Improved synthetic process for preparing (2H-1, 2, 3-triazol-2-yl) phenyl compounds as orexin receptor modulators

Abstract

The present invention relates to an improved synthetic process for the preparation of (2H-1, 2, 3-triazol-2-yl) phenyl compounds as orexin receptor modulators. The present invention describes a process for the preparation of (((3aR, 6aS)-5-(4, 6-dimethylpyrimidin-2-yl) hexahydropyrrolo [3, 4-c] pyrrol-2 (1H)-yl) (2-fluoro-6-(2H-1, 2, 3-triazol-2-yl) phenyl) ketone # imgabs0 #, which can be used in commercial manufacturing. The compounds are orexin receptor modulators and are useful in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by orexin activity, such as insomnia and depression.

Description

[0001] This application is a divisional application of an invention patent application with an application date of August 6, 2020, application number 202080070355.1, and invention name “Improved synthetic method for preparing (2H-1,2,3-triazol-2-yl)phenyl compounds as orexin receptor modulators”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 883,857, filed on August 7, 2019, and U.S. Provisional Patent Application No. 62 / 971,265, filed on February 7, 2020, which are incorporated herein by reference in their entirety. Technical Field

[0004] The present invention relates to a synthetic method for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Seltorexant), which is useful for modulating orexin receptors and for treating disease states, disorders and conditions mediated by orexin receptor activity. Background Art

[0005] Orexin (or hypocretin) signaling is mediated by two receptors and two peptide agonists. Two orexin peptides (orexin A and orexin B), hereinafter referred to as orexins, bind to two high-affinity receptors called orexin-1 and orexin-2 receptors. The orexin-1 receptor selectively prefers to bind orexin A, while the orexin-2 receptor binds to the two orexins with similar affinity. Orexin is a cleavage product of the same gene, pre-orexin pro. In the central nervous system neurons expressing pre-orexin pro, the precursors that produce orexin are present in the nucleus perifencialis, the dorsal hypothalamus, and the lateral hypothalamus (C. Peyron et al., Journal of Neuroscience (J. Neurosci.), 1998, Vol. 18, No. 23, pp. 9996-10015). Orexin cells in these nuclei project to many areas of the brain, extending rostrally to the olfactory bulb and caudally to the spinal cord (van den Pol, AN et al., J. Neurosci., 1999, Vol. 19, No. 8, pp. 3171-3182).

[0006] Citation of references herein should not be construed as an admission that such references are prior art to the present invention.All publications mentioned herein are incorporated by reference in their entirety.

[0007] Substituted diazabicyclic compounds have been reported as central nervous system active agents (International Publication No. WO2001081347, November 1, 2001; US2002 / 0019388, February 14, 2002) for treating cognitive impairment (WO2008067121, June 5, 2008) and for improving cognition (WO 2006 124897, November 23, 2006 and US20060258672, November 16, 2006), α7 acetylcholine receptor modulators (US2005 / 101602, May 12, 2005; US2005 / 0065178, March 24, 2005 and Frost et al., Journal of Medicinal Chemistry). 49, No. 26, pp. 7843-7853), a proline transporter inhibitor, and was reported as an androgen receptor ligand for the treatment of androgen receptor-related disorders including cancer (WO2009081197, July 2, 2009), and was reported as a histone deacetylase inhibitor for the treatment of cancer, neurodegenerative diseases and autoimmune diseases (WO20060123121, November 23, 2006).

[0008] Among the developed compounds, (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone was found to act as an inhibitor of orexin-2 receptor and can be used to treat sleep disorders and major depressive illness (US 8,653,263 B2). As shown in Scheme 1 below, the compound is built from two key building blocks:

[0009]

[0010] The initial synthesis employed a direct phenyl-triazole coupling. As shown in Scheme 2 below, a mixture of products was generated from non-selective coupling to different nitrogen atoms on the triazole.

[0011]

[0012] The unique synthesis of 2-aryltriazoles can be accomplished by Cu(II)-mediated dihydrazone cyclization, as shown in Scheme 3. However, this method suffers from poor atom economy, as the diaddition of phenylhydrazine to glyoxal results in 50% conversion of the aryl-forming starting materials to aniline byproducts (see, e.g., J. Org. Chem. 1948, 13, 815; for recent improvements on dihydrazone methods, see Russian Journal of Organic Chemistry 2009, 45, 1683; and Chemistry of Heterocyclic Compounds 2010, 46, 79).

[0013]

[0014] Other attempts to prepare 2-substituted triazoles have been reported (Tomé, AC Science of Synthesis 2004, Section 13.13.2, pp. 528-540; Topics Heterocycl. Chem. 2015, 40, 51; Org. Let. 2009, 11, 5026; OPRD 2019, 23, 234; Angew. Chem. Int. Ed. 2011, 50, 8944; and Heterocycles 1980, 14, 1279.) But in all cases, when the 4- and 5-positions of the triazole ring are not substituted, the method of cyclization to 2-aryl triazole derivatives via intermediates has low yields.

[0015] The object of the present invention is to provide a process for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone which utilizes exclusive N2-aryltriazole production to reduce waste, to eliminate the need to separate undesirable coupling products, and to reduce manufacturing costs. Summary of the invention

[0016] The present invention includes a method for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

[0017]

[0018] The method comprises the following steps:

[0019] Cyclization of the hydrazone of formula I to give the 2-phenyl-2H-1,2,3-triazole of formula II in a single step

[0020]

[0021] in

[0022] R 1 -H, -CO 2 H or -CO 2 C (1-4) alkyl;

[0023] X is -OH, -OC (1-4) Alkyl, -OCH 2 Ph, -OPh, -OC(O)CH 3 、-OSO 2 CH 3 、-N(CH 3 ) 2 , piperidin-1-yl, -NHC(O)CH 3 、-NHSO 2 PhC 3 or -N(CH 3 ) 3 I. DETAILED DESCRIPTION

[0024] The present invention includes a method for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

[0025]

[0026] The method comprises the following steps:

[0027] Cyclization of the hydrazine of formula I to give the 2-phenyl-2H-1,2,3-triazole of formula II in a single step

[0028]

[0029] in

[0030] R 1 -H, -CO 2 H or -CO 2 C (1-4) alkyl;

[0031] X is -OH, -OC (1-4) Alkyl, -OCH 2 Ph, -OPh, -OC(O)CH 3、-OSO 2 CH 3 、-N(CH 3 ) 2 , piperidin-1-yl, -NHC(O)CH 3 、-NHSO 2 PhC 3 or -N(CH 3 ) 3 I.

[0032] In another embodiment of the present invention:

[0033] The present invention includes a method for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

[0034]

[0035] The method comprises the following steps:

[0036] Cyclization of the hydrazine of formula I to give the 2-phenyl-2H-1,2,3-triazole of formula II in a single step

[0037]

[0038] in

[0039] R 1 -H or -CO 2 CH 3 ;

[0040] X is -OC (1-2) Alkyl, -OC(CH 3 ) 3 、-OCH 2 Ph, -N(CH 3 ) 2 or -N(CH 3 ) 3 I.

[0041] In another embodiment of the present invention:

[0042] The present invention includes a method for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

[0043]

[0044] The method comprises the following steps:

[0045] a) Cyclization of the hydrazine of formula I to give the 2-phenyl-2H-1,2,3-triazole of formula II in a single step

[0046]

[0047] in

[0048] R 1 is -H;

[0049] X is -OC (1-2) Alkyl, -OC(CH 3 ) 3 、-OCH 2 Ph, -N(CH 3 ) 2 or -N(CH 3 ) 3 I.

[0050] b) carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid,

[0051]

[0052] The carboxylation is characterized by using isopropyl-MgCl and CO 2 .

