Untitled record

Full description

Background of the invention

The invention relates to compounds suitable for modulating receptors and their ligands related to sensation or chemosensory reaction or sensation or reaction related to the chemosensory aspect.

5 The taste system provides sensory information about the chemical composition of the outside world. The transmission of taste signals is one of the most advanced forms of chemically induced sensation in animals. Taste signals are found in all organisms of the animal kingdom, from the simplest metazoans to the most complex vertebrates. Mammals are thought to sense five different types of taste: sweet, bitter, sour, salty, and umami (the taste of monosodium glutamate).

10 glutamate, also known as savory taste.

Obesity, diabetes, and cardiovascular disease are growing health concerns globally, but they are growing at alarming rates in the United States. Sugar and calories are essential components that can be reduced to have a positive nutritional impact on health. High-strength sweeteners can provide the sweet taste of sugar, with multiple properties

15 To taste. Because these sweeteners are several times sweeter than sugar, it takes much less of the sweetener to replace the sugar.

High-intensity sweeteners have a wide range of chemically different compositions and therefore have diverse properties, such as, but not limited to, aroma, flavour, mouthfeel and aftertaste. These characteristics, especially the flavor and aftertaste

20 Taste is known to vary over tasting time, so all temporal properties are related

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Tunaley, A., "Perceptual Characteristics of Sweeteners", Progress in Sweeteners, T. H. Grenby, Ed. Elsevier Applied Science, 1989.

Sweeteners such as saccharin and 6-methyl-1,2,3-oxathiazine-4(H3)-one-2,2-dioxide5 potassium salt (acesulfame potassium) generally leave a bitter and/or metallic aftertaste. It is claimed that products prepared using 2,4-dihydroxybenzoic acid leave a slight unpleasant aftertaste in the case of sweeteners, at concentrations lower than those that make their taste possible. In addition, reports have indicated that high-strength sweeteners such as sucralose and aspartame have problems with the metabolism of sweeteners.

SG Wiet, et al., J. Food (10 Sweet taste transfer, i.e. delayed and slowed onset of sweet taste.) Sci., 58(3):599-602, 666 (1993

Reports have also indicated that an extracellular domain, such as the Venus flytrap domain of a chemosensory receptor, and in particular one or more interaction sites within the Venus flytrap domain, is a suitable target for compounds or substances.

15 Others regulate the chemosensory receptor and/or its ligands. Some compounds have been reported to be regulators of T1R family chemoreceptors and/or their ligands and are described in the four patent applications listed below.

(1) Application for registration of a patent in the United States bearing serial number 260,562/11, entitled

Modulation of Chemosensory Receptors and Associated Ligands"

20 “Therewith,” filed June 8, 2002; and (2) U.S. Patent No.

2,628,111, entitled “Modulation of Chemosensory Receptors and Ligands Associated Therewith,” issued April 16, 2011; and (3) Global Registration Application No. PCT/US2008/065650, entitled “Modulation of Chemosensory Receptors and Ligands Associated Therewith,” filed on June 3, 2008. 25 The entire content of such applications is incorporated herein by reference for all purposes.

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There is a need in the field to develop new and innovative compounds suitable for modulating receptors and/or their ligands related to chemosensory sensation or reaction or sensation or reaction related to the chemosensory aspect.

5 General description of the invention

In one example, the present invention provides a compound with structural formula (I):

(I)

Or a salt or solvate (a solution of a solvent and a solute) of that compound; where

A is an optionally substituted cyclic acetate ring consisting of four to eight atoms;

10 X is a covalent bond or ––NR1;

R1 is a hydrogen or alkyl composed of carbon atoms C1 to C6; And

Y is an alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, 15 carbocyclyl, substituted carbocyclyl, or heterocyclyl

or aryl, substituted heterocyclyl, or heterocyclyl

A substituted aryl or a heteroaryl or a heteroaryl aryl

substituted aralkyl substituted heteroaryl

aralkyl or heteroaryl alkyl or substituted heteroaryl alkyl

.substituted heteroarylkyl 20

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In another embodiment, the present invention provides an ingestible composition containing a compound of the present invention; An ingestibly acceptable excipient is optionally ingestible.

In another embodiment, the present invention provides a method for increasing the sweet taste of a swallowable composition.

5 It includes coupling said ingestible composition with a compound of the present invention to form a ingestible composition with^{^}coffee pot. In the method, the present compound may be a chemosensory receptor modifier or a chemosensory receptor ligand modifier or both, i.e. a partial chemosensory receptor modifier and a partial chemosensory ligand modifier. For example, it could

10 The present compound is either a sweet receptor agonist or a sweet modulator or a partial sweet receptor agonist and a partial sweet modulator.

In another embodiment, the present invention provides a sweet-tasting composition containing a compound of the present invention in an amount that is effective in providing sweetening when mixed with an initial amount of sweetener,

15 The sweetening is more than the sweetening provided by the initial amount of sweetener without adding the compound.

In another embodiment, the present invention provides a flavoring concentrate formulation containing a) a compound of the present invention as a flavor-modifying ingredient; b) a carrier; and c) optionally, at least one excipient.

In another embodiment, the present invention provides a method for treating a condition, disease or disorder.

20 Linked to a chemosensory receptor, it consists of administering to a person in need of such treatment a therapeutically effective quantity of one of the compounds of the present invention, a salt, a dissolution product, and/or a prodrug.

Detailed description:

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These representations, analogies, and characteristics of the present invention, as well as other representations, analogies, and characteristics, are presented in the sections below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as would be commonly understood by a person with expertise in the field to which this invention relates.

5 Definitions

The term "alkyl" refers, alone or as part of another substituent, to a saturated or unsaturated cyclic or straight-chain monovalent hydrocarbon radical resulting from the removal of a single hydrogen atom from a single carbon atom of an alkane, alkene, or basic alkyne. The term “alkyl” includes “cycloalkyl” as defined below. Typical alkyl groups include, but are not limited to, methyl; and ethyls such as ethylene, ethylene, ethylene; And propanes such as propane-1-yl, propane-2-yl, cyclic propane-1-yl, propane-1-ene-1-yl, propane-1-ene-2-yl, prop-2-ene-1-yl (allyl), prop-1-ene-1-allyl cycl; and prop-2-ene-1-allyl,

Prop-1-yn-1-yl, Prop-2-yn-1-yl, etc.; Butyls such as butane-1-yl, butane-2-yl, 2-methyl-propane-1-yl, 2-methyl-propane-2-yl, butane-1-yl, butane-1-ene-1-yl ,

15 but-1-ene-2-yl,2-methyl-prop-1-ene-1-yl,but-2-ene-1-yl,but-2-ene-2-yl,

buta-1,3-diene-1-yl,buta-1,3-diene-2-yl,but-1-ene-1-ylcycloyl,but-1-ene-3-ylcycloyl,buta-3, 1-diene-1-cyclic, but-1-ene-1-yl, but-1-ene-3-yl, bute-3-ene-1-yl, etc.; And the like. The term “alkyl” is specifically intended to include groups with any degree or level of saturation, i.e., groups containing exclusively single carbon-carbon bonds, 20 groups containing one or more even carbon-carbon bonds, and groups containing On one or more tertiary carbon-carbon bonds, and groups containing mixed single, double and triple carbon-carbon bonds. When a specific level of saturation is intended, the expressions alkanyl, alkenyl, and alkynyl are used. In some representations, the alkyl group contains between 1 and 20 carbon atoms (C1-C20 alkyl). In others,

25 The alkyl group contains between 1 and 12 carbon atoms (C1-C12 alkyl). In the representations

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Also, an alkyl group has between 1 and 6 carbon atoms (C1-C6 alkyl). It is noted that when one of the alkyl groups is additionally attached to another atom, it becomes an “alkylene” group. In other words, the term “alkylene” refers to Divalent alkyl For example, -CH2CH3 is ethyl, while -CH2CH2- is ethylene. i.e. 5 that the term “alkylene” refers, alone or as part of another substituent, to a saturated or unsaturated divalent hydrocarbon radical that is branched or straight-chained - resulting from the removal of two hydrogen atoms from a single carbon atom or from two different carbon atoms of an alkane or alkene Or a basic alkyne. The term “alkylene” includes “cyclic alkylene” as defined below. The term “alkylene” is specifically intended to include groups with any degree or level of saturation, i.e., groups containing 10 exclusively carbon-carbon single bonds, groups containing one or more carbon-carbon double bonds, and groups containing 10 carbon-carbon bonds -One or more tertiary carbons and groups containing mixed single, double and triple carbon-carbon bonds. When a certain level of saturation is intended, the expressions “alkanylene,” “alkenylene,” and “alkynylene” are used. In some representations, the alkylene group contains between 1 and 20 carbon atoms (C1-C20 alkylene). In other representations, the alkylene group contains between 1 and 12 carbon atoms (C1-C12 alkylene). In still others, An alkylene group contains between 1 and 6 carbons (alkylene C1-6).

The term “alkanyl,” alone or as part of another substituent, refers to a cyclic or straight-chain branched saturated alkyl radical resulting from the removal of a hydrogen atom from a single carbon atom 20 of the primary alkane. The term “alkanyl” includes the term “cycloalkanyl” as defined below.

Typical alkanyl groups include, but are not limited to, methanyl, ethyl, propanilates such as propane-1-yl, propane-2-yl (isopropyl), cyclopropanyl-1-yl, etc.; and butanilates such as butane-1-yl and butane-2-yl ( cycla-butyl), 2-methyl-propane-1-yl (isobutyl), 2-methyl-propane-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

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The term "alkenyl" refers, alone or as part of another substituent, to a cyclic or straight-chain branched unsaturated alkyl radical containing at least one carbon-carbon double bond resulting from the removal of one hydrogen atom from a single carbon atom of a primary alkene. The term “alkenyl” includes the term “cyclic alkenyl” as defined below. The group can be in the form of 5 cis-coupled or trans-linked around the double bond(s). Typical alkenyl groups include, but are not limited to, ethinyl; Propenyls such as prop-1-ene-1-yl, prop-1-ene-2-yl, prop-2-ene-1-yl (allyl), prop-2-ene-2-yl, and prop-1-ene-1-yl Cycloprop-2-ene-1-yl and butynyls such as buty-1-ene-1-yl, buty-1-ene-2-yl and 2-methyl-prop-1-ene-1-yl and buty-2-yl -1 -yl and but-2 -yn- 1 -yl

10 Butyota-2-diene-2-yl, butyota-1,3-diene-1-yl, butyota-1,3-diene-2-yl, butyota-1-diene-1-yl, cyclic butyota-1-diene-3-yl cyclic buta-1,3-diene-1-ylcyclic, etc.; And the like.

The term “alkynyl,” alone or as part of another substituent, refers to a cyclic or straight-chain branched unsaturated alkyl radical containing at least one tertiary carbon-carbon bond resulting from the removal of a single hydrogen atom from a single carbon atom of a primary alkyne. Typical 15 alkynyl groups include, but are not limited to, ethylene; propylenes such as prop-1-en-1-yl, prop-2-en-1-yl, etc.; Butanelates such as buty-1-en-1-yl

and peyote-1-in-3-yl and peyote-3-in-1-yl, etc.; And the like.

The term “alkoxy,” alone or as part of another substituent, refers to a radical with the structure R199-O, where R199 is an alkyl group or a substituted alkyl as defined herein.

20 The term "acyl" refers, alone or as part of another substituent, to the C(O)R200 radical, where R200 is a hydrogen atom or one of the alkyl groups, a substituted alkyl, an aryl, a substituted aryl, an aryl alkyl, a substituted aryl alkyl, or an alkyl Heterocyclic, substituted heteroaryl alkyl, heteroaryl alkyl, or heteroaryl substituted alkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, 25-cyclohexylcarbonyl, 25-hexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

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The term aryl, alone or as part of another substituent, refers to a monovalent aromatic hydrocarbon group resulting from the removal of a single hydrogen atom from a single carbon atom of a basic aromatic ring system, as defined herein. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acephthylene, acephenanthrylene, anthracene, azulene, and benzene

5 Alkarisin, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexaline, and as-indacene

And s-indacene, indane, indane, naphthalene, octacene, octaphene, octalene, ovaline, penta-2,4-diene, pentacene, pentalene, pentaphene, p-arylene, phenalene, phenanthrene, picene, pliadine, pyrene, p-aryrnthrene, rubicin, triphenylene, tri-naphthalene and the like. In some examples, the aryl group contains between 6 and 20 carbon atoms (C20-C6 aryl), i.e. an aryl ring consisting of 6 to 10 20 atoms. In other examples, the aryl group contains between 6 and 15 carbon atoms )Aryl

C15-C6), i.e. an aryl ring consisting of 6 atoms to 15 atoms. In other examples, the aryl group contains between 6 and 15 carbon atoms (aryl C10-C6), i.e. an aryl ring consisting of 6 atoms to 10 atoms. The art.

The term "arylalkyl" or "aralkyl", alone or as part of another substituent, 15 refers to a noncyclic alkyl group in which one of the hydrogen atoms attached to a carbon atom is replaced,

It is usually a terminal carbon atom, or sp3, with an aryl group, as it is defined here. That is, the aryl alkyl group consists of an aryl group attached to an alkylene group, which in turn is attached to another part of a molecule. The alkylene group in the aryl alkyl group, or arylkyl, can be an alkylene that has between 1 and 12 carbon atoms, or 1 to 6 carbon atoms, or 1

20 To 3 carbon atoms. Typical aryl alkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethene-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylethene-1-yl, and naphthobenzyl-1-yl. Naphthophenylethane-1-yl, and the like. When specific alkyl moieties are intended, the designations arylalkenyl, arylalkenyl, and/or arylalkenyl are used. In some representations, the arylalkyl group is an arylalkyl (C30-C6), e.g.

25 For example, the alkane, alkenyl, or alkynyle portion of the aryl alkyl group is

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Alkyl (C10-C1) and the aryl moiety is an aryl (C20-C6). In other representations, the aryl alkyl group is an aryl alkyl (C20-C6), for example, the alkane, alkenyl or alkynyle moiety in the aryl alkyl group is is an alkyl (C8-C1) and the aryl moiety is an aryl (C6-C12). In still other representations, the aryl alkyl group is

5 For aryl alkyl (C15-C6), for example, the alkane, alkenyl, or alkenyl portion of the aryl alkyl group is an alkyl (C1-C5) and the aryl portion is an aryl (C10-C6).

The term “cycloalkyl” or “carbocyclyl,” alone or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical, as defined herein. Likewise, the term “cycloalkylene” or “carbocyclylene,” alone or as part of another substituent, refers to a saturated or unsaturated 10-cycloalkylene radical, as defined herein. When a specific level of saturation is intended, the nomenclature “cycloalkenyl,” “cycloalkenyl,” or “cycloalkenyl” is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In some embodiments, the cyclic alkyl group has between 3 and 10 atoms per ring (15 C10-C3 cycloalkyl). In other embodiments, the cyclic alkyl group has between 3 and 2 atoms per ring.

The ring (C7-C3 cycloalkyl). Cyclic alkyls can also be replaced by one or more heteroatoms including, but not limited to, nitrogen (N), phosphorus (P), oxygen (O), sulfur (S), and silicon (Si), which The carbon atoms in cyclic alkyls are linked through monovalent or multivalent bonds.

20 The terms “heteroalkyl”, “heteroalkanyl”, “heteroalkenyl” and “heteroalkynyl” refer, alone or as part of other substituents, to alkyl, alkanyl, alkenyl and alkenyl groups, respectively, in which a single atom is substituted or more carbon atoms (and optionally any associated hydrogen atoms), independently of each other, heteroatoms or 25 similar or different heteroatom groups. Likewise, the terms “non-alkylene” refer to...

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"homogeneous" and "heteroalkenylene" and "heteroalkenylene" and "heteroalkenylene", alone or as part of other substituents, into alkylene and alkanylene and alkenylene and alkynylene groups, respectively, in which one or more carbon atoms (and optionally any hydrogen bonded), independently of each other, or heterogeneous atoms

5 Heterogeneous atomic groups that are similar or different. Typical heteroatoms or heteroatom groups that can replace carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, and -S(O) -2(S(O)-, -S(O)NH-, -S(O)2NH- and the like, and compounds of such atoms or groups. Heteroatoms or heteroatomic groups may be placed at any internal position From alkyl, alkenyl, or groups

10 Alkenyl. Typical heterogeneous atomic groups that can be included in these groups include, for example the

Inventory, -O-, -S-, -OO-, -SS-, -SO-, -NR201R202- and =NN=

NR203R204-N=N-F -N=N-F

SnR207R208-f -SO2-f -SO-f -P(O)2-O-f -POR206-f -P(O)2-f -PR205-f

15 - And the like, which are R201, R202, R203, R204, R205, R206, and R207.

R208 is independently a hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic alkyl, substituted heterocyclic alkyl, heterocyclic alkyl, heteroaryl, heteroaryl, or Substituted heteroaryl, heteroaryl alkyl, or substituted heteroaryl alkyl.

<p dir="rtl">20 The term "cycloheteroalkyl" or "heterocyclyl", alone or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and optionally any hydrogens attached to them) are replaced Similar or different heterocyclic radical. Likewise, the term “heterocyclic alkylene” or “heterocyclic” refers, alone or as part of another substituent, to a saturated cyclic alkylene radical.</p>

<p dir="rtl">25 Or unsaturated in which one or more carbon atoms (and optionally any hydrogen atoms) are replaced</p>

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The heterocyclic alkyl can also be replaced by one or more heteroatoms, including, but not limited to, nitrogen (N), phosphorus (P), oxygen (O), sulfur (S), and silicon (S). Si), which are linked to the carbon atoms in the heterocyclic alkyl via single or multivalent bonds. The atoms include

<p dir="rtl">5 Typical heteroatoms that replace carbon atom(s) include, but are not limited to, nitrogen (N), phosphorus (P), oxygen (O), sulfur (S), silicon (Si), etc. When a specific level of saturation is intended, Use of the nomenclature “heterocyclic alkenyls” or “heterocyclic alkenyls” Heterocyclic alkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiaranes, and imidazolidines.</p>

<p dir="rtl">10 And morpholine, piperzine, piperidine, pyrrolidine, pyrrolidone, quinoclidine, and the like. In some embodiments, the heterocyclic alkyl group has between 3 and 10 molecules in the ring (3-10 heterocyclic alkyl group) and in other representations, the cycloalkyl group has between 5 and 2 molecules in the ring ( The heterocyclic alkyl group is composed of 2-5 atoms. The heterocyclic alkyl group can be replaced at the heteroatom position,</p>

<p dir="rtl">15 For example, a nitrogen atom with an alkyl group (C6-C1). As specific examples, the definition of “heterocyclic alkyl” includes N-methyl-imidazolidinyl and N-methyl-morpholinyl</p>

And N -methyl-piparzenyl, N -methyl-piperidinyl, N -methyl-p-arzolidinyl, and N -methyl-pyrrolidinyl. The heterocyclic alkyl group may be linked to the rest of the molecule via a carbon atom of the ring or a heteroatom of the ring.

<p dir="rtl">20 In one example, the heterocyclyl includes an “azacyclyl” which refers to a heterocyclic ring in which one or more nitrogen atoms are present. An azcyclyl can also contain other additional heteroatoms, such as oxygen and sulfur. An azcyclyl can be a four-, five-, six-, seven-, or eight-atom ring in which one or more nitrogen atoms are present, such as azitidine, imidazolidine, and morpholine. And piperzine, piperidine, bi-arzolidine, and pyrrolidone</p>

25 And diazepan, azepan, diazocan, and azocan.

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The term “compounds” refers to compounds included in the structural formulas disclosed herein, such as (I), (Ia), (Ib), (Ic), (Id), and (Ie) and includes any compounds identified within such formulas that are disclosed About their structure here. Compounds can be identified by their chemical structure and/or chemical name. When the chemical structure conflicts with the chemical name, it is the chemical structure that determines the identity of the compound. The compounds described here may contain one or more chiral centers and/or double bonds and may therefore exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), optical isomers, or Non-optical encounters. Thus, the chemical structures represented herein include all possible isomers and stereoisomers of the compounds shown, including the stereoisomerically pure formula (e.g., 10 geometrically pure, enantiomerically pure, or enantiomerically pure) and mixtures Optically opposed and isosterically isomerized. Optically isomerized mixtures can be decomposed into optical enantiomers and their component stereoisomers using separation methods or methods for making enantiomeric structures that are well known to those skilled in the art. Compounds can also exist in nucleotide forms including enol form, keto form, and mixtures thereof. Thus, the 15 chemical structures represented here include all possible isoforms of the compounds described. The term "isomers" as used here refers to syndromes that change into each other's forms very easily so that they can exist together in equilibrium. In general, compounds can be hydrated, dissolved, or in liquid form

Amino oxides. Some compounds can exist in multiple crystalline or amorphous forms. 20 In general, all physical forms are equivalent to the uses discussed herein and are intended to be within the scope of this invention. In addition, it should be understood that, when showing partial structures of compounds, parentheses indicate the point at which the partial structure is attached to the rest of the molecule.

The term "halo" refers, alone or as part of another substituent, to the radical fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

The term heteroaryl refers, alone or as part of another substituent, to a monovalent heteroaromatic 25 radical resulting from the removal of a hydrogen atom from a single atom in a ring system.

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Basic heteroaromaticity, as defined here. Heteroaryl groups include, but are not limited to, acridine-derived groups, beta-carboline, chromane, chromine, cinnoline, furane, imidazole, indazole, indole, indolysine, isobenzofuarne, isochromene, isoindole, isoandoline, isoquinoline, isothiazole, isoxazole, naphthyridine

5 Oxadiazole, oxazole, pyrimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrene, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolyzine, quinazoline, quinoline, quinolysine, quinoxaline, tetaryzole, thiadiazole, thiazole, thiophene, triazole, azanthene, and the like. In some representations, the heteroaryl group contains between 5 and 20 atoms per ring (5-20 heteroaryl group

10 atom). In other representations, the heteroaryl group has between 5 and 10 atoms per ring (5-10 atom heteroaryl group). Examples of heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuarne, and benzimidazole. Indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazole.

<p dir="rtl">15 Heteroarylalkyl, alone or as part of another substituent, refers to a noncyclic alkyl group in which one of the hydrogens attached to a carbon atom, usually a terminal or sp3 carbon, is replaced by a heteroaryl group. That is, the heteroaryl alkyl group consists of a heteroaryl group attached to an alkylene group, which in turn is attached to another part of the molecule. The alkylene group present in...</p>

<p dir="rtl">20 A heteroaryl alkyl group is an alkylene that has between 1 and 12 carbon atoms, or</p>

<p dir="rtl">1 To 6 carbon atoms or 1 to 3 carbon atoms. When specific alkyl moieties are intended, the designations heteroarylalkenyl, heteroarylalkenyl, and/or heteroarylalkenyl are used. In some embodiments, the heteroaryl alkyl group is a 6-21 atom heteroaryl alkyl group, for example, the alkaneline moiety or</p>

25 A. The alkylene or alkylene present in the heteroaryl aryl alkyl is an alkylene (C6-C1)

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The heteroaryl moiety is a heteroaryl aryl consisting of 5-15 atoms. In other representations, the heteroaryl alkyl is a 6-13 atom heteroaryl alkyl, e.g., the alkaneline, alkenylene, or alkynyline moiety is an alkylene (C3-C1) and the heteroaryl moiety is a heteroaryl aryl Homogeneous consisting of 5 - 10

5 The art.

The term “protecting group” refers to a group of atoms that, when attached to a reactive functional group in any molecule, blocks, reduces, or prevents the reactive potential of the functional group. Examples of protective groups can be found in Green et al., “Protective

Harrison et al., “Groups in Organic Chemistry”, (Wiley, 2nd ed. 1991

John Wiley and ( 8-“Compendium of Synthetic Organic Methods”, Vols. 1 10

1971 Examples of amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzylbenzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), and 2- Trimethylsilyl-ethanesulfonyl (“SES”), trityl, substituted trityl groups, allyl oxycarbonyls, and 6-fluorenyl

15 Methyl oxycarbonyl (“FMOC”), nitro-vartryloxycarbonyl (“NVOC”) and the like. Examples of hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acetylated or alkylated such as benzyl ethyl ether, along with Alkyl ethers, tetrahydroaryl ethers, tri-alkylsilyl ethers, and allyl ethers.

The term “salt” refers to the salt of any compound, which possesses the required pharmacological activity of the primary compound20. Such salts include: (1) acidic salts, which consist of non-acidic acids

Organic such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; Or it consists of organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, and...

25 Maleic acid, fumaric acid, tartaric acid, citric acid and benzoic acid

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3-(4-Hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, and 4-hydroxybenzoyl acid. Toluene sulfonic acid, camphor sulfonic acid, and 4-methyldimethyl acid

5 Cyclo]2,2,2[-oct-2-ene-1-carboxylic acid, glucoheptonic acid, and 3-phenylpropionic acid

Trimethyl acetic acid, tert butyl acetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, myuconic acid and the like; or (2) salts formed when an acidic proton present in the basic compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordination compounds with an organic base such as ethanolamine, diethanolamine, triethanolamine, and N -Methylglucamine and the like.

“Solvate” is a compound formed by dissolution (mixing of solvent molecules with solute molecules or ions) or a combination consisting of a solute ion or molecule, i.e. a compound of the present invention, with one or more solvent molecules. When water 15 is the solvent, and the “hydrate” is the corresponding dissolution product.

"N-oxide", also known as amine oxide or amine-N-oxide, is a compound derived from a compound of...

Compounds of the present invention by oxidation of the amine group of the compound of the present invention. N-oxide usually contains the functional group R3N+-O- (sometimes written as R3N=O or

.)R3N→O

20 The expression “substituted,” when used to modify a given radical or group, means that one or more of the hydrogen atoms of the given radical or group are each replaced, independently of each other, by a similar or different substituent(s). The term "optically substituted" is either substituted or unsubstituted. For example, an optionally substituted acyclic means that the acyclic ring can be either substituted or unsubstituted, including groups

25 A valid substituent is a saturated carbon atom in the given root or group, e.g

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Examples: -Ra, halo, -O-, =O, -ORb, -SRb, -S-, =S, -NRcRc, =NRb, =ORb-N, trihalomethyl, -CF3, -CN, -OCN -SCN, -NO, -NO2, =N2

OS(O)2Rb-F-S(O)2ORb-F-S(O)2O-F-S(O)2NRb-F-S(O)2Rb-F-N3-F-OS(O)2ORb-F-OS(O) )2O-f

C(S)Rb-and C(O)Rb-and -P(O)(ORb)(ORb)(and -P(O)(ORb)(O-(and -P(O)(O-)25 and C(O)NRcRc-F C(S)ORb-F-C(O)ORb-F-C(O)O-F-C(NRb)Rb-F

OC(O)ORb-, -OC(O)O-, OC(S)Rb-, OC(O)Rb-, C(NRb)NRcRc-,

NRbC(O)ORb-and NRbC(O)O-and NRbC(S)Rb-and NRbC(O)Rb-and OC(S)ORb-and

-NRbC(S)ORb, -NRbC(O)NRcRc, -NRbC(NRb)Rb, and -NRbC(NRb)NRcRc, 10 where Ra is chosen from the group consisting of alkyl, cyclic alkyl, and non-alkyl.

Homocyclic, heterocyclic alkyl, aryl, aryl alkyl, heteroaryl and heterocyclic alkyl; Each Rb is independently a hydrogen or Ra; Each Rc is an Rb independently, or alternatively, both Rc groups may combine with their associated nitrogen atom to form a 4-, 5-, 6-, or 2-atomic heterocyclic alkyl that may optionally include 15 Between 1 to 4 additional heterogeneous, similar or different ones to choose from

The group consisting of oxygen (O), nitrogen (N), and sulfur (S). As specific examples, -NRcRc is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, and N-morpholinyl. As another specific example, substituted alkyl is intended to include -alkylene- Ortho-alkyl, -Heteroaryl alkylene, -Heterocyclic alkylene, -Alkylene-C(O)ORb, -Alkylene-C(O)NRb, Rb 20, -CH2-CH2-C(O)-CH3 One or more substitutive groups may be formed, studied

Together with their associated atoms, a cyclic ring includes cyclic alkyl and heterocyclic alkyl.

Similarly, valid substituent groups for substitution of unsaturated carbon atoms in the radical or given group include, but are not limited to, -Ra, halo, -O-, -ORb, -SRb 25, -S-, -NRcRc, tri-halomethyl, and - CF3, -CN, -OCN, -SCN, -NO, and -NO2

٤٨٥٨

-١٨-

OS(O)2Rb-F-S(O)2ORb-F-S(O)2O-F-S(O)2Rb-F-N3-F

)- P(O)(ORb)(O- 2 and )- P(O)(O- and OS(O)2ORb- and -OS(O)2O- and

C(O)ORb-and C(O)O-and C(NRb)Rb-and C(S)Rb-and C(O)Rb-and (P(O)(ORb)(ORb-OC) S)Rb-and OC(O)Rb-and C(NRb)NRcRc-and C(O)NRcRc-and C(S)ORb-and

NRbC(S)Rb-and NRbC(O)Rb-and OC(S)ORb-and OC(O)ORb-and-OC(O)O-5 and

NRbC(O)NRcRc-and NRbC(S)ORb-and NRbC(O)ORb-and -NRbC(O)O-and

and -NRbC(NRb)Rb and -NRbC(NRb)NRcRc, where Ra, Rb, and Rc are as defined above.

Valid substituent groups for substituting nitrogen atoms in non-10 homogeneous alkyl groups and heterocyclic alkyl groups include, but are not limited to, -Ra, -O-, and -ORb

-SRb, -S-, -NRcRc, trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2Rb

OS(O)2ORb-and -OS(O)2O-and OS(O)2Rb-and S(O)2ORb-and-S(O)2O-and

C(S)Rb-and C(O)Rb-and )P(O)(ORb)(ORb-and )-P(O)(ORb)(O-2 and )-P(O)(O-and C(NRb)NRcRc- and C(O)NRcRc- and C(S)ORb- and C(O)ORb- and C(NRb)Rb- and NRbC(O)Rb- and OC(S)ORb- and OC (O)ORb-, OC(S)Rb-, and OC(O)Rb-15

NRbC(O)NRcRc- and NRbC(S)ORb- and NRbC(O)ORb- and NRbC(S)Rb-

and -NRbC(NRb)Rb and -NRbC(NRb)NRcRc, where Ra, Rb, and Rc are as defined above.

Replaceable groups from the above lists that are valid for replacing other 20 groups or elements will be obvious to those skilled in the art.

The substituents referred to above as represented by chemical formulas are also easily identified by their chemical names known to a person skilled in the art. For example, these substituents include alkyl, heteroalkyl, halo, hydroxyl, alkoxy, amino, alkyl amino, cyano, nitro, haloalkyl, carboxylic acid, amide, ester, acyl, thiol, alkylthio, sulfonamide 25, among others.

٤٨٥٨

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Substituents used to replace a specific group can be further replaced, usually by one or more similar or different groups selected from the several groups specified above.

The term “treating” or “treating” any condition, disease or disorder means improving that condition, disease or disorder (that is, reducing or reducing the worsening of the condition, disease or disorder or at least one of its clinical symptoms). (In other representations, “treatment” or “treatment” refers to improvement of at least one physical parameter, of which the patient may not be aware. In still other representations, “treatment” or “cure” refers to the alleviation of a condition, disease, or disorder, either physically (i.e., stabilizing a perceptible symptom) or physiologically (i.e., stabilizing a parameter 10 Physical) or both. In other representations as well, “treatment” or “treatment” refers to delaying the onset of the condition, disease or disorder.

The expression “therapeutically effective amount” refers to the amount of the present compound that, when administered to a patient to treat a condition, disease or disorder, is sufficient to produce such a therapeutic effect for the condition, disease or disorder. The “therapeutically effective amount” will vary depending on the compound, condition, disease or disorder, the severity of each, the age, weight, etc. of the patient being treated. In one embodiment, a therapeutically effective amount is different from a taste-regulating amount, such as a sweet-taste receptor-regulating amount, a sweet-taste-receptor ligand-regulating amount, a sweet-flavor-regulating amount, or a sweet-flavoring amount.

The term “vehicle” refers to a diluent, adjuvant, excipient or carrier that is administered with the compound.

20 As used herein, the term “ingestible composition” includes any substance that can be taken orally, either alone or with another substance, whether intended for consumption or not. Swallowable composition includes both “food or beverage products” and “non-edible products.” “Food or beverage products” means any edible product intended for consumption by humans or animals, including solids, semi-solids or liquids (e.g., beverages).

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The term “non-edible product” or “non-edible formula” includes any product or formula that can be ingested by humans or animals for purposes other than consumption or other than as a food or beverage. For example, a non-edible product or non-edible formulation includes dietary supplements, pharmaceutical nutrients, and functional food products (e.g., any fresh or processed foods claimed to have health-promoting and/or disease-preventive properties beyond nutritional function).

Essential products (providing nutrients), pharmaceutical and over-the-counter medications, oral care products such as dental cleansers and mouthwashes, cosmetic products such as sweetened lip balms and other personal care products that may or may not contain any sweetener.

“A carrier or acceptably swallowable excipient” is an intermediate and/or composition used to prepare a desired dispersing dosage form of the inventive compound, in order to administer the inventive compound

In a diluted/dispersed form, such that the biological effectiveness of the compound of the invention is doubled. The medium and/or composition may be in any form depending on the intended use of the product, e.g., in solid or semi-solid form, liquid, paste, gel, lotion, cream, foam, suspension, solution or any compounds thereof (e.g. Liquid containing solid contents (including materials

15 Acceptably swallowable carriers of many common food ingredients, such as water at neutral, acidic or basic pH, fruit or vegetable juices, vinegars, marinades, beer and wine, natural water/fat emulsions such as milk or condensed milk, edible oils, edible margarines, fatty acids and derived alkyl esters Including low molecular weight propylene glycol, fatty acid glyceryl ester, diffusing solutions or emulsions.

20 For such hydrophobic substances prepared in aqueous media, salts such as sodium chloride and wheat flours, solvents such as ethanol, edible solid diluents such as vegetable powders, flour or other liquid intermediates; Factors enabling spread or suspension; surfactants; isotonic agents; Thickening or emulsifying agents and preservatives; solid gripping materials; Lubricants and the like.

