BR122018001911B1 - compounds derived from heteroaryl piperidine and piperazine, composition comprising them, method for controlling harmful phytopathogenic fungi, process for producing compositions and using compounds - Google Patents

Abstract

the invention relates to heteroaryl piperidine and piperazine derivatives of formula (i) (i) wherein each of a, x, y, l1, l2, g, q, p, r1, r2 and r10 has the meanings defined in the description, and salts, metal complexes and n-oxides of the compounds of formula (i), their use for the control of harmful phytopathogenic fungi and processes for the preparation of compounds of formula (i).

Description

HETEROARYL-PIPERIDINE AND PIPERAZINE DERIVED COMPOUNDS, UNDERSTANDING THEM, METHOD FOR THE CONTROL OF HARMFUL PHYTOPATOGENIC FUNGI, PROCESS FOR THE

PRODUCTION OF COMPOSITIONS AND USE OF COMPOUNDS Divided from BR1120130104970, deposited on 10/25/2011 [0001] The invention concerns derivatives of heteroaryl-piperidine and -piperazine, their active salts from the agrochemical point of view, their use and methods and compositions for the control of harmful phytopathogenic fungi in and / or on plants or in and / or on plant seeds, processes for the production of such treated compositions and seeds and their use for the control of harmful phytopathogenic fungi in agriculture, horticulture and forestry, animal health, material protection and the domestic and hygiene sector. The present invention also relates to a process for the preparation of heteroaryl-piperidine and -piperazine derivatives.

[0002] It is already known that it is possible to use heterocyclic substituted thiazoles as fungicidal agents for the protection of particular cultures (see, patent applications numbers: WO 07/014290, WO 08/013925, WO 08/013622, WO 08 / 091594, WO 08/091580, WO 09/055514, WO 09/094407, WO 09/094445, WO 09/132785, WO 10/037479, WO10 / 065579, WO2010 / 066353, WO2010 / 149275, WO2011 / 051243,

WO2011 / 051244, WO 2011/076510, WO 2011/018415, WO 2011/018401, WO 2011/076699; see also invention patent applications with application numbers: DE102010000662.9,

PCT / EP2011 / 056594, PCT / EP2011 / 057912, PCT / EP2011 / 058330,

PCT / EP2011 / 063783, PCT / EP2011 / 064527). However, in

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2/191 particularly for relatively low application rates, the fungicidal efficacy of these compounds is not always adequate.

[0003] Since ecological and economic needs for agents for the protection of modern crops are constantly increasing, for example, with respect to the spectrum of activity, toxicity, selectivity, application rate, waste formation and favorable production, and there may still be problems, for example, with resistance, there is a constant need for the development of new agents for the protection of crops, in particular fungicides, which, at least in some areas, have advantages over those already known.

[0004] It has now surprisingly been found that the present heteroaryl-piperidine and piperazine derivatives present satisfy at least some aspects of the objects mentioned and are suitable for use as agents for the protection of cultures, in particular as fungicides.

[0005] The invention provides compounds of formula (I)

(I) in which each of the radicals has the meanings defined below:

the symbol A represents phenyl which can contain up to five substituents, where each of the substituents is selected

Petition 870180056486, of 06/29/2018, p. 10/206

3/191 independent between the symbol ZA-1, or the symbol A represents a heteroaryl, with 5 or 6 members, unsubstituted or substituted, optionally benzofused which can contain up to four substituents, where each of the substituents on the carbon is independently selected between the ZA-2 symbol and each of the substituents on nitrogen is selected independently from the ZA-3 symbol, the ZA-1 symbols represent the same or different groups, each independently selected from hydrogen, halogen, hydroxyl, thioxy, nitro, cyano, -C (= O) H, -C (= O) OH, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, halocycloalkenyl, hydroxyalkyl, cyanoalkyl, formylalkyl, alkoxy, alkoxy, alkyl alkynyloxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylaminoalkyl, haloalkylaminoalkyl, cycloalkylaminoalkyl, dialkylaminoalkyl, alkylcarbonyl lquilo, alkylsulfonylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkoxy, alkylcycloalkylalkyl, halocycloalkoxy, alkylthio, haloalkylthio, cycloalkylthio, alkynylthio, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, alkylcarbonyloxy, haloalquilcarboniloxi, cycloalkylcarbonyloxy, cycloalkylamino, alkylcarbonylamino, cycloalkylcarbonylamino alkoxycarbonylamino, alkylsulfonylamino,

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4/191 haloalquilsulfonilamino, phenylsulfonylamino, cycloalkylalkyl, halocycloalkylalkyl, cycloalkylcycloalkyl, alkoxyalkoxyalkyl, alkylaminocarbonyloxy, alquilcarbonilalcoxi, cycloalkylaminocarbonyl, cycloalkylalkoxycarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, trialkylsilyl, -SF 5, phenyl, C (= O) NR3R4 or -NR3R4, the symbols ZA-2 and RG1 represent an equal or different group and each independently represents hydrogen, halogen, hydroxyl, thioxy, nitro, cyano, C (= O) H, -C (= O) OH, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, hydroxyalkyl, formylalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkylcycloalkyl, alkoxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy alkylc arboniloxi, haloalquilcarboniloxi, cycloalkylcarbonylamino, alkylsulfonylamino, haloalquilsulfonilamino, phenylsulfonylamino, cycloalkylalkyl, halocycloalkylalkyl, cycloalkylcycloalkyl, alkoxycarbonyloxy, alquilcarboniltio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyloxy, -C (= O) NR3R4 or -NR3R4, the symbols ZA-3, RG2 and Z2 represent an equal or different group and each of them represents

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5/191 independently hydrogen, -C (= O) H, -C (= O) NR3R4, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylsulfonyl, alkylsulfonyl phenylsulfonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, cycloalkoxycarbonyl, phenyl or benzyl, R3 and R4 represent an equal or different group and each independently represents hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, benzyl or benzyl or benzyl symbol L1 represents NRL12 or C (RL11) 2, symbols RL11 represent an equal or different group and each independently represents hydrogen, halogen, hydroxyl, cyan, -C (= O) H, -C (= O) OH, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, alkylthio, haloalkylthio, halo alkoxy, alkylcarbonyloxy, alkylcarbonylamino, alkylcarbonylthio, alkylsulfonyl, haloalkylsulfonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, trialkylsilyloxy, -NR3R4 or -C (= O) NR3R4, or are combined with the radicals R, 11 or form a cyclopropyl ring or the two radicals RL11 represent = CH2, = COR3, = NOR3 or = CHN (R7) 2, the symbol RL12 represents hydrogen, -C (= O) H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,

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6/191 haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylaminocarbonyl, haloalkyl, aminocarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, cycloalkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, phenyl or benzyl, R7 is alkyl, alkenyl , alkynyl, haloalkyl, cycloalkyl, benzyl or phenyl, the symbol Y represents sulfur or oxygen, the symbol X represents a carbon or nitrogen, the symbol R2 represents hydrogen, alkyl, alkenyl, haloalkyl, alkoxy, halogen, cyano or hydroxyl, the symbol R10 represents oxo, alkyl, alkenyl, haloalkyl, alkoxy, halogen, cyano or hydroxyl, the symbol p represents 0, 1 or 2, the symbol G represents a 5-membered heteroaryl that is substituted with Q or it can be unsubstituted or substituted , in which each of the substituents on the carbon are independently taught between the RG1 symbol and each of the substituents on nitrogen are independently selected from the RG2 symbol, the Q symbol represents a saturated or partially or totally unsaturated 5-membered heterocyclyl, which is replaced with the radical L2-R1 and can, on the contrary, to be unsubstituted or substituted, where each of the substituents is selected independently from the symbol R5, each of the symbols R5 represents a group equal to or

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7/191 different and is independently:

bonded to the carbon of the 5-membered radical of the Q radical:

hydrogen, oxo, halogen, cyano, hydroxyl, nitro, CHO, -C (= O) OH, -C (= O) NH2, -C (= O) NR3R4, -NR3R4, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl , haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, halocycloalkylalkyl, alquilcicloalquil alkyl, cycloalkenyl, halocycloalkenyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkoxyalkyl, alkoxyalkoxyalkyl, alkylthioalkyl, formylalkyl, alkylcarbonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalquilaminoalquilo, cycloalkylaminoalkyl, alkylcarbonyl , haloalkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, cycloalkylaminocarbonyl, hydroxy, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, cycloalkylalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkynyloxy, alkoxyalkoxy, alkylcarbonyloxy, haloalquilcarboniloxi, cycloalkylcarbonyloxy, alkylcarbonylalkoxy, alkylthio, haloalkylthio, cycloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, trialkylsilyl, alkylsulfonylamino, haloalkylsulfonylamino, linked to the 5-membered heterocyclic radical

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8/191 hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, phenyl, benzyl, alkylsulfonyl, -C (= O) H, alkoxycarbonyl or an alkylcarbonyl symbol , O, C (= O), S (O) m, CHR20 or NR21, the symbol m represents 0, 1 or 2, the symbol R20 represents hydrogen, alkyl or haloalkyl, the symbol R21 represents hydrogen, alkyl, haloalkyl, cycloalkyl , alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl or haloalkoxycarbonyl, the symbol R1 represents phenyl which is substituted once with a substituent Z4 and may optionally contain yet another substitution, where each of these additional substituents is independently selected from the radicals Z4 and Z1, or R1 represents naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, hexahydronaphthalenyl, octahidronaphthalenyl or indenyl, which is replaced once with a su substitutent Z5 and may optionally contain yet another substitution, where each of these additional substituents is independently selected from the radicals Z5 and Z1, or the symbol R1 represents a substituted 5- or 6-membered heteroaryl, optionally benzofused, which is

Petition 870180056486, of 06/29/2018, p. 16/206

9/191 substituted once on carbon with a Z6 substituent or on nitrogen with a Z7 substituent and can optionally also be substituted with other substituents, where each of the additional substituents on the carbon is independently selected from the radicals Z1 and Z6 and each of the additional substituents on nitrogen is selected independently from the radicals Z2 and Z7, the symbol Z1 represents hydrogen, halogen, hydroxyl, nitro, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl haloalkoxy, alkylcarbonyl, alkoxycarbonyl, alkyl, cycloalkoxyalkyl, cycloalkylamino, alkylthio, haloalkylthio, cycloalkylthio, cycloalkylalkyl, alkylcarbonyloxy, alkylcarbonylamino, haloalquilcarbonilamino, alquilcarboniltio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyloxy, haloalquilsulfoniloxi, alkylcycloalkylalkyl, C (= O) NR3R4, -NR3R4 or - L3Z3, the L3 symbol represents a direct bond, -CH2-, -C (= O) -, sulfur, oxygen, -C (= O) O-, -C (= O) NH-, -OC (= O) - or NHC (= O) -, the symbol Z3 represents a phenyl radical, naphthalenyl radical or a 5- or 6-membered heteroaryl radical, each of which may contain 0, 1, 2 or 3 substituents, each of which substituents is selected independently from the following listing:

a) substituents on carbon: halogen, cyano, nitro, hydroxyl, amino, -SH, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, alkylcarbonyl,

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10/191 haloalkylcarbonyl, alkoxycarbonyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, alkylamino, dialkylamino, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsalkyl, alkylphenyl, alkylsulfyl, alkyl

b) nitrogen substituent: hydrogen, -C (= O) H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylsulfonyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl alkoxycarbonyl, haloalkoxycarbonyl, cycloalkoxycarbonyl, -C (= O) NR3R4, phenyl or benzyl, the symbol Z4 represents SH, C (= O) H, cycloalkyl (C7-C8), halocycloalkyl (C7-C8), cycloalkylcycloalkyl, halocycloalkyl, halocycloalkyl, halocycloalkyl , halocycloalkenyl, (C4-C6) alkoxy (C1-C4) alkyl, (C3-C4) alkoxy (C2-C4) alkyl, alkoxyalkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl carbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, cycloalkylaminocarbonyl, haloalkoxyalkyl, hydroxyalkyl (C5-C 6), (C5-C6) alkoxy, (C5-C6) haloalkoxy, cycloalkoxy, halocycloalkoxy, cycloalkylalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkyloxy, alkoxyalkoxy, cyanoalkoxy, haloalkylalkylalkyl (alkoxyalkyl) C5-C6) -thio, (C5-C6) alkylsulfinyl,

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11/191 halo (C5-C6) -sulfinyl, halo (C5-C6) -sulfonyl, (C5-C6) alkyl-sulfonyl, cycloalkylsulfonyl, tri ((C3-C4) alkyl)) - silyl, alkylsulfonylamino or haloalkylsulfonylamino symbol Z5 represents tri ((C2-C4) alkyl) - silyl, benzyl, phenyl, SH, (C5-C6) alkoxy (C5-C6) haloalkoxy (C2-C6) alkenyloxy (C2-C6) alkynyloxy (C2-C6), alkyl ( C5-C6) -thio or haloalkyl (C5-C6) -thio, the symbol Z6 represents SH, cycloalkylcycloalkyl or tri (alkyl (C3-C4)) - silyl, the symbol Z7 represents alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, alkylsulfonyl, C (= O) H, benzyl or phenyl, and salts, metal complexes and N-oxides of the compounds of formula (I), provided that the following compounds are excluded:

F where the symbols have the following meanings:

the symbol Y represents oxygen or sulfur, the symbol R2 represents hydrogen or halogen, the symbol Q represents Q ²⁴ -1 = r5 y

O /

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12/191

Q ²⁴ -3 =

Q ¹¹ -1 =

the symbol R5 represents hydrogen, cyano, alkyl (C1C3) or haloalkyl (C1-C3), the symbol L2 represents a direct bond and the symbol R1 has the meanings defined above, where, in the case of the symbol R1 represents a substituted phenyl group , naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, hexahydronaphthalenyl, octahydronaphthalenyl or indenyl or a 5- or 6-membered optionally benzofused heteroaryl, then no more than two substituents are present in the referred carbocycles or heterocycles.

[0006] The invention further provides the use of compounds of formula (I) as fungicides.

[0007] The heteroaryl-piperidine and piperazine derivatives of structural formula (I) according to the invention, and their salts, metal complexes and N-oxides, are quite suitable for the control of harmful phytopathogenic fungi. In particular, the aforementioned compounds of the invention exhibit a potent fungicidal activity and can be used for crop protection, in the domestic and hygiene sectors and for the protection of materials.

[0008] The compounds of structural formula (I) can be present in pure form or as a mixture of different possible isomeric forms, in particular stereoisomers, such as E and Z isomers, threus and erythro and also optical isomers, such as isomers R and S or

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13/191 atropisomers, and, if appropriate, also as tautomers. The E and Z isomers, the threus and erythro isomers, as well as the optical isomers, and any desired mixtures of these isomers, as well as the possible tautomeric forms, are claimed.

[0009] The preferred, most preferred and even more preferred radical definitions of the compounds of the invention of formula (I) have the following definitions:

the symbol A preferably represents phenyl which can contain up to two substituents, where each of the substituents is selected independently from the following listing:

halogen, cyano, hydroxyl, -NR3R4, -C (= O) NR3R4, nitro, alkyl (C1-C6), alkenyl (C2-C6), alkynyl (C2-C6), cycloalkyl (C3-C6), haloalkyl (C1 -C6), haloalkenyl (C2C6), haloalkynyl (C2-C6), halocycloalkyl (C3-C6), alkoxy (C1-C4), haloalkoxy (C1-C4), alkenyloxy (C1-C4), alkenyloxy (C1-C4) , (C1-C4) alkylthio, (C1-C4) alkyl sulfonyl, halo (C1-C4) -thio, haloalkyl (C1-C4) sulfonyl, alkoxy (C1-C4) -alkyl (C1-C6), hydroxyalkyl (C1-C4), (C1-C6) alkylcarbonyl, (C1-C6) alkoxy carbonyl, (C1-C6) alkylcarbonyloxy or -C (= O) H or A symbol preferably represents a heteroaromatic radical selected from the set consisting of: furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, pyrrole-1-yl, pyrrole -2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl , isothiazol-4-yl, isothiazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-1-yl,

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14/191 imidazol-2-yl, imidazol-4-yl, 1,2,3-triazol-1-yl, 1,2,4triazol-1-yl, pyridine-2-yl, pyridine-3-yl, pyridine -4yl, pyridazine-3-yl, pyridazine-4-yl, pyrazine-2-yl, pyrazine-3-yl, pyrimidine-2-yl, pyrimidine-4-yl or pyrimidine-5-yl, which may contain up to two substituents, each of which is independently selected from the following listing:

substituents on carbon:

halogen, cyano, hydroxyl, nitro, -NR3R4, (C1C6) alkyl, alkenyl (C2-C6), alkynyl (C2-C6), cycloalkyl (C3C6), haloalkyl (C1-C6), haloalkenyl (C2-C6), haloalkynyl (C2-C6), halocycloalkyl (C3-C6), alkoxy (C1C4), haloalkoxy (C1-C4), alkyl (C1-C4) -thio, alkyl (C1-C4) sulfonyl, haloalkyl (C1-C4) -io , halo (C1-C4) sulfonyl, (C1-C4) alkoxy (C1-C4) alkyl, (C1-C4) hydroxyalkyl, (C1-C6) alkylcarbonyl, (C1-C6) alkoxy carbonyl, (C1) alkyl -C6) -carbonyloxy or phenyl, substituents on nitrogen:

alkyl (C1-C6), alkenyl (C2-C6), alkynyl (C2-C6), haloalkyl (C1-C6), haloalkenyl (C2-C6), haloalkyl (C2C6), cycloalkyl (C3-C10) -alkyl (C1 -C6), halo (C1-C6) alkylcarbonyl, phenyl, benzyl, (C1-C4) alkylsulfonyl, halo (C1-C4) alkylsulfonyl, phenylsulfonyl, -C (= O) H or (C1-C6 alkyl) ) -carbonyl, the symbol A most preferably represents phenyl, which can contain up to two substituents, where each of the substituents is selected independently from the following listing:

fluorine, bromine, iodine, chlorine, cyano, nitro, methyl, ethyl, n-propyl, 1-methylethyl, 1,1-dimethylethyl,

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15/191 chlorofluoromethyl, dichloromethyl, dichlorofluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, cyclopropyl, ethoxy, 1-methylethoxy, n-propoxy, methoxy, trifluoromethoxy, difluoromethoxy, 1-methylethylthio, trifluoromethyl, trifluoromethyl, methylthio symbol A represents even more preferably a heteroaromatic radical selected from the group consisting of: furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isoxazol-3-yl, isoxazol-4- yl, isoxazol-5yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol- 4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazole-

5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 1,2,3triazol-1-yl, 1,2,4-triazol-1-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine- 4-yl or pyrimidine-5-yl, which can contain up to two substituents, where the substituents are the same or different and each is independently selected from the following listing:

substituents on carbon:

fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-propyl, 1-methylethyl, 1,1-dimethylethyl, chlorofluoromethyl, dichloromethyl, dichlorofluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, cyclopropyl, ethoxy, 1-methyl n-propoxy, methoxy, trifluoromethoxy, difluoromethoxy, 1-methylethylthio, methylthio, ethylthio, n-propylthio, difluoromethylthio, trifluoromethylthio or

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16/191 phenyl, substituents on nitrogen:

methyl, ethyl, n-propyl, 1-methylethyl, methylsulfonyl, trifluoromethylsulfonyl, methylcarbonyl, trifluoromethylcarbonyl, chloromethylcarbonyl, 2,2trifluoroethyl, 2,2-difluoroethyl, 2,2-dichloro-2fluoroethyl, 2-chloro-2-difluoro chloro-2-fluoroethyl, the symbol A represents much more preferably phenyl which can contain up to two substituents, where each of the substituents is selected independently from the following listing:

methyl, ethyl, iodine, chlorine, bromine, fluorine, methoxy, ethoxy, difluoromethyl or trifluoromethyl or the symbol A most preferably represents pyrazol-1-yl which can contain up to two substituents, each of which is independently selected from from the following listing:

methyl, ethyl, chlorine, bromine, fluorine or trifluoromethyl, R3 and R4 preferably represent an equal or different group and each independently represents hydrogen, (C1-C6) alkyl, alkenyl (C2C6), alkynyl (C2-C6) , halo (C1-C6), cycloalkyl (C3C8), benzyl or phenyl, and more preferably hydrogen, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl or 1,1dimethylethyl, the symbol L1 preferably represents C (RL11 ) 2 (more preferably CHRL11) or NRL12 and even more preferably CH2, the symbol RL11 preferably represents hydrogen, methyl, ethyl or cyclopropyl,

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17/191 or the two radicals RL11, together with the carbon atom to which they are attached, form a cyclopropyl ring or the two radicals RL11 represent = CHN (R7) 2, the symbol RL11 most preferably represents hydrogen or methyl, the RL12 preferably represents hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C3-C8) cycloalkyl, (C1-C4) alkylsulfonyl, (C1-C4) alkoxycarbonyl, more preferably hydrogen or methyl and even more preferably hydrogen, the symbols R7 preferably represent an equal or different group and independently represent alkyl (C1-C6), alkenyl (C2-C6), alkynyl (C2-C6), haloalkyl (C1-C6), cycloalkyl (C3 -C8), benzyl or phenyl, and more preferably hydrogen, methyl, ethyl, npropyl, 1-methylethyl, n-butyl or 1,1-dimethylethyl, the symbol Y preferably represents oxygen or sulfur and more preferably oxygen, the symbol X represents carbon or nitrogen and preferably carbon, R2 preferably represents hydrogen, (C1-C4) alkyl, alkenyl (C1-C4), haloalkyl (C1-C4), alkoxy (C1-C4), halogen, cyano or hydroxyl, more preferably hydrogen, fluorine, chlorine, bromine or hydroxyl and even more preferably hydrogen or fluorine (and particularly just hydrogen), R10 preferably represents oxo, (C1-C4) alkyl, alkenyl (C1-C4), haloalkyl (C1-C4), alkoxy (C1-C4) , halogen, cyan or hydroxyl, plus

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18/191 preferably fluorine, chlorine, bromine or hydroxyl and even more preferably fluorine, the symbol p preferably represents and more preferably 0, the symbol G represents preferably

G ¹

_R G1

G ²

R ^G1

G ³

G ⁴

G ⁷

G ¹⁰ r ^g1

R

O"

N

G ⁵

O

R

G ⁶ .w

G1 _G 11

G ⁹

where the connection identified by v is directly linked to the symbol

X and where the connection identified by w is directly linked to the symbol Q, the symbol G most preferably represents G1, G2 or

G3 and even more preferably G1, the symbol RG1 preferably represents hydrogen or halogen and more preferably hydrogen, the symbol Q preferably represents

Q ¹ s \ v- #

Q ²

R ⁵

The # * ___ | _

N

Q ³ n \ / # ^N , Q ⁴ .5 *

#

Petition 870180056486, of 06/29/2018, p. 26/206

19/191

Q ⁵ *

#

Q ⁶ *

#

Q ⁷ , 5

#

R \. ^The #

*

#

Q8

R \ N ^ V # k I '^ X

Q ¹³

r5

Q ¹⁷

Q ²¹

Q ²⁵

Q ²⁹ _Q 33

Q ³⁷

Q ⁴¹ r5 r5 r ⁵

N

N

r5

Q ¹⁸

Q ²²

N

*

#

Q ¹⁹

Q ²³

S * ____ | _

Q ²⁰

HI

#

N *

#

Q ²⁴ *

#

#

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20/191

where the link identified by * is directly linked to the symbol G and where the link identified by # is linked directly to the symbol L2, or where the link identified by * is linked directly to the symbol L2 and where the link identified by # is directly linked to the G symbol, the symbol most preferably represents

Q .5

Q ²⁴ -2

Q ¹¹ -1 ^y R ⁵

O

Q ²⁴ -3

Q ²⁴ -4 =

where the bond identified by x is directly linked to the symbol G and where the bond identified by y is directly linked to the symbol L2, the symbol Q most preferably represents Q24-3, the symbols R5 preferably represent the same or different groups and independently represent a carbon-linked group of the 5-membered heterocyclyl of the symbol Q:

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21/191 hydrogen, cyano, -NR3R4, (C1-C6) alkyl, alkenyl (C2C6), alkynyl (C2-C6), haloalkyl (C1-C6), haloalkenyl (C2C6), haloalkynyl (C2-C6), cycloalkyl ( C3-C8), halocycloalkyl (C3-C8), halocycloalkyl (C3-C8), alkyl (C1-C4) -cycloalkyl (C3-C8), cycloalkyl (C3-C8) alkyl (C1-C4), alkoxy (C1-) C4) -C1-C4alkyl, (C3-C8) cycloalkoxy-(C1-C4) alkyl, (C1-C4) alkoxy-(C1C4) alkoxy-(C1-C4) alkyl, (C1-C4) alkyl - thio-alkyl (C1-C4), alkoxy (C1-C6), haloalkoxy (C1-C6), cycloalkoxy (C3-C8), halocycloalkoxy (C3-C8), cycloalkyl (C3-C8) -alkoxy (C1-C4) , alkenyloxy (C2-C6), haloalkenyloxy (C2-C6), alkynyloxy (C2C6), haloalkynyloxy (C2-C6), alkoxy (C1-C6) -alkoxy (C1-C4), alkyl (C1-C6) -carbonyloxy, halo (C1-C6) -carbonyloxy, (C3-C8) cycloalkyl-carbonyloxy, (C1-C6) alkyl-carbonylalkoxy (C1-C6), (C1-C6) alkylthio, haloalkyl (C1-C6) -io, cycloalkyl (C3-C8) -thio, linked to the nitrogen of the heterocyclyl with 5 members of the symbol Q:

hydrogen, -C (= O) H, (C1-C3) alkyl, (C1-C6) alkyl, carbonyl, (C1-C6) alkoxy-carbonyl or benzyl, R5 most preferably represents hydrogen, cyano, methyl, trifluoromethyl, difluoromethyl or methoxymethyl or the symbol R5 represents even more preferably hydrogen, the symbol L2 preferably represents a direct bond, -O-, -C (= O) -, -S (O) m-, -CHR20- or -NR21-, more preferably a direct link, -C (= O) -, -CHR20- or NR21- and even more preferably the symbol L2 represents a direct link,

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22/191 the symbol m preferably represents 0 or 2, the symbol R20 preferably represents hydrogen, (C1-C4) alkyl, haloalkyl (C1-C4) and more preferably hydrogen, methyl, ethyl, trifluoromethyl, the symbol R21 preferably represents hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkyl carbonyl, halo (C1-C6) -carbonyl, alkoxy (C1-C6) carbonyl or halo (C1-C6) -carbonyl and more preferably hydrogen or methyl, the symbol R1 preferably represents phenyl which is substituted once with a substituent Z4 and which may optionally contain other substitutions, where each of the additional substituents is selected independently from the symbols Z4 and Z1-1 or the symbol R1 preferably represents naphthalene-1yl, naphthalene-2-yl, 1,2,3,4-tetrahydronaphthalene-1-yl,

1,2,3,4-tetrahydronaphthalene-2-yl, 5,6,7,8-tetrahydronaphthalene-1-yl, 5,6,7,8-tetrahydronaphthalene-2-yl, decalino-1- yl, decalino-2-yl, 1H-indeno-1-yl, 2,3-dihydro-1H-indeno-1-yl, 1H-indeno-2-yl, 1H-indeno-3-yl, 1H-indeno- 4-yl, 1H-indeno-5-yl, 1H-indeno-6-yl, 1Hindeno-7-yl, indano-1-yl, indano-2-yl, indano-3-yl, indano-4-yl or indano-5-yl, where each of these is substituted once with a Z5 substituent and may additionally and optionally contain other substitutions, where each of the additional substituents is independently selected from the symbols Z5 and Z1-2 or the symbol R1 preferably represents a 5- or 6-membered heteroaryl radical that is substituted once,

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23/191 on a carbon with a Z6 substituent or on a nitrogen with a Z7 substituent, and may additionally and optionally contain other substitutions, where each of the additional substituents on the carbon is independently selected from the symbols Z1-3 and Z6 and each of the additional substituents on nitrogen are independently selected from the symbol Z2 or the symbol R1 preferably represents a substituted and 6-membered heteroaryl with benzofused that is substituent with a Z4 substituent and may additionally and optionally contain other substitutions, where each of the additional substituents on carbon is selected independently from the symbol Z1-2 and each of the additional substituents on nitrogen is selected

regardless between the Z2 symbol. [0010] O symbol R1 represents more preferably phenyl that can contain 1, 2 or 3 substituents, in that a substituent is selected in between O

symbol Z4 and any other substituents are selected from the following list: fluorine, chlorine, bromine, iodine, cyan, nitro, hydroxyl, amino, -SH, -C (= O) H, methyl, ethyl, npropyl, 1-methylethyl, n-butyl, 1,1-dimethylethyl, 1,2dimethylethyl, ethenyl, ethynyl, trifluoromethyl, difluoromethyl, trichloromethyl, dichloromethyl, cyclopropyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, 1,1dimethylethoxy, methylcarbonyl, tricarbonyl, ethylcarbonyl, tricarbonyl methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 1-methylethoxycarbonyl, 1,1dimethylethoxycarbonyl, 1-ethyleneoxy, 2-propenyloxy, 2propynyloxy, methylcarbonyloxy, trifluoroalkylcarbonyloxy,

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24/191 chloromethylcarbonyloxy, methylthio, ethylthio, methylsulfonyl, methylsulfonylamino, trifluoromethylsulfonylamino or -L3R3 or the symbol R1 even more preferably represents naphthalene-1-yl, naphthalene-2-yl, 1,2,3,4-tetrahydronaphthalene-1-yl , 1,2,3,4-tetrahydronaphthalene-2-yl, 5,6,7,8-tetrahydronaphthalene-1-yl, 5,6,7,8-tetrahydronaphthalene-2-yl, decalin-1 -yl, decalino-2-yl, 1Hindene-1-yl, 2,3-dihydro-1H-indeno-1-yl, 1H-indeno-2yl, 1H-indeno-3-yl, 1H-indeno-4 -yl, 1H-indeno-5-yl, 1Hindeno-6-yl, 1H-indeno-7-yl, indano-1-yl, indano-2-yl, indano-3-yl, indano-4-yl or indane -5-yl, where each of these can be substituted at least once with a substituent Z5 and can additionally and optionally contain other substitutions, where each of the additional substituents is selected independently from the symbol Z5 and from the group consisting of methyl, methoxy, cyano, fluorine, chlorine, bromine and iodine, in which, according to a particularly preferable variant a maximum of three substituents are present or R1 is much more preferably furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isoxazol-3-yl, isoxazole -4-yl, isoxazol-5-yl, pyrrol-1yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl , thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-1 -yl, imidazol-2-yl, imidazol-4-yl, 1,2,4-oxadiazol-3-yl,

1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3, 4-thiadiazol-2yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3

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25/191 triazol-4-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,

1,2,4-triazol-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine- 4-yl, pyrimidine-5-yl or pyrazine-2-yl, each of which may contain 1 or 2 substituents, where one substituent is on carbon and is selected from the symbol Z6 or else it is on nitrogen and is selected from among the Z7 symbol and any other substituents are selected from the following listing:

carbon substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, methyl, ethyl, n-propyl, 1methylethyl, n-butyl, 1,1-dimethylethyl, 1,2-dimethylethyl, ethylene, ethynyl, trifluoromethyl, difluoromethyl, trichloromethyl, dichloromethyl, cyclopropyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, 1,1-dimethylethoxy, methylcarbonyl, ethylcarbonyl, trifluoromethylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 1-methyloxycarbonyl, 1-methyloxycarbonyl, 1 1-ethenyloxy, 2-propenyloxy, 2propiniloxi, methylcarbonyloxy, trifluoroalquilcarboniloxi, clorometilcarboniloxi, methylcarbonylamino, trifluoroalquilcarbonilamino, clorometilcarbonilamino, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, methylsulfonyloxy, trifluoroalquilsulfoniloxi, methylsulfonylamino or trifluorometilsulfonilamino, the nitrogen substituents: methyl, ethyl, n-propyl, -C (= O) H, methylcarbonyl, trifluoromethylcarbonyl, chloromethylcarbonyl, methylsulfonyl, trifluoromethylsulfonyl, phenylsulfonyl, phenyl o or 2propynyl or R1 most preferably represents indole-1

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26/191 yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-1-yl, benzimidazol2-yl , benzimidazol-4-yl, benzimidazol-5-yl, indazol-1yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-

6-yl, indazol-7-yl, indazol-2-yl, 1-benzofuran-2-yl, 1benzofuran-3-yl, 1-benzofuran-4-yl, 1-benzofuran-5yl, 1-benzofuran-6- yl, 1-benzofuran-7-yl, 1benzothiophene-2-yl, 1-benzothiophene-3-yl, 1-benzothiophene-4yl, 1-benzothiophene-5-yl, 1-benzothiophene-6-yl, 1benzothiophene-7- yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,3benzothiazol-7-yl, 1, 3-benzoxazol-2-yl, 1,3-benzoxazol-4yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3benzoxazol-7-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl, quinoline-8-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline- 4-yl, isoquinoline-5-yl, isoquinoline-6-yl, isoquinoline-7-yl or isoquinoline-8yl, which is substituted with a substituent, either on carbon by the symbol Z6 or on nitrogen by the symbol Z7, and has additional and optionally another substituent selected from the following list:

carbon substituents: fluorine, chlorine, bromine, iodine, methyl, methoxy, nitrogen substituents: methyl, ethyl, n-propyl, -C (= O) H, methylcarbonyl, trifluoromethylcarbonyl, chloromethylcarbonyl, methylsulfonyl, trifluoromethylsulfonyl, phenylsulfonyl, phenylsulfonyl, phenylsulfonyl 2propynyl, the symbol Z1-1 represents hydrogen, halogen, cyan,