[0053] In another embodiment of the present invention:

[0054] The present invention includes a method for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

[0055]

[0056] The method comprises the following steps:

[0057] a) cyclization of the hydrazine of formula I to give in a single step the 2-phenyl-2H-1,2,3-triazine of formula II

[0058] Azoles

[0059]

[0060] in

[0061] R 1 is -H;

[0062] X is -OC (1-2) Alkyl, -OC(CH 3 ) 3 、-OCH 2 Ph, -N(CH 3 ) 2 or -N(CH 3 ) 3 I;

[0063] b) carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid,

[0064]

[0065] The carboxylation is characterized by using isopropyl-MgCl and CO 2 ;

[0066] c) Reaction of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid with (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0067]

[0068] The reaction is characterized in that SOCl 2 .

[0069] In another embodiment of the present invention:

[0070] The present invention includes a method for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

[0071]

[0072] The method comprises the following steps:

[0073] a) Cyclization of the hydrazine of formula I to give the 2-phenyl-2H-1,2,3-triazole of formula II in a single step

[0074]

[0075] in

[0076] R 1 is -H;

[0077] X is -OC (1-2) Alkyl, -OC(CH 3 ) 3 、-OCH 2 Ph, -N(CH 3 ) 2 or -N(CH 3 ) 3 I;

[0078] b) carboxylation of 2-(3-fluorophenyl)-2H-1,2,3-triazole to give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid,

[0079]

[0080] The carboxylation is characterized by using LiCl, isopropyl-MgCl and CO 2 ;

[0081] c) Reaction of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid with (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole to form (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0082]

[0083] The reaction is characterized in that SOCl 2 .

[0084] The present invention also includes a method for preparing a compound of formula I

[0085]

[0086] The method comprises:

[0087]

[0088] (3-Fluorophenyl)hydrazine hydrochloride reacts with glyoxal in the presence of water and / or methanol to form (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde in a yield of over 90%;

[0089] in

[0090] R 1 For H, CO 2H or -CO 2 C (1-4) alkyl;

[0091] and

[0092] X is -OH, -OC (1-4) Alkyl, -OCH 2 Ph, -OPh, -OAc, -N(CH 3 ) 2 , piperidinyl, -NHC(O)CH 3 、-NHSO 2 PhC 3 or -N(CH 3 ) 3 I.

[0093] Another embodiment of the present invention is a compound of formula I:

[0094]

[0095] in

[0096] R 1 For H, CO 2 H or -CO 2 C (1-4) alkyl.

[0097] Another embodiment of the present invention is a compound selected from the group consisting of:

[0098]

[0099] as well as

[0100]

[0101] Another embodiment of the present invention is a compound selected from the group consisting of:

[0102]

[0103]

[0104] as well as

[0105]

[0106] Another embodiment of the present invention is a compound selected from the group consisting of:

[0107] as well as

[0108]

[0109] The invention may be more fully understood by reference to the following description, including the following glossary and concluding examples.For the sake of brevity, the disclosures of the publications (including patents) cited in this specification are incorporated herein by reference.

[0110] As used herein, the terms "including," "containing," and "comprising" are used herein in their open, non-limiting sense.

[0111] definition

[0112] The term "(((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone" means

[0113]

[0114] The product of the chemical reaction described in this specification may directly react with another reagent, or may be separated before subsequent reactions. The term "separated" means that the reaction product is partially or completely separated from other materials in the reaction vessel. These other materials include, but are not limited to, solvents, unreacted raw materials, reagents used in the reaction, by-products, impurities, and reagent products used in the reaction.

[0115] The term "prepared" means synthesized by chemical methods.

[0116] Additionally, any formula given herein is intended to also refer to hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if such forms are not explicitly listed.

[0117] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 O. 17 O. Such isotope-labeled compounds can be used for metabolic studies (preferably with 14 C) reaction kinetics studies (e.g. 2 H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)], including tissue distribution assays of drugs or substrates, or may be used for radiation therapy of patients. In addition, heavier isotopes such as deuterium (i.e. 2 H) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements. Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents to carry out the procedures disclosed in the schemes described below or in the examples and preparations.

[0118] Those skilled in the art will recognize that the compounds of the present invention may exist as stereoisomers where at least one double bond is present in the compound. The present invention contemplates both (E) and (Z) stereoisomers and all mixtures thereof.

[0119] Those skilled in the art will recognize that the compounds and reagents used in the reactions of the present invention may exist as salts. The present invention contemplates the use of all salts of any compound used in the reactions exemplified herein.

[0120] Examples of salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioate, hexyne-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetate, phenylpropionate, phenylbutyrate, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0121] When the compounds or reagents used in the reactions of the present invention contain a basic nitrogen, the salts can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, or the like; or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranose, or the like. Glycosuric acids (such as glucuronic acid or galacturonic acid), α-hydroxy acids (such as mandelic acid, citric acid or tartaric acid), amino acids (such as aspartic acid, glutaric acid or glutamic acid), aromatic acids (such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid), sulfonic acids (such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), any compatible mixtures of acids such as those given as examples herein, and any other acids and mixtures thereof deemed to be equivalent or acceptable substitutes according to the ordinary skill level in the art.

[0122] Those skilled in the art will recognize that a variety of reagents can be used for the saponification of esters. And those reagents are both varied and known to the skilled practitioner. The present invention contemplates the use of all common methods for converting esters to carboxylic acids, including those described in "Protective Groups in Organic Synthesis" edited by TW Green and PGM Wuts, Wiley-Interscience, New York, 1999, pp. 579-580, 744-747.

[0123] Exemplary reactions that can be used in the methods of the present invention will now be described with reference to exemplary synthesis schemes for their general preparation and subsequent specific examples below. Those skilled in the art will recognize that the reaction can be carried out in any suitable solvent. Those skilled in the art will also recognize that, unless explicitly limited, the reaction can be carried out over a wide temperature range. Unless otherwise specified, the reaction can be carried out between the melting point and reflux temperature of the solvent, and preferably between 0° C. and the reflux temperature of the solvent. Conventional heating or microwave heating can be used to heat the reaction. The reaction can also be carried out in a closed pressure vessel at a normal reflux temperature higher than the solvent.

[0124] abbreviation

[0125] Herein and throughout the specification, the following abbreviations may be used:

[0126]

[0127]

[0128] Example

[0129] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0130] Unless otherwise indicated, the reaction mixture was stirred at room temperature (rt) under a nitrogen atmosphere. Where mixtures, solutions and extracts were "concentrated", they were typically concentrated under reduced pressure. Reactions under microwave irradiation conditions were carried out in a Biotage Initiator or CEM Discover instrument.

[0131] Normal phase fast column chromatography (FCC) uses pre-packed extraction cartridges on silica gel (SiO 2 ) and eluted with the specified solvent.

[0132] Unless otherwise indicated, mass spectra (MS) were obtained using electrospray ionization (ESI) in positive mode on a Bruker QTOF, Waters QTOF Ultima instrument, or electron impact (EI) on a Waters GC-TOF. Calculated masses (calcd.) correspond to the exact masses.

[0133] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker spectrometer. 1 The format of H NMR data is: chemical shift (ppm) downfield from tetramethylsilane reference (multiplicity, coupling constant J (Hz), integration).

[0134] Chemical names were generated using ChemDraw Ultra 6.0.2 (CambridgeSoft Corp., Cambridge, MA) or ACD / Name version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).

[0135] Conventional solution

[0136]

[0137] Phenylhydrazine III or corresponding salt can react with glyoxal and water or water-methanol to form hydrazonoacetaldehyde IV in the presence of sodium acetate. The present invention uses phenylhydrazine to be slightly soluble in water-glyoxal mixture therein, to complete required single condensation with relatively small amount of excessive glyoxal. Required single condensation product can be obtained with high yield by suitable solvent (such as mixture of water or methanol and water), which minimizes the concentration of the hydrazine starting material in the solution, and also allows the product of the single condensation product to be precipitated from solution when formed.

[0138] With H 2 Condensation of NX affords hydrazone I. The product is formed as a mixture of E / Z stereoisomers that interconvert upon heating; there is no need to separate the stereoisomers from each other. Cyclization of the hydrazone mixture affords 2-phenyl-2H-1,2,3-triazole II in a single step of I.