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According to the present invention, a chemosensory receptor can be any receptor associated with a chemosensory sensation or signal transmission stimulated by a chemosensory ligand, for example, via taste receptors or taste-related receptors represented by taste buds or internal organs. For the body, such as the gastrointestinal tract, etc. In one representation,

5 A chemosensory receptor is a receptor that belongs to the large family of heptad transmembrane receptors or known as G protein-coupled receptors (GPCRs). In another representation, a chemosensory receptor is a receptor that transmits a signal via one or more G proteins. In Another representation is that a chemosensory receptor is a receptor belonging to the C family or class C of G protein-coupled receptors. In one

<p dir="rtl">10 Other representations Also, the chemosensory receptor is a receptor belonging to the T1R family. In yet another representation, the chemosensory receptor is a receptor belonging to the T1R1, T1R2, T1R3 family, their equivalents, variants thereof, or a combination thereof. In yet another representation, the chemosensory receptor is a heterodimer of the T1R2 and T1R3 family or their equivalents or variants thereof.</p>

<p dir="rtl">15 The term “modulator” here refers to an acceptably ingestible compound or salt or dissolution product</p>

of it, which regulates (increases) the activation of a particular receptor, preferably a chemosensory receptor, for example, a T1R3/T1R2 receptor. Such regulators here will act to enhance the activation of the chemosensory receptor through its ligand. The “regulator” will usually Specific to a specific ligand, i.e. it will not enhance activation of a chemosensory receptor by chemosensory ligands other than the ligand

<p dir="rtl">20 or specific closely related chemosensory ligands. Some regulators, at their enhanced ligand concentration level, do not activate the particular receptor on their own. That is, the ligand-enhancing properties of these regulators are concentration levels of the regulators that increase or enhance the activation of a specific receptor by a ligand without activating the specific receptor to a significant extent by the regulators themselves. In some representations, some organizations can also, when used at a higher level of concentration</p>

25 ligand-enhancer, activating a particular receptor alone in addition to regulating (for example, increasing or...

٤٨٥٨

-٢٢-

Improvement) activation of the receptor. For example, some regulators, when used at a concentration level higher than the enhancing concentration of the ligand, can be a sweetener (i.e., a sweet flavoring/sweet flavoring substance) as well. In other representations, some regulators can Activating a particular receptor alone as well as regulating (e.g., increasing or enhancing) receptor activation at the same time and at the same level

5 the focus. In other words, some regulators are also sweeteners (i.e., a sweet flavoring/sweet flavoring substance) at the same time.

The term “flavor” here refers to the perception of taste in an object, which includes sweet, sour, salty, bitter, and umami. The organism may be humans or animals.

The term “flavoring agent” here refers to a compound, the acceptably ingestible salt, or the dissolution product of that compound, which elicits a flavor or taste in an animal or human. The flavoring can be natural, semi-synthetic or synthetic.

The term “flavor modifier” or “flavor modifying agent” here refers to a compound or acceptably ingestible salt or the dissolution product of that compound that modifies, including enhancing and/or arousing, the tastes of a flavor in an animal or human. .

15 The term “flavor modulator” here refers to a compound or an acceptable ingestible salt of that compound that modulates (enhances) and/or amplifies the flavors of a flavoring or ingestible formulation containing the flavoring.

The term "sweet flavor" refers to the sweet taste that a sugar, such as fructose, typically elicits in an animal or human.

20 The term “sweet flavoring agent,” “sweet flavor entity,” “sweetener,” or “sweet compound” herein refers to a tolerably ingestible compound or salt of that compound that produces a detectable sweet flavor sensation in an organism Live, for example, fructose or a compound that activates the T1R3/T1R2 receptor in the laboratory. The organism may be humans or animals.

٤٨٥٨

-٢٣-

The term “sweet flavor modifier” or “sweet flavor modifying agent” herein refers to a tolerably ingestible compound or salt or the dissolution product of that compound which modifies, including enhancing, arousing or blocking, the sweet taste of a flavoring agent. Sweet to an animal or human. The sweet flavor modulator includes both the sweet flavor regulator and the flavorant

5 Sweet.

The terms “sweet flavor modulator” or “sweet flavor modulating agent” herein refer to a sweet flavor modulator where the term modulator is the same as the term defined above.

The term “sweet receptor activating 10 compound” or “sweet receptor agonist” here refers to a compound that activates a sweet receptor, such as the T1R3/T1R2 receptor. An example of a sweet taste receptor-activating compound is a sweetener, such as fructose.

The term “sweet receptor modulating compound” here refers to a compound that modulates (activates, blocks, or enhances/reduces the activation of) a taste receptor.

15 Sweet like the T1R3/T1R2 receiver. For example, a sweet taste receptor-regulating compound may potentiate the effect of a sweet receptor-regulating compound, such as fructose.

The present sweet taste receptor-regulating compound, at its ligand-enhancing concentration level, may or may not activate the particular receptor on its own. Certain sweet taste receptor regulating compounds or sweet flavor regulators can also activate a particular receptor

20 On their own, in addition to regulating (increasing) receptor activation. For example, some compounds that regulate the sweet taste receptor or regulate sweet taste can also activate a sweet taste receptor, such as the T1R3/T1R2 receptor, playing the role of receptor agonists.

The term “sweet flavor modulating amount” here refers to an amount of one of the compounds of Formula (I) sufficient to modulate the sweet taste in an ingestible formulation, or a compound

٤٨٥٨

-٢٤-

Advanced enough to be perceived by a human being. In many embodiments of the invention, at least about 0.001 ppm of the present compound would be required to

Most human beings are able to regulate the sweet flavor of a swallowable formulation containing the compound

Present. It can range from a wide range of concentrations

would normally be used

In order to save

5 The degree of regulation required for sweet flavor is economically between about 0.001 ppm and 100 ppm, or in a narrow range ranging from about 0.1 ppm to about 10 ppm. Alternative ranges for sweet flavor regulating amounts can be from about 0.01 ppm to about 30 ppm, or from about 0.05 ppm to about 15 ppm, or from about 0.1 ppm million to about 5

<p dir="rtl">10 A ppm, or between about 0.1 ppm and about 3 ppm. in</p>

In some examples, the sweet flavor regulator amount is the amount corresponding to the enhancing concentration (concentration) of the ligand for the sweet flavor regulators of the flavors of the present invention.

The term “sweet receptor modulating amount” here refers to an amount of a compound sufficient to regulate (activate, enhance, or block) a sweet receptor protein.

<p dir="rtl">15 In many embodiments of the invention, a regulating amount of a sweet taste receptor is at least about 10 nmol or at least about 100 nmol (i.e., about 0.1 micromole), or at least about 1 micromole, or at least about 10 micromole. A “T1R3/T1R2 receptor activator” is an amount of a compound sufficient to regulate or activate a T1R3/T1R2 receptor. A “sweet taste receptor” is a taste receptor that can be regulated by a sweet compound.</p>

<p dir="rtl">20 Preferably, the sweet taste receptor is one of the G protein-coupled receptors, and more preferably the T1R3/T1R2 receptor.</p>

Vehicles

In one example, the present invention provides a compound with structural formula (I):

٤٨٥٨

-٢٥-

<img file="SA4858B1_D0001.tif" />

(I)

Or a salt or dissolution product (a solution of a solvent and a solute) of that compound; where

A is an optionally substituted four-, five-, six-, seven-, or cyclic A-ring

eight dhaart;

X is a covalent bond or ––NR1;

R1 is a hydrogen or alkyl formed from carbons C1 to C6; And

10

Y is an alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted heteroaryl, arylkyl, or a Substituted aryl alkyl, heteroaryl alkyl, or hetero-substituted aryl alkyl.

In one embodiment of the present invention, formula (I) does not include the following compounds:

<img file="SA4858B1_D0002.tif" />

<img file="SA4858B1_D0003.tif" />

٤٨٥٨

-٢٦-

<img file="SA4858B1_D0004.tif" />

<img file="SA4858B1_D0005.tif" />

<img file="SA4858B1_D0006.tif" />

<img file="SA4858B1_D0007.tif" />

<img file="SA4858B1_D0008.tif" />

<img file="SA4858B1_D0009.tif" />

<img file="SA4858B1_D0010.tif" />

<img file="SA4858B1_D0011.tif" />

<img file="SA4858B1_D0012.tif" />

<img file="SA4858B1_D0013.tif" />

<img file="SA4858B1_D0014.tif" />

٤٨٥٨

-٢٧-

<img file="SA4858B1_D0015.tif" />

In one representation of formula (I), X is NH.

In one representation of formula (I), X are covalent bonds.

In one representation of formula (I), A is an optionally substituted cyclase consisting of five

5 Or six or seven days. In one representation of formula (I), A is an optionally substituted six-a-ring. In one representation of formula (I), A is an optionally substituted piperidine.

In one representation of formula (I), it can be represented as:^{^}The compound has the structural formula (Ia):

, (Ia)

<img file="SA4858B1_D0016.tif" />

10 where,

m can be 1, 2, 3, 4, 5, or 6;

n can be 0, 1, 2, or 3; With the reservation that the value of m+n is more than 1 and less than 2;

q can be 0, 1, 2, 3, 4, 5, or 6; With the reservation that the value of q is less than the value of m+n;

15 X is a covalent bond or –-NR1;

٤٨٥٨

-٢٨-

R1 is a hydrogen or alkyl C1 to C6;

Y is an alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or a substituted heteroaryl.

5 or a substituted arylkyl, heteroaryl alkyl, or heterocyclic substituted aryl alkyl; And

Each R2 is independently selected from the pool consisting of alkyl, hetero-alkyl, halo-hydroxyl, alkoxy, amino, alkyl-amino, cyano-nitro, haloalkyl, carboxylic acid, amide, ester, acyl, thiol, alkylthio, and sulfonamide.

In one representation of the formula (Ia), X is NH.

10 In one representation of the formula (Ia), X is a covalent bond.

In one representation of the formula (Ia), m has the value of 1, 2, 3, or 4; n has the value of 0, 1, or

2.

In one representation of the formula (Ia), q has the value 1, 2, or 3.

In one representation of the formula (Ia), q is 0.

15 In one representation of the formula (Ia), m is 4; n is 0; or m is 3, n is 1; or both m and n are 2.

In one representation of the formula (Ia), it can be represented^{^}The compound has the structural formula (Ib):

<img file="SA4858B1_D0017.tif" />

<img file="SA4858B1_D0018.tif" />

(Ib)

where,

٤٨٥٨

-٢٩-

Y is an alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted heteroaryl, or A substituted arylkyl, heteroaryl alkyl, or heterocyclic substituted aryl alkyl.

5 In one representation of the formula (Ia), the compound can be represented by the structural formula (Ic):

, (Ic)

<img file="SA4858B1_D0019.tif" />

where,

Y is an alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, 10-substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or a substituted heteroaryl.

or a substituted arylkyl, heteroaryl alkyl, or heterocyclic substituted aryl alkyl.

In one representation of the formula (Ia), it can be represented^{^}The compound has the structural formula (Id):

, (Id)

<img file="SA4858B1_D0020.tif" />

where,

15 Y is an alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted heteroaryl, arylkyl, or a Substituted aryl alkyl, heteroaryl alkyl, or hetero-substituted aryl alkyl.

٤٨٥٨

-٣٠-

In one representation of the formula (Ia), it can be represented^{^}The compound has the structural formula (Ie):

, (Ie)

<img file="SA4858B1_D0021.tif" />

where,

Y is an alkyl, a substituted alkyl, a heteroalkyl, or a heteroalkyl

5 Substituted or Carbocyclyl or Substituted Carbocyclyl or Heterocyclic or Heterocyclic

Substituted or aryl or Substituted aryl or Heteroaryl or Substituted heteroaryl or Substituted aryl or Substituted aryl or Heteroaryl alkyl or Substituted heteroaryl alkyl.

In one representation of the formula (Ib), (Ic), (Id), or (Ie), Y is an alkyl with carbons between C1 to C12, a substituted alkyl with carbons between C1 to C12, or a heterogeneous 10th alkyl with A carbon atom between C1 to C12 or a substituted heterogeneous alkyl is formed

A carbon remains between C1 to C12.

In one representation of the formula (Ib), (Ic), (Id), or (Ie), Y is a three- to ten-atomic carbocyclyl, a three- to ten-substituted carbocyclyl, or a three- to ten-atomic heterocyclic Or a substituted heterocyclic compound consisting of three to 15 tenths.

In one representation of the formula (Ib), (Ic), (Id), or (Ie), Y is a six- to fifteen-atom aryl, a six- to fifteen-atom substituted aryl, or a hetero-aryl A five- to ten-atom or substituted heteroaryl consisting of five to ten atoms.

٤٨٥٨

-٣١-

In one representation of the formula (Ib), (Ic), (Id), or (Ie), Y is a -(alkylene C1 to C3)-aryl or -(alkylene C1 to C3)-substituted aryl.

In one representation of the formula (Ib), (Ic), (Id), or (Ie), Y is a -(alkylene C1 to C3)-heteroaryl or -(alkylene C1 to C3)-substituted heteroaryl.

5 In one representation of the formula (Ic) or (Ie), Y is an alkyl with one carbon between C1 to C12, a substituted alkyl with two carbons between C1 to C12, a five- to six-carbon heteroaryl, or a heteroaryl Substituted five to six atoms or – (alkylene C1 to C3) – (heteroaryl substituted five to six atoms) or – (alkylene C1 to C3) – (substituted heteroaryl consisting five to six atoms) In any of these 10 representations, the heteroaryl is a pyrrole, pyridine, pyrimidine, or Pyridazine or p-arzine, each of which is an optional substitute. In any of these representations, the heteroaryl is an optionally substituted pyridine.

In one of the representations of the formula (Ib) or (Id), Y is a carbon-substituted alkyl from C1 to C12, a substituted alkyl from C1 to C12, or a non-carbon alkyl.

15 A homogeneous alkyl composed of a carbon element between C1 to C12 or a substituted heterogeneous alkyl composed of a carbon element between C1 to C12. In any of these representations, either the optionally substituted alkyl from C1 to C12 or the optionally substituted heteroalkyl from C1 to C12 can be straight or branched.

In one representation of the formula (Ib) or (Id), Y is a cycloalkyl consisting of three, 20 four, five, six, or seven atoms or a substituted cycloalkyl consisting of three, four, five, six, seven atoms, or a cyclyl Five-, six-, or seven-atomic heterogeneous or substituted five-, six-, or seven-atomic heterocyclic In any of these representations, the cyclic alkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or heptyl. Cyclocyclic, and each of these compounds is optionally substituent. In any of these previous representations,

٤٨٥٨

-٣٢-

The heterocyclic is either a tetrahydrofuarne or a tetrahydroarene, each of which is optionally substituted.

In one representation of the formula (Ib) or (Id), Y is phenyl or substituted phenyl.

In one representation of the formula (Ib) or (Id), Y is a single-ring heteroaryl aryl

5 Optionally substituted consisting of a five-, six-earth, or bicyclic heteroaryl substituted

Optionally consisting of ten to twelve atoms. In any of these representations, the heteroaryl is selected from the group consisting of pyrrole, pyridine, pyrimidine, pyridazine, pyridine, pyridine N-oxide, quinoline, imidazopyridine, and pyrazolopyridine, each of which is optionally substituted.

10 In one representation of the formula (Ib) or (Id), Y is phenyl–CH2– or phenyl2(C(CH3–) substituted.

In one representation of the formulas (Ib) or (Id), Y is a heteroaryl –CH2– or a substituted heteroaryl –2(C(CH3) ). In any of these representations, the heteroaryl is a pyrrole or Pyridine, pyrimidine, pyridazine, or p-arzine, and each of these is

15 Optional replacement vehicles. In any of these representations, the heteroaryl is an optionally substituted pyridine.

In some specific representations of the formula (I), the compound is chosen from the group consisting of

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Installations

The present compounds may be used in one or more ways of the present invention, e.g., modification

<p dir="rtl">5 The receptors and their ligands related to the chemosensory sensation or reaction or the sensation or reaction related to the chemosensory aspect. According to the present invention, one method of regulating a chemosensory receptor and/or its ligands includes regulating the activity, structure, function, manifestation and/or modification of the chemosensory receptor as well as regulating, manipulating or taking a protective action against A condition, for example, a physiological or pathological condition related to a sensory receptor</p>

<p dir="rtl">10 Chemical. In general, a physiological or pathological condition related to a chemosensory receptor includes a condition, disease, or disorder related to a chemosensory receptor and/or its ligands, e.g., gastrointestinal disorders, metabolic disorders, functional gastrointestinal disorders, etc. In one embodiment, the method includes increasing or enhancing the sweet flavour. In another embodiment, the method includes regulating a sweet taste receptor and/or its ligand that appears in the body.</p>

<p dir="rtl">15 Other than taste buds, like an internal organ. In general, the compounds of the present invention may be provided, individually or combined, in a composition, e.g., an ingestible composition. In one embodiment, the present compound can impart temporary properties and/or sugar-like flavor characteristics to the sweetener composition by blending one or more of the present compounds with one or more sweeteners in the sweetener composition. In another embodiment, the present compound can increase or enhance the sweet taste of one of the compositions.</p>

<p dir="rtl">20 By connecting the aforementioned composition to one or more of these compounds to form a composition with^{^}coffee pot. And in one</p>

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In other representations, the present compound may be in a formulation that regulates sweet taste receptors and/or their ligands appearing in the body in areas other than the taste buds.

Compounds of the formulas (Ie), (Id), (Ic), (Ib), (Ia), (I), their subgenera and various types, and their salts and/or dissolution results, should preferably be reasonably edible materials, e.g. 5 Be qualified as suitable for consumption in food or drink from the perspective of administering unadulterated edible formulations^{^}Provide an enhanced sweet and/or delicious taste and not be significantly toxic or cause irritating or undesirable pharmaceutical or toxicological effects in animals or humans and at concentrations typical of those used in the case of flavorings for edible formulations.

One way to prove that a flavoring compound is plausibly edible is by an Expert 10 Panel of the Flavor and Extract Manufacturers' Associations.

The FEMA/GRAS Association (FEMA) has tested and/or evaluated the compound and declared it “Generally Recognized As Safe”. Well known to those of ordinary skill in the preparation of food products, as discussed 15 by Smith, et al in the article “21 GRAS Flavoring Substances,”

Food Technology Magazine, Volume 52(5), pp. 46-56, May 2003, the entire contents of which are incorporated herein by reference. In addition to the expert committee of the Flavor and Extract Manufacturers' Associations, the manufacturer may establish an independent, qualified expert committee Opinions in relevant scientific disciplines are used to evaluate the safety of a specific compound and the extent to which it meets the “deemed safe” status for 20 years. This process is known as “generally considered safe” self-determination. Another way to prove that a flavoring compound is acceptably edible is to obtain a positive evaluation by the Joint Expert Committee on Food Additives or JECFA of the World Health Organization (WHO)/Food and Agriculture Organization (FAO). . There are also other evaluation methods, such as independent review by the regulatory agency25, which are generally known to those of ordinary skill in preparing food products.

Yes

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In one embodiment, the compounds of the present invention may be used at their ligand-enhancing concentration levels, e.g., very low concentrations at the level of a few parts per million in combination with one or more known sweeteners, natural or artificial, so as to lower the concentration of the sweetener. The knowledge necessary to prepare a swallowable formula that has the required degree of sweetness.

In one embodiment of the present invention, the present compounds can enhance, i.e. increase or multiply, the sweetness of a sweetener over a wide range of pH, for example from low pH to neutral pH. Includes lower and lower pH levels

Neutral acidity, for example, is a pH ranging from about 2.1 to about 8.5; And between about 2.3 to about 8.0; And between about 2.5 to about 2.5; And between 10 and about 2.6 to about 2.3. In one representation, the existing compounds can be strengthened, that is, increased or

The sweetness of a sweetener is doubled within a range of pH levels from about 2.8 to about 2.1. In some embodiments, the present compounds may enhance the perceived sweetness of a fixed concentration of a sweetener in taste tests at a concentration level of the compound of approximately 50 µM, 40 µM, 30 µM, 20 µM, or 10 µM at each of the two values.

15 Low to neutral pH. In some embodiments, the present compound hardening agent at lower pH closely resembles the present compound hardening agent at neutral pH. Such a consistent sweetness-enhancing property over a wide range of pHs makes the current compounds good candidates for broad use in a wide range of foods and beverages.

20 Well-known or other artificial sweeteners used in such sweetener compounds include, but are not limited to, common disaccharide sweeteners, for example, sucrose, fructose, and glucose, and sweetener compounds that contain natural sugars, such as corn syrup (including high-fructose corn syrup). Fructose) or other syrups or concentrates Sweeteners derived from natural fruit and vegetable sources and semi-artificial sweeteners “sugar alcohols” such as erythritol

25 Isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin and similar sweeteners

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Synthetic products such as aspartame, saccharin, acesulfame potassium, cyclamate, sucralose, and itam. Sweeteners also include cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, and hydrogenated glucose syrup.

hydrogenated starch hydrolyzate and hydrogenated starch hydrolyzate (HGS) glucose syrup 5

(HSH), stevioside, rebaudioside A and other stevia-based sweet glycosides, karelium and other guanidine-based sweeteners, etc. The term “sweeteners” also includes compounds of sweeteners as disclosed herein.

In one embodiment, the present compound is added to a non-edible formulation or non-edible product 10, such as dietary supplements, pharmaceutical nutrients, and functional food products (e.g., any foods

Fresh or processed products claimed to have health-promoting and/or disease-protective properties beyond the basic nutritional function of providing nutrients), pharmaceutical products, over-the-counter (OTC) products, and oral care products, such as dental cleansers and mouthwashes , and beauty products such as sweetened lip balms and other 15 personal care products.

In general, over-the-counter (OTC) and oral care products generally refer to products intended for home and/or personal use that can be sold without a prescription and/or without a visit to a medical professional. Examples of over-the-counter products include: 20. Vitamins, nutritional supplements, topical anesthetics, cough, cold and allergy treatments;

And compounds thereof. Vitamins and nutritional supplements include, but are not limited to, vitamins, nutritional supplements, prepackaged nutritional fortifiers/drinks, children's vitamins, nutritional supplements, other nutrition products, products related to nutrition or providing nutrition, and compounds thereof. Analgesics and/or local anesthetics include any topical cream/ointment/gel 25 used to relieve superficial or persistent aches and pains, for example, muscle pain; Teething gel;

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and patches containing an analgesic component; And compounds thereof. Cough, cold, and allergy treatments include, but are not limited to, decongestants, cough syrups, and lotions.

Nasopharyngeal medications, sweets containing medication, antihistamines, and cough, cold, and allergy remedies intended for children; and composite products. These include antihistamines and/or medications

5 Allergies, including but not limited to any systemic treatments for hay fever, allergic rhinitis, and insect bites and stings. Examples of oral care products include, but are not limited to:

Oral cleansing strips, toothpaste, toothbrushes, mouthwash/rinse, and care products

With dentures, mouth fresheners and bleaches

Dentures intended for home use

Dental cleaners and dental floss.

<p dir="rtl">10 In another representation, the existing compounds are added to food or beverage products or formulations. Examples of food and beverage products or compositions include, but are not limited to, the sweet coating, icing sugar, smooth coating of edible products, or any substances included in the soup category, dried processed foods category, beverage category, and/or beverage category. Ready meals and/or canned or preserved foods category and/or food category</p>

<p dir="rtl">15 Frozen Processed and/or Refrigerated Processed Foods Category and/or Snacks Category and/or Baked Goods Category and/or Confectionery Category and/or Dairy Products Category and/or Ice Cream Category and/or Meal Replacements Category and/or Pasta and Noodles Category ( Noodles) and/or the Condiments, Sauces and Dressings category and/or the Baby Foods category and/or the Spreads category.</p>

20

25

In general, the Soup category refers to canned/preserved, dried, instant, refrigerated, ultra-high-temperature soups, and frozen soups. For the purpose of this definition, the term soup means food prepared from meat, poultry, fish, vegetables, grains, fruit and other ingredients cooked in a liquid and the soup may include visible bits of some or all of those ingredients. Soups can be clear (such as broth), thick (such as chowder), smooth, pureed, with large chunks, ready-to-serve or semi-thick.^{^}F or Mukth^{^}It can be served hot or cold, or served as a first course or as a main course in any meal or as a meal

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Light between meals (sip like a drink). Soup can be used as an ingredient to prepare other meal components, which can range from broth (consommé) to sauces (cream- or cheese-based soups).

Dehydrated and Culinary Food Category

<p dir="rtl">5 Typically: (a) Cooking aids such as: powders, granules, pastes and liquid products</p>

Concentrates include concentrated broth and broth-like products in the form of compressed cubes, tablets, powder or granules, which are sold separately as a finished product or as an ingredient in a product, recipe mixtures and sauces (regardless of the technology used to prepare them); (b) meal solution products Such as: dried or freeze-dried soups, including soup mixtures

<p dir="rtl">10 Dried instant soups, dried ready-to-cook soups and ready-to-cook dishes</p>

Dried or ambient temperature form - single meals and main dishes including pasta, potato and rice dishes; (c) Meal garnish products such as condiments, dressings, salad dressings, dips, breads, buttermilk mixtures, spreads that are not affected by storage, barbecue sauces, liquid recipe mixtures, concentrates, sauces or mixtures

<p dir="rtl">15 Sauces, including recipe mixtures for salad that are sold as a ready-made product or as an ingredient in other products, whether dried, liquid or frozen.</p>

The Beverage category usually means beverages and mixtures of beverage concentrates, and includes, for example, carbonated and non-carbonated beverages, alcoholic and non-alcoholic beverages, ready-to-drink beverages, and liquid concentrate formulations for preparing beverages such as

<p dir="rtl">20 Soda, and avant-garde mixtures of drinks in dry powder form. The drinks category also includes alcoholic beverages, soft drinks, sports drinks, isotonic drinks, and hot drinks. Alcoholic beverages include but are not limited to beer, ciders, flavored liqueurs, wines and spirits. Soft drinks include, but are not limited to, soft drinks such as Coke and non-Coke drinks;</p>

25 Fruit juice, such as juice, fruit drinks, juice drinks and fruit-flavored drinks;

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Bottled water, which includes sparkling water and spring water

purified water/table water; Drinks

Functional drinks, which can be carbonated or non-carbonated, include sports drinks and beverages

energy and elixir; Raka Azt like Raka Azt powders and liquids that come in a ready-to-drink standard. Beverages, whether cold or hot, include but are not limited to coffee or coffee

5 Iced coffee, such as instant, fresh and blended coffee; Tea or iced tea, such as black, green, white, flavored, and oolong tea; Other drinks include powders, granules, cubes, or tablets that are mixed with milk or water and are based on plants, malt, or flavorings.

The Snack Food category generally refers to any foods that can be a snack and casual snack and includes but is not limited to sweet and salty snacks and snack bars. Examples of snack foods include, but are not limited to, fruit snacks, chips/crackers, extruded snack foods, tortilla chips/corn, popcorn, pretzels, nuts, and other sweet and salty snacks. Examples of snack bars include but are not limited to granola/muesli bars, breakfast bars, energy bars, fruit bars and other snack bars.

15 The baked goods category generally refers to any edible product that involves exposure to heat or intense sunlight. Examples of baked goods include, but are not limited to, breads, cakes, cookies, muffins, cereals, toasted pastries, pastries, waffles, tortillas, cookies, pies, bagels, tarts, quiches, cakes, any baked foods and any combination thereof.

20 The Ice Cream category generally refers to frozen desserts that contain cream, sugar, and flavoring. Examples of ice cream include, but are not limited to: ice cream that is eaten immediately; Ice cream to take home; Artisanal frozen yogurt and ice cream; Ice creams based on soy, oats, legumes (such as red beans and mung beans), and rice.

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The Confectionary category generally refers to edible products that are sweet in taste. Examples of confectionery include, but are not limited to, candy, gelatin confectionery, chocolate confectionery, sugar-gum confectionery and the like, and any products thereof.

5 The Meal Replacement category generally refers to any foods intended to replace regular meals, especially for people with health or fitness concerns. Examples of meal replacements include, but are not limited to, slimming and recovery products.

The Ready Meal category generally refers to any foods that can be served 10 as meals without extensive preparation or processing. Ready meals include products to which the manufacturer has added his skills and recipes to produce products with a high degree of readiness, completeness and suitability. Examples of ready meals include but are not limited to canned/preserved, frozen, dried and chilled ready meals; dinner mixtures; House Is Frozen; Refrigerated house; And ready-made salads.

15 The Pasta and Noodle category includes any type of pasta and/or vermicelli, including but not limited to canned, dried and chilled/fresh pasta; Regular, instant, chilled, frozen and prepared vermicelli as a snack.

The Canned/Preserved Food category includes, but is not limited to, meat and canned/preserved meat products, fish/seafood 20, vegetables, tomatoes, legumes, fruit, ready meals, soups, pasta, foods

Other canned/preserved foods.

The Frozen Processed Food category includes, but is not limited to, frozen processed red meat, processed poultry, and fish/seafood.

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Processed and processed vegetables, meat substitutes, processed potatoes, baked goods, desserts, ready meals, pizza, soups, noodles and other frozen foods.

The Dried Processed Food category includes but is not limited to rice, dessert mixes, dried ready meals, dried soups, instant soups, dried pasta, regular noodles, and instant noodles.

The Chill Processed Food category includes but is not limited to chilled processed meat, processed fish/seafood products, lunch preparations, fresh fruit, ready meals, pizza, ready salads, soups, fresh pasta and noodles.

10 The Condiments category includes, but is not limited to, tomato paste and puree, stock cubes, herbs, spices, monosodium glutamate (MSG), table sauces, soy-based sauces, pasta sauces, cooking sauces/liquid sauces, and dry sauces/powder mixtures. Ketchup, mayonnaise, mustard, salad dressings and sauces

<p dir="rtl">15 Vinegars, dips, pickled products, sauces, dressings and other condiments.</p>

The Baby Food category includes, but is not limited to, milk- or soy-based formulas; Prepared, dried baby foods and other baby foods.

The Spreads category includes, but is not limited to, jams of all kinds, honey, chocolate spreads, and spreads based on nuts or yeast20.

The Dairy Product category generally refers to edible products produced from the milk of mammals. Examples of dairy products include, but are not limited to, drinkable milk products, cheeses, yogurt, sour-milk drinks, and other dairy products.

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Additional examples of edible compositions, especially food and beverage products or compositions, are given as follows: Typical edible compositions include one or more candies, chocolate confectionery, lozenges, candy bars, packaged candy assortments, plain packaged candy assortments, and rolled candy assortments

<p dir="rtl">5 Chocolate for different occasions, chocolate with toys, Al-Fakhour candy, other chocolate candy, mint candy, regular mint candy, sharp-tasting mint candy, hard candy made by boiling, love-shaped candy, gummies, gelatin candy, chewy candy, toffee candy, caramel candy, nougat, processed candy, lollipops, and licorice candy. Other sugar candy, gum, chewing gum and chewing gum</p>

<p dir="rtl">10 Lozenges, sugar-free gum, functional gum, bubble gum, bread, packaged/artisanal bread, unpackaged/artisan bread, pastries, cakes, packaged/artificial cakes, unpackaged/artisan cakes, biscuits, chocolate-coated biscuits, sandwich biscuits, stuffed biscuits, salty biscuits, pastry Flatbreads, bread substitutes, breakfast cereals, rye cereals, family breakfast cereals, flakes, breakfast cereals</p>

<p dir="rtl">15 With nuts, dried fruits, other grains, baby cereals and cereals</p>

Hot, instant ice cream, instant ice cream, single serving dairy ice cream, single serving water ice cream, multi-portion dairy ice cream, multi-portion water ice cream, take-home ice cream, dairy ice cream

<p dir="rtl">20 Take-home ice cream desserts, non-packaged ice creams, unpackaged take-home ice creams, frozen yoghurt ice creams, artisan ice creams, dairy products, milk, fresh/pasteurized milk, fresh/pasteurized whole milk, fresh/pasteurized semi-skimmed milk, aged milk Long shelf life/ultraviolet sterilized and long shelf life milk/ultimately sterilized whole milk and low-fat milk</p>

<p dir="rtl">25 Long Shelf Life/UHT Skimmed Milk, Long Shelf Life/UHT Skim Milk, Goat's Milk, Concentrated/Condensed Milk, and Milk</p>

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10

15

Unflavored concentrate and condensed milk^{^}And functional and other types of concentrated milk and dairy milk drinks^{^}Flavors and milk drinks^{^}Which contain only dairy products and dairy drinks^{^}Flavors containing fruit juice, soy milk, sour milk drinks, fermented dairy product drinks, coffee creamers, powdered milk, and non-fat powdered milk drinks.^{^}Flavor, cream, cheese, processed cheese, spreadable processed cheese, hard cheese, packed hard cheese, unpacked hard cheese, yogurt, unfatty yogurt^{^}K/Natural yoghurt and manna^{^}Fruit yogurt, probiotic yogurt, yogurt drink, regular yogurt drink, probiotic yogurt drink, refrigerated desserts designed to be stored at room temperature, dairy-based desserts, soy-based desserts, refrigerated snacks, soft brie and unsalted brie^{^}And soft white cheese^{^}Salty and brie, sweet and salty snacks, fruit snacks, chips/crackers, extruded snacks, tortilla chips/corn, popcorn, pretzels, nuts, other sweet and salty snacks, snack bars, granola bars, breakfast bars, energy bars, fruit bars and other snack bars other meal replacement products, slimming products, recovery drinks, ready meals, packaged ready meals, frozen ready meals, meals Dried ready-made

Chilled Ready Meals, Dinner Mixes, Frozen Pits, Refrigerated Pits, Soups, Canned Soups, Dried Soups, Instant Soups, Chilled Soups, Hot Soups, Frozen Soups, Pasta, Canned Pasta, Dried Pasta, Chilled/Fresh Pasta, Vermicelli, Regular Noodles 20, Instant Noodles, Instant Noodles in Cups/ Bowls, Instant Noodles in Bags, chilled noodles, noodles for snacks, canned food, canned meat, canned meat products, fish/fruit Canned sea, canned vegetables, canned tomatoes, canned beans, canned fruits, canned ready meals, canned soup, canned pasta, other canned foods, frozen food, frozen processed red meat, processed poultry

<p dir="rtl">25 Frozen processed fish/seafood Frozen processed vegetables Frozen meat substitutes Frozen potatoes Frozen oven-baked potato chips Frozen potato products</p>

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Other oven baked, non-oven baked frozen potatoes, frozen baked goods, frozen desserts, frozen ready meals, frozen pizzas, frozen soups, frozen noodles, other frozen foods, dried foods, dessert mixes, dried ready meals, dried soups, instant soups, dried pasta, unbaked noodles^{^}Kiha, instant vermicelli and vermicelli

<p dir="rtl">5 Instant in cups/bowls, bagged noodles, chilled foods, chilled processed meats, chilled fish/seafood products, chilled processed fish, chilled smoked fish, chilled lunch kits, chilled ready meals, chilled pizzas, chilled soups, chilled/fresh pasta, chilled vermicelli, oils and fats, olive oil, vegetable oils Seeds, cooking fats, butter, margarine, oils, spreadable fats, and transmissible fats</p>

<p dir="rtl">10 For functional spreads, sauces, dressing mixes, condiments, tomato pastes, crushed tomatoes, stock cubes, herbs, stock cubes, stock granules, liquid stocks, herbs, seasonings, fermented sauces, soy-based sauces, pasta sauces, liquid sauces, dried sauce mixes/powders, ketchup, mayonnaise, regular mayonnaise, mustard, salad dressing mixes and salad dressing mixes Regular, low-fat salad dressing blends, and vinegar and oil blends</p>

<p dir="rtl">15 Dips, pickles, other sauces, seasoning mixes, condiments, infant foods, infant formula, regular infant formula, formula for infants over 6 months, formula for infants over 1 year, hypoallergenic infant formula, ready-to-eat infant food, powdered infant food, other infant foods and specialty foods For spreads, jams, preserved foods, honey, chocolate intended for spreads and foods</p>

<p dir="rtl">20 Spreads made from nuts and spreads made from yeast. Typical edible compositions also include candy, baked goods, ice cream, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pasta, noodles, canned foods, frozen foods, dried foods, refrigerated foods, oils and fats, infant foods or spreads, or combinations thereof.</p>

<p dir="rtl">25 Installations. Typical edible formulations also include breakfast cereals or beverages</p>

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Sweet or liquid substrate formulations for the preparation of beverages, ideally to enable a reduction in the concentration of previously known polysaccharide or artificial sweeteners.

