C5-C2c)hydrocarbyl, (C5Cig)hydrocarbyl, (Cs-Ciejhydrocarbyl, (C5-Ci7)hydrocarbyl, (Cs-Ci6)hydrocarbyl, (Cs-Cisjhydrocarbyl, (C5-Ci4)hydrocarbyl, (C5-Ci3)hydrocarbyl, (Cs-C^hydrocarbyl, (Cs-Cujhydrocarbyl, (Cs-Ciojhydrocarbyl, (C5-Cg)hydrocarbyl, (C5Cs)hydrocarbyl, (C5-C7)hydrocarbyl, and (Cs-Cejhydrocarbyl.

[60] In different embodiments of the present invention, R is selected from: (C6-C2c)hydrocarbyl, (CeCi9)hydrocarbyl, (Ce-Ci9)hydrocarbyl, (C6-Ci7)hydrocarbyl, (Ce-Ci9)hydrocarbyl, (C6-Ci4)hydrocarbyl, (C6-Ci3)hydrocarbyl, (C6-Ci2)hydrocarbyl, (C6-Cu)hydrocarbyl, (C6-Ci9)hydrocarbyl, (CeCi9)hydrocarbyl, and (C6-C7)hydrocarbyl.

[61] In different embodiments of the present invention, R is selected from: (C7-C2o)hydrocarbyl, (C7Cig)hydrocarbyl, (C7-Ci8)hydrocarbyl, (C7-Ci7)hydrocarbyl, (C7-Ci6)hydrocarbyl, (C7-Ci5)hydrocarbyl, (C7-Ci4)hydrocarbyl, (C7-Ci3)hydrocarbyl, (C7-Ci2)hydrocarbyl, (C7-Cii)hydrocarbyl, (C7-Ci1)hydrocarbyl, (C7-C9)hydrocarbyl, and (C7 Csjhydrocarbyl.

[62] In different embodiments of the present invention, R is selected from: (C8-C2o)hydrocarbyl, (C8Cig)hydrocarbyl, (C8-Ci8)hydrocarbyl, (Cs-Ci7)hydrocarbyl, (Cs-Ci6)hydrocarbyl, (C8-Ci5)hydrocarbyl, (C8-Ci4)hydrocarbyl, (C8-Ci3)hydrocarbyl, (C8-Ci2)hydrocarbyl, (C8-Cn)hydrocarbyl, (C8-Ci0)hydrocarbyl, and (C8-C9)hydrocarbyl.

[63] In different embodiments of the present invention, R is selected from: (C9-C2c)hydrocarbyl, (C9Cig)hydrocarbyl, (C9-Ci8)hydrocarbyl, (C9-Ci7)hydrocarbyl, (C9-Ci6)hydrocarbyl, (Cg-Ci5)hydrocarbyl, (Cg-Ci4)hydrocarbyl, (Cg-Ci3)hydrocarbyl, (C9-Ci2)hydrocarbyl, (C9-Cn)hydrocarbyl, and (C9-Ci0)hydrocarbyl.

[64] In different embodiments of the present invention, R is selected from: (Cio-C2o)hydrocarbyl, (CwCi9)hydrocarbyl, (Cio-Ci8)hydrocarbyl, (Cio-Ci7)hydrocarbyl, (Cio-Ci6)hydrocarbyl, (Cio-Ci5)hydrocarbyl, (C10Ci4)hydrocarbyl, (Cio-Cisjhydrocarbyl, (Cio-Ci2)hydrocarbyl, and (Cio-Cu)hydrocarbyl.

[65] In different embodiments of the present invention, R is selected from: (Cu-C2o)hydrocarbyl, (CuCig)hydrocarbyl, (Cn-Ci8)hydrocarbyl, (Cn-Cvjhydrocarbyl, (Cu-Ci6)hydrocarbyl, (Cu-Ci5)hydrocarbyl, (CuCi4)hydrocarbyl, (Cn-Ci3)hydrocarbyl, and (Cu-Ci2)hydrocarbyl.

[66] In different embodiments of the present invention, R is selected from: (Ci2-C2o)hydrocarbyl, (Ci2Ci9)hydrocarbyl, (Ci2-Ci8)hydrocarbyl, (Ci2-Ci7)hydrocarbyl, (Ci2-Ci6)hydrocarbyl, (Ci2-Ci5)hydrocarbyl, (C12Ci4)hydrocarbyl, and (Ci2-Ci3)hydrocarbyl.

[67] In different embodiments of the present invention, R is selected from: (Ci3-C2o)hydrocarbyl, (C13Cig)hydrocarbyl, (Ci3-Ci8)hydrocarbyl, (Ci3-Ci7)hydrocarbyl, (Ci3-Ci6)hydrocarbyl, (Ci3-Ci5)hydrocarbyl, and (C13Ci4)hydrocarbyl.

[68] In different embodiments of the present invention, R is selected from: (Ci4-C2o)hydrocarbyl, (C14Ci9)hydrocarbyl, (Ci4-Ci8)hydrocarbyl, (Ci4-Ci7)hydrocarbyl, (Ci4-Ci6)hydrocarbyl, and (Ci4-Ci5)hydrocarbyl.

[69] In different embodiments of the present invention, R is selected from: (Ci5-C2o)hydrocarbyl, (C15Ci9)hydrocarbyl, (Ci5-Ci8)hydrocarbyl, (Ci5-Ci7)hydrocarbyl, and (Ci5-Ci6)hydrocarbyl.

[70] In different embodiments of the present invention, R is selected from: (Ci6-C2o)hydrocarbyl, (CwCi9)hydrocarbyl, (Ci6-Ci8)hydrocarbyl, and (Ci6-Ci7)hydrocarbyl.

[71] In different embodiments of the present invention, R is selected from: (Ci7-C2o)hydrocarbyl, (C17Ci9)hydrocarbyl, and (Ci7-Ci8)hydrocarbyl.

[72] In different embodiments of the present invention, R is (Ci8-C2o)hydrocarbyl or (Ci8Cig)hydrocarbyl.

[73] In different embodiments of the present invention, R is (Cig-C2o)hydrocarbon.

[74] In different embodiments of the present invention, R is selected from: (C2o)hydrocarbyl, (Cig)hydrocarbyl, (Ci8)hydrocarbyl, (Ci7)hydrocarbyl, (Ci6)hydrocarbyl, (Ci5)hydrocarbyl, (Ci4)hydrocarbyl, (Ci3)hydrocarbyl, (Ci2)hydrocarbyl, (Cn)hydrocarbyl, (Cwjhydrocarbyl, (C9)hydrocarbyl, (C8)hydrocarbyl, (C7)hydrocarbyl, (C6)hydrocarbyl, (C5)hydrocarbyl, (C4)hydrocarbyl, and (C3)hydrocarbyl.

[75] In some embodiments of the present invention, R is selected from: (Ci-C20) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (CrCig) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci8) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci7) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci6) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Cij) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups with the condition that R contains twenty carbons or less,(CrCu) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci3) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci2) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Cn) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Cio) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (CrCg) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Cs) hydrocarbyl optionally substituted aliphatic with one or two phenyl groups,(Ci-Cy) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (Ci-C6) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (Ci-Cs) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (Cr C4) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, and (Ci-C3) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups.

[76] In different embodiments of the present invention, R is selected from: (C2-C2o) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2Cig) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci8) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci7) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci6) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci5) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups provided that R contains twenty carbons or less,(C2Ci4) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci3) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci2) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Cn) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Cio) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2Cg) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-C8) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups,(C2-C7) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (C2-C6) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (C2-C5) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (C2-C4) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, and (C2-C3) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups.

[77] In different embodiments of the present invention, R is selected from: (C3-C2o) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3Cig) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-Cisj) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-Ci7) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-Ci6) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-Ci5) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that that R contains twenty carbons or less,(C3Ci4) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-Cisj) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-Ci2) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-C11) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-Cio) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3Cs) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-Csj aliphatic hydrocarbyl optionally substituted with one or two phenyl groups,(Cs-Cyj aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (C3-C6) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (Ca-Csj aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (C3C4) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups.,

[78] In different embodiments of the present invention, R is selected from: (C4-C2o) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4C1g) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-C18) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-C17) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-C16) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-C15) aliphatic hydrocarbyl optionally substituted with one or two groups phenyl on the condition that R contains twenty carbons or less,(C4C1) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4C1) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4C1) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4C1) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4C1) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4C8) hydrocarbyl optionally substituted aliphatic with one or two phenyl groups,(C4-C7) aliphatic hydrocarbon optionally substituted with one or two phenyl groups, (C4-C6) aliphatic hydrocarbon optionally substituted with one or two phenyl groups, and (C4-C5) aliphatic hydrocarbon optionally substituted with one or two phenyl groups.

[79] In different embodiments of the present invention, R is selected from: (C5-C2o) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C5C1g) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C5-C17) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C5-C15) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C5-C15) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups provided that R contains twenty carbons or less,(C5Ci4) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-Cisj) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C5-Ci2) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C5-C11) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-Cioj) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C5Cg) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-Csj aliphatic hydrocarbyl optionally substituted with one or two phenyl groups,(C5-C7) aliphatic hydrocarbon optionally substituted with one or two phenyl groups, and (C5-C7) aliphatic hydrocarbon optionally substituted with one or two phenyl groups.

[80] In different embodiments of the present invention, R is selected from: (Ce-C2o) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (CeCig) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6-Cis) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6-Ci7) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ce-Ciej) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6-Ci5) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that that R contains twenty carbons or less,(CeCi4) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C6-Ci3) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C6-Ci2) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (Ce-Cu) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C6-Cio) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C8Cg) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C6-C8) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups,and (C6-C7) aliphatic hydrocarbon optionally substituted with one or two phenyl groups.

[81] In different embodiments of the present invention, R is selected from: (Cz-C2o) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7Cig) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Cis) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Ci7) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Ci6) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cz-Ci5) aliphatic hydrocarbyl optionally substituted with one or two groups phenyl on the condition that R contains twenty carbons or less,(C7Ci4) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Ci3) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Ci2) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-C11) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Ci) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7Cg) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, and (C7-C8) aliphatic hydrocarbon optionally substituted with one or two phenyl groups.

[82] In different embodiments of the present invention, R is selected from: (C8-C2o) aliphatic hydrocarbon optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C8C19) aliphatic hydrocarbon optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C8-C18) aliphatic hydrocarbon optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C8-C17) aliphatic hydrocarbon optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C8-C16) aliphatic hydrocarbon optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C8-C15) aliphatic hydrocarbon optionally substituted with one or two groups phenyl on the condition that R contains twenty carbons or less,(C8Ci4) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (Cs-Cnj) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C8-Ci2) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C8-Ci 1 ) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C8-Cio) aliphatic hydrocarbyl, MA / t / ZUZÓ / UIZ / UZ optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, and (CeCg) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less.

[83] In different embodiments of the present invention, R is selected from: (C9-C2o) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C9C19) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C9-C18) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C6-C17) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C9-C16) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C9-C15) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C9-C14) aliphatic hydrocarbon optionally substituted with a phenyl group,(C9-Ci3) aliphatic hydrocarbyl optionally substituted with a phenyl group, (C9Ci2) aliphatic hydrocarbyl optionally substituted with a phenyl group, (C9-Cn) aliphatic hydrocarbyl optionally substituted with a phenyl group, and (Cg-Cio) aliphatic hydrocarbyl optionally substituted with a phenyl group.

[84] In different embodiments of the present invention, R is selected from: (Cio-C2o) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C10C19) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cio-Cwj) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cio-Cvj) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cio-Ci6) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cio-Ci5) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cio-Cwj aliphatic hydrocarbyl optionally substituted with a phenyl group,(Cio-Ci3) aliphatic hydrocarbon optionally substituted with a phenyl group, (CwCi2) aliphatic hydrocarbon optionally substituted with a phenyl group, and (Cio-Cn) aliphatic hydrocarbon optionally substituted with a phenyl group.

[85] In different embodiments of the present invention, R is selected from: (Cn-C2o) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (CnC19) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cn-C18) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cn-C17) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C11-C11) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cn-C11) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less less, (Cn-Ci4) aliphatic hydrocarbyl optionally substituted with a phenyl group,(Cn-Ci3) aliphatic hydrocarbon optionally substituted with a phenyl group, and (CnCi2) aliphatic hydrocarbon optionally substituted with a phenyl group.

[86] In different embodiments of the present invention, R is selected from: (C12-C20) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C12C19) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C12-C18) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C12-C17) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C12-C16) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C12-C15) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that that R contains twenty carbons or less, (Ci2-Ci4) aliphatic hydrocarbyl optionally substituted with a phenyl group,and (Ci2-Ci3) aliphatic hydrocarbyl optionally substituted with a phenyl group.

[87] In different embodiments of the present invention, R is selected from: (Ci3-C2o) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C13C19) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci3-Cis) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci3-Ci7) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C13-Cie) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci3-Ci5) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, and (Ci3-Ci4) aliphatic hydrocarbyl optionally substituted with a phenyl group.

[88] In different embodiments of the present invention, R is selected from: (Ci4-C2o) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C14Cw) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci4-Ci8) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci4-Ci7) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cu-Cwj) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, and (Ci4-Ci5) aliphatic hydrocarbyl optionally substituted with a phenyl group, provided that R contains twenty carbons. or less.

[89] In different embodiments of the present invention, R is selected from: (Ci5-C2o)aliphatic hydrocarbyl, (Ci5-Cig)aliphatic hydrocarbyl, (Ci5-Ci8)aliphatic hydrocarbyl, (Ci5-Ci7)aliphatic hydrocarbyl, and (Ci5-Ci6)aliphatic hydrocarbyl.

[90] In different embodiments of the present invention, R is selected from: (Ci6-C2o)aliphatic hydrocarbyl, (Ci6-Ci9)aliphatic hydrocarbyl, (Cie-Ciejaliphatic hydrocarbyl, and (Cie-Cvjaliphatic hydrocarbyl.

[91] In different embodiments of the present invention, R is selected from: (C17-C2o)aliphatic hydrocarbyl, (C17-C1g)aliphatic hydrocarbyl, and (C17-C18)aliphatic hydrocarbyl.

[92] In different embodiments of the present invention, R is (Ci8-C2o)aliphatic hydrocarbyl or (Ci8Cig)aliphatic hydrocarbyl.

[93] In different embodiments of the present invention, R is (Cig-C2o) aliphatic hydrocarbyl.

[94] In different embodiments of the present invention, R is selected from: (C2o) aliphatic hydrocarbyl, (Cig) aliphatic hydrocarbyl, (Ci8) aliphatic hydrocarbyl, (Ci7) aliphatic hydrocarbyl, (Ciej) aliphatic hydrocarbyl, (Ci5) aliphatic hydrocarbyl, (Ci4) aliphatic hydrocarbyl optionally substituted with a phenyl group, (Ci3) aliphatic hydrocarbyl optionally substituted with a phenyl group, (Ci2) aliphatic hydrocarbyl optionally substituted with a phenyl group, (Cn) aliphatic hydrocarbyl optionally substituted with a phenyl group, (Cio) aliphatic hydrocarbyl optionally substituted with a phenyl group, (Cg) aliphatic hydrocarbyl optionally substituted with a phenyl group, (C8) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (C7) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (Cj aliphatic hydrocarbyl optionally substituted with one or two phenyl groups,(Csj aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, (C4) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, and (Caj aliphatic hydrocarbyl optionally substituted with one or two phenyl groups.,

[95] In some embodiments of the present invention, R is selected from: (Ci-C2o) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci9) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cr Cia) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci7) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci6) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci5) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci4) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less,(Ci-Ci3) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Ci2) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Cn) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-Cio) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ci-C9) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (CrCs) alkyl optionally substituted with one or two phenyl groups, (Ci-C7) alkyl optionally substituted with one or two phenyl groups, (CrCeJ) alkyl optionally substituted with one or two phenyl groups, (Ci-Cs) alkyl optionally substituted with one or two phenyl groups, (Ci-C4)alkyl optionally substituted with one or two phenyl groups,and (Ci-C3)alkyl optionally substituted with one or two phenyl groups.

[96] In different embodiments of the present invention, R is selected from: (C2-C2o) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Cig) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2Cisj) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci7) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci6) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci5) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci4) alkyl optionally substituted with one or two groups phenyl on the condition that R contains twenty carbons or less,(C2-Ci3) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Ci2) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Cn) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-C1o) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2-Cg) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C2Csj) alkyl optionally substituted with one or two phenyl groups, (C2-C7) alkyl optionally substituted with one or two phenyl groups, (C2-C6) alkyl optionally substituted with one or two phenyl groups, (C2-C5)alkyl optionally substituted with one or two phenyl groups, (C2-C4)alkyl optionally substituted with one or two phenyl groups,and (C2-C3)alkyl optionally substituted with one or two phenyl groups.

[97] In different embodiments of the present invention, R is selected from: (C3-C2o)alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-C19)alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-C17)alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-C18)alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-C19)alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-C14)alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less phenyl on the condition that R contains twenty carbons or less,(C3-C13) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-C12) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-C1n) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-C10) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3-C9) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C3C1) alkyl optionally substituted with one or two phenyl groups, (C3-C7) alkyl optionally substituted with one or two phenyl groups, (C3-C6) alkyl optionally substituted with one or two phenyl groups, (C3-Cs)alkyl optionally substituted with one or two phenyl groups, (C3-C4)alkyl optionally substituted with one or two phenyl groups.

[98] In different embodiments of the present invention, R is selected from: (C4-C2o) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-Ci9) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-Ci7) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-Ci6) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-Ci5) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-Ci4) alkyl optionally substituted with one or two groups phenyl on the condition that R contains twenty carbons or less,(C4-C13) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-C12) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-C1n) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-C10) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-Cg) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C4-Csj) alkyl optionally substituted with one or two phenyl groups, (C4-C7) alkyl optionally substituted with one or two phenyl groups, (C4-C6) alkyl optionally substituted with one or two phenyl groups, and (C4-C5)alkyl optionally substituted with one or two phenyl groups.

[99] In different embodiments of the present invention, R is selected from: (Cs-C10j alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-C1gj alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C5C1a) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C5-C17) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-C1ej alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-C1sj alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-C1sj alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-C1uj alkyl optionally substituted with one or two phenyl groups with the condition that R contains twenty carbons or less,(Cs-Cnj alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C5-C12)alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C5-Cn)alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (Cs-C10j alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C5-C9)alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C5Cs)alkyl optionally substituted with one or two phenyl groups, (Cs-C10j alkyl optionally substituted with one or two phenyl groups, and (Cs-C10j alkyl optionally substituted with one or two phenyl groups.

[100] In different embodiments of the present invention, R is selected from: (C6-C2o) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6-Cig) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (CeCis) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6-Ci7) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6-Ci6) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (CeCisj) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6-Ci4) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less,(C6-Ci3) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ce-Ci2) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6-Cn) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6-Cio) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6-C9) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C6C8) alkyl optionally substituted with one or two phenyl groups, and (C6-Cz) alkyl optionally substituted with one or two phenyl groups.

[101] In different embodiments of the present invention, R is selected from: (C7-C2o) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Ci9) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Ci7) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Ci6) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Ci5) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C7-Ci4) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less,(C7-Ci3) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C7-Ci2) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C7-Cn) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C7-Cio) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C7-Cg) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, and (C7Csj) alkyl optionally substituted with one or two phenyl groups.

[102] In different embodiments of the present invention, R is selected from: (C8-C2o) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Cs-Ci9) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C8-Ci7) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (Ce-Ci4) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C8-Ci5) alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less, (C8-Ci4) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less,(C8-Ci3) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C8-Ci2) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (C8-Cn) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, (Cs-Cio) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less, and (Cs-Cgj) alkyl optionally substituted with one or two phenyl groups on the condition that R contains twenty carbons or less.

[103] In different embodiments of the present invention, R is selected from: (C9-C2o)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C9-Ci9)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C9-Ci8)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cg-Cpj)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cg-Cwj)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C9-Ci5)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C9-Ci4)alkyl optionally substituted with a phenyl group, (C9-Ci3)alkyl optionally substituted with a phenyl group, (C9-Ci2)alkyl optionally substituted with a phenyl group,(Cg-Cn)alkyl optionally substituted with a phenyl group, and (Cg-Cio)alkyl optionally substituted with a phenyl group.