[0139] The synthesis of 2-phenyl-2H-1,2,3-triazole II is as follows: 1 For -CO 2 C (1-4) Alkyl groups are formed by saponification, or when R 1 When H is present, it is completed by carboxylation to give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. Adding LiCl to the reaction mixture reduces the undesired -CO 2 Double addition.

[0140] The product, 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid, is activated using thionyl chloride or any suitable activating agent and reacted with (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole to form ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

[0141] Example 1: Synthesis of hydrazide acetaldehyde of formula IV

[0142] Example 1a: Synthesis of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde .

[0143]

[0144] The aqueous solution (613g, 4.22mol) of 40w / w% glyoxal was added to a suspension of 177g (1.06mol) (3-fluorophenyl) hydrazine (hydrochloride) in 1.24L water, and then a solution of 129.9g (1.58mol) sodium acetate in 708mL water was added over 2 hours. After stirring at room temperature for several hours, the suspension was filtered, and the filter cake was washed with 0.89L water and dried in vacuo to provide 172.8g (95% yield) of the title compound as a yellow solid.

[0145] mp 118℃-119℃.

[0146] 1 H NMR (DMSO-d 6 )δ: 11.80 (br s, 1H), 9.49 (d, J = 7.7Hz, 1H), 7.36 (d, J = 7.9Hz, 1H), 7.32-7.39 (m, 1H), 6.96-7.03 (m, 2H), 6.75-6.83 (m, 1H). 13 C NMR (DMSO-d 6 )δ:190.4,163.0(br d,J=242.7Hz),144.7(br d,J=10.8Hz), 136.3, 131.2(d,J=10.0Hz), 110.0(d,J=2.3Hz), 108.5(d,J=21.6Hz), 100.6(d,J=27.0Hz). 19 F NMR (DMSO-d 6 )δ:-111.72.

[0147] HRMS (EI-TOF) m / z: C 8 H 8 FN 2 O's [M+H] + The calculated value is 167.0621; the measured value is 167.0611.

[0148] Example 1b: Synthesis of methyl (E)-2-fluoro-6-(2-(2-oxoethylidene)hydrazino)benzoate

[0149]

[0150] At 10 ℃ in 10 minutes, the solution of 2-fluoro-6-hydrazinobenzoic acid methyl ester (17.65g, 0.08mol) in methanol-water (90ml+180ml) was added to a mixture of 40w% glyoxal aqueous solution (58.04g, 0.8mol), water (100ml) and sodium acetate (9.85g, 0.12mol). The mixture was then stirred for about 1.5 hours and then filtered. The filter cake was washed with water (2×50mL) and vacuum dried. The dried solid (16.12g) was redissolved in ethyl acetate (50ml) at 50 ℃, then crystallized by slowly adding heptane (200ml) and cooling to 5 ℃. The obtained solid was filtered, rinsed with heptane (2×15ml) and vacuum dried. The desired product (13.33g, 74% yield) was obtained as a yellow solid. mp 110.8 ℃.

[0151] 1 H NMR (DMSO-d 6 )δ:11.74(s,1H),9.41(d,1H),7.49(m,2H),7.19(d,1H),6.92(m,1H),3.84(s,3H).

[0152] MS (ESI-TOF) m / z: 225.1 ([M+H] + ).

[0153] Example 1c: Synthesis of (E)-2-fluoro-6-(2-(2-oxoethylidene)hydrazino)benzoic acid

[0154]

[0155] 2-Fluoro-6-hydrazinobenzoic acid was reacted with excess aqueous glyoxal to provide the desired compound 2-fluoro-6-(2-(2-oxoethylidene)hydrazino)benzoic acid as a yellow solid in 64% yield. This compound was used as such in the next step.

[0156] Example 2: Synthesis of hydrazine of formula I

[0157] Example 2a: Synthesis of (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime.

[0158]

[0159] A solution of 59.7 g (715 mmol) of methoxyamine hydrochloride and 58.6 g (715 mmol) of sodium acetate in 210 mL of water was added to a solution of 70 g (408 mmol) of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde in 350 mL of methanol over 1.5 hours, followed by 210 mL of water. After stirring at room temperature for 2 hours, the suspension was cooled to 0° C. and stirred overnight at this temperature, then filtered. The filter cake was washed with 70 L of water and dried in vacuo to provide 77.4 g (92% yield) of the title compound as a yellow solid. NMR analysis showed the presence of 2 isomers (approximately 1 / 1 ratio).

[0160] Separation of isomers.

[0161]

[0162] 10 g of the isomers of the reaction product of Example 2a were purified by supercritical fluid chromatography (SFC-eluent: supercritical CO 2 isocratic 7% acetonitrile in 5% acetonitrile) to give 6 g (63% yield) of isomer 1 (E,E) and 2.7 g (28% yield) of isomer 2 (E,Z).

[0163] Isomer 1 (E, E):

[0164] mp:90℃.

[0165] 1 H NMR (DMSO-d 6 )δ:10.89(s,1H),7.83(d,J=8.8Hz,1H),7.54(dd,J=8.8,0.7Hz,1H),7.20-7.28(m,1H),6.74-6.83(m,2H),6.54-6.62(m,1H),3.84(s,3H). 13 C NMR (DMSO-d 6 )δ:163.2(br d,J=241.2Hz),148.3,146.1((br d, J=10.8Hz), 132.8, 130.8 (d, J=10.0Hz), 108.4 (d, J=2.3Hz), 105.9 (d, J=21.6Hz), 98.9 (d, J=27.0Hz), 61.7. 19 F NMR (DMSO-d 6 )δ:-112.30.

[0166] HRMS (EI-TOF) m / z: C 9 H 11 FN 3 O's [M+H]+ The calculated value is 196.0881; the measured value is 196.0876.

[0167] Isomer 2 (E, Z):

[0168] mp 114℃.

[0169] 1 H NMR (DMSO-d 6 )δ: 11.04 (s, 1H), 7.96 (dd, J = 8.6, 0.9Hz, 1H), 7.25 (d, J = 8.4Hz, 1H), 7.21-7.29 (m, 1H), 6.78-6.86 (m, 2H), 6.59-6.66 (m, 1H), 3.85 (s, 3H). 13 C NMR (DMSO-d 6 )δ=163.2(br d,J=242.0Hz),145.8(br d, J=10.8Hz), 145.4, 130.8 (d, J=10.0Hz), 127.9, 108.8 (d, J=2.3Hz), 106.6 (d, J=21.6Hz), 99.3 (d, J=26.2Hz), 61.7. 19 F NMR (DMSO-d 6 )δ:-112.18.

[0170] HRMS (EI-TOF) m / z: C 9 H 11 FN 3 O's [M+H] + The calculated value is 196.0881; the measured value is 196.0876.

[0171] Example 2b: Alternative synthesis of (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime from compound (3-fluorophenyl)hydrazine (hydrochloride), glyoxal and methoxyamine hydrochloride without drying (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde.

[0172] 4.5kg (3-fluorophenyl) hydrazine (hydrochloride) and 36L water were loaded into the first reactor. The suspension was stirred for 1 hour at 65°C. 6.15kg glyoxal and 4.6L water were loaded into the second reactor and cooled to 10°C. The aqueous solution of (3-fluorophenyl) hydrazine (hydrochloride) was transferred from the first reactor to the second reactor in 2 hours. The reaction mixture was further stirred for 3 hours, then filtered and washed with water solid (E) -2- (2- (3-fluorophenyl) hydrazono) acetaldehyde. The wet cake was reloaded into the reactor together with 18kg methanol. Then 3.77kg hydroxylamine hydrochloride, 3.7kg sodium acetate and 9kg water were added under effective stirring. The suspension was stirred for 30 minutes to 60 minutes, 18kg water was added, and the final mixture was cooled to 5°C and stirred for 1 hour to 2 hours. The mixture of the products (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime and (1E,2Z)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime was filtered, washed with water and dried in vacuo to provide 5.01 kg of yellow solid (yield: 93%) with a purity of >99%.