Typically, a sweet taste receptor buffer, a sweet taste receptor ligand buffer, a sweet taste receptor buffer, a sweet flavoring agent, or

<p dir="rtl">5 A therapeutically effective amount of at least one or more of the present compounds to the ingestible composition, optionally in the presence of known sweeteners, e.g., for the composition to have a sweet flavor with^{^}The swallowable formula provides an increase in sweet taste compared to the swallowable composition prepared without the compounds of the present invention, as governed by humans and animals in general, or in the case of testing compositions, as governed by most</p>

Members of a panel of eight human taste testers, using known procedures

10 General in the field.

It is certain that the concentration of sweet flavoring is required to regulate or improve the flavor of the formula

Swallowing will depend on a variety of factors, including the specific type of swallowable formulation and its ingredients

various other flavors, in particular the presence of other known flavourings, the concentrations of those flavourings, the natural genetic variation and preferences of people, and the health conditions of the various people who

15 They taste the compositions and subjective effect of certain compounds when tasting those chemosensory compounds.

One application of the present compounds is to regulate (excitation, potentiation or inhibition) the sweet taste or other taste properties of other natural or synthetic sweet taste stimulants and ingestible compositions made thereof. In one embodiment, the compounds of the present invention are used or provided in Turkey. For example, a wide but low range of concentration concentrations of the compounds or substances of the present invention would be required, for example, typically between about 0.001.

ppm to 100 ppm or alternative narrower ranges from about 0.1 ppm to about 10 ppm or from about 0.01 ppm to about 30 ppm or from about 0 ppm 05 ppm to about 10 ppm, or about 0.01 ppm, to about 5 ppm, or about 0.02.

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ppm to about 2 ppm or between about 0.01 ppm to about 1 ppm.

In one embodiment, the present invention provides a structured composition for a sweet taste. The sweet-tasting composition contains a compound of the present invention in an amount that is effective in providing a sweetener, such as a regulated amount

5 For a sweet taste mixed with an initial amount of sweetener, where the sweetening is greater than the sweetness provided by the initial amount of sweetener without the compound.

In one embodiment, the present invention provides a swallowable composition containing the sweet taste regulating composition of the present invention. In some embodiments, the present ingestible composition is in the form of a food or beverage, a pharmaceutical formulation, a food product, a nutritional supplement, or a dispensable drug.

10 Prescription or oral care product.

In one embodiment, the present invention provides a substitute composition for a sweetener containing one or more compounds of the present invention in an amount effective in providing a sweetener, e.g., at a concentration higher than its enhancing concentration of the ligands when the sweetener is absent, e.g., sucrose other than the present compounds.

According to another aspect of the invention, the compounds of the present invention are presented in a flavoring concentrate composition, at

15 For example, suitable for subsequent processing to produce a ready-to-use (i.e., ready-to-serve) product. “Flavoring substrate formulation” means a formulation that must be reconstructed with one or more dilution media to become a ready-to-use formulation. The term “ready-to-use formulation” is used herein interchangeably with “flavoring substrate formulation” “Swallowable” means any substance that can be taken orally, either alone or with another substance, whether or not intended for consumption. In one embodiment, the ready-to-use composition includes a composition that can be consumed

20 Human or animal directly. Typically, a flavoring substrate composition is used by mixing it with or diluting with one or more dilution media, e.g., any consumable or ingestible ingredient or product, to impart or modify one or more flavors in the dilution medium. This process of use is often referred to as rebuilding. Reconstruction can be performed in a home or industrial environment. For example, a consumer in a kitchen might rebuild a substrate

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Juice frozen fruit with water or another aqueous medium to obtain a ready-to-use fruit juice drink. In another example, an industrial entity on large industrial scales could reconstruct a soft drink drinker's substrate with water or another aqueous medium to produce ready-to-use soft drinks. Since a flavored substrate formulation has a flavoring or flavor modifier at a higher concentration than a ready-to-use formulation, a flavored substrate formulation is typically not suitable for direct consumption without reconstruction. There are many benefits to using and producing a flavoring concentrate formulation. For example, one benefit is reduced weight and volume for transport since the flavoring substrate composition can be reconstructed at the time of use by adding the appropriate solvent, solid or liquid.

10

15

In one embodiment, the flavoring substrate composition contains a) a compound of the present invention as a flavor-modifying ingredient; b) a carrier; and c) optionally, at least one excipient. The term “flavor-modifying ingredient” indicates that the compound of the present invention Acts as a flavoring or flavor modifier (as a flavor regulator, for example) in the formulation. The term “carrier” refers to an accessory, usually inactive, such as a solvent, binder, or other inert intermediate, which is used in a composition with the existing compound and one or more optional auxiliaries to make up the composition. For example, water or starch can be the carrier for a flavoring substrate formulation. In some embodiments, the carrier is the same as the dilution medium used to reconstitute the flavoring substrate composition; In other representations, the carrier differs from the dilution medium. The term “carrier” as used herein includes, but is not limited to, a carrier material that is acceptably ingestible.

The term “adjuvant” refers to an additive that serves to supplement, stabilize, or enhance

20 Or maintaining the required function or effectiveness of the active substance, such as the compound of the following invention. In one embodiment, the at least one excipient contains one or more flavourings. The flavoring may be any flavor known to the person skilled in the art or to consumers, such as chocolate, coffee, tea, mocha, French vanilla, peanut butter, spiced tea, or combinations thereof. In another representation, one adjuvant contains:

25 At least one or more flavourings. One or more of the local^s can be on either

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Sweeteners described in this application. In another embodiment, the at least one adjuvant contains one or more components selected from the group consisting of an emulsifier, a stabilizer, an antimicrobial preservative, an antioxidant, vitamins, minerals, fats, starches, oracases, protein isolates, and salts and compounds thereof. There are examples of emulsifiers and stabilizers

<p dir="rtl">5 Antimicrobial preservatives, antioxidants, vitamins, minerals, fats, starches, enzymes, protein isolates, and salts are described in US No. 6,468,576, the contents of which are incorporated herein in full by reference for all purposes.</p>

In one embodiment, the present flavoring substrate composition can be in a form selected from the group containing a liquid, including a solution, a suspension, a solid, a foam, a paste, a gel 10, a cream, and a composition thereof, such as a liquid containing a certain amount of solid contents. In one representation,

The flavoring substrate composition is in liquid form including water-based and non-water-based liquid. The current flavoring substrate composition can be carbonated or non-carbonated.

The flavoring substrate composition may also contain a freezing point inhibitor, a nucleophilic agent, or both as at least one adjuvant. A freeze point inhibitor is a compound or solvent agent

<p dir="rtl">15 For acceptable ingestion which can stabilize the freezing point of the liquid or solvent to which the compound or agent is added. That is, a liquid or solution that contains a freezing point inhibitor has a lower freezing point than a liquid or solvent that does not contain a freezing point inhibitor. In addition to inhibiting the freezing onset point, a freezing point inhibitor may also reduce the water activity of the flavoring substrate formulation. Examples of a freezing point inhibitor include, but are not limited to, carbohydrates</p>

<p dir="rtl">20 Oils, ethyl alcohol, polyols, such as glycerol and compounds thereof. Nucleigenic factor refers to a tolerably swallowable compound or agent capable of facilitating the formation of nucleoli. The presence of a nucleating agent in the flavoring concentrate formulation can improve the mouthfeel of crushed ice in an iced slush drinker and help maintain the physical properties and functionality of the slush drink at freezing temperatures by increasing the number of ice crystallization centers required. Examples of component factors include:</p>

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The cores include, but are not limited to, calcium silicates, calcium carbonate, titanium dioxide, and compounds thereof.

In one embodiment, the flavoring substrate composition is prepared to have low activity in water to have a long shelf life. Water activity is the ratio of water vapor pressure in combination to...

<p dir="rtl">5 The vapor pressure of pure water at the same temperature. In one embodiment, the flavoring substrate composition has a water activity of less than about 0.85. In another example, the flavoring substrate composition has a water activity of less than about 0.80. In another embodiment, the flavoring substrate composition has a water activity of less than about 0.25.</p>

In one embodiment, the flavoring substrate composition contains the present compound in a concentration at least twice

<p dir="rtl">10 Concentrate the compound into a ready-to-use formulation. In one embodiment, the flavoring substrate composition contains the present compound in a concentration that is at least 5 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavoring substrate composition contains the present compound in a concentration that is at least 10 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavoring substrate composition contains the present compound in a concentration that is at least 15 times the concentration of the compound in the finished composition</p>

15 To use. In one embodiment, the flavoring substrate composition contains the present compound in a concentration that is at least 20 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavoring substrate composition contains the present compound in a concentration that is at least 30 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavoring substrate composition contains the present compound in a concentration that is at least 40 times the concentration of the compound in the ready-to-use composition. In one representation, it contains...

20 Flavoring substrate composition The existing compound is at a concentration that is at least 50 times the concentration of the compound in a ready-to-use formulation. In one embodiment, the flavoring substrate composition contains the present compound in a concentration that is at least 60 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavoring substrate composition contains the present compound in a concentration up to 100 times the concentration of the compound in a ready-to-use composition.

25 Therapeutic uses

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In one aspect of the present invention, the present compounds may be used for therapeutic purposes. That is, existing compounds can be used in ways to regulate a chemosensory receptor and/or its ligand to achieve a therapeutic effect. For example, the current method involves regulation of a chemosensory receptor and/or its ligand that is expressed in the body in non-bud areas

5 Taste.

In one embodiment, the method of the present invention includes, for example, regulating a chemosensory receptor and/or its ligand, regulating the production, secretion, and/or functional level of T1R receptor-producing cells related to hormone, peptide, and enzyme production. In one example, the method of the present invention includes regulating a glucose level, for example, receptor inhibitors may be used

10 A chemosensory receptor such as T1R2 can help lower glucose levels (e.g., glucose uptake) in an organism. In another example, the method of the present invention includes regulating the level of incretins, for example, a chemosensory receptor agonist such as T1R2 can be used to increase peptide glucagon-like (1-GLP) and thus increasing insulin production. In yet another example, the method of the present invention includes regulating the level of production, secretion, and/or activity

15 Hormones or peptides produced by T1R receptor-producing cells or gastrointestinal hormone-producing cells, e.g., 5-HT receptor ligands (e.g., serotonin) and incretins (e.g., glucagon-like peptide-1 and glucose-dependent insulin secreting polypeptide (GIP) (), gastrin, secretin, pepsin, cholecystokinin, amylase, ghrelin, leptin, somatostatin, etc. In yet another example, the method of the invention includes

20 Current regulation of pathways related to hormones, peptides and/or enzymes secreted by cells producing T1R receptors.

In another embodiment, the method of the present invention includes, for example, regulating a chemosensory receptor and/or its ligand, regulating the activity of T1R receptors (e.g., T1R1, T1R2, or T1R3), and from such cells, e.g. Liver (e.g., cells).

25 Hepatocytes, endothelial cells, Kupffer cells, stellate cells, epithelial cells of the duct,

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etc.), cardiac cells (e.g., endothelial cells, cardiac cells, smooth muscle cells, etc.), pancreatic cells (e.g., alpha cell, beta cell, delta cell, pancreatic neurosecretory polypeptide cell, D1 cell, etc.) and cells in of the nipple (e.g., ductal epithelial cells, etc.) and stomach cells (e.g., mucus cells, parietal cells, principal cells, G cells,

5 P/D1), intestinal cells (e.g., enteroendocrine cells, brush cells, etc.), and gland cells

Salivary cells (e.g., mucous serous cells, mucous cells, myoepithelial cells, intercalated duct cells, striated duct cells, etc.), L cells (e.g., GLP-1-producing cells, etc.), and chromophile enteric cells (e.g., GLP-producing cells serotonin), intestinal chromaffin-like cells, G cells (e.g., gastrin-producing cells) and D cells (delta cells, e.g.

10 somatostatin-producing cells), I cells (e.g., cholecystokinin (CCK)-producing cells), K cells (e.g., gastric inhibitory polypeptide-producing cells), P/D1 cells (e.g., ghrelin-producing cells), chief cells (e.g., pepsin-producing cells), and S cells (e.g. , secretin-producing cells). In one example, the method of the present invention includes increasing the level of production of T1R receptors in T1R-producing cells. In another example, the method of the present invention includes

15 Increasing the secretion level of cells producing T1R receptors.

In yet another embodiment, the method of the present invention includes, for example, regulating a chemosensory receptor and/or its ligand, and regulating, treating and/or taking a preventive action against a condition associated with the gastrointestinal tract including, For example, but not limited to, conditions associated with esophageal motility (e.g., cricopharyngeal achalasia, hysterical condyle, achalasia).

20 Achalasia, diffuse esophageal spasm, related motility disorders, esophageal scleroderma, etc.), inflammatory disorders (e.g., gastroesophageal reflux, esophagitis, infectious esophagitis, etc.), peptic ulcer, duodenal ulcer, gastric ulcer, gastrinoma, ulcers, stress erosions, ulcers drug-related complications, gastritis, esophageal cancer, stomach tumors, and absorption disorders (e.g., absorption of certain nutrients, such as

<p dir="rtl">25 Carbohydrates, protein, amino acids, fats, cholesterol, and soluble vitamins</p>

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fats, water, sodium, calcium, iron, water-soluble vitamins, etc.), dyspepsia disorders, mucosal dysfunction (e.g., inflammatory or infiltrative disorders, biochemical or genetic anomalies, endocrine disorders, metabolic disorders, protein-losing enteropathy, etc. (And the mother of the land of autoimmunity in the digestive tract) such as,

<p dir="rtl">5 Celiac disease, Crohn's disease, ulcerative colitis, etc.) Colorectal cancer, small intestine tumors, anal cancers, hepatic metabolic disorders, hyperbilirubinemia, hepatitis, and other diseases.</p>

<p dir="rtl">10 Alcohol-related liver disease, cirrhosis, biliary cirrhosis, liver tumors, infiltrative and metabolic diseases affecting the liver (e.g., fatty liver, Rey's syndrome, diabetic glycogenosis, glycogen storage disease, Wilson's disease, hemochromatosis), diseases of the gallbladder and bile ducts, and Pancreatic tumors (eg, pancreatitis, exocrine exocrine insufficiency, pancreatic cancer, etc.), endocrine tumors of the gastrointestinal tract and pancreas, etc.</p>

<p dir="rtl">15 In yet another embodiment, the method of the present invention includes, for example, regulating a chemosensory receptor and/or its ligand, regulating, treating and/or taking a preventive action against a condition associated with metabolic disorders, e.g. Appetite, body weight, food or fluid intake, the reaction of any organism to food or fluid intake, a state of satiety, or any organism’s perception of a state of satiety, food intake and its regulation (for example, resulting malnutrition</p>

<p dir="rtl">20 (e.g., hypothyroidism, Cushing's disease, insulinoma, hypothalamic disorders, etc.) and eating disorders (e.g., anorexia nervosa, Bulimia, etc.), deficiency and hypervitaminosis, insulin metabolism, diabetes (type 1 and type 2) and its complications (for example, circulatory disorders, retinopathy, nephropathy</p>

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Diabetes, diabetic neuropathy, diabetic foot ulcers, etc.), glucose metabolism, lipid metabolism, hypoglycemia, hyperglycemia, hyperlipoproteinemia, etc.

In yet another embodiment, the method of the present invention includes, for example, regulating a chemosensory receptor and/or its ligand, regulating, treating and/or taking a preventive action against

<p dir="rtl">5 A condition associated with functional gastrointestinal disorders, for example, in the absence of any specific pathological condition such as peptic ulcer or cancer, the organism has abdominal indigestion, for example, a feeling of flatulence, nausea, vomiting, abdominal pain, or loss of appetite Or gastric acid reflux or abnormal bowel movements (constipation, diarrhea, etc.), optionally depending on the retention of contents within the gastrointestinal tract, especially in</p>

<p dir="rtl">10 Stomach. In one example, a functional gastrointestinal disorder includes a condition without any organic disease of the gastrointestinal tract but with one or more reproducible gastrointestinal symptoms that affect the quality of life of an organism, for example, a human being.</p>

Examples of functional gastrointestinal disorders include, without limitation, functional dyspepsia and diarrhea

<p dir="rtl">15 Gastroesophageal reflux, diabetic gastroparesis, reflux esophagitis, gastrointestinal dysfunction after surgical or similar operations, nausea, vomiting, feeling unwell, heartburn, feeling of flatulence, heaviness in the stomach, belching, cramping pain, chest pain, stomach discomfort, loss of appetite, dysphagia, gastric acid reflux. Abdominal pain, constipation, diarrhea, difficulty breathing, feeling of suffocation, low motivation or energy level, and blockage.</p>

<p dir="rtl">20 Pharynx, feeling of foreign matter, feeling tired easily, neck stiffness, tonic muscle spasm, dry mouth (dry mouth, thirst, etc.), rapid breathing, burning sensation in the gastrointestinal tract, feeling of coldness in the extremities, difficulty concentrating, restlessness, restless sleep, headache, feeling generally unwell, palpitations, night sweats, anxiety Dizziness, dizziness, sudden fever, excessive sweating, depression, etc.</p>

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In yet another embodiment, the method of the present invention includes, for example, regulating a chemosensory receptor and/or its ligand to increase or enhance the digestion, absorption, and/or level of a nutrient in the blood and/or movement of the gastrointestinal tract in Any organism that, for example, promotes gastric emptying (ie, the emptying of stomach contents) and reduces flatulence in the early period

<p dir="rtl">5 After meals, improving the state of anorexia, etc. In general, such an enhancement can be achieved either directly or by increasing the secretion of one of the regulatory substances, e.g., hormones, etc.</p>

In yet another embodiment, the method of the present invention includes, for example, regulating a chemosensory receptor and/or its ligand, augmenting one or more gastrointestinal functions of an organism, for example, to improve quality of life or health status Atheist

10 Organisms.

In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the present invention or a salt, dissolution product and/or prodrug of such composition, optionally together with a suitable amount of a pharmaceutically acceptable intermediate. In another embodiment, the pharmaceutical composition contains a therapeutically effective amount of one or more compounds of the invention.

<p dir="rtl">15 the present, salt, dissolution product and/or prodrug of that composition; An appropriate amount of a pharmaceutically acceptable intermediate substance to provide the appropriate dosage form for administration to the patient.</p>

In one embodiment, the compounds of the present invention and optional pharmaceutically acceptable intermediates are sterile, when administered to any patient. In one embodiment, water is a preferred feedstock when one of the compounds of the present invention is to be used intravenously. Solutions can also be used

<p dir="rtl">20 Saline, aqueous dextrose and glycerol solutions are used as liquid intermediates, especially for injection solutions. Suitable pharmaceutical intermediates include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice flour, lime, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. It can also, if desired, be included</p>

<p dir="rtl">25 Current pharmaceutical formulations contain minor amounts of wetting or emulsifying agents or agents</p>

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Regulating the degree of acidity. In addition, auxiliary agents, stabilizing agents, thickening agents, softening agents and coloring agents can be used.

Pharmaceutical compositions containing a compound of the present invention may be manufactured by conventional mixing, dissolution, granulation, dressing, crushing, or converting processes

<p dir="rtl">5 To emulsion, encapsulation, detention or lyophilization. Pharmaceutical compositions may be prepared by conventional methods using one or more physiologically acceptable carriers, diluents, excipients or cofactors, which facilitate the process of converting the compounds of the present disclosure into preparations that can be used pharmaceutically. Proper installation depends on the method of use chosen.</p>

<p dir="rtl">10 Existing pharmaceutical formulations can take the form of solutions, suspensions, emulsions, tablets, tablets, pellets, capsules, liquid capsules, powders, extended-release formulations, suppositories, emulsions, aerosols, aerosols, suspensions, or any other form suitable for use. In some embodiments, the pharmaceutically acceptable intermediate is...</p>

Grosswald et al., United States Patent No. , capsule (see e.g

<p dir="rtl">15 5,698,155). Other examples of suitable pharmaceutical intermediates have been described in the field (see</p>

Remington: The Science and Practice of Pharmacy, Philadelphia College

.)of Pharmacy and Science, 20th Edition, 2000

For topical use, any compound of the present invention may be prepared in the form of a solution, ointment, cream, suspension, etc. as is well known in the art.

20 Systemic formulations include those designed for parenteral use, for example, subcutaneous, intravenous, intramuscular, intracanal, or intraperitoneal use, as well as those designed for cutaneous, transmucosal, or oral use. Or pulmonary. Systemic formulations may be prepared by compounding them with another active ingredient that improves mucociliary clearance of airway mucus or

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Reduces the viscosity of mucus. These active ingredients include, but are not limited to, sodium channel blockers, antibiotics, N-acetylcysteine, homocysteine, and phospholipids.

In some embodiments, the compounds of the present invention are prepared according to routine procedures as a pharmaceutical composition intended for intravenous use in humans. Compounds of the present invention adapted for intravenous use are typically solutions in sterile isotonic aqueous buffer. For injection, one of the compounds of the present invention may be prepared in aqueous solutions, preferably in physiologically compatible control agents such as Hank's solution, Ringer's solution, or physiological buffer saline. The solution may contain formulation agents such as suspending, stabilizing and/or diffusing agents. When required, pharmaceutical formulations may also include a dissolution inducing agent.

<p dir="rtl">10 Pharmaceutical compositions for intravenous use may optionally include a local anesthetic such as lignocaine to relieve pain at the injection site. In general, the components are supplied either separately or mixed together in the form of injection units, for example, as a lyophilized powder or a water-free substrate in a tightly closed container such as an ampoule or sachet indicating the amount of active ingredient. When the compound of the present invention is administered by infusion, it can</p>

<p dir="rtl">15 It is dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or sterile saline solution. When the compound of the present invention is used by injection, an ampoule may be provided containing sterile water for injection or saline so that the components can be mixed before use.</p>

For transmucosal administration, penetrating materials are used

<p dir="rtl">20 Suitable for the barrier that will be penetrated in the composition. Such insightful material is generally well known in the industry.</p>

Pharmaceutical compositions intended for oral administration can be in the form of tablets, lozenges, aqueous or oil suspensions, granules, powders, emulsions, capsules, syrups or elixirs, for example. Pharmaceutical formulations for oral use may contain an agent

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optionally one or more, for example, sweeteners such as fructose, aspartame or saccharin; and flavorings such as peppermint, Canada tea oil, or cherry; Colors and preservatives, to provide a pharmaceutically palatable preparation.

10

Furthermore, when pharmaceutical formulations are in the form of tablets or pills, they can be coated to slow disintegration and absorption in the gastrointestinal tract, thus providing sustained effectiveness for an extended period of time. Selectively permeable membranes surrounding an osmotically active parent compound are also suitable for orally administered compounds of the present invention. In these methods, the main compound absorbs liquid from the environment surrounding the capsule and swells to expel the agent or agent formulation through an opening. These delivery vehicles can provide delivery profiles that are considered to be zero-grade compared to those of immediate-release formulations with peaks of release. A time-slowing substance such as monostia glycerol or stiaart glycerol can also be used. Oral formulations may include standard intermediates such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such intermediates should preferably be of pharmaceutical grade.

15 For oral liquid preparations such as, for example, suspensions, elixirs, and solutions, the appropriate carriers, excipients, or diluents include water, saline, alkylene glycolate (e.g., propylene glycol), and polyalkylene glycolate (e.g., propylene glycol). polyethylene), oils, alcohols, and insulating materials with a low pH between pH 4 and pH 6 (e.g., acetate, stearate, 20 ascorbate at a concentration of about 5.0 mM And about 50.0 mM) etc. In addition, flavours, preservatives, colourings, yellow salts, acylcarnitines and the like can be added.

For buccal administration, pharmaceutical formulations can take the form of tablets, lozenges, etc. which are prepared in a traditional way.

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Liquid drug compositions suitable for use with nebulizers, liquid nebulizers, and electrohydrodynamic nebulizers will typically comprise one of the compounds of the present invention together with a pharmaceutically acceptable intermediate. The pharmaceutically acceptable mediator is preferably a liquid such as alcohol, water, polyethylene glycol, or perfluorocarbon. Another material can optionally be added to change the spray properties

5 For the solution or suspension of the compounds of the invention. Preferably, this substance is a liquid such as alcohol, glycol, polyglycol or fatty acid. Other methods for preparing liquid drug solutions or suspensions suitable for use in nebulizers are known to those skilled in the art (see, on

Biesalski, United States Patent No. 5,112,598; Biesalski, United, for example

.)States Patent No. 5,556,611

10 A compound of the present invention may also be prepared in the form of rectal or vaginal pharmaceutical compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the previously described compositions, one of the compounds of the present invention may be prepared as a stock preparation. Such extended-release formulations can be used by implantation (on...

15 (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, one of the compounds of the present invention may be prepared using polymeric or hydrophobic materials (e.g., as an emulsion in acceptable oil), an ion-exchanged arginine, or As a poorly soluble salt.

One of the compounds of the present invention and/or pharmaceutical compositions of those compounds will generally be used in an amount effective to achieve the intended purpose. When using compounds of the present invention and/or compositions

20 Pharmaceutical ones for the treatment or prevention of diseases or disorders, given or used in a therapeutically effective quantity.

The amount of a compound of the present invention that will be effective in treating a specific disorder or condition disclosed herein will depend on the nature of the disorder or condition and such amount may be determined by standard clinical methods known in the art. In addition, assays can be used

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Optionally in vitro or in vivo to help determine optimal dose ranges. The amount of a compound of the present invention will, of course, depend, among other factors, on the organism being treated, the weight of the organism, the severity of the disease, the method of use, and the judgment of the treating physician.

For example, the dose in a pharmaceutical formulation may be delivered by a single application or

5 Multiple uses or controlled release. In some embodiments, the compounds of the present invention are delivered by extended-release oral administration. Doses may be repeated intermittently, may be given alone or with other drugs, and may be continued as necessary to achieve effective treatment of the disease or disorder.

Suitable dose ranges for oral use depend on strength, but generally range from about 10 0.001 mg to about 200 mg of one of the compounds of the present invention per kilogram of body weight.

the body. Dosage ranges can be easily determined using methods known to those of ordinary skill in the art.

The appropriate dose ranges for intravenous use range from about 0.01 mg to about 100 mg per kilogram of body weight.

15 Intranasal dosage is generally between about 0.01 mg/kg body weight and about 1 mg/kg body weight. The suppositories generally contain about 0.01 milligram to about 50 milligram of one of the compounds of the present invention per kilogram of body weight and contain an active ingredient in the range from about 0.5% to about 10% by weight. The recommended doses are for transdermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, or intraperitoneal use.

20 The brain is in a range that ranges between about 0.001 mg and about 200 mg per kilogram of body weight. Effective doses can be inferred from dose-response curves from typical in vitro or animal test systems. Such models and systems applied to animals are well known in the field.

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In one embodiment, a therapeutically effective dose of a compound of the present invention described herein will provide a therapeutic benefit without causing significant toxicity. The toxicity of the compounds of the present invention can be determined using standard pharmaceutical procedures and can be easily ascertained by someone well versed in the art. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index. Will be

5 It is preferable that one of the compounds of the present invention exhibits high therapeutic indicators in the treatment of diseases and disorders. It would preferably be that the dose of a compound of the present invention described herein falls within a range of common concentrations that include an effective dose with little or no toxicity.

In some embodiments of the present invention, the compounds of the present invention and/or pharmaceutical compositions thereof may be used in combination therapy with at least one other agent. Vehicles can

10 The present invention and/or pharmaceutical compositions thereof and the other factor are that they work collectively or,

More preferably, synergistically. In some examples, a compound of the present invention and/or a pharmaceutical composition thereof is used in conjunction with the use of another agent, which may be part of the same pharmaceutical composition as the compound of the present invention or a different pharmaceutical composition. In other representations, a pharmaceutical composition of the present invention is administered before or after the use of another agent.

15 Preparation operations

The starting materials used in the preparation of the compounds of the invention, i.e. the various structural subclasses and types of synthetic precursor compounds of the present compounds of formulation (I), are often known compounds, or may be synthesized using known methods described in the literature or compounds commercially available from sources 20 For example, Sigma-Aldrich Corporation of St. Louis, Missouri, USA, and its subsidiaries Fluka and Riedel-de Haen, in various Their other offices spread around the world, and other well-known chemical suppliers such as Fisher Scientific and TCI America in Philadelphia, Pennsylvania, ChemDiv in San Diego, California, Chembridge in San Diego, California, Asinex in Moscow, Russia, and SPECS/BIOSPECS in the Netherlands

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Maybridge in Cornwall, England, Acros and TimTec in Russia, Comgenex in South San Francisco, California, and ASDI Biosciences in Newark, Delaware.

It is known that an experienced organic chemist can easily synthesize many starting materials and perform subsequent treatments without any additional guidance. This means that it is

5 It falls within the scope of practice of those skilled in the field and any of them can perform many of the required treatments. These treatments include the reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, electrophilic and nucleophilic aromatic substitution, etherification, esterification, saponification, nitration, hydrogenation, reductive amination, and the like. These treatments are discussed in the texts

March's Advanced Organic Chemistry (3d Edition, 1985), standard scientific e.g

Feiser and Feiser's Reagents for Organic and Wiley-Interscience, New York 10 oϊMethoden der Organischen Chemie and in various Synthesis volumes and publications

Houben-Weyl) and the like. Several general methods for preparing starting materials containing heterocyclic rings, heteroaryl rings and variously substituted aryl rings (precursors Ar, hAr1 and/or hAr2) can be found in Methoden der

15 Organischen Chemie (Houben-Weyl), the various volumes and editions of which are available from Georg Thieme Verlag, Stuttgart. All disclosures of the above theses are hereby incorporated herein in their entirety by reference for the instructions they contain regarding methods for synthesizing organic compounds and their precursors.

Those skilled in the art will also readily appreciate that some reactions are best performed when another function in the molecule is blocked or protected, thus avoiding any unwanted side reactions.

And/or increase the reaction yield. Professionals in the art often use protecting groups to achieve such an increase in reaction yield or to avoid unwanted reactions. These interactions are found in scholarly publications and also fall within the sphere of practice of those skilled in the field. Can be found at

T. Greene and P. Wuts, examples of many of these treatments eg in

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Protecting Groups in Organic Synthesis, 3r Ed., John Wiley &amp; Sons. (1999)

Some examples of manufacturing methods that can be used to prepare existing compounds or intermediates thereof can be found in WO 2010/014666, entitled “Processes and Intermediates for”

5 “Making Sweet Taste Enhancers” published on February 4, 2010.

Examples

Having described the invention in general terms, the above will be more easily understood by referring to the following examples, which are given by way of illustration and are not intended to be limiting. It is understood that various modifications and changes may be made to the representations disclosed herein without departing from the concept and scope of the invention.

Example 1: (4)((-3(-1-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl)butane-1-one

(S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )butan-1-one

15

Aqueous sodium hydroxide (2.0 pM, 32 mL, 24.61 mmol) was added at room temperature to a stirred solution of (2-)S-sulfamoylamino-6-))1-butyrylpiperidine-3. -yl(methoxy)benzonitrile (Example 1a, 6.5 g, 24.62 mmol) in ethanol (65 mL). The reaction mixture was subjected to reflux for 4 hours and then cooled to 0°

20 C and carefully neutralize it with hydrochloric acid at a concentration of 2p. Sedimentation was collected by

Filtration, recrystallization from ethanol/water, and drying under vacuum to obtain the compound mentioned in

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The title is in the form of a white solid (6 g) with 63% of the yield. 1H NMR (400 MHz).

DMSO-d6,) δ 0.82-0.86 (m, 3H), 1.30-1.51 (m, 4H), 1.65 (m, 1H), 1.82 (m, 1H), 2.01-2.21 (m, 2H), 2.22-2.27 (m, 2H), 2.71-3.12 (m, 2H), 3.63-3.86 (m, 1H), 4.03 (m, 2H), 4.12 (m, 1H), 6.60 (m, 1H), 6.75 (t, J = 8.0 Hz, 1H), 7.43-7.45 (m, 1H), 7.77 (d, J = 20 Hz, 1H), 8.36 (m, 5

) 381 MH1H), 10.91 (s, 1H). MS+). Calculated element analysis: C 53.62%; H 6.36%; N 14.23%. It was found: C 53.64%; H 6.63%; N 14.23%.

Example 1a: Benzonitrile (2-)S-sulfamoylamino-6-(1-butyrylpiperidin-3-yl(methoxy)

(S)-2-sulfamoylamino-6-((1-butyrylpiperidin-3-yl)methoxy)benzonitrile 10

Sulfamoyl chloride (Ex. 1F, 10.54 g, 61.58 mmol) was added at room temperature under a nitrogen gas atmosphere to a solution of (2-)S-amino-6-))1-butyrylpiperidine- 3-yl(methoxy)benzonitrile (Example 1b, 6.2 g, 30.53 mmol) in diethyl 15 amine (60 mL). The reaction mixture was stirred at room temperature under a nitrogen gas atmosphere overnight, then concentrated under pressure and diluted with ethyl acetate. It was then washed with sodium bicarbonate, water, and salt water, respectively, dried over sodium sulphate, filtered, and the solution was removed under pressure. Low to obtain the compound mentioned in the title in the form of a colorless gel (6.5 g) with 82% of the yield. (381 MH+) MS.