[104] In different embodiments of the present invention, R is selected from: (Cio-C2o)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cio-Ci9)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cio-Ci8)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cio-Ci7)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cw-Ciej)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cio-Ci5)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cio-Cu)alkyl optionally substituted with a phenyl group, (Cio-Ci3)alkyl optionally substituted with a phenyl group, (Cw-Ci2)alkyl optionally substituted with a phenyl group,and (Cio-Cn)alkyl optionally substituted with a phenyl group.

[105] In different embodiments of the present invention, R is selected from: (Cn-C2o)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cn-C19)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cn-C18)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cn-C11)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cn-C11)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C11-C15)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Cn-Cu)alkyl optionally substituted with a phenyl group, (Cn-Ci3)alkyl optionally substituted with a phenyl group, and (Cn-Ci2)alkyl optionally substituted with a phenyl group.

[106] In different embodiments of the present invention, R is selected from: (Ci2-C2o)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci2-Ci9)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci2-Ci8)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci2-Ci7)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci2-Ci6)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci2-Ci5)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci2-Cu)alkyl optionally substituted with a phenyl group, and (Ci2-Ci3)alkyl optionally substituted with a phenyl group.

[107] In different embodiments of the present invention, R is selected from: (Ci3-C2o) alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci3-Ci9) alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci3-C18) alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C13-Ci7) alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci3-Ci6) alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (C13-C15) alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, and (Ci3-Ci4) alkyl optionally substituted with a phenyl group.

[108] In different embodiments of the present invention, R is selected from: (Ci4-C2o)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci4-Ci9)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci4-Ci8)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci4-Ci7)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, (Ci4-Ci6)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less, and (Ci4-Ci5)alkyl optionally substituted with a phenyl group, provided that R contains twenty carbons or less.

[109] In different embodiments of the present invention, R is selected from: (Ci5-C2o)alkyl, (C15Cig)alkyl, (Ci5-Ci8)alkyl, (Cis-Cnjalkyl, and (Cis-Cwjalkyl.

[110] In different embodiments of the present invention, R is selected from: (Ci6-C2o)alkyl, (C16Cig)alkyl, (Ci6-Ci8)alkyl, and (Ci6-Ci7)alkyl.

[111] In different embodiments of the present invention, R is selected from: (Ci7-C2o)alkyl, (C17Ci9)alkyl, and (Ci7-Ci8)alkyl.

[112] In different embodiments of the present invention, R is (Ci8-C2o)alkyl or (Ci8-Cig)alkyl.

[113] In different embodiments of the present invention, R is (Cig-C2o)alkyl.

[114] In different embodiments of the present invention, R is selected from: (C2o)alkyl, (Cig)alkyl, (Ci8)alkyl, (Ci7)alkyl, (Ciej)alkyl, (Ci5)alkyl, (Ci4)alkyl optionally substituted with a phenyl group, (Ci3)alkyl optionally substituted with a phenyl group, (Ci2)alkyl optionally substituted with a phenyl group, (Cn)alkyl optionally substituted with a phenyl group, (Cio)alkyl optionally substituted with a phenyl group, (Cg)alkyl optionally substituted with a phenyl group, (Cs)alkyl optionally substituted with one or two phenyl groups, (C7)alkyl optionally substituted with one or two phenyl groups, (Ce)alkyl optionally substituted with one or two phenyl groups, (C5)alkyl optionally substituted with one or two phenyl groups, (C4)alkyl optionally substituted with one or two phenyl groups, (C3)alkyl optionally substituted with one or two phenyl groups, ethyl optionally substituted with one or two phenyl groups,and methyl optionally substituted with one or two phenyl groups.

[115] In different embodiments of the present invention, R is CnHm. In some of these embodiments, ML / t / ZUZÓ / UIZ lUZ n is 1 and m is 3, (i.e., methyl). In some of these forms, n is 2 and m is 5, (i.e., ethyl). In some of these modalities, n is 3 and m is chosen from: 3, 5, and 7. In some of these modalities, n is 4 and m is chosen from: 5, 7, and 9. In some of these modalities, n is 5 and m is chosen from: 7, 9, and 11. In some of these modalities, n is 6 and m is chosen from: 5, 7, 9, 11, and 13. In some of these modalities, n is 7 and m is chosen from: 7, 9, 11, 13, and 15. In some of these modalities, n is 8 and m is chosen from: 5, 7, 9, 11, 13, 15, and 17. In some of these modalities, n is 9 and m is chosen from: 7, 9, 11, 13, 15, 17, and 19. In some In some of these modalities, n is 10 and m is chosen from: 7, 9, 11, 13, 15, 17, 19, and 21. In some of these modalities, n is 11 and m is chosen from: 9, 11, 13, 15, 17, 19, 21, and 23. In some of these modalities, n is 12 and m is chosen from: 7, 9, 11, 13, 15, 17, 19, 21, 23, and 25.In some of these modalities, n is 13 and m is chosen from: 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some of these modalities, n is 14 and m is chosen from: 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, and 29. In some of these modalities, n is 15 and m is chosen from: 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, and 31. In some of these modalities, n is 16 and m is chosen from: 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, and 33. In some of these In some of these modalities, n is 17 and m is chosen from: 11, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, and 35. In some of these modalities, n is 18 and m is chosen from: 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some of these modalities, n is 19 and m is chosen from: 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 39. In some of these modalities, n is 20 and m is chosen from: 11,13,15,17,19,21,23,25, 27, 29, 31,33, 35, 37, 39, and 41.

[116] In some embodiments, R is chosen from: n-propyl, isopropyl, cyclopropyl, n-butyl, 1-methylpropyl, 2-ethylbutyl, 1-methyl-2-ethylbutyl, 2-methylpropyl, tert-butyl, 2-methylcyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopropylmethyl (i.e., ) n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, cyclobutylmethyl (i.e., ), 2-(cyclopropyl)ethyl (i.e., ), cyclopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 3-(cyclopropyl)propyl (i.e., V), 2-(cyclobutyl)ethyl (i.e., ), cyclopentylmethyl (i.e., ), cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, dicyclohexylmethyl, n-octyl, benzyl, diphenylmethyl, decyl, dodecyl, tetradecyl, hexadecyl, hexadec-9-enyl, octadecyloctadec-9-enyl, octadec-9,12-dienyl, 2-propylpentyl, 2-butylhexyl, 2-pentylheptyl, 2-hexyloctyl.,

[117] As used herein, and as would be understood by a person experienced in the matter, mention of “a compound” - unless expressly limited - is intended to include salts of that compound.

[118] The term “pharmaceutically acceptable salt” refers to salts whose counterion is derived from pharmaceutically acceptable nontoxic acids and bases. Pharmaceutically acceptable acids suitable for the salts of the amino-substituted compounds of the present invention include, for example, acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besilate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, and succinic acids. sulfuric, tannic, tartaric, theoclastic, p-toluenesulfonic and similar.Pharmaceutically acceptable base addition salts suitable for the carboxylate-substituted compounds of the present invention include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, arginine, N,N'-benzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Additional pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium cations and carboxylate, sulfonate, and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.

[119] It shall be recognized that the compounds of this invention may exist in radiolabeled form, that is, the compounds may contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number generally found in nature. Alternatively, a plurality of molecules of a single structure may include at least one atom occurring in an isotopic ratio different from the isotopic ratio found in nature. Radioisotopes of hydrogen, carbon, phosphorus, fluorine, chlorine, and iodine include 2H, 3H, 11C, 13C, 14C, 15N, 35S, 18F, 36Cl, 125I, 124I, and 131I, respectively. Compounds containing these radioisotopes and / or other radioisotopes of other atoms are within the scope of this invention. Experts in the field acknowledge that deuterium has been used to improve the metabolic stability of compounds, and that in principle it can be applied to these compounds.Tritiated radioisotopes, i.e., 3H, and carbon-14, i.e., 14C, are particularly preferred for their ease of preparation and detectability. Compounds containing isotopes 11C, 13N, 15O, 124I, and 18F are very suitable for positron emission tomography. The radiolabeled compounds of Formulas I and II of this invention and prodrugs thereof can generally be prepared by methods well known to those experienced in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes, substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.

[120] Although this invention is susceptible to embodiments in many different forms, preferred embodiments of the invention are shown. However, it should be understood that the present disclosure is to be regarded as an exemplification of the principles of this invention and is not intended to limit the invention to the embodiments illustrated. Upon examination, it may be found that certain members of the claimed genus are not patentable for the inventors in this application. In this case, the subsequent exclusions of species from the scope of the applicants' claims should be regarded as artifacts of the patent process and not a reflection of the inventors' concept or description of their invention; the invention encompasses all members of genus I that are not yet in the public domain.

[121] The terms “subject” and “subject in need” are used interchangeably in this document. These terms refer to a patient who has been diagnosed with the underlying disorder to be treated. This subject may currently be experiencing symptoms associated with the disorder or may have experienced symptoms in the past. Additionally, a “subject in need” may be a patient at risk of developing a particular disease, or a patient who reports one or more of the physiological systems of a disease, even if a diagnosis of that disease has not been made. By way of non-limiting example, a “subject in need,” for the purposes of this application, may include a subject who is currently diagnosed with epilepsy or was diagnosed with epilepsy in the past, or who is at risk of seizures, regardless of current symptomatology.

[122] As used herein, the terms “treatment” and “treat” are used interchangeably. These terms refer to an approach to achieving beneficial or desired results, including, but not limited to, therapeutic benefit. Therapeutic benefit includes the eradication or improvement of the underlying disorder being treated; it also includes the eradication or improvement of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the patient, regardless of whether the patient may still be affected by the underlying disorder.

[123] The compounds described herein are useful for treating epilepsy and pain. For the purposes of “treating epilepsy,” the term includes the improvement of seizures and convulsions. For the purposes of “treating pain,” the term includes the improvement of neuropathic pain, chemotherapy-induced pain, back pain, bone pain, abdominal pain, postoperative pain, pain from traumatic injury, menstrual pain, muscle pain, joint pain, headache, migraine, dental pain, evoked pain, and pain due to inflammation. Chemical synthesis of compounds

[124] In general, the compounds of the present invention can be prepared by the methods illustrated in the general reaction schemes as described, for example, below, or by modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures. In these reactions, it is also possible to make use of variants that are themselves known but not mentioned here. The starting materials are commercially available, synthesized as described in the examples, or can be obtained by methods well known to persons skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and transformations and manipulations of Functional groups can be readily obtained from relevant scientific literature or standard textbooks in the field. It will be appreciated that while typical or preferred process conditions are given (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.), other process conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the particular reactants or solvent used. Those experienced in the subject will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds described. The complete list of abbreviations used by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry.The list, which is usually presented in a table titled “List of Standard Abbreviations”, provides definitions for abbreviations not found in the following list of abbreviations: °C degrees Celsius. ACN acetonitrile Cl chloride CS2CO3 cesium carbonate DCC Λ / ,Λ / '-dicyclohexylcarbodiimide DCM dichloromethane or methylene chloride DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine or A / ,A / -dimethylaminopyridine DMF Λ / , / V-dimethylformamide EDC W-(3-dimet¡laminoprop¡l)-W'-ethylcarbod¡mide hydrochloride eq. equivalent(s) EtOAc ethyl acetate EtOH ethanol ESI ionization by electrospray g gram(s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-thazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU 2-(1 / - / -benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HCl hydrochloric acid HPLC high-performance liquid chromatography h hour(s) Iodide LC / MS liquid chromatography / mass spectrometry LDA lithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide K2CO3 potassium carbonate KHMDS potassium bis(trimethylsilyl)amide KMηθ4 potassium permanganate M molarity concentration pm mine MeOH methanol mg milligram(s) min minute(s) mL milliliter(s) mmol millimole(s) Normal concentration Na2CC>3 sodium carbonate NaH sodium hydride NaHCO3 sodium carbonate hydrogen Sodium NaHMDS bis(trimethylsilyl)amide NaOH sodium hydroxide NMR nuclear magnetic resonance OMs mesylate OTf triflate OTs tosylate Pd / C palladium on carbon Ph phenyl psi pounds per square inch PyBOP (benzotriazol-1-lox)tripyrrolidinophosphono hexafluorophosphate Ru / C ruthenium on carbon TBTU 2-(1H-benzotrazol-1-¡l)-1,1,3,3-tetramethylamino tetrafluoroborate TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TMS-I iodotrimethylsilane TLC thin layer chromatography

[125] The terminology related to “protection group,” “deprotection,” and “protected” functionalities appears throughout this application. Such terminology is well understood by people experienced in the subject and is used in the context of processes involving sequential treatment with a series of reagents. In that context, a protection group refers to a group used to mask a functionality during a process step in which it would otherwise react, but where the reaction is undesirable. The protection group prevents the MA / t / ZUZÓ / UIZ lUZ reaction in that step, but it can be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere. Therefore, when a sequence of reagents is specified, as in the processes described in this document, an experienced person can easily foresee those groups that would be suitable as “protecting groups.” Groups suitable for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W. Greene and P.G.M. Wuts [John Wiley & Sons, New York, 1999].

[126] List of protection groups and their abbreviations: Acetyl (Ac) Adiales Carboallyloxy (Alloc) Benzoyl (Bz) Benzyl (Bn, Bnl) Benzyl esters Carbamate Carbobenzyloxy (Cbz) Dimetoxitritilo, [bis-(4-metox·phenyl)phenylmet·lo] (DMT) Ditianes Éteres etoxietílicos (EE) Fluorenylmethyloxoxacarbon(Fmoc) Éter metoximetílico (MOM) Metoxitritilo [(4-metoxifen·l)d·fen·lmetilo], MMT) Éteres metílicos Metilo (Me) Esteres metílicos Éter metiltiometílico Ortoésteres Oxazolina Pivaloil (Piv) Ftalimido p-Metoxibencilcarbonyl (Moz o MeOZ) p-Metoxibencil (PMB) p-Metoxifenil (PMP) Alcoholes propargílicos Groups sililo (for example, trimetylsililo (TMS), tert-butyldimethylsililo (TBDMS), tri-iso-propylsililoximetililo TOM) and triisopropylsililo (TIPS)) μΛ / t / ZUZO / UIZ lUZ esters sililocos esters tert-butilocos Terc-Butyloxycarbonyl (Boc o tBoc) Tetrahydropyranilide (THP) Tosilo (Ts oTos) Chloroformate of trichloroethyl (Trac) Trimethylsilylethoxymethyl (SEM) Triphil (triphenylmethyl, Tr) β-methoxyethoxymethyl ether (MEM) (4-Nitrophenyl)sulfon¡lo (4-nitrophenyl)(dioxide)-lambda(6)-sulfanyl) (Nosyl) 2-Cyanoethyl 2-Nitrophenylsulfenyl (NPS) 3,4-Dimethoxybenzyl (DMPM) 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) I. Generic chemical synthesis section

[127] The compounds of the present invention are prepared using methods illustrated in the general synthetic schemes and experimental procedures detailed below. These general synthetic schemes and experimental procedures are presented for illustrative purposes and are not intended to be limiting. The starting materials used to prepare the compounds of the present invention are commercially available or can be prepared using routine methods known in the field. Where available, the compound names are generated using ChemAxon's Instant JChem v6.1 for desktop computers and the IUPAC Naming Plugin.

[128] Intermediate compounds I, V, and VIII are made using protocols previously described in the literature (B. Huff “Excitatory amino acid receptor antagonists”, U.S. Patent 5,284,957, 1994; A.M. Brian Arnold, et al. “Process for preparing isoquinoline compounds”, U.S. Patent 5,648,492, 1997; Paul L. Ornstein, et al. “(3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl)ethyl] decahydroisoquinoline-3-carboxylic Acid: A Structurally Novel, Systemically Active, Competitive AMPA Receptor Antagonist”). (3SR,4aRS,6RS,8aRS)-6-[2-(1Htetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid: A structurally novel, systemically active, competitive AMPA receptor antagonist). J. Med. Chem., 1993, 36, 2046-2048; Paul L. Ornstein, et al. “Syntheses of Oxodecahydroisoquinoline-3-carboxylates.Useful Intermediates for the Preparation of Conformationally Defined Excitatory Amino Acid Antagonists'', (Synthesis of oxodecahydroisoquinoline-3-carboxylates. Useful intermediates for the preparation of conformationally defined excitatory amino acid antagonists). J. Org. Chem., 1991, 56,4388-4392).

[129] Scheme 1 illustrates a general synthetic scheme for making the desired compounds IV from ketone I. In step 1, the methyl carbamate-protected carboxylic acid I is treated with iodotrimethylsilane at room temperature, or alternatively, with 6 N hydrochloric acid at 90°C, to remove the methyl carbamate protecting group and obtain the amino acid ketone II. Compound II is reacted, under basic conditions (e.g., 2 N aqueous NaOH, triethylamine, diisopropylethylamine, etc.), with benzyl chloroformate (Cbz), di-tert-butyl dicarbonate (Boc), or a similar reagent to obtain carbamate-protected carboxylic acids III. Compound III is esterified to make ketone IV carbamate esters. Several methods are possible: 1) Compound III is esterified with alcohols (HO-R1) using a coupling reagent (e.g., Λ / ,Λ / '-dicyclohexylcarbodiimide (DCC), EDC, HBTU, HATU, PyBOP, etc.).) under basic conditions (e.g., triethylamine, diisopropylethylamine, pyridine, N,N-4 dimethylaminopyridine, etc.), 2) compounds III are alkylated with an activated alkane (X-R1, where X = OTf, OTs, OMs, I, Br, and Cl) under basic conditions (e.g., NaOH, NaH, NaCO3, K2CO3, CS2CO3, NaHCO3, etc.), and 3) compounds III are esterified with alcohols (HO-R1) using Mitsunobu conditions (e.g., diethyl azodicarboxylate and triphenylphosine, or similar reagents). Scheme 1. General synthesis of ketone IV carbamate esters from ketone I.

[130] Scheme 2 illustrates a general synthetic scheme for making the desired compounds III from ketone ester V. In step 1, the methyl carbamate-protected ethyl ester V is treated with iodotrimethylsilane at room temperature to remove the methyl carbamate protecting group and obtain the amino ester VI. The ethyl ester VI is then reacted, under basic conditions (e.g., 2 N aqueous NaOH, triethylamine, diisopropylethylamine, etc.), with benzyl chloroformate (Cbz), di-tert-butyl dicarbonate (Boc), a similar protecting group that is stable under basic conditions but can be more easily removed than methyl carbamate, to obtain carbamate-protected ethyl ester VII. Next, the Vil compounds are hydrolyzed under standard aqueous basic conditions (e.g., 2 N aqueous NaOH in alcoholic solvent or similar aqueous miscible organic solvent) to obtain carbamate-protected acids III.Next, compounds III are esterified, as described in Scheme 1, to make ketone carbamate esters IV. Scheme 2. General synthesis of ketone carbamate acids III from ketone ester V. Step 1 Step 3

[131] Scheme 3 illustrates a general synthetic scheme for making the desired compounds IX from protected ketone carbamate esters IV. Wittig's tetrazole reagent VIII (made as previously described in U.S. Patent 5,284,957 to B. Huff) is deprotonated under strong basic conditions (e.g., LiHMDS, NaHMDS, LDA, etc.) and reacted with ketones IV to make the compounds defined as IX. Scheme 3. General synthesis of compounds of definition IX from ketone carbamate esters IV.