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27/191 hydroxyl, nitro, -C (= O) NR3R4, -NR3R4, (C1-C6) alkyl, alkenyl (C2-C6), alkynyl (C2-C6), haloalkyl (C1-C6), haloalkenyl (C2- C6), haloalkynyl (C2-C6), cycloalkyl (C3C6), halocycloalkyl (C3-C8), alkoxy (C1-C6) -alkyl (C1-C6), alkoxy (C1-C6) -carbonyl, alkoxy (C1-C4) ), (C1-C4) haloalkoxy, (C1-C6) alkylcarbonyloxy, (C1-C4) alkylthio, halo (C1-C4) -thio, cycloalkyl (C3-C6) -io or -L3Z3, symbols Z1-2 represent the same or different groups and each independently represents hydrogen, halogen, cyano, nitro, -NR3R4, -C (= O) NR3R4, alkyl (C1-C6), alkenyl (C2-C6), alkynyl (C2 -C6), halo (C1-C6), haloalkenyl (C2-C6), haloalkynyl (C2C6), alkoxy (C1-C4) -alkyl (C1-C4), alkoxy (C1-C6) -carbonyl, alkoxy (C1- C4), (C1-C4) haloalkoxy, (C1-C6) alkylcarbonyloxy, (C1-C6) alkylcarbonylthio, (C1-C4) alkylthio or halo (C1-C4) -ioium, the symbol Z1-3 represents hydrogen, halogen, cyano, hydroxyl, nitro, -C (= O) NR3R4, -NR3R4, (C1-C6) alkyl, alkenyl (C2-C6), alkynyl (C 2-C6), halo (C1-C6), haloalkenyl (C2-C6), haloalkynyl (C2-C6), cycloalkyl (C3C8), halocycloalkyl (C3-C8), alkoxy (C1-C6) -alkyl (C1-C6) ), (C1-C6) alkylcarbonyl, (C1-C6) alkoxy-carbonyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) alkyl carbonyloxy, (C1-C6) alkylthio , halo (C1-C6) -thio or cycloalkyl (C3-C6) -thio, the symbols Z2 represent the same or different groups and, preferably, independently represent hydrogen, (C1-C6) alkyl, alkenyl (C2-C6), alkynyl (C2C6), halo (C1-C6), haloalkenyl (C2-C6), haloalkynyl (C2-C6), alkoxy (C1-C4) -alkyl (C1-C4), phenyl,

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28/191 benzyl, (C1-C4) haloalkyl, sulfonyl, (C1-C6) alkoxy carbonyl, halo (C1-C6) -carbonyl, phenylsulfonyl, (C1-C4) alkylsulfonyl, -C (= O) H, halo (C1-C3) carbonyl or (C1-C3) alkylcarbonyl, the L3 symbol preferably represents a direct bond, -CH2-, sulfur, oxygen and more preferably a direct bond, the Z3 symbol preferably represents a phenyl, naphthalenyl radical or a 5- or 6-membered heteroaryl radical that can contain up to two substituents, each of which is independently selected from the following listing:

carbon substituents: halogen, cyano, nitro, hydroxyl, amino, -SH, (C1-C4) alkyl, alkenyl (C2-C4), alkynyl (C2-C4), haloalkyl (C1-C4), haloalkenyl (C2-C4) ), halo (C2-C4) alkoxy (C2-C4) alkoxy (C1-C6) alkyl, carbonyl, halo (C1-C6) -carbonyl, alkoxy (C1-C6) carbonyl, alkoxy (C1-C4), haloalkoxy ( C1-C4), alkenyloxy (C2C6), alkynyloxy (C2-C6), alkyl (C1-C4) -thio, haloalkyl (C1C4) -thio, alkyl (C1-C4) -sulfonyl, haloalkyl (C1-C4) sulfonyl or (C1-C4) alkylamino, di- ((C1-C4) alkyl) amino, substituents _____ on _____ nitrogen: (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl ), halo (C2-C6) halo, (C2-C6) haloalkynyl, (C1-C4) alkoxy (C1-C4) alkyl, phenyl, benzyl, halo (C1-C4) sulfonyl, (C1-C6) alkoxy-carbonyl, halo (C1-C6) carbonyl, phenylsulfonyl, (C1-C4) alkylsulfonyl, -C (= O) H or (C1-C3) alkylcarbonyl and the symbol Z3 most preferably represents a phenyl radical which may contain up to two substituents, in

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29/191 that each of the substituents is independently selected from the following listing:

chlorine, bromine, iodine, fluorine, cyano, nitro, hydroxyl, amino, -SH, methyl, ethyl, n-propyl, 1-methylethyl, 1,1dimethylethyl, ethylene, propene-2-yl, ethynyl, propine-2yl, trifluoromethyl , difluoromethyl, methoxymethyl, methylcarbonyl, ethylcarbonyl, trifluoromethylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 1methylethoxycarbonyl, 1,1-dimethylethoxycarbonyl, methoxy, ethoxy, n-propoxy, 1-methyloxymethoxy, 2-methyloxyethoxy, 2-methyloxyethoxy -propenyloxy, ethynyloxy, 2propynyloxy, methylthio, ethylthio, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, propylthionyl, 1methylethylthio, trifluoromethylsulfonyl, methylamino, ethylamino, n-propylamino, 1-methylethylamino (1, methylethylamino) ) H, (C7-C8) cycloalkyl, (C3-C6) cycloalkyl (C3C6), cycloalkenyl (C3-C6), alkoxy (C4-C6) -alkyl (C1-C4), alkoxy (C4-C6) - (C1-C4) alkyl, (C3) alkoxy (C2-C4) alkyl, (C1-C3) alkoxy (C2-C3) alkoxy (C1-C3) alkyl, (C1-C4) alkyl thio-al (C1-C2) alkyl, (C1-C4) alkylsulfinyl-(C1-C2) alkyl, (C1-C4) alkyl (C1-C2) alkyl, (C1-C4) alkyl (C1-) alkyl C2), dialkyl (C1-C2) -amino-alkyl (C1-C2), haloalkyl (C1-C4) -amino-alkyl (C1-C2), cycloalkyl (C3-C6) amino-alkyl (C1-C2), (C4-C6) alkylcarbonyl, (C1-C4) haloalkyl-carbonyl, (C3-C6) cycloalkyl (C3-C6) -carbonyl, (C3-C6) -cycloalkyl (C1C2) -carbonyl, cycloalkyl (C3-C6) -aminocarbonyl, haloalkoxy (C1-C4) -alkyl (C1-C2), hydroxyalkyl (C5-C6),

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30/191 alkoxy (C5-C6), haloalkoxy (C5-C6), cycloalkoxy (C3-C6), halocycloalkoxy (C3-C6), cycloalkyl (C3-C6) -alkoxy, alkenyloxy (C2-C6), haloalkenyloxy (C2 -C6), alkynyloxy (C2C6), haloalkynyloxy (C2-C6), alkoxy (C1-C4) -alkoxy (C1-C4), cyano-alkoxy (C1-C4), haloalkyl (C1-C4) -carbonyloxy, cycloalkyl ( C3-C6) -carbonyloxy, (C1-C4) alkyl (C1-C4) alkyl, (C5-C6) alkylthio, halo (C5-C6) -thio, (C5-C6) alkylsulfinyl, haloalkyl ( C5-C6) -sulfinyl, (C5-C6) alkylsulfonyl, halo (C5-C6) -sulfonyl, cyclo (C3-C6) -sulfonyl, tri- ((C3-C4) alkyl) - silyl, (C1) alkyl -C4) -sulfonylamino or haloalkyl (C1-C4) sulfonylamino, the symbol Z4 most preferably represents C (= O) H, cycloheptyl, cyclopropylcyclopropyl, cyclohexenyl, nbutoxymethyl, n-propoxyethyl, methoxyethoxymethyl, ethoxymethoxymethyl, methylethoxymethylmethoxy , methylsulfinylmethyl, ethylsulfinylmethyl, methylsulfonylmethyl, ethylsulfonylmethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, trifluoromethylaminomethyl, cycl opropilaminometilo, nbutilcarbonilo, n-pentylcarbonyl, trifluoromethylcarbonyl, cyclopropylcarbonyl, cyclohexylcarbonyl, ciclopropoxicarbonilo, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cyclopropylaminocarbonyl, ciclopentilaminocarbonilo, cycle-hexylaminocarbonyl, difluorometoximetilo, trifluorometoximetilo, n-pentoxy, halo-n-pentoxy, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, allyl, 3-methylbut-2-ene-1yloxy, prop-2-yn-1-yloxy, but-2-yn-1-yloxy, pent-2-yn-1yloxy, haloalkynoxy, methoxyethoxy, methoxypropoxy,

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31/191 ethoxyethoxy, 3,3,3-trifluoropropanyloxo, cyanomethoxy, trifluoromethylcarbonyloxy, cyclopropylcarbonyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, methylcarbonylmethoxy, pentylsulfonyl, methylsulfonylamino, methylsulfonylamino, methylsulfonylamino, preferably , (C2-C6) alkynyloxy, (C5C6) alkylthio or halo (C5-C6) -thio, the symbol Z6 preferably represents cycloalkyl (C3-C6) -cyclopropyl, cycloalkyl (C3-C6) -cyclohexyl or tri- ( (C3-C4) alkyl - silyl, the symbol Z7 preferably represents alkenyl (C2C6), alkynyl (C2-C6), haloalkyl (C1-C6), cycloalkyl (C3C6), alkyl (C1-C4) -cycloalkyl (C3- C6), cycloalkyl (C3-C6) cyclopropyl, cycloalkyl (C3-C6) -cyclohexyl, cycloalkylalkyl, (C1-C4) alkylsulfonyl, C (= O) H, benzyl or phenyl.

[0011] The heteroaryl-piperidine and piperazine derivatives usable according to the invention are defined in general terms by the structural formula (I). The definitions of radicals presented before and presented specifically after structural formula (I) apply to the final products of structural formula (I), as well as to all intermediates (see also Process and intermediary clarifications).

[0012] The definitions and elucidations of the radicals presented above and below, in general terms or in preferred areas, can be combined with each other as desired, that is, including combinations between particular areas and areas of preference. They are applied to

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32/191 final products and, correspondingly, precursors and intermediaries. In addition, individual definitions may not apply.

[0013] Preferred are those compounds of formula (I) in which all radicals have the preferred definitions mentioned above.

[0014] Particularly preferred are compounds of formula (I) in which all radicals have the most preferred definitions mentioned above.

[0015] Particularly preferred are those compounds of formula (I) in which all radicals have the even more preferred definitions mentioned above.

[0016] Also preferred are compounds of structural formula (I) and their salts, metal complexes and N-oxides active under the point of agrochemical, in which:

A represents 5-methyl-3- (trifluoromethyl) -1Hpyrazol-1-yl, 5-chloro-2-methylphenyl or 2,5-bis (difluoromethyl) -phenyl, L1 represents -CH2- or -NH- , the symbol L2 represents a direct bond, the symbol Y represents oxygen, the symbol X represents carbon, the symbol p represents 0, the symbol G represents G1, the symbol RG1 represents hydrogen, the symbol Q represents Q24-3, the symbol R2 represents hydrogen, the symbol R5 represents hydrogen, the symbol R1 represents 3-formylphenyl, 2-formylphenyl

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33/191 or 2 - [(methylsulfonyl) -amino] -phenyl.

[0017] The definitions of the radicals mentioned above can be combined with each other as desired. Furthermore, the individual definitions may not apply.

[0018] According to the type of substituents defined above, the compounds of formula (I) have acidic or basic properties and can form salts, possibly internal salts or adducts, with inorganic or organic acids or with bases or with metal ions. If the compounds of formula (I) support an amino, alkylamino or other groups that induce basic properties, then these compounds can react with acids to obtain salts or else they are obtained directly as salts by synthesis. If the compounds of formula (I) support hydroxyl, carboxyl or other groups that induce acidic properties, then these compounds can be reacted with bases to obtain salts. Suitable bases include, for example, hydroxides, carbonates, hydrogen carbonates of alkali metals and alkaline earth metals, in particular those of sodium, potassium, magnesium and calcium, as well as ammonia, primary, secondary and tertiary amines that have alkyl groups (C1- C4), mono-, di- and trialcanol-amines of alcohols (C1-C4), choline and chlorocholine.

[0019] The salts thus obtained also have fungicidal properties.

[0020] Examples of inorganic acids include hydrohalogen acids, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide, sulfuric acid, phosphoric acid and nitric acid, and acidic salts, such as NaHSO4 and KHSO4.

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34/191

Useful organic acids include, for example, formic acid, carbonic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid and propionic acid, as well as glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, benzoic acid , cinnamic acid, oxalic acid, saturated or mono- or di-unsaturated C6-C20 fatty acids, alkyl sulfuric monoesters, alkyl sulfonic acids (sulfonic acids with straight or branched chain alkyl radicals that have between 1 and 20 carbon atoms), aryl sulfonic acids or aryl-disulfonic acids (aromatic radicals, such as phenyl and naphthyl, which support one or two sulfonic acid groups), alkylphosphonic acids (phosphonic acids that have straight or branched chain alkyl radicals that have between 1 and 20 carbon atoms), arylphosphonic acids or aryldiphosphonic acids (aromatic radicals, such as phenyl and naphthyl, which I suppose (including one or two phosphonic acid radicals), where the alkyl and aryl radicals can support other substituents, for example, p-toluenesulfonic acid, salicylic acid, p-amino-salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, etc. ..

[0021] Useful metal ions in particular refer to ions from the elements of the second main group, in particular calcium and magnesium, from the third and fourth main groups, in particular aluminum, tin and lead, and also from the first to the eighth groups transition, in particular chromium, manganese, iron, cobalt, nickel, copper, zinc and others. Metal ions of the elements of the fourth period are particularly preferred. Here, metals can be present in the various valences they can assume.

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35/191 [0022] The optionally substituted groups can be mono- or poly-substituted, where the substituents in the case of polysubstitutions can be the same or different.

[0023] In the definitions of the symbols in the previous structural formulas, collective terms were used, which are usually representative of the following substituents:

Halogen: fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine, bromine and more preferably fluorine, chlorine.

[0024] Alkyl: saturated straight or branched chain hydrocarbyl radicals having between 1 and 8, preferably between 1 and 6 and more preferably between 1 and 3 carbon atoms, for example (but without limitation) alkyl (C1-C6), such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2 ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. This definition is also applied to alkyl as part of a compound substituent, for example, cycloalkylalkyl, hydroxyalkyl, etc., unless otherwise defined, such as, for example, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl or haloalkylthio. When alkyl is found in that of a compound substituent, such as, for example, in

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36/191 alkylcycloalkyl, the part of the substituent compound at the beginning, for example, cycloalkyl, can be mono- or polysubstituted, in the same or different way, and in each case independently, with alkyl. The same also applies to compound substituents in which other radicals, for example, alkenyl, alkynyl, hydroxyl, halogen, formyl, etc., are found at the end.

[0025] Alkenyl: unsaturated straight or branched chain hydrocarbyl radicals having between 2 and 8 and preferably between 2 and 6 carbon atoms and a double bond in any position, for example (but without limitation), alkenyl (C2-C6), such as ethylene, 1-propenyl, 2-propenyl, 1-methylethyl, 1butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2methyl-1-propenyl, 1-methyl- 2-propenyl, 2-methyl-2propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl1-butenyl, 1-methyl- 2-butenyl, 2-methyl-2-butenyl, 3methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,

3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1methyl- 2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2methyl-3-pentenyl, 3-methyl-3-pentenyl, 4- methyl-3pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2butenyl, 1,1-dimethyl-3- butenyl, 1,2-dimethyl-1-butenyl,

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37/191

1.2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butyl, 2,2-dimethyl- 3-butenyl, 2,3-dimethyl-1-butenyl,

2.3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2trimethyl-2-propenyl, 1-ethyl-1-methyl-2- propenyl, 1-ethyl-2methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl. This definition also applies to alkenyl as part of a compound substituent, for example, haloalkenyl, etc., unless otherwise defined.

[0026] Alquinyl: straight or branched chain hydrocarbyl groups having between 2 and 8 and preferably between 2 and 6 carbon atoms and a triple bond in any position, for example (but without limitation), alkynyl ( C2-C6), such as ethynyl, 1-propynyl,

2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4pentinyl, 1-methyl-2-butynyl, 1-methyl-3- butynyl, 2-methyl-

3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4hexynyl, 5-hexynyl, 1-methyl- 2-pentynyl, 1-methyl-3pentinyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4pentinyl, 4-methyl- 1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3, 3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butyl and 1ethyl-1-methyl-2-propynyl. This definition also applies to

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38/191 alkynyl as part of a compound substituent, for example, haloalkynyl, etc., unless otherwise defined.

[0027] Alkoxy: saturated straight or branched chain alkoxy radicals having between 1 and 8, preferably between 1 and 6 and more preferably between 1 and 3 carbon atoms, for example (but without limitation), alkoxy (C1-C6), such as methoxy, ethoxy, propoxy,

1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1,1dimethylpropoxy, 1,2- dimethylpropoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2 trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2methylpropoxy. This definition also applies to alkoxy as part of a compound substituent, for example, haloalkoxy, alkynylalkoxy, etc., unless otherwise indicated.

[0028] Alkylthio: saturated straight or branched chain alkylthio radicals having between 1 and 8, preferably between 1 and 6 and more preferably between 1 and 3 carbon atoms, for example (but without limitation), alkyl (C1-C6) -thio, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3methylbutylthio, 2,2- dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1

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39/191 methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio,

1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2trimethylpropylthio, 1-ethyl-1-methylpropylthio and 1-ethyl-2methylpropylthio. This definition also applies to alkylthio as part of a compound substituent, for example, haloalkylthio, etc., unless otherwise defined.

[0029] Alkoxycarbonyl: an alkoxy group that has between 1 and 6 and preferably between 1 and 3 carbon atoms (as specified above) and is linked to the main structure through a carbonyl group (-CO-). This definition also applies to alkoxycarbonyl as part of a compound substituent, for example, cycloalkylalkoxycarbonyl, etc., unless otherwise defined.

[0030] Alkylsulfinyl: saturated straight or branched chain alkylsulfinyl radicals having between 1 and 8, preferably between 1 and 6 and more preferably between 1 and 3 carbon atoms, for example (but without limitation), alkyl (C1-C6) -sulfinyl, such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, 1methylethylsulfinyl, butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl, 3-methylsulfinyl, 2-methylsulfinyl, 2-methyl 1-ethylpropylsulfinyl, hexylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2dimethylpropylsulfinyl, 1-methylpentylsulfinyl, 2Petition 870180056486, 06/29/2018, p. 47/206

40/191 methylpentylsulfinyl, 3-methylpentylsulfinyl, 4methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3-methylsulfinyl, 3-methyl , 1,2-trimethylpropylsulfinyl, 1,2,2 trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl and 1ethyl-2-methylpropylsulfinyl. This definition also applies to alkylsulfinyl as part of a compound substituent, for example, haloalkylsulfinyl, etc., unless otherwise defined.

[0031] Alkylsulfonyl: saturated straight or branched chain alkylsulfonyl radicals having between 1 and 8, preferably between 1 and 6 and more preferably between 1 and 3 carbon atoms, for example (but without limitation), alkyl (C1-C6) -sulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1methylethylsulfonyl, butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, 1,1-dimethylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 3-methylsulfonyl, 3-methylsulfonyl, 2-methyl 1-ethylpropylsulfonyl, hexylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2dimethylpropylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,2 2dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2

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41/191 trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl and 1ethyl-2-methylpropylsulfonyl. This definition also applies to alkylsulfonyl as part of a compound substituent, for example, alkylsulfonylalkyl, etc., unless otherwise defined.

[0032] Cycloalkyl: monocyclic saturated hydrocarbyl groups having between 3 and 10, preferably between 3 and 8 and more preferably between 3 and 6 ring carbon members, for example (but without limitation), cyclopropyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as part of a compound substituent, for example, cycloalkylalkyl, etc., unless otherwise defined.

[0033] Cycloalkenyl: partially unsaturated monocyclic hydrocarbyl groups having between 3 and 10, preferably between 3 and 8 and more preferably between 3 and 6 ring carbon members, for example (but without limitation), cyclopropenyl, cyclopentenyl and cyclohexenyl. This definition also applies to cycloalkenyl as part of a compound substituent, for example, cycloalkenylalkyl, etc., unless otherwise defined.

[0034] Cycloalkoxy: monocyclic saturated cycloalkyloxy radicals having between 3 and 10, preferably between 3 and 8 and more preferably between 3 and 6 ring carbon members, for example (but without limitation), cyclopropyloxy, cyclopentyloxy and cyclohexyloxy. This definition also applies to cycloalkoxy as part of a compound substituent, for example, cycloalkoxyalkyl, etc., unless defined

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42/191 otherwise.

[0035] Haloalkyl: straight or branched chain alkyl groups having between 1 and 8, preferably between 1 and 6 and more preferably between 1 and 3 carbon atoms (as specified above), where some or all of the hydrogen atoms these groups may be replaced by halogen atoms, as specified above, for example (but without limitation), halo (C1-C3) alkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl , dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2 , 2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1trifluoroprop-2-yl. This definition also applies to haloalkyl as part of a compound substituent, for example, haloalkylaminoalkyl, etc., unless otherwise defined.

[0036] Haloalkenyl and haloalkynyl are defined in a similar way to haloalkyl, except that, instead of alkyl groups, alkenyl and alkynyl groups are present as part of the substituent.

[0037] Haloalkoxy: straight or branched chain alkoxy groups having between 1 and 8, preferably between 1 and 6 and more preferably between 1 and 3 carbon atoms (as specified before), where some or all of the hydrogen atoms in these groups can be replaced by halogen atoms, as specified before, by

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43/191 example (but without limitation), haloalkoxy (C1-C3), such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoro-methoxy, 1-chloro-fluoro-methoxy, 1-chloro -fluoroethoxy, 2-fluoroethoxy, 2,2difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2 , 2-trichloroethoxy, pentafluoroethoxy and 1,1,1trifluoroprop-2-oxy. This definition also applies to haloalkoxy as part of a compound substituent, for example, haloalkoxyalkyl, etc., unless otherwise defined.

[0038] Haloalkylthio: straight or branched chain alkylthio groups having between 1 and 8, preferably between 1 and 6 and more preferably between 1 and 3 carbon atoms (as specified before), where some or all of the hydrogen atoms these groups may be replaced by halogen atoms, as specified above, for example (but without limitation), haloalkyl (C1-C3) -thio, such as chloromethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio , chlorofluoromethylthio, dichlorofluoromethylthio, chlorodifluoromethylthio, 1-chloroethylthio, 1-bromoethylthio, 1-fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 2,2,2trifluoroethylthio, 2-chloro-2-fluoroethylthio, 2-chloroethylthio, 2-chloroethyl , 2-dichloro-2-fluoroethylthio, 2,2,2trichloroethylthio, pentafluoroethylthio and 1,1,1-trifluoroprop2-ylthio. This definition also applies to haloalkylthio

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44/191 as part of a compound substituent, for example, haloalkylthioalkyl, etc., unless otherwise defined.

[0039] Heteroaryl: monocyclic ring system totally unsaturated with 5 or 6 members that contains one to four heteroatoms of the oxygen, nitrogen and sulfur set, if the ring contains more than one oxygen atom, then these are not directly adj accents;

5-membered heteroaryl that contains one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 5-membered heteroaryl groups that, in addition to carbon atoms, can contain one to four nitrogen atoms or one to three nitrogen atoms and a sulfur or oxygen atom as members of the ring, for example (but not limited to), 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyrrolyl, 3pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl,

4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2imidazolyl, 4-imidazolyl, 1,2,4-oxadiazol-3-yl, 1, 2,4oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5yl, 1,2,4-triazol-3-yl, 1,3,4-oxadiazole- 2-yl, 1,3,4-thiadiazol-2-yl and 1,3,4-triazol-2-yl;

Nitrogen-linked 5-membered heteroaryl that contains one to four nitrogen atoms or 5-membered nitrogen-bonded heteroaryl that contains one to three nitrogen atoms: 5-membered heteroaryl groups that, in addition to carbon atoms, may contain one to four atoms

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45/191 of nitrogen or one to three nitrogen atoms, as ring members, and where two adjacent ring carbon members or one nitrogen and one adjacent carbon ring member can be connected in point through a buta-1 group , 3-diene-

1.4- diyl, in which one or two carbon atoms can be replaced by nitrogen atoms, in which these rings are attached to the main structure through one of the nitrogen members of the ring, for example (but without limiting this) , 1-pyrrolyl, 1-pyrazolyl,

1.2.4- triazol-1-yl, 1-imidazolyl, 1,2,3-triazol-1-yl and

1.3.4-triazol-1-yl;

6-membered heteroaryl that contains one to four nitrogen atoms: 6-membered heteroaryl groups that, in addition to carbon atoms, can contain, respectively, one to three and one to four nitrogen atoms as ring members, for example ( but without limitation), 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazine2-yl , 1,2,4-triazine-3-yl and 1,2,4,5-tetrazine-3-yl;

Benzofused 5-membered heteroaryl containing one to three nitrogen atoms or one nitrogen atom and one oxygen or sulfur atom: for example (but not limited to), indol-1-yl, indole-2yl, indole -3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazole-5 -yl, indazol-1-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, indazol-2-yl, 1-benzofuran-2 -yl, 1benzofuran-3-yl, 1-benzofuran-4-yl, 1-benzofuran-5

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46/191 yl, 1-benzofuran-6-yl, 1-benzofuran-7-yl, 1benzothiophene-2-yl, 1-benzothiophene-3-yl, 1-benzothiophene-4yl, 1-benzothiophene-5-yl, 1 -benzothiophene-6-yl, 1benzothiophene-7-yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazole-

4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,3benzothiazol-7-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl and 1,3benzoxazol-7-yl,

6-membered benzofused heteroaryl that contains one to three nitrogen atoms: for example (but without limitation), quinoline-2-yl, quinoline-

3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl, quinoline-8-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4- yl, isoquinoline-5-yl, isoquinoline-6-yl, isoquinoline-7-yl and isoquinoline-8yl.

[0040] This definition also applies to heteroaryl as part of a compound substituent, for example, heteroarylalkyl, etc., unless otherwise defined.

[0041] Heterocyclyl: saturated or partially unsaturated heterocycles that have three to fifteen members and preferably three to nine members that contain one to four heteroatoms of the set of oxygen, nitrogen and sulfur: mono-, bi- or tricyclic heterocycles that contain, for in addition to the carbon members of the ring, one to three nitrogen atoms and / or an oxygen or sulfur atom or one or two oxygen and / or sulfur atoms; if the ring contains more than one oxygen atom, then they are not directly adjacent; for example (but without this constituting any

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47/191 limitation), oxiranyl, aziridinyl, 2-tetrahydrofuranyl,

3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3isothiazolidinyl, 4-isothiazolidinyl, 4-isothiazolidinyl, 4-isothiazolid pyrazolidinyl, 5-pyrazolidinyl, 2oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2imidazolidinyl, 4-imidazolidinyl, 1,2,4-oxadiazolidine-3yl, 1,2,4-oxadiazine 5-yl, 1,2,4-thiadiazolidine-3yl, 1,2,4-thiadiazolidine-5-yl, 1,2,4-triazolidin-3-yl,

1.3.4- oxadiazolidine-2-yl, 1,3,4-thiadiazolidine-2-yl,

1.3.4- triazolidine-2-yl, 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-di- hydrofur-3yl, 2,3-dihydrothieno-2-yl, 2,3-dihydrothieno-3-yl, 2,4dihydrothieno-2-yl, 2,4-dihydrothieno-3-yl, 2-pyrroline2-yl, 2-pyrroline-3-yl, 3-pyrroline-2-yl, 3-pyrroline-3yl, 2-isoxazoline-3-yl, 3-isoxazoline-3-yl, 4isoxazoline-3-yl, 2-isoxazoline-4-yl, 3-isoxazoline-4yl, 4-isoxazoline-4-yl, 2-isoxazoline-5-yl, 3isoxazoline-5-yl, 4-isoxazoline-5-yl, 2-isothiazoline-3yl, 3-isothiazoline-3-yl, 4-isothiazoline-3-yl, 2isothiazoline-4-yl, 3-isothiazoline-4-yl, 4-isothiazoline-4-yl, 2-isothiazoline-5-yl, 3-isothiazoline- 5-yl, 4 isothiazoline-5-yl,

2,3-dihydropyrazol-1-yl,

2,3-dihydropyrazol-2-yl,

2,3-dihydropyrazol-3-yl,

2,3-dihydropyrazol-4-yl,

2,3-dihydropyrazol-5-yl,

3,4-dihydropyrazol-1-yl,

3,4-dihydropyrazol-3-yl,

3,4-dihydropyrazol-4-yl,

3,4-dihydropyrazol-5-yl,

4,5-dihydropyrazol-1-yl,

4,5-dihydropyrazol-3-yl,

4,5-diPetição 870180056486, dated 06/29/2018, p. 55/206

48/191 hydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4 -yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4 -dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-piperidinyl, 3-piperidinyl, 4piperidinyl , 1,3-dioxane-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydrinyl , 2-piperazinyl, 1,3,5-hexahydrotriazine-2-yl and 1,2,4-hexahydrotriazine-3-yl. This definition also applies to heterocyclyl as part of a compound substituent, for example, heterocyclylalkyl, etc., unless otherwise defined.

[0042] Removable group: SN1 or SN2 removable group, for example, chlorine, bromine, iodine, alkylsulfonates (-OSO2alkyl, e.g., -OSO2CH3, -OSO2CF3) or arylsulfonates (-OSO2aryl, e.g., -OSO2Ph, -OSO2PhMe).

[0043] It is not included that they are against natural laws and would be excluded, for this reason, by experts in the field based on their knowledge. For example, ring structures that have three or more adjacent oxygen atoms are excluded.

Elucidation of the preparation processes and intermediates [0044] The heteroaryl-piperidine and piperazine derivatives of structural formula (I) can be prepared in different ways. Initially, the feasible processes are shown below schematically. Except when

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49/191 otherwise indicated, each of the radicals has the meanings defined above.

[0045] The processes according to the invention for the preparation of the compounds of formula (I) are optionally carried out using one or more reaction aids.

[0046] Useful reaction aids include, if necessary, basic acceptors or inorganic or organic acids. These preferably comprise acetates, amides, carbonates, hydrogen carbonates, hydrides, hydroxides or alkoxides of alkali metals or alkaline earth metals, for example, sodium acetate, potassium acetate or calcium acetate, lithium amide, amide sodium, potassium amide or calcium amide, sodium carbonate, potassium carbonate or calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or calcium hydrogen carbonate, lithium hydride, sodium hydride potassium or calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, methoxide, ethoxide, n- or i-propoxide, n-, i-, s- or sodium t-butoxide or methoxide , ethoxide, nou i-propoxide, n-, i-, s- or potassium t-butoxide; and also basic organic nitrogen compounds, for example, trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, N, N-dimethylcyclohexylamine, dicyclohexylamine, ethyl dicyclohexylamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, pyridine -, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 2,6-dimethyl-, 3,4-dimethyl- and 3,5-dimethyl-pyridine, 5-ethyl-2-methylpyridine, 4-dimethylaminopyridine, N -methylpiperidine, 1,4-diaza

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50/191 bicycles [2.2.2] octane (DABCO), 1,5-diazabicycles [4.3.0] non-5eno (DBN) or 1,8-diazabicycles [5.4.0] undec-7-ene (DBU).

[0047] The processes according to the invention are optionally carried out using one or more diluents. Useful diluents include practically all inert organic solvents. Preferably, these comprise aliphatic and aromatic hydrocarbons, optionally halogenated, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, tetrachloride carbon, chlorobenzene and o-dichlorobenzene, ethers, such as diethyl ether and dibutyl ether, dimethylglycolic ether and dimethyldiglycolic ether, tetrahydrofuran and dioxane, ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methylisobutyl ketone, esters, such as methyl acetate and ethyl acetate, nitriles, for example, acetonitrile and propionitrile, amides, for example, dimethylformamide, dimethylacetamide and N-methylpyrrolidone, and also dimethyl sulfoxide, tetramethylene-sulfone and hexamethylphosphide and hexamethylsulfone and hexamethylphonyl. and DMPU.

[0048] In the process according to the invention, the reaction temperatures can vary over a relatively wide range. In general, a temperature between 0 ° C and 250 ° C and preferably a temperature between 10 ° C and 185 ° C is used.

[0049] The reaction time varies as a function of the reaction scale and the reaction temperature, but is usually between a few minutes and 48 hours.

[0050] In general, the processes according to

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51/191 the invention are carried out under normal pressure. However, it is also possible to work under high or reduced pressure.

[0051] For the performance of the processes according to the invention, the necessary starting materials in each house are normally used in approximately equimolar amounts. However, it is also possible to use one of the

components, used in each case, on one excess relatively large. Process A Scheme 1: process A

R ² W ¹⁰ —LR ¹ r ² } -n7x-gvv ⁹ ---- VnÇ ^ x-gq-lr ¹

A ~ L '-p one or more steps / \ - | _ \ / (”*>, (r'% (XXIV) (I) [0052] The symbols W9 and W10 represent functional groups suitable for the formation of the desired heterocycle and each of the symbols A, G, Y, X, p, Ll, L2, R1, R2 and RIO has the meanings defined in the description.

[0053] In general, it is possible to prepare the compounds of structural formula (I) from the corresponding compounds (XXIII) and (XXIV) with suitable functional groups W9 and W10 (I) (see scheme 1, process A). Possible functional groups for the symbols W9 and W10 include, for example, aldehydes, ketones, esters, carboxylic acids, amides, thioamides, nitriles, alcohols, thiols, hydrazines, oximes, amidines, amide oxides, olefins, acetylenes, halides, alkyl halides, methanesulfonates, trifluoromethane-sulfonates, boronic acids, boronates, etc., which can form the heterocycle

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52/191

Q desired under suitable reaction conditions. There are several methods in the literature for preparing heterocycles (see document W02008 / 013622; Comprehensive Heterocyclic

Chemistry Vol. 4-6, A. R. Katritzky and C. W. Rees editors, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Vol 2-4, A. R. Katritzky, C. W. Rees and E. F. Scriven editors, Pergamon Press, New York, 1996; The Chemistry of Heterocyclic Compounds, E. C. Taylor, editor, Wiley, New York; Rodd's Chemistry of Carbon Compounds, Vol. 2-4, Elsevier, New York; Synthesis, 1982, 6, 508-509; Tetrahedron, 2000, 56, 1057-1094; and literature cited therein).

Process B

Scheme 2: process B

(HQ

(le) [0054] Each of the symbols A, G, X, Y, p, LI, L2, R1, R2, R5 and R10 has the meanings defined in the description.

[0055] A particular means for the preparation of the compounds of structural formula (le) from the corresponding compounds (III) by reaction with the compounds (Ila) or (Ilb) is shown in scheme 2.

[0056] Alkenes and alkynes (Ila) and (Ilb) are commercially available or can be prepared from commercially available precursors by methods described in the literature (for example, from ketones or

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53/191 aldehydes by Wittig or HornerWadsworth-Emmons olefin: Chem. Rev. 1989, 89, 863-927 and Julia olefination: Tetrahedron Lett., 1973, 14, 4833-4836; Peterson olefin: J. Org. Chem. 1968, 33, 780; with the Bestmann-Ohira reagent: Synthesis 2004, 1, 59-62).

[0057] A compound of structural formula (Ie) is obtained from an alkene of structural formula (IIa) or from an alkene of structural formula (IIb) and a compound (III) by a cycloaddition reaction (see, for example, example, WO 08/013622 and Synthesis, 1987, 11, 998-1001).