20 Example 1b: (2-)S-amino-6-))1-butyrylpiperidin-3-yl(methoxy)benzonitrile

(S)-2-amino-6-((1-butyrylpiperidin-3-yl)methoxy)benzonitrile

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<img file="SA4858B1_D0076.tif" />

10

15

20

Iron powder (5.5 g, 68.26 mmol) was added at room temperature to a solution of (1)(-2-) S-butyrylpiperidin-3-yl(methoxy)-6-nitrobenzenetrile (e.g. 1g, 6.62 g, 32.62 mmol) in acetic acid (60 ml) and tetrahydrofuran (60 ml). The reaction mixture was heated to a temperature of 20 °C, stirred for an hour, then cooled to room temperature and diluted with Ethyl acetate and its filtration via sialyte. The filtrate was concentrated under reduced pressure, then redissolved in ethyl acetate and washed with sodium bicarbonate, water, and salt water; It was dried over magnesium sulphate, filtered and evaporated. The precipitate of dichloromethane/ethyl acetate was crystallized to obtain the compound mentioned in the title in the form of a yellowish-white solid (6.62 g, 63% for two steps). (302 MH+) MS.

Example 1c: (1)(-2-) S-butyryl piperidine-3-yl(methoxy)-6-nitrobenzonitrile

(S)-2-((1-butyrylpiperidin-3-yl)methoxy)-6-nitrobenzonitrile

Triethylamine (6.2 ml, 65.84 mmol) was added to a suspension of (2-)S-nitro-6-(piperidin-3-ylmethoxy(benzonitrile) hydrochloride (Example 1D, 6.8 g, 32.62 mmol) in dichloromethane (550 ml) and dimethylformamide (50 ml). After the reaction mixture was stirred at room temperature for 5 minutes, a solution consisting of butyric acid (3.33 ml, 36.21 mmol), EDCI (6.64 g, 36.21 mmol), and hydroxybenzotriazole (6.64 g, 36.21 mmol) was added. 4.86 g, 36.21 mmol) in dichloromethane (50 ml), and then the reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with

٤٨٥٨

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Chloromethane and washed with 0.5 N hydrochloric acid, water, sodium bicarbonate, and salt water. It was dried over magnesium sulphate, filtered, and evaporated to obtain the raw product in the form of a light brown gel, and it was used in this form in the next step. (+MS 332 (MH.

Example 1d: (2-)S-nitro-6-(piperidine-3-ylmethoxy(benzonitrile) hydrochloride

(S)-2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride 5

<img file="SA4858B1_D0077.tif" />

3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate

A solution of N4 hydrochloric acid in dioxane (20 mL, 280 mmol) was added to a solution of (S)-tert-butyl 3-))2-cyano-3-nitrophenoxy(methyl(piperidine-1-carboxylate) (Example 1e). (41.24 g) in dioxane (115 ml) was cooled to 0 10 °C in an ice bath. The reaction mixture was stirred at room temperature overnight and then evaporated under reduced pressure. Diethyl ether (diethyl ether) was added 200 ml) to the precipitate and the solution was re-flowed for one hour. The solid was collected by filtration and dried under high vacuum to produce (2-)S-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride as a pale peach colored solid (24.64 g, 86% yield). In two steps (1H NMR

(400 MHz, DMSO-d6) δ 1.47 – 1.30 (m, 1H). 1.77 – 1.62 (m, 1H), 1.84 15

(t, J = 12.4 Hz, 2H), 2.32 (d, J = 9.4 Hz, 1H), 2.87 – 2.68 (m, 2H), 3.27 – 3.16 (m, 2H), 4.15 (dd, J = 9.7, 7.2 Hz, 1H), 4.25 (dd, J = 9.7, 5.4 Hz, 1H), 7.72 (dd, J = 7.6, 1.9 Hz, 1H), 7.96 – 7.86 (m, 2H), 9.20 –

.) + MH8.89 (m, 2H). MS 262 (

20 Example 1e: (S)-tert-butyl3-))2-cyano-3-nitrophenoxy(methyl(piperidine-1-carboxylate)

(S)-tert-butyl

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Aqueous tetrahydrofuran (200 ml) and sodium hydride (60% by weight, 3.60 g, 62.5 mmol) were added to a 2-litre, 3-mouth round-bottom laboratory flask equipped with an adding funnel and a thermometer. The suspension was cooled in Isopropanol/dry ice bath until temperature is reached

5 Inland to about -20°C. (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (20.0 g, 62.6 mmol) dissolved in anhydrous tetrahydrofuran (300 mL) was added distillate by an adding funnel while maintaining the temperature Internal temperature between -20°C and -15°C Once addition was completed, the reaction mixture was stirred for 45 minutes at a temperature between 0°C to 10°C and the reaction mixture was then cooled

10 to a temperature of -20 °C and a solution of 2,6-dinitrobenzonitrile (16.6 g, 103 mmol) in aqueous dimethylformamide (200 ml) was added dropwise with an adding funnel. The reaction mixture was allowed to warm gradually. It was brought to room temperature overnight and the tetrahydrofuran was removed under reduced pressure. The remaining solution was cooled in an ice bath and treated with chilled saturated ammonium chloride solution (200 ml). The resulting mixture was diluted.

15 Using ethyl acetate and washing it with water and salt water respectively. The organic layer was dried over sodium sulfate, filtered, and evaporated under low pressure to produce (S)-tert-butyl-3-(2-cyano-3-nitrophenoxy(methyl)piperidine-1-carboxylate (41.24 g) as a raw solid. Orange in color: 262 MH+ - Boc (MS). This material was used without purification in the next step.

20 Example 1f: Sulfamoyl chloride

A solution of formic acid (12.4 ml, 461 mmol) in dichloromethane (100 ml) was added dropwise to a solution of chlorosulfonyl isocyanate (65.2 g, 461 mmol) in dichloromethane (100 ml) at temperature The mixture was stirred at 0°C

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At 0°C for 1 hour, warmed to room temperature and stirred for 18 hours. The mixture was then cooled to a temperature of -28°C, then stirred for two hours, and the bulk of the solvent was emptied into another container. The resulting solid was dried under vacuum to provide sulfamoyl chloride (48 g, 60%) as a white solid.

5 Example 2: (4)))-3)-1-(S-amino-2,2-dioxide-1H-benzo[6,2,1[]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl(-2-cyclopropylethanone)

(S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)-2-cyclopropylethanone

10 Triethylamine (228 μL, 2.0 mmol) was added to a solution of (4-(S-amino-5(piperidine-3-ylmethoxy)-1H-benzo[6,2,1]]c[thiadiazine). 2,2-Dihydrochloride (Example 2a, 664 mg, 2.0 mmol) in water/acetonitrile (5 mL, 1:1). After stirring at room temperature for 5 minutes, a solution of acid 2 was added -Cyclopropyl acetic acid (200 mg, 2.0 mmol), hydroxybenzotriazole (222 mg, 2.0 mmol) and EDCI-acid

15 HCl (382 mg, 2.0 mmol) in water/acetonitrile (5 mL, 1:1) was added to the mixture. An additional equivalent amount of triethylamine (228 μL, 2.0 mmol) was added and the reaction mixture was stirred in The product was separated from the solution at room temperature overnight, precipitated, and collected via vacuum filtration. The compound was purified by high-performance reversed-phase liquid chromatography (10 to 60% ethanol in water) and then diluted with 10 ml of water.

20 200 mg of sodium bicarbonate was added. The solution was heated at 60°C for 20 minutes until the compound was completely dissolved, then cooled to 0°C and neutralized with a 1p hydrochloric acid solution. The product is deposited, collected by filtration and dried

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To give the compound mentioned in the title (410 mg, 52.3%). 1H NMR, 400 (DMSO-d6).

MHz, 80°C: 0.12 (br s, 2H), 0.44 (m, 2H), 0.96 (br s, 1H), 1.42 (m, 2H), 1.70 (m, 1H), 1.88 (m, 1H) , 1.98 (br s, 1H), 2.09 (m, 1H), 2.26 (br s, 2H), 2.91 (br s, 2H), 3.67 (br s, 0.5H), 3.85 (br s, 0.5H), 4.09 (m, 3H), 6.65 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 8.4 Hz, 5

.1H), 7.75 (br s, 1H), 8.16 (br s, 1H), 10.79 (br s, 1H). M+H = 393

Example 2a: 2,2-dihydrochloride (4-)S-amino-5-(piperidine-3-ylmethoxy)-1H-benzo[6,2,1][c]thiadiazine

(S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride 10

A solution of (S(-tert-butyl-3-))4-amino-2,2-dioxide-1H-benzo[6,2,1[]c[thiadiazine-5-yl(oxy(methyl)) was stirred. Piperidine-1-carboxylate (Example 2b, 2.0 g, 12.1 mmol) in HCl:concentrated methanol (1:1, 120 mL) at temperature

15 room for 4 hours. The precipitate was collected by filtration under vacuum and dried to give the desired product (3.25 g, 63.2%) in the form of a white solid. 1,400 H NMR (DMSO-d6).

(m, 2H), 3.20 (d, J = 8.0 Hz, 1H), 3.27 (d, J = 11.2 Hz, 1H), 4.10 (d, J = 6.0 Hz, 3H), 6.27 (d, J = 8.4 Hz , 1H), 6.75 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.68 (s, 1H), 8.35 (br s, 1H), 8.74 (m, 1H), 9.05 (m, 20

.)+MH1H), 10.98 (s, 1H). MS 311 (

٤٨٥٨

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Example 2b: (S(-tert-butyl-3-)))4-amino-2,2-dioxide-1H-

Benzo[6,2,1[]c[thiadiazine-5-yl(oxy(methyl(piperidine-1-carboxylate)

(S)-tert-butyl 3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-carboxylate

5

Pyridine (13.4 ml, 166 mmol) and sulfamoyl chloride (2.64 g, 66.4 mmol) were added in small quantities to a solution of (S)-tert-butyl-3-))3-amino-2-

Cyanophenoxy(methyl(piperidine-1-carboxylate) (Example 2C, 11.0 g, 33.2 mmol) in diethylamine (100 mL). The mixture was stirred at room temperature in a N10 atmosphere for 1 hour. Until the reaction was completed according to the liquid chromatography-mass spectrometry process.

Saturated sodium bicarbonate was added until the mixture became neutral and the solution was extracted with ethyl acetate (X3). The combined organic layers were dried on sodium sulfate and concentrated. The precipitate was diluted with ethanol (100 ml) and sodium hydroxide (66.4 ml, 132 ml) was added. (8 mmol, 2 M solution) and the solution was heated to a temperature of 15 80 °C for 3 hours. The reaction mixture was then cooled to reach room temperature.

The solution was then brought to a temperature of 0°C and neutralized with hydrochloric acid at a concentration of 2p. Water was added and the desired product was then separated from the solution and sedimented. The product was then filtered and dried to produce the compound mentioned in the title (2.0 g, 51.4%). (M+H) –

.Boc = 311

20 Example 2c: (S)-tert-butyl-3-))3-amino-2-cyanophenoxy(methyl(piperidine-1-carboxylate)

(S)-tert-butyl 3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

٤٨٥٨

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<img file="SA4858B1_D0078.tif" />

A palladium/carbon catalyst (3.82 g, 3.6 mmol 10% solution) was added to a solution of (S)-tert-butyl-3-))2-cyano-3-nitrophenoxy(methyl(piperidine-1-) Carboxylate (Example 1e, 13 g, 36 mmol) in ethanol (200 ml) and the mixture was stirred at a temperature

5 The room was in a hydrogen gas atmosphere for 6 hours until the reaction was complete. The mixture was filtered and concentrated. The precipitate was purified by silica gel chromatography (ethyl acetate/hexane) to produce the compound mentioned in the title (11 g, 62.3%). (Boc = 232 – ) M+ H.

Example 3: (4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl(-2-)pyridin-4-yl(methanone)

(S)-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5- 10

yl)oxy)methyl)piperidin-1-yl)(pyridin-4-yl)methanone

<img file="SA4858B1_D0079.tif" />

It was prepared as in Example 2 from 5-(S-)piperidine-3-ylmethoxy(-H1-benzo[6,2,1[]c[thiadiazine-4-amine-2,2-dioxide) hydrochloride (Example 2a) and isonicotinic acid (product

15 (55%). Melting temperature: &lt;250 1H NMR (400 MHz, DMSO-d6) δ C.

1.41-1.89 (m, 4H), 2.22 (m, 1H), 2.92-3.09 (m, 2H), 3.36-3.55 (m, 1H), 3.91-3.99 (m, 1H), 4.12-4.31 (m, 2H )+ MH10.95 (s, 1H). MS 416 (

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Example 4: (4)((-3(-1-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl(pentane-1-one).

(S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)pentan-1-one

<img file="SA4858B1_D0080.tif" />

It was prepared as in Example 2 from 5-(S-)piperidine-3-ylmethoxy(-1H-benzo[6,2,1[]c[thiadiazine-4-amine-2,2-dioxide) hydrochloride (Example 2a) and pentanoic acid (produced in percentage).

1H NMR (DMSO-d6, 400 MHz, 80oC): 0.85 (t, 3H, J = 7.0 .)% 24,6

Hz), 1.28 (sext, 2H, J = 7.0 Hz), 1.40 (m, 2H), 1.47 (pent, 2H, J = 7.3

Hz), 1.68 (m, 1H), 1.87 (m, 1H), 2.06 (m, 1H), 2.27 (t, 2H, J = 7.3 Hz), 10 2.93 (m, 2H), 3.93 (m, 1H) , 4.08 (m, 3H), 6.64 (d, 1H, J = 8.0 Hz), 6.74 (d, 1H, J = 8.3 Hz), 7.43 (t, 1H, J = 8.3 Hz), 7.78 (br s, 1H ), 7.99 (br s,

1H), 10.69 (s, 1H). M+H = 395.

Example 5: (4)))-3)-1-(S-amino-2,2-dioxide-1H-benzo[6,2,1[]c[thiadiazine-5-

15 yl(oxy(methyl(piperidine-1-yl)-3-methylbutan-1-one)

(S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-3-methylbutan-1-one

<img file="SA4858B1_D0081.tif" />

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A 2P sodium hydroxide solution (84 mL) was added to a stirred solution of (S(-2-sulfamoylamino-6-))1-)3-methylbutanoyl(piperidin-3-yl(methoxy(benzonitrile)) (Example 5a, 16.5 g, 46.4 mmol) in ethanol (130 mL) at room temperature. The reaction mixture was then heated at 65 °C until liquid chromatography/mass spectrometry5 confirmed that The starting material was stored for approximately 18 hours. The mixture was concentrated to remove the ethanol, diluted with water (500 ml) and washed with ethyl acetate (50 ml x 2). Ethanol (100 ml) was added to the aqueous medium and the mixture was acidified using a 1 M aqueous hydrochloric acid solution until pH = 3. The precipitate that formed was collected via filtration under vacuum to give a white solid, which was then suspended in 10 ethanol (300 ml) and the solution was heated to reflux for one hour and then cooled to a temperature of 0 °C. The precipitate was collected and dried under vacuum to give the compound mentioned in the title in the form of a solid substance with a yellowish-white color (12, 2g, 82% yield. This material was combined with several other batches prepared following the same procedure. A suspension from the combined batch (23.6 g, 186.52 mmol) in water (1500 ml) was treated with a solution of sodium bicarbonate (36.18 g, 15 466.43 mmol, 2.5 equiv) in water (500 ml) and heated to a temperature of 68 degrees

Celsius for 12 hours until completely melted. The hot solution was then filtered to remove undissolved microparticles, and the filtered liquid was cooled to room temperature and treated by distillation with 0.3 M hydrochloric acid until a neutral pH was reached, and then with 2 M hydrochloric acid until a neutral pH was reached. pH 3 The solution 20 was then stirred further for 30 minutes. The precipitate that was formed was collected through filtration under vacuum, washed with water, and dried under vacuum to produce the compound mentioned in the title in the form of a white-white powder.

1H NMR (400 MHz, DMSO-d6, 80°C) δ 0.89 (d, 6H, J) (22.44 g = 4.0 Hz), 1.37-1.47 (m, 2H), 1.67-1.72 (m, 1H), 1.86-1.91 (m, 1H), 1.94-2.19 (m, 4H), 2.96 (br.s, 2H), 3.55-4.14 (m, 4H), 6.66 (d, 1H, J =

4.0 Hz), 6.75 (d, 1H, J = 8.0 Hz), 7.45 (t, 1H, J = 8.0 Hz), 7.78 (br.s, 25

.+MH). Mp 237-2381H) 8.00 (br.s, 1H), 10.69 (br.s, 1H). MS 395 (

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Example 5a: (2-(S-sulfamino-6-))1-)3-methylbutanoyl(piperidine-3-)

yl(methoxy(benzonitrile).

(S)-2-sulfamoylamino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile

<img file="SA4858B1_D0082.tif" />

Sulfamoyl chloride (55 g, 426 mmol) was added in two portions (20 g and 35 g) to a stirred solution of (2-(S-amino-6-)(1-)3-methylbutanoyl(piperiden-3-yl(methoxy(benzonitrile) (Example 5b, 54.55 g, 122.65 mmol) in dimethylamine (110 mL) cooled to 0 °C in an ice bath. The reaction mixture was stirred for 30 minutes at 0 °C

10 Celsius in a nitrogen gas atmosphere, then at room temperature for 4 hours. The reaction mixture was slowly poured into cold water (2 litres) and rapidly stirred to obtain a milk-like solution. An additional 800 ml of water was added in multiple portions to precipitate the desired product (at this point the milk-like solution became transparent). The precipitate was collected By pouring water, it was suspended in ethyl acetate (500 ml) and then stirred rapidly until it became a smooth white solid.

15 The solid material was filtered under vacuum and dried under vacuum to obtain (2-(S-sulfamoylamino-6-))1-(3-methylbutanoyl(piperidin-3-yl(methoxy(benzonitrile) as a white solid) 56.25 g. 150.2 mmol (82% yield). MS 395 (MH) +

Example 5b: (2-(S-amino-6-))1-)3-methylbutanoyl(piperiden-3-yl(methoxy(benzonitrile)

(S)-2-amino-6-((1-(3-methylbutanoyl)piperidin-3-

yl)methoxy)benzonitrile 20

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<img file="SA4858B1_D0083.tif" />

Iron powder (2.02 g, 36.1 mmol) was added to a solution of (3)-1))-2-(S-methylbutanoyl(piperidin-3-yl(methoxy(-6-nitrobenzonitrile)) (Example 5c). (43.26 g, ~18.0 mmol) in ice-cold acetic acid (35 mL) cooled to 0°C in an ice bath. Stirred

5 The solution was placed under a nitrogen balloon at 0°C for 10 minutes and then at room temperature overnight and filtered through a surface of silite soil, rinsed well with ethyl acetate. The ethyl acetate solution was then washed successively with sodium carbonate at a concentration of 2p, water and salt water, dried over sodium sulfate, filtered and concentrated to obtain the crude product as orange-colored oil. The precipitate was purified by silica gel chromatography using...

10 It is composed of 0-60% ethyl acetate/hexane, followed by crystallization of ethyl acetate/hexane, so that the compound mentioned in the title becomes a pale yellow solid (22.01 g, 85.63 mmol, 21% in two steps). -0.79 1H NMR (400 MHz, DMSO-d6) 20°C) δ

0.92 (3xd, J = 6.4 Hz, 6H), 1.19-1.46 (m, 2H), 1.51-2.01 (m, 4H),

2.03-2.25 (m, 2H), 2.57 (dd, J = 10.4, 12.8 Hz, 0.3H), 2.75-2.88 (m, 0.6H), 2.92-3.10 (m, 1H), 3.65-4.08 (m, 3.6 H), 4.27-4.40 (dm, 0.3H), 15

5.98 &amp; 6.00 (s &amp; s, 2H), 6.18 (pseudo t, J = 8.4 &amp; 9.2 Hz, 1H), 6.32

.)+MH(pseudo d, J = 8.4 Hz, 1H), 7.11-7.21 (m, 1H). MS 316 (

Alternatively, (2-(S-amino-6-)(1-)3-methylbutanoyl(piperidine-3-) can be prepared

(S)-2-amino-6-((1-(3-methylbutanoyl)piperidin-3-yl(methoxy(benzonitrile)

20 yl(methoxy) benzonitrile (Example 5b) as follows:

A solution of (3)-1-(S-(hydroxymethyl(piperidin-1-yl)-3-methylbutan-1-one) (Example 5D) (42 g, 210.25 mmol, 1.2 equiv) was added to Aqueous tetrahydrofuran (300 ml) by distillation at 0 °C of a suspension containing a compound in the form of sodium hydride (60%)

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in mineral oil, 8.43 g, 223.62 mmol, 1.63 equiv) in aqueous tetrahydrofuran (600 ml). The mixture was warmed to a temperature of about 25 °C and stirred for 1 hour, keeping the temperature lower from 25 °C and a solution of 2-amino-6-fluorobenzonitrile (22.65 g, 168.6 mmol, 1 eq) in tetrahydrofuran (300 ml) was added.

5 By distillation. The reaction was slowly heated until reflow and stirred overnight. The mixture was cooled to room temperature and concentrated to make the concentration equal to about 400 ml of the precipitate. Saturated ammonium chloride (200 ml) was added. After stirring vigorously for 15 minutes, ethyl acetate (800 ml) was added, stirring continuously for an additional 30 minutes. The organic media was washed with water and salt water, respectively, and dried over sodium sulphate.

10 The solvent was removed under vacuum, and the precipitate was separated on silica gel (hexane/ethyl acetate) to obtain the desired product (44.6 g, 141.40 mmol, 83.82%). 1H NMR

(400 MHz, DMSO-d6, 20°C) δ 0.79-0.92 (3xd, J = 6.4 Hz/each, 6H), 1.19-1.46 (m, 2H), 1.51-2.01 (m, 4H), 2.03-2.25 (m, 2H), 2.57 (dd, J = 10.4, 12.8 Hz, 0.3H), 2.75-2.88 (m, 0.6H), 2.92-3.10 (m, 1H), 3.65

4.08 (m, 3.6H), 4.27-4.40 (dm, 0.3H), 5.98 &amp; 6.00 (s &amp; s, 2H), 6.18 15

(pseudo t, J = 8.4 &amp; 9.2 Hz, 1H), 6.32 (pseudo d, J = 8.4 Hz, 1H), 7.11

)+7.21 (m, 1H). MS 316 (M.H

Example 5c: (3)-1))-2-(S-methylbutanoyl(piperiden-3-yl(methoxy(-6-nitrobenzonitrile)

(S)-2-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)-6-nitrobenzonitrile

<img file="SA4858B1_D0084.tif" />

20

Triethylamine (42 ml, 300.64 mmol) was added to a suspension of (2-(S-nitro-6-(piperidin-3-ylmethoxy)benzonitrile) hydrochloride (Example 1d, 35.84 g, 120.41 mmol ( in

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Dichloromethane (600 mL) was cooled to 0 °C in an ice bath, followed by the addition of isovaleryl chloride (2.22 mL, 132.35 mmol) dropwise. The reaction mixture was stirred under a nitrogen gas atmosphere for 30 minutes at °C. At 0°C, then at room temperature overnight, the solution was diluted with dichloromethane and washed successively with citric acid

5 10%, saturated sodium bicarbonate solution, water, and salt water, then dried on sulfate.

Sodium, filtering and concentrating it to obtain crude (3)-1))-2-(S-methylbutanoyl(piperiden-3-yl(methoxy)-6-nitrobenzonitrile as golden brown oil (43.26 g). 346 MH+) MS). Use this material without purification in the next step.

Example 5d: (3)-1-(S-)hydroxymethyl(piperidin-1-yl)-3-methylbutan-1-one

(S)-1-(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one 10

<img file="SA4858B1_D0085.tif" />

(S)-piperidine-3-yl methanol hydrochloride (10 g, 65.65 mmol) in water (25 ml) was treated by distillation at 0 °C with sodium hydroxide solution (13.2 g, 330 mmol, 5 eq.) in water (25 ml). The mixture was stirred for 15 minutes and a solution of isovaleryl chloride 15 (15.60 g, 131.6 mmol, 2 eq.) in anhydrous tetrahydrofuran (25 ml) was distilled and stirred vigorously. After 30 minutes and at 0°C. The reaction was slowly warmed to room temperature and stirred overnight. 500 ml (Et2O) was added to the reaction mixture with vigorous stirring. The organic layer was separated, washed with salt water, dried over sodium sulfate and concentrated to obtain a precipitate that was purified by chromatography on silica 20 (hexane/ethyl acetate 0-100) to obtain the desired compound as oil without Color (16,22

g, 82.62 mmol, 64%(. 1 0.88 H NMR (400 MHz, DMSO-d6, 20°C) δ

(pseudo d, J = 6.4 Hz, 6H), 1.06-1.75 (m, 5H), 1.88-2.05 (m, 1H), 2.07-2.23 (m, 2H), 2.30 (dd, J = 10.8, 12.8 Hz, 0.5H), 2.64 (ddd, J =

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3.2, 10.8, 13.2 Hz, 0.5H), 2.78 (dd, J = 10.4, 13.2 Hz, 0.5H), 2.93 (dd, J = 2.4, 11.6, 13.6 Hz, 0.5H), 3.14-3.35 (m, 2H ), 3.70-3.85 (m, 1H), 4.08-4.18 (dm, 0.5H), 4.31-4.40 (dm, 0.5H), 4.49 (t, J = 5.2 Hz,

.)+0.5H), 4.58 (t, J = 5.2 Hz, 0.5H). MS 200 (M.H

5 Alternatively, (3)-1-(S-hydroxymethyl(piperidin-1-yl)-3-methylbutane-1- can be prepared.

Example((S)-1-(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one

5d) as follows:

A solution of (S)-ethyl 1-(3-methylbutanoyl)piperidine-3-carboxylate (Example 5e, 32.4 g, 154.62 mmol) in aqueous tetrahydrofuran (200 mL) was cooled to a temperature of 0

10 °C and treated with lithium chloride (12 gm, 401.04 mmol). After stirring for 5 minutes, sodium borohydride (15 gm, 366.50 mmol) was added at the same temperature. The reaction was further cooled to Temperature -20 °C and aqueous ethanol (400 ml) was added dropwise. The reaction was kept in a cold bath, left to warm slowly to room temperature and stirred overnight. Ethanol (100 ml) was added and the reaction was processed

15 The mixture was mixed with a saturated aqueous citric acid solution (600 ml) and stirred for another 30 minutes. The volatile materials were removed under vacuum to obtain a thick, colorless substance. Water (100 ml) and dichloromethane (800 ml) were added to the precipitate and the mixture was stirred. Vigorously for 15 minutes, the media was separated and the aqueous medium was extracted with dichloromethane (2 x 800 ml). The combined organic extract was washed with salt water and dried over sodium sulphate.

20 The solvent was removed under vacuum to obtain a transparent precipitate that was purified by gel chromatography

Silica (3 Rinse: hexane/ethyl acetate 0-100) to obtain a clean product (26.65 g, 148.26 mmol, 66%).

Example 5e: (S)-ethyl 1-(3-methylbutanoyl)piperidine-3-carboxylate

(S)-ethyl 1-(3-methylbutanoyl)piperidine-3-carboxylate

٤٨٥٨

-٨٩-

<img file="SA4858B1_D0086.tif" />

Ethyl (S)-piperidine-3-carboxylate (25 g, 156.02 mmol) in anhydrous dichloromethane (500 mL) was cooled to 0 °C and treated with triethylamine. Isovaleryl chloride solution was added. 23.22 ml, 160.08 mmol, 1.2 equiv) in binary

5 Anhydrous chloromethane (200 ml) was distilled at 0°C. The resulting reaction mixture was kept in a cooling bath and left to warm slowly to room temperature. After 6 hours, the reaction was successively washed with aqueous hydrochloric acid solution (2 M concentration). , saturated sodium carbonate, salt water, dried over sodium sulfate, filtered, concentrated under vacuum, and purified by filtration on a short silica gel column using ethyl acetate as a solvent, and the solvent was removed

10 Under vacuum to obtain the desired product in the form of a pale yellow oil (32.4 g, 154.62 mmol, 62.5%), it was used in the next step without further purification. 1H NMR

(400 MHz, DMSO-d6, 20°C) δ 0.88 (pseudo d, J = 6.4 Hz, 6H), 1.13

1.23 (m, 3H), 1.26-1.45 (m, 1H), 1.47-1.75 (m, 2H), 1.82-2.03 (m,

2H), 2.10-2.28 (m, 2H), 2.28-2.39 (m, 0.5H), 2.45-2.56 (m, 0.5H),

2.84 (dd, J = 10.0, 12.8 Hz, 0.5H), 2.97-3.11 (m, 1H), 3.38 (dd, J = 15

8.8, 13.6 Hz, 0.5H), 3.63-3.83 (m, 1.5H), 4.00-4.14 (m, 2H), 4.26

.) (MH4.36 (dm, 0.5H). MS 242

Example 6: (4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl(-2-)cyclohexyl(methanone)

(S)-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5- 20 yl)oxy)methyl)piperidin-1-yl) (cyclohexyl)methanone

٤٨٥٨

-٩٠-

It was prepared as in Example 2 from 2,2-dicyclohexanecarboxylic acid hydrochloride and 2,2-dihydrochloride (4-(S-amino-5-(piperidine-3-ylmethoxy)-H1-benzo[6,2, 1[c]thiadiazine (Example 2a) in 25% yield. 1H NMR (DMSO-d6).

400 MHz, 80° C): 1.07-1.50 (m, 7H), 1.51-1.77 (m, 5H), 1.88 (m, 2H), 5

2.08 (m, 2H), 2.95 (br m, 2H), 3.88 (br m, 2H), 4.09 (m, 2H), 6.65 (d, 1H, 8.4 Hz), 6.76 (d, 1H, 8.0 Hz), 7.45 (t, 1H, 8.4 Hz), 7.75 (br s, 1H),

.8.14 (br s, 1H), 10.78 (s, 1H). M+H = 421

Example 2: (4))(2,2-)-1-(S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-10yl(oxy) Methyl(piperidine-1-yl(-2,2-dimethylpropan-1-one).

(S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-2,2-dimethylpropan-1-one

Pivalic acid (21 mg, 0.662 mmol), 1H-benzo[1,2,3][d[trizol-1-ol 15 (112 mg, 0.865 mmol) and 1-dimethylaminopropyl)-3- were applied. Ethyl hydrochloric acid

Carbodiimide (166 mg, 10.8 mmol) was added to a 20 ml microwavable laboratory beaker and diluted tetrahydric cerium diammonium pentart (12 ml) and then 2,2-dihydrochloride (4-)S-amino solution was added. -5-(Piperidine-3-ylmethoxy)-1H-benzo[6,2,1[]c]thiadiazine (Example 2a, 200 mg, 0.522 mmol) and quaternary ethylammonium (320 μM, 2.30

٤٨٥٨

-٩١-

mmol) in dimethylformamide (2 ml). The mixture was heated with stirring in the microwave at 130 °C for 1 hour, then cooled to room temperature, transferred to a 250 ml round-bottomed laboratory flask and concentrated by circular evaporation The precipitate was purified by preparative phase reversed high-performance liquid chromatography (10 to 60% acetonitrile).

5 The pure quantities were collected, dried, then diluted with water (6 ml), sodium bicarbonate (100 mg) was added, and the solution was heated to a temperature of 60 degrees Celsius for 15 minutes until the compound dissolved completely. The solution was then cooled to reach a temperature of It was heated to 0°C and neutralized using a solution of hydrochloric acid with a concentration of 1H. The precipitate was collected and dried to obtain the compound mentioned in the title (110 mg, 48%). 1H NMR (DMSO-d6).

400 MHz, 80°C: 1.15 (s, 9H), 1.35 (m, 2H), 1.68 (br s, 1H), 1.85 (br s, 10 1H), 2.05 (br s, 1H), 2.83 (br s , 2H), 2.16 (br s, 2H), 4.06 (d, J = 8 Hz,

2H), 4.12 (d, J = 12 Hz, 1H), 4.20 (d, J = 16 Hz, 1H), 6.60 (d, J = 8 Hz,

1H), 6.76 (d, J = 8 Hz, 1H), 7.44 (t, J = 8 Hz, 1H), 7.78 (s, 1H), 8.37 (s,

.1H), 10.93 (s, 1H). M+H = 395

15 Example 8: (4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl(-2-)cyclopentyl(methanone)

(S)-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( cyclopentyl)methanone

<img file="SA4858B1_D0087.tif" />

20 Sodium bicarbonate (640 mg, 2.60 mmol) was added to the hydrochloride solution (-3-(S4))-amino-2,2-dioxide-1H-benzo[6,2,1[]c[thiadiazine] 5-yl(oxy(methyl(piperidinium) (Example 2A, 528 mg, 1.52 mmol) in water:tetrahydrofuran (20 mL, 2:1).

٤٨٥٨

-٩٢-

Add cyclopentane carbonyl chloride (645 μl, 2.60 mmol) dropwise, upon complete dissolution of sodium bicarbonate. The reaction was stirred at room temperature overnight. The precipitate was collected by filtration under vacuum and purified by preparative high-performance liquid chromatography (10). -60% acetonitrile in water. The pure quantities were mixed, concentrated, and then dissolved in a sodium bicarbonate solution.

5 (250 mg in 10 ml of water). After complete dissolution, the mixture was cooled in an ice bath and neutralized.

With hydrochloric acid at a concentration of 1 p. The resulting white solid was collected by filtration under vacuum to obtain the desired product (322 mg, 52%) as a solid. 1H NMR (DMSO-d6).

400 MHz, 80°C: 1.43 (m, 2H), 1.51-1.80 (m, 10H), 1.90 (m, 1H), 2.09

(m, 1H), 2.96 (m, 2H), 4.01 (br m, 2H), 4.12 (d, J = 6.4 Hz, 2H), 6.67

(d, J = 7.8 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 8.3 Hz, 1H), 10

.) = 407 (+MH MS7.92 (br s, 2H), 10.70 (br s, 1H).

Example 6: (4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl(-2-)cyclobutyl(methanone)

(S)-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)(cyclobutyl)methanone 15

It was prepared as in Example 8 from 2,2-dihydrochloride (4-(S-amino-5-(piperidine-3-ylmethoxy)-1H-benzo[6,2,1[]c[thiadiazine) (Example 2a). (And cyclobutanecarboxylic acid

1H NMR (DMSO-d6, 400 MHz, 60° C): 1.35 (m, 2H), (output: 43.4%).