[132] Scheme 4 illustrates a general synthetic scheme for making the desired compounds X from the definites IX. Free-radical hydrofluorination of IX yields a mixture of fluorinated carbamate esters X (J. Am. Chem. Soc., 2012, 134, 33, 13588-13591 “Fe(III) / NaBH4-Mediated Free Radical Hydrofluorination of Unactivated Alkenes”. Timothy J. Barker and Dale L. Boger). The isomers can be separated by crystallization or chromatography to obtain isomerically pure fluorinated carbamate X esters. Additionally, alternative hydrofluorination conditions can be used, including but not limited to protocols using the KHSO4-13HF complex (J. Am. Chem. Soc., 2017, 139, 18202-18205 “Widely Applicable Hydrofluorination of Alkenes via Bifunctional Activation of Hydrogen Fluoride”, Zhichao Lu, Xiaojun Zeng, Gerald B. Hammond, and Bo Xu), and fluorine cobalt complexes (Org. Lett., 2013, 15, 20, 5158 “Cobalt-Catalyzed Hydrofluorination of Unactivated Olefins: A Radical Approach of Fluorine Transfer”, Hiroki Shigehisa, Eriko Nishi, Mayu Fujisawa, and Kou Hiroya), Superacid HF / SbF5 (Chem. Commun., 2007, 31,98. “A novel, facile route to beta-fluoroamines by hydrofluorination using superacid HF / SbF5”, (A novel, easy route to beta-fluoroamines by hydrofluorination using superacid HF / SbF5). Sébastien Thibaudeau, Agnés Martin-Mingot, Marie-Paule Jouannetaud, Omar Karamb, and Fabien Zuninob) and HFPyridine (Org. Synth., 1978, 58, 75 “Fluorinations With Pyridinium Polyhydrogen Fluoride”, (Fluorations with pyridinium fluoride and polyhydrogen). George A. Olah and Michael Watkins. Scheme 4. General synthesis of fluorinated carbamate esters MA / t / ZUZÓ / UIZ / UZ

[133] Scheme 5 illustrates a general synthetic scheme for making fluorinated ester amine prodrugs IX from fluorinated carbamate esters X. The carbamate protecting group is removed using established published protocols (e.g., hydrogenation using hydrogen gas and a Pd / C catalyst for Cbz conditions, TFA or 4 N HCl for Boc, etc.). The isomers are separated by crystallization or chromatography to obtain isomerically pure fluorinated ester amines XI. Scheme 5. General synthesis of fluorinated ester amine prodrugs XI from fluorinated carbamate ester X.

[134] Scheme 6 illustrates a general synthetic scheme for making the desired fluorinated amino acid compound from fluorinated amino esters XI. The esters are hydrolyzed under standard aqueous basic conditions (e.g., 2 N aqueous NaOH or 2 N NaOH in alcoholic solvent or similar aqueous miscible organic solvent) to yield fluorinated amino acid XII. Scheme 6. General synthesis of fluorinated decahydroisoquinoline amino acids XII.

[135] Final purification and isolation yield fluorinated decahydroisoquinoline amino acids 1 and 2. II. Section of experimental chemical synthesis