[0173] Example 2c: (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde and X-NH 2 Synthesis of compounds of formula I.

[0174]

[0175] Unless otherwise stated, compounds of formula I (wherein R 1 H) from (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde and X-NH 2 Prepared according to the procedure of Example 2a or a very similar procedure and used crudely either purified by crystallization or by chromatography. The results are reported in Table 1.

[0176]

[0177] Table 1

[0178] (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde oxime Yellow solid. mp 135°C.

[0179] Isomer 1 (major): 1 H NMR (400 MHz, DMSO-d 6)δ=11.33(s,1H),10.70(s,1H),7.77(d,J=8.6Hz,1H),7.59(dd,J=0.4,8.8Hz,1H ),7.27-7.17(m,1H),6.80-6.76(m,1H),6.75(d,J=1.5Hz,1H),6.59-6.51(m,1H). 13 C NMR (101 MHz, DMSO-d 6 )δ=163.24(br d,J=241.2Hz),147.88,146.46(br d, J = 10.8Hz), 134.44, 130.74 (d, J = 10.0Hz), 108.29 (d, J = 2.3Hz), 105.56 (d, J = 21.6Hz), 98.71 (d, J = 26.2Hz). 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.36.

[0180] HRMS (EI-TOF) m / z: C 8 H 9 FN 3 O's [M+H] + The calculated value is 182.0730; the measured value is 182.0726.

[0181] Isomer 2 (minor): 1 H NMR (400 MHz, DMSO-d 6 )δ=11.28(s,1H),10.90(s,1H),8.06(dd,J=0.7,8.4Hz,1H),7.27-7.17(m,2H),6.83-6.80(m,1H),6.80-6.76(m,1H),6.63-6.59(m,1H). 13 C NMR (101 MHz, DMSO-d 6 )δ=163.21(br d,J=241.2Hz),146.16(br d, J = 10.8Hz), 144.96, 130.82 (d, J = 10.0Hz), 128.71, 108.65 (d, J = 2.3Hz), 106.14 (d, J = 21.6Hz), 99.09 (d, J = 26.2Hz). 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.26.

[0182] HRMS (EI-TOF) m / z: C 8 H9 FN 3 O's [M+H] + The calculated value is 182.0730; the measured value is 182.0727.

[0183] (1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)acetaldehyde O-ethyl oxime

[0184] Yellow solid. mp: 82.7°C and 101.7°C (mixture of isomers).

[0185] Isomer 1 (major): 1 H NMR (400 MHz, DMSO-d 6 )δ=10.88(s,1H),7.82(d,J=8.6Hz,1H),7.56(d,J=8.8Hz,1H),7.29-7.18(m,1H), 6.85-6.73(m,2H),6.61-6.52(m,1H),4.10(q,J=7.0Hz,2H),1.22(t,J=7.0Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ=163.21(br d,J=241.2Hz),148.02,146.20(br d, J=10.8Hz), 133.08, 130.73 (d, J=10.0Hz), 108.40 (d, J=2.3Hz), 105.84 (d, J=20.8Hz), 98.86 (d, J=26.2Hz), 69.24, 14.31. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.34.

[0186] HRMS (EI-TOF) m / z: C 10 H 13 FN 3 O's [M+H] + The calculated value is 210.1043; the measured value is 210.1035.

[0187] Isomer 2 (minor): 1 H NMR (400 MHz, DMSO-d 6 )δ=11.05(s,1H),8.00(d,J=8.6Hz,1H),7.29-7.18(m,2H),6.85-6.73(m,2H),6.66-6.58(m,1H),4.11(q,J=7.0Hz,2H),1.22(br t,J=7.0Hz,3H).13 C NMR (101 MHz, DMSO-d 6 )δ=163.16(br d,J=241.2Hz),145.86(brd,J=11.6Hz),145.17,130.80(br d, J=10.0Hz), 128.15, 108.78 (d, J=2.3Hz), 106.46 (d, J=21.6Hz), 99.25 (d, J=27.0Hz), 69.20, 14.38. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.22.

[0188] HRMS (EI-TOF) m / z: C 10 H 13 FN 3 O's [M+H] + The calculated value is 210.1043; the measured value is 210.1035.

[0189] (1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)acetaldehyde O-(tert-butyl)oxime

[0190]

[0191] Yellow solid. mp: 93.8°C (mixture of isomers).

[0192] Isomer 1: 1 H NMR (400 MHz, DMSO-d 6 )δ=10.80(s,1H),7.80(d,J=8.6Hz,1H),7.60(d,J=9.0Hz,1H),7.29-7.18(m,1H),6.84-6.75(m,2H),6.60–6.53(m,1H),1.28(s,9H). 13 CNMR (101MHz, DMSO-d 6 )δ=163.23(br d,J=241.2Hz),147.19,146.33(br d, J=10.8Hz), 133.76, 130.63 (d, J=10.0Hz), 108.35 (d, J=2.3Hz), 105.66 (d, J=21.6Hz), 98.84 (d, J=26.2Hz), 78.78, 27.18. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.36.

[0193] HRMS (EI-TOF) m / z: C 12 H 17 FN 3 O's [M+H] + The calculated value is 238.1356; the measured value is 238.1351.

[0194] Isomer 2: 1 H NMR (400 MHz, DMSO-d 6 )δ=11.02(s,1H),8.03(d,J=9.0Hz,1H),7.29-7.18(m,2H),6.84-6.75(m,2H),6.60–6.53(m,1H),1.29(s,9H). 13 C NMR (101 MHz, DMSO-d 6 )δ=163.18(br d,J=242.0Hz),146.01(br d,J=10.8Hz),144.37,130.69(br d, J=10.0Hz), 128.56, 108.70 (d, J=2.3Hz), 99.17 (d, J=26.2Hz), 78.40, 27.18. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.29.

[0195] HRMS (EI-TOF) m / z: C 12 H 17 FN 3 O's [M+H] + The calculated value is 238.1356; the measured value is 238.1351.

[0196] Isomer 3: 1 H NMR (400 MHz, DMSO-d 6 )δ=10.93(s,1H)7.80(m,1H),6.89(m,1H),7.29-7.18(m,1H),6.84-6.75(m,2H),6.60–6.53(m,1H),1.34(s,9H). 13 C NMR (101 MHz, DMSO-d 6)δ=163.30(br d,J=241.2Hz),146.66(d,J=11.6Hz),141.90,137.58,130.69(br d,J=10.0Hz,1C),130.63(d,J=10.0Hz,1C),130.56(d,J=10.0Hz,1C),128.56,127. 44, 108.13 (d, J = 2.3Hz), 105.04 (d, J = 21.6Hz), 98.49 (d, J = 26.2Hz), 79.63, 27.11. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.16.

[0197] HRMS (EI-TOF) m / z: C 12 H 17 FN 3 O's [M+H] + The calculated value is 238.1356; the measured value is 238.1351.

[0198] Isomer 4: 1 H NMR (400 MHz, DMSO-d 6 )δ=11.35(s,1H),8.28(d,J=6.8Hz,1H),7.29-7.18(m,1H),6.84-6.75(m,3H),6.60–6.53(m,1H),1.27(s,9H). 13 C NMR (101 MHz, DMSO-d 6 – detected signal)δ=163.30(br d, J=241.2Hz,1C),163.23(br d, J=241.2Hz,1C),163.18(br d, J=242.0Hz,1C),144.28,127.44,108.86(d, J=2.3Hz),106.56(d, J=21.6Hz),99.38(br d, J=26.2Hz),27.06. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.22.

[0199] (1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)acetaldehyde O-benzyl oxime

[0200]

[0201] Yellow solid. mp: 105.6°C (mixture of isomers).