1.62-1.80 (m, 2H), 1.82-1.98 (m, 2H), 2.00-2.23 (m, 5H), 2.76 (br s, 20 0.5H), 2.88 (br s, 1H), 3.07 (br s, 0.5H), 3.30(m, 1H), 3.54 (br s, 0.5H), 3.70 (br s, 3H), 4.09 (d, J = 6.8 Hz, 2H), 4.14 (m, 1H), 6.73 (d , J = 8.0

٤٨٥٨

-٩٣-

Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.74 (br s, .1H), 8.20 (br s, 1H), 10.79 (s, 1H). M+H = 393

Example 10: (4)))-3)-1-(S-amino-2,2-dioxide-H1-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl(-2-)pyridin-4-yl(ethanone)

(S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-2-(pyridin-4-yl)ethanone

<img file="SA4858B1_D0088.tif" />

10

15

It was prepared as in Example 2 from 2,2-dihydrochloride (4-(S-amino-5-(piperidine-3-ylmethoxy)-1H-benzo[6,2,1[]c[thiadiazine) (Example 2a). ) and 2-(pyridin-4-yl)acetic acid

1H NMR (400 MHz, DMSO-d6, 80° C) δ: 1.35 (m, 2H), 34.6%.)

1.68 (br s, 1H), 1.79 (br s, 1H), 1.89 (br s, 1H), 2.09 (br s, 2H), 3.55 – 3.91 (br s, 3H), 4.01 (br s, 3H), 6.57 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 8.4 Hz, 1H), 7.74 (br s, .)+2H), 8.55 (d, 2H, 8.4 Hz), 10.54 (br s, 1H). MS 430 (M.H

Example 11: (4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl(-2-)pyridazine-4-yl(methanone)

(S)-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( pyridazin-4-yl)methanone

<img file="SA4858B1_D0089.tif" />

٤٨٥٨

-٩٤-

It was prepared as in Example 2 from 2,2-dihydrochloride (4-(S-amino-5-(piperidine-3-ylmethoxy)-1H-benzo[6,2,1[]c[thiadiazine) (Example 2a). (Pyridazine-4-carboxylic acid

1H NMR (400 MHz, DMSO-d6, 80° C) δ: 1.41 (m, 2H), 40.8% (.) br s, 1H), 2.16 (br s, 2H), 3.65 – 4.00 (br s, 1H), 4.08 (br s, 3H), 6.65 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 5

8.4 Hz, 1H), 7.43 (t, J = 8.4 Hz, 1H), 7.86 (br s, 2H), 8.12 (d, J = 8.0 Hz, 1H), 9.49 (d, J = 8.0 Hz, 1H,) , 9.82 (s, 1H), 10.69 (br s, 1H). MS

.)+417 (MH.)

Example 12: (4)))-3)-(S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

10 yl(oxy(methyl(piperidin-1-yl()2-methylamino(pyridin-4-yl(methanone)

(S)-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( 2-(methylamino)pyridin-4-yl)methanone

<img file="SA4858B1_D0090.tif" />

It was prepared as in Example 2 from 2,2-dihydrochloride (4-(S-amino-5-(piperidine-3-15ylmethoxy)-1H-benzo[6,2,1[]c[thiadiazine) (Example 2a) and 2-(methylamino)acid

Isonicotonic. (Output: 44%). 1.45 1H NMR (400 MHz, DMSO-d6, 60oC) δ

(br m, 2H), 1.68 (br m, 1H), 1.91 (br m, 1H), 2.15 (br m, 1H), 2.77 (d, J = 7.6 Hz, 3H), 3.02 (br m, 1H) , 1.97 (br m, 1H), 2.13 (br m, 2H), 2.80 (br m, 2H), 3.19 (br m, 1H), 3.30 – 4.09 (br m, 4H), 6.34 (br m, 1H) , 6.38 (br m, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.74 (m, 1H), 7.42 (t, J = 8.4 20

.)+Hz, 1H), 7.73 (br s, 2H), 8.01 (m, 1H), 10.70 (br s, 1H). MS 445 (M.H

٤٨٥٨

-٩٥-

Example 13: (4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl()2-methylpyridin-4-yl(methanone)

(S)-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)(2-methylpyridin-4-yl)methanone

<img file="SA4858B1_D0091.tif" />

10

15

It was prepared as in Example 2 from 2,2-dihydrochloride (4-)S-amino-5-(piperidine-3-ylmethoxy(-1H-benzo[6,2,1[]c[thiadiazine)) (Example 2a). ) and 2-methyl isonicotinic acid

1H NMR (400 MHz, DMSO-d6, 60oC) δ 1.48 (br m, 2H), (result: 15%)

1.70 (br m, 1H), 1.90 (br m, 1H), 2.16 (br m, 1H), 3.02 (br m, 2H), 3.30 – 4.09 (br m, 4H), 6.57 (d, J = 6.4 Hz , 1H), 6.62 (m, 1H), 7.10 (m, 1H), 7.16 (s, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.53 s, 1H), 8.48 (d, J = 4.8 Hz, .)+1H), 10.56 (s, 1H). MS 430 (M.H

Example 14: (4)))-3)-(S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl()2-dimethylamino(pyridin-4-yl(methanone)

(S)-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( 2-(dimethylamino)pyridin-4-yl)methanone

<img file="SA4858B1_D0092.tif" />

It was prepared as in Example 2 from 2,2-dihydrochloride (4-)S-amino-5-(piperidine-3-ylmethoxy(-1H-benzo[6,2,1[]c[thiadiazine)) (Example 2a). (and 2-)dimethylamino(acid).

٤٨٥٨

-٩٦-

1H NMR (400 MHz, DMSO-d6, 60oC) δ 1.45 (br m, 8%) , 3.00 (s, 6H), 3.30 – 4.09 (br m, 4H), 6.44 (d, J = 5.6 Hz, 1H), 6.47 (s, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 6.8 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.67

)+(br s, 2H), 10.67 (br s, 1H). MS 459 (MH 5

Example 15: (4)))-2)-1-(R-amino-2,2-dioxide-1H-benzo[6,2,1[]c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl)-3-methylbutan-1-one)

(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one

<img file="SA4858B1_D0093.tif" />

10

Added triethylamine (366 μL, 2.88 mmol), 3-methylbutanoic acid (156 μL, 1.44 mmol), EDCI-HCl (226 mg, 1.44 mmol), and hydroxybenzotriazole (220 mg, 1.44 mmol) for the solution of 2,2-dihydrochloride (4-)R-amino-5-(piperidine-2-ylmethoxy(-1H-benzo[6,2,1]]c[thiadiazine) solution

15 (Example 15a, 500 mg, 1.44 mmol) in dimethylformamide (12 ml). The mixture was stirred

The reaction took place at room temperature in a nitrogen gas atmosphere for 18 hours, then it was filtered and purified by preparative high-performance liquid chromatography (10-60% acetonitrile in water). The pure quantities were mixed, concentrated, and crystallized from ethanol and water to obtain the compound mentioned in Title as a white solid (23 mg, 13% yield). 1H NMR (400 MHz).

DMSO-d6, 80oC) δ 0.89 (d, J = 6.8 Hz, 6H), 1.37 (m, 1H), 1.51 – 1.70 20

(m, 4H), 1.78 (d, J = 12.8 Hz, 1H), 2.01 (m, 1H), 2.13 -2.27 (m, 2H), 3.02 (br s, 1H), 3.89 (br s, 1H), 4.18 (br s, 1H), 4.48 (t, J = 9.2 Hz, 1H),

٤٨٥٨

-٩٧-

5.02 (br s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 7.42 .)+(t, J = 8.4 Hz, 1H), 7.82 (br s, 2H), 10.63 (s, 1H). MS 395 (M.H

Example 15a: (4)((-2-)R-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

L(oxy(methyl)piperidinium hydrochloride

(R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5- 5

yl)oxy)methyl)piperidinium hydrochloride

<img file="SA4858B1_D0094.tif" />

Hydrochloric acid in ethanol (104 ml, 2.5 M, 261 mmol) was added to a solution of (R(-tert-butyl-2-))4-amino-2,2-dioxide-1H-benzo[6]. ,2,1[]c[thiadiazine-

10 5-yl(oxy(methyl(piperidine-1-carboxylate) (Ex. 15b, 10.2, 26.1 mmol) in

Ethanol (125 ml). The reaction was stirred at a temperature of 60 degrees Celsius for 4 hours. The compound was collected by filtration in the form of a yellowish-white solid (2.20 g, 85% yield).

1H NMR (400 MHz, DMSO-d6) δ 1.03 – 1.90 (br m, 6H), for three steps.

2.89 (br t, J = 2.8 Hz, 1H), 3.27 (br m, 1H), 3.61 (br m, 1H), 4.27 -4.40

(br m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 7.46 (t, J 15 = 8.0 Hz, 1H), 7.79 (br s, 1H ), 8.35 (br s, 1H), 9.26 (br s, 2H), 10.97 (br

.)+s, 1H). MS 311 (M.H

Example 15b: (R(-tert-butyl-2-)))4-amino-2,2-dioxide-1H-

Benzo[6,2,1[]c[thiadiazine-5-yl(oxy(methyl(piperidine-1-carboxylate)

(R)-tert-butyl-2-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5- 20

yl)oxy)methyl)piperidine-1-carboxylate

٤٨٥٨

-٩٨-

<img file="SA4858B1_D0095.tif" />

Aqueous sodium hydroxide (concentration of 2p, 130 mL, 26.1 mmol) was added to the (R)-tert-butyl-2-))2-cyano-3-(sulfamoylamino(phenoxy(methyl)piperidine-1-carboxylate) solution. 5 (Example: 15g, 10.2g, 26.1 mmol) in ethanol (130 ml). The solution was refluxed for 18 hours under nitrogen gas. After cooling to room temperature, the solution was cooled to 0°C and neutralized with hydrochloric acid at a concentration of 1p. The mixture was partially concentrated and the product was collected by filtration to obtain (R(-tert-butyl 2-)))4-amino-2,2-dioxide-1H-benzo[6,2,1[]c[thiadiazine-5- yl(oxy(methyl(piperidine-1-carboxylate),

Which is used directly in the next step. (MS 311 (MH+ - boc.

10 Example 15c: (R)-tert-butyl-2-)(2-cyano-3-(sulfamino)phenoxy(methyl)piperidine-1-carboxylate

(R)-tert-butyl-2-((2-cyano-3-(sulfamoylamino)phenoxy)methyl)

piperidine-1-carboxylate

<img file="SA4858B1_D0096.tif" />

<img file="SA4858B1_D0097.tif" />

15 Pyridine (8.44 ml, 104 mmol) and sulfamoyl chloride (6.03 g, 52.2 mmol) were added to a solution of (R)-tert-butyl-2-(3-amino-2-cyanophenoxy) Methyl(piperidine-1-carboxylate) (Example 15D, 8.65 g, 26.1 mmol) in dimethylacetamide (48 mL). The mixture was stirred at room temperature for 1 hour and neutralized with bicarbonate solution.

٤٨٥٨

-٩٩-

Aqueous saturated sodium and extracted with ethyl acetate. The extract was dried over sodium sulphate

It was filtered and concentrated to give the compound mentioned in the title in the form of pure oil, which was obtained

Use it immediately in the next step. (MS 311 (MH+ - boc.

Example 15d: (R)-tert-butyl-2-)3-amino-2-cyanophenoxy(methyl(piperidine-1-carboxylate)

(R)-tert-butyl-2-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

<img file="SA4858B1_D0098.tif" />

10

15

10% palladium/carbon catalyst (1.08 g, 3 mmol) was added to a solution of (R)-tert-butyl-2-))2-cyano-3-nitrophenoxy(methyl(piperidine-1-carboxylate) Example 15e, 10.8 g, 26.85 mmol) in ethyl acetate (86 ml). Hydrogen was added by balloon and the mixture was stirred for 48 hours at room temperature. Once complete, the mixture was filtered through a sialyte pad and Remove the solvent under vacuum. The precipitate of ethyl acetate/hexane was recrystallized to yield (R)-tert-butyl-2-(3-amino-2-cyanophenoxy(methyl)piperidine-1-carboxylate (8.65 g, 88%) in the form of MS. Yellowish white solid

.323 (MH+ - boc)

Example 15e: (R(-tert-butyl-2-))2-cyano-3-nitrophenoxy(methyl(piperidine-1-carboxylate)

(R)-tert-butyl-2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate

<img file="SA4858B1_D0099.tif" />

٤٨٥٨

١٠٠-

Sodium hydride (60% diffusion in oil, 1.45 g, 36.3 mmol) was added to a solution of (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate (Ex. 15f, 2, 10 gm,

33.0 mmol) and 2,6-dinitrobenzonitrile (6.32 g, 33.0 mmol) in tetrahydrofuran (142 mL) was cooled to -28 °C. The reaction mixture was left to warm

5 Bring it to room temperature and continue stirring for 18 hours. Once complete, the reaction mixture was cooled to 0°C and then rapidly cooled with water. The mixture has been extracted

With ethyl acetate, the organic extracts were collected and dried on anhydrous sodium sulfate

Filtration and concentration. The precipitate was recrystallized from ethyl acetate/hexanes to produce (R)-tert-

Butyl-2-(2-cyano-3-nitrophenoxy(methyl)piperidine-1-carboxylate (10.8 g, 61%) in

10 Forms a yellow solid. (MS 282 (MH+ - boc.

Example 15F: (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate

(R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate

<img file="SA4858B1_D0100.tif" />

A solution of (1-)R-(tert-butoxycarbonyl(piperidine-2-carboxylic acid) was cooled (ex.

15 15 g, 18.5 g, 80.2 mmol) in aqueous tetrahydrofuran (44.4 mL) to temperature

0 Celsius. Dimethyl sulfide (44.4 ml, 88.8 mmol) was added dropwise over 15 minutes. After the addition was complete, the mixture was allowed to warm to room temperature and continued stirring for 18 hours. The mixture was cooled The mixture was quickly mixed with water and extracted with ethyl acetate. The organic extract was dried over aqueous sodium sulfate, filtered, and concentrated

20 The product was deposited by rapid chromatography on silica gel (35% ethyl acetate in hexane)

To give (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). (MS 116 (MH+ - boc)

Example 15g: (1-) R-(tert-butoxycarbonyl(piperidine-2-carboxylic acid)

٤٨٥٨

-١٠١-

(R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid

<img file="SA4858B1_D0101.tif" />

10

Di-tert-butyl carbonate (23.2 g, 106 mmol) and triethylamine (13.5 ml, 66.8 mmol) were added to a solution of (R)-piperidine-2-carboxylic acid (12, 5 g, 66.8 mmol) in water (88 ml) and 1,4-dioxane (133 ml). The solution was stirred at room temperature for 20 hours. The mixture was concentrated under vacuum, diluted with ethyl acetate (200 ml), and washed. Using a concentration of 5% aqueous hydrochloric acid. The organic media was separated, dried with aqueous sodium sulfate, filtered, and concentrated to produce the compound in the form of a white solid (18.5 g, 83%). MS 130 (MH+ - boc).

Example 16: (4)((-2(-1-) R-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-yl(oxy(methyl(piperidine) -1-yl(butan-1-one

(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)butan-1-one

<img file="SA4858B1_D0102.tif" />

15

20

Sulfamoyl chloride (2.68 g, 23.21 mmol) was added at room temperature under a nitrogen gas atmosphere to a solution of (2-)R-amino-6-(1-butyrylpiperidin-2-yl) Methoxy)benzonitrile (Example 16a, 1.0 g, 3.32 mmol) in diethylamine (15.0 mL). The mixture was then stirred at room temperature under a nitrogen gas atmosphere for 2 hours and the solution was diluted with ethyl acetate. Wash it with water and salt water and dry it on sodium sulfate. The solvent was removed under low pressure and the precipitate was purified using a Biotag 1-SP system (S40 drum) with

٤٨٥٨

-١٠٢-

Rinse with ethyl acetate/hexane (10%-20%). The medium was dissolved in ethanol (25.0 ml) and aqueous sodium hydroxide (concentration 2.0 5.0 N ml) was added at room temperature. The reaction mixture was refluxed overnight, then cooled to 0°C and carefully neutralized with 1 N hydrochloric acid. The precipitate was collected by

<p dir="rtl">5 Filtration and recrystallization using 20% water/ethanol to obtain the compound mentioned in the title in the form of a white solid (6 g, 58% yield).</p>

) δ 0.86 (t, J = 7.6 Hz, 3H), 1°H NMR (400 MHz, DMSO-d6, 1.35-1.76 (m, 8H), 2.28-2.32 (m, 2H), 3.14 (t, J = 13.6 Hz, 1H), 3.74 ), 4.50 (t, J = isomer(d, J = 14 Hz, 1H), 4.07-4.11 (m, 1H), 4.25-4.38 (m, 10 Hz, 1H), 5.16 (t, J = 4.4 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.84 (d, J 10 ), 7.77 (s, 1H), 8.0 = isomer Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.68 (s, ), 10.89 (s, 1H). 1H NMR (400 MHz, DMSO-8.23 isomer (s, 1H), 8.36 (s, d6, 80oC) δ 0.88 (t, J = 7.6 Hz, 3H), 1.35-1.40 (m, 1H), 1.49-1.67 ( m, 7H), 1.77 (d, J = 11.6 Hz, 1H), 2.27-2.32 (m, 2H), 3.85-3.90 (m, 1H), 4.18-4.20 (m, 1H), 4.07-4.11 (m, 1H), 4.46 (t, J = 10 Hz, 1H), 5.00- 15

<p>5.03 (m, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 7.42 (t, .)J = 8.0 Hz, 1H), 7.81 (s, 2H ), 10.64 (s, 1H).MS 381 (MH+</p>

Example 16a: (2-)R-amino-6-))1-butyrylpiperidin-2-yl(methoxy)benzonitrile

(R)-2-amino-6-((1-butyrylpiperidin-2-yl)methoxy)benzonitrile

<img file="SA4858B1_D0103.tif" />

10% palladium/carbon catalyst (300 mg) was added to a solution of (1)(-2-) R-butyrylpiperidin-2-yl(methoxy(-6-nitrobenzonitrile) (Example 16b, 1.5 g, 4, 53 mmol)

20

٤٨٥٨

-١٠٣-

in ethanol (40 ml). The reaction mixture was saturated with a balloon of hydrogen at room temperature overnight and then filtered through sialyte and concentrated under reduced pressure. The precipitate was purified using a Biotag 1-SP system (S40 drum type) with rinsing Ethyl acetate/hexanes (10%-20%) to obtain the desired product in oil form (1.1 g,

1H NMR (400 MHz, DMSO-d6) δ 0.86 (t, J = 7.2 Hz, 3H), -1.46%81 5

1.65 (m, 7H), 1.77-1.85 (m, 1H), 2.24-2.30 (m, 1H), 2.38-2.42 (m,

1H), 2.56-2.63 (m, 0.5H), 3.1-3.16 (m, 0.5H), 3.71-3.74 (m, 0.3H), .)+3.92-3.98 (m, 1H), y 2H), 7.15 -7.19 (m, 1H). MS 302 (M.H

Example 16b: (1)(-2-) R-butyryl piperidine-2-yl(methoxy)-6-nitrobenzonitrile

(R)-2-((1-butyrylpiperidin-2-yl)methoxy)-6-nitrobenzonitrile 10

Triethylamine (4.2 mL, 30.1 mmol) was added to a solution of 2,2,2-trifluoroacetate (2)(-2-) R-cyano-3-nitrophenoxy(methyl(piperidine-1-) day (e.g. 16g, 2.26g, 6.03 mmol) in aqueous dichloromethane (50 ml). The reaction mixture was cooled to

15 At 0°C, butyryl chloride (0.65 ml, 6.05 mmol) was added and stirred.

Leave the solution at room temperature overnight. Then the solvent was removed under low pressure, the precipitate was diluted with ethyl acetate (150 ml), the organic layer was washed with water and salt water respectively, dried over sodium sulphate, filtered, and evaporated. The precipitate was purified using a Biotag 1-SP system (S40 drum type). Rinse with ethyl acetate/hexane (10

20 %-20%) to obtain the desired product (1.5 g, 25%). (+MS 332 (MH.

Example 16c: 2,2,2-trifluoroacetate (2))-2-(R-cyano-3-

Nitrophenoxy(methyl(piperiden-1-day)

٤٨٥٨

-١٠٤-

(R)-2-((2-cyano-3-nitrophenoxy)methyl)piperidin-1-ium 2,2,2-

trifluoroacetate

<img file="SA4858B1_D0104.tif" />

Trifluoroacetic acid (4.2 ml, 30.1 mmol) was added to a solution of 2,2,2-

5 Trifluoroacetate (R(-tert-butyl-2-))2-cyano-3-nitrophenoxy(methyl(piperidine-1-)

Carboxylate (e.g. 15F, 2.18 g, 6.03 mmol) in aqueous dichloromethane (65 mL) at room temperature. The reaction mixture was stirred at room temperature over 1 hour. The solvent was removed under Low pressure and the precipitate was dried under vacuum to obtain the compound mentioned in the title which could be used in the next step reaction without additional 262 MS purification

(MH+) 10

Example 12: (4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl)()cyclohexyl(methanone).

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( cyclohexyl)methanone

<img file="SA4858B1_D0105.tif" />

It was prepared as in Example 15 from 2,2-dihydrochloride (4-)R-amino-5-)piperiden-

2-Lylmethoxy(-H1-benzo[6,2,1][c]thiadiazine (Example 15a) and carboxylic acid

Cyclohexane (yield: 23%). -1.80 1H NMR (400 MHz, DMSO-d6, 80° C) δ

1.20 (m, 17H), 2.55-2.52 (m, 1H), 4.00-3.90 (m, 1H), 4.20-4.16 (m,

٤٨٥٨

-١٠٥-

1H), 4.51-4.20 (m, 1H), 5.04-5.00 (m, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.80 (br s, 2H), 10.5 .)+(br s, 1H). MS 421 (M.H

Example 18: (4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl()cyclobutyl(methanone).

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( cyclobutyl)methanone

<img file="SA4858B1_D0106.tif" />

10

15

It was prepared as in Example 15 from 2,2-dihydrochloride (4-)R-amino-5-(piperidine-2-ylmethoxy(-1H-benzo[6,2,1[]c[thiadiazine)) (Example 15a (And the carboxylic acid cyclobuta n

1H NMR (400 MHz, DMSO-d6, 80° C) δ 1.67-1.35 (m, 6H), (yield: 25%)

1.94-1.85(m, 2H), 2.16-2.10(m, 3H), 2.33-2.24(m, 2H), 3.40-3.30(m, 1H), 3.68-3.60(m, 1H), 4.21-4.20(m , 1H), 4.50-4.20 (m, 1H), 5.11-5.00 (m, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), .)+7.44 (t, J = 8.4 Hz, 1H), 7.81 (br s, 2H), 10.6 (br s, 1H), MS 393 (MH

Example 16: (4)((-2(-1-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl(-2-)4-methoxyphenyl(ethanone)

(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-2-(4-methoxyphenyl)ethanone

٤٨٥٨

-١٠٦-

<img file="SA4858B1_D0107.tif" />

10

It was prepared as in Example 8 from (4)((-2-) R-amino-2,2-dioxide-1H-benzo[6,2,1[]c[thiadiazine-5-yl(oxy(methyl) hydrochloride) (Pyridinium (Example 15a) and 2-)4-methoxy chloride

1H NMR (DMSO-d6, 400 MHz, 80°C): 14% phenyl(acetyl) in the product.

1.15-1.29 (m, 1H), 1.44-1.65 (m, 4H), 1.70-1.78 (m, 1H), 3.01 (m, 1H), 3.66 (s, 2H), 3.70 (s, 3H), 3.90 ( br s, 1H), 4.19 (br s, 1H), 4.43 (t, J = 12 Hz, 1H), 5.03 (br s, 1H), 5.64 (d, J = 8 Hz, 1H), 6.80 (t, J = 8 Hz, 3H), 7.13 (d, J = 8 Hz, 2H), 7.41 (t, J = 8 Hz, 1H), 7.81 (br s, 2H), −0.63 (s, 1H). M+H = 459

Example 20: (4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl()2,4-dihydroxyphenyl(methanone)

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( 2,4-dihydroxyphenyl)methanone

<img file="SA4858B1_D0108.tif" />

It was prepared as in Example 15 from 2,2-dihydrochloride (4-)R-amino-5-(piperidine-2-ylmethoxy(-1H-benzo[6,2,1[]c[thiadiazine)) (Example 15a and 2,4-dihydroxybenzoic acid (yield: 10%) as a white solid. 1H NMR (400 MHz, DMSO-d6).

80°C) δ 1.81-1.51 (m, 6H), 3.71-3.70 (m, 1H), 4.30-4.26 (m, 2H),

15

٤٨٥٨

-١٠٧-

4.60-4.52 (m, 1H), 5.02-5.00 (m, 1H), 6.23 (dd, J = 2.4, 8.4 Hz, 1H),

6.30 (d, J = 2.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 7.42 ( t, J = 8.0 Hz, 1H), 7.90 (br s, 2H), .)+9.24 (br s, 1H), 9.40 (br s, 1H), 10.6 (br s, 1H). MS 447 (M.H

Example 21: (4)((-2(-1-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-yl(oxy(methyl(piperidine) -1-yl(-3-)pyridine-3-yl(propane-1-one

(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-3-(pyridin-3-yl)propan-1-one

<img file="SA4858B1_D0109.tif" />

10

15

20

It was prepared as in Example 15 from 3-(pyridin-3-yl)propanoic acid and 2,2-dihydrochloride (4-)R-amino-5-(piperidin-2-ylmethoxy(-1H-benzo[6), 2, 1[]c[thiadiazine

1H NMR (DMSO-d6, 400 MHz, 60° C): 22.1%. Example 15a)

1.20-1.40 (m, 1H), 1.45-1.67 (m, 4H), 1.74 (m, 1H), 2.68 (m, 2H), 2.86 (m, 2H), 3.17 (s, 1H), 3.76 (br s) , 1H), 4.17 (br s, 1H), 4.45 (t, J = 9.6 Hz, 1H), 5.13 (br s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 7.24 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.64 (m, 1H), 7.74 (br s, 1H), 8.07 (br s, 1H), 8.36 ( m, 1H), 8.46 (s, 1H), 10.74 (s, 1H). (444.)+MH

Example 22: (4)((-2(-1-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl(-3-)pyridin-4-yl(propan-1-one)

٤٨٥٨

-١٠٨-

(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-3-(pyridin-4-yl)propan-1-one

<img file="SA4858B1_D0110.tif" />

It was prepared as in Example 15 from (4)((-2-) R-amino-2,2-dioxide-1H-5 benzo[6,2,1]]c[thiadiazin-5-yl(oxy) hydrochloride. Methyl(piperidinium) (Example 15a) in a 23% yield.

1H NMR (DMSO-d6, 400 MHz, 80 °C): 1.34 (m, 1H), 1.59 (m, 4H), 1.76 (m, 1H), 2.67 (br t, J = 7.3 Hz, 2H), 2.86 ( t, J = 7.3 Hz, 2H), 3.01 (m, 1H), 3.87 (br s, 1H), 4.20 (m, 1H), 4.46 (t, J = 10.0 Hz, 1H), 5.02 (br s, 1H), 6.64 (dd, J = 8.2, 0.8 Hz, 1H), 6.82 (dd, J = 8.2, 0.8 Hz, 1H), 7.22 (d, J = 5.1 Hz, 2H), 7.43 (t, J = 8.3 Hz, 1H), 7.76 (br s, 1H), 7.91 (br s, 10 .1H), 8.40 (m, 2H), 10.65 (s, 1H). MS 444 (MH+)

Example 23: (4)((-2(-1-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-yl(oxy(methyl(piperidine) -1-yl(-2-)pyridine-3-yl(ethanone

(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-2-(pyridin-3-yl)ethanone 15

<img file="SA4858B1_D0111.tif" />

It was prepared as in Example 15 from 2-(pyridin-3-yl)acetic acid and 2,2-dihydrochloride (4-)R-amino-5-(piperidin-2-yl methoxy)-1H-benzo[6,2]. , 1[[c]thiadiazine (Example 15a) in

٤٨٥٨

-١٠٩-

1H NMR (400 MHz, DMSO-d6, 80oC) δ 1.31 (br m, 1H), .40% yield

1.60 (br m, 3H), 1.77 (br m, 2H), 3.04 (br m, 1H), 3.77 (br m, 2H), 3.95 (br s, 1H), 4.23 (br s, 1H), 4.49 (m , 1H), 5.02 (br s, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 7.26 (m, 1H), 7.43 (t, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.82 (br s, 1H), 8.39 (m, 1H), 8.43(m, 1H), 5

.10.66 (s, 1H). MS 430 (MH+)

Example 24: (4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl()cyclopentyl(methanone).

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( cyclopentyl)methanone 10

<img file="SA4858B1_D0112.tif" />

It was prepared as in Example 15 from (4)((-2-)R-amino-2,2-di-H1-benzo[6,2,1]]c[thiadiazin-5-yl(oxy(methyl)hydrochloride Piperidinium (Example 15a) and carboxylic acid

1H NMR (DMSO-d6, 400 MHz, 80°C): 1.40% 25% cyclopentyl

(m, 1H), 1.53 (m, 2H), 1.63 (m, 8H), 1.77 (m, 4H), 3.00 (m, 1H), 3.97 15

(br m, 1H), 4.20 (m, 1H), 4.50 (t, , J = 8.0 Hz, 1H), 5.06 (br s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.84 (d , J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.80 (br s, 2H), 10.6 (br s, 1H). MS = 407 (MH+)

Example 25: (4)((-2(-1-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-20yl(oxy(methyl) Piperidine-1-yl(-2-)pyridine-4-yl(ethanone

٤٨٥٨

-١١٠-

(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)-2-(pyridin-4-yl)ethanone

<img file="SA4858B1_D0113.tif" />

It was prepared as in Example 15 from [4)((-2-) R-amino-2,2-dioxide-1H-5 benzo[6,2,1][c[thiadiazin-5-yl(oxy)]hydrochloride. Methyl(piperidinium) (Example 15a) and 2-(pyridin-4-)

1H NMR (DMSO-d6, 400 MHz, 80° C): 22% acetic acid in the product.

1.21-1.37(m, 1H), 1.48-1.70 (m, 4H), 1.71-1.82 (m, 1H), 3.01 (m, 1H), 3.78 (br s, 3H), 4.22 (br s, 1H), 4.43 (t, J = 8 Hz, 1H), 5.05 (br s, 1H), 6.64 (d, J = 8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 7.21 (d, J = 8 Hz, 2H), 7.42 (t, J = 8 Hz, 1H), 7.82 (br s, 2H), 8.43 (d, J = 8 Hz, 2H), 10.67 (s, 10

.1H). M+H = 430

Example 26: 2-)))4-amino-2,2-dioxide-1H-benzo[6,2,1[]c[thiadiazine-5-

yl(oxy(methyl(-N-ethylpiperidine-1-carboxamide).

2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)-N-ethylpiperidine-1-carboxamide 15

<img file="SA4858B1_D0114.tif" />

Sodium hydroxide at a concentration of 2 M (1.52 mL, 1.52 mmol) was added to a solution of 2-)(2-cyano-3-)sulfamoylamino(phenoxy(methyl)-N-ethylpiperidin-1-

٤٨٥٨

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Carboxamide (Example 26a, 0.6 g, 1.52 mmol) in ethanol (10 ml) and the reaction mixture was heated at 100 °C for 2 hours. The solution was then evaporated to dryness. The precipitate was diluted with Water (2.0 ml) and acetic acid at a concentration of 10% (3.5 ml, 3.5 mmol) were added at a temperature of 0 ° C to obtain a white precipitate, which was

5 Filter it, wash it with cold water, and purify it using a Biotag purification system (120 g Silicycle column, dichloromethane:tetrahydrofuran = 4:1 as rinsing agent) to obtain the compound mentioned in the title (0.318 g, 53%). (MS 382+ (MH).

Example 26a:))2-cyano-3-)sulfamoylamino(phenoxy(methyl(-N-ethylpiperidin-1-carboxamide)

((2-cyano-3-(sulfamoylamino)phenoxy)methyl)-N-ethylpiperidine-1-

carboxamide 10

<img file="SA4858B1_D0115.tif" />

Sulfamoyl chloride (0.234 mg, 2.02 mmol) was added to a solution of 2-(3-amino-2-cyanophenoxy(methyl(-N-ethylpiperidin-1-carboxamide)) (Example 26B, 0.402 g, 1, 35 mmol) in diethylamine (5 ml) and the reaction mixture was stirred vigorously at room temperature for 15 hours, then extracted using water/ethyl acetate. The collected organic media were washed with salt water, dried over magnesium sulphate, filtered, and evaporated. The precipitate was purified using a Biotag purification system (120 g Silicycle column, dichloromethane:tetrahydrofuran = 4:1 as eluent) to obtain the desired product (0.606 g, 60%). MS

.382 (MH+)

20 Example 26b: 2-))3-Amino-2-cyanophenoxy(methyl(-N-ethyl piperidine-1-carboxamide)

((3-amino-2-cyanophenoxy)methyl)-N-ethylpiperidine-1-carboxamide-2

٤٨٥٨

-١١٢-

<img file="SA4858B1_D0116.tif" />

Cyclohexene (0.24 mL, 2.3 mmol) and a 10% palladium/carbon catalyst (0.146 mg) were added to a solution of 2-()2-cyano-3-nitrophenoxy(methyl)-N- Ethyl piperidine-1-carboxamide (Example 26g, 0.458 g, 1.46 mmol) in ethanol (20

5 The reaction mixture was heated at 100 °C for 40 min, then filtered through sialyte, washed with ethanol (100 ml) and evaporated to obtain 2-()3-amino-2-

Cyanophenoxy(methyl)-N-ethyl piperidine-1-carboxamide (0.402 g, 62%) which was used in the next step without any further purification. (+MS 303 (MH).

Example 26c: 2-))2-cyano-3-nitrophenoxy(methyl(-N-ethyl piperidine-1-carboxamide)

((2-cyano-3-nitrophenoxy)methyl)-N-ethylpiperidine-1-carboxamide-2 10

<img file="SA4858B1_D0117.tif" />

Triethylamine (0.514 ml, 3.2 mmol) and ethyl isocyanate (0.2 ml, 2.52 mmol) were added to a solution of 2-nitro-6-(piperidin-2-ylmethoxy(benzonitrile) hydrochloride. Example 26: 0.5 g, 1.68 mmol) in tetrahydrofuran and the reaction mixture was stirred in

15 Room temperature in a nitrogen gas atmosphere for 3 hours. The solution was then diluted with water and extracted with ethyl acetate, and the collected organic media were washed with salt water, dried over magnesium sulfate, filtered, and evaporated to obtain 2-(2-cyano-3-nitrophenoxy(methyl)-N-ethyl piperidine-1- Carboxamide (0.485 g, 82%) which was used in the next step without any further purification. (+MS 333 (MH).