[136] All reagents were purchased commercially and used without further purification. Reactions were performed under an air / nitrogen atmosphere according to requirements. Column chromatography was carried out on silica gel 60 (230–400 mesh), and analytical TLC was performed on silica gel-coated plates. The TLC plates were stained with ceric ammonium molybdate (CAM), p-anisaldehyde (Anis), potassium permanganate (KMnO4), or ninhydrin staining solutions. Routine 1H NMR spectra were recorded using a Bruker 300 MHz or Varian 300 MHz instrument with deuterium oxide, chloroform-d, or methanol-O4 as solvents. HPLC spectra were recorded using Agilent Series 1100 HPLC using a Zorbax SB-C18 column (4.6 x 150 mm) with gradient elution from 5%B to 95%B (Mobile Phase A: 0.05% HCIO4 in water; Mobile Phase B: acetonitrile) for 8.5 min and UV detection at 205 nm or a Waters Sunfire C18 column (4.6 x 75 mm, 3.5 pm, Part No. 186002552) with gradient elution from 5%B to 95%B (Mobile Phase A: 0.1% TFA in water; Mobile Phase B: 0.1% TFA in acetonitrile) for 8.6 min and UV detection at all wavelengths. Mass spectrometry was performed using an Advion Expression CMS (ESI) or Agilent (Hewlett Packard Series 1100 MSD) with MassLynx interface (ESI: positive or negative ion mode) or a Waters 29996, Micromass ZQ (ESI: positive or negative ion mode). Preparative reversed-phase chromatography was performed using a Gilson system with a Waters Sunfire C18 OBD preparative column (30 x 150 mm, 10 pm column, Part No. 186002670). In some cases, normal-phase silica gel column chromatography was performed using a Teledyne ISCO CombiFlash system. Preparation of (3S,4aS,8aR)-6-oxo-decahydroisoquinoline-3-carboxylate ethyl (1-01): 1-01 To a solution of (3S,4aS,8aR)-6-oxo-decahydroisoquinoline-2,3-dicarboxylate of 3-ethyl 2-methyl (35.42 g, 125 mmol) in methylene chloride (600 mL) under nitrogen, iodotrimethylsilane (100 g, 500 mmol) was added in a portion at room temperature. The reaction mixture was stirred overnight and cooled with ethanol (250 mL). The solution was concentrated under vacuum and dried for 3 h under reduced pressure to obtain the desired crude amino ester 1-01 as a golden yellow solid (43 g crude) which was used directly without purification in the next step.1H NMR (300.13 MHz, CD3OD) δ 4.31 (q, J = 5.3 Hz, 2H), 4.17 (d, J = 9.6 Hz, 1H), 3.31-3.21 (m, 1H), 3.14 (dd, J = 9.6, 3.2 Hz, 1H), 2.21 (d, J = 9.5 Hz, 1H), 2.13-2.08 (m, 2H), 2.00 (dt, J = 10.1, 3.1 Hz, 1H), 1.88-1.69 (m, 4H), 1.58 (d, J = 9.9 Hz, 1H), 1.40-1.35 (m, 1H), 1.32 (t, J = 5.3 Hz, 3H) ppm. Batch upscale: To a solution of (3S,4aS,8aR)-6-oxo-decahydroisoquinoline-2,3-dicarboxylate of 3-ethyl 2-methyl (74.4 g, 262.6 mmol) in methylene chloride (1200 mL) under nitrogen, iodotrimethylsilane (200 g, 1.0 mol) was added in one portion at room temperature. The reaction mixture was stirred overnight and cooled with ethanol (280 mL). The solution was concentrated under vacuum and dried for 3 h under reduced pressure to obtain the desired crude amino ester 1-01 as a golden-yellow solid (90.5 g crude) which was used directly without further purification. Synthesis of ketone carbamate esters IV: Preparation of (3S,4aS,8aR)-6-oxo-decahydroisoquinoline-2,3-dicarboxylate of 2-benzyl 3-ethyl (I-O2): To a 1-01 slurry (crude, 6.25 mmol) in methylene chloride (50 mL), triethylamine (3.5 mL, 25.1 mmol) was added at 5-10°C and the mixture was stirred for 10 min under a nitrogen atmosphere. Benzyl chloroformate (1.12 mL, 7.62 mmol) was slowly added at 5-10°C. The mixture was heated to room temperature and stirred for 2–3 h (the reaction was monitored by TLC and KMnO₄ incision). The mixture was adjusted to pH 3–4 using 3 N HCl and diluted with ethyl acetate (50 mL). The layers were separated, and the combined organic layers were washed with brine (15 mL), dried on sodium sulfate, and concentrated under vacuum. The resulting residue was purified by flash column chromatography (silica gel, 0–40% ethyl acetate / hexane) to obtain I₂O₂ as a light yellow oil (2.12 g, 94% yield).¹H NMR (300.13 MHz, CDCi₃) δ 7.36–7.27 (m, 5H), 5.14 (d, J = 24.6, 14.1 Hz, 2H). 4.92 (dd, J = 41.3, 8.3 Hz, 1H), 4.22-4.14 (m, 2H), 4.02 (dd, J = 22.5,13.5 Hz, 1H), 3.27 (ddd, J = 34.5,13.5, 3.0 Hz, 1H), 2.59 (dd, J = 16.5, 6.0 Hz, 1H), 2.38-1.65 (m, J = 16.5, 1.26), J. Hz, 1.5H), 1.21 (t, J = 7.2 Hz, 1.5H) ppm. Preparation of (3S,4aS,8a / ?)-6-oxo-decahydroisoquinoline-2,3-dicarboxylate from 2-ferc-butyl 3-ethyl (I-03): 1-01 g crude (125 mmol) from a previous reaction was dissolved in methylene chloride (600 mL) and triethylamine (60.7 mL, 435 mmol) was added. After stirring for 15 minutes, a solution of di-ferc-butyl-bicarbonate (32.7 g, 150 mmol) in methylene chloride (100 mL) was added. The resulting mixture was stirred overnight at room temperature and then concentrated under vacuum. The resulting solid was suspended in ethyl acetate (300 mL) and filtered. The filtrate was washed with 1 N HCl (60 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by instant column chromatography (silica gel, 0% to 25% ethyl acetate / hexane) to obtain I-O3 as a colorless oil (30.0 g, 74% yield).1H NMR (300.13 MHz, CDCh) δ4.82 (dd, J = 65.0, 3.9 Hz, 1H), 4.17-4.14 (m, 2H), 3.90 (dd, J = 27.9, 10.2 Hz, 1H), 3.15 (dd, J = 39.7, 10.1 Hz, 1H), 2.56 (dd, J = 10.7, 4.3 Hz, 1H), 2.41-2.30 (m, 2H), 2.16-1.97 (m, 5H), 1.95-1.78 (m, 1H), 1.75-1.65(m, 1H), 1.42 (s, 4.5H), 1.40 (s, 4.5H), 1.23 (t, J = 4.3 Hz, 3H) ppm. Batch upscale: 1-01 Crude (393.9 mmol) from a previous reaction was dissolved in methylene chloride (1.8 L) and triethylamine (219.3 mL, 1573 mmol) was added. After stirring for 15 minutes, a solution of di-tert-butyl bicarbonate (343.3 g, 1573 mmol) in methylene chloride (300 mL) was added. The resulting mixture was stirred overnight at room temperature and then concentrated under vacuum. The resulting solid was suspended in ethyl acetate (900 mL) and filtered. The filtrate was washed with 1 N HCl (180 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting colorless oil (151 g crude, quantitative yield) was used directly without further purification. Preparation of (3S,4aS,8a / ?)-2-[(ferc-butoxy)carbonyl]-6-oxo-decahydroisoquinoline-3-carboxylic acid (I-O4): To a solution of I-O3 (35.2 g, 108 mmol) in THF (100 mL) 2 N NaOH (486 mL, 972 mmol) was added at room temperature under a nitrogen atmosphere. The solution was stirred at room temperature for 24 hours and then concentrated under vacuum to remove most of the THF. The aqueous layer was extracted with MTBE (3 x 150 mL) to remove organic impurities, acidified with 1 N HCl to pH ~2, and extracted with ethyl acetate (4 x 300 mL). The combined organic layers were washed with brine (250 mL), dried on sodium sulfate, and concentrated under vacuum to obtain I-04 as a white foamy solid (24.9 g, 78% yield).1H NMR (300.13 MHz, CDCI3) δ 4.92 (d, J = 58.3 Hz, 1H), 3.95 (dd, J = 29.7, 10.1 Hz, 1H), 3.21 (dd, J = 32.9, 10.2 Hz, 1H), 2.61 (d, J = 10.2 Hz, 1H), 2.421.71 (m, 9H), 1.46 (s, 4.5H), 1.44 (s, 4.5H) ppm. Up-scale batch: To a solution of I-O3 (crude 151 g, 393.9 mmol) in THF (360 mL) 2 N NaOH (1772 mL, 3545 mmol) was added at room temperature under a nitrogen atmosphere. The solution was stirred at room temperature for 24 h and then concentrated under vacuum to remove most of the THF. The aqueous layer was extracted with MTBE (3 x 250 mL) to remove organic impurities, acidified with 1 N HCl to pH ~2, and extracted with ethyl acetate (4 x 600 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated under vacuum to obtain I-O4 as a white, foamy solid (crude 122 g, quantitative yield). Preparation of (3S,4aS,8a / ?)-2-[(tert-butoxy)carbonyl]-6-oxo-decahydroisoquinoline-3-carboxylic acid (1-05): Solid NaHCO3 (49.4 g, 588 mmol) and 3-(iodomethyl)pentane (23.33 g, 110 mmol) were added to a solution of 1-O4 (24.9 g, 83.7 mmol) in DMF (110 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred at 3540°C for 4 h. The reaction was monitored by HPLC, and after the reaction was complete, the mixture was filtered, and the solid was washed with acetonitrile (400 mL). The combined organic layers were concentrated, and the crude residue obtained was redissolved in ethyl acetate (500 mL). The solution was washed with water (300 mL), brine (300 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by instant column chromatography (silica gel, 0% to 40% ethyl acetate / hexane) to obtain I-05 as a red semisolid (15.2 g, yield of 49% pure and 3.5 g, yield of 11% less pure).1H NMR (300.13 MHz, CDCI3) δ 4.86 (d, J = 63.5 Hz, 1H), 4.163.97 (m, 2.5H), 3.88 (d, J = 10.1 Hz, 0.5H), 3.15 (dd, J = 31.3, 9.8 Hz, 1H), 2.58 (d, J = 8.4 Hz, 1H), 2.35 (m, 2H), 2.181.48 (m, 8H), 1.44 (m, 9H), 1.40-1.30 (m, 4H), 0.87 (m, 6H) ppm. Batch upscale: To a crude I-O4 solution (426.8 mmol) in DMF (500 mL), solid NaHCO3 (231.6 g, 2.76 mol) and 3-(iodomethyl)pentane (159.7 g, 754.5 mmol) were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at 35-40°C for 3 days. The reaction was monitored by HPLC, and after the reaction was complete, the mixture was filtered, and the solid was washed with acetonitrile (1.5 L). The combined organic layers were concentrated, and the resulting crude residue was redissolved in ethyl acetate (2 L). The solution was washed with water (500 mL), brine (500 mL), dried over sodium sulfate, and concentrated under vacuum to obtain crude product I-05 as a red semi-solid (92.6 g, 57% yield) which was used directly without further purification. Preparation of (3S,4aS,8a / ?)-6-oxo-decahydroisoquinoline-2,3-dicarboxylate of 2-tert-butyl 3-nonyl (I-O6): I-06 To a solution of I-O4 (0.5 mmol) in DMF (2.0 mL), NaHCO3 (3.5 mmol) and 1-iodononane (1.3 mmol) were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction was monitored by HPLC, and after completion, the solution was poured into water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried on sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash column chromatography (silica gel, ethyl acetate / hexane) to obtain I-O6. Preparation of (3S,4aS,8a / ?)-6-oxo-decahydroisoquinoline-2,3-dicarboxylate of 3-(2R)-butan-2-yl 2-tert-butyl (IO?): To a mixture of I-04 (0.5 mmol) and (2R)-butanol (0.6 mmol) in dichloromethane (1.0 mL), DCC (0.6 mmol) and catalytic DMAP are added under a nitrogen atmosphere. The mixture is stirred at room temperature for 18 minutes and monitored by TLC or HPLC. After this time, acetonitrile (10 mL) is added, and the mixture is stirred for 5 to 10 minutes. The solid precipitate is removed by filtration through a sintered glass funnel, and the solid is washed with acetonitrile (10 mL). The filtrate is concentrated under vacuum, and the residue is purified by flash column chromatography (silica gel, ethyl acetate / hexane) to obtain I-07. Synthesis of olefin compounds IX: Preparation of (3S,4aR,6E,8a / ?)-6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethylidene]-decahydroisoquinoline-2,3-carboxylate of 2-benzyl 3-ethyl (I-08): nn n iH'l\IH H I-08 To a solution of triphenyl[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]phosphonium(VIII, 9.09 g, 20.7 mmol) bromide salt and ketone (1-O2, 6.2 g, 17.25 mmol) in anhydrous DMF (50 mL) 2.0 M NaHMDS (24.15 mL, 48.3 mmol) in THF at 0°C to -10°C under a nitrogen atmosphere. The internal reaction temperature was maintained at 0°C during the addition. The mixture was stirred at this temperature for 30 min and then allowed to warm to room temperature. After stirring for 18 h at room temperature, the mixture was slowly cooled with ice-cold brine solution (120 mL) and extracted with MTBE (7 x 250 mL) to partially remove triphenylphosphine oxide. The pH of the aqueous layer was adjusted to pH 2 using 3 N HCl and extracted with ethyl acetate (4 x 250 mL). The combined organic layers were washed with water (2 x 200 mL), brine (200 mL), dried over sodium sulfate, and concentrated under vacuum.The residue was purified by flash column chromatography (silica gel, 10% to 60% ethyl acetate / hexane) to obtain I-08 as a pure white foamy solid (2.0 g, 26% yield) and as a less pure yellow oil (2.0 g, 26% yield).1H NMR (299.96 MHz, CDCI3) δ 7.38-7.27 (m, 5H), 5.50 (t, J = 6.7 Hz, 0.5H), 5.32 (dt, J = 21.5, 6.4 Hz, 0.5H), 5.23-5.14 (m, 1.5H), 5.06 (d, J = 12.9 Hz, 0.5H), 4.89 (d, J = 27.0 Hz, 1H), 4.17 (q, J = 6.8 Hz, 2H), 3.95-3.87 (m, 1H), 3.76-3.69 (m, 2H), 3.25 (d, J = 14.3 Hz, 0.5H), 3.15 (d, J = 12.9 Hz, 0.5H), 2.65 (d, J = 12.6 Hz, 0.5H), 2.47 (d, J = 13.8 Hz, 0.5H), 2.34 (d, J = 13.2 Hz, 0.5H), 2.24 (d, J = 11.4 Hz, 0.5H), 2.08-1.65 (m,. 6Η), 1.62-1.47 (m, 2H), 1.20 (d, J = 7.8 Hz, 3H) ppm. Preparation of (3S,4a / ?,8a / ?)-6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethylidene]-decahydroisoquinoline-2,3-dicarboxylate of 2-tert-butyl 3-ethyl (I-09): Nn | 'nh' To a solution of triphenyl[2-(1 / 7-1,2,3,4-tetrazol-5-yl)ethyl]phosphonium(VIII, 6.16 g, 14.0 mmol) bromide salt and ketone (I-O3, 3.8 g, 11.7 mmol) in anhydrous DMF (35 mL) 2.0 M NaHMDS (16.4 mL, 32.8 mmol) in THF at 0°C to -10°C under a nitrogen atmosphere was added. The internal reaction temperature was maintained at 0°C during the addition. The mixture was stirred at this temperature for 30 min and then allowed to warm to room temperature. After stirring for 18 h at room temperature, the mixture was slowly cooled with ice-cold brine solution (50 mL) and extracted with MTBE (8 x 60 mL) to partially remove triphenylphosphine oxide. The pH of the aqueous layer was adjusted to pH 2 using 3 N HCl and extracted with ethyl acetate (4 x 250 mL). The combined organic layers were washed with water (2 x 200 mL), brine (200 mL), dried over sodium sulfate, and concentrated under vacuum to obtain I-09 as a red oil (6.1 g crude).1H NMR (300.13 MHz, CDCh) δ 5.37 (m, 1H), 4.82 (dd, J = 48.5, 3.5 Hz, 0.5H), 4.77 (d, J = 45.5 Hz, 0.5H), 4.21-4.18 (m, 2H), 3.87-3.78 (m, 1H), 3.25-3.12 (m, 3H), 2.49-2.47 (m, 1.5H), 2.34 (d, J = 13.1 Hz, 0.5H), 2.1.0-1.60 (m, 8H), 1.54-1.46 (m, 9H), 1.30-1.22 (m, 3H) ppm. Preparation of (3S,4a / ?,8a / ?)-6-[2-(1H-1,2,3,4-tetrazol-5-il)etilideno]-decahidroisoquinolina-2,3-dicarboxilato of 2terc-butilo 3-(2-etilbutilo) (1-10): To a solution of Wittig's tetrazole salt (VIII, 23.37 g, 53.2 mmol) and ketone (I-O4, 16.9 g, 44.3 mmol) in anhydrous DMF (150 mL) 2.0 M NaHMDS (62 mL, 124 mmol) in THF was added at 0°C to -10°C under a nitrogen atmosphere. The internal reaction temperature was maintained at 0°C during the addition. The mixture was stirred at this temperature for 1 min and then allowed to warm to room temperature. After stirring for 2 h at room temperature, the mixture was slowly cooled with a 10% brine solution (200 mL) and extracted with MTBE (4 x 300 mL) to partially remove triphenylphosphine oxide. The pH of the aqueous layer was adjusted to pH 2 using 3 N HCl and extracted with ethyl acetate (4 x 300 mL). The combined organic layers were washed with water (2 x 150 mL), brine (200 mL), dried over sodium sulfate, and concentrated under vacuum.The residue was purified by flash column chromatography (silica gel, 0% to 50% ethyl acetate / hexane) to obtain 1-10 as a foamy solid (13.1 g, 64% pure yield) and as a pale yellow semi-solid (2.6 g, 13% yield, less pure).1H NMR (299.96 MHz, CDCI3) δ 5.55 (t, J = 7.0 Hz, 0.4H), 5.38 (dt, J = 20.3, 16.8 Hz, 0.6H), 4.84 (d, J = 46.8 Hz, 1H), 4.09-4.00 (m, 2H), 3.89-3.73 (m, 3H), 3.14-3.03 (m, 1H), 2.69 (t, J = 10.6 Hz, 0.6H), 2.49 (dd, J = 13.6, 6.1 Hz, 0.4H), 2.34 (d, J - 13.5 Hz, 0.6H), 2.31-2.21 (m, 0.4H), 2.09 (d, J - 14.7 Hz, 1H), 2.01 (t, J - 11.7 Hz, 1H), 1.90-1.75 (m, 4H), 1.65-1.40 (m, 3H), 1.45 (s, 9H), 1.40-1.26 (m, 5H), 0.91-0.85 (m, 6H) ppm. Batch upscale: To a solution of Wittig's tetrazole salt (VIII, 121.8 g, 277.3 mmol) and crude ketone (I-O4, 88 g, 230.7 mmol) in anhydrous DMF (670 mL) 2.0 M NaHMDS (323.3 mL, 646.6 mmol) in THF at 0°C to -10°C under a nitrogen atmosphere. The internal reaction temperature was maintained at 0°C during the addition. The mixture was stirred at this temperature for 30 min and then allowed to warm to room temperature. After stirring for 2 h at room temperature, the mixture was slowly cooled with a 10% brine solution (500 mL) and extracted with MTBE (2 x 400 mL) to partially remove triphenylphosphine oxide. The pH of the aqueous layer was adjusted to pH 2 using 3 N HCl and extracted with ethyl acetate (4 x 1 L). The combined organic layers were washed with water (2 x 1 L), brine (500 mL), dried over sodium sulfate, and concentrated under vacuum.The residue was purified by instant column chromatography (silica gel, 0% to 50% ethyl acetate / hexane) to obtain 1-10 as a foamy solid (51.6 g, 49% yield). Synthesis of X-fluorinated carbamate esters: Preparation of (3S,4aS,8a / ?)-6-fluoro-6-[2-(1 H-1,2,3,4-tetrazol-5-yl)ethyl]-decah hydroxyisoquinoline-2,3-dicarboxylate of 2-benzyl 3-ethyl (1-11): N. .CX Ph A 500 mL three-neck flask was prepared with a nitrogen inlet, temperature probe, and cooling bath. Water (85 mL) was added to the flask, followed by iron(III) nitrate nonahydrate (Fe(NO3)3·9H2O) (1.46 g, 3.04 mmol), and the mixture was stirred until dissolved (Solution A). Acetonitrile (85 mL) was added to a 500 mL round-bottom flask, followed by I-O8 (667 mg, 1.517 mmol) and Selectfluor® (1.61 g, 4.55 mmol), and the mixture was stirred until dissolved (Solution B). Solution B was added to Solution A while stirring at 22–25°C. A clear yellow solution was observed, and the pH of the solution was measured as pH 2. The reaction was degassed using nitrogen bubbling for 10 min, and the mixture was cooled to -10°C. Sodium borohydride (591.2 mg) in 4 increments as a solid for 5-10 min. The mixture was stirred at -10°C for 2 h, then the mixture was heated to 22-25°C and stirring was continued for 5 h monitoring by HPLC.The mixture was concentrated to remove acetonitrile under vacuum using a rotary evaporator. To this mixture, 1 N HCl (110 mL) was added while stirring and maintaining the temperature below 25°C to adjust to pH 2. The solution was extracted with ethyl acetate (4 x 100 mL). The organic layers were washed with water (2 x 100 mL) and brine (100 mL). The solution was dried over sodium sulfate and concentrated under vacuum using a rotary evaporator to obtain crude product (690 mg, 100%). The resulting residue was purified by flash column chromatography (silica gel, 0% to 6% methanol / dichloromethane) to obtain 1-11 as a white foamy solid (590 mg, 85% yield).1H NMR (299.96 MHz, CDCb) δ 7.357.26 (m, 5H), 5.25-5.09 (m, 2H), 4.93 (dd, J = 24.9, 5.4 Hz, 0.6H), 4.62 (m, 0.4H), 4.21-4.10 (m, 2H), 4.00 (t, J = 11.2 Hz, 0.6H), 3.61 (dd, J = 12.9, 6.6 Hz, 0.4H), 3.43 (dd, J = 13.5, 3.6 Hz, 0.4H), 3.27 (t, J = 14.5 Hz, 0.6H), 3.17-3.05 (m, 2H), 2.39-1.36 (m, 12H), 1.27-1.21 (m, 3H) ppm. Preparation of (3S,4aS,8a / ?)-6-fluoro-6-[2-(1 H-1,2,3,4-tetrazol-5-yl)et yl]-decah and droi soqu inol ina-2,3-di carboxy late of 2-tert-butyl 3-ethyl (1-12): A 3 L three-necked flask with a nitrogen inlet, temperature probe, and cooling bath was prepared. Water (1.0 L) was charged into the flask, followed by iron(III) nitrate nonahydrate (Fe(NO3)3·9H2O, 44.17 g, 109.34 mmol), and the mixture was stirred until dissolved (Solution A). Acetonitrile (1.0 L) was charged into a 2 L round-bottom flask, followed by I-09 (14.3 g, 35.27 mmol) and Selectfluor® (38.73 g, 109 mmol), and the mixture was stirred until dissolved (Solution B). Solution B was charged into Solution A while stirring at 22–25°C. A clear yellow solution was observed and the pH of the solution was measured as pH 2. The reaction was degassed using nitrogen bubbling for 30 min and the mixture was cooled to -10°C. Sodium borohydride (13.34 g, 353 mmol) was charged in ten increments as a solid for 10-15 min.The mixture was stirred at -10°C for 2 h, then heated to 22–25°C and stirred for 5 h while being monitored by HPLC. The mixture was concentrated under vacuum to remove acetonitrile using a rotary evaporator. 1 N HCl (500 mL) was added to this mixture while stirring and maintaining the temperature below 25°C, and the pH was adjusted to 2. The solution was extracted with ethyl acetate (4 x 500 mL). The combined organic layers were washed with water (2 x 500 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under vacuum using a rotary evaporator to obtain crude product (13.5 g, 90%). The resulting residue was purified by flash column chromatography (silica gel, 0% to 70% ethyl acetate / heptane) to obtain 1-12 as a white foamy solid (11.36 g, 76% yield) as a mixture of diastereomers.1H NMR (299.962 MHz, CDCI3) δ 4.86 (dd, J = 51.3, 5.1 Hz, 0.5H), 4.49 (t, J = 5.1 Hz, 0.5H), 4.25-4.14 (m, 2H), 3.90 (t, J = 15.0 Hz, 0.5H), 3.47 (dd, J = 13.3, 7.3 Hz, 0.5H), 3.37 (dd, J = 13.2, 4.8 Hz, 0.5H), 3.22-3.14 (m, 2H), 3.14-3.04 (m, 0.5H), 2.34-1.53 ​​(m, 12H), 1.49-1.46 (m, 9H), 1.27 (t, J =6.8 Hz, 3H) ppm. Preparation of (3S,4aS,8a / ?)-6-fluoro-6-[2-(1H-1,2,3,4-tetrazol-5-il)et il]-decah from the bottom of the inol ina-2,3-di carboxy lato of 2-terc-butilo 3-(2-etilbutilo) (1-13): A 2 L three-necked flask with a nitrogen inlet, temperature probe, and cooling bath was prepared. Water (400 mL) was charged into the flask, followed by iron(III) nitrate nonahydrate (Fe(NO3)3·9H2O, 34.2 g, 84.63 mmol), and the mixture was stirred until dissolved (Solution A). Acetonitrile (400 mL) was charged into a 1 L round-bottom flask, followed by 1-10 (12.6 g, 27.3 mmol) and Selectfluor® (30 g, 84.63 mmol), and the mixture was stirred until dissolved (Solution B). Solution B was charged into Solution A while stirring at 22–25°C. A clear yellow solution was observed, and its pH was measured as pH 2. The reaction was degassed using nitrogen bubbling for 30 min, and the mixture was cooled to -10°C. Sodium borohydride (10.33 g, 273 mmol) was added in ten increments as a solid for 10–15 min. The mixture was stirred at -10°C for 2 h, then heated to 22–25°C, and stirring continued for 5 h, monitored by HPLC.The mixture was concentrated under vacuum to remove acetonitrile using a rotary evaporator. To this mixture, 1 N HCl (300 mL) was added while stirring and maintaining the temperature below 25°C, and the mixture was adjusted to pH 2. The solution was extracted with ethyl acetate (3 x 350 mL). The combined organic layers were washed with water (400 mL) and brine (300 mL), dried over sodium sulfate, and concentrated under vacuum using a rotary evaporator to obtain crude product. The resulting residue was purified by flash column chromatography (silica gel, 0% to 50% ethyl acetate / heptane) to obtain 1-13 as a white foamy solid (8.03 g, 61% yield) as a mixture of diastereomers.1H NMR (299.96 MHz, CDCI3) δ 5.55 (t, J = 7.0 Hz, 0.4H), 5.38 (dt, J = 20.3, 16.8 Hz, 0.6H), 4.84 (d, J = 46.8 Hz, 1H), 4.09-4.00 (m, 2H). 3.89-3.73 (m, 3H), 3.14-3.03 (m, 1H), 2.69 (t, J = 10.6 Hz, 0.6H), 2.49 (dd, J = 13.6, 6.1 Hz, 0.4H), 2.34 (d, J = 13.5 Hz, 0.6H), 2.31-2.21 (m, 0.4H), 2.09 (d, J = 14.7 Hz, 1H), 2.01 (t, J = 11.7 Hz, 1H), 1.90-1.75 (m, 4H), 1.65-1.40 (m, 3H), 1.45 (s, 9H), 1.40-1.26 (m, 5H), 0.91-0.85 (m, 6H) ppm. Ascending batch: A 5 L three-necked flask with a nitrogen inlet, temperature probe, and cooling bath was prepared. Water (1.5 L) was charged into the flask, followed by iron(III) nitrate nonahydrate (Fe(NO3)3·9H2O, 72.3 g, 178.96 mmol), and the mixture was stirred until dissolved (Solution A). Acetonitrile (1.5 L) was charged into a 3 L round-bottom flask, followed by 1-10 (26.6 g, 57.9 mmol) and Selectfluor® (63.4 g, 178.96 mmol), and the mixture was stirred until dissolved (Solution B). Solution B was charged into Solution A while stirring at 22–25°C. A clear yellow solution was observed and the pH of the solution was measured as pH 2. The reaction was degassed using nitrogen bubbling for 30 min and the mixture was cooled to -10°C. Sodium borohydride (21.8 g, 576.2 mmol) was charged in ten increments as a solid for 10-15 min.The mixture was stirred at -10°C for 2 h, then heated to 22–25°C and stirred for 5 h, monitored by HPLC. The mixture was concentrated under vacuum to remove acetonitrile using a rotary evaporator. One N HCl (640 mL) was added to this mixture while stirring and maintaining the temperature below 25°C, and the pH was adjusted to 2. The solution was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated under vacuum using a rotary evaporator to obtain crude product. The resulting residue was purified by instant column chromatography (silica gel, 0% to 50% ethyl acetate / heptane) to obtain 1-13 as a white foamy solid (21.7 g, 61% yield) as a mixture of diastereomers. Preparation of (3S,4aS,8a / ?)-2-[(benzyloxycarbonyl]-6-fluoro-6-[2-(2H-1,2,3,4-tetrazol-5-1)ethyl]decahydroisoquinoline-3-carboxylic acid (1-14): Compound 1-11 (0.59 g, 1.28 mmol) was dissolved in 9:1 ethanol-water (2.0 mL) and 2 N NaOH (5.3 mL) was added. The mixture was stirred at room temperature for 4 h. The reaction was diluted with water (50 mL) and extracted with MTBE (50 mL) to remove organic impurities. The aqueous layer was acidified with 6 N HCl to pH 2. The mixture was extracted with ethyl acetate (3 x 50 mL) and washed with brine (50 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum using a rotary evaporator to obtain crude product 1-14 as a white solid (435 mg, 79% yield). The crude product was used without further purification in a subsequent step. Preparation of (3S,4aS,8a / ?)-2-[(tert-butoxy)carbonyl]-6-fluoro-6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]·decahydroisoquinoline-3-carboxylic acid (1-15): Compound 1-12 (185 mg, 0.435 mmol) was dissolved in 9:1 ethanol-water (1.0 mL) and 2 N NaOH (2.5 mL) was added. The mixture was stirred at room temperature for 4 h. The reaction was diluted with water (50 mL) and extracted with MTBE (50 mL) to remove organic impurities. The aqueous layer was acidified with 6 N HCl to pH ~2. The mixture was extracted with ethyl acetate (3 x 50 mL) and washed with brine (50 mL). The organic layers were combined, dried on sodium sulfate, and concentrated under vacuum using a rotary evaporator to obtain crude product (183 mg), which was purified by silica gel column chromatography (using a 0% to 10% methanol-dichloromethane ISCO gradient system) to obtain 1-15 as an oil (53 mg, 83% yield). This material was used directly in a subsequent step. Preparation of (3S,4aS,8aR)-6-fluoro-6-[2-(1 H-1,2,3,4-tetrazol-5-yl)et yl]-decah and droisoqu inol ina-2,3-di carboxylate 2-benzyl 3-cyclohexyl (1-16): Ph Compound 1-14 (51.5 mg, 0.12 mmol) and cyclohexanol (14.4 mg, 0.144 mmol) were dissolved in dichloromethane (1 mL). Diisopropylcarbodiimide (20 mg, 0.16 mmol) and catalytic 4-dimethylaminopyridine (5 mg, 0.04 mmol) were added to the mixture under a nitrogen atmosphere, and the reaction was stirred at room temperature for 16–18 h. The reaction was monitored by HPLC, and at completion, acetonitrile (1 mL) was added, and the mixture was stirred for 5–10 min. The solid precipitate was removed by filtration through a sintered glass funnel, and the solid was washed with acetonitrile (5 mL). The filtrate was concentrated under vacuum and the receipt was purified by instant silica gel column chromatography (0% to 5% methanol / dichloromethane) to obtain 1-16 as a colorless oil (40.4 mg, 66% yield).1H NMR (299.96 MHz, CDCI3) δ 7.35-7.27 (m, 5H), 5.23-5.07 (m, 2H), 4.95-4.50 (m, 2H), 3.97 (t, J = 12.3 Hz, 0.4H), 3.89-3.73 (m, 0.4H), 3.61 (dd, J = 13.6, 6.7 Hz, 0.4H), 3.40 (dd, J = 12.9, 4.2 Hz, 0.3H), 3.32-3.20 (m,. 0.5Η), 3.16-3.05 (m, 2H), 2.34-1.65 (m, 13H), 1.51-1.25 (m, 8H), 1.16 (d, J = 6.3 Hz, 1H) ppm. Preparation of (3S,4aS,8a / ?)-6-fluoro-6-[2-(1 H-1,2,3,4-tetrazol-5-yl)ethyl]-decahydroisoquinoline-2,3-dicarboxylate from 2-benzyl 3-octyl (1-17): ΜΛ / t / ZUZÓ / UIZ lUZ Compound 1-14 (54.8 mg, 0.127 mmol) and 1-octanol (20 mg, 0.153 mmol) were dissolved in dichloromethane (1.0 mL). Dicyclohexylcarbodiimide (35 mg, 0.168 mmol) and catalytic 4-dimethylaminopyridine (5 mg, 0.037 mmol) were added to the mixture under a nitrogen atmosphere, and the reaction was stirred at room temperature for 16–18 h. The reaction was monitored by HPLC, and at completion, the solid precipitate was removed by filtration through a sintered glass funnel, and the solid was washed with acetonitrile (5 mL). The filtrate was concentrated under vacuum and the receipt was purified by instant silica gel column chromatography (0% to 5% methanol / dichloromethane) to obtain I17 as a colorless oil (40.2 mg, 58% yield).1H NMR (299.96 MHz, CDCh) δ 7.40-7.25 (m, 5H), 5.25-5.10 (m, 2H), 4.94 (d, J = 25.5 Hz, 0.65H), 4.65 (s, 0.35H), 4.10-3.95 (m, 3H), 3.70-3.60 (m, 1H), 3.45-3.20 (m, 1H), 3.19-3.05 (m, 2H), 2.35-1.56 (m, 24H), 0.87 (m, 3H) ppm. Synthesis of fluorinated ester amine prodrugs XI: Preparation of (3S,4aS,6S,8a / ?)-6-fluoro-6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-ethyl decahydroisoquinoline-3-carboxylate (3): Compound 1-12 (4.14 g, 9.73 mmol) was dissolved in 7:1 dioxane-anisole (57 mL, 0.17 M) and treated with 4 N HCl in dioxane (10 eq, 24 mL). After 1 h at room temperature, the reaction was checked by HPLC, which showed that the reaction was incomplete. An additional 4 N HCl (5 eq, 12 mL) was added, and stirring continued at room temperature. After 1 h, HPLC showed that the reaction was incomplete, so another 4 N HCl (5 eq, 12 mL) was added. After 30 min, HPLC again showed an incomplete reaction, so another 4 N HCl (2 eq, 5 mL) was added. The reaction was complete after 4 h. Gaseous nitrogen was bubbled through the reaction to purge the solution of excess HCl, and then the solvent was partially evaporated under vacuum to half volume. Hexanes were added to precipitate the HCl salt, and the supernatant was discarded.The residue was ground with dioxane (2 mL), and hexanes (2 mL) were added to completely precipitate the HCl salt of the desired product. The residue was vacuum dried to obtain crude product 3 (3.48 g, 99.3% yield) as a mixture of fluorinated diastereomers. The residue was purified by SFC chromatography {SFC Analytical Method Column: 4.6 x 100 mm ethylpyridine column from Chromegabond (ES Industries, West Berlin, NJ); Solvent A: CO2, Solvent B: Methanol with 0.1% triethylamine; Gradient method: 5% to 65% B for 4 minutes, hold at 65% B for 1 minute, and return to initial conditions at 4 mL / min; System pressure: 125 bar; Column temperature: 40°C; Sample diluent: Methanol} Retention time (3): 2.07 min; Retention time (C6-F-isomer): 1.06 min. SFC Method Preparative - Column: 3.0 x 25.0 cm 2-Ethylpyridine (Princeton Chromatography Inc., Princeton, NJ); Solvent A: CO2, Solvent B: Methanol with 0.5% triethylamine; Isocratic method: 25% Solvent B at 100 g / min; System pressure: 100 bar; Column temperature: 25°C; Sample diluent: Methanol with 0.5% triethylamine) to obtain 3 as a semisolid (414 mg, isomeric purity of 96.2%). The material was further purified by Gilson reversed-phase chromatography (from 5% to 50% acetonitrile with 0.1% TFA - water with 0.1% TFA and then from 5% to 95% acetonitrile - water) to provide a pure compound for testing. 1H NMR (299.96 MHz, CD3OD) δ 4.31 (q, J = 7.1 Hz, 2H), 4.04 (dd, J = 12.9, 3.9 Hz, 1H), 3.20 (t, J = 13.0 Hz, 1H), 3.09 (dd, J = 12.7, 4.3 Hz, 1H), 3.00 (t, J = 8.1 Hz, 2H), 2.33-2.42 (m, 1H), 2.15-1.90 (m, 7H), 1.84-1.65 (m, 3H), 1.57-1.45 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H) ppm.19F NMR (282.22 MHz, CD3OD) δ -160.70 (m, uncorrected, TFA reference -76.97) ppm. Mass analysis (ES+) = 326.24 [M+H] (Formula: C15H24FN5O2, Exact mass: 325.19). Preparation of (3S,4aS,6S,8aR)-6-fluoro-6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-decahydroisoquinoline-3-carboxylates of 2-ethylbutyl (4): To a solution of 1-13 (2.2 g, 4.57 mmol) in anhydrous THF (15 mL) 4 N HCl in dioxane (11.4 mL, 45.7 mmol) was added at room temperature while stirring. After stirring for 4 h at room temperature, the reaction was shown to be complete by HPLC. Nitrogen gas was bubbled through the reaction mixture to purge the excess HCl, and the solvent was partially evaporated under vacuum to half volume. The mixture was diluted with MTBE-Heptane 1:1 (15 mL), resulting in the separation of an oily layer, which was ground, and the supernatant was discarded. The oily residue was further ground with MTBE-Heptane 1:1 (15 mL) to remove additional lipophilic impurities, and the supernatant was discarded. The oily residue was placed under vacuum to remove residual solvent and to obtain crude product as a white solid and a mixture of fluorinated diastereomers that was further dried under high vacuum at constant weight (1.6 g crude, 84% yield).The residue was purified by SFC chromatography (SFC Analytical Method - Column: 4.6 x 100 mm Chiralpak IC SFC (Chiral Technologies, West Chester, PA); Solvent A: CO2, Solvent B: Ethanol with 0.1% triethylamine; Gradient Method: 5%-65% Solvent B for 4 minutes at 4 mL / min; System Pressure: 125 bar; Column Temperature: 40°C; Sample Diluent: Ethanol; SFC Retention Time (4): 3.40 min); Preparative SFC Method - Column: 2.1 x 25.0 cm Chiralpak IC (Chiral Technologies, West Chester, PA); Solvent A: CO2, Solvent B: Ethanol with 0.25% triethylamine; Isocratic Method: 40% Solvent B at 70 g / min; System pressure: 100 bar; Column temperature: 25°C; Sample diluent: Ethanol with 0.25% triethylamine) to obtain 4 as a thick, colorless oil (96.9% isomeric purity). The material was further purified by Gilson reversed-phase chromatography (15% to 60% acetonitrile with 0.1% TFA - water with a 0.1% TFA and then from 10% to 98% acetonitrile - water) to provide a pure compound for testing. 4.07 (dd, J = 12.6, 4.2 Hz, 1H), 3.19 (t, J = 13.0 Hz, 1H), 4.07 (dd, J = 12.6, 4.2 Hz, 1H), 2.98 (t, J = 7.9 Hz, 2H), 2.13-1.90 (m, 6H), 1.84-1.65 (m, 3H), 1.60-1.30 (m, 7H), 0.93 (t, J = 7.2 Hz, 6H) ppm. -76.95) ppm. Mass analysis (ES+) = 282.23 [M+H] (Formula: Ci9H32FNsO2, Exact mass: 381.25). Ascending Batch: To a solution of 1-13 (21.7 g, 45.06 mmol) in anhydrous THF (15 mL), 4 N HCl in dioxane (112.5 mL, 450.0 mmol) was added at room temperature while stirring. After stirring for 4 h at room temperature, the reaction was shown to be complete by HPLC. Nitrogen gas was bubbled into the reaction mixture to purge the excess HCl, and the solvent was partially evaporated under vacuum to half volume. The mixture was diluted with 1:1 MTBE-Heptane (150 mL), resulting in the separation of an oily layer, which was ground, and the supernatant was discarded. The oily residue was further ground with 1:1 MTBE-Heptane (150 mL) to remove additional lipophilic impurities, and the supernatant was discarded.The oily residue was placed under vacuum to remove residual solvent and to obtain crude product as a white solid and a mixture of fluorinated diastereomers that was further dried under high vacuum at constant weight (14 g crude, 75% yield). The residue was purified by SFC chromatography (SFC Analytical Method - Column: 4.6 x 100 mm Chiralpak IC SFC (Chiral Technologies, West Chester, PA); Solvent A: CO2, Solvent B: Ethanol with 0.1% ammonium hydroxide; Gradient method: 5%-65% Solvent B for 4 minutes at 4 mL / min; System pressure: 125 bar; Column temperature: 40°C; Sample diluent: Ethanol; SFC retention time (4): 2.90 min; SFC Preparative Method 1 - Column: 2.1 x 25.0 cm Chiralpak IC (Chiral Technologies, West Chester, PA); Solvent A: CO2, Solvent B: Ethanol with 0.25% ammonium hydroxide; Isocratic method: 35% Solvent B at 70 g / min; System pressure: 100 bar; Column temperature: 25°C; Sample diluent: Ethanol with 0.25% ammonium hydroxide; SFC Method Preparative 2 Column: 2.0 x 25.0 cm PVA-Sil (YMC, Allentown, PA); Solvent A: CO2, Solvent B: Ethanol with 0.25% ammonium hydroxide; Isocratic method: 50% Solvent B at 80 g / min; System pressure: 100 bar; Column temperature: 25°C. MA / t / ZUZÓ / UIZ / UZ Sample diluent: Ethanol with 0.25% ammonium hydroxide. The desired diastereomer fraction was then further purified by reversed-phase chromatography (Column: 19 x 50 mm XBridge OBD Prep C18 5pm, 5% acetonitrile and 95% water with 0.1% ammonium hydroxide for 2 minutes, followed by 5% to 95% acetonitrile-water with 0.1% ammonium hydroxide for 3 minutes; Flow rate: 25 mL / min; Column temperature: 40°C; Sample diluent: 2:1:1 Ethanol:Acetonitrile:Water). The desired fractions were concentrated by rotary evaporation at 35°C. The dried material was reconstituted in acetonitrile:water 1:1 and the solution was concentrated by rotary evaporation to remove the acetonitrile and then frozen and lyophilized to obtain 4 as a white solid (2.42 g, 90% purity, 97.8% ee). Preparation of (3S,4aS,6 / ?,8aR)-6-fluoro-6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-decahydroisoquinoline-3-carboxylate of 2-ethylbutyl (5): SFC chromatography to provide compound 4 also provided C6-F-isomer 5 (SFC retention time: 3.04 min) as a thick colorless oil (97.9% isomeric purity). The material was further purified by Gilson reversed-phase chromatography (from 15% to 60% acetonitrile with 0.1% TFA - water with 0.1% TFA and then from 10% to 98% acetonitrile - water) to provide a pure compound for testing. 1H NMR (299.96 MHz, CD3OD) δ 4.30-4.25 (m, 2H), 4.18 (dd, J = 10.9, 5.5 Hz, 1H), 3.35-3.27 (m, 2H), 3.09 (t, J = 8.1 Hz, 2H), 2.28-1.94 (m, 7H), 1.86-1.69 (m, 5H), 1.59 (p, J = 6.1 Hz, 1H), 1.46-1.36 (m, 4H), 0.94 (t, J = 7.3 Hz, 6H)ppm. Preparation of (3S,4aS,6S,8aR)-6-fluoro-6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-decahydroisoquinoline-3-carboxylate (6): Compound 1-16 (100 mg, 0.2 mmol) was dissolved in THF (20 mL) and 10% Pd / C (100 mg) was added. This mixture was degassed using three hydrogen purge cycles (vacuum, release, and pressurization with hydrogen to 0.36 MPa (52 psi)). The mixture was stirred under hydrogen overnight and then monitored by HPLC. The mixture was filtered through Celite®, washed with THF (20 mL), and the filtrate was concentrated under vacuum. The residue was dissolved in THF (20 mL) and fresh 10% Pd / C catalyst (100 mg) was added, followed by hydrogen purge cycles as before. The mixture was stirred under hydrogen overnight and monitored by HPLC. The mixture was filtered through Celite®, washed with THF (100 mL), and the filtrate was concentrated under vacuum. The crude product was purified by Gilson reversed-phase chromatography (20% to 60% acetonitrile with 0.1% TFA - water with 0.1% TFA) to obtain 6 as the TFA salt (17).0 mg, 2° pico) and the salt of C6-F-lsómero TFA (21.7 mg, 1° pico). The desired isomer was purified additionally by Gilson reverse phase chromatography medium (from 10% to 98% acetone - water) to provide the pure compound 6 for the 1H NMR tests (299.96 MHz, CD3OD) δ 4.89-4.94 (m, 1H), 4.01 (dd, J 12.9, 3.9 Hz, 1H), 3.17 (t, J = 12.7 Hz, 1H), 3.06 (dd, J = 13.0, 4.6 Hz, 1H), 2.98 (t, J = 7.9 Hz, 2H), 2.33-2.42 (m, 1H), 1.97-2.15 (m, 5H), 1.83-1.96 (m, 3H), 1.64-1.82 (m, 5H), 1.25-1.62 (m, 8H) ppm.19F NMR (282.22 MHz, CD3OD) δ-160.20 (m, without correction, TFA reference -76.97) ppm. Mass analysis (ES+) = 380.19 [M+H] (Formula: C19H30FN5O2, Mass exacta: 379.24). Preparation of (3S,4aS,6S,8aR)-6-fluoro-6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-decahidroisoqu¡nolina-3-octylocarboxylate (7): Compound 1-17 (40 mg, 0.074 mmol) was dissolved in THF (10 mL) and 10% Pd / C (100 mg) was added. This mixture was degassed using three hydrogen purge cycles (vacuum, release, and pressurization with hydrogen to 0.36 MPa (52 psi)). The mixture was stirred under hydrogen overnight and then monitored by HPLC. The mixture was filtered through Celite®, washed with THF (20 mL), and the filtrate was concentrated under vacuum. The residue was dissolved in THF (20 mL) and fresh 10% Pd / C catalyst (100 mg) was added, followed by hydrogen purge cycles as before. The mixture was stirred under hydrogen overnight and monitored by HPLC. The mixture was filtered through Celite®, washed with THF (100 mL), and the filtrate was concentrated under vacuum. The crude product was purified by Gilson (30% to 60% acetonitrile with 0.1% TFA - water with 0.1% TFA) to obtain 7 as the TFA salt (2.9 mg, 2nd peak) and the C6-F-isomer TFA salt (4.5 mg, 1st peak).1H NMR (299.96 MHz, CD3OD) δ 4.26 (dt, J = 6.6,1.8 Hz, 2H), 4.10 (dd, J = 12.7, 4.0 Hz, 1H), 3.23 (d, J = 13.2 Hz, 1H), 3.17-3.09 (m, 3H), 2.43-2.36 (m, 1H), 2.20-1.93 (m, 1H), 1.89-1.52 (m, 1H), 1.45-1.30 (m, 1H), 0.91 (t, J = 6.9 Hz, 3H) ppm. Mass analysis (ES+) = 410.17 [M+H] (Form: C21H36FN5O2, Mass exacta: 409.29).