[0202] Isomer 1 (major): 1 H NMR (400 MHz, DMSO-d 6 )δ=10.91(s,1H),7.94(d,J=8.8Hz,1H),7.56(d,J=9.0Hz,1H),7.42-7.27(m ,5H),7.27-7.19(m,1H),6.87-6.76(m,2H),6.62-6.54(m,1H),5.13(s,1H). 13 C NMR (101 MHz, DMSO-d 6 )δ=163.20(d,J=241.2Hz),148.86,146.13(br d,J=10.8Hz,1C),137.43,132.71,130.74(d,J=9.2Hz),128.25,128.00,127 .74, 108.46 (d, J = 2.3Hz), 105.96 (d, J = 21.6Hz), 98.95 (d, J = 26.2Hz), 75.51. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.23.

[0203] HRMS (EI-TOF) m / z: C 15 H 15 FN 3 O's [M+H] + The calculated value is 272.1199; the measured value is 272.1198.

[0204] Isomer 2 (minor): 1 H NMR (400 MHz, DMSO-d 6 )δ=11.08(s,1H),8.06(d,J=9.0Hz,1H),7.56(d,J=9.0Hz,1H),7.42-7.27 (m,5H),7.27-7.19(m,1H),6.87-6.76(m,2H),6.66-6.62(m,1H),5.14(br s,1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ = 163.16 (br d, J = 241.2Hz), 145.94, 137.50, 108.83 (d, J = 2.3Hz), 106.58 (d, J = 21.6Hz), 99.31 (d, J = 26.2Hz) 75.56. 19 F NMR (377 MHz, DMSO-d 6)δ=-112.12.

[0205] HRMS (EI-TOF) m / z: C 15 H 15 FN 3 O's [M+H] + The calculated value is 272.1199; the measured value is 272.1199.

[0206] Isomer 3: HRMS (EI-TOF) m / z: C 15 H 15 FN 3 O's [M+H] + The calculated value is 272.1199; the measured value is 272.1200.

[0207] (1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)acetaldehyde O-phenyloxime

[0208]

[0209] Yellow solid. mp: 93.4°C (mixture of isomers).

[0210] Isomer 1 (major): 1 H NMR (400 MHz, DMSO-d 6 )δ=11.17(s,1H),8.28(d,J=8.6Hz,1H),7.70(d,J=8.8Hz,1H),7.45-7.32(m,2H),7.32-7.23(m ,1H),7.18(d,J=7.9Hz,2H),7.09-7.01(m,1H),6.93-6.81(m,2H),6.64(dt,J=2.2,8.6Hz,1H). 13 C NMR (101 MHz, DMSO-d 6 )δ=163.17(br d,J=241.2Hz),158.61,151.99,145.82(br d, J = 11.6Hz), 131.57, 130.87 (d, J = 9.2Hz), 129.44, 122.43, 114.18, 108.72 (d, J = 2.3Hz), 106.48 (d, J = 21.6Hz), 99.62 (d, J = 26.2Hz). 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.13.

[0211] HRMS (EI-TOF) m / z: C 14 H 13 FN3 O's [M+H] + The calculated value is 258.1043; the measured value is 258.1038.

[0212] Isomer 2 (minor): 1 H NMR (400 MHz, DMSO-d 6 )δ=11.38(s,1H),8.19(d,J=8.6Hz,1H),7.69(br d,J=8.4Hz,1H),7.45-7.32(m,2H),7.32-7.23(m,1H),7.18(d,J=7.9Hz ,2H),7.09-7.01(m,1H),6.93-6.81(m,2H),6.69(dt,J=2.2,8.6Hz,1H). 13 C NMR (101 MHz, DMSO-d 6 )δ=163.13(br d,J=242.0Hz),158.66,148.82,145.47(br d, J=10.8Hz), 130.95 (d, J=10.0Hz), 129.44, 127.23, 122.33, 114.21, 109.14 (d, J=2.3Hz), 107.14 (d, J=21.6Hz), 99.62 (d, J=26.2Hz). 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.02.

[0213] HRMS (EI-TOF) m / z: C 14 H 13 FN 3 O's [M+H] + The calculated value is 258.1043; the measured value is 258.1038.

[0214] (1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)acetaldehyde O-acetyl oxime

[0215]

[0216] 1.16 ml of 50w% aqueous hydroxylamine solution (19 mmol) was added to a solution of 3 g (18 mmol) of compound (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde in 15 ml of methanol. After stirring overnight at room temperature, 3.6 ml (19 mmol) of acetic anhydride was added in two portions. After stirring overnight, 15 ml of water was added to complete precipitation. The desired compound was filtered, washed with a few ml of water, and dried in vacuo to provide 2.6 g (65% yield) of a yellow solid.

[0217] Yellow solid. mp: 100.8°C (mixture of isomers).

[0218] Isomer 1:

[0219] 1 H NMR (400 MHz, DMSO-d 6 )δ=11.31(br s,1H),8.20(d,J=8.8Hz,1H),7.63(d,J=8.8Hz,1H),7.36-7.22(m,1H),6.93-6.79(m,2H),6.78-6.60(m,1H),2.15(s,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ=167.88,163.15(br d,J=242.0Hz),155.53,145.54(br d, J=10.8Hz), 131.12 (d, J=10.0Hz), 130.58, 108.93 (d, J=2.3Hz), 106.94 (d, J=21.6Hz), 99.44 (d, J=26.2Hz), 19.25. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.07.

[0220] HRMS (EI-TOF) m / z: C 10 H 11 FN 3 O 2 [M+H] + The calculated value is 224.0835; the measured value is 224.0835.

[0221] Isomer 2:

[0222] 1 H NMR (400 MHz, DMSO-d 6 , visible signals)δ=11.46(br s,1H),7.36-7.22(m,1H),6.99(s,1H),6.93-6.79(m,2H),6.78-6.60(m,1H),1.91(s,3H). 13 C NMR (101 MHz, DMSO-d 6)δ=171.93,163.02(br d,J=242.7Hz),151.84,144.63(br d, J=10.8Hz), 130.95 (d, J=10.0Hz), 130.97, 109.45 (d, J=2.3Hz), 108.23 (d, J=21.6Hz), 100.16 (d, J=26.2Hz), 21.00. 19 F NMR (377 MHz, DMSO-d 6 )δ=-111.71.

[0223] HRMS (EI-TOF) m / z: C 10 H 11 FN 3 O 2 [M+H] + The calculated value is 224.0835; the measured value is 224.0836.

[0224] Isomer 3:

[0225] 1 H NMR (400 MHz, DMSO-d 6 )δ=11.85(br s,1H),7.97(d,J=8.4Hz,1H),7.74(d,J=8.4Hz,1H),7.36-7.22(m,1H),6.93-6.79(m,2H),6.78-6.60(m,1H),2.17(s,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ=167.91,163.11(br d,J=242.0Hz),155.53,145.20(br d, J = 10.0Hz), 131.66 (d, J = 9.3Hz), 126.80, 109.35 (d, J = 2.3Hz), 107.57 (d, J = 21.6Hz), 99.85 (d, J = 27.0Hz), 19.37. 19 F NMR (377 MHz, DMSO-d 6 )δ=-111.95.

[0226] (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1-dimethylhydrazine

[0227]

[0228] Yellow solid. mp: 134.4°C (single isomer).

[0229] 1 H NMR (400 MHz, DMSO-d 6 )δ=10.27(s,1H),7.58(d,J=7.9Hz,1H),7.23-7.13(m,1H),7.02(d,J=8.1Hz,1H),6.77-6.67(m,2H),6.52-6.42(m,1H),2.89(s,6H). 13 C NMR (101 MHz, DMSO-d 6 )δ=163.33(br d,J=240.4Hz),147.21(d,J=10.8Hz),139.63,130.69,130.55(d,J=10.0Hz ), 107.80 (d, J = 1.5Hz), 104.33 (d, J = 21.6Hz), 98.06 (d, J = 26.2Hz), 42.24. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.61.