٤٨٥٨

-١١٣-

Example 26d: 2-nitro-6-)piperidine-2-ylmethoxy(benzonitrile) hydrochloride

nitro-6-(piperidin-2-ylmethoxy)benzonitrile hydrochloride-2

<img file="SA4858B1_D0118.tif" />

Hydrochloric acid was added at a concentration of 1.25% in ethanol (11.3 ml, 14.13 mmol).

5 to a solution of tert-butyl-2-))2-cyano-3-nitrophenoxy(methyl(piperidine-1-)

Carboxylate (Example 26H, 1.02 g, 2.83 mmol) in ethanol (20 ml) and the reaction mixture was stirred at a temperature of 80 °C in an atmosphere of nitrogen gas for an hour. After it cooled to room temperature The reaction mixture was concentrated under vacuum. The oily precipitate was washed with hexane:dichloromethane (1:4) and the solvent was concentrated under vacuum to obtain hydrochloride 2.

10 Nitro-6-(piperidine-2-ylmethoxy(benzonitrile) (0.682 g, 116%). (+MS 262 (MH).

Example 26e: 2-))2-cyano-3-nitrophenoxy(methyl(piperidine-1-tert-butyl carboxylate)

tert-Butyl 2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate

<img file="SA4858B1_D0119.tif" />

Sodium hydride (0.32 g, 8 mmol) was added at -20 °C to 15 solutions of 2-(hydroxymethyl)piperiden-1-tert-butyl carboxylate (0.86 g, 4

mmol) in dry tetrahydrofuran (30 ml) and the mixture was stirred for 10 minutes at 20 °C and then for another 20 minutes at room temperature. The reaction mixture was then cooled to -20 °C and 2 6, dinitrobenzonitrile (0.222 g, 4 mmol) in dry tetrahydrofuran (10 ml) and dimethylformamide (1 ml) by distillation over

٤٨٥٨

-١١٤-

15 minute. The solution was stirred in an atmosphere of nitrogen gas at room temperature for 18 hours, diluted with water, and extracted with ethyl acetate. The collected organic media were washed with salt water, dried over magnesium sulfate, filtered, and evaporated. The precipitate was purified using a Biotag purification system (120 g Silicycle column, hexane:ethyl acetate =

5 3:2 As a rinse (to obtain 2-))2-cyano-3-nitrophenoxy(methyl(piperidine-1-)

Tert-butyl carboxylate (1.02 g, 20.6%). +[MS 262 [M+H-Boc.

Example 22: (4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(-N-)pyridin-4-ylmethyl(piperidine-1-carboxamide)

(R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-(pyridin-4- ylmethyl)piperidine-1-carboxamide 10

<img file="SA4858B1_D0120.tif" />

It was prepared as in Example 26 from (2)(-2-) R-cyano-3-(sulfamoylamino(phenoxy(methyl)-N-)pyridin-4-ylmethyl(piperidine-1-carboxamide) (Example 22a). 28% yield as a yellowish-white solid 1.35:1H NMR (400 MHz, DMSO-d6) δ

(m, 1H), 1.59 (m, 4H), 1.77 (m, 1H), 3.86 (m, 1H), 4.03 (dd, J = 7.6, 15

5.2 Hz, 1H), 4.16 (t, J = 7.6 Hz, 1H), 4.24 (dd, J = 13.2, 4.4 Hz, 1H), 4.34 (dd, 1H, J = 10.4, 4.4 Hz), 4.71 (m, 1H), 6.05 (d, J = 6.0 Hz, 1H), 6.19 (dd, J = 6.8, 0.8 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 4.4

.)+Hz, 1H), 7.24 (m, 2H), 8.47 (m, 2H). MS 445 (M.H

20 Example 22a: (2)(-2-) R-cyano-3-)sulfamoylamino(phenoxy(methyl)-N-)pyridine-4-ylmethyl(piperidine-1-carboxamide)

٤٨٥٨

-١١٥-

(R)-2-((2-cyano-3-(sulfamoylamino)phenoxy)methyl)-N-(pyridin-4-ylmethyl)piperidine-1-carboxamide

<img file="SA4858B1_D0121.tif" />

It was prepared as in Example 26a from (3)(-2-) R-amino-2-(cyanophenoxy(methyl)-N-)pyridin-5-4-ylmethyl(piperidine-1-carboxamide) (Example 22b). Yield: 48% as a white solid (MS 445 (MH).

Example 22b: (3)(-2-) R-amino-2-)cyanophenoxy(methyl(-N-)pyridin-4-yl

Methyl(piperidine-1-carboxamide

(R)-2-((3-amino-2-cyanophenoxy)methyl)-N-(pyridin-4-ylmethyl)piperidine-1-carboxamide 10

<img file="SA4858B1_D0122.tif" />

Iron powder (164 mg, 2.64 mmol) was added to a solution of (2)(-2-) R-cyano-3-nitrophenoxy(methyl(-N-)pyridin-4-ylmethyl(piperidin-1). -Carboxamide (Example 22C, 365 mg, 0.68 mmol) in tetrahydrofuran/acetic acid (20 ml, 1:1). 15 The reaction was heated during the reflux over 15 minutes in a nitrogen gas atmosphere and

Stir it during the recirculation process over a period of 30 minutes. When the process was completed, the reaction was cooled to room temperature, concentrated, diluted with ethyl acetate, and successively washed with a saturated solution of

٤٨٥٨

-١١٦-

Sodium bicarbonate, dried on sodium sulfate, filtered, concentrated, and treated by rapid chromatography (0-10% methanol in dichloromethane) to obtain the desired product (141 mg, 40%). (+MS = 366 (MH).

Example 22c: (2)(-2-) R-cyano-3-nitrophenoxy(methyl(-N-)pyridin-4-ylmethyl(piperidine-5-1-carboxamide)

(R)-2-((2-cyano-3-nitrophenoxy)methyl)-N-(pyridin-4-ylmethyl)piperidine-1-carboxamide

<img file="SA4858B1_D0123.tif" />

Triethylamine (420 μl, 3.01 mmol) was added to a solution of 2,2,2-

10 Trifluoroacetate (2))-2-(R-cyano-3-nitrophenoxy(methyl(piperidinium) (Example 16g, 1.12 g, 2.66 mmol) in dichloromethane (5 mL) was added. A suspension of pyridine was added. 4-Nitrophenylmethylcarbamate (Example 22d, 680 mg, 3.56 mmol) in dichloromethane (5 mL) was added to this mixture, followed by triethylamine (420 μL, 3.01 mmol). After stirring For 23 hours at room temperature, additional parts of pyridine-

15 4-ylmethylcarbamate 4-nitrophenyl (680 mg, 3.56 mmol) and triethylamine (420 μL, 3.01 mmol), and the resulting reaction mixture was stirred for an hour, during which time it was poured into water and washed with Saturated aqueous sodium bicarbonate, water and salt water, respectively, dried over magnesium sulphate, filtered, concentrated and purified by rapid chromatography (0-100% ethyl acetate in hexane followed by 0-10% methanol in dichloromethane) to obtain

20 On(2)(-2-)R-cyano-3-nitrophenoxy(methyl(-N-)pyridine-4-ylmethyl(piperidine-1-)

Carboxamide (365 mg, 32%). (+MS = 396 (MH).

٤٨٥٨

-١١٧-

Example 22d: Pyridine-4-ylmethylcarbamate-4-nitrophenyl

nitrophenylpyridin-4-ylmethylcarbamate-4

<img file="SA4858B1_D0124.tif" />

10

A solution of pyridine-4-ylmethanamine (505 μL, 5 mmol) and p-nitrophenyl chloroformate (1.0 g, 5 mmol) was stirred in dichloromethane (20 mL) at room temperature for 5 hours. Upon completion of the process, the product was collected by vacuum filtration, washed with dichloromethane, and purified by preparative high-performance liquid chromatography (10-60% acetonitrile in water) to yield pyridine-4-ylmethylcarbamate 4-nitrophenyl as a white solid. Color. (+MS = 274 (MH.

Example 28: (4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(-N-)pyridin-4-yl(piperidine-1-carboxamide)

(R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-(pyridin-4- yl)piperidine-1-carboxamide

<img file="SA4858B1_D0125.tif" />

15

Potassium carbonate (414 mg, 3.0 mmol) was added to a solution of 2,2-dihydrochloride (4-)S-amino-5-(piperidine-3-ylmethoxy)-1H-benzo[6]. 2,1[[c]thiadiazine (Example 15a, 246 mg, 1.0 mmol) and pyridine-4-yl carbamate 4-nitrophenyl (Example 28a, 518 mg, 2.0 mmol) in dimethylformamide (10 ml (The mixture was stirred

٤٨٥٨

-١١٨-

10

Reaction at room temperature for two hours. The compound was purified by preparative reversed-phase high-performance liquid chromatography (10 to 60% acetonitrile in water) to obtain the desired product (120 mg, 28%). 1H NMR (DMSO-d6, 400 MHz): 1.47 (m).

1H), 1.65 (m, 4H), 1.80 (m, 1H), 3.12 (t, 1H, J = 12.0 Hz), 4.03 (m, 1H), 4.17 (m, 1H), 4.61 (t, 1H, J = 10.4 Hz), 4.93 (br s, 1H), 6.61 (d, 1H, J = 8.4), 6.89 (d, 1H, J = 8.4), 7.48 (m, 3H), 7.99 (br s, 1H), 8.30 (d, 2H, J = 5.6 Hz), 8.35 (br s, 1H), 8.92 (s, 1H), 10.94 (s, 1H). M+H = .431

Example 28a: Pyridine-4-yl carbamate 4-nitrophenyl

nitrophenylpyridin-4-ylcarbamate-4

<img file="SA4858B1_D0126.tif" />

15

It was prepared as in Example 22d from pyridine-4-amine and p-nitrophenyl chloroformate to obtain the compound in the form of a yellowish-white solid. (+MS = 260 (MH.

Example 26: (4)((3-(-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(-N-)pyridin-4-ylmethyl(piperidine-1-carboxamide)

(S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-(pyridin-4- ylmethyl)piperidine-1-carboxamide

<img file="SA4858B1_D0127.tif" />

٤٨٥٨

-١١٩-

A solution of 4-nitrophenyl(pyridin-4-ylmethyl)carbamate (Example 22d, 22.3 mg, 100 μmol) and (4)((-3-) S-amino-2,2-dioxide) hydrochloride was stirred. 1H-

Benzo[6,2,1[]c[thiadiazin-5-yl(oxy(methyl(piperidinium) (Example 2a, 34.6 mg, 0.10 mmol) and potassium carbonate in dimethylformamide (1 mL) at °C 5. Leave the room overnight. The resulting mixture was filtered and purified by high-performance liquid chromatography (60-10% acetonitrile in water) to obtain the product mentioned in the title in the form of a white solid.

.MS = 445 (MH+)

Example 30: (4)((3-(-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(-N-)pyridin-4-yl(piperidine-1-carboxamide)

(S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5- 10

yl)oxy)methyl)-N-(pyridin-4-yl)piperidine-1-carboxamide

It was prepared as in Example 26 from pyridine-4-yl carbamate 4-nitrophenyl (Example 28a) and (4)((-3-) S-amino-2,2-dioxide-1H-benzo[6,2, 1[]c[thiadiazine-5-

15 yl(oxy(methyl(piperidinium) (Example 2a). MS = 431 (MH+).

Example 31: (4)((-3(-1-) S-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-yl(oxy(methyl(piperidine) -1-yl(-2-)pyrimidine-2-yl(ethanone

(S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-2-(pyrimidin-2-yl)ethanone

٤٨٥٨

-١٢٠-

<img file="SA4858B1_D0128.tif" />

It was prepared as in Example 2 from (5-)S-(piperidine-3-ylmethoxy(-H1-benzo[6,2,1]]c[thiadiazine4-amino-2,2-dihydroxyhydrochloride) (Example 2a) and 2-(pyrimidine-2-yl)acetic acid (Example 31a) (10% yield). -1H NMR (400 MHz, DMSO

d6) δ 1.31-1.47 (m, 2H), 1.57-1.76 (m, 1H), 1.85 (m, 1H), 2.00 (d, 1H, 5

J = 7.9 Hz), 2.03-2.25 (m, 1H), 3.00 (m, 1H), 3.69-4.22 (m, 6H), 6.56 (m, 1H), 6.65 (m, 1H), 7.32 (t, 1H) , J = 4.9 Hz), 7.39 (t, 1H, J = 4.9 Hz), 7.53-7.84 (m, 2H), 8.70 (d, 1H, J = 4.9 Hz), 8.76 (d, 1H, J = 4.9 Hz ),

(MH+) 10.98 (br s, 1H). MS 431

10 Example 31a: 2-(pyrimidine-2-yl)acetic acid

(pyrimidin-2-yl)acetic acid-2

<img file="SA4858B1_D0129.tif" />

Sodium hydroxide at a concentration of 2p (2 ml) was added to a solution of 2-(pyrimidine-2-yl)ethyl acetate (Example 31b, 410 mg, 2.42 mmol) in ethanol (5 ml) at 15°C, room temperature The reaction mixture was stirred at room temperature in a nitrogen gas atmosphere

of nitrogen gas for 22 hours, then it was concentrated under low pressure. The precipitate was ground with ethanol and concentrated under low pressure to obtain the compound mentioned in the title, which was used in the next step without any further purification. 139 MH+(MS).

Example 31b: 2-(pyrimidine-2-yl)ethyl acetate

ethyl 2-(pyrimidin-2-yl)acetate 20

٤٨٥٨

-١٢١-

<img file="SA4858B1_D0130.tif" />

Sodium hydride (1.26 g, 52.38 mmol, 60% diffusion in mineral oil) was added to a solution of diethyl malonate (6.65 ml, 43.65 mmol) in dimethylformamide (30 ml (At a temperature of -28°C. The reaction was stirred for 10 minutes

5 At -28 °C, it was warmed to room temperature and 2-chloropyrimidine (1.0 g, 8.23 mmol) in dimethylformamide (3 mL) was added. The reaction mixture was heated to 80 °C. Celsius for 22 hours, then to 120°C for 18 hours. When the process was completed, it was cooled to room temperature. The solution was quickly cooled by adding hydrochloric acid at a concentration of 1 p and neutralizing it with saturated aqueous sodium bicarbonate.

10 It was extracted using ethyl acetate (X3). The collected organic materials were dried on sodium sulfate, filtered, concentrated and purified by rapid chromatography on silica gel (0-100% ethyl acetate in hexanes) to obtain the compound mentioned in the title in the form of yellow-orange oil ( 1.34 g, 62%(167 MH+(MS).

Example 32: (4)((-2(-1-) R-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

15 yl(oxy(methyl(piperidin-1-yl(-2-)pyrimidine-2-yl(ethanone)

(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)-2-(pyrimidin-2-yl)ethanone

<img file="SA4858B1_D0131.tif" />

٤٨٥٨

-١٢٢-

It was prepared as in Example 15 from (4)((-2-) R-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazin-5-yl(oxy(methyl) hydrochloride). Piperidinium (Example 15a) and 2-(pyrimidine-2-yl)acetic acid (Example 31a) (36% yield).) 1H NMR (400 MHz, DMSO-d6)

δ 1.25 (m, 1H), 1.47-1.67 (m, 4H), 1.76 (m, 1H), 3.16 (t, 1H, J = 12.6 Hz), 2.77-4.20 (m, 3H), 4.27-4.72 (m , 2H), 5.13 (m, 1H), 6.57 (d, 1H, J 5 = 8.2 Hz), 6.78 (br d, 1H, J = 7.6 Hz), 7.35 (t, 1H, J = 5.0 Hz), 7.40 (br

t, 1H, J = 8.2 Hz), 7.71 (br s, 1H), 7.91 (br s, 1H), 8.71 (m, 2H), 10.90

.)MH+( (br s, 1H). MS 431

Example 33: (4)((-2(-1-) R-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

10 yl(oxy(methyl(piperidin-1-yl(-2-)pyrimidine-4-yl(ethanone)

(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)-2-(pyrimidin-4-yl)ethanone

<img file="SA4858B1_D0132.tif" />

It was prepared as in Example 15 from R-amino-2,2-dioxide-1H-(4)((-2-) hydrochloride.

15 Benzo[6,2,1[]c[thiadiazine-5-yl(oxy(methyl(piperidinium) (Example 15a) and 2-)pyrimidine-4-

Acetic acid (Example 33a) (44% yield). 1H NMR (400 MHz, DMSO-d6)

δ 1.35 (m, 1H), 1.54-1.68 (m, 4H), 1.79 (m, 1H), 3.21 (t, 1H, J = 12.3

Hz), 3.84 (m, 1H), 3.98 (m, 2H), 4.16 (dd, 1H, J = 10.0, 4.6 Hz), 4.29

4.75 (m, 1H), 5.16 (m, 1H), 6.60 (d, 1H, J = 8.6 Hz), 6.81 (br d, 1H, J =

7.9 Hz), 7.43 (d, 1H, J = 11.0 Hz), 7.45 (d, 1H, J = 8.3 Hz), 7.72 (br s, 20

٤٨٥٨

-١٢٣-

1H), 8.07 (br s, 1H), 8.70 (d, 1H, J = 5.0 Hz), 9.08 (m, 1H), 10.91 (br s,

.)MH+(1H). MS 431

Example 33a: 2-(pyrimidine-4-yl)acetic acid

(pyrimidin-4-yl)acetic acid-2

5

Sodium hydroxide at a concentration of 2p (2 ml) was added to a solution of 2-(pyrimidine-4-yl)ethyl acetate (Example 33b, 450 mg, 2.21 mmol) in ethanol (5 ml) at room temperature at Nitrogen atmosphere. The reaction mixture was stirred at room temperature in a nitrogen gas atmosphere for 24 hours, then concentrated under low pressure and suspended in ethanol

10 The solid matter was removed by filtration under vacuum, and the filtered product was concentrated under low pressure

Grind it with ethanol, concentrate it again and transfer it to the next stage without any additional purification. 139 MS

(MH+)

Example 33b: 2-(pyrimidine-4-yl)ethyl acetate

ethyl 2-(pyrimidin-4-yl)acetate

15

4-Methylpyrimidine (1.0 g, 10.63 mmol) was added slowly to a laboratory beaker containing lithium di(trimethylsilyl(lithium)amide (32 mL, 31.86 mmol), at a concentration of 1.0 M in tetrahydrofuran. ) at -20 °C. After stirring for 5 minutes at -20 °C, diethyl carbonate (1.63 mL, 15.65 mmol) was added, and the reaction was slowly warmed to

20 Bring to room temperature and stirred for 4 days. The reaction mixture was quickly cooled by adding 1 N hydrochloric acid, neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (X3). The combined organics were dried over sulfate

٤٨٥٨

-١٢٤-

10

15

Sodium, filtered, concentrated under low pressure, and purified by rapid chromatography on a silica gel (0-100% ethyl acetate in hexanes) to obtain the compound mentioned in the title in the form of a yellow oil (1.38 g, 28% MS). 167 MH+).

Example 34: (4)((-3(-1) R-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl)-3-methylbutan-1-one)

(R)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-3-methylbutan-1-one

It was prepared as in Example 5 from benzonitrile (2-)R-sulfamoylamino-6-)1-(3-methylbutanoyl(piperidin-3-yl(methoxy)) (Example 34a) (54% yield). NMR(400MHz

DMSO-d6, 80°C) δ 0.89 (d, 6H, J = 4.0 Hz), 1.41 (m, 2H), 1.69 (m, 1H), 1.88 (m, 1H), 1.98 (m, 1H), 2.07 (m, 1H), 2.17 (m, 2H), 2.96 (br.

s, 2H), 3.55-4.14 (m, 4H), 6.66 (d, 1H, J = 8.2 Hz), 6.75 (d, 1H, J = 8.2 Hz), 7.44 (t, 1H, J = 8.2 Hz), 7.75 (br.s, 1H) 8.00 (br.s, 1H), 10.69 (s, .)MH+(1H). MS 395

Example 34a: Benzonitrile (2-)R-sulfamoylamino-6-(1-)3-methylbutanoyl(piperidine-3-yl(methoxy)

(R)-2-sulfamoylamino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile

٤٨٥٨

-١٢٥-

<img file="SA4858B1_D0133.tif" />

It was prepared as in Example 5a from (2-)R-amino-6-)(1-(3-methylbutanoyl(piperiden-3-yl(methoxy(benzonitrile) (Example 34b). 395 MH+) MS).

Example 34b: (2-)R-amino-6-))1-)3-methylbutanoyl(piperiden-3-yl(methoxy(benzonitrile)

(R)-2-amino-6-((1-(3-methylbutanoyl)piperidin-3-

yl)methoxy)benzonitrile

<img file="SA4858B1_D0134.tif" />

10

15

Sodium hydride (44 mg, 1.06 mmol, 60% diffusion in mineral oil) was added to a solution of (3)-1-) R-(hydroxymethyl(piperidin-1-yl)-3-methylbutane). -1-One (Example 34C) (145 mg, 0.23 mmol) in tetrahydrofuran (15 mL) at 0°C. The reaction was warmed to room temperature and stirred for 15 minutes, during which time the 2-Amino-6-fluorobenzonitrile (106 mg, 0.80 mmol). The mixture was heated at 80°C overnight, rapidly cooled with water, concentrated under reduced pressure to remove tetrahydrofuran, and extracted with ethyl acetate (X3). The combined extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid chromatography on a silica gel (acetate Ethyl/hexanes). The precipitate was further purified by mirrorless preparative high-performance liquid chromatography (normal medium, ethanol/isopropanol/methanol/hexanes) to yield the compound mentioned in the title as a white solid (66 mg, 41%). 316 MH+) MS(.

٤٨٥٨

-١٢٦-

Example 34c: (3(-1-) R-(hydroxymethyl(piperidin-1-yl)-3-methylbutan-1-one)

(R)-1-(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one

<img file="SA4858B1_D0135.tif" />

10

Dimethyl boron sulfide (1.2 ml, 13.0 mmol) was added to a solution of (R(-1-)3-methylbutanoyl(piperidine-3-carboxylic acid) (Example 34d) (2.52 g). (11.84 mmol) in tetrahydrofuran (20 mL) at 0°C, by distillation over 15 minutes. The reaction was warmed to room temperature, stirred overnight, cooled to 0°C, quickly cooled with water, and concentrated under Low pressure to remove tetrahydrofuran and extract it with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate, dried over sodium sulphate, filtered, concentrated under low pressure, and purified by rapid chromatography on a silica gel (ethyl acetate/hexane) to obtain the compound mentioned in the title (184 mg, 6%) (MS (200 MH+). .

Example 34d: (3(-1-) R-methylbutanoyl(piperidine-3-carboxylic acid)

(R)-1-(3-methylbutanoyl)piperidine-3-carboxylic acid

<img file="SA4858B1_D0136.tif" />

15

20

Sodium bicarbonate (3.30 g, 38.20 mmol) and 3-methylbutanoyl chloride (2.8 ml, 23.2 mmol) were added to a solution of (R)-piperiden-3-carboxylic acid (2, 0 g, 15.48 mmol) in water (40 ml) and tetrahydrofuran (20 ml) at room temperature. The reaction was stirred overnight, concentrated under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (X1). The aqueous medium was acidified with hydrochloric acid at a concentration of 1 p and extracted using ethyl acetate (X3), and the extracts were dried.

٤٨٥٨

-١٢٧-

Collected over sodium sulfate, it was filtered and concentrated under low pressure to obtain the compound mentioned in the title (2.53 g, 26%). 214 MH+ (MS).

Example 35: (4)((-2() R-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl()pyridin-4-yl(methanone)

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5- 5

yl)oxy)methyl)piperidin-1-yl)(pyridin-4-yl)methanone

<img file="SA4858B1_D0137.tif" />

It was prepared as in Example 15 from (4)((-2-) R-amino-2,2-dioxide-H1-benzo[6,2,1]]c[thiadiazin-5-yl(oxy(methyl) hydrochloride). Piperidinium (Example 15a) and isonicotinic acid

1H NMR (400 MHz, DMSO-d6, 80°C) δ 1.48 (m, 1H), 26% 10).

1.58-1.87 (m, 5H), 3.19 (br t, 1H, J = 12.4 Hz), 3.19 (br s, 1H), 4.30 (m, 1H), 4.64 (t, 1H, J = 8.8 Hz), 4.99 (br s, 1H), 6.64 (d, 1H, J = 8.8 Hz), 6.80 (br s, 1H), 7.28 (dd, 2H, J = 6.4 Hz), 7.40 (t, 1H, J = 8.0 Hz) , 7.86 (br s, 2H), 8.60 (dd, 2H, J = 5.2 Hz), 10.66 (br s, 1H). MS 416

(MH+) 15

Example 36: (4)((-2(-1-)R-amino-2,2-dioxide-1H-benzo[6,2,1[c[thiadiazine-5-)

yl(oxy(methyl(piperidin-1-yl(-2-)pyridin-4-yl(ethanone)

(R)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-2-(pyridin-4-yl)ethanone

٤٨٥٨

-١٢٨-

<img file="SA4858B1_D0138.tif" />

It was prepared as in Example 15 from (4)((-2-) R-amino-2,2-dioxide-1H-benzo[6,2,1]]c[thiadiazin-5-yl(oxy(methyl) hydrochloride). (Pipyridinium (Example 15a) and 2-)Pyridinium-4-

1H NMR (400 MHz, DMSO-d6, 80°C). 1H), 3.01 (m, 1H), 5

3.90 (br s, 3H), 4.22 (br s, 1H), 4.45 (t, 1H, J = 8.0 Hz), 5.06 (br s, 1H), 6.64 (d, 1H, J = 8.0 Hz), 6.82 ( d, 1H, J = 8.0 Hz), 7.19 (ddd, 1H, J = 8.0, 4.8, 0.8 Hz), 7.27 (d, 1H, J = 8.0 Hz), 7.42 (t, 1H, J = 8.0 Hz), 7.67 (dt, 1H, J = 8.0, 2.0 Hz), 7.80 (br s, 2H), 8.43 (dq, 1H, J = 8.0 Hz, MH).+(0.8 Hz), 10.65 (s, 1H). MS 430 10

Example 32: (4)()(-2(-)R-amino-2,2-dioxide-1H-benzo[6,2,1[c[thiadiazine-5-]

yl(oxy(methyl(piperidin-1-yl()2-hydroxy-6-methylpyridin-4-yl(methanone)

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( 2-hydroxy-6-methylpyridin-4-yl)methanone

<img file="SA4858B1_D0139.tif" />

It was prepared as in Example 15 from (4))-2-(R-amino-2,2-dioxide-1H-benzo[6,2,1[]c[thiadiazin-5-yl(oxy(methyl)) hydrochloride Piperidinium (Example 15a) and 2-hydroxy-6-methyl

1H NMR (400 MHz, DMSO-d6) δ 1.42 (m, 1H), 1.54 - isonicotinic acid.

٤٨٥٨

-١٢٩-

1.72 (m, 5H), 1.80 (m, 1H), 2.16 (s, 3H), 3.21 (m, 1H), 3.44 (m, 1H), 4.19 (dd, 1H, J = 10.3, 4.2 Hz), 4.37 (m, 1H), 4.61 (t, 1H, J = 10.0 Hz), 5.14 (m, 1H), 5.88 (s, 1H), 6.02 (s, 1H), 6.61 (d, 1H, J = 8.4 Hz) , 6.86 (d, 1H, J = 8.4 Hz), 7.44 (t, 1H, J = 8.4 Hz), 7.75 (br s, 1H), 8.34 (br s, .)MH+( 1H), 10.92 (s, 1H ). MS 446

Example 38: (4)((-2(-)R-amino-2,2-dioxide-1H-benzo[6,2,1[c[thiadiazine-5-)

yl(oxy(methyl(piperidine-1-yl()2,6-dimethylquinoline-4-yl(methanone)

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)(2,6-dimethylquinolin-4-yl)methanone

<img file="SA4858B1_D0140.tif" />

10

15

20

It was prepared as in Example 15 from (4))-2-(R-amino-2,2-dioxide-H1-benzo[6,2,1[]c[thiadiazin-5-yl(oxy(methyl) hydrochloride) Piperidinium (Example 15a) and -dimethylquinoline -

1H NMR (400 MHz, DMSO-d6) δ 1.12-1.53 (m, 2H), .4-carboxylic acid

1.58-1.84 (m, 4H), 1.98 (s, 3H), 2.64 (s, 3H), 3.02 (m, 1H), 3.19 (m, 1H), 4.18 (dd, 1H, J = 9.9, 3.1 Hz) , 4.95 (t, 1H, J = 10.2 Hz), 5.45 (m, 1H), 6.66 (m, 1H), 7.01 (d, 1H, J = 8.2 Hz), 7.27 (s, 1H), 7.38 (s, 1H), 7.46-7.61 (m, 2H), 7.81 (d, 1H, J = 8.6 Hz), 7.98 (br s, 1H), 8.26 (br s, .)MH+( 1H), 10.94 (s, 1H) . MS 494

Example 36: (4)()(-2(-)R-amino-2,2-dioxide-1H-benzo[6,2,1[c[thiadiazine-5-]

yl(oxy(methyl(piperidin-1-yl()2-)methylamino(pyridine-4-yl(methanone)

٤٨٥٨

-١٣٠-

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( 2-(methylamino)pyridin-4-yl)methanone

<img file="SA4858B1_D0141.tif" />

It was prepared as in Example 15 from (4))-2-(R-amino-2,2-dioxide-1H-5 benzo[6,2,1][c[thiadiazin-5-yl(oxy)]hydrochloride. Methyl(piperidinium) (Ex. 15a) and 2-(methylamino)acid

1H NMR (400 MHz, DMSO-d6) δ 1.41 (m, 1H), 1.52-1.74. (m, 1H), 3.40 (m, 1H), 4.19 (dd, 1H, J = 9.9, 3.6 Hz,), 4.65 (t, 1H, J = 10.1 Hz,), 5.20 (m, 1H), 6.30 ( s, 1H), 6.61 (m, 2H), 6.88 (d, 1H, J = 8.5 Hz), 7.46 (t, 1H, J

= 8.6 Hz,), 7.83 (br s, 1H), 8.01 (d, 1H, J = 5.4 Hz,), 8.30 (br s, 1H), 10

(MH+) 10.93 (s, 1H). MS 445

Example 40: (4)()(-2(-)R-amino-2,2-dioxide-1H-benzo[6,2,1[c[thiadiazine-5-]

yl(oxy(methyl(piperidin-1-yl()2-hydroxypyridin-4-yl(methanone)

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( 2-hydroxypyridin-4-yl)methanone 15

<img file="SA4858B1_D0142.tif" />

٤٨٥٨

-١٣١-

It was prepared as in Example 15 from (4))-2-(R-amino-2,2-dioxide-1H-benzo[6,2,1[]c[thiadiazin-5-yl(oxy(methyl)) hydrochloride Piperidinium (Example 15a) and 2-hydroxy acid

1H NMR (400 MHz, DMSO-d6) δ 1.41 (m, 1H), 1.52-1.74. 4.19 (dd, 1H, J = 10.1, 3.8 Hz), 4.62 (t, 1H, J = 10.5 Hz), 5.16 (m, 1H), 6.06 (d, 1H, J = 5

7.0 Hz), 6.23 (s, 1H), 6.61 (d, 1H, J = 8.0 Hz,), 6.87 (d, 1H, J = 8.7 Hz), 7.45 (m, 2H), 7.75 (br s, 1H) , 8.36 (br s, 1H), 10.92 (s, 1H), 11.73

.)MH+( (br s, 1H). MS 432

Example 41: (4)()(-2(-)R-amino-2,2-dioxide-1H-benzo[6,2,1[c[thiadiazine-5-]

10 yl(oxy(methyl(piperidin-1-yl()3-hydroxypyridin-4-yl(methanone)

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( 3-hydroxypyridin-4-yl)methanone

<img file="SA4858B1_D0143.tif" />

It was prepared as in Example 15 from benzo[6,2,1][c[thiadiazin-5-yl(oxy)](4))-2-(R-amino-2,2-dioxide-1H-15) hydrochloride. Methyl(piperidinium) (Example 15a) and 3-hydroxy acid

1H NMR (400 MHz, DMSO-d6) δ 1.45 (m, 1H), 1.52-1.74 Isonicotonic (m, 4H), 1.84 (m, 1H), 3.19 (m, 2H), 4.18 (dd, 1H, J = 10.2, 4.0 Hz), 4.64 (t, 1H, J = 10.0 Hz), 5.25 (m, 1H), 6.61 (d, 1H, J = 8.2 Hz), 6.87 (d, 1H, J = 8.2 Hz), 7.08 (d, 1H, J = 5.5 Hz), 7.46 (t, 1H, J = 8.2 Hz), 7.84 (br s, 1H), 8.07 (d, 1H, J = 5.5 Hz), 8.19 (s, 1H) , 8.29 (br s, 1H), 20

.)MH+ (10.28 (s, 1H), 10.9 (br s, 1H). MS 432

٤٨٥٨

-١٣٢-

Example 42: (4)((-2(-)R-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl()6-methylquinoline-4-yl(methanone)

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( 6-methylquinolin-4-yl)methanone

<img file="SA4858B1_D0144.tif" />

It was prepared as in Example 15 from (4))-2-(R-amino-2,2-dioxide-1H-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl) hydrochloride) Piperidinium (Example 15a) and -dimethylquinoline -

1H NMR (400 MHz, DMSO-d6) δ 1.34-1.53 (m, 2H), .4-carboxylic acid

1.59-1.86 (m, 4H), 2.01 (s, 3H), 3.01 (m, 1H), 3.20 (m, 1H), 4.19 (dd, 1H, J = 10.1, 3.2 Hz), 4.95 (t, 1H, J = 10.6 Hz), 5.46 (m, 1H), 6.67 (d, 10

1H, J = 8.1 Hz), 7.01 (d, 1H, J = 8.3 Hz,), 7.34 (s, 1H), 7.48-7.56 (m, 2H), 7.60-7.68 (m, 1H), 7.92 (d, 1H, J = 8.7 Hz), 7.99 (br s, 1H), 8.27

.)MH+( (br s, 1H), 8.87 (d, 1H, J = 4.4 Hz), 10.94 (s, 1H). MS 480

Example 43: (4)((-2(-)R-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-5-

15 yl(oxy(methyl(piperidin-1-yl()2-methylpyridin-3-yl(methanone)

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( 2-methylpyridin-3-yl)methanone

٤٨٥٨

-١٣٣-

<img file="SA4858B1_D0145.tif" />

It was prepared as in Example 15 from (4)((-2-)R-amino-2,2-dioxide-H1-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl)hydrochloride) Piperidinium (Example 15a) and 2-methyl acid

1H NMR (400 MHz, DMSO-d6) δ 1.35 (m, 1H), 1.48-1.81 (m, Nicotinic 4H), 1.86 (m, 1H), 2.24 (s, 3H), 3.12 (m, 1H), 3.24 (m, 1H), 4.16 (m, 5

1H), 4.77 (t, 1H, J = 9.8 Hz), 5.32 (m, 1H), 6.62 (d, 1H, J = 8.0 Hz), 6.90 (d, 1H, J = 8.3 Hz), 7.27 (m, 1H), 7.47 (t, 1H, J = 8.3 Hz), 7.66 (m, 1H), 7.93 (br s, 1H), 8.31 (br s, 1H), 8.47 (dd, 1H, J = 5.1, 1.7 Hz ),

.)+10.92 (s, 1H). MS 430 (M.H

10 Example 44: (4)((-2(-)R-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-5-

yl(oxy(methyl(piperidine-1-yl()pyridazine-4-yl(methanone)

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)(pyridazin-4-yl)methanone

<img file="SA4858B1_D0146.tif" />

15 It was prepared as in Example 15 from (4)((-2-)R-amino-2,2-dioxide-H1-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl)hydrochloride) Piperidinium (Example 15a) and pyridazine-4-acid

1H NMR (400 MHz, DMSO-d6) δ 1.46-1.89 (m, 6H), 2.24 (s, carboxylic

3H), 3.28 (m, 2H), 4.26 (m, 1H), 4.64 (t, 1H, J = 10.1 Hz), 5.29 (m,

٤٨٥٨

-١٣٤-

1H), 6.62 (d, 1H, J = 8.2 Hz), 6.87 (d, 1H, J = 8.2 Hz), 7.46 (t, 1H, J =

8.2 Hz), 7.69 (dd, 1H, J = 5.0, 1.8 Hz), 7.77 (br s, 1H), 8.37 (br s, 1H),

.)MH+ (9.26 (m, 1H), 9.35 (d, 1H, J = 5.0 Hz), 10.94 (s, 1H). MS 417

Example 45: (4)((-2(-)R-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-5-

5 yl(oxy(methyl(piperidin-1-yl()isoquinoline-1-yl(methanone)

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)(isoquinolin-1-yl)methanone

<img file="SA4858B1_D0147.tif" />

It was prepared as in Example 15 from benzo[6,2,1](4)((-2-)R-amino-2,2-dioxide-H1-10[[c[thiadiazine-5-yl(oxy)hydrochloride) Methyl(piperidinium) (Example 15a) and isoquinoline-1-acid

1H NMR (400 MHz, DMSO-d6) δ 1.33 (m, 1H), 1.47 (m, 1H), carboxylic 1.56-1.74 (m, 2H), 1.81 (m, 1H), 1.93 (m, 1H), 3.00 (m, 1H), 3.21 (m, 1H), 4.26 (dd, 1H, J = 10.1, 3.7 Hz), 4.82 (t, 1H, J = 10.1 Hz,), 5.45 (m, 1H), 6.66 ( d, 1H, J = 8.0 Hz,), 6.95 (d, 1H, J = 8.5 Hz), 7.50 (t, 1H, J =

8.5 Hz,), 7.61 (m, 1H), 7.74-7.90 (m, 3H), 7.97 (br s, 1H), 8.02 (d, 1H, 15

J = 8.0 Hz), 8.28 (br s, 1H), 8.49 (d, 1H, J = 5.8 Hz,), 10.94 (s, 1H).