[137] Using the previous protocols, you can make additional cetona carbamate ethers IV and then react with fluoridated Wittig tetrazol VIII and deprotect them to generate the new fluoridated ester amine perfumes (XI) as shown in Table 1. Table 1: Profármacos de amina de éster fluorado (XI). Compuesto No. Estructura 3 HN-N o N II F Η Η II .NH H 4 HN'N N ' iL f ' N - - hh 0 d Η II d 5 nn K i - h 'nh 7 hn-n ν' hfh ' N / \ - H 0 h 11 ^nh 8 hn-n o N 11 FHHH ' N o H 9 HN-n N |l F 'NF 1- 0 Η II ^^NH 10 HN-n Nx lí 'N^ F 0 IH t1 u 1 ^\^NH H 11 HN-n N || F 'NFFQZ (.ni IT \ ^=° O 4 12 HN-n N 11 FFF 0 1 Η Η 1 13 HN-n N II F 'NFF 0 I Η η 1 \^NH ΜΛ / IZ / ¿O / U1 ¿ / U¿ 14 HN-n N, II F 'N 0 Η Η II H 15 hn-n Ns '1 FHHO i Η II 1 ^NH 16 hn-n NI F 'N - o K' 1 H II 1 \^NH H 17 hn-n Nx |í F ' II N1 H 0 Η i \ \ HN-n N ¿ F ' N 0 1 Η II x^NH 1 19 hn-n Ní F 0 Η H II o \^nh 1 ΜΛ / IZ / ¿O / U1 ¿ / U¿ 20 HN-n Ns lí FO r^^' H Η Η 1 H 21 hn-n N |1 F 'NHHO Η II ^NH 22 HN-n o N |l F Η Η II H 23 HN-n Nx lí 'NF 0 H y ii Ns '\í^nH F-H 2 | π Ο7Ί '\^NH H 25 hn-n N lí F 'n HH 0 r^úi Η K f J ^NH 26 hn-n O Nx II F Η Η II Η I ' no H 27 n — m II N\ Jk nh^^-^7'' - 0 1 HII < ^C) < NH 28 N nf N\ X 0 1 Η I / \ / NH 29 / / N' F o H \ 1 NH | | / ^C) - NH 30 / / N”* N ![ NH í - C lo ' · H 31 / / N Nλ J - NH 32 / / NN 0 n Η h II NH -- / H Synthesis of fluorinated decahydroisoquinoline amino acids XII. Preparation of (3S,4aS,6S,8aR)-6-fluoro-6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-decahydroisoquinoline-3ccarboxylic acid (1): NN To a solution of Compound 3 (1.29 g, 3.97 mmol) in water (2 mL), 2 N NaOH (9 mL, 16.9 mmol) was added at room temperature under a nitrogen atmosphere. The solution was stirred at room temperature for 12 minutes and then cooled with 1 N HCl (18.5 mL) to adjust the pH to between pH 2 and 3. The compound was purified by resin capture and release using Dowex 50WX8 200-400 mesh resin (Sigma-Aldrich, 1.7 eq / mL wet, 14 mL), which was washed with water until the pH was neutral in a coarse-pored sintered glass funnel. Resin (5 mL) was added to the compound solution, and the mixture was stirred for 10 minutes at room temperature. The fresh resin (9 mL) was placed in a column with a coarse frit, and the mixture was gently transferred to the column (including all the resin). The top of the resin column was covered with cotton to prevent disturbance of the layer.The solution was allowed to elute slowly, and then the resin was washed with water (3 x 30 mL) to remove salts, THF:water 1:1 (3 x 30 mL) to remove organic impurities, water (2 x 30 mL), and finally 6% ammonium hydroxide (300 mL) to release the desired compound. The fractions were collected, and the desired compound was detected using ninhydrin staining on reversed-phase TLC plates (10% acetonitrile-water). The desired fractions were combined and concentrated under vacuum to obtain the crude product. The crude product was dissolved in water and lyophilized to obtain 1 as a white solid (1.02 g, 86% yield).1H NMR (299.96 MHz, D2O) δ 3.58 (dd, J = 12.9, 3.9 Hz, 1H), 3.11 (dd, J = 19.2, 12.9 Hz, 1H), 3.08 (s, 1H), 2.97 (dd, J = 8.8, 7.0 Hz, 2H), 2.35-2.28 (m, 1H), 2.14-1.61 (m, 9H), 1.56-1.47 (m, 1H), 1.38 (dtd, J = 42.6, 14.6, 4.6 Hz, 1H) ppm.19F NMR (282.22 MHz, D2O) δ -157.59 (m, uncorrected) ppm. Mass analysis (ES+) = 298.12 [M+H] (Formula: C13H20FN5O2, Exact mass: 297.16). Preparation of (3S,4aS,6R,8a / ?)-6-fluoro-6-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-decahydroisoquinoline-3ccarboxylic acid (2): Using a similar protocol to make compound 1, compound 5 of the C6-F-isomer was hydrolyzed with NaOH and purified by resin capture and release to obtain 2. Ή NMR (299.96 MHz, D2O) δ 3.75 (dd, J = 10.6, 3.4 Hz, 1H), 3.29-3.14 (m, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.22 (dt, J = 7.8, 3.6 Hz, 1H), 2.13 (dt, J = 7.8, 3.2 Hz, 1H), 2.10-1.86 (m, 3H), 1.84-1.61 (m, 5H) ppm.19F NMR (282.22 MHz, D2O) δ -167.27 (uncorrected, TFA reference -75.69) ppm. Mass analysis (ES+) = 298.26 [M+H] (Formula: C13H20FN5O2, Exact mass: 297.16). III. Materials, methods and experimental data of in vitro biology and in vivo pharmacology

[138] This disclosure relates to the chemical composition of matter (molecules) and characterizes the biological and pharmacological activity of the molecules as AMPA receptor antagonists (AMPARs) or prodrugs of such molecules. This disclosure also discloses uses for the treatment of pain, seizures, convulsions, epilepsy, and status epilepticus.