[0230] HRMS (EI-TOF) m / z: C 10 H 14 FN 4 [M+H] + The calculated value is 209.1202; the measured value is 209.1200.

[0231] (1E,2E)-2-(2-(3-Fluorophenyl)hydrazono)-N-(piperidin-1-yl)ethane-1-imine

[0232]

[0233] Yellow solid. mp: 155.4°C (single isomer).

[0234] 1 H NMR (400 MHz, DMSO-d 6 )δ=10.36(s,1H),7.58(d,J=8.1Hz,1H),7.31(d,J=7.9Hz,1H),7.25-7.08(m,1H),6.83-6.62(m,2H),6.48(dt,J=2.3,8.5Hz,1H),3.06(br t,J=5.4Hz,4H),1.81-1.52(m,4H),1.52-1.23(m,2H). 13 C NMR (101 MHz, DMSO-d 6)δ=163.31(d,J=240.4Hz,1C),147.05(d,J=10.8Hz,1C),139.45,132.82,130.55(br d,J=10.0Hz,1C),107.88(br d, J=2.3Hz, 1C), 104.54 (d, J=21.6Hz, 1C), 98.17 (br d, J=26.2Hz, 1C), 51.14, 24.43, 23.48. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.59.

[0235] HRMS (EI-TOF) m / z: C 13 H 18 FN 4 [M+H] + The calculated value is 249.1515; the measured value is 249.1518.

[0236] N'-((1E,2E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)acetylhydrazine

[0237]

[0238] Yellow solid. mp: 265.1°C (mixture of isomers).

[0239] Isomer 1 (rotator 1, major):

[0240] 1 H NMR (400 MHz, DMSO-d 6 )δ=11.22(s,1H),10.85(s,1H),7.75(d,J=8.4Hz,1H),7.57(d,J=8.6Hz,1H),7.25(q,J=7.8Hz,1H),6.93-6.73(m,2H),6.59(br t,J=7.8Hz,1H),2.13(s,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ=190.43,171.62,163.26(d,J=241.2Hz,1C),146.20(br d,J=10.8Hz,1C),142.49,136.15,130.79(d,J=10.0Hz,1C),108.44(d,J=2.3Hz,1C),105.84(br d,J=21.6Hz,1C),98.86(br d, J=26.2Hz, 1C), 20.07. 19F NMR (377 MHz, DMSO-d 6 )δ=-112.21.

[0241] Isomer 1 (rotator 2, minor):

[0242] 1 H NMR (400 MHz, DMSO-d 6 )δ=11.37(s,1H),10.92(s,1H),7.87(d,J=8.4Hz,1H),7.62(d,J=8.4Hz,1H),7.25(q,J=7.8Hz,1H),6.93-6.73(m,2H),6.59(br t,J=7.8Hz,1H),1.96(s,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ=190.43,165.52,163.26(d,J=241.2Hz,1C),146.17(br d,J=10.8Hz,1C),145.05,136.32,130.79(d,J=10.0Hz,1C),108.48(brd,J=2.3Hz,1C),105.91(br d,J=21.6Hz,1C),98.89(br d,J=26.2Hz,1C),21.56. 19 FNMR (377 MHz, DMSO-d 6 )δ=-112.21.

[0243] HRMS (EI-TOF) m / z: C 10 H 12 FN 4 O's [M+H] + The calculated value is 223.0995; the measured value is 223.0994.

[0244] N'-((1E,2E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-4-methylbenzenesulfonylhydrazide

[0245]

[0246] Yellow solid. mp: 146.7°C (single isomer).

[0247] 1 H NMR (400 MHz, DMSO-d 6)δ=11.48(s,1H),10.84(s,1H),7.71(d,J=8.4Hz,2H),7.61(d,J=8.4Hz,1H),7.42(br d,J=8.6Hz,1H),7.41(br d,J=8.1Hz,2H),7.27-7.17(m,1H),6.79-6.70(m,2H),6.63-6.52(m,1H),2.37(s,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ=163.18(br d,J=241.2Hz),146.37,145.99(br d,J=10.8Hz),143.46,136.07,135.31,130.83(d,J=10.0Hz),129.68,127. 05, 108.52 (d, J = 2.3Hz), 106.07 (d, J = 21.6Hz), 98.92 (d, J = 26.2Hz), 20.96. 19 F NMR (377 MHz, DMSO-d 6 )δ=-112.20.

[0248] HRMS (EI-TOF) m / z: C 15 H 16 FN 4 O 2 S's [M+H] + The calculated value is 335.0978; the measured value is 335.0982.

[0249] (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1,1-trimethylhydrazine-1- Iodide

[0250]

[0251] To a solution of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde (1 mmol, 1.0 equiv) and NaOAc (1.5 mmol, 1.5 equiv) in MeOH (3 mL) was added 1,1-dimethylhydrazine hydrochloride (1.2 mmol, 1.2 equiv) in one portion at 25°C. After the starting material was consumed (approximately 30 min), water (3 mL) was added to the reaction mixture. The suspension was then filtered and the filter cake was washed with water. The intermediate dihydrazone (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1-dimethylhydrazine was dried under vacuum at 50°C for 3 h. To a solution of (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1-dimethylhydrazine (1.0 mmol, 1.0 equiv) (isolated or non-isolated intermediate) thus obtained in ACN (2 mL) was added MeI (5.0 mmol, 5.0 equiv) in one portion at 25°C. After stirring overnight or until the starting material was consumed, EtOAc (3 mL) was added to the suspension. The suspension was filtered and the filter cake was washed with EtOAc. The hydrazine salt (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1,1-trimethylhydrazine-1- The iodide was dried under vacuum at 30°C to provide 315 mg of a yellow solid (yield: 90%).

[0252] mp:166.8℃.

[0253] 1 H NMR (400 MHz, DMSO-d 6 ): δ11.82(s,1H),8.73(d,J=8.0Hz,1H),7.63(d,J=8.1Hz,1H),7.35(dd,J=15.1,8.2Hz,1H),6.99–6.90(m,2H),6.82–6.71(m,1H),3.47(s,9H). 13 C NMR (101MHz, DMSO-d6): δ164.73,163.18,162.32,145.32,145.22,131.81 ,131.72,131.12,110.01,108.77,108.56,100.55,100.29,55.52,55.46.

[0254] HRMS(ESI):C 11 H 16 FN 4 + The calculated value [M +]:223.1359, measured value: 223.1348. MP: 166.8℃.

[0255] Example 2d: Synthesis of methyl 2-fluoro-6-(2-(2-(methoxyimino)ethylidene)hydrazino)benzoate

[0256]

[0257] A solution of methoxyamine hydrochloride (3.61 g, 43.2 mmol) and sodium acetate (3.55 g, 43.2 mmol) in water (80 ml) was added to a solution of (E)-methyl 2-fluoro-6-(2-(2-oxoethylidene)hydrazino)benzoate (8.07 g, 36.0 mmol) in methanol (40 ml). After stirring overnight at room temperature, the title compound was filtered, rinsed with water (2 x 15 ml) and dried in vacuo. The desired product (7.85 g, 79% yield) was obtained as a yellow solid. NMR showed the presence of several isomers. mp 90.0 °C.

[0258] 1 H NMR (DMSO-d 6 – major isomer)δ:10.87(s,1H),7.76(m,2H),7.40(m,1H),7.11(m,1H),6.72(m,1H),3.86(s,3H),3.83(s,3H).

[0259] MS (ESI-TOF) m / z: 254.2 ([M+H] + ).