(MH+) MS 466

Example 46: (4)((-2(-)R-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-5-

yl(oxy(methyl(piperidin-1-yl()2-methylpyridin-4-yl(methanone)

٤٨٥٨

-١٣٥-

(R)-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)( 2-methylpyridin-4-yl)methanone

<img file="SA4858B1_D0148.tif" />

It was prepared as in Example 15 from (4)((-2-)R-amino-2,2-dioxide-1H-5benzo[6,2,1[[c[thiadiazin-5-yl(oxy)hydrochloride) Methyl(piperidinium) (Example 15a) and 2-methyl acid

1H NMR (400 MHz, CD3OD) δ 1.51-2.00 (m, 6H), 2.57 (s, 3H), 3.27 (m, 1H), 3.45 (m, 1H), 4.28 (m, 1H), 4.73 ( t, 1H, J = 10.5 Hz), 5.42 (m, 1H), 6.66 (d, 1H, J = 8.1 Hz), 6.87 (d, 1H, J = 8.1 Hz,), 7.22 (m, 1H), 7.26 (s, 1H), 7.48 (t, 1H, J = 8.6 Hz), 8.50 (d, 1H, J = 4.8

.)MH+(Hz). MS 430 10

Example 42: (4)((-2(-1-)S-amino-2,2-dioxide-1H-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl(piperidine) -1-yl(-3-methylbutane-1-one

(S)-1-(2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-

yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one

<img file="SA4858B1_D0149.tif" />

15

It was prepared as in Example 5 from (2-(S-sulfamino-6-))1-(3-methylbutanoyl(piperidin-2-yl(methoxy(benzonitrile)) (Example 42a) (41% yield). 1H NMR(400MHz

٤٨٥٨

-١٣٦-

DMSO-d6) δ 0.86 (d, 3H, J = 6.9 Hz), 0.88 (d, 3H, J = 6.9 Hz), 1.35 (m, 1H), 1.46-1.68 (m, 4H), 1.75 (m, 1H ), 1.99 (sept, 1H, J = 6.9 Hz), 2.22 (d, 2H, J = 6.8 Hz), 3.15 (m, 1H), 3.78 (m, 1H), 4.08 (dd, 1H, J = 10.1, 4.1 Hz), 4.53 (t, 1H, J = 9.9 Hz), 5.17 (m, 1H), 6.59 (d, 1H, J = 8.2 Hz), 6.84 (d, 1H, J = 8.2 Hz), 7.44 (t , 1H, J = 8.7 Hz), 7.81 (br. s, 5 .)MH+( 1H) 8.22 (br. s, 1H), 10.88 (s, 1H). MS 395

Example 42a: (2-)S-sulfamoylamino-6-))1-)3-methylbutanoyl(piperidine-2-)

yl(methoxy(benzonitrile).

(S)-2-sulfamoylamino-6-((1-(3-methylbutanoyl)piperidin-2-

yl)methoxy)benzonitrile 10

<img file="SA4858B1_D0150.tif" />

Prepared as in Example 5a from (2-(S-amino-6-)(1-(3-methylbutanoyl(piperidin-2-yl(methoxy(benzonitrile)) (Example 42b) (100% yield). 395 MH+) MS(.

Example 42b: (2-)S-amino-6-))1-)3-methylbutanoyl(piperiden-2-yl(methoxy(benzonitrile)

(S)-2-amino-6-((1-(3-methylbutanoyl)piperidin-2- 15 yl)methoxy)benzonitrile

<img file="SA4858B1_D0151.tif" />

٤٨٥٨

-١٣٧-

It was prepared as in Example 2c from (3)-1((-2-)S-methylbutanoyl(piperidin-2-yl(methoxy)-6nitrobenzonitrile (Example 42c) (66% yield). 316 MH+ (MS).

Example 42c: (3)-1)((-2-)S-methylbutanoyl(piperidin-2-yl(methoxy)-6-nitrobenzonitrile

(S)-2-((1-(3-methylbutanoyl)piperidin-2-yl)methoxy)-6-nitrobenzonitrile

<img file="SA4858B1_D0152.tif" />

5

It was prepared as in Example 34d from (S)-2-nitro-6-(piperidin-2-ylmethoxy)benzonitrile hydrochloride (Example 42d) and isovaleryl chloride (40% yield). 346 MS

(MH+)

Example 42d: (2-)S-nitro-6-(piperidine-2-ylmethoxy(benzonitrile) hydrochloride

(S)-2-nitro-6-(piperidin-2-ylmethoxy)benzonitrile hydrochloride 10

<img file="SA4858B1_D0153.tif" />

It was prepared as in Example 1d from (S)-tert-butyl-2-)2-cyano-3-nitrophenoxy(methyl(piperidine-1-carboxylate) (Example 42e). (MS 262 (MH+-HCl).

Example 42e: (S)-tert-butyl-2-))2-cyano-3-nitrophenoxy(methyl(piperidine-1-carboxylate)

(S)-tert-butyl 2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1- 15

carboxylate

٤٨٥٨

-١٣٨-

<img file="SA4858B1_D0154.tif" />

It was prepared as in Example 1e from (S)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate (Example 42f) and 2,6-dinitrobenzonitrile (61% yield). +MS 262 (MH)

.- boc)

Example 42f: (S)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate

(S)-tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate

<img file="SA4858B1_D0155.tif" />

10

It was prepared as in Example 15 and from (1-)S-)tert-butoxycarbonyl(piperidine-2-carboxylic acid.) (MS 116 (MH+ - boc.

Example 48: 2,2-di(4-)S-amino-5-))1-)3-methylbutanoyl(piperidine-3-yl(methoxy(benzo[6,2,1][[c[thiadiazine- 1-Sodium hand

sodium(S)-4-amino-5-((1-(3-methylbutanoyl)piperidin-3-

yl)methoxy)benzo[c][1,2,6]thiadiazin-1-ide 2,2-dioxide

<img file="SA4858B1_D0156.tif" />

15

Sodium bicarbonate (425 mg, 5.02 mmol) was added to a suspension of (4)((-3(-1-)S-amino-2,2-dioxide-1H-benzo[6,2,1]] c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl))

٤٨٥٨

-١٣٩-

3-Methylbutane-1-one (2.0 g, 5.02 mmol) (Example 5) in water (25 ml). The reaction was heated until reflow and complete dissolution of the solid, and then it was concentrated under reduced pressure The resulting precipitate was dissolved in water and dried to obtain the compound mentioned in the title in the form of a beige solid (2.1 g, 100%). (1H NMR (400 MHz, DMSO-d6).

δ 0.78 – 0.96 (m, 6H), 1.21 – 1.50 (m, 2H), 1.55 – 1.75 (m, 1H), 1.78 – 5

2.07 (m, 3H), 2.10 – 2.25 (m, 2H), 2.60 – 2.78 (m, 1H), 2.88 – 3.15 (m, 2H), 3.65 – 3.97 (m, 3H), 4.00 – 4.41 (m, 1H ), 5.97 (t, 1H, J = 8.0 Hz), 6.21 (d, 1H, J = 8.8 Hz), 6.57 (br.s, 2H), 6.95 (d, 1H, J = 8.0, 3.2 Hz).

.)MS 395 (MH+-Na.)

10 Example 46: 1-(3-)Hydroxymethyl(piperidin-1-yl(-3-methylbutan-1-one)

(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one-1

<img file="SA4858B1_D0157.tif" />

It was prepared as in Example 5 from 2-sulfamoylamino-6-)1-)3-methylbutanoyl(piperiden-3-yl(methoxy(benzonitrile) (Example 46a) (86% yield). -1H NMR (400 MHz) , DMSO

d6, 80 °C) δ 0.88 (d, 6H, J = 6.3 Hz), 1.40 (t, 2H, J = 9.2, 9.2 Hz), 15 1.63-1.73 (m, 1H), 1.80-1.90 (m, 1H ), 1.90-2.20 (m, 4H), 2.88-2.98 (m, 2H), 3.58-4.25 (m, 4H), 6.64 (dd, 1H, J = 8.2, 1.1 Hz), 6.74 (d, 1H, J = 8.4 Hz), 7.43 (t, 1H, J = 8.2, 8.2 Hz), 7.79 (br s, 1H), 7.95 (br s,

.)MH+(1H), 10.68 (s, 1H). MS 395

20 Example 46a: 2-sulfamoylamino-6-))1-)3-methylbutanoyl(piperiden-3-yl(methoxy(benzonitrile)

٤٨٥٨

-١٤٠-

sulfamoylamino-6-((1-(3-methylbutanoyl)piperidin-3--2 yl)methoxy)benzonitrile

<img file="SA4858B1_D0158.tif" />

It was prepared as in Example 5a from 2-amino-6-))1-)3-methylbutanoyl(piperidine-3-).

5 Ly(methoxy(benzonitrile) (Example 46B) (68% yield). (+MS 395 (MH)

Example 46b: 2-Amino-6-))1-)3-methylbutanoyl(piperidine-3-yl(methoxy(benzonitrile)

amino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile-2

<img file="SA4858B1_D0159.tif" />

It was prepared as in Example 34b from 1-(3-)hydroxymethyl(piperidin-1-yl(-3-methyl)

10 Butan-1-one (Example 46c). 316 MH+ (MS).

Example 46c: 1-(3-)hydroxymethyl(piperidin-1-yl(-3-methylbutan-1-one)

(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one-1

<img file="SA4858B1_D0160.tif" />

A solution of sodium hydroxide (13.86 g, 342.31 mmol) was added to water (25

15 ml) by distillation at 0 °C to a solution of piperidine-3-yl methanol (10 g,

86.83 mmol) in water (25 ml). The mixture was stirred for 15 minutes, and after this time, a solution of 3-methylbutanoyl chloride (20.64 g, 123.66 mmol) was added in tetramer.

٤٨٥٨

-١٤١-

hydrofuran (25 ml) by distillation while stirring vigorously. The reaction mixture was slowly warmed to a

Once finished, it was diluted with diethyl ether (500 ml) and added with vigorous stirring. After 15 minutes, the media were separated and the aqueous medium was extracted with diethyl ether (X2). The combined organic extracts were washed with salt water and dried over sulfur

5 Sodium, concentrated under low pressure, and treated by rapid chromatography on silica gel (0-100% ethyl acetate in hexane) to obtain the compound mentioned in the title in the form of a colorless oil (16.22 g, 64% (MS). 200 MH+).

Example 50: Ethanesulfonate (4)((-3(-4(-5-) S-amino-2,2-dioxide-1H-)

Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)-2-methyl-4-oxobutane-2-

10 yl(-2-methoxyphenyl

(S)-5-(4-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin- 1-yl)-2-methyl-4-oxobutan-2-yl)-2-methoxyphenyl ethanesulfonate

<img file="SA4858B1_D0161.tif" />

15 It was prepared as in Example 2 from 2,2-dihydrochloride (4-)S-amino-5-)piperidine-

3-ylmethoxy(-1H-benzo[6,2,1[[c]thiadiazine) (Example 2a) and 3-(4-methoxy-3-)(methylsulfonyl(oxy(phenyl)-3-methylbutanoic acid) (Example 2a) 50a) (23% yield). 1H NMR

(400 MHz, DMSO-d6) δ 1.17-1.26 (m, 1H), 1.30-1.34 (m, 7H), 1.46

1.57 (m, 1H), 1.74-1.76 (m, 1H), 1.90 (brs, 1H), 2.56-2.93 (m, 4H), 3.28-3.29 (m, 3H), 3.49-3.61 (m, 1H), 3.68 (s, 1.5H), 3.77 (s, 1.5H), 20

3.89-4.03(m, 3H), 6.58-6.63(m, 1H), 6.69-6.75(m, 1H), 6.98-7.05

٤٨٥٨

-١٤٢-

(m, 1H), 7.13-7.28 (m, 2H), 7.44-7.46 (m, 1H), 7.72-7.74 (m, 1H), .)MH+( 8.33-8.38 (m, 1H), 10.95 (s, 1H).MS 595

Example 50a: 3-)4-methoxy-3-))methylsulfonyl(oxy(phenyl)-3-methylbutanoic acid

(4-methoxy-3-((methylsulfonyl)oxy)phenyl)-3-methylbutanoic acid-3

<img file="SA4858B1_D0162.tif" />

10

15

20

Concentrated sulfuric acid (11 ml, 66%, 206.3 mmol) was added at 0 °C to a mixture of 2-methoxyphenyl methanesulfonate (Example 50b) (82 g, 406.4 mmol) and 3- Methyl-2-butanoic acid (20.3 g, 203.2 mmol). The reaction mixture was stirred at 0 °C for 15 minutes, then heated to 20 °C and stirred under a nitrogen gas atmosphere. Throughout the night. Once complete, the reaction mixture was cooled to room temperature and quickly cooled with ice-cold water (500 ml) and extracted with ether (X1). The media was separated and the organic layer was washed with 2N NaOH (X1). The combined aqueous layers were acidified to Acidity of 1 using hydrochloric acid with a concentration of 12p at a temperature of 0°C and extracted with ether (X1). The organic layer was washed with salt water, dried over sodium sulfate, filtered, and concentrated under low pressure to obtain the compound mentioned in the title in the form of a reddish-brown oil (14.4 g,

1H NMR (400 MHz, DMSO-d6) contains &gt; 20% of 3-methyl-2-butanoic acid δ 1.33 (s, 6H), 2.53 (s, 2H), 3.31 (s, 3H), 3.79 (s, 3H), 7.08-7.31(m,

.)3H), 11.87 (s, 1H

Example 50b: 2-methoxyphenyl methanesulfonate

methoxyphenyl methanesulfonate-2

٤٨٥٨

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<img file="SA4858B1_D0163.tif" />

Methanesulfonyl chloride (32.6 ml, 483.3 mmol) was added at 0 °C in a nitrogen gas atmosphere to a solution of 2-methoxyphenol (50 g, 402.8 mmol) and triethylamine ( 84.2 ml, 604.2 mmol) in aqueous dichloromethane (300 ml).

5 The reaction mixture was stirred at 0°C for 2 hours and quickly cooled with ice water (250 ml) and transferred to a separator funnel. The organic medium was washed with a solution of sodium hydroxide (8 g) in ice water (200 ml), salt water and dried over sulfate. Sodium, filtering and concentrating it under low pressure to obtain the compound mentioned in the title in the form of a colorless liquid (81,44

1H NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3H), 3.83 (s, 3H), % 100 g

.)6.96-7.0 (m, 1H), 7.18-7.2 (m, 1H), 7.27-7.33 (m, 2H 10

Example 51: (4)((-3(-1-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c]thiadiazine-5-yl(oxy(methyl(piperidine) -1-yl(-3-)3-hydroxy-4-methoxyphenyl(-3-methylbutan-1-one)

(S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl )-3-(3-hydroxy-4-methoxyphenyl)-3- 15 methylbutan-1-one

<img file="SA4858B1_D0164.tif" />

Anhydrous sodium hydroxide at a concentration of 2P (0.34 ml) was added to a solution of (4)((-3(-4(-5-) methanesulfonate) S-amino-2,2-dioxide-1H-benzo[6]. ,2,1[[c[thiadiazine-5-

20 yl(oxy(methyl(piperidin-1-yl)-2-methyl-4-oxobutane-2-yl)-2-methoxyphenyl (200 mg, 0.34 mmol) (Example 50) in ethanol (20 ml) The reaction mixture was stirred at a temperature

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10

Heat at 85°C for 3 hours, then cooled to 0°C and neutralized with hydrochloric acid at a concentration of 2p. The solution was concentrated under low pressure and purified by preparative high-performance liquid chromatography (10-60% acetonitrile in water) to obtain the compound mentioned in the title (28 mg, 45%). 1H NMR (400 MHz, DMSO-d6)

δ 1.17-1.32 (m, 8H), 1.43-1.64 (m, 2H), 1.74-1.8 (m, 1H), 2.52-2.67 (m, 2H), 2.77-2.83 (m, 0.5H), 3.51-3.54 (m, 0.5H), 3.65-3.68 (m, 4H), 3.73-3.84 (m, 2H), 4.1-4.18 (m, 1H), 5.9-5.94 (m, 1H), 6.15-6.19 (m, 1H ), 6.5 (brs, 1H), 6.66-6.78 (m, 3H), 6.89-6.95 (m, 1H), 8.71 (s, 1H). (MH+) MS 517

Example 52: (1H(-2(-) S-imidazole-1-yl(pyridine-4-yl()3-))4-amino-2,2-dioxide-1H-benzo[6,2, 1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)methanone)

(S)-(2-(1H-imidazol-1-yl)pyridin-4-yl)(3-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6) ]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)methanone

<img file="SA4858B1_D0165.tif" />

15

20

It was prepared as in Example 2 from (5-)S-(piperidine-3-ylmethoxy(-1H-benzo[6,2,1[[c]thiadiazine-4-amine-2,2-dioxide) hydrochloride (Example 2a) and (2-(1H-imidazole-1-yl)isonicotinic acid (Example 52a) (42% yield). 1H NMR (400 MHz).

DMSO-d6, 80oC) δ 1.42-1.60 (m, 2H), 1.71 (m, 1H), 1.93 (m, 1H),

2.22 (m, 1H), 3.11 (m, 1H), 3.34-3.75 (m, 1H), 3.92-4.42 (m, 2H),

6.63 (m, 1H), 6.74 (br s, 1H), 7.11 (s, 1H), 7.29 (m, 1H), 7.42 (m, 1H), 7.52-8.28 (br s, 2H), 7.76 (m, 1H), 7.93 (m, 1H), 8.52 (m, 2H), 10.71 .)MH+( (br s, 1H). MS 482

٤٨٥٨

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Example 52a: 2-(H1-imidazole-1-yl)isonicotinic acid

(1H-imidazol-1-yl)isonicotinic acid-2

Copper iodide (126 mg, 0.626 mmol) was added to a solution of acid 2

5 Bromoisonicotinic acid (1.82 g, 6.26 mmol), 1H-imidazole (523 mg, 8.42 mmol) and cesium carbonate (6.03 g, 18.5 mmol) in dimethyl sulfoxide (18.6 The mixture was heated to 125°C, stirred for 18 hours, cooled to room temperature, filtered, and purified by preparative high-performance liquid chromatography (10-60% acetonitrile in water) to obtain the compound mentioned in the title in the form material

10 Light pink solid (1.22 g, 68%). 190 MH+ (MS).

Example 53: (H1(-2(-) R-imidazole-1-yl(pyridine-4-yl()2-))4-amino-2,2-dioxide-1H-benzo[6,2, 1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)methanone)

(R)-(2-(1H-imidazol-1-yl)pyridin-4-yl)(2-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6) ]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)methanone

<img file="SA4858B1_D0166.tif" />

It was prepared as in Example 15 from (4)((-2-) R-amino-2,2-dioxide-1H-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl) hydrochloride) Piperidinium (Example 15a) and 2-(1H-imidazole-1-yl)isonicotinic acid (Example 52a) (22% yield). 1H NMR (400 MHz).

DMSO-d6) δ 1.47-1.91 (m, 6H), 3.02 (m, 1H), 3.35 (m, 1H), 4.28 (dd

٤٨٥٨

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1H, J = 10.4, 4.4 Hz), 4.65 (t, 1H, J = 10.4 Hz), 5.24 (m, 1H), 6.63 (d,

1H, J = 8.2 Hz), 6.90 (d, 1H, J = 8.5 Hz), 7.31 (d, 1H, J = 5.2 Hz), 7.48

(d, 1H, J = 8.2 Hz), 7.77 (s, 1H), 7.84 (br s, 1H), 8.00 (s, 1H), 8.44 (br

.)MH+( s, 1H), 8.52-8.59 (m, 2H), 10.95 (br s, 1H). MS 482

5 The compounds listed in Table A below were prepared following the procedures described above.

Table A:

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>381</p></td><td><p dir="rtl">1-)3-)))4-amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-]</p><p dir="rtl">5-yl(oxy(methyl(piperidine-1-yl)butane-1-one</p><p>1-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)butan-1-one</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>381</p></td><td><p dir="rtl">(4)((-3(-1-) R-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)(butan-1-)</p><p dir="rtl">One</p><p>(R)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)butan-1-one</p></td><td></td></tr><tr><td><p>416</p></td><td><p dir="rtl">(3-)))4-Amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl(-2-)) Pyridine-4-yl(methanone</p><p>(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(pyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>432</p></td><td><p dir="rtl">1-(4)((-3(-4-) S-amino-2,2-dioxide-1H-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl(piperidine) oxide) -1-carbonyl(pyridine</p><p>(S)-4-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-</p><p>carbonyl)pyridine 1-oxide</p></td><td></td></tr><tr><td><p>432</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )2-Hydroxypyridin-4-yl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-hydroxypyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>430</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()3-methylpyridin-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3-methylpyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>442</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl())3,4-dihydroxyphenyl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3,4-dihydroxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>381</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl)piperidine-1-yl(-2-methyl)</p><p dir="rtl">Propan-1-one</p></td><td></td></tr><tr><td></td><td><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-2-methylpropan-1-one</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>326</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-)</p><p dir="rtl">Lyl( cyclopropyl)methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(cyclopropyl)methanone</p></td><td></td></tr><tr><td><p>362</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)</p><p dir="rtl">Hydroxy-2-methylpropan-1-one</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-hydroxy-2-methylpropan-1-one</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>406</p></td><td><p dir="rtl">((4)((-3-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)()tetrahydrofuran-2-yl(methanone)</p><p>((S)-3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(tetrahydrofuran-2-yl)methanone</p></td><td></td></tr><tr><td><p>383</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl)-3-hydroxypropan-1-one)</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-3-hydroxypropan-1-one</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>423</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)()tetrahydro-H2-pyrn-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(tetrahydro-2H-pyran-4-yl)methanone</p></td><td></td></tr><tr><td><p>366</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl)-2-hydroxyethanone)</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-hydroxyethanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>362</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)(-3-)</p><p dir="rtl">Methoxypropane-1-one</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-3-methoxypropan-1-one</p></td><td></td></tr><tr><td><p>383</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)</p><p dir="rtl">Methoxyethanone</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-methoxyethanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>445</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )3-Methoxyphenyl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(3-methoxyphenyl)methanone</p></td><td></td></tr><tr><td><p>415</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl)()phenyl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(phenyl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>412</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()pyrimidine-2-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(pyrimidin-2-yl)methanone</p></td><td></td></tr><tr><td><p>431</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )4-Hydroxyphenyl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(4-hydroxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٥٧-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>440</p></td><td><p dir="rtl">(4)((-3(-4-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-)</p><p dir="rtl">Carbonyl(benzonitrile</p><p>(S)-4-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-carbonyl)benzonitrile</p></td><td></td></tr><tr><td><p>412</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()pyrimidine-5-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(pyrimidin-5-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٥٨-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>423</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )2,3-binary</p><p dir="rtl">Hydrobenzo]4,1[]b[dioxin-6-yl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanone</p></td><td></td></tr><tr><td><p>366</p></td><td><p dir="rtl">2-)))4-Amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-]</p><p dir="rtl">yl(oxy(methyl(-N-propylpiperidine-1-carboxamide).</p><p>2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-</p><p>propylpiperidine-1-carboxamide</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>410</p></td><td><p dir="rtl">2-)))4-Amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-]</p><p dir="rtl">yl(oxy(methyl(-N-)tert-butyl(piperidine-1-carboxamide)</p><p>2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-(tert-</p><p>butyl)piperidine-1-carboxamide</p></td><td></td></tr><tr><td><p>382</p></td><td><p dir="rtl">(4)((-2-) R-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-5-yl(oxy(methyl)-N-ethyl piperidine-1) -Carboxamide</p><p>(R)-2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-</p><p>ethylpiperidine-1-carboxamide</p></td><td></td></tr>

٤٨٥٨

-١٦٠-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>382</p></td><td><p dir="rtl">(4)((-2-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-5-yl(oxy(methyl)-N-ethyl piperidine-1) -Carboxamide</p><p>(S)-2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-</p><p>ethylpiperidine-1-carboxamide</p></td><td></td></tr><tr><td><p>410</p></td><td><p dir="rtl">3-)))4-Amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(-N-butylpiperidine-1-carboxamide)</p><p>3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-</p><p>butylpiperidine-1-carboxamide</p></td><td></td></tr>

٤٨٥٨

-١٦١-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>410</p></td><td><p dir="rtl">3-)))4-Amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(-N-)tert-butyl(piperidine-1) -Carboxamide</p><p>3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-(tert-butyl)piperidine-1-carboxamide</p></td><td></td></tr><tr><td><p>442</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) 2,5-dihydroxyphenyl(methanone).</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2,5-dihydroxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٦٢-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>381</p></td><td><p dir="rtl">1-)2-)))4-amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)(butane-) 1-one</p><p>1-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)butan-1-one</p></td><td></td></tr><tr><td><p>381</p></td><td><p dir="rtl">(4)((-2(-1-) R-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)(butan-1-)</p><p dir="rtl">One</p><p>(R)-1-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)butan-1-one</p></td><td></td></tr>

٤٨٥٨

-١٦٣-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>353</p></td><td><p dir="rtl">(4)((-2(-1-) R-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl)ethanone)</p><p>(R)-1-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)ethanone</p></td><td></td></tr><tr><td><p>434</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )3-Fluoropyridine-4-yl(methanone</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3-fluoropyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٦٤-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>442</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )3,5-Dihydroxyphenyl(methanone).</p></td><td></td></tr><tr><td></td><td><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(3,5-dihydroxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>480</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidine-1-yl()3-methylquinoline-4-yl(methanone)</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3-methylquinolin-4-yl)methanone</p></td><td></td></tr><tr><td><p>466</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()quinoline-4-yl(methanone)</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(quinolin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٦٦-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>430</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()3-methylpyridin-4-yl(methanone)</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3-methylpyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>412</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()pyrimidine-4-yl(methanone)</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(pyrimidin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٦٧-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>423</p></td><td><p dir="rtl">((4)((-3-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (Tetrahydro-H2-pyarn-2-yl)methanone</p><p>((S)-3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(tetrahydro-2H-pyran-2-yl)methanone</p></td><td></td></tr><tr><td><p>353</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl)ethanone)</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)ethanone</p></td><td></td></tr>

٤٨٥٨

-١٦٨-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>406</p></td><td><p dir="rtl">((4)((-3-)S-amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-)</p><p dir="rtl">5-yl(oxy(methyl(piperidine-1-yl()tetrahydrofuran-3-yl(methanone)</p><p>((S)-3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(tetrahydrofuran-3-yl)methanone</p></td><td></td></tr><tr><td><p>445</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )2-Methoxyphenyl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-methoxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٦٩-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>423</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )2,3-binary</p><p dir="rtl">Hydrobenzo]4,1[]b[dioxin-5-yl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanone</p></td><td></td></tr><tr><td><p>433</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidine-1-yl()2-fluorophenyl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(2-fluorophenyl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٧٠-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>416</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()pyridin-2-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(pyridin-2-yl)methanone</p></td><td></td></tr><tr><td><p>440</p></td><td><p dir="rtl">(4)((-3(-3-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-)</p><p dir="rtl">Carbonyl(benzonitrile</p><p>(S)-3-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-carbonyl)benzonitrile</p></td><td></td></tr>

٤٨٥٨

-١٧١-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>434</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()2-fluoropyridin-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(2-fluoropyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>445</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )4-Methoxyphenyl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(4-methoxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٧٢-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>431</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) 2-Hydroxyphenyl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(2-hydroxyphenyl)methanone</p></td><td></td></tr><tr><td><p>433</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()4-fluorophenyl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(4-fluorophenyl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٧٣-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>432</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )6-Hydroxypyridin-3-yl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(6-hydroxypyridin-3-yl)methanone</p></td><td></td></tr><tr><td><p>440</p></td><td><p dir="rtl">(4)((-3(-2-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-)</p><p dir="rtl">Carbonyl(benzonitrile</p><p>(S)-2-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-carbonyl)benzonitrile</p></td><td></td></tr>

٤٨٥٨

-١٧٤-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>442</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )2-methoxypyrimidine-5-yl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(2-methoxypyrimidin-5-yl)methanone</p></td><td></td></tr><tr><td><p>423</p></td><td><p dir="rtl">(4)((-2(-1-) R -amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)4-ethoxyphenyl(ethanone)</p><p>(R)-1-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-(4-ethoxyphenyl)ethanone</p></td><td></td></tr>

٤٨٥٨

-١٧٥-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>458</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)</p><p dir="rtl">Methyl-2-(pyridin-4-yl(propane-1-one).</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-methyl-2-(pyridin-4-yl)propan-1-one</p></td><td></td></tr><tr><td><p>458</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)</p><p dir="rtl">Methyl-2-(pyridin-2-yl(propane-1-one).</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-methyl-2-(pyridin-2-yl)propan-1-one</p></td><td></td></tr>

٤٨٥٨

-١٧٦-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>456</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)4-methoxyphenyl(ethanone)</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-(4-methoxyphenyl)ethanone</p></td><td></td></tr><tr><td><p>412</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()pyrimidine-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(pyrimidin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٧٧-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>480</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidine-1-yl()6-methylquinoline-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(6-methylquinolin-4-yl)methanone</p></td><td></td></tr><tr><td><p>512</p></td><td><p dir="rtl">4((-3(-)S(-amino-2,2-dioxide-1H-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (1-Isopropyl-6-methyl-1H-bi-arzulu]3,4-b[pyridin-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(1-isopropyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4- yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٧٨-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>430</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()2-methylpyridin-3-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(2-methylpyridin-3-yl)methanone</p></td><td></td></tr><tr><td><p>446</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )2-Hydroxy-6-methylpyridin-4-yl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-hydroxy-6-methylpyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٧٩-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>442</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) 2,5-dihydroxyphenyl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2,5-dihydroxyphenyl)methanone</p></td><td></td></tr><tr><td><p>430</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)</p><p dir="rtl">(Pyridine-3-yl(ethanone).</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-(pyridin-3-yl)ethanone</p></td><td></td></tr>

٤٨٥٨

-١٨٠-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>455</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (Imidazo[1,2-a[pyridin-2-yl)methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(imidazo[1,2-a]pyridin-7-yl)methanone</p></td><td></td></tr><tr><td><p>442</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )3,5-Dihydroxyphenyl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(3,5-dihydroxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٨١-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>466</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (Isoquinoline-1-yl)methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(isoquinolin-1-yl)methanone</p></td><td></td></tr><tr><td><p>466</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )6-Hydroxy-2-methylquinoline-4-yl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(6-hydroxy-2-methylquinolin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٨٢-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>464</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )2,6-Dimethylquinoline-4-yl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2,6-dimethylquinolin-4-yl)methanone</p></td><td></td></tr><tr><td><p>444</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)(-3-)</p><p dir="rtl">(pyridine-3-yl(propane-1-one).</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-3-(pyridin-3-yl)propan-1-one</p></td><td></td></tr>

٤٨٥٨

-١٨٣-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>442</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) 2,4-dihydroxyphenyl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2,4-dihydroxyphenyl)methanone</p></td><td></td></tr><tr><td><p>480</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidine-1-yl()3-methylquinoline-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3-methylquinolin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٨٤-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>466</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()quinoline-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(quinolin-4-yl)methanone</p></td><td></td></tr><tr><td><p>480</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidine-1-yl()2-methylquinoline-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(2-methylquinolin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٨٥-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>468</p></td><td><p dir="rtl">4((-3(-)S(-amino-2,2-dioxide-1H-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (1,3,6-Trimethyl-1H-bi-arzulu]3,4-b[pyridin-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(1,3,6-trimethyl-1H-pyrazolo[3,4-b]pyridin-4- yl)methanone</p></td><td></td></tr><tr><td><p>423</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)4-ethoxyphenyl(ethanone)</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-(4-ethoxyphenyl)ethanone</p></td><td></td></tr>