[0058] Process B is carried out in the presence of an adequate base. Preferred bases include amines

tertiary (e.g., triethylamine) and carbonates, hydrogen carbonates and metal phosphates alkaline or metals alkaline earth. [0059] In preferably the process B is done using one or more thinners. To performance of process B, organic solvents inert constitute a

preferred option (for example, toluene and hexane). Water is also a possible solvent. Alternatively, process A can be carried out in an excess of alkene (IIa) or alkaline (IIb).

[0060] Processing is carried out by usual methods. If necessary, the compounds are purified by recrystallization or chromatography or can optionally be used in the next step without further purification.

Process C

Scheme 3: process C

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54/191

X-G

a) ΝΗ, ΟΗ

b) chlorination .OH

XG (R ¹ % (IV) '' P (III) [0061] Each of the symbols A, G, Y, X, p, LI, R1, R2, R5 and RIO has the meanings defined in the description.

[0062] A means for the preparation of the intermediate (III) from the compound (IV) is shown in scheme 3 (process C).

[0063] A compound of structural formula (III) is obtained by condensing an aldehyde of structural formula (IV) with hydroxylamine and subsequent chlorination (see, for example, WO 05/0040159, WO 08/013622 and Synthesis, 1987, 11, 998-1001).

[0064] In process C, the aldehyde (IV) and hydroxylamine (scheme 4, step (a)) are first reacted. The corresponding oxime is subsequently subjected to chlorination in the presence of a suitable chlorination agent. Preferred chlorinating agents include N-chlorosuccinimide, HCl and chlorine. After step (a) of process C, the reaction mixture can be processed by standard methods or converted directly to step (b).

[0065] Preferably, process C is carried out using one or more diluents. In step (a) of process C according to the invention, it is preferable to use protic solvents, for example, ethanol, as a solvent. After the formation of the corresponding oxime from compound (IV), the reaction mixture in step (b) is diluted with another solvent, for example, tetrahydrofuran, and then aqueous sodium hypochlorite is added. Similarly, the reaction of

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55/191 chlorination can be carried out with the aid of N-chlorosuccinimide in DMF.

[0066] Processing is carried out by usual methods. If necessary, the compounds are purified by recrystallization or chromatography or can optionally be used in the next step without further purification.

Process D

Scheme 4: Process D

W ¹ —QLR ¹ (XXV) one or more steps

(xxvi) (i) [0067] The symbols Wil and W12 represent functional groups suitable for the formation of the desired heterocycle

and each of A symbols, G, Q, Y, p, LI, L2, Rl, R2, R5 and R10 has the Meanings defined in the description. [0068] In a way general, it is possible prepare the intermediate in formula structural (I) a from the corresponding compounds (XXVI) and (XXV) with groups

functional Wil and W12, (I) (see diagram 4, process D). The possible functional groups for Wil and W12 include, for example, aldehydes, ketones, esters, carboxylic acids, amides, thioamides, nitriles, alcohols, thiols, hydrazines, oximes, amidines, amide oxides, olefins, acetylenes, halides, halides of alkyl, methanesulfonates, trifluoromethane-sulfonates, boronic acid, boronates, etc. They can form the desired 5-membered heterocyclic under suitable reaction conditions. There are several methods in the literature for preparing heterocycles (see

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56/191 the document WO 2008/013622; Comprehensive Heterocyclic Chemistry Vol. 4-6, editors: A. R. Katritzky and C. W. Rees, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Vol. 2-4, editors: A. R. Katritzky, C. W. Rees and E. F. Scriven, Pergamon Press, New York, 1996; The Chemistry of Heterocyclic Compounds, editor: E. C. Taylor, Wiley, New York; Rodd's Chemistry of Carbon Compounds, Vol. 2-4, Elsevier, New York).

Process E

Scheme 5: process E (IX) [0069] (R ¹⁰ ) p (Ie)

The symbol W2 represents a removable group and each of the symbols A, Y, p, L1, L2, R1, R2, R5 and R10 has the meanings defined in the description.

[0070]

A particular form for the synthesis of compounds of structural formula (Ie) from compounds (IX) with compounds (VIII) is shown in the scheme (process E).

[0071]

Thiocarboxamides (IX) can be obtained by methods known in the literature, for example, by thionation of the corresponding commercially available carboxamide, using, for example, Lawesson's reagent (WO2008 / 013622, Org. Synth.Vol. 7, 1990, 372 ).

[0072]

Α-halo-ketones or corresponding ketones that have a removable group (e.g., toluene-sulfonyloxy-ketones) can also be obtained by

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57/191 methods known in the literature (for examples, see document WC2008 / 013622), (diagram 6).

Scheme 6

[0073] The symbol W2 represents a removable group, the symbol W3 represents N, N-dimethylamino, N-methoxy-Nmethylamino or morpholine-1-yl and each of the symbols L2, Rl, R2 and R5 has the meanings defined in the description .

[0074] Thiazoles (le) are obtained by synthesizing Hantzsch's thiazole from thiocarboxamides (IX) and α-halo-ketones or corresponding ketones that have a removable group (VIII) (see, for example, Comprehensive Heterocyclic Chemistry, Pergamon Press, 1984; vol. 6, pages 235-363, Comprehensive Heterocyclic Chemistry II, Pergamon Press, 1996; vol. 3, pages 373-474 and references cited therein, and in WO 07/014290).

[0075] Preferably, process E is carried out using one or more diluents. In carrying out process E, inert organic solvents are a preferred option (for example, N, N-dimethylformamide and ethanol).

[0076] If appropriate, an auxiliary base, for example, triethylamine, is used.

[0077] If necessary, the compounds are purified by recrystallization or chromatography or can,

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58/191 optionally be used in the next step without further purification.

Process F

Figure 7: Process F

R ² R

O / - \ | tionaçAog xgql ² -r ¹ Vn xgqlr ¹ ,, 62 ^ 1.22 ^ ^- ^ ^RR (R ^ p ^RR (r ¹ % (Ia) (lb) [0078] Each of the symbols A, Q, G, L2, p, Rl, R2, RL22 and RIO have the meanings defined in the description.

[0079] The amides (Ia), obtained during the execution of process G according to the invention (scheme 8), can be converted by means of methods described in the literature, to the corresponding thioamides (Ib) (eg, Bioorganic & Medicinal Chemistry Letters, 2009, 19 (2), 462-468). This step typically involves the reaction of the compounds of formula (Ia) with phosphorus pentasulfide or 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphethane (disulfide reagent) Lawesson) (see diagram 7, process F).

[0080] Preferably, process F according to the invention is carried out using one or more diluents. Preferred solvents include toluene, tetrahydrofuran and 1,2-dimethoxyethane.

[0081] After finishing the reaction, the compounds (Ib) are separated from the reaction mixture using one of the usual separation techniques. If necessary, the compounds are purified by recrystallization or chromatography.

Process G

Figure 8: Process G

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59/191 ^ R ²

H-N, X-G-Q-L2R

2, -, 1 (R1% (XIII)

R ^L22 L22 ^A W ⁴

The _r (IV)

O

R ²

XGQ-L2R ^{1 RR} (R ¹⁰ ) p (Ia) [0082] symbol

W4 = OH or Cl and each of the symbols

A, Q, G, L2

R1, R2

RL22

R10 has the meanings defined in the description.

[0083]

A way of preparing the compounds of structural formula (Ia) from the corresponding compounds (XIII) with the compounds (IV) is shown in scheme 8 (process G).

[0084] The compounds (IV) are either commercially available or can be prepared by processes described in the literature (see, for example, WO 2008/013622 and WO 2008/013925).

[0085] A compound with structural formula (Ia) can be synthesized in a manner analogous to methods described in the literature (see, for example, WO 2007/147336), by means of a compound coupling reaction with the corresponding structural formula (XIII) with a substrate of structural formula (IV), in which the symbol W4 represents chlorine, optionally in the presence of an acid / base scrubber.

[0086] At least one equivalent of an acid / base scrubber (eg Hunig's base, triethylamine or commercially available polymeric scrubbers) is used in relation to the starting material of structural formula (XIII). If the starting material is a salt, at least two equivalents of the acid scrubber are required.

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60/191 [0087] Alternatively, it is also possible to synthesize a compound of structural formula (Ia) from the corresponding compound of structural formula (XIII) with a substrate of structural formula (IV), in which the symbol W4 represents hydroxyl, in the presence of a coupling reagent, in a manner analogous to that described in the literature (for example, Tetrahedron 2005, 61, 10827-10852 and references cited therein).

[0088] Suitable coupling reagents include, for example, peptide coupling reagents (for example, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide mixed with 4-dimethylaminopyridine, N- (3dimethylaminopropyl) -N'- ethylcarbodiimide mixed with 1-hydroxybenzotriazole, bromotripyrrolidine-phosphonium hexafluorophosphate, O- (7azabenzotriazol-l-yl) -N, N, Ν ', N'-tetramethyl-uronium, etc.).

[0089] After finishing the reaction, the compounds (Ia) are separated from the reaction mixture using one of the usual separation techniques. If necessary, the compounds can be purified by recrystallization or chromatography.

Process H

Figure 9: Process H

A ¹ —H (XXVIII) base (VII) θ 2 1

ΑίΛΝ xgq- _L 2r ¹ (Rhp (If) [0090]

The symbol Ά1 represents a 5-membered heteroaryl that can contain up to four substituents, where

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61/191 each of the substituents on the carbon is independently selected from the symbol ZA-2 and where the hydrogen in the symbol A1-H is linked by means of a nitrogen atom, the symbol W13 = removable group and each of the symbols A1 , Q, G, L2, p, R1, R2, R5 and R10 have the meanings defined in the description.

[0091] A way to prepare the compounds of structural formula (If) from the corresponding compounds (VII) with the compounds (XXVIII) is presented in scheme 9 (process H).

[0092] The starting materials (VII), in which the symbol W13 represents a removable group, can be prepared using methods described in the literature from compounds (V), (XVIIe) (figure 1) or from ( XIII) (see, for example, mesylation: Organic Letters, 2003,

2539-2541; tosylation: JP60156601; halogenation: Australian Journal of Chemistry, 1983, 2095-2110). Typically, compounds of formula (VII, W13 = chlorine) are prepared from an amine of formula (XIII) and chloroacetyl chloride. Compounds (V) in (figure 1) are prepared in a manner analogous to process G with glycolic acid or hydroxyacetyl chloride from (XIII) (see, for example, WO 2007103187, WO

2006117521, Bioorganic & Medicinal Chemistry Letters, 2007,

6326-6329).

Figure 1

N, X-G-Q-L-R

R ² xgql ² -r (A (R ¹⁰ ) p (V) (XVIIe)

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62/191 [0093] Each of the symbols Q, G, L2, p, R1, R2, R5 and R10 has the meanings defined in the description.

[0094] At least one equivalent of a base (e.g., sodium hydride, potassium carbonate) is used in relation to the starting material of structural formula (XXVIII).

[0095] After finishing the reaction, the compounds (If) are separated from the reaction mixture using one of the usual separation techniques. If necessary, the compounds can be purified by recrystallization or chromatography or can, if desired, be used in the subsequent step without further purification.

Process I

Scheme 10: process I

HN XGQ-L2R ¹ (R ¹⁰ ) p (XIII)

AN = Y _r (XXX)

R ²

Y ^ 1 2 1> ^ N XGQ-L2R ¹

AN ^H (R ¹⁰ ) p (Ic) [0096] Each of the symbols A, Q, G, Y, L2, p, R1, R2, R5 and R10 has the meanings defined in the description.

[0097] A way to prepare the compounds of formula (Ic) from the corresponding compounds (XIII) with the compounds (XXX) is shown in scheme 10 (process I).

[0098] A compound of structural formula (Ic) can be synthesized in a manner analogous to the methods described in the literature (see, for example, WO 2009/055514), through a coupling reaction of a compound of corresponding structural formula (XIII) with a substrate of structural formula (XXX), optionally in the presence of a

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63/191 acid / base scrubber, for example, triethylamine, 1,8diazabicyclo [5.4.0] undec-7-ene or Hünig's base.

[0099] After finishing the reaction, the compounds (Ic) are separated from the reaction mixture using standard separation techniques. If necessary, the compounds can be purified by recrystallization or chromatography.

Process J

Figure 11: J _R ² H process

Y ₂ 1 AN _k An, XGQL ² R ¹ R ^l11 (XVI)

Y - ^R

An xgqlr ¹ (R ¹⁰ ) p (XV) ^R (R ¹⁰ ) p (Id) [0100] The symbol W5 represents chlorine or imidazole-1yl and each of the symbols A, G, Q, Y, L2, p, R1 , R2, RL11 and R10 have the meanings defined in the description.

[0101] A way to prepare the compounds of structural formula (Id) from the corresponding compounds (XVa, see figure

2) or (XVb, see figure 2) with the compounds

Figure (XVI) is shown in diagram 11 (process J).

R ² y, „

An. x-g-q

-L2R ¹

R ²

Y, x, An, x-g

-qlr ¹ (R ¹⁰ ) p (XVa) v ^R / p (XVb) [0102] Each of the symbols Q, G, L2, p, R1, R2, R5 and R10 has the meanings defined in the description.

[0103] The starting materials, carbamoyl and thiacarbamoyl chlorides of structural formula (XVa), can be prepared using methods described in the literature, from compounds (XIII) (see, for example, Tetrahedron, 2008, 7605 ; Journal of Organic Chemistry, 2004,

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3787; Journal of Organic Chemistry, 1983, 4750; European Journal of Organic Chemistry, 2006, 1177). Typically, compounds of formula (XVa) are prepared from amines of formula (XIII) and phosgene, thiophosgene or their equivalents.

[0104] Alternative starting materials, carbamoyl- and thiocarbamoyl-imidazoles of structural formula (XVb), can be prepared using methods described in the literature (see, for example, Tetrahedron Letters, 2008, 5279; Tetrahedron, 2005, 7153 ). Typically, compounds of structural formula (XVb, W5 = imidazol-1-yl) are prepared from amines of structural formula (XIII) and 1,1'-carbonyl diimidazole or 1,1'-thiocarbonyl diimidazole.

[0105] Optionally, process J is carried out in the presence of a suitable acid acceptor.

[0106] Alternatively, the compounds (Id) obtained during the execution of process J according to the invention, can, in some cases, also be obtained in the absence of the use of an acid acceptor, such as the corresponding acid chloride [ (Id) -HCl]. If necessary, the compounds (Id) are released using standard methods.

[0107] After completing the reaction, the compounds (Id) are separated from the reaction mixture using one of the usual separation techniques. If necessary, the compounds can be purified by recrystallization or chromatography.

Process K

Figure 12: Process K

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65/191 \ I 2 1

W-N X-G-Q-L-R •• protection group setting

(XVII)

R ²

HN, XGQL ² R ¹ (R ^ p (XiH) [0108] The symbol W6 represents acetyl, alkoxy (ClC4) -carbonyl, benzyl or benzyloxycarbonyl and each of the symbols Q, L2, p, Rl, R2 and RIO has the meanings defined in the description.

[0109] A way to prepare the compounds of structural formula (XIII) from the corresponding compounds (XVII) is presented in scheme 12 (process K).

[0110] A compound of structural formula (XVII) is converted to a compound of structural formula (XIII) using one of the methods suitable for removing groups described in the literature (Protective Groups in Organic Synthesis; Theodora W. Greene, Peter GM Wuts ; WileyInterscience; Third Edition; 1999 494-653).

[0111] The tert-butoxycarbonyl and benzyloxycarbonyl protecting groups can be removed in an acidic medium (for example, with hydrochloric acid or trifluoroacetic acid). The acetyl protecting groups can be removed under basic conditions (for example, with potassium carbonate or cesium carbonate). The benzyl protecting groups can be removed hydrogenolytically with hydrogen in the presence of a catalyst (for example, palladium on activated carbon).

[0112] As acids that can be used for this deprotection reaction of the tert-butoxycarbonyl and benzyloxycarbonyl groups are, for example, trifluoroacetic acid, hydrochloric acid or other acids, as described in the literature (for example, Protective

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66/191

Groups in Organic Synthesis; Theodora W. Greene, Peter G. M. Wuts; Wiley-Interscience; Third Edition; 1999; 494-653).

[0113] After finishing the reaction, the compounds (XIII) are separated from the reaction mixture using one of the usual separation techniques. If necessary, the compounds can be purified by recrystallization or chromatography or can, if desired, be used in the subsequent step without further purification. It is also possible to isolate the compound of formula (XIII) in the form of a salt, for example, a salt of hydrochloric acid or trifluoroacetic acid.

Process L

Figure 13: L _r 2 W ¹¹ —QLR ^{1 process} . ₁₂ (XXV) _{62 1}

V ^ -N, XW ¹² -------------- WN. XGQLR ¹ \ I / one or more steps \ 1 / (í% (r ¹ % (XXII) (XVII) [0114] The symbol W6 represents acetyl, (C1-4) alkoxycarbonyl, benzyl or benzyloxycarbonyl, the symbols Wil and W12 represent functional groups suitable for the formation of the desired heterocycle and each of the symbols Q, L2, p, R1, R2 and RIO has the meanings defined in the description.

[0115] In general, it is possible to prepare the intermediate (XVII) from the corresponding compounds (XXII) with compounds (XXV). Process L (scheme 13) is carried out in a similar way to process D (scheme 4).

Process M

Figure 14: Process M

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[0116] The symbol W2 represents a removable group, the symbol W6 represents acetyl, (C1-C4) alkoxy-carbonyl, benzyl or benzyloxycarbonyl and each of the symbols L2, p, R1, R2 _f R5 and R10 has the meanings defined in description.

[0117] Another way to prepare the intermediate of structural formula (XVIIa) from the corresponding compounds (XXI) is presented in scheme 14 (process M). Compounds (XXI) are either commercially available or can be prepared by processes described in the literature (see, for example, WO 2008/013622 and WO

2007/014290). Process M is carried out in a similar way to process E (diagram 5).

Process N

Figure 15: Process N _R ² HGQLR ^{1 (XIX)} ----.

base (R ¹ % (XX)

(XVIIb) [0118] The Ga symbol represents a 5-membered heteroaryl; in compounds of structural formula (XVIIb), the 5-membered heteroaryl is linked by means of a nitrogen atom to the radical piperidine, the symbol W6 represents acetyl, (C1-C4) alkoxy-carbonyl, benzyl or

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68/191 benzyloxycarbonyl, the symbol W7 represents a removable group and each of the symbols Q, L2, p, R1, R2 and R10 has the meanings defined in the description.

[0119] A compound with the structural formula (XVIIb) can be synthesized in a manner analogous to methods described in the literature by means of a coupling reaction of a compound with the corresponding structural formula (XX) with a substituted one of the structural formula (XIX ), optionally in the presence of a base (scheme 15, process N). (See, for example, for coupling with Zn / Pd: WO 2008/147831, WO 2006/106423 (pyridine), Shakespeare, WC et al Chem. Biol. Drug Design 2008, 71, 97-105 (pyrimidine derivatives) , Pasternak, A. et al Bioorg. Med. Chem. Lett. 2008, 18, 994-998 (diazines); Coleridge, BM; Bello, C.

S. ; Leitner, A. Tetrahedron Lett. 2009, 50, 4475-4477; Bach,

T., Heuser, S. Angew. Chem. Int. Ed. 2001, 40, 3184-3185. (thiazoles); for nucleophilic substitutions: documents WO 2008/104077; WO 2006/084015 (pyrazoles with N-substitution)).

[0120] At least one equivalent of a base (e.g., sodium hydride, potassium carbonate) is used in relation to the starting material of structural formula (XX).

[0121] After finishing the reaction, the compounds (XVIIb) are separated from the reaction mixture using one of the usual separation techniques. If necessary, the compounds can be purified by recrystallization or chromatography or can, if desired, be used in the subsequent step without further purification.

Process O

Figure 16: Process O

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69/191

W — GQLR ¹

..λ (XIV)

WN. NH ---- ^S ------ »base (R ¹ % (XXIX) w- NG- ^b QLR ¹ Ψ (R ¹ % (XVIIc) [0122] The symbol Gb represents 5-membered heteroaryl; in compounds of structural formula (XVIIc), the 5-membered heteroaryl is linked by means of a carbon atom to the piperazine ring, the symbol W6 represents acetyl, (C1-C4) alkoxycarbonyl, benzyl or benzyloxycarbonyl, the symbol W8 represents a group removable and each of the symbols Q, L2, p, Rl and RIO have the meanings defined in the description.

[0123] A compound having the structural formula (XVIIc) can be synthesized in a manner analogous to methods described in the literature (see, for example, for nucleophilic substitutions: Li, CS, Belair, L., Guay, J. et al Bioorg. Med. Chem. Lett. 2009, 19, 5214-5217; WO 2008/062276; for copper coupling: Yeh, VSC; Wiedeman, PE Tetrahedron Lett. 2006, 47, 60116016; for palladium couplings: document WO 2008/157500), by means of a coupling reaction of a compound that has the corresponding structural formula (XXIX) with a substrate of structural formula (XIV), optionally in the presence of a base (scheme 16, process O).

[0124] At least one equivalent of a base (e.g., sodium hydride, potassium carbonate) is used in relation to the starting material of structural formula (XXIX).

[0125] After finishing the reaction, the compounds

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70/191 (XVIIc) are separated from the reaction mixture using one of the usual separation techniques. If necessary, the compounds can be purified by recrystallization or chromatography or can, if desired, be used in the subsequent step without further purification.

Process P

Figure 17: Process P

R ²

WN X-GW ⁹ '(H (XXVII) w ¹⁰ - l ² -r' (XXIII) one or more steps ^ R ²

VlF— N X-GQ-LR ¹ (Í% (XVII) [0126] The symbol W6 represents acetyl, alkoxy (ClC4) -carbonyl, benzyl or benzyloxycarbonyl, the symbols W9 and W10 represent functional groups suitable for the formation of the desired heterocycle and each of the symbols Q, L2, G, p, R1, R2 and RIO has the meanings defined in the description.

[0127] In general, it is possible to prepare the intermediate (XVII) from the corresponding compounds (XXVII) and (XXIII). Process P (scheme 17) is carried out in a similar way to process A (scheme 1).

Process Q

Scheme 18: process, OH 2N

R ⁵ = LR ¹ (llb) f XI 'WN. XG (r ¹ % (XVIII)

(read)

(XVIId) [0128] The symbol W6 represents acetyl, alkoxy (ClPetição 870180056486, dated 06/29/2018, page 78/206

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C4) -carbonyl, benzyl or benzyloxycarbonyl and each of the symbols X, L2, G, p, R1, R2, R5 and R10 has the meanings defined in the description.

[0129] A particular way to prepare the intermediate (XVIId) from the corresponding compounds (XVIII) is shown in scheme 18 (process Q). The starting material of structural formula (XVIII) can be prepared using methods described in literature (see, for example, WO 2008/013622) and process Q is carried out in a similar way to process B (scheme 2).

[0130] The invention further provides for the non-medical use of the heteroaryl-piperidine and piperazine derivatives of structural formula (I) of the invention for the control of unwanted microorganisms.

[0131] The new compounds are those that satisfy structural formula (VII)

R ²

O

N, XGQ-L2-R ¹ (R ¹⁰ ) p (VII) and its salts, metal complexes and N-oxides, where each of the symbols R2, X, G, Q, L2, R1, R10 and p has the meanings general, preferred, most preferred and even more preferred defined above and the symbol W13 represents a removable group.

[0132] The new compounds are those that satisfy structural formula (XVIId), G ^ L ² 1 _R 2N ₅ R ¹ R ^ JbR ⁵ '' ^{1 f}

WN, XG (R ¹ % (XVIId)

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72/191 for example, (XVIIf)

W-N

W-N

S (XVIIf) and its salts, metal complexes and N-oxides, in which the symbol W6 represents acetyl, (C1-C4) alkoxycarbonyl, benzyl or benzyloxycarbonyl and each of the radicals X, L2, p, R1, R2, R5 and R10 have the general, preferred, most preferred and even more preferred meanings defined above.

[0133] The new compounds are those that satisfy the structural formula (XlIIa)

HN, XG (R ¹⁰ ) p (XlIIa) e.g. (XIIIb)

HN (XIIIb) and its salts, metal complexes and N-oxides, wherein the symbols X, L2, p, G, R1, R2, R5 and R10 have the general, preferred, most preferred and even more preferred meanings defined above.

[0134]

The invention further provides a composition for the control of unwanted microorganisms, which comprises at least one heteroaryl-piperidine and -piperazine derivative according to the present invention.

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73/191 [0135] The invention also relates to a method for the control of unwanted microorganisms, characterized by the fact that the heteroaryl-piperidine and -piperazine derivatives of the invention are applied to the microorganisms and / or in their habitat.

[0136] The invention also relates to seeds treated with at least one heteroaryl-piperidine and -piperazine derivative of the invention.

[0137] Finally, the invention provides a method for protecting seeds against unwanted microorganisms by using seeds treated with at least one heteroaryl-piperidine and -piperazine derivative according to the present invention.

[0138] The substances of the invention have a potent microbicidal activity and can be used for the control of unwanted microorganisms, such as fungi and bacteria, in crop protection and material protection.

[0139] The heteroaryl-piperidine and piperazine derivatives of structural formula (I) of the invention have very good fungicidal properties and can be used for crop protection, for example, for the control of Plasmodiophoromycetes, Oomycetes, Chytridiomycetes, Zygomycetes, Ascomycetes , Basidiomycetes and Deuteromycetes.

[0140] Bactericides can be used to protect crops, for example, to control Pseudomonadaceae, Rhizobiaceae, Enterobacteriaceae, Corynebacteriaceae and Streptomycetaceae.

[0141] The fungicidal compositions of the invention can be used for a curative or protective control of

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74/191 phytopathogenic fungi. Therefore, the invention also concerns curative and protective methods for the control of phytopathogenic fungi through the use of the active ingredients or compositions of the invention, which are applied to seeds, plants or parts of plants, fruits or the soil on which plants grow.

[0142] The compositions of the invention for the control of phytopathogenic fungi in the protection of crops comprise an effective but non-toxic amount of the active ingredients of the invention. The term effective but non-toxic amount means an amount of the composition of the invention that is sufficient to satisfactorily control fungal diseases of plants or to eradicate fungal disease completely and, at the same time, does not cause any significant symptoms of phytotoxicity. In general, such an application rate can vary over a relatively wide range. It depends on several factors, for example, the fungus to be controlled, the plant, the climatic conditions and the ingredients of the compositions of the invention.

[0143] According to the invention, it is possible to treat all plants and parts of plants. The term "plants" used herein means all plants and plant populations, such as desired and unwanted wild plants or crop plants (including naturally occurring crop plants). As crop plants it is possible to refer to plants that can be obtained by conventional methods of cultivation and optimization or by methods of biotechnology and genetic engineering or by a combination of such methods, including transgenic plants and varieties of plants that may or may not be protected by

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75/191 plant variety rights. The term “plant parts” is intended to refer to all the aerial and underground parts and organs of plants, such as shoots, leaves, flowers and roots, and it is possible to mention as examples the leaves, needles, stems, trunks, flowers, carpophores, fruits and seeds and also roots, tubers and rhizomes. The plant parts also comprise the harvest material and the vegetative and generative propagation material, for example, cuttings, tubers, rhizomes, rooted cuttings and seeds.

[0144] According to the invention, as plants that can be treated refer to the following: cotton, flax, vines, fruits, vegetables, such as Rosaceae sp. (for example, seeded fruits, such as apples and pears, but also stone fruits, such as apricots, cherries, almonds and peaches and soft fruits, such as strawberries), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceae sp. (for example, banana trees and plantations), Rubiaceae sp. (e.g., coffee), Theaceae sp., Sterculiceae sp., Rutaceae sp. (for example, lemons, oranges and grapefruits); Solanaceae sp. (for example, tomatoes), Liliaceae sp., Asteraceae sp. (for example, lettuce), Umbelliferae sp., Cruciferae sp., Chenopodiaceae sp., Cucurbitaceae sp. (e.g., cucumber), Alliaceae sp. (for example, leek, onion), Papilionaceae sp. (for example, peas); main crop plants, such as Gramineae sp. (for example, maize, grass, cereals, such as wheat, rye, rice, barley, oats, millet and triticale), Asteraceae sp. (per

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76/191, sunflower), Brassicaceae sp. (for example, white cabbage, red cabbage, broccoli, cauliflower, Brussels sprouts, pak choi, kohlrabi, horseradish and rapeseed, mustard, horseradish and watercress), Fabacae sp. (for example, beans, peanuts), Papilionaceae sp. (for example, soybeans), Solanaceae sp. (for example, potatoes), Chenopodiaceae sp. (eg sugar beet, fodder beet, Swiss cabbage, beet); useful plants and ornamental plants in gardens and forests; and genetically modified varieties of each of these plants.

[0145] As non-limiting examples of pathogens of fungal diseases that can be treated according to the invention are:

diseases caused by powdery mildew pathogens, for example, Blumeria species, for example, Blumeria graminis; of the species Podosphaera, for example, Podosphaera leucotricha; Sphaerotheca species, for example, Sphaerotheca fuliginea; of the species Uncinula, for example, Uncinula necator;

diseases caused by pathogens of rust disease, for example, Gymnosporangium species, for example, Gymnosporangium sabinae; of the Hemileia species, for example, Hemileia vastatrix; Phakopsora species, for example, Phakopsora pachyrhizi or Phakopsora meibomiae; of the Puccinia species, for example, Puccinia recondita, Puccinia graminis or Puccinia striiformis; Uromyces species, for example, Uromyces appendiculatus;

diseases caused by pathogens of the Oomycetes group, for example, of the Albugo species, for example, Albugo candida; Bremia species, for example, Bremia lactucae; of the species

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Peronospora, for example, Peronospora pisi or P. brassicae; Phytophthora species, for example, Phytophthora infestans; Plasmopara species, for example, Plasmopara viticola; of the species Pseudoperonospora, for example, Pseudoperonospora humuli or Pseudoperonospora cubensis; Pythium species, for example, Pythium ultimum;

leaf spot diseases and leaf wilt diseases caused, for example, by the Alternaria species, for example, Alternaria solani; Cercospora species, for example, Cercospora beticola; Cladosporium species, for example, Cladosporium cucumerinum; Cochliobolus species, for example, Cochliobolus sativus (conideal form: Drechslera, syn: Helminthosporium) or Cochliobolus miyabeanus; Colletotrichum species, for example, Colletotrichum lindemuthanium; Cycloconium species, for example, Cycloconium oleaginum; Diaporthe species, for example, Diaporthe citri; Elsinoe species, for example, Elsinoe fawcettii; Gloeosporium species, for example, Gloeosporium laeticolor; Glomerella species, for example, Glomerella cingulata; Guignardia species, for example, Guignardia bidwelli; Leptosphaeria species, for example, Leptosphaeria maculans; Magnaporthe species, for example, Magnaporthe grisea; Microdochium species, for example, Microdochium nivale; Mycosphaerella species, for example, Mycosphaerella graminicola, Mycosphaerella arachidicola or Mycosphaerella fijiensis; Phaeosphaeria species, for example, Phaeosphaeria nodorum; Pyrenophora species, for example, Pyrenophora teres or Pyrenophora tritici repentis; Ramularia species, for example, Ramularia collo-cygni or Ramularia areola; Rhynchosporium species, for example, Rhynchosporium secalis; species

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Septoria, for example, Septoria apii or Septoria lycopersici; species Stagonospora, for example, Stagonospora nodorum; Typhula species, for example, Typhula incarnata; Venturia species, for example, Venturia inaequalis;

root and stem diseases caused, for example, by the species Corticium, for example, Corticium graminearum; Fusarium species, for example, Fusarium oxysporum; Gaeumannomyces species, for example, Gaeumannomyces graminis; Plasmodiophora species, for example, Plasmodiophora brassicae; Rhizoctonia species, for example, Rhizoctonia solani; Sarocladium species, for example, Sarocladium oryzae; Sclerotium species, for example, Sclerotium oryzae; Tapesia species, for example, Tapesia acuformis; Thielaviopsis species, for example, Thielaviopsis basicola;

ear and panicle diseases (including ears of corn) caused, for example, by the species Alternaria, for example, Alternaria spp .; Aspergillus species, for example, Aspergillus flavus; Cladosporium species, for example, Cladosporium cladosporioides; Claviceps species, for example, Claviceps purpurea; Fusarium species, for example, Fusarium culmorum; Gibberella species, for example, Gibberella zeae; Monographella species, for example, Monographella nivalis; species Stagnospora, for example, Stagnospora nodorum;

diseases caused by caries fungi, for example, Sphacelotheca species, for example, Sphacelotheca reiliana; Tilletia species, for example, Tilletia caries or controversial Tilletia; Urocystis species, for example, Urocystis occulta; Ustilago species, for example, Ustilago nuda;

fruit rot caused by, for example, the species

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Aspergillus, for example, Aspergillus flavus; Botrytis species, for example, Botrytis cinerea; Penicillium species, for example, Penicillium expansum or Penicillium purpurogenum; Rhizopus species, for example, Rhizopus stolonifer; Sclerotinia species, for example, Sclerotinia sclerotiorum; Verticilium species, for example, Verticilium alboatrum;

rot and wilt diseases from seeds and soil, and cuttings diseases, caused, for example, by the species Alternaria, for example, Alternaria brassicicola; Aphanomyces species, for example, Aphanomyces euteiches; Ascochyta species, for example, Ascochyta lentis; Aspergillus species, for example, Aspergillus flavus; Cladosporium species, for example, Cladosporium herbarum; Cochliobolus species, for example, Cochliobolus sativus (conideal form: Drechslera, Bipolaris syn: Helminthosporium); Colletotrichum species, for example, Colletotrichum coccodes; Fusarium species, for example, Fusarium culmorum; Gibberella species, for example, Gibberella zeae; Macrophomina species, for example, Macrophomina phaseolina; Microdochium species, for example, Microdochium nivale; Monographella species, for example, Monographella nivalis; Penicillium species, for example, Penicillium expansum; Phoma species, for example, Phoma lingam; Phomopsis species, for example, Phomopsis soybean; Phytophthora species, for example, Phytophthora cactorum; Pyrenophora species, for example, Pyrenophora graminea; Pyricularia species, for example, Pyricularia oryzae; Pythium species, for example, Pythium ultimum; Rhizoctonia species, for example, Rhizoctonia solani; species

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Rhizopus, for example, Rhizopus oryzae; Sclerotium species, for example, Sclerotium rolfsii; Septoria species, for example, Septoria nodorum; Typhula species, for example, Typhula incarnata; Verticillium species, for example, Verticillium dahliae;

cancers, tumors and witches' broom caused, for example, by the species Nectria, for example, Nectria galligena;

wilting diseases caused, for example, by the species Monilinia, for example, Monilinia laxa;

deformations of leaves, flowers and fruits caused, for example, by the species Exobasidium, for example, Exobasidium vexans; Taphrina species, for example, Taphrina deformans;

degenerative diseases in diseases + for wood caused, for example, by the species Esca, for example, Phaeomoniella chlamydospora, Phaeoacremonium aleophilum or Fomitiporia mediterranea; Ganoderma species, for example, Ganoderma boninense;

flower and seed diseases caused, for example, by the species Botrytis, for example, Botrytis cinerea;

plant tuber diseases caused, for example, by the species Rhizoctonia, for example, Rhizoctonia solani; Helminthosporium species, for example, Helminthosporium solani;

diseases caused by bacterial pathogens, for example, of the species Xanthomonas, for example, Xanthomonas campestris pv. oryzae; Pseudomonas species, for example, Pseudomonas syringae pv. lachrymans; Erwinia species, for example, Erwinia amylovora.