[139] Additionally, the biological activity of compounds as antagonists of AMPA receptors or NMDA receptors (also referred to as ionotropic glutamate-gated ion channels) was carried out using ex vivo functional electrophysiological assays of pyramidal neurons in slices of rat brain prefrontal cortex. The effects of test compounds, see reference compounds, were studied by means of whole-cell patch-fixation electrophysiological recordings of s-AMPA-induced currents or NMDA-induced currents, respectively, using pyramidal neurons of the prefrontal cortex (layer V) of rat brain slices. Cerebral section preparation protocol. Male Sprague Dawley rats were supplied by Charles River Laboratories (Wilmington, Massachusetts EDA) and housed 4 per cage in a temperature (20.5-23.5°C) and humidity (30-80%) controlled environment on a 12-hour light / dark cycle with access to food (Teklad Global Soy Protein, Cat. No. T.2920X10, Envigo, Indianapolis, IN, USA) and water ad libitum. At 4 to 6 weeks of age, the rats were terminally anesthetized using isoflurane [(1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) supplied by Baxter Healthcare Corp, Deerfield, Illinois, USA], and decapitated. The brain was removed, and 300 µm thick coronal sections of prefrontal cortex (PFC) or sagittal sections of hippocampus were sectioned using a Vibratome microtome. After brain removal, and during sectioning, the tissue was immersed in ice-cold aqueous cerebrospinal fluid (aCSF).Once the sections were obtained, they were transferred to a beaker containing aCSF and left at room temperature for a minimum of 1 hour before starting electrophysiological recordings. After this period, individual sections were transferred to a recording chamber continuously perfused with aCSF at a flow rate of 4 to 6 mL / min before beginning the experimental protocols. aCSF composition (in mM): NaCl, 127; KCl, 1.9; KH₂PO₄, 1.2; CaCl₂, 2.4; MgCl₂, 1.3; NaHCO₃, 26; D-glucose, 10; in water equilibrated with 95% oxygen gas and 5% CO₂ gas (reagent suppliers listed below). Experiments investigating NMDA currents used aCSF supplemented with 10 μM glycine (reagent suppliers listed below). All experiments were conducted following protocols with the approval of an Institutional Animal Care and Use Committee (IACUC). MA / t / ZUZÓ / UIZ / UZ Reagents for electrophysiology studies. Fisher Scientific (Fairlawn, New Jersey, USA) supplied NaCl product # S271; KCl product # P330; CaCl2 product # C79; MgQ2 product # M33; D-glucose product # D16; HEPES product # BP310; sucrose product # S5; and NaHCO3 product # S233. Millipore-Sigma (St. Louis, Missouri, USA) supplied Mg-ATP product # A9187; CsCl product # C3032; EGTA-Na product # E4378; GTP product # G8877; glycine product # G7126; KOH product # 417661; and potassium D-gluconate product # G4500. EMD Chemicals (Gibbstown, New Jersey, USA) supplied KH2PO4 product # PX1565. Tocris and BioTechne (Bristol, UK and Minneapolis, Minnesota USA) supplied (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid, s-AMPA, product # 0254; and supplied N-methyl-D-aspartic acid, NMDA, product # 0114. Thermo Scientific (Rockford, Illinois USA) supplied DMSO, product # 20688. Electrophysiological recording of s-AMPA or NMDA induced currents in pyramidal neurons of brain slices from the prefrontal cortex of rats. Whole-cell patch-fixation recordings were performed on pyramidal neurons from the Layer V prefrontal cortex at room temperature using the "visualized" version of the patch-fixation technique. Neurons were visualized using a BX51 upright microscope equipped with a 40X LUMPlanFl water immersion objective (Olympus, Richmond Hill, Ontario, Canada). The microscope was connected to a C2400 CCD camera (Hamamatsu Bridgewater, NJ, USA), and the images were displayed on a VM 5516 B / W monitor (Sanyo, Moriguchi, Osaka Prefecture, Japan). Electrophysiological recordings were obtained using a Multiclamp 700B patch-fixation amplifier (Molecular Devices, Sunnyvale, California, USA), with analog signals digitized on a Digidata 1440a (Molecular Devices, Sunnyvale, California, USA).Patch pipettes were extracted using a Flaming / Brown P-87 micropipette extractor (Sutter, Novato, CA, USA), made of GC150TF-10 thin-walled borosilicate glass (Harvard Apparatus, Saint-Laurent, Quebec, Canada) that had resistances between 3 and 8 MΩ when filled with intracellular solution. The intracellular solutions used for PFC neuron recordings had the following composition (mM): Potassium D-gluconate, 140; KCl, 10; EGTA-Na, 1; HEPES, 10; Mg-ATP, 4; GTP, 0.3; with pH and osmolarity compensated with potassium hydroxide and sucrose, respectively, in all intracellular solutions (reagent suppliers listed above). All test compound experiments were performed in the whole-cell patch-fixation recording setup, and all recordings were made at a holding potential of -60 mV. Recordings were monitored on a Dell personal computer (PC) running Axon pClamp software (Molecular Devices, Sunnyvale, California, USA) and digitized at 10 kHz. Biological activity assay of the AMPA receptor of the Compounds in brain section neurons. The compounds were tested in whole-cell patch-fixation electrophysiology experiments to measure their antagonistic effect on s-AMPA-induced currents. These experiments examined the effects of a single concentration of each test compound on 20 μM s-AMPA evoked currents in pyramidal neurons. MA / t / ZUZÓ / UIZ lUZ from the prefrontal cortex of layer V of rat brain sections. Concentrations of 1 μM and 10 μM of Compound 1 and a concentration of 1 μM of Compound 2 were tested, respectively, in different experiments in the brain sections by bath perfusion from 50 mL syringes arranged in series with the main perfusion line of the aCSF reservoir. 20 μM of s-AMPA were expelled under pressure for 100–1000 ms every 1–2 minutes using a Pneumatic Picopump NPI PDES-02DX (npi Electronic GmbH, Tamm, Germany) connected directly to a microelectrode positioned 200 pm from the recorded neuron. Each protocol was repeated three times. If the peak current was reduced by more than 70% after the first application of a test compound at 10 μM, then a single experiment was carried out at this compound concentration of 10 μM.In that case, the single 10 μM test of the compound was followed by testing the compound at a concentration of 1 μM three times. Biological activity assay of the NMDA receptor of the Compounds in brain section neurons. The compounds were tested in whole-cell patch-fixation electrophysiology experiments to measure their antagonistic effect on NMDA-induced currents. The NMDA-induced current experiments examined the effects of a single concentration of each test compound on 50 μM NMDA evoked currents in pyramidal neurons of the layer V prefrontal cortex of rat brain slices. A 30 μM concentration of Compound 1 was administered to the slice by bath perfusion from 50 mL syringes connected in series with the main perfusion line of the aCSF reservoir. 50 μM of NMDA was expelled under pressure for 100–1000 ms every 1–2 minutes using a Pneumatic Picopump NPI PDES-02DX (npi Electronic GmbH, Tamm, Germany) connected directly to a microelectrode positioned 200 µm from the recorded neuron. Compound 1 was tested at a concentration of 30 μM in three experiments. Formulation of test compounds or reference compounds or s-AMPA inducer or NMDA inducer. The test compounds (Sea Pharmaceuticals LLC, Cambridge, Massachusetts, USA) were prepared as 10 mM or 30 mM stock solutions in 100% DMSO solvent (solvent supplier listed above). The current inducers, s-AMPA or NMDA, were made as 20 μM or 50 μM stock solutions, respectively, in aCSF. The stock solutions of the test compound were diluted in the appropriate external recording solution to the final test concentrations indicated immediately before use. All compounds were stored at 20°C prior to use. Reference compound tests. Tezampanel was tested as a reference compound at concentrations of 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, and 0.1 μM in the electrophysiological assay of s-AMPA. This compound showed concentration-dependent inhibition of peak amplitude responses of rat cerebral cortex PFC pyramidal neurons at 20 μM of s-AMPA (an IC50 concentration was observed where 50% of the signal was inhibited at 481 + / - 84 nM in s-AMPA-induced currents in rat cerebral cortex pyramidal neurons, n = 4 to 5 experiments per concentration). Tezampanel was tested at a concentration of 30 μM in the NMDA electrophysiological assay. Tezampanel at this concentration showed partial inhibition (40% + / - 2%, n = 4 experiments) of peak amplitude responses of rat cerebral cortex PFC pyramidal neurons to NMDA-induced currents of 50 μM NMDA in rat cerebral cortex pyramidal neurons. Data and statistical analysis of electrophysiology experiments.

[140] All data were sampled using the pClamp Clampex acquisition software, with all offline analyses performed using Clampfit (MDS Analytical Technologies). Data compilation and figure construction were carried out using Excel (Microsoft). One-way repeated measures analysis of variance (ANOVA, Prism, Graphpad) with Dunnett's post hoc comparison was used for statistical analysis. Table 2: Summary of in vitro biology data for Compound #1 and Compound #2. Compound No. Electrophysiological assays for antagonist activity. % inhibition + / - SEM of s-AMPA or NMDA-induced currents in neurons (whole-cell patch-fixation recordings in rat cerebral cortex slices) s-AMPA (Tested at 1 μM) s-AMPA (Tested at 10 μM) NMDA (Tested at 30 μM) 1 55.6 ± 5.8 (n = 3) >90 (n = 1) 61.0 ± 6.3 (n = 3) 2 21.4 ±2.1 (n = 3) NT NT NT = Not Tested. SEM = Standard Error of the Mean, n = number of experiments.

[141] In vivo pharmacology of the compounds after rodent treatment, including in vivo rodent epilepsy or seizure models and in vivo rodent pain model.

[142] Formulation and preparation of the compound for administration in animals:

[143] The test compound dosage suspensions or solutions were formulated as specified in either of two formulations: (i) DMSO in aqueous methylcellulose (referred to as DMC) or (ii) pH-adjusted saline solution (referred to as SPHA). For the DMC formulation test, Compounds 3, 4, or 6 were dissolved in DMSO and diluted in 0.5% methylcellulose (containing a final DMSO concentration of up to 3%). 0.5% methylcellulose (0.5% MC, Sigma, Catalog M-0430, St. Louis, Missouri) was prepared in water according to the manufacturer's instructions. The DMC mixtures of the compounds were homogenized by vortex stirring and stirred on a hot plate (~40°C) until either of the test compound mixtures was a homogeneous suspension or completely dissolved. The SPHA formulation was used for some test items that were higher aqueous soluble compounds or salts.For the SPHA formulation, powder of the compound was mixed directly into physiological (normal) saline (0.9% NaCl). Then, 0.1 N or 1 N sodium hydroxide solution at pH 9 to pH 9.5 was carefully added, and the samples were vortexed and heated to approximately 40°C until completely dissolved (up to 15 minutes). Afterward, 0.1 N or 1 N hydrochloric acid solution was carefully added to adjust the pH to pH 7.1 to pH 7.3. Alternatively, normal saline could be substituted with 0.5% methylcellulose solution in water. The vehicle solution was prepared using this same protocol without the compound present. Dosage mixtures were allowed to equilibrate at room temperature before administration. Dosage mixtures were freshly prepared on the day of testing and used within 3 hours.All dosage solutions or dosage suspensions were thoroughly mixed prior to administration.

[144] Compound # 1 was formulated in SPHA. Similarly, other carboxylic acid isomers and their salts can be formulated. Levetiracetam dosage solution (TCI America, Portland, Oregon) was prepared in 0.5% methylcellulose (MC) in water.

[145] Compounds can be formulated in alternative vehicle formulations not limited to those presented above.

[146] Animal handling protocols and compound or vehicle administration in rodent attack models (in mice or rats).

[147] Male Carworth Farms (CF-1) mice (25–35 g) or young male Sprague-Dawley (SD) rats (100–150 g) were obtained from Charles River Laboratories Inc. (Wilmington, Massachusetts, USA). CF-1 mice were generally used for the 6 Hz psychomotor seizure model (6 Hz model described in the next section) but could also be used for the maximal electroshock seizure (MES) model if performed in mice (maximal electroshock seizure model described in the next section). SD rats were generally used for the MES model but could also be used for the 6 Hz psychomotor seizure model if performed in rats. Animals were allowed free access to food and water, except during the testing periods.After the animals were handed over from the supplier's laboratory to the in vivo pharmacology testing laboratory, they were allowed sufficient time to acclimate to the housing conditions before testing. The animals were housed in plastic cages in rooms with controlled humidity, ventilation, and lighting (12 hours of light and 12 hours of darkness). The animals were housed and fed in a manner consistent with the recommendations in the "Guide to the Care and Use of Laboratory Animals" (National Research Council) and in accordance with guidelines established by the Institutional Animal Care and Use Committee (IACUC). Animal experiments were conducted in accordance with the guidelines for Animal Research: Reporting of In Vivo Experiments (ARRIVE) (UK) and were approved by an IACUC.The test compounds or their respective vehicle (placebo) were administered using an optimum fluid volume to body fluid ratio. Solutions or suspensions of test compounds, reference compounds, or vehicles were administered to mice or rats at a volume of 0.01 mL / g body weight (mice) or 0.004 mL / g body weight (rats) by subcutaneous (sc) injection, intraperitoneal (ip) injection, or oral (po) gavage unless otherwise indicated. The reference drug Levetiracetam or vehicle was administered by intraperitoneal (ip) injection.

[148] Literature description and in vivo pharmacological validation of the six hertz (6 Hz) psychomotor seizure model in rodents.

[149] Dr. James E.P. Tornan first described the 6 Hz psychomotor seizure model in 1951. The 6 Hz psychomotor seizure model was extensively characterized and pharmacologically validated in mice using clinically used anti-epileptic drugs (AEDs) by pharmacologist Louis S. Goodman in 1953, who demonstrated that certain clinically used AEDs were ineffective in the 6 Hz mouse model compared to the MES mouse model (described in another section later) and were found to be resistant to treatment with certain AEDs such as phenytoin. The 6 Hz mouse psychomotor seizure model was little used for the next 50 years until it was reviewed by H. Steven White and Harold H. Wolf in 2001, who pharmacologically compared several classes of AEDs. Toman JE 1951. Neurology 1:444-460. Brown WC et al. 1953. J Pharmacol Exp Ther 107:273-283. Barton ME et al. 2001. Epilepsy Res 47:217-227. Metcalf CS et al.2017a. Epilepsia 58:484-493. Metcalf CS. 2017b. Epilepsia 58:1073-1084.

[150] 6 Hz psychomotor attack test of compounds for anti-attack activity.

[151] Mice were given a topical anesthetic on the cornea of ​​each eye before corneal electrode placement. Psychomotor seizures at 6 Hz were induced in mice (generally 8 animals per group) using electrical stimulation via corneal electrodes (6 Hz, 0.2 millisecond rectangular pulse, 3-second duration at 22 mA using a Grass 48 stimulator instrument as described in Barton ME et al 2001. Epilepsy Res 47:217-227). Prior to placement of the corneal electrodes for electrical stimulation, 0.5% tetracaine drops in saline (Sigma) were applied to each eye. Attacks and behaviors arising from electrical stimulation in the 6 Hz model include a minor clonic attack phase followed by stereotypical automatic behaviors including stunning, cloning of the forelimbs, vibrissa spasms, and Straub's tail.For a period of 1 minute after stimulation, the behaviors of these animals were observed by a pharmacologist. If any of the following behaviors were observed, the animal was considered to have had a seizure. Animals that did not exhibit any of these behaviors were considered “protected” from seizures. This serves as a screening tool for the in vivo pharmacological activity of test articles or reference antiepilepsy drugs and defines anti-seizure activity as shown in several publications [Barton ME et al. 2001. Epilepsy Res. 47:217-227; Barton ME et al. 2003 Epilepsy Res. 56:17-26; Brown WC et al. 1953. J Pharmacol Exp Ther 107:273-283. Metcalf CS et al. 2017a. Epilepsia 58:484-493.; Metcalf CS et al. 2017c. Epilepsy 58:239-246.

[152] Unless otherwise noted, pretreatment times for mice or rats were normally 0.5 hours for the respective vehicle, Compounds 1, 3, 4, 6, or other compounds administered subcutaneously or intraperitoneally (unless other times noted). A pretreatment time of 1 hour was used for Compounds 3, 4, 6, or other compounds administered orally unless other times noted. The respective test compounds or vehicles were, in some cases, tested at other pretreatment times, as noted. A median effective dose (ED50) and 95% confidence interval (CI) were calculated using Prism (Graphpad software).

[153] References for rodent 6 Hz psychomotor seizure models. Toman JE 1951. Neurology 1:444-460. “Neuropharmacologic considerations in psychic seizures”. Brown WC, Schiffman DO, Swinyard EA, Goodman LS. 1953. J Pharmacol Exp Ther 107:273-283. “Comparative Assay of an Antiepileptic Drug by Psychomotor Seizure Test and Minimal Electroshock Threshold Test. Barton ME, Klein BD, Wolf HH, White HS. 2001. Epilepsy Res 47:217-227. “Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy”. Metcalf CS, Klein BD, Smith MD, Pruess T, Ceusters M, Lavreysen H, Pype S, Van Osselaer N, Twyman R, White HS. 2017a. Epilepsia 58:484-493. “Efficacy of mGlu2 positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures; Metcalf CS, West PJ, Thomson KE, Edwards SF, Smith MD, White HS, Wilcox KS. 2017b. Epilepsia 58:1073-1084. “Development and pharmacologic characterization of the rat 6 Hz model of partial seizures”. Metcalf CS, Klein BD, McDougle DR, Zhang L, Kaufmann D, Grzegorz Bulaj G, White HS. 2017c. Epilepsia 58:239-246. “Preclinical Evaluation of Intravenous NAX810-2, a Novel GalR2-preferring Analog, for Anticonvulsant Efficacy and Pharmacokinetics.”

[154] Literature description of the maximal electroshock attack model (MES) for testing molecules for anticonvulsant, anti-seizure, and antiepileptic activity in rodents.

[155] Pharmacologist Louis S. Goodman extensively characterized the in vivo pharmacology of the MES model in treatment studies of experimental anticonvulsant, antiseizure, and antiepileptic agents compared with antiepileptic drugs (AEDs) in the 1950s to 1970s. Subsequent work from 1980 to 2010 by H. Steve White and Harold H. Wolf further extended the use of the MES seizure model for the pharmacological characterization of antiepileptic compounds.

[156] The MES model materials, methods, and validation of several clinically used antiepileptic drugs are described in Swinyard EA, et al. 1952. J Pharmacol Exp Ther 106:319-330. Goodman's methods for the MES model used an electrical stimulation instrument and electrodes described in Woodbury LA, Davenport VD. 1952. Arch Int Pharmacodyn Ther 92:97-107. The MES animal model and this type of MES instrument have been widely used for in vivo pharmacological characterization of the efficacy of anticonvulsant agents and antiepileptic drugs (AEDs) during the last few decades by the US National Institutes of Health in the selection of compounds for anticonvulsant activity (the first two references are chapters from two books) White HS, et al. (1995). In Levy RH, Mattson RH, Meldrum BS (Eds) book title: Antiepileptic Drugs. 4th edition, pp. 99-110; White HS, et al. (2002) In Levy R, Mattson R, Meldrum B, Perucca E (Eds) Book title: Antiepileptic Drugs. 5th edition, pp. 36-48; White HS et al. 1995. Italian Journal of Neurological Sciences 16:73-77; White HS, et al. 1998. Advances in Neurol 76:29-39. (Review); White HS, et al. 2008. Epilepsia 49:1213-1220. (Methods: updated description of the MES model); Barton ME, Peters SC, Shannon HE. 2003 Epilepsy Res. 56:17-26 (methods detailed in 6 Hz mouse and mouse MES models);

[157] References for the rodent maximal electroshock attack (MES) model in rats and mice. Swinyard EA, Brown WC, Goodman LS. 1952. J Pharmacol Exp Ther 106:319-330. “Comparative assays of antiepileptic drugs in mice and rats”. Woodbury LA, Davenport VD. 1952. Arch Int Pharmacodyn Ther 92:97-107. “Design and use of a new electroshock seizure apparatus, and analysis offactors altering seizure threshold and pattern (Design and use of a new electroshock seizure apparatus, and analysis of factors that alter seizure threshold and pattern). White HS, Woodhead JH, Franklin MR. Swinyard EA, Wolf HH. (1995) “General principles: experimental selection, quantification, and evaluation of antiepileptic drugs''. In Levy RH, Mattson RH, Meldrum BS (Eds) title of the book: Antiepileptic Druqs. 4aedición. Raven, New York, pp. 99-110; White HS, Woodhead JH, Wilcox KS, Stables JP, Kupferberg HJ, Wolf HH. (2002) “Discovery and preclinical development of antiepileptic drugs. In Levy R, Mattson R, Meldrum B, Perucca E (Eds) book title: Antiepileptic Druqs. 5aedición. Lippincott Williams & Wilkins, Philadelphia, pp. 36-48; White HS, Johnson M, Wolf HH, Kupferberg HJ. 1995. Italian Journal Neurological Sciences 16:73-77. “The early identification of anticonvulsant activity: role of the maximal electroshock and subcutaneous pentylenetetrazol seizure models (Review); White HS, Wolf HH, Woodhead JH, Kupferberg HJ. 1998. Advances in Neurol 76:29-39. “The national institutes of health anticonvulsant drug development program: screening for efficacy. (Review); White HS, Franklin MR, Kupferberg HJ, Schmutz M, Stables JP, Wolf HH. 2008. Epilepsia 49:1213-1220. “The anticonvulsant profile of rufinamide (CGP 33101) in rodent seizure models. Leander JD, Rathbun RC, Zimmerman DM. 1988. Brain Res. 454:368-732 “Anticonvulsant effects of phencyclidine-like drugs: relation to N-methyl-D-aspartic acid antagonism”, (Anticonvulsant effects of phencyclidine-like drugs: relation to N-methyl-D-aspartic acid antagonism). Leander JD. 1989. Epilepsy Res. 4: 28-33 “Evaluation of dextromethorphan and carbetapentane as anticonvulsants and N-methyl-D-aspartic acid antagonists in mice”. Yamaguchi S, Donevan SD, Rogawski MA. 1993. Epilepsy Res. 15:179-184 “Anticonvulsant activity of AMPA / kainate antagonists: comparison of GYKI52466 and NBOX in maximal electroshock and chemoconvulsant seizures MA / t / ZUZÓ / UIZ / UZ models”, (Anticonvulsant activity of AMPA / kainate antagonists: comparison of GYKI52466 and NBOX in peak electroshock and chemoconvulsive attack models). Barton ME, Peters SC, Shannon HE. 2003 Epilepsy Res. 56:17-26 “Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electroshock seizure models”. Metcalf CS, West PJ, Thomson KE, Edwards SF, Smith MD, White HS, Wilcox KS. 2017c. Epilepsia 58:1073-1084. “Development and pharmacologic characterization of the rat 6 Hz model of partial seizures.”

[158] Maximum electroshock attack model (MES) in in vivo pharmacology test of compounds for anti-attack activity in rats.