[0260] Example 2: (E)-2-((E)-2-(2-(3-fluoro-2-(methoxycarbonyl)phenyl)hydrazono)ethylidene)-1,1,1-trimethylhydrazine-1- Iodide

[0261]

[0262] A suspension of 1,1-dimethylhydrazine hydrochloride (0.76g, 7.9mmol) and sodium acetate (0.74g, 9.0mmol) in methanol (10ml) is slowly added to a solution of (E)-2-fluoro-6-(2-(2-oxoethylidene)hydrazine)methyl benzoate (1.68g, 7.5mmol) in toluene-methanol (25ml+6ml). After stirring at room temperature for 1 hour, the mixture is concentrated in vacuo, and the residue is distributed between water and ethyl acetate (10ml+20ml). After phase separation, the water layer is extracted with ethyl acetate (20ml), and the combined organic layer is concentrated in vacuo. The obtained oil is purified by chromatography (silica gel, eluent: ethyl acetate-heptane, 1 / 8), and a yellow solid intermediate dihydrazone (1.8g) is obtained. The intermediate (1.6 g) was then redissolved in acetonitrile (12 ml), iodomethane (5.11 g, 36.0 mmol) was added, and the reaction mixture was stirred at 36° C. for 8 hours. After cooling to room temperature, the solid was filtered, rinsed with acetonitrile (2×20 ml), and dried in vacuo to provide the desired compound (2.0 g, 65% overall yield) as a yellow solid. mp: 177.5° C.

[0263] 1 H NMR (DMSO-d 6 )δ:11.51(s,1H),8.57(d,1H),7.84(m,2H),7.50(m,1H),7.25(m,1H),6.88(m,1H),3.86(s,3H),3.45(s,9H). 19 F NMR (DMSO-d 6 )δ:-111.49.

[0264] MS (ESI-TOF) m / z: 281.1 ([hydrazine ion] + ).

[0265] Example 2f: Synthesis of 2-fluoro-6-(2-((1E,2E)-2-(methoxyimino)ethylidene)hydrazino)benzoic acid

[0266]

[0267] 2-Fluoro-6-(2-(2-oxoethylidene)hydrazino)benzoic acid was reacted with methoxyamine hydrochloride and sodium acetate in water-methanol to provide 2-fluoro-6-(2-((1E,2E)-2-(methoxyimino)ethylidene)hydrazino)benzoic acid as a yellow solid in 52% yield. The desired compound was used as such in the next step.

[0268] Example 3: 2-phenyl-2- H- Synthesis of 1,2,3-Triazole

[0269]

[0270] Example 3a: Synthesis of 2-(3-fluorophenyl)-2-H-1,2,3-triazole, wherein X is -N + Me 3 I - .

[0271] At 25°C, the hydrazine salt (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1,1-trimethylhydrazine-1- Iodide (X = -N + Me 3 I - -1.0 mmol, 1.0 equiv) in DMF (3 mL) was added K 2 CO 3 or KHCO 3 (2.0 mmol, 2.0 equiv). The suspension was heated to 50°C. After stirring for 2 h or until the starting material was consumed, the reaction was cooled to 25°C and heated with H 2 O and EtOAc. The organic layer was partitioned and extracted twice with EtOAc. The combined organics were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo. Purify by flash column chromatography using heptane / ethyl acetate as eluent to give 2-(3-fluorophenyl)-2H-1,2,3-triazole in 87% yield.

[0272] When using KHCO 3 Replace K 2 CO 3 The yield increased to 96%.

[0273] Example 3b: Synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazole using other -X groups.

[0274] For various -X leaving groups, the following procedures can be used to remove the compound of formula I (wherein R 1 Synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazole for H):

[0275] 5 mmol of a compound of formula I (wherein R 1 A solution / suspension of 2-(3-fluorophenyl)-2H-1,2,3-triazole and 0.25 mmol of copper sulfate pentahydrate or copper methanesulfonate hydrate in 5 to 7 mL of n-butanol or ethylene glycol (EG) was stirred at 110° C. for several hours, then cooled to room temperature, washed with 7.5 ml of 1 M aqueous HCl, and analyzed by LC for 2-(3-fluorophenyl)-2H-1,2,3-triazole.

[0276] Table 2 below illustrates the yields obtained for each -X leaving group under the listed conditions. The reaction conditions are not optimized, and the present invention contemplates the reaction conditions for each -X group, as well as significant variations thereof. Examples of various screening conditions that can be used for the optimization of the reaction of any -X leaving group are shown in Example 3c (where -X is -OCH 3 )middle.

[0277]

[0278] Table 2

[0279] Example 3c: Synthesis of 2-(3-fluorophenyl)-2H-1,2,3-triazole from (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime (screening of conditions).

[0280]

[0281] A solution of (1E,2E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime (1 equivalent) and a catalyst in a solvent was heated at 110°C-120°C for 20 minutes, overnight, then cooled to room temperature, and LC analyzed for 2-(3-fluorophenyl)-2H-1,2,3-triazole. The reaction conditions and yields are summarized in Table 3.

[0282]

[0283] Table 3

[0284] Example 3d: Formation and Isolation of 2-(3-fluorophenyl)hydrazono)acetaldehyde O-methyloxime (fluorophenyl)-2H-1,2,3-triazole .

[0285] The reactor was charged with 0.31 kg of copper sulfate pentahydrate and 26.8 kg of EG, made inert and heated to 120°C-130°C with stirring. 4.8 kg of (1E, 2E)-2-(2-(3-fluorophenyl) hydrazono) acetaldehyde O-methyloxime was added in 5 portions. After stirring at 120°C-130°C for 1 hour, a portion of the reaction mixture was distilled in vacuo. The distillate (13L, 2-(3-fluorophenyl)-2H-1,2,3-triazole + EG) was distributed between 3.3 kg of heptane and 4.8 kg of 2w / w% HCl aqueous solution. The two layers were separated and the polar layer was extracted with 3.3 kg of heptane. The two heptane layers were combined, washed with 4.8 kg of water and concentrated in vacuo to provide 3.09 kg of colorless to light yellow oily 2-(3-fluorophenyl)-2H-1,2,3-triazole (yield: 77%).

[0286] 1 H NMR (400 MHz, DMSO-d 6)δ=8.14(s,2H),7.87(dd,J=1.3,8.1Hz,1H),7.79(td,J=2.2,10.1Hz,1H),7.60(dt,J=6.4,8.3Hz,1H),7.26(ddt,J=0.9,2.5,8.5Hz,1H). 13 CNMR (101MHz, DMSO-d 6 )δ=162.38(br d,J=244.3Hz), 140.32(d,J=1.5Hz), 136.88, 131.63(d,J=9.2Hz), 114.34(d,J=3.1Hz), 114.37(d,J=20.8Hz), 105.79(d,J=27.7Hz). 19 F NMR (377 MHz, DMSO-d 6 )δ=-110.88.

[0287] HRMS (EI-TOF) m / z: C 8 H 6 FN 3 [M] +℃ The calculated value is 163.0546; the measured value is 163.0521.

[0288] Example 3e Part 1: Synthesis from methyl 2-fluoro-6-(2-(2-(methoxyimino)ethylidene)hydrazino)benzoate Methyl 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoate

[0289]

[0290] Methyl 2-fluoro-6-(2-(2-(methoxyimino)ethylidene)hydrazino)benzoate (4.05 g, 16 mmol) was added in four portions to a solution of copper sulfate pentahydrate (250 mg, 1.0 mmol) in ethylene glycol (25 ml), maintained at 125° C. The resulting mixture was stirred at 125° C. for more than 3 hours and then cooled to 60° C. Water (60 ml), heptane (30 ml) and ethyl acetate (20 ml) were added and the layers were separated. 1.3 g (37% yield) of the desired product was obtained after concentration of the organic layer and purification of the residue by column chromatography (silica gel, heptane-ethyl acetate 8 / 1). mp 56.9° C.

[0291] When methyl 2-fluoro-6-(2-(2-(methoxyimino)ethylidene)hydrazinyl)benzoate (633 mg, 2.50 mmol) and copper sulfate pentahydrate (31 mg, 0.125 mmol) were first mixed in ethylene glycol (5 ml) at room temperature, then heated to 120° C. (the chemicals were completely dissolved upon heating) for about 4 hours, then cooled to room temperature, diluted with water, extracted with isopropyl acetate and purified by column chromatography, the yield of methyl 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoate was improved to 54%. When the above procedure was repeated with a solution of 1.00 mmol starting material, 0.05 mmol copper sulfate pentahydrate in 10 ml ethylene glycol, and a heating time of about 8 hours, a yield of 57% was obtained.