[0146] Preferably, it is possible to control the

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81/191 following soy diseases:

fungal diseases on leaves, stems, pods and seeds caused, for example, leaf spots by Alternaria (Alternaria spec. atrans tenuissima), anthracnose (Colletotrichum gloeosporoides dematium var. truncatum), brown spots (Septoria glycines), machas and leaf degradation by cercospora (Cercospora kikuchii), leaf degradation by choanephora (Choanephora infundibulifera trispora (Syn.)), leaf spots by dactuliophora (Dactuliophora glycines), downy mildew (Peronospora manshurica), degradation by eye stains, Drechsera and Drechslera (Drechslera) frog (Cercospora sojina), leaf spots by leptosphaerulina (Leptosphaerulina trifolii), leaf spots by phyllostica (Phyllostictaoyaecola), wilting of the pods and stem (Phomopsis soye), downy mildew (Microsphaera diffusa), leaf spots by pyrenochaeta (pyrenochaeta) glycines), wilting of aerial parts, foliage and structure by rhizoctonia (Rhizoctonia solani), rust (Phakopsora pa chyrhizi, Phakopsora meibomiae), scabies (Sphaceloma glycines), wilting of the leaves by stemphylium (Stemphylium botryosum), target spots (Corynespora cassiicola).

[0147] Fungal diseases at the base of the roots and stem caused, for example, by black root rot (Calonectria crotalariae), coal rot (Macrophomina phaseolina), pod and collar rot, root rot and fusarium degradation and wilting ( Fusarium oxysporum, Fusarium orthoceras, Fusarium semitectum, Fusarium equiseti), root rot by mycoleptodiscus (Mycoleptodiscus terrestris), neocosmospora (Neocosmospora

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82/191 vasinfecta), stem and pod wilting (Diaporthe phaseolorum), stem cancer (Diaporthe phaseolorum var. Caulivora), phytophthora rot (Phytophthora megasperma), brown stem rot (Phialophora gregata), pythium rot (Pythium aphanidermatum, Pythium irregulare, Pythium debaryanum, Pythium myriotylum, Pythium ultimum), dehumidification, stem degradation and root rot by rhizoctonia (Rhizoctonia solani), stem degradation by sclerotinia (Sclerotinia sclerotiorum), southern wilt (sclerotinia sclerotiorum) root rot by thielaviopsis (Thielaviopsis basicola).

[0148] The active ingredients of the invention also have a very good forcing action on plants. As such, they can be used to mobilize the plant's own defenses against attacks by unwanted microorganisms.

[0149] As plant-fortifying substances (resistance inducers) we intend to designate, in the present context, those substances that are capable of stimulating the defense system of plants in such a way that the treated plants, when subsequently inoculated with unwanted microorganisms , develop a high degree of resistance against these microorganisms.

[0150] In the present case, unwanted microorganisms are intended to designate phytopathogenic fungi and bacteria. The substances of the invention can thus be used to protect plants, for a certain period of time after treatment, against attack by said pathogens. The period of time during which the

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83/191 protection is conferred is normally between 1 and 10 days and preferably between 1 and 7 days, after treatment of the plants with the active ingredients.

[0151] The fact that the active ingredients are well tolerated by the plants in the concentrations necessary for the control of plant diseases allows the treatment of the aerial parts of the plants, feet and seeds and the soil.

[0152] The active ingredients of the invention can be used with particular success in disease control in wineries and growth of potatoes, fruits and vegetables, for example, particularly against mildew fungi, Oomycetes, for example, of the species Phytophthora, Plasmopara, Pseudoperonospora and Pythium.

[0153] The active ingredients of the invention are also suitable for increasing crop yields. In addition, they have low toxicity and are well tolerated by plants.

[0154] If appropriate, the compounds of the invention can, for certain application rates, also be used as herbicides, phytoprotective agents, growth regulators or as agents to improve plant properties, or as microbicides, for example, as fungicides, antimycotics, bactericides, viricides (including agents against viroids) or as agents against MLO (mycoplasma-like organisms) and RLO (rickettsia-like organisms). If appropriate, they can also be used as insecticides. If appropriate, they can also be used as intermediates or precursors for the synthesis of other active ingredients.

[0155] When well tolerated by plants,

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84/191 active ingredients of the invention have favorable homothermal toxicity and are well tolerated by the environment, being suitable for the protection of plants and plant organs, to increase crop yields, to improve the quality of material harvested in agriculture, horticulture, animal husbandry, forests, gardens and recreational facilities, the protection of stored products and materials and the hygiene sector. Preferably, they can be used as agents for crop protection. They are effective against normally sensitive and resistant species and against all or some stages of development.

[0156] The treatment according to the invention of plants and parts of plants with the active ingredients or compositions is carried out directly or through the action in their surroundings, habitat or storage space through conventional treatment methods, for example , immersion, spraying, atomization, irrigation, evaporation, dusting, dusting, misting, dissemination, foam application, brushing, diffusion, rinsing (spraying), drip irrigation and, in the case of propagating material, in particular in in the case of seeds, by dry seed treatment, by wet seed treatment, by paste treatment, by incrustation, by coating with one or more layers, etc. It is also possible to apply the active ingredients by the ultra-volume method reduced or by injection of the active ingredient itself / preparation of active ingredient into the soil.

[0157] Active ingredients or compositions can also be used to protect industrial materials

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85/191 against attacks and destruction by unwanted microorganisms, for example, fungi.

[0158] In the present context, the term "industrial materials" is intended to mean inanimate materials that have been prepared for industrial use. For example, as industrial materials that are intended to be protected with the active ingredients according to the invention against microbial modification or destruction, it is possible to refer to adhesives, glues, paper and cardboard, textiles, leather, wood, paints and plastics, soft materials and others materials that can be infected or destroyed by microorganisms. Among the materials to be protected, it is also possible to mention the parts of factory installations, for example, water cooling circuits, which can be damaged by the proliferation of microorganisms. Within the scope of the present invention, preferable industrial materials include adhesives, glues, paper and cardboard, leather, wood, paints, cooling materials and other materials that can be infected or destroyed by microorganisms. The set of materials to be protected also comprises parts of production facilities, for example, water cooling circuits, which can be damaged by the proliferation of microorganisms. Preferably, industrial materials falling within the scope of the present invention include adhesives, glues, paper and cardboard, leather, wood, paints, cooling materials and heat transfer fluids, and more preferably wood. The ingredients or compositions according to the present invention can prevent adverse effects, such as rot, degradation,

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86/191 discoloration or mold formation.

[0159] The method according to the invention for controlling unwanted fungi can also be used to protect stored goods. Stored goods are intended to be designated natural substances of animal or vegetable origin or their processed products that are of natural origin, and for which long-term protection is desired. Stored goods of plant origin, for example, plants or parts of plants, such as stems, leaves, tubers, seeds, fruits, grains, can be protected moments after harvesting or after processing by (pre-) drying, wetting, fragmentation , grinding, compression or roasting. Stored goods also comprise wood, whether unprocessed, such as construction timber, electricity poles and barriers, or in the form of finished products, such as furniture. Stored goods of animal origin include, for example, hides, skins and hair. The active ingredients of the invention can prevent adverse effects, such as rot, degradation, discoloration or mold formation.

[0160] Microorganisms capable of degrading or altering industrial materials include, for example, bacteria, fungi, yeasts, algae and mucilaginous organisms. Preferably, the active ingredients of the invention act against fungi, in particular molds, wood decolorizing fungi and wood destroying fungi (Basidiomycetes), as well as against mucilages and algae. As examples it is possible to mention the microorganisms of the following genera: Alternaria, such as Alternaria tenuis; Aspergillus, such as Aspergillus niger;

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Chaetomium, such as Chaetomium globosum; Coniophora, such as Coniophora puetana; Lentinus, such as Lentinus tigrinus; Penicillium, such as Penicillium glaucum; Polyporus, such as Polyporus versicolor; Aureobasidium, such as Aureobasidium pullulans; Sclerophoma, such as Sclerophoma pityophila; Trichoderma, such as Trichoderma viride; Escherichia, such as Escherichia coli; Pseudomonas, such as Pseudomonas aeruginosa; Staphylococcus, such as Staphylococcus aureus.

[0161] The present invention also relates to a composition for controlling unwanted microorganisms, which comprises at least one of the heteroarylpiperidine and -piperazine derivatives of the invention. Preferably, these are fungicidal compositions comprising agriculturally suitable auxiliaries, solvents, vehicles, surfactants or fillers.

[0162] According to the invention, a vehicle is an organic or inorganic substance, natural or synthetic, with which the active ingredients are mixed or combined to improve applicability, in particular for application to plants or parts of plants or seeds . In general, the vehicle, which can be solid or liquid, is inert and should be suitable for use in agriculture.

[0163] Useful solid vehicles include: for example, ammonium salts and flours of natural rocks, such as kaolins, clays, talc, chalk, quartz, atapulgite, montmorillonite or diatomaceous earth, and synthetic rock flours, such such as finely divided silica, aluminum oxide and silicates; as solid vehicles useful for granules refers: for example, broken natural rocks and

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88/191 fractionated, such as calcite, marble, pumice, sepiolite and dolomite, as well as synthetic granules of inorganic and organic flours and granules of organic materials, such as paper, sawdust, coconut husks, corn cobs and tobacco stalks; useful emulsifiers and / or foams include: for example, non-ionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example, alkylaryl-polyglycolic ethers, alkylsulfonates, sulfates of alkyl, arylsulfonates and also protein hydrolysates; suitable dispersants include non-ionic and / or ionic substances, for example, from the alcohol-POE and / or -POP ether class, acid and / or POP POE esters, alkylaryl ethers and / or POP POE, adducts fatty and / or POP POE, derivatives of POEe / or POP-polyol, adducts of POE- and / or POP-sorbitan or sugar, alkyl or aryl sulfates, alkyl or aryl sulfonates and alkyl or aryl phosphates or the corresponding PO ether adducts. Also suitable are oligomers or polymers, for example those obtained from vinyl monomers, from acrylic acid, from EO and / or PO alone or in combination, for example, with (poly) alcohols or ( poly) -amines. It is also possible to use lignin and its derivatives of sulfonic acid, unmodified and modified celluloses, aromatic and / or aliphatic sulfonic acids, as well as their adducts with formaldehyde.

[0164] The active ingredients can be converted into conventional formulations, such as solutions, emulsions, wetting powders, suspensions based on water and oil, powders,

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89/191 dust, pastes, soluble powders, soluble granules, granules for dissemination, concentrates of suspoemulsions, natural products impregnated with active ingredient, synthetic substances impregnated with active ingredient, fertilizers and also microencapsulations in polymeric substances.

[0165] The active ingredients can be applied as is, in the form of their formulations or in forms of use prepared from them, such as ready-to-use solutions, emulsions, water or oil based suspensions, powders, wetting powders , pastes, soluble powders, dust, soluble granules, granules for dissemination, concentrates of suspoemulsions, natural products impregnated with active ingredient, synthetic substances impregnated with active ingredient, fertilizers and also microencapsulations in polymeric substances. The application is carried out in a conventional manner, for example, by rinsing, spraying, atomizing, spreading, spreading, applying foam, diffusion, etc. It is also possible to apply the active ingredients by the ultra-low volume method or to inject the active ingredient preparation or the active ingredient itself into the soil. It is also possible to treat plant seeds.

[0166] The mentioned formulations can be prepared in a manner known per se, for example, by mixing the active ingredients with at least one filler, solvent or diluent, emulsifier, dispersant and / or binder or fixing agent, wetting agent, repellent conventional water sources and, if appropriate, desiccants and UV stabilizers and, if appropriate, dyes and pigments, defoamers, preservatives, secondary thickeners, adhesives, gibberellins

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90/191 and also other processing aids.

[0167] The present invention comprises ready-to-use formulations that can be applied using a device suitable for plants or seeds, as well as commercial concentrates that will have to be diluted before use.

[0168] The active ingredients of the invention can be present as such or in the form of their (commercial) formulations and in the forms of uses prepared from these formulations as a mixture with other (known) active ingredients, such as insecticides, attractants, sterilizers , bactericides, acaricides, nematicides, fungicides, growth regulators, herbicides, fertilizers, phytoprotective and / or semi-chemical agents.

[0169] The auxiliaries used can be those substances that are suitable to give particular properties to the composition itself and / or to the preparations derived therefrom (for example, sprayable liquors, seed coatings), such as certain technical properties and / or also biological properties private individuals. Typical auxiliaries include: cargo, solvents and vehicles.

[0170] Suitable fillers include, for example, water, polar and non-polar organic chemical liquids, for example, classes of aromatic and non-aromatic hydrocarbons (such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), alcohols and polyols (which can also be optionally substituted, esterified and / or esterified), ketones (such as acetone, cyclohexanone), esters (including fats and

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91/191 oils) and unsubstituted and substituted (poly) ethers, amines, amides and lactams (such as N-alkylpyrrolidones) and lactones, sulfones and sulfoxides (such as dimethyl sulfoxide).

[0171] Liquefied gaseous cargoes or vehicles are intended to be designated liquids that are gaseous at standard temperature and standard pressure, for example, aerosol propellants, such as halohydrocarbons, or butane, propane, nitrogen and carbon dioxide.

[0172] In formulations, it is possible to use adhesives, such as carboxymethylcellulose, natural and synthetic polymers in the form of powders, granules or agglomerates, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, or else natural phospholipids, such such as cephalins and lecithins and synthetic phospholipids. Like other additives, it is possible to mention mineral and vegetable oils.

[0173] If the load used is water, it is also possible to use, for example, organic solvents as auxiliary solvents. As useful liquid solvents there are essentially aromatic hydrocarbons, such as xylene, toluene or alkylnaphthalenes, chlorinated or chlorinated aliphatic aromatic hydrocarbons, such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons, such as cyclohexane or paraffins, for example, fractions petroleum, alcohols, such as butanol or glycol and their ethers and esters, ketones, such as acetone, methyl ethyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents such as dimethylformamide and dimethyl sulfoxide, or water.

[0174] The compositions of the invention may also contain

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92/191 other components, for example, surfactants. Suitable surfactants include emulsifiers and / or foaming agents, dispersants or wetting agents that have ionic or non-ionic properties, or mixtures of these surfactants. Examples include salts of polyacrylic acid, salts of lignosulphonic acid, salts of phenolsulphonic acid or naphthalenesulphonic acid, polycondensates of ethylene oxide with fatty alcohols or with fatty amines, substituted phenols (preferably alkylphenols or arylphenols), salts of sulfo-succinic esters, taurine derivatives (preferably alkyl taurates), phosphoric esters of polyoxyethylated alcohols or phenols, fatty esters of polyols and derivatives of compounds containing sulphates, sulphonates and phosphates, for example, polyglycyl alkyl ethers, alkylsulfonates, alkyl sulfates, arylsulfonates, protein hydrolysates, residual lignosulphite liquors and methyl cellulose. The presence of a surfactant is necessary if one of the active ingredients and / or one of the inert vehicles is insoluble in water, when the application takes place in water. The proportion of surfactants is between 5% and 40% by weight of the composition of the invention.

[0175] It is possible to use dyes, such as inorganic pigments, for example, iron oxide, titanium oxide and Prussian blue, and organic dyes, such as alizarin dyes, azo dyes and metallic phthalocyanine dyes, and trace nutrients, such as iron, manganese, boron, copper, cobalt, molybdenum and zinc salts.

[0176] Like other additives it is possible to mention

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93/191 perfumes, mineral and vegetable oils, optionally modified oils, waxes and nutrients (including trace nutrients), such as iron, manganese, boron, copper, cobalt, molybdenum and zinc salts.

[0177] As additional components, it is possible to mention stabilizers, such as cold stabilizers, preservatives, antioxidants, light stabilizers or other agents that improve chemical and / or physical stability.

[0178] If appropriate, it is also possible to have other additional components present, for example, protective colloids, binders, adhesives, thickeners, thixotropic substances, penetrants, stabilizers, sequestrants, complexing agents. In general, the active ingredients can be combined with any solid or liquid additive commonly used for formulation purposes.

[0179] In general, formulations contain between 0.05% and 99% by weight, preferably between 0.01% and 98% by weight

weight preferably in between 0.1% and 95% in Weight, more preferably in between 0.5% and 90% by weight and still more preferably in between 10% and 70% by weight of ingredient active. [0180] The formulations described before can to be

used in a method according to the invention for the control of unwanted microorganisms, in which the heteroaryl-piperidine and -piperazine derivatives of the invention are applied to the microorganisms and / or their habitat.

[0181] The active ingredients of the invention can also be used, either as or in the form of their

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94/191 formulations, in a mixture with known fungicides, bactericides, acaricides, nematicides or insecticides, to widen, for example, the spectrum of activity or to prevent the development of resistance.

[0182] Useful mixing partners include, for example, known fungicides, insecticides, acaricides, nematicides or bactericides (see also Pesticide Manual, 14th ed.).

[0183] It is also possible to mix with other known active ingredients, such as herbicides, or with fertilizers and growth regulators, phytoprotective and / or semi-chemical agents.

[0184] The application is carried out in a conventional manner suitable for the forms of use.

[0185] The invention further comprises a method for treating seeds.

[0186] According to another aspect, the present invention relates in particular to seeds treated with at least one of the heteroaryl-piperidine and -piperazine derivatives of the invention. The seeds of the invention are used in methods for protecting seeds from attacks by harmful phytopathogenic fungi. In these methods, seeds treated with at least one active ingredient of the invention are used.

[0187] The active ingredients or compositions of the invention are also suitable for seed treatment. A large part of the damage to crop plants caused by harmful organisms is triggered by infection of the seed during storage or after cultivation, both during and after germination of the plant. This phase is

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95/191 particularly critical since the roots and shoots of the growing plant are particularly sensitive and even minor damage can cause the plant to die. Therefore, there is a great interest in protecting seeds and the germinating plant through the use of suitable compositions.

[0188] The control of harmful phytopathogenic fungi through the treatment of plant seeds has been known for a long time and is subject to constant improvements. However, seed treatment entails a set of problems that cannot always be satisfactorily solved. For example, it is desirable to develop methods to protect seeds and the germinating plant, which dispense, or at least significantly reduce, the additional application of crop protection agents after cultivation or after the emergence of plants. It is also desirable to optimize the amount of active ingredient used, in order to provide the best possible protection for the seed and for the germinating plant against attack by phytopathogenic fungi, without however damaging the plant itself by the active ingredient used. In particular, seed treatment methods should take into account the intrinsic fungicidal properties of transgenic plants to achieve optimum protection of the seed and the germinating plant with a minimum amount of crop protection agents.

[0189] Therefore, the present invention also concerns a method for the protection of germinating seeds and plants against attack by harmful animal pests and / or harmful phytopathogenic fungi through seed treatment

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96/191 with a composition of the invention. The invention also concerns the use of the compositions of the invention for the treatment of seeds for the protection of seeds and germinating plants against phytopathogenic fungi. The invention also relates to seeds treated with a composition of the invention for protection against phytopathogenic fungi.

[0190] Animal pests and / or harmful phytopathogenic fungi that damage post-emergence plants are mainly controlled by treating the soil and exposed parts of the plants with crop protection agents. Due to concerns about the possible influence of crop protection agents on the environment and the health of humans and animals, efforts are needed to reduce the amount of active ingredients applied.

[0191] One of the advantages of the present invention is that, due to the particular systemic properties of the compositions according to the invention, the treatment of seeds with these compositions not only protects the seeds themselves, but also the resulting plants after emergence, against harmful animal pests and / or phytopathogenic fungi. In this way, immediate treatment of the crop at the time of cultivation or after a short time can be dispensed with.

[0192] It is also considered advantageous that the active ingredients or compositions according to the invention can be used particularly in seeds, in which case the plant that grows from such seeds is capable of expressing a protein that acts against

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97/191 pests. The treatment of such seeds with the active ingredients or compositions of the invention, simply by expressing the protein, for example, an insecticidal protein, can provide control of certain pests. Surprisingly, it is possible to observe another synergistic effect in this case, which further increases the effectiveness of protection against attack by pests.

[0193] The compositions of the invention are suitable for the protection of seeds of any variety of plants used in agriculture, greenhouses, forests or horticulture. In particular, the seed is a cereal seed (such as wheat, barley, rye, millet and oats), corn, cotton, soy, rice, potatoes, sunflower, beans, coffee, beet (eg sugar beet and fodder beet) ), peanuts, vegetables (such as tomatoes, cucumbers, onions and lettuce), grass and ornamental plants. The treatment of cereal seeds (such as wheat, barley, rye and oats), corn and rice is particularly significant.

[0194] As described below, the treatment of transgenic seeds with the active ingredients or compositions of the invention is of particular importance. This refers to plant seeds that contain at least one heterologous gene that allows the expression of a polypeptide or protein that has insecticidal properties.

[0195] The heterologous gene in the transgenic seed may come, for example, from microorganisms of the species Bacillus, Rhizobium, Pseudomonas, Serratia, Trichoderma, Clavibacter, Glomus or Gliocladium. Preferably, this heterologous gene comes from Bacillus sp.

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98/191 that the gene product is effective against the European corn borer and / or chrysomelid of the corn root system. Most preferably, the heterologous gene comes from Bacillus thuringiensis.

[0196] In the context of the present invention, the composition of the invention is applied, to the seed, alone or in a suitable formulation. Preferably, the seed is treated in a state in which it is sufficiently stable to prevent damage during treatment. In general, the seed can be treated at any time between harvest and cultivation. It is customary to use seeds that have been separated from the plant and released from leaves, bark, stems, coatings, hair or flesh of the fruits. For example, it is possible to use seeds that have been harvested, cleaned and dried to a moisture content of less than 15% by weight. Alternatively, it is also possible to use seeds that, after drying, for example, have been treated with water and then dried again.

[0197] During seed treatment, it should normally be ensured that the amount of composition according to the invention applied to the seeds and / or the amount of other additives is selected in such a way that the germination of the seed is not impaired or that the resulting plant is not damaged. This should be particularly guaranteed in the case of active ingredients that exhibit phytotoxic effects for certain application rates.

[0198] The compositions of the invention can be applied directly, that is, in the absence of any other components and without having to be diluted. In

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99/191 in general, it is preferable to apply the compositions to the seeds in the form of a suitable formulation. Suitable formulations and methods for seed treatment are known to those skilled in the art and are described, for example, in the following documents: US 4 272 417, US 4 245 432, US 4 808 430, US 5 876 739, US 2003/0176428, WO 2002/080675, WO 2002/028186.

[0199] The active ingredients usable according to the invention can be converted into conventional seed coating formulations, such as solutions, emulsions, suspensions, powders, foams, pastes and other seed coating compositions, as well as ULV formulations.

[0200] These formulations are prepared in a known way, by mixing the active ingredients or combinations of active ingredients with conventional additives, for example, fillers and solvents or diluents, dyes, wetting agents, dispersants, emulsifiers, defoamers, preservatives , secondary thickeners, adhesives, conventional gibberellins and also water.

[0201] As useful dyes that may be present in the seed coating formulations usable according to the invention are all dyes conventionally used for such purposes. It is possible to use pigments, which are poorly soluble in water, or dyes, which are soluble in water. Examples include dyes known by the names' Rhodamine B ',' C.I. Pigment Red 112 'and' C.I. Solvent Red 1 '.

[0202] As useful wetting agents that may be

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100/191 present in seed coating formulations usable according to the invention refers to all substances that promote wetting and that are conventionally used for the formulation of active agrochemical ingredients. Preferably, alkylnaphthalene sulfonates, such as diisopropyl- or diisobutyl naphthalene sulfonates, are used.

[0203] As useful dispersants and / or emulsifiers that may be present in seed coating formulations usable according to the invention, all nonionic, anionic and cationic dispersants conventionally used for the formulation of active agrochemical ingredients are referred to. Preferably, nonionic or anionic dispersants or mixtures of nonionic or anionic dispersants are used. In particular, useful non-ionic dispersants include block polymers of ethylene oxide / propylene oxide, polyglycolic alkylphenol ethers and polyglycolic tristryrylphenol ether, and their phosphate or sulfate derivatives. In particular, suitable anionic dispersants include lignosulfonates, polyacrylic acid salts and arylsulfonate / formaldehyde condensates.

[0204] As defoamers that may be present in seed coating formulations usable according to the invention, all foam inhibiting substances conventionally used for the formulation of active agrochemical ingredients are referred to. Preferably, silicone defoamers and magnesium stearate are used.

[0205] As preservatives that may be present

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101/191 in seed coating formulations usable according to the invention refers to all substances usable for such purposes in agrochemical compositions. Examples include dichlorophene and hemiformal benzyl alcohol.

[0206] As secondary thickeners that may be present in seed coating formulations usable according to the invention, all substances usable for such purposes in agrochemical compositions refer. Preferred examples include cellulose derivatives, acrylic acid derivatives, xanthan, modified clays and finely divided silica.

[0207] As adhesives that may be present in seed coating formulations usable according to the invention are all conventional binders usable in seed coating products. Preferred examples include polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose.

[0208] Preferably, the gibberellins which may be present in the seed coating formulations usable according to the invention may be gibberellins A1, A3 (= gibberellic acid), A4 and A7; the use of gibberellic acid is particularly preferred. Gibberellins are known (cf. R. Wegler Chemie der Pflanzenschutzund Schâdlingsbekâmpfungsmittel [Chemistry of Crop Protection Agents and Pesticides], vol. 2, Springer Verlag, 1970, p. 401-412).

[0209] Seed coating formulations usable according to the invention can be used

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102/191 to treat several different types of seeds, either directly or after previous dilution with water. For example, concentrates or preparations obtained from this by diluting with water can be used to coat cereal seeds, such as wheat, barley, rye, oats and triticale, as well as maize, rice, rapeseed, peas, beans , cotton, sunflowers and beets, or a variety of different vegetable seeds. Seed coating formulations usable according to the invention, or their diluted preparations, can also be used to coat seeds from transgenic plants. In this case, an additional synergistic effect may occur in the interaction with the substances formed by expression.

[0210] For the treatment of seeds with the seed coating formulations according to the invention, or with the preparations prepared therefrom by adding water, all mixing units conventionally used for seed coating are useful. In particular, the seed coating procedure consists of placing the seeds in a mixer, adding the particular desired amount of seed coating formulations, as such or after previous dilution with water, and mixing everything until the formulation is evenly distributed over the seeds. If appropriate, after steps, a drying operation follows.

[0211] The application rate of the seed coating formulations according to the invention can vary over a relatively wide range. This is guided by the particular content of active ingredients in the formulations and

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103/191 seeds. In general, the application rates of the active ingredient combination are between 0.001 and 50 g per kilogram of seeds and preferably between 0.01 and 15 g per kilogram of seeds.

[0212] In addition, the compounds of formula (I) of the invention also have a very good antimycotic action. They have a very broad spectrum of antimycotic activity, in particular against dermatophytes and yeasts, molds and diphasic fungi (for example, against Candida species, such as Candida albicans, Candida glabrata), and Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species, such as Microsporon canis and audouinii. The enumeration of these fungi is not intended, in any way, to constitute a restriction of the mycotic spectrum covered, and is only illustrative.

[0213] Thus, the active ingredients of structural formula (I) can be used in medical and non-medical applications.

[0214] The active ingredients can be used as is, in the form of their formulations or in forms of use prepared from them, such as ready-to-use solutions, suspensions, wetting powders, pastes, soluble powders, dust and granules. The application is carried out in a conventional way, for example, by rinsing, spraying, atomizing, spreading, spreading, applying foam, dispersion, etc. It is also possible to apply the active ingredients by the ultra volume method

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104/191 reduced or inject the active ingredient preparation or the active ingredient itself into the soil. It is also possible to treat plant seeds.

[0215] When the active ingredients of the invention are used as fungicides, application rates can vary over a relatively wide range, depending on the type of application. The application rate of the active ingredient of the invention is included in the case of the treatment of parts of plants, for example, leaves: between 0.1 and 10 000 g / ha, preferably between 10 and 1000 g / ha and more preferably between 50 and 300 g / ha (in the case of rinsing or dripping, it is even possible to reduce the application rate, in particular,

When are used substrates inert, such how there mineral ); • at the case seed treatment: between 2 and 200 g per 100 kg seeds, preference between 3 and 150 g per 100

kg of seeds, more preferably between 2.5 and 25 g per 100 kg of seeds and even more preferably between 2.5 and 12.5 g per 100 kg of seeds;

• in the case of soil treatment: between 0.1 and 10 000 g / ha and preferably between 1 and 5000 g / ha.

[0216] These application rates are given by way of example only and are not limiting the scope of the invention.

[0217] The active ingredients of the invention are used in the veterinary sector and in animal husbandry in a known manner, for enteral administration in the form, for example, of tablets, capsules, potions, lotions, granules, pastes, large pills , through

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105/191 feeding process and suppositories, for parenteral administration, for example, by injection (intramuscular, subcutaneous, intravenous, intraperitoneal and the like), implants, by nasal administration, by dermal application in the form, for example, immersion or bathing, spraying, spreading and staining, washing and sprinkling, as well as with the help of molded articles containing the active ingredient, such as collars, ear tags, tail tags, banding for limbs, halters, marking devices and the like.

[0218] When used for livestock, poultry, domestic animals and the like, the active ingredients of structural formula (I) can be used as formulations (for example, powders, emulsions, or fluidizable products) that comprise the active ingredient in an amount between 1% and 80% by weight, either directly or after a 100- to 10,000-fold dilution, or else they can be used in the form of a chemical bath.

[0219] Ready-to-use compositions may also optionally comprise other insecticides and, optionally, one or more fungicides.

[0220] With regard to possible additional mixing partners, refer to the aforementioned insecticides and fungicides.

[0221] The compounds in invention can to be used, simultaneously for the protection of obj etos what contact with salt water or water brackish, in particular, hulls, screens, nets, buildings, ties and systems in signaling, against fouling.

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106/191 [0222] Furthermore, the compounds of the invention can be used, as antifouling compositions, alone or in combinations with other active ingredients.

[0223] The treatment method according to the invention can be used for the treatment of genetically modified organisms (GMO), e.g., plants or seeds. Genetically modified plants (or transgenic plants) are plants in which a heterologous gene has been stably integrated into the genome. The term heterologous gene essentially designates a gene that comes from or is assembled outside the plant and that when introduced into the nuclear, chloroplastic or mitochondrial genome provides the transformed plant with new or improved agronomic or other properties through the expression of a protein or polypeptide relevant or by internalizing or silencing other gene (s) that are present in the plant (using, for example, antisense technology, co-suppression technology or RNA-RNAi interference technology). A heterologous gene that is located in the genome is called a transgene. A gene that is defined by its particular location in the plant's genome is called a transgenic transformation or event.

[0224] Depending on the species of the plant or the varieties of the plant, its location and growing conditions (soils, climate, vegetation period, diet), the treatment according to the invention can also provide over-additive (“synergistic) effects . Thus, for example, it is possible to achieve a reduction in application rates and / or a broadening of the activity spectrum and / or an increase in the activity of active ingredients and usable compositions.

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107/191 according to the invention, better plant growth, greater tolerance to high or reduced temperatures, greater tolerance to drought or to the salt or water content of the soil, greater flowering performance, greater ease of harvest, accelerated ripening, higher yields, larger fruits, higher plant height, greener leaf color, faster flowering, better quality and / or higher nutritional value of the harvested products, a higher concentration of sugar in the fruits , greater storage stability and / or easier processing of harvested products, effects that exceed the effects that could be predicted in reality.

[0225] For certain application rates, active ingredient combinations can also have a strengthening effect on plants. Therefore, they are suitable for mobilizing the plant's defense system against attacks by unwanted phytopathogenic fungi and / or microorganisms and / or viruses. If appropriate, this may be one of the reasons for the increased activity of the combinations according to the invention, for example, against fungi.

[0226] As plant-fortifying substances (resistance inducers) we intend to designate, in the present context, those substances that are capable of stimulating the defense system of plants in such a way that the treated plants, when subsequently inoculated with phytopathogenic fungi unwanted and / or microorganisms and / or viruses, develop a high degree of resistance against these unwanted phytopathogenic fungi and / or microorganisms and / or viruses. In the present case, as phytopathogenic fungi

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108/191 undesired and / or microorganisms and / or viruses is intended to refer to phytopathogenic fungi, bacteria and viruses. Thus, the substances according to the invention can be used to protect plants against attacks by the aforementioned pathogens after a certain period of time after treatment. The period of time during which protection is conferred is usually between 1 and 10 days and preferably between 1 and 7 days, after treating the plants with the active ingredients.

[0227] The plants and varieties of plants that are preferably treated according to the invention include all plants that have genetic material that provides useful and particularly advantageous characteristics to these plants (whether obtained by means of culture and / or biotechnological means) .

[0228] Plants and plant varieties that are also preferably treated according to the invention are resistant against one or more biotic stresses, that is, said plants have a better defense against animal and microbial pests, such as against nematodes, insects, mites, phytopathogenic fungi, bacteria, viruses and / or viroids.

[0229] The plants and varieties of plants that can also be treated according to the invention are those plants that are resistant to one or more abiotic stresses. Abiotic stress conditions may include, for example, drought, exposure to cold temperatures, exposure to heat, osmotic stress, flooding, increased soil salinity, increased exposure to minerals, exposure to ozone, elevated exposure to light, limited availability in

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109/191 nitrogen nutrients, limited availability of phosphorus nutrients, absence of shade.

[0230] The plants and plant varieties that can also be treated according to the invention are those plants characterized by increased yield characteristics. The increased yield in said plants may be the result, for example, of an improvement in plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved nitrogen utilization, improved carbon assimilation , improved photosynthesis, increased germination efficiency and accelerated maturation. In addition, yield can be affected by improved plant architecture (under stress conditions and in the absence of stress), including, but not limited to, this. Faster flowering, flowering control for hybrid seed production, shoot vigor, plant size, internodal number and distance, root growth, seed size, fruit size, pod size, number of pods and ears, number of seeds per pod or ear, seed mass, increased seed filling, reduced seed dispersion, reduced pod dehiscence resistance to lodging. Other yield characteristics include seed composition, such as carbohydrate content, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.