[159] Male Sprague Dawley rats (body weight 100–150 grams at the time of testing) were supplied by Charles River Laboratories, Wilmington, Massachusetts, USA (8–10 animals per group). The test article (experimental compounds, or vehicle, or positive control reference anticonvulsant compounds) was administered to the rats via intraperitoneal (ip), subcutaneous (sc), intravenous (iv), or oral (po) gavage routes. The corneas of the rats were anesthetized with 0.5% tetracaine in saline at the time of dosing and again prior to corneal stimulation. Unless otherwise stated, the pretreatment time for Compound 1 was 30 minutes (the pretreatment time for vehicles or other test compounds was 60 minutes or as stated) prior to the application of stimulation to the cornea by means of electrodes (60 Hz, 150 mA alternating current electrical stimulation for 0.2 seconds for rats). Note that if mice are used, the stimulus parameters would follow the published procedures of 60 Hz, 50 mA alternating current for 0.2 seconds [Metcalf CS, et al. 2017c. Epilepsia 58:1073-1084; White HS et al. 1995. Italian Journal Neurological Sciences 16:73-77; Barton ME, et al. 2003 Epilepsy Res. 56:17-26 (contains detailed description of MES and 6 Hz models both in mice); Leander JD, Rathbun RC, Zimmerman DM. Brain Res. 1988,454:68-72; Leander JD 1989 Epilepsy Res. 4:28-33; and Yamaguchi S, Donevan SD, Rogawski MA. [1993 Epilepsy Res. 15:179-184] If animals do not show extension of the hind limbs, they are considered protected from the convulsive effect of electroshock.In some cases, the effective dose (ED50 and 95% confidence interval) of the test compound or the reference compound that suppressed the tonic-extensor component of the seizure in 50% of the animals is calculated from dose-response data [Litchfield, JT Jr, Wilcoxon. 1949. J. Pharmacol. Exp. Ther. 96:99-113 “A simplified method of evaluating dose-effect experiments.”] One group of animals always receives the vehicle treatment (negative control) and one group of animals always receives the reference compound treatment (positive control) for each experiment.

[160] AMPA receptor antagonist activity of compounds in vivo.

[161] The in vivo activity of AMPA receptor antagonist compounds can be tested using the maximal electroshock (MES) seizure model in mice or rats or the 6 Hz psychomotor seizure model in mice or rats. In vivo efficacy data for treatment with the AMPA receptor antagonist tezampanel have been shown in a mouse MES model in Ornstein PL et al. 1993. J Med. Chem 36:2046-2048 and in both the mouse MES and 6 Hz psychomotor seizure models in Barton ME et al. 2003. Epilepsy Res 56:17-26. In vivo efficacy data for the treatment of mice with perampanel, an FDA-approved AMPA receptor antagonist antiepileptic drug (AMPARA, AMPA Receptor Antagonist), in both the 6 Hz seizure model and the MES model of maximal electroshock seizure in mice, were presented by Hanada T et al. 2011. Epilepsia 52:1331-1340.In vivo efficacy data for the experimental AMPA receptor antagonist compound (AMPARA) YM928 tested in the mouse model of MES were shown in Yamashita H, et al. 2004. J Pharmacol Exp Ther 308:127-133. In vivo efficacy data comparing the experimental therapeutic compound AMPARA YM928 against its derivatives, referring to a clinically studied treatment of AMPARA (talampanel) mice in the MES model, were shown in Inami H, et al. 2019. Chem Pharm Bull (Tokyo) 67:699-706.

[162] References for treatment with AMPA receptor antagonist compound or drug in models of MES or 6 Hz psychomotor attack. Ornstein PL, Arnold MB, Augenstein NK, Lodge D, Leander JD, Schoepp DD. 1993. J Med. Chem 36:2046-2048. “(3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl)ethyl] decahydroisoquinoline-3-carboxylic acid: a structurally novel, systemically active, competitive AMPA receptor antagonist” (tezampanel); Barton ME, Peters SC, Shannon HE. 2003. Epilepsy Res 56:17-26. “Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electroshock seizure models” (tezampanel); Hanada T, Hashizume Y, Tokuhara N, Takenaka O, Kohmura N, Ogasawara A, Hatakeyama S, Ohgoh M, Ueno M, Nishizawa Y. 2011. Epilepsia 52:1331-1340. “Perampanel: A Novel, Orally Active, Noncompetitive AMPA-receptor Antagonist That Reduces Seizure Activity in Rodent Models of Epilepsy, (Perampanel: a novel, orally active, noncompetitive AMPA receptor antagonist that reduces seizure activity in rodent models of epilepsy) (FDA-approved antiepileptic drug, AMPA receptor antagonist, perampanel in 6 Hz or MES seizure models in mice); Yamashíta H, Ohno K, Amada Y, Hattori H, Ozawa-Funatsu Y, Toya T, Inami H, Shishikura Jl, Sakamoto S, Okada M, Yamaguchi T. 2004. J Pharmacol Exp Ther 308:127-133. “Effects of 2-[N-(4-chlorophenyl)-N-methylamino]-4Hpyrido[3.2-e]-1,3-thiazin-4-one (YM928), an orally active alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, in models of generalized epileptic seizure in mice and rats, (Effects of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), an orally active alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, in models of generalized epileptic seizure in mice and rats) (experimental AMPA receptor antagonist compound (AMPARA), YM928, tested in the MES mouse model); Inami H, Shishikura Jl, Yasunaga T, Hirano M, Kimura T, Yamashíta H, Ohno K, Sakamoto S. 2019. Chem Pharm Bull (Tokyo) 67:699-706. “Synthesis and pharmacological evaluation of 3-[(4-oxo-4H-pyrido[3,2-e][1,3]thiazin-2 ML / t / ZUZÓ / UIZ lUZ yl)(phenyl)amino]propanenitrile derivatives as orally active AMPA receptor antagonist, (Synthesis and pharmacological evaluation of 3-[(4-oxo-4H-pyrido[3,2-e][1,3]tazin-2-yl)(phenyl)amino]propanenitrile derivatives as orally active AMPA receptor antagonists), (in vivo efficacy data comparing the experimental therapeutic compound AMPARA YM928 against its derivatives, see a clinically studied AMPARA (talampanel) in the MES mouse model).

[163] Rotarod test for motor deterioration.

[164] The rotarod test of mice was conducted in conjunction with 6 Hz psychomotor seizure model stimulation to verify whether the administered doses produced substantial motor impairment. The rotarod test was performed immediately before the 6 Hz psychomotor seizure model test. Thus, each treatment group underwent rotarod testing followed immediately by the 6 Hz psychomotor seizure model test. When mice are placed on a 2.54 cm (1 in) grooved bar rotating at 6 rpm, the animals can maintain their balance for extended periods. Motor impairment was assessed by determining whether the mice remained on the rotarod for a 1-minute observation period; that is, three falls during a 1-minute period is considered a rotarod failure.

[165] Behavioral pharmacology observations of rats for signs of motor impairment by a trained observer. Rats were monitored after dosing for any signs of impairment from Compound 1 administered as a 6 mg / kg dose subcutaneously. No neurological or tolerability changes were observed. All rats were alert, upright, and behaved normally during the 30-minute observation period after administration.

[166] Statistical analysis.

[167] Data on protection against attacks and rotarod motor impairment are presented as # (the number of animals protected against attacks) / N (the size of the treatment group consisting of the number of animals tested with the vehicle or compound at a given dose) and # with motor impairment / N of animals tested, respectively. Fisher's exact test was used to compare motor impairment values ​​for specific treatment groups with animals treated with the vehicle. For dose-response analysis, 50% EDso (and 95% Cl) efficacy values ​​were calculated using Prism analysis (Graphpad software) where at least three treatment groups (N = 6 to 10 animals per group) were used in the calculation. Plasma levels are presented as mean ± standard error and were compared using a Student's t-test.

[168] Table 3 shows the results of in vivo attack protection studies of Compound 1 in the maximal electroshock attack model (MES) test in rats after single acute systemic administration. Each of the Compound 1 treatment or the vehicle treatment was tolerated by the rats.

[169] Table 3: Results of Compound 1 treatment in the maximal electroshock attack (MES) model in rats. Test item treatment Dose (mg / kg) Treatment time Route Formulation Test results MES (# protected rats) * (hours) of attacks 1 # rats tested) Compound 1 6 0.5 sc SPHA 6 / 6 DMC Vehicle - 1 po DMC 1 / 8 * Before corneal stimulation.

[170] Table 4 shows the test results of in vivo attack protection studies of Compounds 1, 3, 4, and 6 in the 6 Hz psychomotor attack model test in mice after single acute systemic administration.

[171] Table 4: Results of treatment with Compounds 1, 3, 4, and 6 in the 6 Hz psychomotor attack model in mice. Test Item Treatment Dose (mg / kg) Treatment Time* (hours) Route Formulation Test Results 6 Hz (# mice protected from attacks 1 # mice tested) Compound 1 10 0.5 sc SPHA 8 / 8 Compound 1 6 0.5 sc SPHA 7 / 8 Compound 1 3 0.5 sc SPHA 5 / 8 Compound 1 1 0.5 sc SPHA 3 / 8 Compound 1 0.6 0.5 sc SPHA 3 / 8 Compound 1 0.3 0.5 sc SPHA 1 / 8 Vehicle SPHA - 1 sc SPHA 0 / 8 Compound 3 13 0.5 sc DMC 8 / 8 Compound 4 13 0.5 sc DMC 8 / 8 Compound 3 13 1 po DMC 5 / 8 Compound 4 13 1 po DMC 6 / 7 Compound 6 13 1 po DMC 8 / 8 DMC Vehicle - 1 type DMC 1 / 8 'Treatment of the Compound in doses shown or treatment of the Vehicle 30 minutes subcutaneously or 60 minutes orally, before stimulation of the cornea.

[172] Model of attack of subcutaneous pentylenetetrazole (scPTZ, subcutaneous Pentylenetetrazole) in rodents.

[173] The scPTZ model can be carried out using mice or rats. The materials, methods, and protocol are described in White HS, Johnson M, Wolf HH, Kupferberg HJ. 1995. Italian Journal of Neurological Sciences 16:73-77. “The early identification of anticonvulsant activity: role of the maximal electroshock and subcutaneous pentylenetetrazol seizure models” (review) and see the reviews (2 chapters in 2 books) White HS, Woodhead JH, Franklin MR, Swinyard EA, Wolf HH. (1995) “General principles: experimental selection, quantification, and evaluation of antiepileptic drugs”. In Levy RH, Mattson RH, Meldrum BS (Eds) Book title: Antiepileptic Drugs. 4th edition. Raven, New York, pp. 99-110; and White HS, Woodhead JH, Wilcox KS, Stables JP, Kupferberg HJ, Wolf HH. (2002) “Discovery and preclinical development of antiepileptic drugs.” In Levy R, Mattson R, Meldrum B, Perucca E (Eds) book title: Antiepileptic Druqs. 5th edition.Lippincott Williams & Wilkins, Philadelphia, pp. 36-48.

[174] Lithium-pilocarpine-induced status epilepticus rat model.

[175] Long-Evans or Sprague-Dawley rats can be used following published procedures for inducing status epilepticus in animals (see Metcalf CS, Radwanski PB, Bealer SL. “Status epilepticus produces chronic alterations in cardiac sympathovagal balance”. Epilepsia. 2009, 50 (4), 747-54; Clifford, DB, Olney, JW, Maniotis, A., Collins, RC, Zorumski, CF “The functional anatomy and pathology of lithium-pilocarpine and high-dose pilocarpine seizures”. Neuroscience, 1987, 23, 953-968; Hanada T, Ido K, Kosasa T.“Effect of perampanel, a novel AMPA antagonist, on benzodiazepine-resistant status epilepticus in a lithium-pilocarpine rat model.” Pharmacol. Res. Perspect. 2014, 2 (5), e00063; Wu T, Ido K, Osada Y, Kotani S, Tamaoka A, Hanada T “The neuroprotective effect of perampanel in a lithiumpilocarpine rat seizure model.” Epilepsy Res. 2017, 137, 152-158). The effect of the test compounds against the respective vehicle is compared with the reference compounds perampanel or other reference compounds.

[176] Rodent pain model.

[177] The formalin pain test is based on modifications of the descriptions of the original model (Malmberg AB, Yaksh TL. “Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat.” J. Pharmacol Exp. Ther. 1992, 263(1), 136–46 and Wheeler-Aceto H, Porreca F, Cowan A. “The rat paw formalin test: comparison of noxious agents.” Pain. 1990, 40(2), 229–38). In summary, slight modifications can be made to the above methods: young Sprague Dawley rats are used (as described below), and fresh formalin (Sigma) is prepared in sterile saline solution each day.

[178] Adult male Sprague Dawley rats (60–70 g body weight) can be obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). The animals are allowed free access to food and water, except during testing periods. After delivery, the animals are allowed sufficient time to acclimate to the housing conditions prior to testing (approximately 1 week) and are housed in plastic cages in rooms with controlled humidity, ventilation, and lighting (12 hours on, 12 hours off). The animals are housed and fed in a manner consistent with the recommendations in the “Guide to the Care and Use of Laboratory Animals” (National Research Council) and in accordance with the guidelines established by the Institutional Animal Care and Use Committee (IACUC). Experiments with the animals are conducted in a manner consistent with the ARRIVE guidelines (UK).The protocols are pre-approved by the IACUC before the tests.

[179] Test compounds may be administered using an optimum fluid volume ratio to body fluid. Test compounds may be administered at a volume of 0.04 mL / 10 g body weight in rats. Test compounds may be formulated as described above in the 6 Hz attack model section in any of the formulations described. Morphine sulfate may be purchased from Sigma and prepared using the saline formulation. Morphine is generally administered subcutaneously (sc). Test or vehicle items may be administered subcutaneously unless otherwise noted. Other routes of administration (e.g., i.p., sc, po., im, etc.) and methods of compound administration, including vehicle solution and solvent formulations, may be used.

[180] Formalin Pain Model in Rats. The formalin pain model can be carried out in the following manner. The test compounds are administered to the animals either 0.5 or 1 hour before the injection (50 µL; 30-gauge needle) of a synchronous formalin solution [prepared by mixing formalin (Sigma, St. Louis, Missouri) in sterile saline] subdermally into the plantar region of the right hind paw of rats. The formalin test is a well-established model for evaluating the analgesic effects of different compounds in mice and rats. Formalin elicits a distinct biphasic behavioral profile characterized by licking of the affected paw initially (Phase I: 0–10 min post-formalin administration), then, after a brief reduction in paw-licking behavior, the behavior resumes (Phase II: 20–45 min post-formalin administration).After formalin injection, each animal is observed for alternating 2-minute periods of 5 minutes until 45 minutes have elapsed. The cumulative licking duration is measured for each 2-minute period. Area under the curve (AUC) values ​​for Phase I and Phase II are normalized for vehicle-treated (VEH) rats.

[181] In vivo pharmacological methods were used - patented by Sea Pharmaceuticals, LLC in male Sprague-Dawley rats (Charles River Laboratories) for the 3 different test compound studies:

[182] Study I. Acute dose PK (pharmacokinetics) in vivo in rats.

[183] ​​Study II. SAD (single ascending dose) determination of 1 day maximum tolerated dose and bioanalytical determination of exposure-to-dose ratio in vivo in rats.

[184] Study III. MAD (multiple ascending dose) repeated once daily administration for 5-day maximum tolerated dose determination and bioanalytical determination of exposure-to-dose ratio in vivo in rats.

[185] The male Sprague Dawley rats used in the studies were supplied by Charles River Laboratories (Wilmington, Massachusetts, USA). The animals were housed for a 7-day acclimation period at a veterinary-certified animal care facility in the United States. Upon arrival, the rats weighed between 225 and 250 grams. The rats were 7 to 8 weeks old with an average weight of 260 to 280 grams at the time of the PK study. The rats were housed two per cage in a ventilated cage rack system with a HEPA filter. The rats were kept on a normal 12:12 light cycle (12 hours of darkness, 12 hours of light with lights on at 7:00 AM local time). The rats were provided with standard rodent food and water ad libitum for both studies. The rats were not fasted during the study. The animals were handled before the study and randomly assigned by body weight to the treatment groups.The temperature in the holding room and the procedure room was 21–24°C, and the humidity was 40–42% during the experiments (within the normal range for the care facility). All procedures were completed in accordance with IACUC (Institutional Animal Care and Use Committee) and approved protocols for housing and administering test items.

[186] Administration of test articles (each respective compound formulated in excipients).

[187] Intravenous (IV) administration. For IV dosing, each rat was restrained in a decapicone (plastic bag with one open end for breathing) attached to each side of the tail and secured to the table surface with the tail freely accessible. A needle (23G x 1 in. BD Precision Glide catalog # BD305145, manufacturer BD Biosciences, New Jersey, USA) attached to a 1 mL syringe (catalog # BD 301025, manufacturer BD Biosciences, New Jersey, USA) was inserted into the lateral tail vein. Correct placement was confirmed by pulling back on the syringe until a flash of blood was observed. Once confirmed, the required volume was administered.

[188] Oral (PO) administration. To perform PO dosing, each rat was restrained by the scruff of the neck, and the neck, head, and upper body were immobilized to prevent struggling and injury. Once in a stable upright position, the rat was dosed by inserting the feeding tube (18G Instech FTP-18-38, manufacturer Plymouth Meeting, Pennsylvania, USA) attached to a 1 mL (BD 301025, manufacturer BD Biosciences, New Jersey, USA) or 3 mL (BD309588, manufacturer BD Biosciences, New Jersey, USA) syringe, according to the required dose volume, into the rat's esophagus. Once in the appropriate position, the volume was dispensed into the rat's stomach.

[189] Subcutaneous administration. To perform SC dosing, each rat was restrained at the nape of the neck, and the neck, head, and upper body were immobilized to lift the skin. Once in a stable position, a needle (21G x 0.5 in BD Precision Glide BD 305111, manufactured by BD Biosciences, New Jersey, USA) attached to a 1 mL syringe (BD 301025, manufactured by BD Biosciences, New Jersey, USA) was inserted under the animal's fur between the shoulder blades in the lifted area. The volume was then dispensed under the rat's fur.

[190] Blood was collected by tail bleeding (0.0833, 0.25, 0.5, 1, 2, 4 h for IV) and (0.5, 1, 1.167, 1.5, 2, 4, 6 h for PO), and (0.25, 0.5, 1, 2, 4, 6 h for SC). Terminal blood collection was performed by cardiac puncture at 4 h post-dose (IV) and 6 h post-dose (PO and SC). Terminal blood collection was performed by cardiac puncture at 70 minutes for rats undergoing the Irwin test (for certain PO and SC groups). SC as indicated). Terminal blood was obtained by cardiac puncture at 30 minutes for rats for a certain SC group as indicated.

[191] Irwin Test Procedure

[192] Rats were subjected to the Irwin Test Procedure for in vivo evaluation of the effects of test compounds on neurological functions in rodents, which was modified for rats. Rats were acclimated to the procedure room for at least 30 minutes. Rats were assessed based on the characteristics described below. Each rat was scored on a scale of 0 to 3, 0 representing the response in a normal animal and 3 representing an animal with maximum impairment. Note that it is normal for an animal to score within the range of 0 to 1 during the Irwin test. Animals were examined 55–60 min after administration of the test compound. Reference: Irwin, S. September 20, 1968; “Comprehensive observational assessment: 1a. A symptomatic quantitative procedure for assessing the behavioral and physiologic state of the mouse.”A symptomatic quantitative procedure to assess the behavioral and physiological state of the mouse), Psychopharmacologia 13(3): 222-257.