[0292] 1 H NMR (DMSO-d 6 )δ:8.18(s,2H),7.87(d,1H),7.75(m,1H),7.48(t,1H),3.78(s,3H). 13 C NMR (DMSO-d 6 )δ:163.68,159.40(d),137.63,137.6(d),133.27(d),118.00(d),115.86(d),115.8(d),53.28. 19 F NMR (DMSO-d 6 )δ:-114.28.

[0293] Example 3e Part 2: Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid methyl ester 1,2,3-Triazol-2-yl)benzoic acid

[0294]

[0295] A solution of methyl 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoate (360 mg) and lithium hydroxide hydrate (66 mg, 10.2 mmol) in THF-water (2 ml each) was stirred until complete conversion. After neutralization and isolation, the desired product was obtained in 86% yield.

[0296] Example 3f: (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1,1-trimethylhydrazine-1- Synthesis of methyl 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoate from iodide

[0297]

[0298] The (E)-2-((E)-2-(2-(3-fluorophenyl)hydrazono)ethylidene)-1,1,1-trimethylhydrazine-1- A solution of iodide 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid methyl ester (0.61 g, 1.5 mmol) and potassium bicarbonate (0.75 g, 7.5 mmol) in DMF (10 ml) was stirred at 56 ° C for 1 hour and then concentrated in vacuo. The residue was distributed between heptane and water (15 ml + 6 ml). After phase separation, the aqueous layer was extracted with heptane (15 ml), and the combined organic layers were concentrated in vacuo to provide the desired product (0.27 g, 81% yield) as a yellow powder.

[0299] Example 3g: Synthesis from 2-fluoro-6-(2-((1E,2E)-2-(methoxyimino)ethylidene)hydrazino)benzoic acid 2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

[0300]

[0301] 2-Fluoro-6-(2-((1E,2E)-2-(methoxyimino)ethylidene)hydrazino)benzoic acid was reacted in hot ethylene glycol in the presence of copper sulfate pentahydrate to provide 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid in about 25% yield.

[0302] Example 4: Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzene from 2-(3-fluorophenyl)-2H-1,2,3-triazole Formic acid

[0303]

[0304] Example 4a: Screening of bases and additives

[0305] A base was added to the solution of the compound 2-(3-fluorophenyl)-2H-1,2,3-triazole, and the mixture was stirred, and then CO was bubbled. 2 Gas until complete quenching of anions and acidic workup. The resulting mixture was analyzed by LC and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid was isolated after complete workup. The results are reported in Table 4 below.

[0306]

[0307] Table 4

[0308] Example 4b: Synthesis and Isolation of 2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

[0309] A 2M solution of isopropylmagnesium chloride in THF (735 mL, 1.47 mol) was added to a heated (35°C-40°C) solution of 200 g (1.23 mol) of 2-(3-fluorophenyl)-2H-1,2,3-triazole and 25.98 g (0.61 mol) of lithium chloride in one liter of THF. The resulting mixture was stirred at 35°C-40°C for 6 hours and then cooled to -5°C. CO was bubbled into the mixture at a rate that did not allow the reaction temperature to exceed 10°C. 2Gas (67.44g, 1.53mol). The reaction mixture was quenched by adding 800mL toluene, 800mL water and 144mL concentrated HCl solution. After the insoluble particles were dissolved, the two layers were separated and the aqueous layer was discarded. The organic layer was filtered through charcoal and concentrated in vacuo, and the residue was then redissolved in 1.80L toluene and 800mL water; the two-phase mixture was heated to reflux for a few minutes, cooled to 75°C-80°C, seeded, and further cooled to 10°C. After crystallization, the product was isolated by filtration, washed with a few milliliters of water and toluene, and dried in vacuo to obtain 2-fluoro-6-(2H-1,2,3-triazole-2-yl)benzoic acid (212g-217g, 83%-85% yield) as a white to light yellow solid.

[0310] mp 153℃-155℃.

[0311] 1 H NMR (400 MHz, DMSO-d 6 )δ=13.70(br s,1H),8.14(s,2H),7.79(d,J=8.1Hz,1H),7.66(dt,J=6.1,8.3Hz,1H),7.42(ddd,J=1.0,8.4,9.3Hz,1H). 13 C NMR (101 MHz, DMSO-d 6 )δ=164.09,158.90(br d,J=247.4Hz),136.97,136.77(br d,J=6.2Hz),131.82(d,J=9.2Hz),118.03(d,J=3.1Hz),117.25(br d,J=23.1Hz), 115.48 (d,J=22.3Hz). 19 FNMR (377 MHz, DMSO-d 6 )δ=-114.93.

[0312] HRMS (EI-TOF) m / z: C 9 H 7 FN 3 O 2 [M+H] + The calculated value is 208.0517; the measured value is 208.0517.

[0313] Example 5: (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2 Synthesis of (1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0314]

[0315] Thionyl chloride (60 mmol, 4.3 mL) was added to a suspension of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (9.5 g, 46 mmol) in toluene (110 mL) and heated to 55°C for 2.5 hours. The reaction was concentrated in vacuo to a residual volume of about 100 mL (about 20 ml of distilled solvent) and added to a well stirred biphasic mixture of (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (10.2 g, 45.7 mmol) in toluene (44 mL) and aqueous sodium carbonate (44 mL, 68.5 mmol). The resulting biphasic mixture was stirred at 30°C for 3.5 hours and then heated to 70°C. The organic layer was washed twice with 57 mL of water and concentrated in vacuo to a residual volume of about 64 mL. The concentrated mixture was heated to 90°C to obtain a solution, then cooled to room temperature and cyclohexane (64 mL) was added. The resulting suspension was stirred overnight, filtered, washed with cyclohexane (12 mL), washed with water (11 mL), and dried under vacuum to give (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (18.1 g, 97% yield) as a solid. 1 H NMR (400 MHz, pyridine-d 5 )δppm2.33(s,12H)2.81-2.97(m,4H)3.27(dd,J=10.6,5.0Hz,1H)3.33(dd,J=10.5,4.7Hz,1H)3.57(br t,J=7.1Hz,1H)3.59(br t,J=7.0Hz,1H)3.67(dd,J=11.7,4.5Hz,1H)3.70-3.75(m,1H)3.75-3.82(m,2H)3.82 -3.98(m,7H)4.11(dd,J=12.4,7.6Hz,1H)6.29(s,1H)6.29(s,1H)7.19(td,J=8.7,1. 0Hz,1H)7.26(td,J=8.6,0.9Hz,1H)7.46(td,J=8.3,6.2Hz,1H)7.46(td,J=8.3,6.0H z,1H)7.90(dt,J=8.2,0.8Hz,1H)7.90(s,2H)7.98(dt,J=8.2,0.8Hz,1H)8.04(s,2H). 13 C NMR (101 MHz, pyridine-d 5)δppm24.47,24.48,41.74,41.82,42.71,42.93,50.76,50.82,50.90,51.03,51.43,51.62,51.87,52.06,109.27,109.44,115.88(br d,J=22.4Hz),115.89(br d,J=22.4Hz),118.82(br d,J=3.3Hz),118.97(br d,J=3.3Hz),120.48(d,J=24.9Hz),120.55(d,J=24.6Hz),131.53(br High resolution MS (ES, m / z): C 21 H 23 FN 7 O(M+H) + Calculated value: 408.1943; measured value: 408.1946.

[0316] While the above description illustrates the principles of the invention by providing embodiments thereof, it should be understood that the practice of the invention encompasses all general variations, changes and / or modifications within the scope of the following claims and their equivalents.

[0317] All documents cited herein are incorporated by reference.

Claims

1. A compound selected from the group consisting of: as well as 2. A compound selected from the group consisting of: as well as

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