[0231] The plants that can be treated according to the invention are hybrid plants that already express the

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110/191 characteristics of heterosis or hybrid vigor that normally provides better performance, vigor, health and resistance to biotic and abiotic stresses. Typically, such plants are prepared by crossing a sterile inbred male parent line (female parent) with another inbred male fertile parent line (male parent). Typically, hybrid seeds are harvested from sterile male plants and sold to producers. Sterile male plants can sometimes (eg, in corn) be produced by cutting the panicle, that is, mechanical removal of the male reproductive organs (or male flowers), although, more typically, male sterility is the result of genetic determinants in the plant genome. In this case, and particularly when the seed is the desired product to be harvested from hybrid plants, it is typically useful to ensure that male fertility in hybrid plants that contain the genetic determinants responsible for male sterility are fully restored. This can be done because male parents have the appropriate fertility restoring genes, which are capable of restoring male fertility in hybrid plants that contain the genetic determinants responsible for male sterility. The genetic determinants for male sterility may be located in the cytoplasm. Examples of cytoplasmic male sterility (CMS) have been described, for example, for the species Brassica. However, the genetic determinants for male sterility can also be located in the nuclear genome. Plants with male sterility can also be

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111/191 obtained by plant biotechnological methods, such as genetic engineering. A particularly useful means of obtaining plants with male sterility is described in WO 89/10396, in which, for example, a ribonuclease, such as barnase, is selectively expressed in tapetum cells of a ribonulease inhibitor, such as barstar .

[0232] The plants or plant varieties (obtained by plant biotechnology methods, such as genetic engineering) that can be treated according to the invention are herbicide tolerant plants, that is, plants made tolerant to one or more specific herbicides . Such plants can be obtained by genetic transformation or by selecting plants that contain a mutation that gives them such tolerance to the herbicide.

[0233] Herbicide-tolerant plants are, for example, glyphosate-tolerant plants, that is, plants made tolerant to the herbicide glyphosate or its salts. For example, glyphosate-tolerant plants can be obtained by transforming the plant with a gene encoding the enzyme 5-enolpyruvylshiquimato-3-phosphate synthase (EPSPS). Examples of such EPSPS genes include the AroA gene (CT7 mutant) of the bacterium Salmonella typhimurium, the CP4 gene of the bacterium Agrobacterium sp., The genes encoding a petunia EPSPS, a tomato EPSPS, or an EPSUS of eleusin. They can also be a mutated EPSPS. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate oxidoreductase enzyme. Glyphosate-tolerant plants can also be obtained by expressing a gene

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112/191 encoding a glyphosate acetyl transferase enzyme. Glyphosate-tolerant plants can also be obtained by selecting plants that contain naturally occurring mutations of the aforementioned genes.

[0234] Other herbicide-resistant plants include, for example, plants that are made tolerant to herbicides that inhibit the enzyme glutamine synthase, such as bialaphos, phosphinothricin or glufosinate. Such plants can be obtained by expressing a detoxifying enzyme from the herbicide or a mutant glutamine synthase enzyme that is resistant to inhibition. Such an effective detoxifying enzyme is an enzyme that encodes a phosphinothricin acetyl transferase (such as the bar or pat protein from the species Streptomyces). Plants that express an exogenous phosphinothricin acetyl transferase have been described.

[0235] In addition, other herbicide-tolerant plants are also plants that are made tolerant to herbicides that inhibit the enzyme hydroxyphenylpyruvatodioxigenase (HPPD). Hydroxyphenylpyruvate-dioxigenases are enzymes that catalyze the reaction by which parahydroxyphenylpyruvate (HPP) is transformed into homogentisate. Plants tolerant to HPPD inhibitors can be transformed with a gene encoding a naturally occurring resistant HPPD enzyme or a gene encoding a mutated HPPD enzyme. Tolerance to HPPD inhibitors can also be obtained by transforming plants with genes that encode certain enzymes that allow the formation of homogentisate despite the inhibition of the native HPPD enzyme by the HPPD inhibitor. The tolerance of plants to

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113/191 HPPD inhibitors can also be improved by transforming plants with a gene that encodes a prefenate dehydrogenase enzyme in addition to a gene that encodes an HPPD-tolerant enzyme.

[0236] Other herbide-resistant plants are plants that are made tolerant to acetolactate synthase (ALS) inhibitors. Known ALS inhibitors include, for example, the herbicides sulfonylurea, imidazolinone, triazolopyrimidines, pyrimidinyloxy (thio) -benzoates and / or sulfonylaminocarbonyltriazolinone. Different mutations in the ALS enzyme (also known as acetohydroxy acid synthase, AHAS) are known to confer tolerance to different herbicides and groups of herbicides. The production of plants tolerant to sulfonylurea is described in the international publication WO 1996/033270. Other plants tolerant to sulfonylurea and imidazolinone are also described, for example, in WO 2007/024782.

[0237] Other imidazolinone and / or sulfonyl urea tolerant plants can be obtained by induced metagenesis, selection in cell cultures in the presence of the herbicide or creation of the mutation.

[0238] The plants or plant varieties (obtained by biotechnological plant methods, such as genetic engineering) that can also be treated according to the invention are transgenic plants resistant to insects, that is, plants made resistant to attack by certain insects target. Such plants can be obtained by genetic transformation or by selecting plants that contain a mutation that gives plants such resistance

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114/191 to insects.

[0239] A transgenic insect resistant plant, as used herein, includes any plant that contains at least one gene that comprises a coding sequence that encodes:

1) an insecticidal crystal protein from Bacillus thuringiensis or an insecticidal portion thereof, such as the insecticidal crystal proteins described at: http://www.lifesci.sussex.ac.uk/Home/Neil_Crickmore/Bt/, or their insecticidal portions , eg proteins of the Cry, Cry1Ab, Cry1Ac, Cry1F, Cry2Ab, Cry3Aa or Cry3Bb protein classes, or their insecticidal moieties or

2) a crystal protein from Bacillus thuringiensis or a portion thereof that is insecticidal in the presence of a second different crystal protein from Bacillus thuringiensis or a portion thereof, such as the binary toxin consisting of the crystal proteins Cy34 and Cy35 or

3) a hybrid insecticidal protein comprising parts of two different crystal insecticidal proteins from Bacillus thuringiensis, such as a hybrid of the proteins in the previous paragraph 1) or a hybrid of the proteins in the previous paragraph 2), eg, the Cry1A.105 protein produced by the MON98034 corn event (WO 2007/027777) or

4) a protein of any one of the points 1) to 3) above, in which some, in particular, 1 to 10, amino acids have been replaced by other amino acids to obtain superior insecticidal activity for a target insect species and / or for expand the reach of the target insect species affected and / or due to changes introduced in the coding DNA during cloning and transformation, such as the Cry3Bb1 protein in the events in MON863 or MON88017 corn or the Cry3A protein in the event in MIR 604 corn;

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115/191

5) a secreted insecticidal protein from Bacillus thuringiensis or Bacillus cereus, or an insecticidal portion thereof, such as the vegetative insecticidal proteins (VIP) listed at: http://www.lifesci.sussex.ac.uk//Home/Neil_Crickmore / Bt / vip .html, vg, proteins of the VIP3Aa protein class or

6) a secreted protein from Bacillus thuringiensis or Bacillus cereus that is insecticidal in the presence of a second secreted protein from Bacillus thuringiensis or B. cereus, such as the binary toxin consisting of the VIP1A and VIP2A proteins or

7) a hybrid insecticidal protein comprising parts of different secreted proteins from Bacillus thuringiensis or Bacillus cereus, such as a hybrid of the proteins in paragraph 1) above or a hybrid of the proteins in paragraph 2) above or

8) a protein of any one of points 1) to 3) above, in which some, in particular, 1 to 10, amino acids have been replaced by other amino acids to obtain superior insecticidal activity for a target insect species and / or for expand the reach of the target insect species affected and / or due to changes introduced in the coding DNA during cloning and transformation (although they still encode an insecticidal protein), such as the VIP3Aa protein in the COT 102 cotton event.

[0240] As is evident, a transgenic insect-resistant plant, as used herein, also includes any plant that comprises a combination of genes that encode the proteins of any of the previous classes 1 to 8. According to one variant, an insect-resistant plant contains more than one transgene that encodes a protein from any of the previous classes 1 to 8, to expand the range of affected target insect species or

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116/191 to delay the development of insect resistance to plants, using different insecticidal proteins for the same species of target insects, although presenting a different mode of action, such as binding to different receptor binding sites in the insect.

[0241] Plants and plant varieties (obtained by plant biotechnological methods, such as genetic engineering) that can also be treated according to the invention are tolerant to abiotic stresses. Such plants can be obtained by genetic transformation or by selecting plants that contain a mutation that gives them such resistance to stress. Particularly useful stress-tolerant plants include:

The. plants containing a transgene capable of reducing the expression and / or activity of the poly (ADP-ribose) polymerase (PARP) gene in plant cells or plants;

B. plants that contain a transgene that enhances tolerance to stress capable of reducing the expression and / or activity of the genes encoding PARG of plants or plant cells;

ç. plants that contain a transgene that enhances stress tolerance to a functional plant enzyme from the nicotinamide rescue pathway adenine dinucleotides, including nicotinamidase, nicotinate phosphoribosyltransferase, nicotinic acid, adenyltransferase, nicotinamide, adenyltransferase, nicotinamide dynamide .

[0242] Plants and plant varieties (obtained by plant biotechnological methods, such as genetic engineering) that can also be treated according to the invention have a quantity, quality and / or

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117/191 altered storage stability of the harvested product and / or altered properties of specific ingredients of the harvested product, such as:

1) transgenic plants that synthesize a modified starch, which in its physical-chemical characteristics, in particular in the emylose content or in the amylose / amylopectin ratio, in the degree of branching, in the average chain length, in the distribution of the side chain, in the viscosity behavior, gelling strength, starch grain size and / or starch grain morphology, is altered compared to starch synthesized in plant cells or wild type plants, so that this modified starch is best suited for special applications;

2) transgenic plants that synthesize polymers of carbohydrates other than starch or that synthesize polymers of carbohydrates other than starch with altered properties compared to wild type plants without genetic modification. Examples include plants that produce polifructose, in particular of the inulin type, plants that produce alpha-1,4-glucans, plants that produce alpha-1,4-branched alpha-1,6, plants that produce alternan .

3) transgenic plants that produce hyaluronan.

[0243] The plants and plant varieties (obtained by plant biotechnological methods, such as genetic engineering) that can also be treated according to the invention are plants, such as cotton plants, with altered fiber characteristics. Such plants can be obtained by genetic transformation or by selecting plants that contain a mutation that gives them such fiber characteristics, and comprise:

a) plants, such as cotton plants, that contain

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118/191 an altered form

b) plants, an altered rsw3 shape;

c) plants, increased expression

d) plants, increased expression

e) plants, cellulose genes useful as nucleic acid plants such as sucrose phosphate plants such as sucrose synthase plants; more like plants of synthase genes; cotton, which contain; rsw2 or cotton counterparts, with synthase;

cotton, with cotton, in which the moment of plasmodesmatal activation at the base of the fiber cell is altered, e.g., by fiber-selective p-1,3-glucanase deregulation;

f) plants, such as cotton plants, which have fibers with altered reactivity, e.g., through the expression of the N-acetylglucosamine transferase gene, including the nodC and chitin synthase genes.

[0244] The plants and plant varieties (obtained by biotechnological plant methods, such as genetic engineering) that can also be treated according to the invention are plants, such as rapeseed plants or plants associated with Brassica, with altered characteristics of the oil profile. Such plants can be obtained by genetic transformation or by selecting plants that contain a mutation that gives them such altered oil characteristics, and comprise:

a) plants, such as rapeseed plants, which produce oil with a high oleic acid content;

b) plants, such as rapeseed plants, which produce oil with a reduced content of linolenic acid;

c) plants, such as rapeseed plants, which produce oil with a low level of saturated fatty acids.

[0245] As transgenic plants particularly

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119/191 which can be treated according to the invention refer to plants that comprise one or more genes encoding one or more toxins and transgenic plants that are marketed under the following trade names: YIELD GARD® (for example, corn, cotton, soy), KnockOut® (eg corn), BiteGard® (eg corn), BTXtra® (eg corn), StarLink® (eg corn), Bollgard® (cotton), Nucotn® (cotton) , Nucotn 33B® (cotton), NatureGard® (eg, corn), Protecta® and NewLeaf® (potatoes). Examples of herbicide-tolerant plants that can be mentioned include maize varieties, cotton varieties and soybean varieties which are commercially available under the following trade names: Roundup Ready® (glyphosate tolerance, eg maize, cotton , soy), Liberty Link® (tolerance to phosphinothricin, for example, rapeseed), IMI® (tolerance to imidazolinone) and SCS® (tolerance to sulfonylurea), for example, corn. As herbicide resistant plants (plants developed in a conventional way for herbicide tolerance) it is possible to mention the varieties marketed under the trade name Clearfield® (for example, maize).

[0246] As particularly useful transgenic plants that can be treated according to the invention are plants that contain transformation events, or a combination of transformation events, and which are listed, for example, in databases of different regulatory agencies national or regional (see, for example, http://gmoinfo.jrc.it/gmp_browse.aspx and http://www.agbios.com/dbase.php).

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120/191 [0247] The listed plants can be treated according to the invention in a particularly advantageous manner with the compounds of formula (I) and / or with the mixtures of active ingredient according to the invention. The preferred ranges mentioned above for the active ingredients or mixture also apply to the treatment of these plants. Particular importance is given to the treatment of plants with the compounds or mixtures specifically referred to in this text.

[0248] The active ingredients or compositions of the invention can thus be used to protect plants against attacks by the mentioned pathogens for a certain period of time after treatment. The period of time during which protection is conferred is normally between 1 and 28 days, preferably between 1 and 14 days, more preferably between 1 and 10 days, even more preferably between 1 and 7 days after the treatment of the plants with the active ingredients, or up to 200 days after seed treatment.

[0249] The preparation and use of the active ingredients of structural formula (I) are illustrated by the following examples. However, the invention is not limited to these examples.

[0250] General notes: unless otherwise stated, all chromatographic purifications and separation steps were performed on silica gel, using a solvent gradient from 0: 100 ethyl acetate / cyclohexane to 100: 0 acetate ethyl / cyclohexane.

Preparation of the compound (I-5)

Step 1

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4- [4- (5- {2 - [(Methylsulfonyl) -amino] -phenyl} -4,5-dihydro-

Tert-Butyl 1,2-oxazol-3-yl) -1,3-thiazol-2-yl] -piperidine-1-carboxylate (XVIIf-1) [0251] To a solution of 4- {4 - [( Z / E) - tert-butyl (hydroxyimino) methyl] -1,3-thiazol-2-yl} -piperidine-1-carboxylate (1.35 g) and N- (2-vinylphenyl) -methanesulfonamide ( 1.11

g) in ethyl acetate (20 ml), at room temperature, potassium hydrogen carbonate (2.17 g) and N-chlorosuccinimide (0.58 g) were added and then three drops of water. The reaction mixture was stirred at 50 ° C overnight, then ethyl acetate and water were added and the mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography. 4- [4- (5 {2 - [(methylsulfonyl) -amino] -phenyl} -4,5-dihydro-1,2-oxazol3-yl) -1,3-thiazol-2-yl was obtained ] tert-butyl piperidine-1-carboxylate (0.94 g).

Step 2

4- [4- (5- {2 - [(methylsulfonyl) -ammonium] phenyl} -4,5-dihydro-1,2-oxazol-3-yl) -1,3-thiazol-2- il] piperidinium (XIIIb-1) [0252] To a solution of 4- [4- (5- {2 - [(methylsulfonyl) amino] -phenyl} -4,5-dihydro-1,2-oxazole- A solution of 4-tert-butyl 3-yl) -1,3-thiazol-2yl] -piperidine-1-carboxylate (900 mg) in 1,4dioxane (10 ml) was added dropwise at 0 ° C. molar solution of hydrogen chloride in 1,4-dioxane (6.66 ml). The reaction mixture was stirred at 0 ° C and allowed to warm gradually to room temperature. After stirring overnight, the solvent and excess hydrogen chloride were removed. 4- [4- (5- {2 dichloride) was obtained

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122/191 [(methylsulfonyl) -ammonium] -phenyl} -4,5-dihydro-1,2-oxazol-3yl) -1,3-thiazol-2-yl] -piperidinium (1.00 g).

Step 3

N- (2- {3- [2- (1- {[5-Methyl-3- (trifluoromethyl) -1H-pyrazol1-yl] -acetyl} -piperidin-4-yl) -1,3-thiazol-4 -il] -4,5-dihydro-1,2-oxazol-5-yl} -phenyl) -methanesulfonamide (I-5) [0253] 4- [4- (5- {2 dichloride) was dissolved [(methylsulfonyl) -ammonium] -phenyl} -4,5-dihydro-1,2-oxazol-3yl) -1,3-thiazol-2-yl] -piperidinium (201 mg), [5-methyl3 acid - (trifluoromethyl) -1H-pyrazol-1-yl] -acetic (104 mg) and triethylamine (51 mg) in dichloromethane (10 ml) and the mixture was stirred for 10 minutes. The mixture was stirred for another 10 minutes and then bromotris- (pyrrolidine) -phosphonium hexafluorophosphate (254 mg) was added. The reaction mixture was stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, the residue was purified by chromatography. N- (2- {3- [2- (1 - {[5Methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] -acetyl} piperidine-4-yl) -1,3-thiazole was obtained -4-yl] -4,5-dihydro-1,2-oxazol5-yl} -phenyl) -methane-sulfonamide (107 mg).

Preparation of the compound (I-4)

Step 1

N- (2- {3- [2- (1- {[2,5-bis (difluoromethyl) -phenyl] -acetyl} piperidine-4-yl) -1,3-thiazol-4-yl] -4, 5-dihydro-1,2-oxazol5-yl} -phenyl) -methane-sulfonamide (I-4) [0254] 4- [4- (5- {2 [(methylsulfonyl) -ammonium dichloride] was converted ] -phenyl} -4,5-dihydro-1,2-oxazol-3yl) -1,3-thiazol-2-yl] -piperidinium (298 mg) and [2,5-bis (difluoromethyl) - acid phenyl] -acetic (175 mg) in a manner analogous to that described for I-5 (step 3). N- (2- {3- [2- (1Petition 870180056486, of 06/29/2018, page 130/206 was obtained

123/191 {[2,5-bis (difluoromethyl) -phenyl] -acetyl} -piperidine-4-yl) -

1.3-thiazol-4-yl] -4,5-dihydro-1,2-oxazol-5-yl} -phenyl) methanesulfonamide (170 mg).

Preparation of the compound (I-6)

Step 1

N- [2,5-bis- (difluoromethyl) -phenyl] -4- [4- (5- {2 [(methylsulfonyl) -amino] -phenyl} -4,5-dihydro-1,2-oxazole -3yl) -1,3-thiazol-2-yl] -piperidine-1-carboxamide (I-6) [0255] To a 4- [4- (5- {2 [(methylsulfonyl) -ammonium dichloride suspension ] -phenyl} -4,5-dihydro-1,2-oxazol-3yl) -1,3-thiazol-2-yl] -piperidinium (202 mg) in dichloromethane (5 ml) and triethylamine (51 mg) At room temperature, 1,4-bis- (difluoromethyl) -2-isocyanatobenzene (100 mg) and a drop of 1,8-diaza-bicyclo [5.4.0] undec-7-ene (DBU) were added. The mixture was stirred at room temperature for 2 hours and then a saturated ammonium chloride solution was added. The aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography. N- [2,5bis- (difluoromethyl) -phenyl] -4- [4- (5- {2 - [(methylsulfonyl) amino] -phenyl} -4,5-dihydro-1,2- oxazol-3-yl) -1,3-thiazol-2yl] -piperidine-1-carboxamide (150 mg).

Preparation of compounds of structural formula (I-3) Step 1

4- {4- [5- (2-Formylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -

1.3-tert-butyl thiazol-2-yl} -piperidine-1-carboxylate (XVIIf-2) [0256] To a solution of 4- {4 - [(Z / E) - (hydroxyimino) -methyl] -

Tert-butyl 1,3-thiazol-2-yl} -piperidine-1-carboxylate

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124/191 (5.6 g) and 2-vinylbenzaldehyde (2.61 g) in ethyl acetate (70 mL), at room temperature, potassium hydrogen carbonate (7.23 g) and N-chlorosuccinimide were added (2.31

g) and then three drops of water. The reaction mixture was stirred at 60 ° C for 3 hours, then ethyl acetate and water were added and the mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography. The product disclosed is 4- {4- [5- (2-formylphenyl) 4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} -piperidine1-carboxylate tert-butyl (5.69 g).

Step 2

4- {4- [5- (2-formylphenyl) -4,5-dihydro-1,2oxazol-3-yl] -1,3-thiazol-2-yl} -piperidinium chloride (XIIIb-2) [0257] 4- {4- [5- (2-Formylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2-yl} -piperidine- Tert-butyl carboxylate (5.1 g) in a similar manner to that described for I-5 (step 2). 4- {4- [5 (2-formylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2yl} -piperidinium chloride (4, 35 g).

Step 3

N- (5-Chloro-2-methylphenyl) -4- {4- [5- (2-formylphenyl) -4,5dihydro-1,2-oxazol-3-yl] -1,3-thiazol-2 -il} -piperidine-1carboxamide (I-3) [0258] To a suspension of 4- {4- [5- (2formylphenyl) -4,5-dihydro-1,2-oxazol-3-yl chloride ] -1,3-thiazol-2yl} -piperidinium (1.44 g) in dichloromethane (30 ml) and diisopropylethylamine (0.73 ml), at room temperature, 4-chloro-2-isocyanate-1- was added methylbenzene (700 mg) and a drop of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

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The mixture was stirred at room temperature overnight and then water was added. The aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography. N- (5-chloro-2-methylphenyl) -4- {4- [5- (2-formylphenyl) -4,5-dihydro-1,2-oxazol-3-yl] -1,3-thiazole was obtained 2-yl} -piperidine-1carboxamide (1.23 g).

Preparation of the compound (I-7)

2- {3- [2- (1 - {[5-Methyl-3- (trifluoromethyl) -1H-pyrazol-1yl] -acetyl} piperidine-4-yl) -1,3-thiazol-4-yl] - 4,5-dihydro-

1.2- oxazol-5-yl} -benzaldehyde (I-7) [0259] To a solution of [5-methyl-3 (trifluoromethyl) -1H-pyrazol-1-yl] -acetic acid (900 mg) in dichloromethane ( 20 ml), oxalyl chloride (1.50 g) and a drop of N, N-dimethylformamide were added at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. The solvent and excess reagent were removed under reduced pressure. The solid residue was redissolved in dichloromethane and added dropwise at 0 ° C to a solution of 4- {4- [5- (2-formylphenyl) -4,5-dihydro-

1.2- oxazol-3-yl] -1,3-thiazol-2-yl} -piperidinium (1.49 g) and diisopropylethylamine (2.05 ml) in dichloromethane (20 ml). The reaction mixture was stirred at room temperature overnight. Then a concentrated solution of sodium hydrogen carbonate was added, the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. Purified by column chromatography to obtain 2- {3 [2- (1 - {[5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl]

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126/191 acetyl} piperidine-4-yl) -1,3-thiazol-4-yl] -4,5-dihydro-1,2oxazol-5-yl} -benzaldehyde (2.00 g).

Examples

[0260] The structural elements G ¹ and Q ²⁴ -3 shown in Table 1 have the following definitions:

table 1, p = 0 and L ² = direct connection, R ² = Η

Table 1:

Ex. THE LI Y X G _R S1 Q R ⁵ R ¹ Log P 1 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 3- formylphenyl 2.83 [a] 2 5-chloro-2- methylphenyl NH 0 ç G ¹ H Q ²⁴ -3 H 3- formylphenyl 3.05 [a] 3 5-chloro-2- methylphenyl NH 0 ç G ¹ H Q ²⁴ -3 H 2- formylphenyl 3.35 [a] 4 2.5- bis (difluoromet il) -phenyl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- [(methylsulfon il) -amino] - phenyl 2.81 [a] 5 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- [(methylsulfon il) -amino] - phenyl

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Ex. THE LI Y X G _R S1 Q R ⁵ R ¹ Log P 6 2.5- bis (difluoromet il) -phenyl NH 0 ç G ⁴ H Q ²⁴ -3 H 2- [(methylsulfon il) -amino] - phenyl 2.72 [a] 7 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- formylphenyl 3.12 [a] 8 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2,6-difluoro- 3- (prop-2-in1-yloxy) phenyl 9 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 3-fluoro-2 (prop-2-in-liloxy) -phenyl 10 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 3- (prop-2-in- 1-iloxy) - phenyl 3.49 [a]; 3.3 [b] 11 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2-chloro-6 (prop-2-in-liloxy) -phenyl 3.62 [a]; 3.53 [b] 12 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2-fluoro-6 (prop-2-in-liloxy) -phenyl 3.35 [a]; 3.27 [b] 13 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (prop-2-in- 1-iloxy) - phenyl 3.47 [a]; 3.37 [b] 14 3.5- bis (trifluorome til) -1Hpyazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- [(cyclopropyl carbonyl) oxy] -phenyl 4.04 [a] 15 3- (difluoromethyl) -5-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (but-2-in- 1-yloxy) -4methoxyphenyl 3.28 [a] 16 3.5- bis (trifluorome til) -1Hpyazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (cyclopropylmethoxy) -phenyl 4.59 [a]

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Ex. THE LI Y X G _R S1 Q R ⁵ R ¹ Log P 17 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (cyclopropylmethoxy) -phenyl 4.03 [a] 18 5- (difluoromethyl) -3-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - phenyl 3.42 [a]; 3.33 [b] 19 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 3- (allyloxy) - 2.6- difluorophenyl O 20 3- (difluoromethyl) -5-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 4-chloro-2 (prop-2-in-liloxy) -phenyl 3.37 [a]; 3.36 [b] 21 3- (difluoromethyl) -5-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2,4-dichloro- 6- (prop-2-in- 1-yloxy) phenyl 3.66 [a]; 3.57 [b] 22 3- (difluoromethyl) -5-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - 4-methylphenyl 3.62 [a]; 3.66 [b]; 23 3- (difluoromethyl) -5-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 4-methyl-2 (prop-2-in-liloxy) -phenyl 3.23 [a]; 3.23 [b]; 24 3- (difluoromethyl) -5-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - 4.6- dichlorophenyl 3.95 [a]; 3.97 [b]; 25 2.5- dimethylphenyl NH 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - 6- fluorophenyl 3.64 [a]; 3.62 [b] 26 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 4-methyl-2 (prop-2-in-liloxy) -phenyl 3.67 [a]; 3.61 [b] 27 3- (difluoromethyl) -5-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (cyclopropylmethoxy) -4methoxyphenyl 3.5 [a]

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Ex. THE LI Y X G _R S1 Q R ⁵ R ¹ Log P 28 3- (difluoromethyl) -5-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (cyclopropylmethoxy) -6fluorophenyl 3.44 [a] 29 5- (difluoromethyl) -3-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (prop-2-in- 1-iloxy) - phenyl 3.03 [a] 30 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - phenyl 3.86 [a]; 3.73 [b] 31 3- (difluoromethyl) -5-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2-fluoro-6 (prop-2-in-liloxy) -phenyl 2.92 [a] 32 3.5- bis (trifluorome til) -1Hpyazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (prop-2-in- 1-iloxy) - phenyl 3.91 [a] 33 3.5- bis (trifluorome til) -1Hpyazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - phenyl 4.38 [a] 34 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (cyclopropylmethoxy- [(methylsulfon il) -methyl] phenyl 2.6 [a] 35 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- [(methylsulfin il) -methyl] - phenyl 2.34 [a] 36 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- [(ethylsulfini 1) -methyl] - phenyl 2.53 [a] 37 5- (difluoromethyl) -3-methyl-1Hpyrazole-l-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 CH3 2-fluoro-6 (prop-2-in-liloxy) -phenyl 3.11 [a]; 3.12 [b];

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Ex. THE LI Y X G _R S1 Q R ⁵ R ¹ Log P 38 2.5- dimethylphenyl NH 0 ç G ¹ H Q ²⁴ -3 H 2-chloro-6 (prop-2-in-liloxy) -phenyl 3.68 [a]; 3.57 [b] 39 5-chloro-2- methylphenyl NH 0 ç G ⁴ H Q ²⁴ -3 H 2- (allyloxy) - 6-chlorophenyl 4.21 [a]; 4.11 [b] 40 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 3- [(cyclopropyl carbonyl) oxy] -phenyl 3.53 [a]; 3.47 [b] 41 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 3- (allyloxy) - phenyl 3.62 [a]; 3.68 [b]; 42 2.5- dimethylphenyl NH 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - 6-chlorophenyl 3.98 [a]; 3.91 [b] 43 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- [(2,2,2trifluoroethoxy) -methyl] phenyl 3.77 [a] 44 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- [(2 methoxyethoxy) methyl] -phenyl 3.28 [a] 45 2.5- dimethylphenyl NH 0 ç G ¹ H Q ²⁴ -3 H 2- (prop-2-in- 1-iloxy) - phenyl 3.43 [a]; 3.41 [b] 46 2.5- dimethylphenyl NH 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - phenyl 3.91 [a]; 3.81 [b] 47 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 4- [(cyclopropyl carbonyl) oxy] -phenyl 3.49 [a]; 3.4 [b] 48 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2-chloro-6- [(cyclopropyl carbonyl) oxy] -phenyl 3.73 [a]; 3.64 [b] 49 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2-fluoro-6 (2methoxyethoxy) phenyl 3.28 [a]; 3.17 [b] 50 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - 6-chlorophenyl 3.94 [a]; 3.83 [b]

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Ex. THE LI Y X G _R S1 Q R ⁵ R ¹ Log P 51 5-methyl-3- (trifluoromethyl ) -IH-pyrazole- 1-ilo ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - 6- fluorophenyl 3.7 [a]; 3.61 [b] 52 5-methyl-3- (trifluoromethyl) -IH-pyrazole1-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (allyloxy) - 3- fluorophenyl 3.97 [a]; 3.84 [b] 53 5-methyl-3- (trifluoromethyl) -IH-pyrazole1-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2-fluoro-6- formylphenyl 3.03 [a]; 2.95 [b] 54 5-methyl-3- (trifluoromethyl) -IH-pyrazole1-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- [(cyclopropyl carbonyl) oxy] -3fluorophenyl 3.62 [a]; 3.5 [b] 55 5-methyl-3- (trifluoromethyl) -IH-pyrazole1-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- (2methoxyethoxy) phenyl 3.37 [a]; 3.25 [b] 56 5-methyl-3- (trifluoromethyl) -IH-pyrazole1-yl ch ₂ 0 ç G ¹ H Q ²⁴ -3 H 2- [(cyclopropyl carbonyl) oxy] -phenyl 3.52 [a]; 3.41 [b]

[0262] The logP values were measured according to EEC Directive 79/831 annex V.A8 by HPLC (high performance liquid chromatography) on reverse phase columns (C 18), using the methods described below.

[a] The determination of LC-MS in the acidic range is carried out at pH 2.7 with 0.1% aqueous formic acid and acetonitrile (contains 0.1% formic acid) as eluents; linear gradient from 10% acetonitrile to 95% acetonitrile.

[b] The determination of LC-MS in the neutral range is carried out at pH 7.8, using an aqueous solution of

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132/191 0.001 molar ammonium hydrogen carbonate and acetonitrile as eluents; linear gradient from 10% acetonitrile to 95% acetonitrile.

[0263] The calibration is performed with unbranched alkane-2-ones (which have between 3 and 16 carbon atoms) with known logP values (logP values determined based on the retention times by linear interpolation between two successive alkanones).

[0264] The lambda values max. were determined at most of the chromatographic signals, using the UV spectrum from 200 nm to 400 nm.

NMR data from selected examples

NMR peak list method [0265] The 1H NMR data from selected examples are presented in the form of peak lists for 1H NMR. For each signal peak, the δ value in v p.p.m. and then the signal strength in curly brackets. The number of δ-value pairs of signal strength for different signal peaks are listed separately by periods and commas.