[193] Irwin Parameters - Score

[194] 1. General appearance - external appearance a. Grooming, coat color, whiskers, etc. Comment. b. Score from 0 to 3. i. 0: Normal - coat is smooth and shiny; eyes wide open; no wounds ii. 1: Coat slightly disheveled, eyes slightly closed ii. 2: Coat moderately disheveled; eye discharge / eye closure / skin lesions iv. 3: Disheveled coat; bloody nails 2. Hyperactivity a. Cage observation b. Score between 0 and 3 with Absent = 0; Present = 3 i. 0: Normal activity; not hyperactive ii. 1: A touch or stimulus elicits a greater than normal response ii. 2: Grooming interrupted; runs around the cage more than normal exploration iv. 3: Running around actively; jumps out of the cage; does not attempt to groom 3. Hypoactivity a. Cage observation b. Score between 0 and 3 with Absent = 0; Present = 3 i. 0: normal activity, not hypoactive ii. 1: delayed in normal movement, more stationary; stopped without grooming ii. 2: little movement to stimulus, more stationary than mobile iv. 3: no movement, no response to stimulus, stationary ML / J / UI ¿ l 4. Sedation a. Cage observation b. Score between 0 and 3 with Absent = 0; Present = 3 i. 0: normal - no sedation iii. 1: unsteady, staggering gait iii. 2: eyes partially closed iv. 3: fully sedated; eyes closed 5. Attacks a. Score between 0 and 3 with Absent = 0; Present = 3 i. 0: no seizures iii. 1: tremors (shuddering) iii. 2: HIC - manipulation-induced seizures iv. 3: full seizure - running-bouncing clonus or tonic hind limb 6. Positioning the suspended body a. Animal suspended by its tail. The animal must struggle and / or extend all four limbs. b. Score between 0 and 3 with Absent = 3; Present = 0 i. 0: presence of struggle and extends all four limbs iii. 1: extension of some limbs with slight struggle iii. 2: initial struggle, then nothing iv. 3: absence of any struggle or limb movement 7. Crossed extensor reflex a. When the foot of one of the hind limbs is pinched, the opposite hind limb extends b. Score 0 or 3 with Absent = 3; Present = 0 8. Front / Rear Limb Placement Response a. Contact with the rear of each leg in turn by a thin bar results in the leg lifting and placing itself on the surface of the object if the animal is suspended in the air and no other leg touches a solid surface b. Score 0 or 3 with Absent = 3; Present = 0 9. Grasp reflex a. The animal will grasp an instrument when its paw is rubbed b. Score 0 or 3 with Absent = 3; Present = 0 i. 0: immediate grasp of the instrument i. 3: does not respond to paw touch 10. Bar clamping a. The bar support is placed on the animal's front legs and allowed to support its own weight. b. Score 0 or 3 with Absent = 3; Present = 0 i. 0: animal supports weight! i. 3: the animal does not hold the bar after being released / does not stay on the bar 11. Righting reflex test a. Place the animal on its back and judge whether it turns over onto its belly (normal position). b. Score between 0 and 3 with Absent = 3; Present = 0 i. 0: rolls over immediately, cannot lie on their back. ii. 1: lying on their back, rolls over quickly. ii. 2: lying on their back, rolls over slowly, or has difficulty righting themselves. iv. 3: does not attempt to right themselves. 12. Tail pinch response a. The animal will respond to the tail pinch by flinching, pinching ~1 cm from the base of the tail. b. Score 0 or 3 with Absent = 3; Present = 0 i. 0: present, normal movement or escape response i. 3: absent, no movement or escape 13. Auditory startle a. A response should be observed after an auditory startle is initiated after using a dog clicker (noise-making device). b. Score 0 or 3 with Absent = 3; Present = 0: presence of startle, ear movement. i. 0: present, normal startle or ear movement i. 3: absent, no startle response

[195] OFA. Open field activity measurement of spontaneous locomotor activity of live rats.

[196] The animals were acclimated to the procedure room for at least 30 minutes prior to the test. The dose was administered to all animals, and at the specified time post-dose (immediately after the Irwin test), they were placed in the open-field chamber for a 15-minute recording period (60 to 75 minutes post-administration of the test article treatments) (compounds formulated in excipients or vehicle) or untreated controls. All open-field experiments were conducted in an open-roof “open-field sand” box made of transparent plexiglass, measuring 43 x 43 x 30 cm (length x width x height, interior chamber dimensions). Open-Field Apparatus, catalog number ENV515; manufacturer Med Associates Inc., city and state: Fairfax, Vermont, ED.Each ENV-515 consists of 16 x 16 infrared photographic beams with a 2 cm spacing between beams to record movement in three dimensions (x, y, z planes). Movement was recorded using the Activity Monitor™ software designed by Med Associates to determine the endpoints of stereotypical movement counts and ambulatory movement counts (Activity Monitor 7 software developed by Med Associates Inc., manufacturer's city and state: Fairfax, Vermont, USA). Distance traveled and vertical activity were recorded (Activity Monitor 7 software developed by Med Associates Inc., manufacturer's city and state: Fairfax, Vermont, USA).Reference: Rodent open field activity and drug or treatment effects test article: Fox KM, Sterling RC, Van Bockstaele EJ (2009), “Cannabinoids and novelty investigation: influence of age and duration of exposure”, Behavioral Brain Research 196:248-253.

[197] Plasma and tissue collection.

[198] Blood was collected in K2EDTA tubes (BD microtainer, BD Biosciences, New Jersey, USA), and plasma was collected by spinning the blood in a refrigerated centrifuge. The plasma was transferred to a clean microcentrifuge tube, frozen on dry ice, and stored at -80°C until bioanalysis. A minimum of 50 microliters of plasma was collected. The whole brain was dissected at the appropriate termination time point, weighed, and rapidly frozen on dry ice. Cerebrospinal fluid (CSF) was collected at the designated termination time point. CSF and brain samples were stored at -80°C.

[199] Blood collection procedures (for plasma)

[200] Procedure for collecting blood from tail bleeding. With the rat in the domestic cage, the tails were carefully trimmed (cut with scissors) to approximately 1 cm from the tip. Using a BD microtainer, the blood was carefully collected into a K2EDTA tube. After removing the tube, gentle pressure should be applied with cotton or gauze to stop the bleeding.

[201] Cardiac puncture - Procedure for collecting cardiac blood. Rats were anesthetized by placing them in a CO2 chamber. The rat was on a euthanasia plane of anesthesia (fully anesthetized). The animal was placed supine and alcohol was rubbed on the sternum. A needle was inserted under the skin just to the left (animal's left) of the sternum. A 10 mL needle (23G 1” BD305145, manufacturer BD Biosciences, New Jersey, USA) was inserted 5 mm from the center of the animal's thorax toward the jaw, 5–10 mm deep, holding the syringe at a 25–30 degree angle from the chest. The plunger was gently pulled back to create slight negative pressure in the syringe. The needle was advanced to the midpoint of the thoracic cavity. Once the needle reached the heart, blood flowed into the syringe to collect the sample. The cardiac needle was held steady, and the plunger was gently withdrawn to collect the blood sample.The rats were sacrificed by placing them back in the CO2 chamber.

[202] Cerebrospinal fluid (CSF) collection procedure.

[203] The animals were placed in a carbon dioxide euthanasia chamber. The rats were removed from the chamber and positioned in sternal recumbency in a procedure area. The skin of the upper neck was cut with scissors, extending the midline to expose the cranial region of the skull. The head was positioned using the thumb and forefinger of one hand so that the head was flexed downward approximately 45°. CSF was collected by direct needle puncture into the cisterna magna, using the occipital bone and the wings of the atlas as landmarks.

[204] The syringe suction was released using a butterfly needle (EXEL INT 21G x 3 / 4”, thin wall, catalog number #277-04, manufacturer EXEL INT, Redondo Beach, California, USA). The needle was carefully held (beveled upward) in the opposite hand, the midline was carefully followed past the occipital crest, and the needle was gently “passed” or “slided” into the cisterna magna (bony portion) until the operator could feel the needle enter the spinal cavity. Once correct placement was established, a small amount of negative pressure was applied to the syringe; CSF then flowed into the center of the needle (note that if there was no CSF ​​flow, the needle was repositioned and the procedure repeated). Negative pressure was applied with one hand until CSF flowed; the procedure was performed slowly to avoid contamination of the sample with blood.A white sheet of paper was used as a background to monitor the color change in the sample just above the needle during collection (note: upon observing the color change, pressure on the syringe was released or the butterfly needle was held just above the color change). To complete the CSF sample collection: the needle was removed from the syringe. The CSF sample was transferred from the syringe to a microcentrifuge tube (note: if blood displaced the centrifuge tube, it was placed in a clinical microcentrifuge and centrifuged at 13,000 RPM for 1 minute). The CSF supernatant layer was collected, avoiding any blood at the bottom of the tube. The CSF was then immediately frozen on dry ice and stored at -80°C until bioanalysis.

[205] Brain collection procedure.

[206] After CSF collection, the skull was dissected by quickly cutting it using scissors. The brain was gently extracted using forceps and immediately frozen in dry ice and then stored at -80C until bioanalysis.

[207] Dose Sample (DS) Collection Procedure

[208] Dose solutions or dose suspensions of Compound 1 or Compound 2 in excipients were collected after daily administration to the animals. Dose samples were immediately frozen at -80°C until bioanalysis.

[209] Quantitative LCMS bioanalysis of Compound 1 or Compound 2.

[210] The measurement of Compound 1 or Compound 2 from rat samples (plasma, cerebrospinal fluid “CSF” or brain homogenate) was done at high resolution using a sensitive LCMS method.

[211] Extracts of biological samples (either organically solvent-precipitated or organically solvent-extracted i. plasma or ii. CSF or iii. homogenates from whole brains of rats treated with Compound 1 or Compound 2) were subjected to LCMS and compared to freshly prepared standard curves on the exact same LCMS instrument. The standard curves were prepared with Compound 1 or Compound 2 at known concentrations dispensed (enriched) into rat plasma (supplied by Bioivt formerly Bioreclamation, Cat. No. RAT00PLK2Y2N, Bioivt, Hicksville, New York, USA) as male Sprague Dawley rat plasma prepared by collecting blood in potassium-EDTA “K2-EDTA” tubes, centrifuging, and storing at -80°C until use).Standard liquid chromatography-mass spectrometry (LCMS) was performed using an AB Sciex Exion instrument, and mass spectrometry (MS) detection was performed using an API 5500 instrument. An AD multiplate autosampler (AB Sciex) was used. The HPLC method employed a Restek Forcé Biphenyl column (2.1 x 30 mm, 1.8 µm particle size) eluted using a gradient at a flow rate of 0.6 mL / min with two mobile phases (Mobile Phase A: Water with 0.1% formic acid and Mobile Phase B: Acetonitrile with 0.1% formic acid). The MS detection and calibration for Compound 1 or Compound 2 also used tolbutamide as an internal standard. The lower limit of quantification for Compound 1 or Compound 2, based on the conditions used, was 1 ng / mL, and the standard curve was linear at 5000 ng / mL. Compound 2 levels were below the in vivo detection limit.Compound 2 levels were stable in vitro when incubated in physiological buffers with or without fatty acid-free bovine serum albumin (Sigma-Aldrich, St. Louis, Missouri) for 30 minutes at 37°C. Compound 2 was hydrolyzed to Compound 1 in in vitro rat plasma studies within minutes when incubated at 37°C. Hydrolysis of Compound 2 by rat plasma was blocked by pretreatment of the rat plasma (37°C for 5 minutes with a 10-micromolar concentration of the serine hydrolase esterase inhibitor, methyl arachidonic acid fluorophosphonate, supplied by Sigma-Aldrich).

[212] PK (pharmacokinetic) studies of Compounds 1 or 2 in vivo in male Sprague Dawley rats.

[213] Acute administration of either test compound 1 or test compound 2 by the described routes (any PO, SC, or IV) was performed in rats, and samples were collected at the described time points for subsequent LCMS extraction, dissolution, and quantitative bioanalysis. See Figure 4, Figure 5, and Figure 6. These figures, A to E, represent different treatment groups of rats (A, B, C, D, E) that were administered different formulations of either Compound 1 or Compound 2, respectively, by different routes (as specified). Rats in treatment group A received SC administration of Cp#1 (formulated in saline with pH raised to pH 9.5 using NaOH; pH adjusted to 7.3 using HCl). Rats in treatment group B were administered Cp#1 (formulated in saline solution with pH raised to pH 9.5 using NaOH; pH adjusted to 7.3 using HCl) via the intravenous (IV) route.Rats in treatment group C were administered Cp#2 HCl (formulated as a solution at a concentration of 10 mg / ml in 0.5% methylcellulose in water and 3% DMSO) orally. Rats in treatment group D were administered Cp#2 HCl (formulated as a solution at a concentration of 10 mg / ml in 0.5% methylcellulose in water and 3% DMSO) subcutaneously (SC). The PO dose of 10 mg / kg and the SC dose of 6 mg / kg were administered from a Cp#2 solution at a concentration of 10 mg / ml.

[214] Study of SAD of Compound 2 in vivo in male Sprague Dawley rats.

[215] Acute 1-day ascending single-dose (SAD) administration of test compound 2 via the oral (PO) route to rats, and samples were collected at the described time points for extraction, dissolution, and subsequent quantitative LCMS bioanalysis. See Figure 7A-7C. In rat treatment groups A to D, doses (A 10 mg / kg, B 20 mg / kg, C 30 mg / kg, D 50 mg / kg) of a Cp#2 solution formulated in 0.5% methylcellulose in water and 3% DMSO with Compound 2 at a concentration of 10 mg / mL were administered. In rat treatment groups E and F, doses (E 100 mg / kg and F 200 mg / kg) of a stable suspension of Cp#2 formulated in 0.5% methylcellulose in water and 3% DMSO at a concentration of 50 mg / mL were administered.

[216] The Irwin test for live errata was performed in the SAD study 55–60 minutes after treatment with test compound 2 on Day 1 (the only day of the study). See Figure 10A–10D. Note: For the endpoint, data are presented in ascending doses from left to right: 10 mg / kg, 20 mg / kg, 30 mg / kg, 50 mg / kg, 100 mg / kg, 200 mg / kg below each endpoint presented on the x-axis. Normal or very small deviation from normal was observed for many of the doses, and no bar is shown for a zero value.

[217] An open field activity (OFA) of live rats was performed 60-75 minutes after treatment with test compound 2 in this 1-day study. See Figure 8A-8B and Figure 9A-9C.

[218] MAD study of Compound 2 in vivo in male Sprague Dawley rats.

[219] Once-daily, 5-day ascending multiple-dose (MAD) administration of the test compounds was performed on rats, and samples were collected at the described time points for extraction, dissolution, and subsequent quantitative LCMS bioanalysis. In rat treatment groups A to D, doses (A 10 mg / kg, B 20 mg / kg, C 30 mg / kg, D 50 mg / kg) of a Cp#2 solution formulated in 0.5% methylcellulose in water and 3% DMSO with Compound 2 at a concentration of 10 mg / mL were administered. In rat treatment group E, a single dose (E 200 mg / kg) of a stable Cp#2 suspension formulated in 0.5% methylcellulose in water and 3% DMSO at a concentration of 50 mg / mL was administered. See Figures 15A-15B, 16, and 17. The Irwin test for live errata was performed in the MAD study 55-60 minutes after treatment with test compound 2 on two different treatment days (day 3 and day 5). See Figures 13A-13D and 14A-14D.Note: For the endpoint, data are presented in ascending doses from left to right: 10 mg / kg, 20 mg / kg, 30 mg / kg, 50 mg / kg, 100 mg / kg, 200 mg / kg, below each endpoint presented on the X-axis. A normal or very small change from normal was observed for many of the doses, and no bar is shown for a value of zero.

[220] An open field activity (OFA) of live rats was performed 60–75 minutes post-treatment with test compound 2 on two different treatment days (day 3 and day 5). See Figure 11 and Figure 12.

Claims

CLAIMS 1. A compound of formula I: I wherein: R is selected from H and (Ci-C2o)hydrocarbyl.

2. A compound according to claim 1 of formula II: II 3. A compound according to claim 2, wherein R is selected from H and (Cr C2o) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less.

4. A compound according to claim 3, wherein R is selected from H and (Ci-C2o)alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less.

5. A compound according to claim 2, wherein R is H or (Ci-Ci3)hydrocarbyl.

6. A compound according to claim 3, wherein R is H or (Ci-Ci3) aliphatic hydrocarbyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less.

7. A compound according to claim 6, wherein R is H or (Ci-Ci3)alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less.

8. A compound according to claim 7, wherein R is H or (Ci-Cio)alkyl optionally substituted with one or two phenyl groups, provided that R contains twenty carbons or less.

9. A compound according to claim 2, wherein R is H or CnHm, and wherein: n is 1 and m is 3; n is 2 and m is 5; n is 3 and m is 3, 5, or 7; n is 4 and m is 5, 7, or 9; n is 5 and m is 7, 9, or 11; n is 6 and m is 5, 7, 9, 11, or 13; n is 7 and m is 7, 9, 11, 13, or 15; n is 8 and m is 5, 7, 9, 11, 13, 15, or 17; n is 9 and m is 7, 9, 11, 13, 15, 17, or 19; n is 10 and m is 7, 9, 11, 13, 15, 17, 19, or 21; nes 11 and month9,11,13,15,17,19, 21, or 23; nes 12 and month 7, 9,11,13,15,17,19,21,23,0 25; nes 13ymes9,11,13,15,17,19, 21,23, 25, or 27; nes 14ymes9,11,13,15,17,19,21,23,25, 27, or 29; nes 15 and month 11,13,15,17,19,21,23,25, 27,29, or 31; nes 16 and month 9,11,13,15,17,19, 21,23,25, 27, 29, 31, or 33; nes 17 and month 11,15,17,19,21,23, 25,27, 29,31,33, or 35; nes 18 and month 11,13,15,17,19,21,23,25, 27,29,31,33, 35, or 37; n is 19 and m is 13,15,17,19,21, 23, 25,27, 29, 31,33, 35, 37, or 39; o nes 20 and month 11,13,15,17,19,21,23,25, 27,29,31,33, 35, 37, 39,o41.

10. A compound according to claim 3, wherein R is selected from: H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, 1-methylpropyl, 1-methyl-2-ethylbutyl, 2-ethylbutyl, 2-methylpropyl, tert-butyl, 2-methylcyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopropylmethyl (i.e.), n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, cyclobutylmethyl (i.e.), 2-(cyclopropyl)ethyl (i.e., cyclopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 3-(cyclopropyl)propyl (i.e., ), 2-(cyclobutyl)ethyl (i.e., ), cyclopentylmethyl (i.e., ), cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, dicyclohexylmethyl, n-octyl, benzyl, MA / t / ZUZÓ / UIZ lUZ diphenylmethyl, decyl, dodecyl,tetradecyl, hexadecyl, hexadec-9-enyl, octadecyl, octadec-9-enyl, octadec-9,12-dienyl, 2-propylpentyl, 2-butylhexyl, 2-pentylheptyl, 2-hexyloctyl., 11. A compound according to claim 10, wherein R is selected from: H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tere-butyl, 2-methylbutyl, and 2-ethylbutyl.

12. A compound according to claim 11, wherein R is selected from: H, ethyl, isopropyl, cyclohexyl, and 2-ethylbutyl.

13. A compound according to claim 12, wherein R is H.

14. A compound according to claim 12, wherein R is ethyl.

15. A compound according to claim 12, wherein R is isopropyl.

16. A compound according to claim 12, wherein R is cyclohexyl.

17. A compound according to claim 12, wherein R is 2-ethylbutyl.

18. A compound according to claim 2 having the structure: H 19. A compound according to claim 2 selected from:

20. A compound according to claim 19 selected from:

21. A compound according to claim 20 selected from:

22. A compound according to claim 21 selected from 23. A compound according to claim 21 selected from H 35 24. A compound according to claim 21 selected from 25. A compound according to claim 21 selected from 26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.

27. A method for treating epilepsy, comprising administering to a subject a therapeutically or prophylactically effective amount of the compound according to claims 1 to 25.

28. The method according to claim 27, wherein status epilepticus, partial onset seizures, or primary generalized tonic-clonic seizures are treated.

29. The method according to claim 27, wherein partial start attacks are addressed.

30. The method according to claim 27, wherein primary generalized tonic-clonic attacks are treated.

31. The method according to claim 27, wherein the epileptic status is treated.

32. The method according to claim 27, wherein it deals with a seizure disorder that includes a hereditary genetic seizure disorder.

33. The method according to claim 27, wherein it deals with a seizure disorder that may result from a brain tumor.

34. The method according to claim 27, wherein it deals with a seizure disorder that may result from a traumatic brain injury (whether concussive or penetrating).

35. A method for treating pain, comprising administering to a subject a therapeutically or prophylactically effective amount of the compound according to claims 1 to 25.