٤٨٥٨

-١٨٦-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td></td><td></td><td></td></tr><tr><td><p>482</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)4-methoxyphenyl(-2-methylpropan-1-one)</p></td><td></td></tr><tr><td></td><td><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-2-(4-methoxyphenyl)-2-methylpropan-1-one</p></td><td></td></tr>

٤٨٥٨

-١٨٧-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>468</p></td><td><p dir="rtl">4((-2(-)R(-amino-2,2-dioxide-1H-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (1,3,6-Trimethyl-1H-bi-arzulu]3,4-b[pyridin-4-yl(methanone)</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(1,3,6-trimethyl-1H-pyrazolo[3,4-b]pyridin-4- yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٨٨-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>512</p></td><td><p dir="rtl">4((-2(-)R(-amino-2,2-dioxide-1H-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (1-Isopropyl-6-methyl-1H-bi-arzulu]3,4-b[pyridin-4-yl(methanone)</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(1-isopropyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4- yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٨٩-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>461</p></td><td><p dir="rtl">)1,1[-)S'-diphenyl[-3-yl)3-))4-amino-2,2-di-1H-benzo[6,2,1[[c[thiadiazine-5] -yl(oxy(methyl(piperidine-1-yl)methanone).</p><p>(S)-[1,1'-biphenyl]-3-yl(3-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl) )oxy)methyl)piperidin-</p><p>1-yl)methanone</p></td><td></td></tr><tr><td><p>462</p></td><td><p dir="rtl">(4)((-3(-)S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()3-pyridin-4-yl(phenyl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3-(pyridin-4-yl)phenyl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٩٠-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>502</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (3'-Hydroxy-[1,1'-diphenyl[-3-yl)methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(3'-hydroxy-[1,1'-biphenyl]-3-yl)methanone</p></td><td></td></tr><tr><td><p>481</p></td><td><p dir="rtl">(1H(-3(-) S-imidazole-1-yl(phenyl()3-)))4-amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine- 5-yl(oxy(methyl(piperidine-1-yl)methanone).</p><p>(S)-(3-(1H-imidazol-1-yl)phenyl)(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5) -yl)oxy)methyl)piperidin-1-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٩١-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>524</p></td><td><p dir="rtl">4((-3(-)S(-amino-2,2-dioxide-1H-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (2-)2-Isopropyl-1H imidazole-1-yl(pyridin-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(2-(2-isopropyl-1H-imidazol-1-yl)pyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>462</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()2-phenylpyridine-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(2-phenylpyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٩٢-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>508</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (2-)2-Hydroxyphenyl(pyridin-4-yl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-(2-hydroxyphenyl)pyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>510</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (2-)4-Fluorophenyl(pyridin-4-yl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-(4-fluorophenyl)pyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٩٣-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>510</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (2-)3-Fluorophenyl(pyridin-4-yl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-(3-fluorophenyl)pyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>508</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (2-)3-Hydroxyphenyl(pyridin-4-yl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-(3-hydroxyphenyl)pyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٩٤-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>456</p></td><td><p dir="rtl">(4)((-3(-4-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-)</p><p dir="rtl">Carbonyl(picolinamide</p><p>(S)-4-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-carbonyl)picolinamide</p></td><td></td></tr><tr><td><p>444</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()2-ethylpyridin-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(2-ethylpyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٩٥-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>458</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (2-Isopropylpyridin-4-yl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-isopropylpyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>482</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (2-)diethylamino(pyridine-4-yl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-(diethylamino)pyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-١٩٦-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>466</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (2-)piperidine-1-yl(pyridine-4-yl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-(piperidin-1-yl)pyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>501</p></td><td><p dir="rtl">(4)((-3(-4(- N-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-)</p><p dir="rtl">Carbonyl(pyridine-2-yl(isobutyramide).</p><p>(S)-N-(4-(3-((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-</p><p>carbonyl)pyridin-2-yl)isobutyramide</p></td><td></td></tr>

٤٨٥٨

-١٩٧-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>483</p></td><td><p dir="rtl">(4,2,1 1H-(-2(-) S-triazole-1-yl(pyridine-4-yl()3-)))4-amino-2,2-dioxide-1H-benzo] 6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)methanone)</p><p>(S)-(2-(1H-1,2,4-triazol-1-yl)pyridin-4-yl)(3-(((4-amino-2,2-dioxido-1H-benzo[c] [1,2,6]thiadiazin-5-</p><p>yl)oxy)methyl)piperidin-1-yl)methanone</p></td><td></td></tr><tr><td><p>532</p></td><td><p dir="rtl">(1H(-2(-) S-benzo]d[imidazole-1-yl(pyridin-4-yl()3-)))4-amino-2,2-dioxide-1H-benzo[6,2 ,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)methanone)</p><p>(S)-(2-(1H-benzo[d]imidazol-1-yl)pyridin-4-yl)(3-(((4-amino-2,2-dioxido-1H-benzo[c][1) ,2,6]thiadiazin-5-</p><p>yl)oxy)methyl)piperidin-1-yl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td colspan="2"><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>466</p></td><td colspan="2"><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (2-)2-methyl-1H-imidazole-1-yl(pyridin-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-(2-methyl-1H-imidazol-1-yl)pyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>MS</p><p>)+(MH</p></td><td><p>Compound</p></td><td><p dir="rtl">The compound</p></td><td><p>Compound</p><p>No.</p></td></tr>

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>381</p></td><td><p dir="rtl">1-)3-)))4-amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-]</p><p dir="rtl">5-yl(oxy(methyl(piperidine-1-yl)butane-1-one</p><p>1-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)butan-1-one</p></td><td></td></tr><tr><td><p>381</p></td><td><p dir="rtl">(4)((-3(-1-) R-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)(butan-1-)</p><p dir="rtl">One</p><p>(R)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)butan-1-one</p></td><td></td></tr>

٤٨٥٨

٢٠٠-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>416</p></td><td><p dir="rtl">(3-)))4-Amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl(-2-)) Pyridine-4-yl(methanone</p><p>(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(pyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>432</p></td><td><p dir="rtl">1-(4)((-3(-4-) S-amino-2,2-dioxide-1H-benzo[6,2,1[[c]thiadiazine-5-yl(oxy(methyl(piperidine) oxide) -1-carbonyl(pyridine</p><p>(S)-4-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-</p><p>carbonyl)pyridine 1-oxide</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>432</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )2-Hydroxypyridin-4-yl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2-hydroxypyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>430</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()3-methylpyridin-4-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3-methylpyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>442</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) 3,4-Dihydroxyphenyl(methanone).</p></td><td></td></tr><tr><td></td><td><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(3,4-dihydroxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>381</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl)piperidine-1-yl(-2-methyl)</p><p dir="rtl">Propan-1-one</p></td><td></td></tr><tr><td></td><td><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-2-methylpropan-1-one</p></td><td></td></tr>

٤٨٥٨

-٢٠٤-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>326</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()cyclopropyl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(cyclopropyl)methanone</p></td><td></td></tr><tr><td><p>362</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)</p><p dir="rtl">Hydroxy-2-methylpropan-1-one</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-hydroxy-2-methylpropan-1-one</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>406</p></td><td><p dir="rtl">((4)((-3-)S-amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-)</p><p dir="rtl">5-yl(oxy(methyl(piperidine-1-yl()tetrahydrofuran-2-yl(methanone)</p><p>((S)-3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(tetrahydrofuran-2-yl)methanone</p></td><td></td></tr><tr><td><p>383</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)(-3-)</p><p dir="rtl">Hydroxypropane-1-one</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-3-hydroxypropan-1-one</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>423</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (Tetrahydro-H2-pyarn-4-yl)methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone</p></td><td></td></tr><tr><td><p>366</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl)-2-hydroxyethanone)</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-hydroxyethanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>362</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)(-3-)</p><p dir="rtl">Methoxypropane-1-one</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-3-methoxypropan-1-one</p></td><td></td></tr><tr><td><p>383</p></td><td><p dir="rtl">(4)((-3(-1-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl(-2-)</p><p dir="rtl">Methoxyethanone</p><p>(S)-1-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)-2-methoxyethanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>445</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )3-Methoxyphenyl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(3-methoxyphenyl)methanone</p></td><td></td></tr><tr><td><p>415</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) (phenyl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(phenyl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>412</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()pyrimidine-2-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(pyrimidin-2-yl)methanone</p></td><td></td></tr><tr><td><p>431</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )4-Hydroxyphenyl(methanone).</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(4-hydroxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>440</p></td><td><p dir="rtl">(4)((-3(-4-) S-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-)</p><p dir="rtl">Carbonyl(benzonitrile</p><p>(S)-4-(3-(((4-amino-2,2-dioxido-1H-)</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-carbonyl)benzonitrile</p></td><td></td></tr><tr><td><p>412</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()pyrimidine-5-yl(methanone)</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(pyrimidin-5-yl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>423</p></td><td><p dir="rtl">(4)((-3(-) S-amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )2,3-binary</p><p dir="rtl">Hydrobenzo]4,1[]b[dioxin-6-yl(methanone</p><p>(S)-(3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanone</p></td><td></td></tr><tr><td><p>366</p></td><td><p dir="rtl">2-)))4-Amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-]</p><p dir="rtl">yl(oxy(methyl(-N-propylpiperidine-1-carboxamide).</p><p>2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-</p><p>propylpiperidine-1-carboxamide</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>410</p></td><td><p dir="rtl">2-)))4-Amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-]</p><p dir="rtl">yl(oxy(methyl(-N-)tert-butyl(piperidine-1-carboxamide)</p><p>2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-(tert-</p><p>butyl)piperidine-1-carboxamide</p></td><td></td></tr><tr><td><p>382</p></td><td><p dir="rtl">(4)((-2-) R-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-5-yl(oxy(methyl)-N-ethyl piperidine-1) -Carboxamide</p><p>(R)-2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-</p><p>ethylpiperidine-1-carboxamide</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>382</p></td><td><p dir="rtl">(4)((-2-) S-amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-5-yl(oxy(methyl)-N-ethyl piperidine-1) -Carboxamide</p><p>(S)-2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-</p><p>ethylpiperidine-1-carboxamide</p></td><td></td></tr><tr><td><p>410</p></td><td><p dir="rtl">3-)))4-Amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(-N-butylpiperidine-1-carboxamide)</p><p>3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-</p><p>butylpiperidine-1-carboxamide</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>410</p></td><td><p dir="rtl">3-)))4-Amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(-N-)tert-butyl(piperidine-1) -Carboxamide</p><p>3-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)-N-(tert-butyl)piperidine-1-carboxamide</p></td><td></td></tr><tr><td><p>442</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) 2,5-dihydroxyphenyl(methanone).</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(2,5-dihydroxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>381</p></td><td><p dir="rtl">1-)2-)))4-amino-2,2-dioxide-1H-benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)(butane-) 1-one</p><p>1-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)butan-1-one</p></td><td></td></tr><tr><td><p>381</p></td><td><p dir="rtl">(4)((-2(-1-) R-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidine-1-yl)(butan-1-)</p><p dir="rtl">One</p><p>(R)-1-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)butan-1-one</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>353</p></td><td><p dir="rtl">(4)((-2(-1-) R-amino-2,2-dioxide-1H-</p><p dir="rtl">Benzo[6,2,1[[c[thiadiazine-5-yl(oxy(methyl(piperidin-1-yl)ethanone)</p><p>(R)-1-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)ethanone</p></td><td></td></tr><tr><td><p>434</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )3-Fluoropyridine-4-yl(methanone</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3-fluoropyridin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>442</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1[c]thiadiazine-5-yl(oxy(methyl(piperidine-1-yl) )3,5-Dihydroxyphenyl(methanone).</p></td><td></td></tr><tr><td></td><td><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(3,5-dihydroxyphenyl)methanone</p></td><td></td></tr>

٤٨٥٨

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<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>480</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidine-1-yl()3-methylquinoline-4-yl(methanone)</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3-methylquinolin-4-yl)methanone</p></td><td></td></tr><tr><td><p>466</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()quinoline-4-yl(methanone)</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)(quinolin-4-yl)methanone</p></td><td></td></tr>

٤٨٥٨

-٢١٩-

<tr><td><p>MS</p><p>(MH+)</p></td><td><p dir="rtl">The compound</p></td><td><p dir="rtl">Compound number</p></td></tr><tr><td><p>430</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()3-methylpyridin-4-yl(methanone)</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(3-methylpyridin-4-yl)methanone</p></td><td></td></tr><tr><td><p>412</p></td><td><p dir="rtl">(4)((-2(-) R -amino-2,2-dioxide-1H-benzo[6,2,1][c[thiadiazine-</p><p dir="rtl">5-yl(oxy(methyl(piperidin-1-yl()pyrimidine-4-yl(methanone)</p><p>(R)-(2-(((4-amino-2,2-dioxido-1H-</p><p>benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-</p><p>yl)(pyrimidin-4-yl)methanone</p></td><td></td></tr>

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Biological Tests

Existing compounds have been tested and demonstrated sweet taste-enhancing activities. Specifically, the present compounds have shown T1R3/T1R2 receptor activation and enhancement of T1R3/T1R2 receptor activation as well as sweet taste-enhancing activities for sweeteners, such as fructose. that

5 Compounds Q1, J2, K2, L2, B1, and F3 described in Experiment 1 and Experiment 2 below for human taste tests are selected compounds from the compounds mentioned in this document, including examples and compounds listed in Table A.

Experiment 1: Measuring sweet flavor and sweet flavor potentiation using human participants in a paired comparison test

10 Test samples containing the experimental compounds were presented in pairs to participants and they were asked to indicate which sample of the pair tasted sweeter. Existing compounds showed average sweet flavor enhancement over a wide pH value range and this trial provided results for samples tested at a pH of approximately 2.8 or 2.1. A group of 10-16 or more participants participated in each test. Test participants abstained

15 Eat or drink (except water) for at least one hour before the test. Test participants rinse their mouth with water.

Taste tests were conducted using sucrose or corn syrup as the sweetener in the presence or absence of the compound. A 0.2% concentrated solution of a compound in water with sodium bicarbonate was prepared and this concentrated solution was then diluted in the final sample to achieve the final target concentration of the compound. For the sample

20 Evaluated at pH 2.8, the pH of the solution was lowered to approximately pH 2.8 using citric acid. Taste samples were also prepared in low sodium phosphate buffer (pH 2.1; “Low-salt buffer solution” (free of sucrose or corn syrup to evaluate the taste of the compound alone. The low-salt buffer solution consists of sodium phosphate

٤٨٥٨

-٢٢١-

Of 0.3 mmol of potassium chloride, 0.5 mmol of disodium hydrogen phosphate and 0.175 mmol of potassium dihydrogen phosphate. Sample sizes are usually 20 ml.

In a paired comparison test, the participant is presented with two different samples and asked to identify the one with the sweeter taste. Samples in a pairwise comparison test are presented in a counterbalanced random order. Allow

5 Participants were given up to a one-minute delay between taste tests to clear the mouth of any tastes.

Binary probability tables are used to determine the probability of the correct number of answers that come to mind in each test at alpha=5 0.

Results of human taste tests for QI are below. Table 1-A indicates that

10 Participants found that 6% sucrose with 21 micromol [Q] was not significantly different from a solution of 12% sucrose at pH 7.1 in terms of sweet flavour. Table 1B indicates that participants found 6% sucrose t 7.8 μmol QI not significantly different from a 12% sucrose solution pH 8.2 in terms of sweet flavour. Table 2-A indicates that participants found that 6% high fructose corn syrup + 26.3 micromol [Q]

E1 was noticeably different from a solution of 9% high fructose corn syrup, pH 7.1, in terms of sweet flavour. Table 2B indicates that participants found 6% high-fructose corn syrup + 7.8 µmol [Q] not significantly different from a solution of 8% high-fructose corn syrup at pH 2.8 in terms of sweet flavor. Table 3 indicates that only 26.3 micromoles of compound 601 gives the same amount of sweet flavor as a sucrose solution of high concentration.

٢٠ ١/0.

Table 1-A. The sample that participants chose as the one with the sweetest flavor, n = 30 (15 members x 2 repetitions). pH 7.1

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr>

٤٨٥٨

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<tr><td><p dir="rtl">١٨</p></td><td><p dir="rtl">12% sucrose</p></td></tr><tr><td><p dir="rtl">١٢</p></td><td><p dir="rtl">6% sucrose + 2 micromol compound 01)</p></td></tr><tr><td><p dir="rtl">٣٠</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٣٦٢</p></td><td><p dir="rtl">2 1% sucrose (probability value)</p></td></tr>

Table 1-B. The sample chosen by the participants as the one with the sweetest flavour, number -42 (14 members

duplicates). pH 2.8

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢٤</p></td><td><p dir="rtl">12% sucrose</p></td></tr><tr><td><p dir="rtl">١٨</p></td><td><p dir="rtl">6% sucrose + 7.9 micromol compound 01)</p></td></tr><tr><td><p dir="rtl">٤٢</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٤٤١</p></td><td><p dir="rtl">2 1% sucrose (probability value)</p></td></tr>

E Table 2-A. The sample that participants chose as the one with the sweetest flavor, number - 30 (15 members x two repetitions). pH 7.1

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٦</p></td><td><p dir="rtl">9% high fructose corn syrup</p></td></tr><tr><td><p dir="rtl">١٤</p></td><td><p dir="rtl">6% high fructose corn syrup + 26.3 μmol compound 01)</p></td></tr>

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<tr><td><p dir="rtl">٣٠</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٨٥٦</p></td><td><p dir="rtl">9% high fructose corn syrup (p value)</p></td></tr>

Table 2-B. The sample chosen by the participants as the one with the sweetest flavour, numbered 42 (14 members x 3 iterations). pH 2.8

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢١</p></td><td><p dir="rtl">8% high fructose corn syrup</p></td></tr><tr><td><p dir="rtl">٢١</p></td><td><p dir="rtl">6% high fructose corn syrup +7.8</p><p dir="rtl">µmol compound 01)</p></td></tr><tr><td><p dir="rtl">٤٢</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٨٧٨</p></td><td><p dir="rtl">8% high fructose corn syrup (p value)</p></td></tr>

Table 3. The sample chosen by the participants as the one with the sweetest flavour, number -26 (13 members

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٤</p></td><td><p dir="rtl">1% sucrose</p></td></tr><tr><td><p dir="rtl">١٢</p></td><td><p dir="rtl">Low salt buffer solution + 26.3</p><p dir="rtl">µmol compound 01)</p></td></tr>

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<tr><td><p dir="rtl">٢٦</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٨٤٥</p></td><td><p dir="rtl">1% sucrose (p value)</p></td></tr>

Results of human taste tests for compound 2L are below. Table 4a indicates that participants found 6% sucrose + 12.7 µmol HCl2L not significantly different from a solution of 12% sucrose at pH 7.1 in terms of sweet flavour. Table 4-B indicates that participants found that 6% sucrose + 7.12 µM L2 was not significantly different.

A solution of 12% sucrose with a pH of 8.2 has a sweet flavour. Table E-A indicates

Participants found that 6% high fructose corn syrup + 20.4 µmol Complex 2 L was not significantly different from a solution of 9% high fructose corn syrup with a pH of 7.1 in terms of sweet flavour. Table 5-B indicates that participants found 6% corn syrup to be high

10 fructose + 12.7 μmol compound 2 L is not significantly different from a solution of 9% high fructose corn syrup at pH 8.2 in terms of sweet flavour. Table 6 indicates that only 20.4 micromol of compound 2 L gives the same amount of sweet flavor as a sucrose solution with a concentration of g.....

15 Table 4-A. The sample chosen by the participants as the one with the sweetest flavour, n = 51 (17 members x 3

duplicates). pH 7.1

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢٨</p></td><td><p dir="rtl">12% sucrose</p></td></tr><tr><td><p dir="rtl">٢٣</p></td><td><p dir="rtl">6% sucrose + 12.7 micromol compound 2L</p></td></tr><tr><td><p dir="rtl">٥١</p></td><td><p dir="rtl">Total</p></td></tr>

٤٨٥٨

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<tr><td><p dir="rtl">٠,٥٧٥</p></td><td><p dir="rtl">2 1% sucrose (probability value)</p></td></tr>

Table 4-B. The sample chosen by the participants as the one with the sweetest flavour, number -45 (15 members x 3 iterations). pH 2.8

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢٠</p></td><td><p dir="rtl">12% sucrose</p></td></tr><tr><td><p dir="rtl">٢٥</p></td><td><p dir="rtl">6% sucrose + 12.7 micromol compound 2L</p></td></tr><tr><td><p dir="rtl">٤٥</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٥٥١</p></td><td><p dir="rtl">2 1% sucrose (probability value)</p></td></tr>

E Table 5-A. The sample chosen by the participants as the one with the sweetest flavour, number - 39 (13 members for 3 iterations). pH 7.1

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢١</p></td><td><p dir="rtl">9% high fructose corn syrup</p></td></tr><tr><td><p dir="rtl">١٨</p></td><td><p dir="rtl">6% high fructose corn syrup + 20.4 micromol compound 2 l</p></td></tr><tr><td><p dir="rtl">٣٩</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٧٤٩</p></td><td><p dir="rtl">9% high fructose corn syrup (p value)</p></td></tr>

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-٢٢٦-

Table 5-B. The sample that the participants chose as the one with the sweetest flavor, number - 45 (13 members x 3 iterations). pH 2.8

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢٦</p></td><td><p dir="rtl">9% high fructose corn syrup</p></td></tr><tr><td><p dir="rtl">١٩</p></td><td><p dir="rtl">6% high fructose corn syrup + 12.7 micromol compound 2 l</p></td></tr><tr><td><p dir="rtl">٤٥</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٣٩١</p></td><td><p dir="rtl">9% high fructose corn syrup (p value)</p></td></tr>

Table 6. The sample that participants chose as the one with the sweetest flavor, number -26 (13 members &gt; 5 repetitions).

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٤</p></td><td><p dir="rtl">1% sucrose</p></td></tr><tr><td><p dir="rtl">١٢</p></td><td><p dir="rtl">Low salt buffer solution +20.4 µmol compound 2 l</p></td></tr><tr><td><p dir="rtl">٢٦</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٨٤٥</p></td><td><p dir="rtl">1% sucrose (p value)</p></td></tr>

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Results of human taste tests for Κ2 are below. Table 7-A indicates that participants found 6% sucrose + 12.7 μmol Κ2 not significantly different from a 12% sucrose solution at pH 1.7 in terms of sweet flavour. Table 7-B indicates that participants found that 6% sucrose + 12.7 µmol compound Κ2 was not significantly different from a solution of 12% sucrose at pH 8.2 in terms of sweet flavour. Table 8-A indicates

Participants found that 6% high-fructose corn syrup + 12.7 µmol Κ2 complex was not significantly different from a solution of 9% high-fructose corn syrup with a pH of 7.1 in terms of sweet flavor. Table 8-B indicates that participants found 6% high fructose corn syrup + 12.7 µmol Κ2 complex not significantly different from a solution of 8% corn syrup.

10 High fructose with a pH of 2.8 in terms of sweet flavour. Table 9 indicates that only 12.7 micromoles of compound Κ2 gives the same amount of sweet flavor as a sucrose solution with a concentration of

Table 7-A. The sample chosen by the participants as the one with the sweetest flavour, number -36 (1 member x 3

15 iterations). pH 7.1

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢٠</p></td><td><p dir="rtl">11% sucrose</p></td></tr><tr><td><p dir="rtl">١٦</p></td><td><p dir="rtl">6% sucrose + 12.7 μmol compound Κ2</p></td></tr><tr><td><p dir="rtl">٣٦</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٦٨١</p></td><td><p dir="rtl">11% sucrose (p value)</p></td></tr>

٤٨٥٨

Table 7-B. The sample that participants chose as the one with the sweetest flavor, number -36 (18 members x two repetitions). pH 2.8

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢١</p></td><td><p dir="rtl">12% sucrose</p></td></tr><tr><td><p dir="rtl">١٥</p></td><td><p dir="rtl">6% sucrose + 7.6 μmol compound Κ2</p></td></tr><tr><td><p dir="rtl">٣٦</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٤٠٥</p></td><td><p dir="rtl">2 1% sucrose (probability value)</p></td></tr>

Table 8-A. The sample chosen by the participants as the one with the sweetest flavour, number -33 (1 member x 3 iterations). pH 7.1

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٧</p></td><td><p dir="rtl">8% high fructose corn syrup</p></td></tr><tr><td><p dir="rtl">١٦</p></td><td><p dir="rtl">6% high fructose corn syrup + 12.7 μmol Κ2 compound</p></td></tr><tr><td><p dir="rtl">٣٣</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">&gt; ٠,٨٦٠</p></td><td><p dir="rtl">8% high fructose corn syrup (p value)</p></td></tr>

Table 8-B. The sample chosen by the participants as having the sweetest flavour, number - 51 (17 members

duplicates). pH 2.8

٤٨٥٨

-٢٢٩-

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢٥</p></td><td><p dir="rtl">9% high fructose corn syrup</p></td></tr><tr><td><p dir="rtl">٢٦</p></td><td><p dir="rtl">6% high fructose corn syrup + 12.7 μmol Κ2 compound</p></td></tr><tr><td><p dir="rtl">٥١</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">١,٠٠</p></td><td><p dir="rtl">9% high fructose corn syrup (p value)</p></td></tr>

Table 9. The sample that participants chose as the one with the sweetest flavour, number - 51 (17 members &gt; 2 repetitions).

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢٩</p></td><td><p dir="rtl">1% sucrose</p></td></tr><tr><td><p dir="rtl">٢٢</p></td><td><p dir="rtl">Low salt buffer solution + 12.7 µmol compound Κ2</p></td></tr><tr><td><p dir="rtl">٥١</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٤٠١</p></td><td><p dir="rtl">1% sucrose (p value)</p></td></tr>

The results of human taste tests for compound 12 are below. Table 1 indicates that participants found 6% sucrose + 12.7 µmol compound 12 not significantly different from a solution of 12% sucrose at pH 1.7 in terms of sweet flavour. Table 11 indicates that participants found that 6% high fructose corn syrup + 12.7 μmol Complex 12 is not

٤٨٥٨

-٢٣٠-

Noticeably different from a solution of 9% high fructose corn syrup, pH 8.2, in terms of sweet flavour. Table 12 indicates that only 12.7 micromol of compound 12 gives the same amount of sweet flavor as a 1% sucrose solution.

Table 10. The sample chosen by the participants as having the sweetest flavour, number - 42 (14 members

5 repetitions). pH 7.1

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٩</p></td><td><p dir="rtl">12% sucrose</p></td></tr><tr><td><p dir="rtl">٢٣</p></td><td><p dir="rtl">6% sucrose + 12.7 µmol compound 12</p></td></tr><tr><td><p dir="rtl">٤٢</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٦٤٤</p></td><td><p dir="rtl">2 1% sucrose (probability value)</p></td></tr>

Table 11. The sample that the participants chose as the one with the sweetest flavor, number -36 (12 members x 3 iterations). pH 2.8

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٦</p></td><td><p dir="rtl">9% high fructose corn syrup</p></td></tr><tr><td><p dir="rtl">٢٠</p></td><td><p dir="rtl">6% high fructose corn syrup + 12.7 µmol Compound 12</p></td></tr><tr><td><p dir="rtl">٣٦</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٦٨١</p></td><td><p dir="rtl">9% high fructose corn syrup (p value)</p></td></tr>

٤٨٥٨

-٢٣١-

Table 12. The sample chosen by the participants as the one with the sweetest flavour, number 36 (12 members x 3 iterations).

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٩</p></td><td><p dir="rtl">1% sucrose</p></td></tr><tr><td><p dir="rtl">١٧</p></td><td><p dir="rtl">Low salt buffer solution + 12.7 µmol compound 12</p></td></tr><tr><td><p dir="rtl">٣٦</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٨٦٨</p></td><td><p dir="rtl">1% sucrose (p value)</p></td></tr>

The results of human taste tests for compound 81 are below. Table 31 indicates that participants found 6% sucrose (11.9 µmol) compound Β1 not significantly different from a 12% sucrose solution at pH 1.7 in terms of sweet flavour. Table 14 indicates that participants found that 6% high-fructose corn syrup +1.9 µmol compound Β1 was not significantly different from a solution of 9% high-fructose corn syrup with a pH of 8.2.

10 The sweet flavor aspect. Table 12 indicates that only 1.9 micromol of compound B1 gives the same amount of sweet flavor as a 1% sucrose solution.

Table 13. The sample chosen by the participants as the one with the sweetest flavour, number H34 (17 members &gt; 2 repetitions). pH 7.1

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٩</p></td><td><p dir="rtl">12% sucrose</p></td></tr>

٤٨٥٨

<tr><td><p dir="rtl">١٥</p></td><td><p dir="rtl">6% sucrose + 1.9 µmol compound 81</p></td></tr><tr><td><p dir="rtl">P.3</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٦٠٨</p></td><td><p dir="rtl">2 1% sucrose (probability value)</p></td></tr>

Table 14. The sample chosen by the participants as the one with the sweetest flavour, number - 34 (17 members pH 2.8

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">٢٠</p></td><td><p dir="rtl">9% high fructose corn syrup</p></td></tr><tr><td><p dir="rtl">١٤</p></td><td><p dir="rtl">6% high fructose corn syrup + 1.9 micromol compound 81</p></td></tr><tr><td><p dir="rtl">P.3</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٣٩٢</p></td><td><p dir="rtl">9% high fructose corn syrup (p value)</p></td></tr>

Table E1. The sample chosen by the participants as the one with the sweetest flavour, number -45 (15 members x 3 iterations).

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٩</p></td><td><p dir="rtl">1% sucrose</p></td></tr><tr><td><p dir="rtl">٢٦</p></td><td><p dir="rtl">Low salt buffer solution +1.9 µM compound B1</p></td></tr>

٤٨٥٨

-٢٣٣-

<tr><td><p dir="rtl">٤٥</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٣٧١</p></td><td><p dir="rtl">1% sucrose (p value)</p></td></tr>

Human taste test results for F3 are below. Table 61 indicates that participants found 6% sucrose with 9.2 µmol F3 not significantly different from a 10% sucrose solution with pH 1.7 in terms of sweet flavour. Table 17 indicates

5 Participants found that 6% high fructose corn syrup + 9.2 µmol F3 was not significantly different from a solution of 9% high fructose corn syrup with a pH of 8.2 in terms of sweet flavour. Table 18 indicates that only 2.9 micromol of F3 gives the same amount of sweet flavor as a 1% sucrose solution.

Table 16. The sample chosen by the participants as the one with the sweetest flavour, number -33 (11 members

10 repetitions). pH 7.1

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٦</p></td><td><p dir="rtl">0 1% sucrose</p></td></tr><tr><td><p dir="rtl">١٧</p></td><td><p dir="rtl">6% sucrose + 9.2 μmol compound F3</p></td></tr><tr><td><p dir="rtl">٣٣</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">&gt;٠,٧٢٨</p></td><td><p dir="rtl">0 1% sucrose (p value)</p></td></tr>

Table 17. The sample chosen by the participants as having the sweetest flavour, number - 51 (17 members

duplicates). pH 2.8

Debts

Total

٤٨٥٨

-٢٣٤-

<tr><td><p dir="rtl">٢٨</p></td><td><p dir="rtl">9% high fructose corn syrup</p></td></tr><tr><td><p dir="rtl">٢٣</p></td><td><p dir="rtl">6% high fructose corn syrup + 9.2 micromol F3</p></td></tr><tr><td><p dir="rtl">٥١</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٥٧٦</p></td><td><p dir="rtl">9% high fructose corn syrup (p value)</p></td></tr>

Table 18. The sample that participants chose as the one with the sweetest flavor, number - 30 (15 members x two repetitions).

<tr><td><p dir="rtl">Total</p></td><td><p dir="rtl">Debts</p></td></tr><tr><td><p dir="rtl">١٦</p></td><td><p dir="rtl">1% sucrose</p></td></tr><tr><td><p dir="rtl">١٤</p></td><td><p dir="rtl">Low salt buffer solution + 9.2 µmol compound F3</p></td></tr><tr><td><p dir="rtl">٣٠</p></td><td><p dir="rtl">Total</p></td></tr><tr><td><p dir="rtl">٠,٨٥٦</p></td><td><p dir="rtl">1% sucrose (p value)</p></td></tr>

Experiment 2: Measuring sweet flavor and the degree of sweet flavor enhancement in product models using human participants

Experiment 2-1: The degree of sucrose strengthening of compound Κ2 in iced coffee:

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All samples were made in an iced coffee formulation consisting of filter coffee, 2% milk, sucrose, and water. Samples were prepared using a stock of the compound made of 0.2% sodium bicarbonate and water. The test samples were presented in the form of paired samples to the participants and they were asked to indicate which sample of the paired sample tasted sweeter.

5 In a paired comparison test, the participant is presented with two different samples and asked to identify the one with the sweeter taste. Samples in a pairwise comparison test are presented in a counterbalanced random order. Participants are allowed up to one minute of delay between taste tests to clear the mouth of any aftertastes.

Binary probability tables are used to determine the probability of the correct number of answers that 10 come to mind in each test at alpha = 5 0.0.

Table 19 indicates that participants found the 4% sucrose; 7.6 µmol Κ2 compound not significantly different from a solution of iced coffee containing 8% sucrose.

Table 19. The sample chosen by the participants as the one with the sweetest flavour, number 33 (1 member x 3 iterations)

<img file="SA4858B1_D0167.tif" />

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All publications and patent applications cited herein are hereby incorporated by reference to the same extent as if each publication, or patent application, were specifically and individually incorporated by reference.

The above detailed description is provided for illustrative purposes only and no undue restrictions should be taken from it

5 Because the modifications will be clear to those skilled in the field. It is not a representation that any information provided herein is a prior invention or is relevant to the present patented invention or that any publication specifically or implicitly referred to is a prior invention.

Embodiments of this invention are set forth herein, including the best position known by the inventors to implement the invention. Changes to those preferred representations may become apparent to those with skill

10 It is normal in the field when reading the previous explanation. The inventors expect that skilled craftsmen will use these variations appropriately, and it is the inventors' intention that the invention be used in a manner other than specifically described herein. Accordingly, this invention includes all modifications and equivalents with respect to the subject matter mentioned in the claims appended herein as permitted by applicable law. In addition, the invention includes any combination of the elements described above in all possible variations mentioned unless indicated.

<p dir="rtl">15 Otherwise, or the context clearly contradicts that.</p>

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