[0266] The listing of the peaks for an example thus takes the form of:

δ1 (intensity1); δ2 (intensity 2); ........; δί (intensity i); ......; δn (intensity n)

Ex. 1, solvent: DMSO, spectrometer: 399.95 MHz

10, 0344 (6, 63); 8.0579 (0.79) ; 8.0400 (6.68); 7, 9295 (3.74); 7.8988 (2.27); 7.8831 (2.00); 7.8801 (2, 32); 7.7478 (1.88); 7.7285 (2.24); 7.6635 (2.24); 7, 6446 (2.92); 7.6255 (1.19); 6.4922 (4.46); 5.8980 (1, 40); 5.8784 (1.71); 5.8708 (1.52); 5.8515 (1.21); 5, 3605 (0.36); 5.3405 (0.97); 5.2983 (2.90); 5.2496 (2, 81);

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5.2072 (0.87); 4.3847 (1.15); 4.3527 (1.13); 4.0571 (0.96); 4.0393 (2.31); 4.0216 (2.35); 4.0036 (1.55); 3.9837 (2.26); 3.9560 (2.66); 3.9405 (1.98); 3.9130 (1.45); 3.4474 (1.79); 3.4278 (2.00); 3.4041 (2.39); 3.3845 (3.03); 3.3262 (49, 36); 3.3125 ( 313.38); 3.2424 (1.57); 2.8718 (0.91); 2.8449 (1.44); 2.8143 (0.81); 2.6743 (0.45); 2.6701 (0.49); 2.5053 (62.03); 2.5010 (65.38) ; 2.3326 (0.53); 2.3277 (0.56); 2.2097 (16.00); 2.1319 (1.48); 2.1068 (2.42); 2.0766 (1.41); 2.0049 (1.06); 2.0012 (1.21); 1.9971 (1.55); 1.9870 (8.57); 1.8437 (0.61); 1.8238 (1.08); 1.7936 (0.95); 1.7640 (0.44); 1.6093 (0.63); 1.5889 (1.03); 1.5799 (1.02); 1.5581 (0.98); 1.5287 (0.44); 1.1930 (2.83); 1.1854 (0.97); 1.1752 (4.77); 1 ., 1574 (2, 31); -0, 0002 (1, 06); Ex. 2, solvent: DMSO, spectrometer : 399.95 MHz 10, 0350 (7, 37); 9.9023 (0.41) ; 8.6412 (0.39); ; 8.1288 (3.28); 8.0347 (7.77); 7.9318 (3.17); 7,9024 (1.25); 7.8992 (1.80); 7.8956 (1.04); 7.8836 (1.44); 7.8803 (2.04); 7.8768 (1.27); 7.7490 (1.35); 7.7328 (1.52); 7.7297 (1.99); 7.6636 (1.95); 7.6446 (2.84); 7.6256 (1.17); 7.3336 (3.23); 7.3281 (3.30); 7.1991 (2.18); 7.1786 (2.94); 7.0833 (2.27); 7.0777 (2.14); 7.0630 (1.58); 7.0574 (1.50); 5.8976 (1.13); 5.8781 (1.35); 5.8703 (1.29); 5.8507 (1.16); 4.1731 (1.81); 4.1396 (1.90); 4.0578 (1.32); 4.0400 (3.70); 4.0222 (3.72); 4.0044 (1.30); 3.9854 (1.31); 3.9578 (1.48); 3.9421 (1.68); 3.9147 (1.44); 3.4505 (1.74); 3.4309 (1.76); 3.4073 (1.67); 3.3878 (1.85); 3.3567 (1.71); 3.3193 (212.77 ); 3.0448 (1.07) ; 3.0392 (1.19); 3.0104 (2.19); 2.9815 (1.25); 2.5411 (0.60); 2.5108 (12.77); 2.5065 (22.65) ; 2.5021 (28.64) ; 2.4977 (19.62); 2.4934 (9.27);

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2.1877 (0.40); 2.1557 (15.50); 2.0936 (1.51); 2.0679 (1.65); 1.9877 (16.00); 1.7197 (0.52); 1.7101 (0.66); 1.6880 (1.28); 1.6799 (1.42); 1.6579 (1.27); 1.6495 (1.19); 1.6282 (0.48); 1.6190 (0.39); 1.1935 (4.47); 1,1757 (8.72); 1.1579 (4 , 30); -0, 0002 (0, 43); Ex. 3, solvent: DMSO, spectrometer : 399.95 MHz 10, 1834 (6, 76); 8.1195 (3.33) ; 8.0328 (1.90); 8.0289 (1.95); 8.0231 (0.70); 8.0126 (2.50); 8,0099 (2.53); 8.0020 (8.12); 7.7367 (0.79); 7.7335 (0.83); 7.7178 (2.01); 7.6990 (1.52); 7.6957 (1.42); 7.6241 (1.99); 7.6159 (2.62); 7.6074 (2.57); 7.5974 (1.90); 7.5894 (1.20); 7.3298 (3.23); 7.3243 (3.27); 7.1963 (2.20); 7.1758 (2.98); 7.0813 (2.24); 7.0758 (2.11); 7.0610 (1.60); 7.0554 (1.51); 6.4452 (1.19); 6.4290 (1.35); 6.4174 (1.33); 6.4011 (1.21); 4.1613 (1.78); 4.1278 (1.89); 4.0899 (1.41); 4.0620 (1.65); 4.0462 (1.79); 4.0401 (1.35); 4.0222 (1.56); 4.0185 (1.60); 4.0045 (0.46); 3.3155 (190.78) ; 3.2923 (3.19); 3.2755 (1.02); 3.2660 (0.58); 3.2268 (1.72); 3.2106 (1.68); 3.1831 (1.57); 3.1669 (1.55); 3.0251 (1.23); 2.9958 (2.25); 2.9668 (1.27); 2.5107 (11.92); 2.5065 (21.69); 2.5020 (27.90) ; 2.4977 (19.76); 2.4935 (9.77); 2.1503 16.00); 2.0743 (1.51); 2.0485 (1.71); 1.9879 (4.94); 1.6994 (0.51); 1.6904 (0.61); 1.6686 (1.31); 1.6612 (1.39); 1.6386 (1.30); 1.6311 (1.21); 1.6090 (0.50); 1.5996 (0.40); 1.1935 (1.36); 1.1758 (2.65); 1 , 1580 (1 , 31); - 0.0002 (2.28);

Ex. 4, solvent: DMSO, spectrometer: 399.95 MHz

9.2859 (0.81); 8.0295 (0.39); 8.0173 (6.58); 7.7187 (1.27); 7, 6986 (1.91); 7, 6011 (1.48); 7.5812 (1.08);

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7,5052 (2.29); 7.4373 (1.17); 7.4208 (1.52); 7.4168 (1.40); 7.4057 (0.47); 7.3939 (0.45); 7.3784 (1.58); 7.3680 (2.66); 7.3618 (4.78); 7.3593 (4.89); 7.3491 (1.42); 7.3429 (1.39); 7.3367 (1.18); 7.3266 (0.51); 7.3204 (0.50); 7.2856 (1.04); 7.2187 (1.17); 7.1489 (2.16); 7.0796 (2.37); 7.0128 (1.09); 6.9403 (1.18); 6.1207 (0.97); 6.0995 (1.21); 6.0927 (1.20); 6.0723 (1.00); 5.7464 (4.98); 4.4407 (0.61); 4.4116 (0.63); 4.0778 (0.63); 4.0485 (0.87); 4.0392 (0.98); 4.0115 (2.08); 3.9904 (1.99); 3.9505 (1.30); 3.9228 (1.16); 3.9068 (1.34); 3.8789 (1.04); 3.3752 (1.57); 3.3642 (2.39); 3.3080 (1524.29) ; 3.2856 (11.89) ; 3.2635 (3.70); 3.2426 (2.20); 3.2286 (1.24); 3.2084 (0.77); 3.1559 (0.42); 3.1400 (0.52); 3.0603 (1.03); 3.0358 (16.00); 2.9393 (0.46); 2.8903 (1.36); 2.8331 (0.56); 2.7997 (0.92); 2.7683 (0.57); 2.7316 (1.19); 2.6739 (1.32); 2.6692 (1.64); 2.6647 (1.30); 2.5392 (2.28); 2.5221 (7.36); 2.5090 (93, 05); 2.5046 (173.22); 2.5002 (226.03); 2.4958 (157.39) ; 2.4914 (75.79) ; 2.3316 (1.14); 2.3269 (1.48); 2.3224 (1.12); 2.0849 (1.22); 2.0691 (1.99); 1.9867 (1.36); 1.9079 (0.38); 1.7282 (0.53); 1.7038 (0.50); 1.5642 (0.54); 1.5398 (0.53); 1.2373 (0.48); 1.1925 (0.44); 1.1749 (0.77); 1.1571 (0.41); -0,0002 (4.82);

Ex. 5, solvent: DMSO, spectrometer: 399.95 MHz

9.2895 (1.04); 8.0347 (0.61); 8.0224 (6.52); 7.4399 (1 , 29) ; 7.4356 (0.88); 7.4228 (1.56); 7.4191 (1.32); 7, 4070 (0.46); 7.4029 (0.38); 7.3981 (0.62); 7.3923 (0 , 44) ; 7.3782 (1.60); 7.3679 (3.08); 7.3624 (5.05); 7, 3596 (4.74); 7.3499 (1.29); 7.3461 (0.94); 7.3426 (1 , 20) ; 7.3366 (0.93); 7.3268 (0.41); 7.3205 (0.35); 6, 4907 (3.72); 6.1225 (1.00); 6.1019 (1.23); 6.0951 (1 , 18) ; 6.0744 (1.01); 5.3418 (0.63); 5.2993 (2.10);

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5.2489 (2.11); 5.2062 (0.63); 4.3833 (0.64); 4.3517 (0.68); 4.0571 (0.33); 4.0393 (0.99); 4.0216 (1.04); 4.0036 (0.56); 3.9893 (0.65); 3.9556 (1.68); 3.9278 (1.16); 3.9117 (1.37); 3.8841 (1.04); 3.6914 (0.58); 3.4098 (0.54); 3.3999 (0.46); 3.3897 (0.68); 3.3809 (1.08); 3.3716 (0.76); 3.3639 (0.87); 3.3518 (0.89); 3.3415 (0.94); 3.3111 (259.73) ; 3.2902 (3.79); 3.2674 (2.30); 3.2469 (1.47); 3.2388 (0.80); 3.1410 (0.38); 3.0627 (1.24); 3.0367 (16.00), : 2.8689 (0.47); 2.8397 (0.83); 2.8127 (0.49); 2.5227 (0.93); 2.5094 15.18); 2.5051 (28.85); 2.5006 (38.17); 2.4962 (26.96); 2.4919 (13.31) ; 2.2395 (0.55); 2.2089 (13.78); 2.1942 (1.10); 2.1356 (0.66); 2.1070 (1.31); 2.0692 (0.96); 1.9868 (4.35); 1.8229 (0.53); 1.8181 (0.54); 1.7939 (0.54); 1.5861 (0.53); 1.5774 (0.55); 1.5554 (0.54); 1.5469 (0.49); 1.1928 (1.19); 1.1750 (2.37); 1 , 1572 (1 , 17); - 0.0002 (3.61);

Ex. 6, solvent: DMSO, spectrometer: 399.95 MHz

9.2891 (0.72); 8.6090 (2.11); 8.0212 (5.44); 7.7010

(1 , 17); 7.6808 (1.36); 7.5331 (1.79); 7.4826 (1.13); 7, 4629 (0.95); 7.4392 (0.99); 7.4219 (1.32); 7.3812 (0 , 58); 7.3765 (1.02); 7.3737 (0.84); 7.3657 (2.95); 7, 3610 (4.08); 7.3486 (1.19); 7.3386 (0.95); 7.3329 (0 , 62); 7.3231 (0.41); 7.3165 (0.33); 7.2175 (1.04); 7, 2125 (0.84); 7.0783 (2.26); 6.9389 (1.27); 6.1220 (0 , 82); 6.1014 (1.01); 6.0944 (0.95); 6.0738 (0.82); 5, 7462 (2.07); 4.1756 (1.13); 4.1420 (1.16); 4.0571 (1 , 24); 4.0392 (3.64); 4.0215 (3.66); 4.0037 (1.25); 3, 9569 (0.80); 3.9293 (0.95); 3.9132 (1.04); 3.8857 (0 , 86); 3.3658 (0.95); 3.3562 (1.26); 3.3115 (379.65);

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3.2929 (3.24); 3.2881 (3.63); 3.2699 (1.15); 3,2492 (0.96); 3.0674 (0.78); 3.0335 (14.21); 3.0093 (0.89); 2,6696 (0.36); 2.5395 (0.51); 2.5227 (1.67); 2.5094 (21.20) ; 2.550 (39.09); 2.5006 (50.66); 2.4961 (34.76); 2.4917 (16.36); 2.3273 (0.33); 2.2178 (0.36); 2.1093 (0.96); 2.0839 (1.04); 2.0692 (0.85); 1.9868 (16.00); 1.7223 (0.39); 1.7017 (0.78); 1.6925 (0.89); 1.6709 (0.81); 1.6622 (0.78); 1.6401 (0.32); 1.1928 (4.42); 1.1750 (8.83); 1 , 1572 (4 , 29); -0, 0002 (3, 01); Ex. 7, solvent: DMSO, spectrometer : 399.95 MHz 10, 1836 (3.67); 8.0340 (1.04) 1 ; 8.0300 (1.06) ; 8.0234 (0.39); 8.0136 (1.65); 8,0089 (4.95); 7.7370 (0.43); 7.7337 (0.44); 7.7181 (1.11); 7.6992 (0.83); 7.6958 (0.77); 7.6247 (1.02); 7.6151 (1.42); 7.6082 (1.43); 7.5965 (0.99); 7.5902 (0.70); 6.4891 (2.20); 6.4455 (0.64); 6.4295 (0.73); 6.4178 (0.72); 6.4016 (0.65); 5.3357 (0.39); 5.2934 (1.36); 5.2448 (1.33); 5.2022 (0.40); 4.3745 (0.40); 4.3415 (0.42); 4.0904 (0.73); 4.0623 (0.98); 4.0582 (1.38); 4.0465 (1.15); 4.0403 (3.76); 4.0225 (3.92); 4.0047 (1.32); 3.9801 (0.39); 3.9464 (0.42); 3.3867 (0.33); 3.3675 (0.44); 3.3582 (0.71); 3.3486 (0.53); 3.3119 (67.25); 3.2901 (1.13); 3.2567 (0.61); 3.2245 (1.14); 3.2083 (0.92); 3.1808 (0.82); 3.1664 (0.81); 2.8299 (0.49); 2.5242 (0.45); 2.5109 (5.48); 2.5066 (9.98); 2.5022 (12.87); 2.4978 (8.97); 2.4934 (4.35); 2.2075 (8.36); 2.1937 (0.49); 2.1242 (0.38); 2.0859 (0.79); 2.0539 (0.45); 1.9879 (16.00) ; 1.841 (0.33); 1.5593 (0.33); 1.1937 (4.44); 1,1759 (8.69); 1 , 1581 (4 , 32); -0, 0002 (1, 14);

Ex. 8, solvent: DMSO, spectrometer: 399.95 MHz

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8.0325 (7, 66); 7.3371 (0.58); 7.3239 (0.66); 7.3135

(1.27); 7.3006 (1.28); 7.2903 (0.80); 7.2774 (0.69); 7.1557 (0.88); 7.1517 (0.92); 7.1310 (1.53); 7.1282 (1.53); 7.1075 (0.72); 7.1039 (0.75); 6.4985 (4.27); 6.0167 (1.08); 5,9957 (1.29); 5.99867 (1.24); 5.9655 (1.13); 5.7569 (5.74); 5.3556 (0.89); 5.3130 (2.67); 5.2626 (2.59); 5.2199 (0.87); 4.8983 (6.61); 4.8924 (6.85); 4.3934 (0.74); 4.3595 (0.79); 4.0554 (0.42); 4.0376 (1.27); 4.0198 (1.32); 4.0018 (0.93); 3.9614 (0.79); 3.9404 (0.88); 3,9094 (0.93); 3.8967 (1.11); 3.8666 (0.96); 3.6481 (1.57); 3.6423 (3.36); 3,6365 (1.60); 3.5741 (1.15); 3.5528 (1.15); 3.5305 (0.96); 3.5096 (0.94); 3.4245 (0.50); 3.4152 (0.35); 3.4055 (0.61); 3.3964 (1.06); 3.3870 (0.61); 3.3773 (0.38); 3.3676 (0.56); 3.3225 (46.65); 3.3203 (44, 06); 3.2718 (1.05); 3.2434 (0.58); 2.8715 (0.52); 2.8411 (0.95); 2.8131 (0.55); 2.6702 (0.42); 2.5056 (48, 88); 2.5012 (65.94) ; 2.4967 (48.92) ; 2.3322 (0.35); 2.3279 (0.48); 2.3234 (0.37); 2.2090 (16.00); 2.1883 (0.73); 2.1167 (1.47); 2.0843 (0.81); 1.9886 (5.44); 1.8305 (0.63); 1.8063 (0.59); 1.5951 (0.59); 1.5861 (0.66); 1.5648 (0.62); 1.5551 (0.59); 1.2350 (0.41); 1.1921 (1.52); 1.1744 (2.98); 1 , 1565 (1 , 49); -0, 0002 (0, 53); Ex. 9, solvent: DMSO, spectrometer : 601.6 MHz 8.7986 (0.66); 8.0310 (8.32) ; 7.2995 (0.69); 7.2946 (0.76); 7.2881 (0.78); 7.2832 (1.00); 7.2804 (0.82); 7.2719 (1.20); 7.2640 (0.95); 7.1948 (0.36); 7.1816 (1.61); 7.1749 (4.74); 7.1700 (3.35); 7.1620 (0.57); 6.5053 (4.59); 5.99817 (1.40); 5.9695 (1.56); 5.9631 (1.51); 5.9508 (1.40); 5.3490 (1.22); 5.3206 (2.49); 5.2629 (2.73); 5.2345 (1.36); 4.8465 (6.64); 4.8425 (6.72); 4.3803 (0.78); 4.3586 (0.79); 4.0454 (0.50);

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4.0335 (1.51); 4.0217 (1.53); 4,0099 (0.52); 3.9788 (0.77); 3.9559 (0.83); 3.9467 (1.50); 3.9279 (1.43); 3.9180 (1.55); 3.8993 (1.28); 3.6568 (1.85); 3.6528 (3.82); 3.6489 (1.79); 3.4028 (0.55); 3.3968 (0.89); 3.3901 (0.81); 3.3837 (1.25); 3.3774 (2.09); 3.3501 (362.44) ; 3.3314 (3.04); 3.3265 (6.83); 3.3192 (2.05); 3.2812 (0.72); 3.2610 (1.14); 3.2424 (0.63); 3.2383 (0.57); 2.8500 (0.59); 2.8293 (1.02); 2.8118 (0.58); 2.6180 (0.80); 2.6150 (1.06); 2.6119 (0.84); 2.5955 (0.79); 2.5427 (0.99); 2.5242 (3.13); 2.5211 (3.99); 2.5180 (4.63); 2.5091 (55.45); 2.5062 (113.82); 2.5032 (153.80) ; 2.5002 (112.48) ; 2.4973 (52.77) ; 2.3904 (0.76); 2.3874 (1.01); 2.3844 (0.75); 2.2050 (16.00); 2.1921 (0.42); 2.1267 (1.03); 2,1005 (1.11); 2.0964 (1.11); 2.0782 (2.13); 1.9905 (6.69); 1.8367 (0.34); 1.8301 (0.39); 1.8160 (0.72); 1.8101 (0.76); 1.7955 (0.72); 1.7897 (0.64); 1.5690 (0.67); 1.5625 (0.69); 1.5483 (0.68); 1.5424 (0.63); 1.3968 (0.37); 1.2335 (0.74); 1.1860 (1.93); 1.1741 (4.07); 1.1623 (2.09); 1.0380 (0.32); 1.0270 (0.34); 0, 0052 (1 , 52); -0 , 0002 (35 , 42); - 0.0058 ( 1.08); Ex. 10, solvent: CDC13, spectrometer: 601, 7.6273 (0.91); 7.4326 (0.47); 7.3245 (1.12); 6 MHz 7.3113 (2.15); 7.2984 (1.22); 7.2614 (79.66); 7.0850 (0.46); 7.0266 (1.81); 7.0149 (3.61); 6.9414 (1.96); 6.9281 (1.90); 6.3350 (6.11); 5.7351 (0.78); 5.0298 (0.59); 5.0034 (1.60); 4.9737 (1.59); 4.9498 (0.67); 4.7006 (6.62); 4.6971 (6.67); 4.5817 (0.75); 4.5629 (0.74); 4.0571 (0.70); 4.0394 (0.71); 3.8349 (0.45); 3.8052 (0.32); 3.7893 (0.48); 3.6444 (0.47); 3.4187 (0.48); 3.3067 (1.20); 2.9123 (0.46); 2.8936 (0.76); 2.8745

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(0.47); 2.5105 (2.38); 2.5071 (4.68); 2.5036 (2.42); 2.3239 (16.00); 2.2858 (0.44); 2.2145 (0.77); 2.1812 (0.75); 2.1629 (0.73); 1.7957 (0.89); 1.7805 (0.92); 1.5858 (3.62); 1.4787 (0.49); 1.4746 (0.46); 1.4321 (1.33); 1.4270 (0.89); 1.3860 (0.35); 1.3330 (0.38); 1.2928 (0.37); 1.2844 (0.63); 1.2542 (3.05); 0.8801

(0.63); 0.8683 (0.37); 0695 (1.41); 0.0051 (0.53); 0.0002 (16.59); -0.0057 (0.63);

Ex. 11, solvent: DMSO, spectrometer: 399.95 MHz

7.9670 (8.64); 7.4133 (1.85); 7.3924 (3.34); 7.3720 (2.70); 7.1610 (3.06); 7.1564 (4.00); 7.1394 (2.50); 7.1365 (3.63); 6.5060 (4.36); 6.4950 (0.39); 6.2328 (1.37); 6.2083 (1.80); 6.2020 (1.66); 6.1773 (1.43); 5.7627 (11.00); 5.3613 (0.91); 5.3188 (2.57); 5.2700 (2.50); 5.2274 (0.88); 5.2032 (0.65); 4.8393 (0.34); 4.8331 (0.35); 4.7990 (2.74); 4.7910 (3.74); 4.7843 (2.83); 4.7503 (0.35); 4.7444 (0.36); 4.3942 (0.68); 4.3599 (0.74); 4.0366 (0.92); 4.0188 (0.97); 4,0009 (0.80); 3.9622 (0.72); 3.7667 (1.02); 3.7357 (1.26); 3.7247 (1.76); 3.6937 (1.42); 3.5797 (1.57); 3.5551 (1.60); 3.5376 (1.16); 3.5132 (1.16); 3.4596 (1.33); 3.4540 (3.13); 3.4482 (1.65); 3.4179 (0.79); 3.3720 (137.80) ; 3.3689 (145 , 30); 3, 3659 (149.76); 3.3644 (142.87) ; 3.3627 (145 , 05); 3, 3600 (158.31); 3.3560 (182.12) ; 3.3095 (0.97) ; 3.3026 (0.97); 3.2719 (1.19); 3.2437 (0.75); 3.0425 (1.70); 2.8727 (0.55); 2.8540 (1.66); 2.8448 (0.94); 2.8151 (0.55); 2.6774 (0.52); 2.6728 (0.75); 2.6682 (0.55); 2.5431 (0.37); 2.5262 (1.22); 2.5215 1.91); 2.5128 ( 37.79); 2.5083 (83.02); 2.5037 112.86); 2.4991 (80.19); 2.4945 (37.37), ; 2.3350 (0.54); 2.3304 (0.75); 2.3258 (0.59); 2.2082 (16.00); 2.1945 (0.98); 2.1899 (1.51); 2.1522 (0.65); 2.1249 (1.35); 2.0903 (0.76); 2.0774 (1.61); 1.9902 (4.31); 1.8271 (0.61); 1.8026 (0.55); 1.5943 (0.55); 1.5852

Petition 870180056486, of 06/29/2018, p. 148/206

141/191 (0.62); 1.5638 (0.59); 1.5543 (0.58); 1.1920 (1.20); 1.1742 (2.43); 1.1564 (1.18); 0.0080 (0.86); -0.0002 (29, 91); -0.0085 (1.06);

Ex. 12, solvent: DMSO, spectrometer: 399.95 MHz

7.9807 (7.00); 7.9525 (2.03); 7.4372 (0.62); 7.4201

(0 , 81); 7.4161 (1.37); 7.3992 (1.36); 7.3953 (0.92); 7, 3783 (0.71); 7.0116 (2.03); 6.9903 (1.83); 6.9152 (1 , 03); 6.8897 (1.23); 6.8681 (0.97); 6.5040 (3.54); 6, 0725 (0.87); 6.0502 (1.06); 6.0421 (1.05); 6.0198 (0 , 93); 5.7619 (3.47); 5.3612 (0.79); 5.3185 (2.23); 5, 2681 (2.18); 5.2254 (0.77); 5.2021 (0.39); 4.8549 (2 , 83); 4.8494 (4.94); 4.8440 (2.89); 4.3947 (0.60); 4, 3602 (0.65); 3.9953 (0.56); 3.9617 (0.63); 3.8129 (0 , 58); 3.7816 (0.67); 3.7697 (0.84); 3.7394 (0.76); 3, 5560 (1.45); 3.5502 (3.42); 3.5443 (1.54); 3.5246 (1 , 00); 3.5023 (1.02); 3.4818 (0.82); 3.4598 (0.76); 3, 4187 (0.44); 3.4089 (0.41); 3.3998 (0.66); 3.3913 (1 , 02); 3.3798 (0.82); 3.3704 (1.02); 3.3457 (545.02); 3, 3221 (4.34); 3.3102 (1.10); 3.3056 (1.13); 3.3023 (1 , 08); 3.2853 (0.48); 3.2711 (1.05); 3.2430 (0.56); 3, 0425 (0.81); 2.8905 (16.00); : 2.8710 (0.48); 2.8540 (0 , 86); 2.8400 (0.81); 2.8132 (0.46); 2.7305 (13.08); 2, 6765 (0.51); 2.6719 (0.75); 2.6675 (0.56); 2.5251 (1 , 29); 2.5116 (41.13); 2.5073 (87.25); 2.5029 (117.49); 2, 4984 (86.16); 2.4940 (42.72) ; 2.3339 (0.59); 2.3295 (0 , 81); 2.3250 (0.63); 2.2085 (13.04); 2.1948 (1.13); 2, 1521 (0.59); 2.1218 (1.21); 2.0879 (0.69); 2.0769 (1 , 06); 1.8268 (0.53); 1.8037 (0.49); 1.5934 (0.48); 1, 5834 (0.56); 1.5624 (0.51); 1.5537 (0.50); 1.2342 (0 , 40); -0,0002 (8.23); -0.0082 (0.39);

Petition 870180056486, of 06/29/2018, p. 149/206

142/191

Ex. 13, solvent: DMSO, spectrometer: 399.95 MHz

14.0244 (0.35); 8.7870 (0.54); 8.0352 (0.87); 8.0139 (7 , 56); 7,9916 (0.41); 7.4835 (0.44); 7.3543 (0.48); 7, 3427 (0.95); 7.3228 (3.44); 7.3042 (2.77); 7.2237 (0 , 37); 7.1506 (1.98); 7.1313 (1.63); 7.0188 (1.03); 7, 0022 (2.00); 6.9812 (0.94); 6.4963 (4.60); 6.4409 (0 , 35); 5.8865 (0.96); 5.8680 (1.10); 5.8584 (1.12); 5, 8418 (0.94); 5.7554 (7.99); 5.3481 (0.81); 5.3051 (2 , 51); 5.2549 (2.40); 5.2126 (0.97); 4.9731 (0.39); 4, 8801 (5.11); 4.8742 (5.27); 4.8150 (0.71); 4.3826 (0 , 80); 4.3501 (0.83); 4.0743 (0.38); 4.0556 (0.68); 4, 0374 (1.57); 4.0200 (1.64); 4.0020 (0.67); 3.9809 (0 , 75); 3.9478 (1.00); 3.9202 (0.45); 3.8988 (1.16); 3, 8703 (1.18); 3.8556 (1.32); 3.8277 (1.08); 3.6664 (0 , 48); 3.5857 (1.80); 3.5799 (3.73); 3.5739 (1.64); 3, 4875 (0.36); 3.4448 (0.36); 3.3987 (0.82); 3.3776 (1 , 05); 3.3700 (1.49); 3.3581 ( 1.33); 3.3228 (817.78); 3, 2695 (1.87); 3.2515 (1.78); 3.2263 (1.66); 3.2089 (1 , 19); 2.8589 (0.68); 2.8302 (1.05); 2.8000 (0.72); 2, 6750 (1.40); 2.6704 (2.12); 2.6660 (1.35); 2.5407 (1 , 00); 2.5236 (3.21); 2.5096 (115.86); 2.5056 (225.44); 2, 5012 (312.93) ; 2.4970 (220, 11); 2.4928 (110.70); 2.3323 (1 , 37); 2.3278 (1.83); 2.3232 (1.36); 2.2160 (1.34); 2, 2057 (16.00) ; 2.1935 (1.07); 2.1279 (0.79); 2.0993 (1 , 48); 2.0918 (1.41); 2.0733 (1.50); 2.0630 (0.99); 1, 9884 (6.91); 1.9085 (0.84); 1.8351 (0.38); 1.8160 (0 , 73); 1.7837 (0.64); 1.6017 (0.35); 1.5716 (0.65); 1, 5643 (0.65); 1.5516 (0.49); 1.5420 (0.71); 1.5104 (0 , 36); 1.2338 (0.91); 1.1922 (1.92); 1.1745 (3.72); 1, 1567 (1.78); -0,0002 (5.87);

Petition 870180056486, of 06/29/2018, p. 150/206

143/191

Ex. 14, solvent: DMSO, spectrometer: 399.95 MHz

8.3198 (0.45); 8.0443 (16.00); 7, 6053 (8.46); 7.4479

(2.82); 7.4440 (3.38); 7.4289 (3.83); 7.4249 (4.61); 7.4157 (1.89); 7.4115 (1.78); 7.3965 (3.75); 7.3921 (3.24); 7.3771 (3.07); 7.3727 (2.56); 7.3116 (2.76); 7.3090 (3.00); 7.2927 (4.30); 7.2903 (4.41); 7.2742 (1.69); 7.2714 (1.67); 7.1953 (0.33); 7.1890 (0.37); 7.1773 (4.76); 7.1747 (4.70); 7.1646 (0.64); 7.1572 (4.19); 7.1547 (3.90); 7.0597 (0.56); 7.0538 (0.44); 6.9641 (0.42); 6.9357 (0.32); 5.7610 (2.36); 5.7415 (2.76); 5.7327 (2.75); 5.7131 (2.43); 5.6385 (1.87); 5.5956 (4.12); 5.5268 (4.32); 5.4837 (1.93); 5.2693 (1.37); 5.1452 (0.97); 4.3548 (1.53); 4.3219 (1.65); 4.2712 (0.57); 4.2535 (0.57); 4.1720 (0.81); 4.1542 (0.81); 4.0376 (0.50); 4.0198 (0.52); 3.9738 (1.43); 3.9402 (1.61); 3.8975 (2.31); 3.8689 (2.63); 3.8543 (2.98); 3.8258 (2.50); 3.4591 (6.28); 3.4189 (2.28); 3.4100 (1.64); 3.3991 (1.84); 3.3896 (2.54); 3.3804 (1.64); 3.3705 (1.13); 3.3608 (1.37); 3.3524 (0.85); 3.3033 (1.33); 3.2908 (3.27); 3.2715 (5.00); 3,2551 (1.06); 3.2475 (3.40); 3.2283 (2.80); 2.8827 (1.10); 2.8529 (1.97); 2.8254 (1.12); 2.6763 (0.67); 2.6719 (0.93); 2.6674 (0.70); 2.5251 (2.77); 2.5116 (51.56); 2.5073 (103.29); 2.5028 (137.32); 2.4898 (103.49) ; 2.4940 (53.38) ; 2.3383 (0.39); 2.3341 (0.72); 2.3296 (0.98); 2.3250 (0.76); 2.1282 (1.37); 2.0962 (2.94); 2.0665 (1.68); 1.9896 (2.19); 1.8721 (0.77); 1.8557 (1.68); 1.8402 (2.83); 1.8344 (2.00); 1.8291 (2.06); 1.8213 (2.02); 1.8092 (1.64); 1.8011 (1.32); 1.7709 (1.16); 1.7423 (0.46); 1.5818 (0.52); 1.5725 (0.61); 1.5514

Petition 870180056486, of 06/29/2018, p. 151/206

144/191

(1.21); 1.5424 (1.31); 1.5208 (1.42); 1.5096 (1.32); 1.5013 (0.75); 1.4976 (0.58); 1.4893 (1.15); 1.4832 (0.66); 1.4775 (0.66); 1.4697 (0.52); 1.3973 (6.91); 1.3362 (0.81); 1.2837 (0.58); 1.2659 (1.15); 1.2587 (0.35); 1.2486 (1.33); 1.2341 (0.81); 1.2155 (0.95); 1.1977 (1.80); 1.1929 (0.73); 1.1798 (1.22); 1.1751 (1.33); 1.1611 (0.85); 1.1573 (0.83); 1.1435 (0.42); 1.0719 (0.82); 1.0639 (1.00); 1.0562 (1.20); 1.0509 (2.43); 1.0454 (3.02); 1.0299 (5.26); 1.0181 (3.59); 1.0131 (5.32); 1.0065 (4.05); 1,0009 (2.53); 0.9945 (2.60); 0.9852 (2.73); 0.9784 (2.29); 0.9715 (1.96); 0.9603 (2.81); 0.9461 (1.55); 0.9397 (1.46); 0.9268 (0.72); 0.9190 (0.42); 0.8188 (0.79); 0.8116 (1.69); 0.8057 (0.80); 0.7989 (0.71); 0.7916 (1.70); 0.7858 (1.34); 0.7792 (1.57); 0.7723 (1.40); 0.7679 (1.82); 0.7604 (0.79); 0.7031 (0.49); 0.6996 (0.42); 0.6916 (0.93); 0.6717 (0.48); 0.1459 (0.40); 0.0080 (3 , 19); - 0.0002 (88.57); -0.0083 (4.15); -0.1498 (0.41);

Ex. 15, solvent: DMSO, spectrometer: 399.95 MHz

8, 0022 (6.06); 7.2119 (2.20) ; 7.1906 (2.38); 7,0017 (1.16) ; 6, 8 64 5 (2.76); 6.7274 (1.32); 6.6819 (2.46); 6.6761 (2.69); 6.5676 (1.45); 6.5618 (1.32); 6.5464 (1.38) ; 6.5405 (1.27); 6.2950 (2.93); 5,8001 (0.91); 5.7812 (1.08); 5.7726 (1.04); 5.7536 (0.91); 5.2633 (0.66) ; 5.2211 (2.00); 5.1739 (1.99); 5.1317 (0.66); 4.7914 (3.28); 4.7856 (3.33); 4.3874 (0.60); 4.3555 (0.64) ; 4.0550 (0.61); 4.0372 (1.88); 4.0194 (2.07); 4.0016 (1.16); 3.9720 (0.63); 3.8129 (0.51); 3.8030 (0.90) ; 3.7752 (1.07); 3.7601 (1.52); 3.7498 (16.00); 3.7327 (1.19); 3.3994 (0.46); 3.3889 (0.41); 3.3804

Petition 870180056486, of 06/29/2018, p. 152/206

145/191

(0.62); 3.3705 (1.06); 3.3443 (19.58); 3,2887 (1.45); 3,2698 (1.23); 3.2462 (1.44); 3.2269 (1.21); 2.8478 (0.42); 2.8168 (0.73); 2,7894 (0.42); 2.6759 (0.35); 2.6714 (0.50); 2.6667 (0.36); 2.5246 (1.35); 2.5111 (28.23); 2.5067 (57.28); 2.5022 (77.36); 2.4977 59.44); 2.4933 (31.35); 2.3335 (0.45);  2.3290 (0.59); 2.3246 (0.45); 2.1850 (11.90); 2.1215 (0.63); 2.0914 (1.22); 2.0625 (0.73); 1.9894 (8.21); 1.9090 (6.30); 1.8492 (0.43); 1.8437 (0.49); 1.8203 (4.10); 1.8147 (8.12); 1.8090 (4.37); 1.7947 (0.89); 1.7870 (0.79); 1.7650 (0.65); 1.7334 (0.36); 1.7090 (0.40); 1.5650 (0.52); 1.5556 (0.57); 1.5342 (0.54); 1.5248 (0.51); 1.3972 (4.83); 1.1924 (2.19); 1.1746 (4.35); 1 , 1568 (2 , 16); -

0.0002 (4.21);

Ex. 16, solvent: DMSO, spectrometer: 399.95 MHz

8,0006 (2.31); 7, 6034 (1.53); 7.2960 (0.90); 7.2769

(1.11); 7.2613 (0.46); 7.0222 (0.79); 7,0014 (0.64); 6.9487 (0.48); 6.9297 (0.81); 6.9115 (0.38); 5.8714 (0.37); 5.8527 (0.45); 5.8428 (0.41); 5.8247 (0.38); 5.6335 (0.34); 5.5902 (0.75); 5.5240 (0.77); 5.4812 (0.35); 4.0375 (0.46); 4.0198 (0.47); 3.9353 (0.34); 3.9227 (0.42); 3.9055 (0.37); 3.8967 (0.66); 3.8798 (0.68); 3.8683 (0.49); 3.8608 (0.68); 3.8417 (0.85); 3.8254 (0.59); 3.8173 (0.39); 3.7974 (0.51); 3.3817 (0.40); 3.3519 (0.84); 3.3277 (40, 80); 3.3089 (0.72); 3.2908 (0.55); 3.2726 (0.39); 2.8544 (0.37); 2.5065 (34.94); 2.5021 (44, 66); 2.4978 (32.56); 2.0951 (0.53); 1.9892 (1.91); 1.7901 (0.47); 1.3975 (16.00); 1.1926 (0.65); 1.1748 (1.22); 1.1635 (0.38); 1.1569 (0.69); 0.4971 (0.47); 0.4926 (0.48); 0.4770 (0.35); 0.4719

Petition 870180056486, of 06/29/2018, p. 153/206

146/191 (0.39); 0.4383 (0.41); 0.4355 (0.42); 0.4156 (0.53);

0.3161 (0.39); 0.3042 (1.21); 0.2920 (1.16); 0.2798 (0.33); 0.0074 (0.34); -0.0002 (6.70);

Ex. 17, solvent: DMSO, spectrometer: 399.95 MHz

7.9983 (5.82); 7.2945 (1.82); 7.2899 (1.35); 7.2782

(2.10); 7.2749 (2.41); 7.2605 (1.12); 7.2564 (0.65); 7.0215 (1.85); 7,0012 (1.44); 6.9475 (1.09); 6.9288 (1.88); 6,9100 (0.90); 6.4963 (3.32); 5.8720 (0.89); 5.8540 (1.03); 5.8439 (1.00); 5.8256 (0.91); 5.3524 (0.74); 5.3099 (2.04); 5.2561 (2.05); 5.2139 (0.74); 4.3815 (0.61); 4.3486 (0.65); 4.0554 (1.24); 4.0376 (3.73); 4.0198 (3.80); 4.0020 (1.38); 3.9778 (0.62); 3.9512 (0.66); 3.9230 (0.77); 3.9060 (0.81); 3.8974 (1.53); 3.8805 (1.59); 3.8675 (1.14); 3.8613 (1.62); 3.8436 (1.73); 3.8396 (1.60); 3.8247 (1.40); 3.8181 (0.87); 3.7966 (1.17); 3,4009 (0.48); 3.3909 (0.41); 3.3814 (0.57); 3.3722 (0.95); 3.3627 (0.70); 3.3497 (1.79); 3.3276 (79, 63); 3.3070 (1.34); 3.2891 (1.39); 3.2626 (0.80); 3.2345 (0.46); 2.8634 (0.46); 2.8364 (0.77); 2.8052 (0.44); 2.6755 (0.35); 2.6711 (0.48); 2.6666 (0.37); 2.5413 (0.36); 2.5242 (1.94); 2.5109 (26, 73); 2.5066 (52.99); 2.5020 (70, 08); 2.4975 (51.35); 2.4931 (24.86); 2.3334 (0.36); 2.3287 (0.49); 2.3242 (0.35); 2.2060 (12,17); 2.1946 (1.38); 2.1218 (0.64); 2.0943 (1.15); 2.0628 (0.65); 1.9889 (16.00); 1.8140 (0.48); 1.8048 (0.53); 1.7901 (0.65); 1.7831 (0.48); 1.7735 (0.44); 1.5719 (0.45); 1.5629 (0.48); 1.5414 (0.44); 1.3975 (3.38); 1.2981 (0.32); 1.2585 (0.46); 1.1928 (4.73); 1.1823 (0.70); 1.1750 (9.35); 1.1655 (0.93); 1.1572 (4.79); 1.1484 (0.55); 0.5290 (0.41);

Petition 870180056486, of 06/29/2018, p. 154/206

147/191

0.5213 (0.46); 0.5172 (0.45); 0.5093 (0.62); 0.5002 (1.09); 0.4995 (1.09); 0.4799 (0.79); 0.4747 (0.87); 0.4435 (0.90); 0.4399 (0.93); 0.4232 (1.00); 0.4197 (1.14); 0.4111 (0.52); 0.3980 (0.53); 0.3912 (0.48); 0.3410 (0.34); 0.3228 (0.49); 0.3178 (0.85); 0.3058 (2.78); 0.2987 (1.55); 0.2937 (2.71); 0.2888 (0.99); 0.2816 (0.72); 0.2705 (0.33); 0.0079 (0.51); -0,0002 (13.14); -0.0084 (0.45);

Ex. 18, solvent: DMSO, spectrometer: 399.95 MHz

8.0100 (7.83); 7.3118 (1.40); 7.3083 (1.78); 7.3041

(1.62); 7.2943 (2.33); 7.2897 (2.40); 7.2853 (1.75); 7.2763 (1.44); 7.2721 (0.74); 7.2072 (1.33); 7.0725 (3.05); 7.0619 (2.31); 7.0512 (0.40); 7.0415 (1.80); 6.9747 (1.29); 6.9548 (2.22); 6.9378 (2.47); 6.3833 (3.14); 6.0804 (0.38); 6.0679 (0.83); 6.0545 (0.62); 6.0414 (0.95); 6.0372 (0.50); 6.0289 (0.50); 6.0246 (1.01); 6.0117 (0.70); 5,9981 (1.01); 5.9857 (0.48); 5.9181 (1.13); 5.9002 (1.30); 5.8903 (1.27); 5.8723 (1.15); 5.7570 (3.27); 5.4432 (0.61); 5.4389 (1.72); 5.4346 (1.75); 5.4303 (0.63); 5.3999 (0.53); 5.3956 (1.50); 5.3913 (1.52); 5.3870 (0.54); 5.2461 (1.93); 5.2421 (2.23); 5.2232 (0.68); 5.2196 (1.65); 5.2156 (1.65); 5.2119 (0.72); 5.1988 (2.50); 5.1594 (2.44); 5.1170 (0.61); 4.6326 (2.29); 4.6277 (2.51); 4.6207 (2.41); 4.6155 (2.15); 4.3629 (0.64); 4.3301 (0.66); 4.0380 (0.34); 4.0201 (0.36); 4.0020 (0.38); 3.9912 (0.60); 3.9560 (0.65); 3.8912 (1.23); 3.8632 (1.40); 3.8483 (1.59); 3.8205 (1.34); 3.3920 (0.47); 3.3822 (0.34); 3.3726 (0.57); 3.3633 (1.01); 3.3540 (0.59); 3.3439 (0.40); 3.3344 (0.69); 3.3217 (20.52); 3.2980

Petition 870180056486, of 06/29/2018, p. 155/206

148/191

(1.00); 3.2864 (1.56); 3,2684 (1.90); 3.2434 (1.82); 3.2358 (0.93); 3.2257 (1.60); 3.2068 (0.46); 2.8344 (0.45); 2.8070 (0.80); 2.7767 (0.45); 2.5239 (0.38); 2.5104 (8.89); 2.5060 (18.38); 2.5015 (24.50); 2.4969 (17.47) ; 2.4925 (8.24); 2,1608 (16.00); 2.1069 (0.59); 2.0769 (1.25); 2.0475 (0.69); 1.9888 (1.44); 1.7741 (0.52); 1.7658 (0.56); 1.7431 (0.51); 1.7356 (0.48); 1.5590 (0.50); 1.5502 (0.54); 1.5283 (0.51); 1.5194 (0.49); 1.1923 (0.40); 1.1745 (0.79); 1 , 1567 (0 , 39); - 0.0002 (2.77);

Ex. 19, solvent: DMSO, spectrometer: 399.95 MHz

8.0312 (8.75); 7.2693 (0.58); 7.2561 (0.65); 7.2458

(1.28); 7.2329 (1.27); 7.2224 (0.79); 7.2095 (0.70); 7.1053 (0.91); 7.1011 (0.94); 7.0806 (1.50); 7.0776 (1.46); 7.0573 (0.72); 7.0529 (0.72); 6.4986 (4.24); 6.0692 (0.43); 6.0559 (0.90); 6.0428 (0.88); 6.0295 (1.08); 6.0261 (0.60); 6.0129 (2.13); 5.9996 (1.15); 5,9927 (1.37); 5.99862 (1.78); 5.9732 (0.64); 5.9624 (1.15); 5.7570 (0.58); 5.4267 (0.69); 5.4226 (1.94); 5.4184 (1.98); 5.4144 (0.73); 5.3836 (0.61); 5.3795 (1.70); 5.3752 (1.75); 5.3711 (0.66); 5.3554 (0.86); 5.3128 (2.63); 5.2955 (0.92); 5.2922 (1.94); 5.2882 (1.83); 5.2621 (4.13); 5.2201 (0.87); 4.6447 (2.44); 4.6414 (4.03); 4.6380 (2.54); 4.6315 (2.56); 4.6281 (3.94); 4.6248 (2.36); 4.3925 (0.70); 4.3596 (0.74); 4.0555 (0.72); 4.0377 (2.18); 4.0199 (2.24); 4.0020 (1.21); 3.9612 (0.74); 3.9377 (0.84); 3.9073 (0.91); 3.8944 (1.09); 3.8642 (0.96); 3.5677 (3.27); 3.5469 (1.17); 3.5247 (0.95); 3.5037 (0.94); 3.4241 (0.52); 3.4148 (0.36); 3.4049 (0.61); 3.3955 (1.10); 3.3863

Petition 870180056486, of 06/29/2018, p. 156/206

149/191

(0.63); 3.3760 (0.41); 3.3667 (0.58); 3.3557 (0.34); 3.3203 (81.65); 3.2966 (3.58); 3.2716 (0.97); 3.2433 (0.53); 3.0430 (0.53); 2.8705 (0.50); 2.8545 (0.64); 2.8441 (0.89); 2.8134 (0.52); 2.6748 (0.40); 2.6703 (0.56); 2.6657 (0.41); 2.5237 (1.15); 2.5102 (29, 77); 2.5058 (61.50); 2.5012 (81.81); 2.4966 (58.12); 2.4922 (27.28) ; 2.3328 (0.40); 2.3279 (0.56); 2.3233 (0.41); 2.2095 (16.00); 2.1930 (0.82); 2.1885 (0.67); 2,1195 (1.36); 2.0862 (0.74); 1.9886 (9.64); 1.8292 (0.58); 1.8061 (0.53); 1.5944 (0.55); 1.5857 (0.61); 1.5651 (0.56); 1.5559 (0.55); 1.3975 (1.01); 1.1922 (2.65); 1.1744 (5.35); 1 , 1566 (2 , 61); -0, 0002 (8, 47); Ex. 20, solvent: DMSO, spectrometer: 601, 6 MHz 8.0151 (9.12); 7.3155 (3.02) ; 7.3017 (3.39);  7.2357 (3.79); 7.2325 (3.96); 7.0807 (2.16); 7.0775 (2.10); 7.0671 (1.98); 7.0639 (1.94); 6.9503 (1.30); 6.8591 (3.31); 6.7680 (1.51); 6.2923 (3.51); 5.8374 (1.29); 5.8259 (1.41); 5.8191 (1.38); 5.8074 (1.30); 5.7541 (10.11) ; 5.2465 (1.00); 5.2183 (2.32); 5.1637 (2.28); 5.1354 (0.99); 4.9420 (6.32); 4.9380 (6.43); 4.7777 (0.68); 4.3555 (0.71); 4.0469 (0.32); 4.0350 (1.02); 4.0232 (1.03); 4.0113 (0.38); 3.9959 (0.64); 3.9729 (0.69); 3.8884 (1.32); 3.8699 (1.56); 3.8599 (1.67); 3.8414 (1.38); 3.6384 (1.82); 3.6345 (4.09); 3.6305 (1.81); 3.3844 (0.56); 3.3781 (0.34); 3.3717 (0.62); 3.3654 (1.17); 3.3590 (0.65); 3.3526 (0.40); 3.3463 (0.61); 3.3401 (0.36); 3.3188 (83, 66); 3,2697 (0.51); 3.2545 (2.10); 3.2430 (1.81); 3.2303 (0.59); 3.2261 (1.89); 3.2145 (1.53); 2.8372 (0.48); 2.8168 (0.86); 2.7989 (0.49); 2.6162 (0.34); 2.6131 (0.51); 2.6102

Petition 870180056486, of 06/29/2018, p. 157/206

150/191

(0.37); 2.5224 (0.87); 2.5194 (1.10); 2.5163 (1.02); 2.5074 (23.48); 2.5044 (53.22); 2.5014 (75, 43); 2.48984 (54.67) ; 2.4954 (25.33) ; 2.3887 (0.34), : 2.3856 (0.49); 2.3826 (0.36); 2.1853 (16.00); 2.1700 (0.43); 2,1154 (0.59); 2.0879 (0.88); 2.0601 (0.65); 1.9884 (4.41); 1.7835 (0.53); 1.7779 (0.58); 1.7633 (0.55); 1.7572 (0.54); 1.5559 (0.55); 1.5496 (0.60); 1.5358 (0.57); 1.5295 (0.54); 1.3359 (0.43); 1.2588 (0.34); 1.2497 (0.56); 1.1870 (1.23); 1.1751 (2.46); 1.1633 (1.19); 0.0052 (1.80); - 0.0002 65.36); - 0.0058 (2.16);

Ex. 21, solvent: DMSO, spectrometer: 399.95 MHz

8.3164 (0.44); 7.9600 (8.55); 7.3175 (3.41); 7.3128

(4 , 35); 7.2756 (4.09); 7.2709 (3.55); 7,0001 (1.52); 6, 8629 (3.61); 6.7258 (1.69); 6.2950 (3.72); 6.1875 (1 , 31); 6, 1633 (1.68); 6.1568 (1.59); 6.1324 (1.36); 5, 7567 (11.60); 5.2624 (0.81); 5.2202 (2.75); 5.1767 (2 , 65); 5.1344 (0.80); 4.8983 (0.34); 4.8920 (0.36); 4, 8581 (2.93); 4,8500 (3.96); 4.8434 (2.94); 4.8094 (0 , 35); 4.8036 (0.37); 4.3907 (0.77); 4.3577 (0.81); 4, 0374 (0.66); 4.0195 (1.15); 4.0022 (0.65); 3.9783 (0 , 79); 3.7710 (1.02); 3.7399 (1.26); 3.7287 (1.71); 3, 6977 (1.38); 3.5613 (1.55); 3.5370 (1.55); 3.5191 (1 , 13); 3.4949 (1.14); 3.4743 (1.69); 3.4685 (3.90); 3, 4627 (1.72); 3.4108 (0.56); 3.4015 (0.45); 3.3911 (0 , 69); 3.3820 (1.22); 3.3725 (0.78); 3.3628 (0.64); 3, 3258 (206, 04) ; 3,3006 (0.81); 3.2947 (0.77); 3.2641 (1 , 06); 3.2355 (0.57); 2.8630 (0.55); 2.8332 (0.98); 2, 8054 (0.54); 2.6753 (0.82); 2.6708 (1.17); 2.6663 (0 , 88); 2.5236 (6.05); 2 , 5106 (61.29); 2 , 5062 (121.93); 2, 5017 (162.84); 2.4972 (123.45); 2.4930 (63.26); 2.3374

Petition 870180056486, of 06/29/2018, p. 158/206

151/191

(0.43); 2.3329 (0.86); 2.3285 (1.16); 2.3240 (0.88); 2.1878 (16.00); 2,1455 (0.75); 2,1151 (1.49); 2.0825 (0.81); 1.9887 (2.69); 1.7973 (0.64); 1.7738 (0.59); 1.5841 (0.59); 1.5759 (0.65); 1.5544 (0.62); 1.5458 (0.58); 1.3354 (0.34); 1.2981 (0.40); 1.2586 (0.57); 1.2493 (0.45); 1.2332 (0.51); 1.1925 (0.74); 1.1747 (1.43); 1.1569 (0.71); 0.1460 (0.49); 0.0159 (0.96); 0.0079 (4.30); - 0.0002 (106, 55); -0.0083 (4.46); -0.1498

(0.50);

Ex. 22, solvent: DMSO, spectrometer: 601.6 MHz

8.3142 (0.34); 7,9946 (7, 84); 7, 1678 (2.89); 7.1549

(3.09); 6.9506 (1.27); 6.8763 (3.42); 6.8594 (3.09); 6.7684 (3.08); 6.7568 (1.77); 6, 2920 (3.60); 6.0513 (0.42); 6.0431 (0.92); 6.0340 (0.71); 6.0254 (0.99); 6.0226 (0.56); 6.0170 (0.53); 6.0143 (1.04); 6,0053 (0.74); 5,9966 (1.03); 5.9884 (0.49); 5.8617 (1.21); 5.8495 (1.34); 5.8433 (1.28); 5.8310 (1.21); 5.7546 (5.26); 5.4194 (0.67); 5.4167 (1.81); 5.4138 (1.84); 5.4110 (0.69); 5.3879 (1.61); 5.3850 (1.63); 5.3822 (0.61); 5.2475 (1.04); 5.2255 (1.92); 5.2228 (2.29); 5.2197 (2.66); 5.2079 (1.69); 5.2053 (1.70); 5.1630 (2.28); 5.1348 (1.00); 4.6045 (1.74); 4.5967 (3.07); 4.5888 (1.72); 4.5750 (0.34); 4.3765 (0.70); 4.3542 (0.74); 4.0348 (0.33); 4.0230 (0.35); 3.9958 (0.66); 3.9733 (0.72); 3.8315 (1.31); 3.8130 (1.54); 3.8032 (1.64); 3.7847 (1.38); 3.7377 (0.60); 3,3858 (0.59); 3.3795 (0.38); 3.3729 (0.67); 3.3666 (1.18); 3.3605 (0.69); 3.3536 (0.45); 3.3475 (0.71); 3.3222 (44.05); 3.3190 (116.77) ; 3.2722 (0.53) ; 3.2596 (1.82); 3.2475 (2.02); 3.2313 (1.88); 3.2191 (1.46); 2.8397 (0.50);

Petition 870180056486, of 06/29/2018, p. 159/206

152/191

2.8194 (0.91); 2.8017 (0.50); 2.6159 (0.57); 2.6129 (0.82); 2.6098 (0.57); 2.5222 (1.54); 2.5191 (1.95); 2.5160 (1.99); 2.5071 (40.12); 2.5042 (87.09); 2.5011 (121.31 ); 2.4981 (87.79) ; 2.4951 (40.80) ; 2.3885 (0.58); 2.3853 (0.79); 2.3822 (0.55); 2.2873 (14.22); 2.1847 (16.00) ; 2,1701 (0.64); 2.1169 (0.68); 2.0884 (0.99); 2.0612 (0.69); 1.9883 (1.39); 1.7829 (0.56); 1.7775 (0.60); 1.7631 (0.57); 1.7575 (0.52); 1.5568 (0.55); 1.5504 (0.59); 1.5360 (0.55); 1.5300 (0.54); 1.2586 (0.33); 1.2494 (0.42); 1.2351 (0.37); 1.1867 (0.40); 1.1748 (0.77); 1.1630 (0.39); 1.1387 (0.54); 0.0840 (0.56); 0.0704 ( 0.41); 0 , 0052 (0 , 60); -0 , 0002 (18 , 89); - 0.0057 (0.67);

Ex. 23, solvent: DMSO, spectrometer: 600.13 MHz

8.3129 (0.35); 7.9980 (8.12); 7.1849 (2.82); 7.1720

(3.04); 6.9642 (3.46); 6.9516 (1.32); 6.8602 (3.12); 6.8177 (1.81); 6.8048 (1.77); 6.7688 (1.43); 6.2935 (3.75); 5.8333 (1.17); 5.8212 (1.30); 5.8150 (1.26); 5.8027 (1.20); 5.7541 (9.04); 5.2463 (0.99); 5.2179 (2.31); 5.1632 (2.30); 5.1350 (1.00); 4.8484 (6.15); 4.8445 (6.19); 4.3766 (0.70); 4.3548 (0.73); 4.0350 (0.63); 4.0232 (0.64); 3.9961 (0.66); 3.9727 (0.71); 3.8409 (1.23); 3.8224 (1.43); 3.8124 (1.51); 3.7940 (1.30); 3.5695 (1.85); 3.5656 (3.91); 3.5617 (1.77); 3.3964 (0.35); 3.3923 (0.56); 3.3852 (0.84); 3,3793 (0.75); 3.3719 (1.08); 3.3667 (1.90); 3.3611 (1.61); 3.3534 (2.07); 3.3324 (1876.28) ; 3.3130 (1.81); 3.3099 (1.34); 3,3001 (0.44); 3.2903 (0.39); 3.2756 (0.58); 3.2711 (0.58); 3.2515 (1.06); 3.2438 (1.67); 3.2315 (2.00); 3.2152 (1.45); 3.2031 (1.41); 2.8391 (0.48);

Petition 870180056486, of 06/29/2018, p. 160/206

153/191

2.8184 (0.91); 2.8009 (0.50); 2.6199 (0.75); 2.6170 (1.59); 2.6140 (2.18); 2.6110 (1.56); 2.6080 (0.72); 2.5412 (0.38); 2.5230 (3.90); 2.5199 (4.77); 2.5168 (4.61); 2.5079 123.47); 2.550 264.64); 2.5019 ( 362.99); 2.4989 (259.62) ; 2.4960 (118.63); 2.3888 (1.53), 2.3858 (2.11); 2.3828 (1.48); 2,3007 (13.79); 2.1852 (16.00); 2.1711 (0.66); 2,1187 (0.61); 2.0909 (0.94); 2.0644 (0.69); 1.9885 (2.71); 1.7854 (0.55); 1.7792 (0.58); 1.7644 (0.57); 1.7587 (0.53); 1.5569 (0.56); 1.5507 (0.61); 1.5363 (0.57); 1.5305 (0.56); 1.3354 (0.58); 1.2981 (0.40); 1.2586 (0.54); 1.2494 (0.71); 1.1867 (0.75); 1.1748 (1.46); 1.1630 (0.72); 0.0969 (0.58); 0.0053 (4.51); -0,0001 (144.35) ; -0.0057 (4.44); -0.1002

(0.61);

Ex. 24, solvent: DMSO, spectrometer: 399.95 MHz

7.9487 (9.14); 7.2585 (3.72); 7.2537 (4.34); 7,2009

(3.95); 7.1961 (3.40); 7,0001 (1.54); 6.8629 (3.75); 6.7258 (1.74); 6.2956 (3.55); 6.2149 (1.35); 6.1918 (1.71); 6.1839 (1.57); 6.1607 (1.42); 5.7985 (0.35); 5.7847 (0.74); 5.7717 (0.69); 5.7574 (14,11); 5, 7415 (0.99); 5.7283 (0.83); 5.7152 (0.96); 5.7015 (0.48); 5.2670 (1.27); 5.2629 (2.06); 5.2589 (1.98); 5.2552 (0.77); 5.2269 (2.61); 5.2196 (1.95); 5.2156 (1.76); 5.2119 (0.71); 5.1747 (2.44); 5.1324 (0.84); 5.0184 (1.75); 5.0150 (1.72); 4.9921 (1.62); 4.9887 (1.61); 4.6251 (0.50); 4.6117 (0.52); 4.5934 (1.42); 4.5800 (1.39); 4.5623 (1.42); 4.5481 (1.38); 4.5305 (0.54); 4.5162 (0.50); 4.3903 (0.70); 4.3565 (0.74); 4.0375 (0.76); 4.0196 (1.20); 4.0021 (0.60); 3.9793 (0.72); 3.7660 (1.06); 3.7348 (1.32); 3.7238 (1.78); 3.6927

Petition 870180056486, of 06/29/2018, p. 161/206

154/191

(1.43); 3.5552 (1.55); 3.5320 (1.56); 3.5130 (1.14); 3.4899 (1.13); 3.4182 (0.50); 3.4088 (0.34); 3.3989 (0.59); 3.3896 (1.07); 3.3802 (0.60); 3.3707 (0.38); 3.3608 (0.60); 3.3509 (0.37); 3.3264 (87.67); 3.2992 (0.64); 3,2682 (0.96); 3.2394 (0.52); 2.8672 (0.49); 2.8375 (0.88); 2.8104 (0.50); 2.6753 (0.41); 2.6707 (0.57); 2.6662 (0.41); 2.5242 (1.47); 2.5193 (2.32); 2.5108 (31.82); 2.5063 (63.80); 2.5017 (83.72); 2.4971 (60.62) ; 2.4926 (28.73) ; 2.3331 (0.43); 2.3285 (0.59); 2.3238 (0.42); 2.1880 (16.00); 2.1885 (0.65); 2.1047 (1.35); 2.0757 (0.75); 1.9889 (3.17); 1.8040 (0.56); 1.7956 (0.60); 1.7732 (0.58); 1.7656 (0.53); 1.5815 (0.56); 1.5726 (0.61); 1.5505 (0.58); 1.5420 (0.56); 1.3356 (0.49); 1.2584 (0.42); 1.2492 (0.63); 1.2338 (0.37); 1.1924 (0.89); 1.1746 (1.72); 1.1568 (0.85); 1.1382 (0.62); 0.0079 (1.93); - 0.0002 (59.95); -0.0085

(1.93);

Ex. 25, solvent: DMSO, spectrometer: 399.95 MHz

8.0279 (3.87); 7.9601 (9.47); 7.3975 (0.92); 7.3802

(1.19); 7.3765 (1.97); 7.3594 (2.01); 7.3557 (1.30); 7.3385 (1.02); 7.0489 (2.67); 7.0297 (3.22); 6,9979 (3.52); 6.9363 (2.80); 6.9151 (2.60); 6.8606 (2.26); 6.8413 (3.43); 6.8191 (1.39); 6.1066 (1.31); 6.0846 (1.60); 6.0760 (1.51); 6.0540 (1.37); 5.9311 (0.45); 5.9178 (0.95); 5.9047 (0.93); 5.8915 (1.12); 5.8888 (0.67); 5.8782 (0.65); 5.8747 (1.25); 5.8615 (1.08); 5.8482 (1.20); 5.8352 (0.57); 5.7593 (6.99); 5.3448 (0.79); 5.3410 (2.09); 5.3369 (2.15); 5.3330 (0.85); 5.2977 (1.81); 5.2936 (1.86); 5.2898 (0.74); 5.1204 (2.05); 5.1168 (2.04); 5.0941 (1.91); 5.0904 (1.92);

Petition 870180056486, of 06/29/2018, p. 162/206

155/191

4.6232 (0.44); 4.6102 (0.41); 4.5907 (2.08); 4.5780 (3.26); 4.5707 (1.59); 4.5669 (1.99); 4.5480 (0.36); 4.5344 (0.33); 4.1790 (1.94); 4.1451 (2.08); 4.1246 (0.54); 4.1109 (1.03); 4.1069 (0.47); 4.0195 (0.32); 3.8018 (0.92); 3.7708 (1.07); 3.7589 (1.35); 3.7289 (1.23); 3.5378 (1.52); 3.5157 (1.59); 3.5033 (0.37); 3.4946 (1.62); 3.4734 (1.16); 3.3594 (0.67); 3.3299 (55.60) ; 3.3119 (0.73); 3.3021 (0.80); 3.2932 (0.41); 3.0164 (1.33); 2.9868 (2.49); 2.9582 (1.39); 2.6708 (0.39); 2.5240 (1.44); 2.5105 ( 23.49); 2.5062 (46.51); 2.5017 (60, 90); 2.4971 (44.34); 2.4928 (21.71); 2.3331 (0.33); 2.3284 (0.42); 2.3240 (0.32); 2.2329 (16.00); 2.1107 (15.92); 2.0623 (1.95); 1.9891 (1.38); 1.7104 (0.55); 1.7005 (0.69); 1.6794 (1.45); 1.6707 (1.63); 1.6485 (1.53); 1.6407 (1.42); 1.6187 (0.63); 1.6094 (0.50); 1.2152 (0.41); 1.1974 (0.79); 1.1920 (0.42); 1.1795 (0.40); 1.1742 (0.75); 1.1564 (0.39); 1.0734 (0.43); 1.0561. (0.43); - 0.0002 (1 , 81); Ex. 26, solvent: DMSO, spectrometer: 399, 95 MHz 8.0044 (8.17); 7.1884 (2.93) ; 7.1691 (3.29); : 6, 9645 (3.82); 6.8199 (2.03); 6,8005 (1.84); 6.4986 (4.42); 5.8416 (1.17); 5.8235 (1.36); 5.8141 (1.34); 5.7957 (1.22); 5.7589 (1.32); 5.3524 (0.97); 5.3098 (2.81); 5.2586 (2.78); 5.2160 (0.98); 4.8515 (6.30); 4.8457 (6.52); 4.3839 (0.79); 4.3506 (0.83); 4.0554 (0.99); 4.0376 (3.04); 4.0198 (3.09); 4.0020 (1.13); 3.9834 (0.74); 3.9487 (0.81); 3.8553 (1.21); 3.8275 (1.40); 3.8124 (1.59); 3.7847 (1.32); 3.5799 (1.54); 3.5741 (3.36); 3.5683 (1.55); 3.3983 (0.53); 3.3890 (0.37); 3.3788 (0.65); 3.3696 (1.11); 3.3605 (0.68); 3.3502

Petition 870180056486, of 06/29/2018, p. 163/206

156/191

(0.45); 3.3406 (0.78); 3.3264 (27.97); 3.3027 (1.83); 3.2875 (0.62); 3.2541 (2.36); 3.2356 (1.71); 3.2111 (1.44); 3.1929 (1.37); 2.8556 (0.60); 2.8258 (0.99); 2.7983 (0.57); 2.5240 (0.54); 2.5104 (14.51); 2.5061 (30.55) ; 2.5016 (42.55) ; 2.4972 (32.69); 2.4931 (16.62); 2.3331 (0.34); 2.3283 (0.36); 2,3001 (13.88); 2.2054 (16.00) ; 2.1934 (1.03) ; 2.1257 (0.70); 2.0918 (1.50); 2.0643 (0.82); 1.9891 (12.98); 1.8182 (0.63); 1.8094 (0.68); 1.7873 (0.62); 1.7788 (0.58); 1.5707 (0.60); 1.5614 (0.67); 1.5404 (0.63); 1.5310 (0.61); 1.3972 (0.35); 1.2582 (0.37); 1.1922 (3.50); 1.1744 (6.96); 1.1566 (3.45); 0.0080 (0.98); - 0.0002 (31.85); -0.0084

(1.34);

Ex. 27, solvent: DMSO, spectrometer: 600.13 MHz

7.9752 (5.68); 7, 1878 (2.27); 7.1737 (2.38); 6, 9533

(0.98); 6.8618 (2.31); 6.7705 (1.08); 6.5563 (2.43); 6.5524 (2.73); 6.5035 (1.49); 6.4997 (1.31); 6.4895 (1.43); 6.4856 (1.29); 6.2946 (2.97); 5.7876 (0.95); 5.7750 (1.07); 5.7689 (1.05); 5.7561 (0.99); 5.2512 (0.82); 5.2229 (1.82); 5.1646 (1.72); 5.1363 (0.80); 4.3757 (0.58); 4.3538 (0.62); 4.0472 (0.33); 4.0353 (0.98); 4.0234 (1.01); 4.0115 (0.42); 3.9985 (0.58); 3.9781 (0.66); 3.8896 (0.83); 3.8784 (0.88); 3.8726 (1.31); 3.8614 (1.28); 3.8251 (0.53); 3.8178 (1.20); 3.8059 (1.26); 3.8008 (0.88); 3.7889 (0.83); 3.7765 (0.42); 3.7713 (0.94); 3.7523 (1.13); 3.7426 (2.44); 3.7381 (16.00); 3.7241 (1.06); 3.3894 (0.46); 3.3831 (0.34); 3.3766 (0.55); 3.3703 (0.93); 3.3640 (0.57); 3.3550 (1.29); 3.3423 (1.27); 3.3254 (75.46); 3.3141 (1.28); 3.2785 (0.47); 3.2587 (0.83); 3,2393 (0.45);

Petition 870180056486, of 06/29/2018, p. 164/206

157/191

2.8902 (2.01); 2.8476 (0.43); 2.8276 (0.75); 2.8094 (0.44); 2.7313 (1.69); 2.5226 (0.40); 2.5196 (0.50); 2.5164 (0.55); 2.5046 (24.76); 2.5016 (33.47); 2.4987 (24.64) ; 2.1971 (0.62); 2.1869 (11.90); 2.1769 (0.73); 2.1141 (0.58); 2.0870 (0.88); 2.0616 (0.61); 1.9888 (4.15); 1.7792 (0.49); 1.7767 (0.49); 1.7618 (0.46); 1.7564 (0.43); 1.5543 (0.49); 1.5344 (0.46); 1.3971 (1.43); 1.1867 (1.12); 1.1748 (2.20); 1.1629 (1.09); 1.1303 (0.48); 1.1266 (0.45); 1.1186 (0.74); 1, 1106 (0.48); 1.1069 (0.50); 0.4778 (0.33); 0.4766 (0.35); 0.4704 (0.57); 0.4684 (0.53); 0.4629 (0.74); 0.4557 (0.64); 0.4508 (0.44); 0.4483 (0.49); 0.4445 (0.38); 0.3860 (0.37); 0.3824 (0.50); 0.3806 (0.50); 0.3766 (0.47); 0.3735 (0.54); 0.3672 (0.75); 0.3604 (0.58); 0.3524 (0.38); 0.3467 (0.37); 0.2926 (0.41); 0.2853 (0.67); 0.2771 (1.19); 0.2721 (1.47); 0.2668 (1.34); 0.2649 (1.55); 0.2602 (1.06); 0.2519 (0.61); 0.2448 (0.36); 0.0053 (0.32); - 0.0001 (7 , 89); Ex. 28, solvent: DMSO, spectrometer: 399, 95 MHz 7.9638 (7.36); 7.3700 (0.76) ; 7.3492 (1.67); • 7.3319 (1.71); 7.3111 (0.82); 7,0001 (1.52); 6.8633 (4.36); 6.8462 (2.41); 6.8378 (1.50); 6.8131 (1.71); 6.7911 (1.22); 6.7259 (1.68); 6, 2950 (3.99); 6.0878 (1.17); 6.0666 (1.43); 6.0570 (1.34); 6.0360 (1.20); 5.2707 (0.96); 5.2284 (2.60); 5.1725 (2.60); 5.1300 (0.96); 4.3861 (0.85); 4.3540 (0.91); 4.0552 (0.55); 4.0373 (1.66); 4.0195 (2.13); 4.0018 (1.14); 3.9758 (0.92); 3.9028 (1.21); 3.8858 (1.35); 3.8773 (1.72); 3.8606 (1.63); 3.7919 (0.92); 3.7547 (1.94); 3.7504 (1.87); 3.7364 (1.68); 3.7301 (1.42); 3.7187 (1.47); 3.7115

Petition 870180056486, of 06/29/2018, p. 165/206

158/191

(1.31); 3.6042 (1.39); 3.5831 (1.39); 3.5620 (0.94); 3.5412 (1.00); 3.4136 (0.63); 3.4040 (0.49); 3.3938 (0.78); 3.3847 (1.22); 3.3754 (0.83); 3.3650 (0.65); 3.356 (0.93); 3.3272 (76.50); 3.3019 (0.92); 3.2641 (1.16); 3.2353 (0.64); 2.8622 (0.60); 2.8337 (1.08); 2.8044 (0.62); 2.6754 (0.57); 2.6707 (0.75); 2.6665 (0.57); 2.5061 (82.21); 2.5017 (106.35); 2.4974 (80.71); 2.3331 (0.68); 2.3285 (0.80); 2.3241 (0.62); 2.1873 (16.00) ; 2.1616 (0.34); 2.1234 (0.87); 2.0923 (1.72); 2.0629 (0.98); 1.9890 (6.69); 1.8252 (0.35); 1.8156 (0.36); 1.7896 (0.95); 1.7628 (0.71); 1.7556 (0.67); 1.7450 (0.44); 1.5902 (0.34); 1.5619 (0.70); 1.5334 (0.66); 1.1924 (1.85); 1.1746 (3.58); 1.1567 (1.78); 1.0251 (0.36); 1.0100 (0.71); 0.9934 (0.97); 0.9767 (0.83); 0.9598 (0.43); 0.3804 (0.36); 0.3721 (0.52); 0.3545 (0.94); 0.3450 (1.17); 0.3397 (0.98); 0.3306 (0.59); 0.3261 (0.66); 0.3208 (0.53); 0.2060 (0.47); 0.1965 (0.59); 0.1778 (2.77); 0.1712 (2.46); 0.1613 (4.41); 0.1471 (1.81); 0.1306 (0.69); 0, 1239 (0 >, 52); - 0.0002 (18.65); Ex. 29, solvent: DMSO, spectrometer: 399, 95 MHz 8.0135 (7.84); 7.3476 (0.67 ); 7.3434 (0.92); 7.3236 (4.06); 7.3047 (3.74); 7.2072 (1.33); 7.1516 (2.20); 7.1317 (1.88); 7.0725 (2.95); 7.0206 (1.25); 7,0019 (2.21); 6.9833 (1.03); 6.9380 (1.52); 6.3834 (3.20); 5.8869 (1.10); 5.8691 (1.27); 5.8593 (1.24); 5.8414 (1.13); 5.7569 (7.59); 5.2407 (0.62); 5.1983 (2.49); 5.1598 (2.44); 5.1435 (0.40); 5.1174 (0.61); 4, 8819 (6.04); 4.8760 (5.98); 4.3626 (0.64); 4.3296 (0.68); 4.0378 (0.65); 4.0200 (0.68); 4.0021 (0.48); 3.9904

Petition 870180056486, of 06/29/2018, p. 166/206

159/191

(0 , 61); 3.9553 (0.67); 3.8993 (1.18); 3.8714 (1.36); 3, 8563 (1.52); 3, 8286 (1.27); 3.5890 (1.60); 3.5831 (3 , 49); 3.5772 (1.54); 3.3906 (3.30); 3.3733 (1.28); 3, 3630 (1.26); 3.3537 (0.71); 3.3437 (0.44); 3.3342 (0 , 58); 3.2694 (1.85); 3.2515 (1.58); 3.2327 (0.95); 3, 2266 (1.72); 3.2086 (1.62); 2.8326 (0.45); 2.8049 (0 , 82); 2.7747 (0.46); 2.5235 (0.47); 2.5103 (10.63); 2, 5059 (21.60); 2.5013 (28.45); 2.4968 (20.20); 2.4923 (9 , 50); 2.1611 (16.00); 2.1079 (0.61); 2.0790 (1.27); 2, 0498 (0.70); 1.9888 (2.84); 1.7766 (0.52); 1.7681 (0 , 55); 1.7455 (0.52); 1.7377 (0.48); 1,5600 (0.52); 1, 5504 (0.56); 1.5287 (0.52); 1.5202 (0.50); 1.1922 (0 , 79); 1.1744 (1.56); 1 , 1566 (0, 77); -0, 0002 (2, 27);

Ex. 30, solvent: DMSO, spectrometer: 399.95 MHz

8.0106 (9.66); 7.3122 (1.38); 7.3070 (1.86); 7.3034 (1 , 80); 7.2943 (2.51); 7.2886 (2.37); 7.2843 (2.01); 7, 2764 (1.66); 7.2723 (0.83); 7.0618 (2.49); 7.0508 (0 , 46); 7.0417 (1.89); 6.9745 (1.36); 6.9548 (2.36); 6, 9377 (1.12); 6.4962 (4.47); 6.0804 (0.43); 6.0677 (0 , 97); 6.0547 (0.71); 6.0413 (1.09); 6.0370 (0.58); 6, 0288 (0.60); 6.0245 (1.18); 6.0115 (0.82); 5,9980 (1 , 18); 5.99855 (0.55); 5.9178 (1.18); 5.8999 (1.37); 5, 8903 (1.39); 5.8721 (1.23); 5.7554 (3.77); 5.4426 (0 , 62); 5.4384 (1.88); 5.4341 (1.98); 5,4300 (0.73); 5, 3993 (0.58); 5.3952 (1.62); 5.3909 (1.68); 5.3871 (0 , 62); 5.3490 (0.87); 5.3064 (2.59); 5.2534 (2.66); 5, 2461 (2.16); 5.2420 (2.00); 5.2195 (1.83); 5.2153 (2 , 05); 5.2117 (1.56); 4.6321 (2.51); 4.6276 (2.73); 4, 6198 (2.65); 4.6153 (2.44); 4.3814 (0.71); 4.3488 (0 , 71); 4.0557 (0.89); 4.0380 (2.66); 4.0202 (2.74);

Petition 870180056486, of 06/29/2018, p. 167/206

160/191

4.0024 (1.04); 3.9835 (0.69); 3.9517 (0.73); 3.8909 (1.34); 3.8629 (1.47); 3.8482 (1.72); 3.8203 (1.43); 3.3995 (0.56); 3.3894 (0.39); 3.3797 (0.67); 3.3702 (1.17); 3.3609 (0.78); 3 , 3268 (115.28); 3.3247 (244.25); 3.3015 (0.91); 3.2864 (2.05); 3,2682 (2.05); 3.2607 (1.05); 3.2435 (1.55); 3.2256 (1.84); 2.8595 (0.57); 2.8298 (0.90); 2.7999 (0.55); 2.6748 (0.44); 2.6703 (0.54); 2.6664 (0.41); 2.5237 (0.95); 2.5058 (64.08); 2.5015 (86, 96); 2.4974 (61.07); 2.3329 (0.35); 2.3282 (0.54); 2.2059 (16.00); 2.1941 (0.82); 2.1281 (0.63); 2.0918 (1.32); 2.0736 (0.76); 2.0642 (0.77); 1.9885 (11.91) ; 1.8144 (0.55); 1.8073 (0.61); 1.7843 (0.55); 1.7789 (0.51); 1.5723 (0.55); 1.5625 (0.61); 1.5404 (0.55); 1.5319 (0.53); 1.2345 (0.56); 1.1924 (3.16); 1.1746 (6.25); 1.1568 (3.04); 0.0079 (0.33); -0,0002

(11.83); -0.0085 (0.37);

Ex. 31, solvent: DMSO, spectrometer: 399.95 MHz

8.3169 (0.34); 7.9747 (8.93); 7.9522 (0.97); 7.4350

(0.80); 7.4180 (1.07); 7.4139 (1.72); 7.3971 (1.75); 7.3930 (1.11); 7.3762 (0.89); 7.0110 (2.57); 7,0008 (1.74); 6.9899 (2.33); 6.9122 (1.26); 6.8907 (1.42); 6.8870 (1.50); 6.8637 (4.65); 6.7266 (1.72); 6.2950 (3.82); 6.0724 (1.10); 6.0500 (1.32); 6.0419 (1.26); 6.0194 (1.13); 5.2657 (0.82); 5.2232 (2.61); 5.1774 (2.57); 5.1348 (0.81); 4.8525 (3.55); 4.8470 (6.21); 4.8414 (3.66); 4.3937 (0.74); 4.3602 (0.80); 4.0551 (0.76); 4.0373 (2.39); 4.0195 (2.94); 4.0018 (1.14); 3.9812 (0.77); 3.8099 (0.72); 3.7790 (0.84); 3.7698 (0.99); 3.7669 (1.02); 3.7372 (0.91); 3.5476 (1.82); 3.5417 (4.04); 3.5358 (1.85); 3.5253 (1.31); 3.5026

Petition 870180056486, of 06/29/2018, p. 168/206

161/191

(1.25); 3.4824 (0.95); 3,4600 (0.95); 3.4161 (0.53); 3.4070 (0.38); 3.3965 (0.62); 3.3873 (1.11); 3,3783 (0.68); 3.3685 (0.47); 3.3585 (0.75); 3.3498 (0.69); 3.3283 (104.73) ; 3.2962 (0.61); 3.2647 (0.99); 3,2365 (0.56); 2.8903 (8.29); 2.8628 (0.53); 2.8318 (0.94); 2.8049 (0.53); 2.7307 (6.62); 2.6753 (0.50); 2.6709 (0.72); 2.6662 (0.52); 2.5406 (0.38); 2.5384 (0.40); 2.5241 (2.78); 2.5193 (4.33); 2.5107 (39.51); 2.5063 (79.45) ; 2.5018 (104.79) ; 2.4972 (76.32); 2.4928 (37.44); 2.3332 (0.55); 2.3286 (0.74); 2.3241 (0.57); 2.1883 (16.00) ; 2.1884 (0.75); 2.1130 (1.45); 2.0836 (0.83); 1.9888 (10.32); 1.8011 (0.62); 1.7797 (0.58); 1.5861 (0.59); 1.5773 (0.65); 1.5554 (0.62); 1.5467 (0.60); 1.3974 (2.06); 1.1925 (2.75); 1.1747 (5.55); 1.1569 (2.69); 0.0079 (0.70); - 0.0002 (20.09); - 0.0085 ( 0.85); Ex. 32, solvent: DMSO, spectrometer: 399, 95 MHz 8.0176 (3.53); 7.6012 (1.82) ; 7.3438 (0.44); : 7.3239 (1.89); 7.3050 (1.73); 7.1513 (1.01); 7.1313 (0.86); 7.0203 (0.58); 7,0018 (1.01); 6.9830 (0.46); 5.8875 (0.50); 5.8696 (0.59); 5.8598 (0.57); 5.8420 (0.53); 5.6352 (0.42); 5.5923 (0.93); 5.5228 (0.92); 5.7979 (0.41); 4.8815 (2.80); 4.8756 (2.78); 4.3512 (0.34); 4.3165 (0.35); 3.9344 (0.35); 3.9003 (0.52); 3.8724 (0.60); 3.8557 (0.67); 3.8295 (0.57); 3.5881 (0.71); 3.5822 (1.50); 3.5764 (0.68); 3.3790 (0.49); 3.3500 (0.35); 3.3277 (40, 02); 3.2700 (1.02); 3.2523 (0.72); 3.2272 (0.67); 3.2094 (0.60); 2.8910 (2.35); 2.8506 (0.43); 2.7317 (1.82); 2.6713 (0.43); 2.5246 (1.46); 2.5198 (2.36); 2.5112 (24.23); 2.5068 (48.55); 2.5023 (63.46) ; 2.4977 (45.99); 2.4933 (22.44); 2.3289 (0.43);

Petition 870180056486, of 06/29/2018, p. 169/206

162/191

2.0945 (0.63); 2.0639 (0.35); 1.3977 (16.00); -0,0002 (1.78);

Ex. 33, solvent: DMSO, spectrometer: 399.95 MHz

8.3173 (0.68); 8.0139 (16.00); 7.6009 (9.09); 7.3088

(4.66); 7.3047 (4.26); 7.2943 (5.83); 7.2901 (6.33); 7.2765 (3.38); 7.0614 (5.55); 7.0397 (4.29); 6.9733 (3.12); 6.9546 (5.42); 6.9358 (2.50); 6.0796 (0.81); 6.0671 (1.68); 6.0536 (1.40); 6.0405 (1.96); 6.0366 (1.26); 6.0280 (1.17); 6.0238 (2.13); 6.0105 (1.61); 5,9973 (2.06); 5.99849 (1.00); 5.9180 (2.65); 5.9001 (3.04); 5.8902 (3.03); 5.8722 (2.72); 5.6336 (2.15); 5.5908 (4.85); 5.5228 (4.85); 5.7979 (2.17); 5.4387 (3.78); 5.4344 (3.96); 5.4155 (0.38); 5.3954 (3.29); 5.3911 (3.43); 5.3759 (0.33); 5.2445 (3.75); 5.2407 (3.86); 5.2180 (3.49); 5.2142 (3.58); 4.6664 (0.38); 4.6541 (0.44); 4.6318 (5.77); 4.6274 (6.54); 4.6202 (6.39); 4.6156 (5.84); 4.5935 (0.50); 4.5812 (0.41); 4.3499 (1.84); 4.3167 (1.94); 3.9705 (1.72); 3.9352 (1.91); 3.8923 (2.66); 3.8643 (2.99); 3.8494 (3.43); 3.8215 (2.94); 3.4082 (1.20); 3.3989 (0.91); 3,3887 (1.47); 3.3795 (2.48); 3.3704 (1.57); 3.3599 (1.12); 3.3504 (1.69); 3.3269 (87.89); 3.3030 (7.09); 3.2871 (3.80); 3.2691 (5.63); 3.2441 (3.72); 3.2264 (3.21); 2.8786 (1.28); 2.8514 (2.32); 2.8211 (1.31); 2.6757 (0.86); 2.6713 (1.15); 2.6670 (0.87); 2.5414 (0.76); 2.5066 (123.19); 2.5022 (163.13); 2.4979 (124.07); 2.3335 (0.90); 2.3290 (1.20); 2.3248 (0.94); 2.1240 (1.68); 2.0916 (3.54); 2.0619 (1.97); 1.9891 (0.84); 1.8341 (0.60); 1.8240 (0.72); 1.8030 (1.46); 1.7945 (1.59); 1.7721 (1.44); 1.7641 (1.35); 1.7424 (0.61); 1.7329

Petition 870180056486, of 06/29/2018, p. 170/206

163/191

(0 , 47); 1.5797 (0.59); 1.5699 (0.72); 1.5492 (1.44); 1, 5399 (1.58); 1.5186 (1.47); 1.5092 (1.41); 1.4889 (0 , 62); 1.4785 (0.50); 1.3976 (8.31); 1.3512 (0.60); 1, 3361 (1.33); 1.2587 (0.34); 1.2495 (0.99); 1.2251 (1 , 13); 1.1750 (0.46); 0.1460 (0.57); 0 , 0079 (5 , 94); - 0, 0002 (128.33); -0.0083 (6.23); -0.1496 (0.60);

Ex. 34, solvent: CD3CN, spectrometer: 399.95 MHz

7.7083 (6.06); 7.5436 (1.24) ; 7.5244 (2.00); 7.4725 (0.75); 7.4677 (0.83); 7.4555 (1.21); 7.4509 (1.48); 7.4360 (0.76); 7.4314 (1.48); 7.4274 (1.02); 7.4129 (2.75); 7.4081 (1.86); 7.4023 (2.05); 7.3989 (1.79); 7.3852 (1.24); 7.3825 (1.31); 7.3662 (0.41); 7.3628 (0.37); 6.3912 (3.38); 6.0855 (1.21); 6.0633 (1.45); 6.0581 (1.40); 6.0359 (1.26); 5.4747 (5.74); 5.1282 (0.63); 5.0861 (3.18); 5.0549 (3.16); 5.0129 (0.64); 4.5808 (1.36); 4.5455 (2.82); 4.4995 (0.73); 4.4847 (3.37); 4.4639 (0.73); 4.4494 (1.65); 3.9738 (1.43); 3.9462 (2.02); 3.9303 (1.85); 3.9137 (0.75); 3.9028 (1.91); 3.3696 (0.71); 3.3643 (1.81); 3.3508 (0.73); 3.3420 (2.72); 3.3317 (0.72); 3.3208 (1.99); 3,3123 (1.18); 3.2988 (1.58); 3.2815 (0.95); 3.2526 (0.53); 3.2460 (0.49); 2.9728 (0.42); 2.9425 (16.00); 2.8825 (0.46); 2.8759 (0.51); 2.8498 (0.86); 2.8452 (0.88); 2.8188 (0.51); 2.8123 (0.47); 2.2256 (16.31); 2.1817 (12.52) ; 2.1786 (12.84) ; 2.1203 (0.72); 1.9638 (0.83); 1.9575 (0.80); 1.9519 (5.16); 1.9457 (9.51); 1.9396 (13.00) ; 1.9333 (8.89); 1.9272 (4.50); 1.8732 (0.60); 1.8635 (0.62); 1.8421 (0.57); 1.8324 (0.55); 1.7053 (0.63); 1,6953 (0.64); 1.6740 (0.59); 1 , 6643 (0 , 56); - 0.0002 (3.21);

Petition 870180056486, of 06/29/2018, p. 171/206

164/191

Ex. 35, solvent: CD3CN, spectrometer: 399.95 MHz

7.7009 (3.52); 7.6949 (4.85); 7.5121 (1.27); 7,5082 (1 , 60); 7.4918 (2.04); 7.4223 (0.34); 7.4175 (0.72); 7, 4104 (0.57); 7.4006 (1.27); 7.3950 (1.13); 7.3861 (1 , 41); 7.3812 (1.44); 7.3763 (1.15); 7.3677 (2.28); 7, 3640 (2.54); 7.3617 (1.79); 7.3585 (2.13); 7.3522 (2 , 26); 7.3487 (2.27); 7.3418 (1.45); 7.3377 (1.01); 7, 3235 (0.47); 6.3904 (4.15); 6.0731 (0.94); 6.0512 (1 , 11); 6.0456 (1.19); 6.0237 (1.08); 6.0196 (0.87); 6, 0142 (0.75); 5,9917 (0.66); 5.4467 (3.81); 5.1259 (0 , 73); 5.0839 (3.90); 5.0530 (3.81); 5.0317 (0.67); 5, 0109 (0.74); 4.4964 (0.77); 4.4626 (0.80); 4.2284 (1 , 10); 4.1947 (1.44); 4.1428 (0.66); 4.1094 (3.41); 4, 0957 (3.50); 4.0623 (0.68); 3.9871 (1.62); 3.9533 (1 , 80); 3.9362 (1.72); 3.9104 (1.93); 3.9087 (2.05); 3, 8950 (1.38); 3.8929 (1.62); 3.8654 (1.49); 3.3778 (0 , 36); 3.3664 (1.37); 3.356 (1.62); 3.3489 (0.89); 3, 3437 (1.36); 3.3395 (1.57); 3.3337 (1.73); 3.3228 (1 , 26); 3.3121 (2.35); 3,3008 (1.28); 3.2903 (1.64); 3, 2817 (1.12); 3.2527 (0.60); 3.2462 (0.56); 2.8823 (0 , 50); 2.8759 (0.55); 2.8456 (0.98); 2.8188 (0.56); 2, 8124 (0.52); 2.5676 (16.00); 2.5203 (10.63); 2.2257 (18.95) ; 2.2113 (1.50); 2.2100 (1.47); 2.1508 (8.92); 2, 1450 (7.66); 2,1193 (0.89); 2.1068 (0.44); 1.9635 (1 , 26); 1.9573 (1.46); 1.9516 (10.81); 1.9454 20.09); 1, 9392 (27, 69); 1.9330 (18.99) ; 1.92 68 (9.78); 1.9026 (0 , 38); 1.8925 (0.39); 1.8717 (0.71); 1.8624 (0.72); 1, 8409 (0.66); 1.8313 (0.65); 1.7249 (0.36); 1.7047 (0 , 71); 1.6945 (0.74); 1.6736 (0.67); 1 6638 (0 , 65); -

0.0002 (6.43);

Petition 870180056486, of 06/29/2018, p. 172/206

165/191

Ex. 36, solvent: CD3CN, spectrometer: 399.95 MHz

7, 6978 (9, 56); 7, 6946 (9, 81) ; 7,5034 (2.47); : 7.4953 (1.98); 7.4871 (3.22); 7.4786 (2.25); 7.4120 (1.37); 7.4058 (1.29); 7.4041 (1.31); 7.3961 (2.49); 7.3894 (3.75); 7.3832 (1.79); 7.3780 (2.98); 7.3709 (3.94); 7.3642 (5.25); 7.3592 (7.40); 7.3502 (4.68); 7.3463 (4.48); 7.3432 (4.31); 7.3389 (3.50); 7.3255 (0.77); 7.3199 (0.36); 6.3904 (9.09); 6.0559 (2.04); 6.0490 (1.54); 6.0337 (2.46); 6.0279 (3.38); 6.0213 (1.74); 6,0064 (2.11); 5,9989 (1.53); 5.4646 (6.12); 5.1259 (1.72); 5.0837 (8.68); 5.0527 (8.53); 5.0108 (1.70); 4.4966 (1.86); 4.4630 (1.92); 4.1672 (2.48); 4.1336 (3.50); 4.0704 (16.00); 3.9820 (3.65); 3.9483 (4.37); 3.9368 (3.21); 3.9335 (3.07); 3.9090 (4.03); 3.9059 (3.83); 3.8938 (2.76); 3.8900 (2.90); 3.8659 (2.47); 3.8624 (2.68); 3.3719 (4.90); 3.3580 (1.20); 3.3497 (5.82); 3.3392 (3.46); 3.3289 (5.33); 3.3192 (2.12); 3.3068 (4.84); 3.2814 (2.60); 3.2524 (1.42); 3.2458 (1.31); 2.8770 (1.70); 2.8581 (2.13); 2.8442 (3.34); 2.8396 (3.03); 2.8252 (3.07); 2.8203 (2.47); 2.8172 (2.63); 2.8064 (3.31); 2.8032 (2.20); 2.7871 (1.40); 2.7842 (1.81); 2.7653 (0.57); 2.7494 (0.72); 2.7307 (2.29); 2.7121 (2.41); 2.6978 (1.98); 2.6937 (0.98); 2.6795 (2.88); 2.6611 (2.11); 2.6468 (1.21); 2.6427 (0.66); 2.6283 (1.11); 2.6097 (0.36); 2.2254 (41.56); 2.2087 (1.66); 2.2029 (1.75); 2.1611 (2.89); 2.1390 (18.09) ; 2.1203 (2.04); 1.9630 (1.87); 1.9511 (16.20); 1.9450 (29.63); 1.9388 (40.14); 1.9327 (27.43); 1.9265 (14.03) ; 1.9023 (0.82); 1.8919 (0.82); 1.8718 (1.68); 1.8617 (1.74); 1.8404 (1.58); 1.8309 (1.54); 1.8101

Petition 870180056486, of 06/29/2018, p. 173/206

166/191

(0.64); 1.7999 (0.57); 1.7351 (0.72); 1.7243 (0.80); 1.7045 (1.69); 1.6944 (1.75); 1.6737 (1.59); 1.6637 (1.55); 1.6429 (0.64); 1.6325 (0.58); 1.3112 (7.82); 1.2978 (7.09); 1.2924 (15.87); 1.2792 (12.26); 1.2737 (8.02); 1.2605 (5.50); 0.0078 (0 , 36); -0 , 0002 (8 , 65); - 0.0086 (0.33); Ex. 37, solvent: DMSO, spectrometer: 399, 95 MHz 8.0640 (0.47); 7.9724 (5.06) ; 7.9511 (0.92); 7.3757 (0.61); 7.3547 (1.09); 7.3396 (1.18); 7.3184 (0.67); 7.0292 (1.63); 7.0201 (0.65); 7,0080 (1.47); 7,0004 (1.26); 6.8829 (1.40); 6.8633 (2.63); 6.8505 (0.94); 6.8289 (0.81); 6.7465 (0.55); 6.7262 (1.23); 6.3413 (1.14); 6.3002 (3.02); 5.3924 (0.49); 5.2614 (0.62); 5.2194 (1.88); 5.1719 (1.92); 5.1299 (0.63); 5.1053 (3.31); 4.9229 (3.83); 4.9172 (3.95); 4.3945 (0.59); 4.3594 (0.64); 4.2667 (0.94); 4.2556 (1.08); 4.2437 (1.05); 4.0560 (0.58); 4.0383 (1.66); 4.0204 (2.05); 4.0029 (0.99); 3.9777 (0.72); 3.7070 (1.48); 3.7025 (1.60); 3.6939 (2.25); 3.6801 (3.32); 3.6706 (2.57); 3.6521 (5.30); 3.5928 (2.49); 3.5858 (2.97); 3.3779 (5389, 76); 2.8920 (7, 63 ); 2.8662 (0.93); 2.8312 (1.23); 2.8031 (0.88); 2.7325 (6.18); 2.6785 (3.59); 2.6739 (4.83); 2,6694 (3.59); 2.5409 (3.16); 2.5272 (16.53); 2.5224 (24.16); 2.5137 (251.32); 2.5094 502.31); 2.5049 (656.43 ); 2.5003 (472.57 ); 2.4960 (230.06) ; 2.3692 (1.31); 2.3360 (3.51); 2.3315 (4.73); 2.3269 (3.82); 2.2414 (5.87); 2.2071 (0.91); 2,1905 (12.67); 2.1730 (1.01); 2.1055 (1.36); 2.0721 (16.00); 1.9889 (6.86); 1.9101 (1.98); 1.7874 (0.66); 1.7687 (0.63); 1.6120 (1.12); 1.5918 (6.80); 1.5472 (0.60); 1.4104 (0.83); 1.2356

Petition 870180056486, of 06/29/2018, p. 174/206

167/191 (0.72); 1.1928 (1.94); 1.1750 (3.75); 1.1572 (1.90); 0.0002 (2.02);

Ex. 38, solvent: DMSO, spectrometer: 399.95 MHz

8.0193 (3.81); 7.9536 (9.31); 7.9287 (0.71); 7.4111 (1.90); 7.3903 (3.70); 7.3699 (2.77); 7.1618 (3.41); 7.1554 (4.01); 7.1404 (2.83); 7.1355 (3.52); 7.0500 (2.52); 7.0308 (3.07); 6.9990 (3.46); 6.8590 (1.95); 6.8395 (1.66); 6.2332 (1.49); 6.2085 (1.94); 6.2024 (1.88); 6.1777 (1.58); 5.7531 (5.37); 4.8383 (0.39); 4.8325 (0.42); 4.7981 (3.37); 4.7912 (5.19); 4.7841 (3.81); 4.7499 (0.40); 4.7439 (0.43); 4.1809 (1.91); 4.1469 (2.02); 4.0379 (0.72); 4.0201 (0.75); 3.7672 (1.17); 3.7363 (1.43); 3.7251 (2.07); 3.6943 (1.70); 3.5841 (1.95); 3.5593 (1.99); 3.5420 (1.43); 3.5173 (1.40); 3.5040 (0.41); 3.4453 (2.54); 3.4396 (4.79); 3.4338 (2.75); 3.3583 ( 517.73); 3.3548 ( 636.88); 3.3514 (650.80) ; 3.3476 (856.85); 3.1850 (0.58); 3.1755 (0.57); 3.1584 (0.59); 3.1523 (0.69); 3.0153 (1.49); 2.9857 (2.67); 2.9568 (1.50); 2.9081 (0.89); 2.6766 (1.32); 2.6721 (1.80); 2.6676 (1.36); 2.5393 (1.01); 2.5254 (5.57); 2.5206 (8.48); 2.5119 (93.76); 2 , 5075 (189, 89); 2.5030 (252.19) ; 2.48984 (187.91); 2.4941 (94.93); 2.3343 (1.28); 2.3297 (1.75); 2.3252 (1.31); 2.2726 (0.33); 2.2336 (15.38); 2,1124 (16.00); 2.0727 (3.08); 1.9886 (3.35); 1.7027 (0.68); 1.6747 (1.49); 1.6473 (1.35); 1.6187 (0.51); 1.2360 (0.51); 1.1925 (0.89); 1.1747 (1.77); 1.1569 (0.86); - 0.0002 (4 , 40);

Ex. 39, solvent: DMSO, spectrometer: 399.95 MHz

8.1588 (3.15); 7.9410 (9.29); 7.3715 (1.93); 7.3509 (4.10); 7.3300 (4.13); 7.3227 (3.11); 7.2026 (2.15);

Petition 870180056486, of 06/29/2018, p. 175/206

168/191

7.1817 (3.00); 7.1038 (2.36); 7.1016 (3.27); 7.0883 (2.72); 7.0832 (6.50); 7.0681 (1.94); 7.0626 (3.65); 6.2591 (1.36); 6.2356 (1.73); 6.2282 (1.60); 6.2046 (1.40); 5.8317 (0.37); 5.8181 (0.77); 5.8051 (0.72); 5.7917 (0.90); 5.7888 (0.58); 5.7782 (0.52); 5.7748 (0.98); 5.7617 (0.88); 5.7533 (7.80); 5.7488 (1.23); 5.7350 (0.48); 5.2725 (0.61); 5.2686 (1.79); 5.2645 (1.88); 5.2607 (0.73); 5.2291 (0.52); 5.2253 (1.53); 5.2212 (1.58); 5.2173 (0.60); 5.0153 (1.67); 5.0116 (1.68); 4.9889 (1.55); 4.9852 (1.59); 4.5819 (0.45); 4.5687 (0.48); 4.5502 (1.39); 4.5369 (1.39); 4.5231 (1.42); 4.5090 (1.36); 4.4913 (0.49); 4.4809 (0.36); 4.4771 (0.45); 4.1741 (1.49); 4.1408 (1.58); 4.0559 (0.39); 4.0381 (1.22); 4.0202 (1.23); 4.0025 (0.42); 3.7617 (1.06); 3.7306 (1.30); 3.7197 (1.87); 3,6887 (1.52); 3.5785 (1.71); 3.5549 (1.74); 3.5365 (1.20); 3.5130 (1.25); 3 3616 206.47); 3.3582 (217.30); 3.352 (181.25) ; 3.3479 (336.94); 3.0516 (1.16) ; 3.0221 (2.01); 2.9935 (1.15); 2.9264 (0.94); 2.6768 (0.56); 2.6722 (0.78); 2.6677 (0.55); 2.5257 (2.16); 2.5210 (3.11); 2.5123 (41.85); 2.5078 (87.47); 2.5032 (117.61); 2.4986 (86.11); • 2.4940 (42.20) ; 2.3344 (0.60); 2.3299 (0.82); 2.3253 (0.61); 2.1553 (16.00); 2.1044 (1.29); 2.0730 (1.96); 1.9887 (5.62); 1.7272 (0.42); 1.7174 (0.54); 1.6955 (1.13); 1.6874 (1.27); 1.6656 (1.19); 1.6575 (1.10); 1.6361 (0.48); 1.6262 (0.40); 1.2350 (0.36); 1.1926 (1.55); 1.1748 (3.07); 1.1570 (1.50); -0,0002 (2.02); Ex. 40, solvent: DMSO, spectrometer: 399, 95 MHz

8.0340 (9.26); 7.4541 (1.53); 7.4344 (3.45); 7.4147

Petition 870180056486, of 06/29/2018, p. 176/206

169/191

(2.25); 7.2915 (1.97); 7.2722 (1.59); 7.1628 (1.73); 7.1577 (2.93); 7.1533 (2.10); 7.1184 (1.43); 7.1162 (1.62); 7.1127 (1.30); 7.1104 (1.26); 7.0983 (1.34); 7.0961 (1.38); 7.0927 (1.25); 7.0903 (1.15); 6.4980 (4.43); 5.7802 (1.13); 5.7604 (1.37); 5.7531 (1.33); 5.7332 (1.17); 5.3497 (0.88); 5.3073 (2.72); 5.2577 (2.67); 5.2151 (0.88); 5.1965 (0.85); 4.3847 (0.72); 4.3507 (0.77); 4.0557 (0.72); 4.0379 (2.19); 4.0201 (2.25); 4.0023 (0.93); 3.9883 (0.68); 3.9532 (0.75); 3.9232 (1.23); 3.8957 (1.41); 3,8800 (1.64); 3.8527 (1.33); 3.4089 (1.99); 3.3998 (0.57); 3.3890 (2.04); 3.3807 (1.25); 3.3707 (0.96); 3.3655 (1.83); 3.3456 (3.26); 3.3292 (241.15); 3.3261 (302.53) ; 3.2659 (1.26); 3.2371 (0.70); 3.0429 (1.96); 2.8659 (0.52); 2.8546 (1.70); 2.8352 (0.92); 2.8076 (0.53); 2.6753 (0.51); 2.6707 (0.71); 2.6662 (0.53); 2.5409 (0.35); 2.5241 (1.21); 2.5192 (1.89); 2.5106 (36, 46); 2.5061 (78.71); 2.5015 (111.02) ; 2.4969 (83.92) ; 2.4925 (41.55), : 2.3329 (0.55); 2.3283 (0.77); 2.3238 (0.58); 2.2070 (16.00); 2.1924 (1.81); 2.1325 (0.67); 2,1004 (1.39); 2.0735 (1.03); 1.9885 (9.76); 1.9183 (0.43); 1.9063 (0.85); 1.8989 (0.95); 1.8956 (0.73); 1.8870 (1.65); 1.8813 (0.75); 1.8750 (0.97); 1.8676 (1.00); 1.8557 (0.74); 1.8447 (0.33); 1.8248 (0.61); 1.8157 (0.64); 1.7930 (0.58); 1.7849 (0.55); 1.5824 (0.56); 1.5734 (0.62); 1.5523 (0.58); 1.5439 (0.58); 1.3976 (0.58); 1.2355 (0.40); 1.1923 (2.67); 1.1745 (5.40); 1.1567 (2.63); 1.0807 (0.55); 1.0670 (1.78); 1.0595 (3.41); 1.0558 (1.68); 1.0530 (1.79); 1.0470 (1.69); 1.0392 (3.51); 1.0334 (2.18); 1.0311 (2.14); 1.0249 (3.40); 1.0179

Petition 870180056486, of 06/29/2018, p. 177/206

170/191 (3.09); 1.0139 (3.90); 1.0060 (1.80); 0.9919 (0.44);

0.0080 (1.09); -0,0002 (35.44); -0.0085 (1.38);

Ex. 41, solvent: DMSO, spectrometer: 399.95 MHz

8.0259 (9.47); 7.3231 (1.61); 7.3190 (0.50); 7.3027 (3 , 67); 7.2952 (0.37); 7.2825 (2.20); 6.9632 (4.18); 6, 9580 (3.28); 6.9534 (2.20); 6.9445 (1.95); 6.9304 (1 , 59); 6.9278 (1.49); 6.9245 (1.19); 6.9221 (1.11); 6, 9097 (1.41); 6,9079 (1.39); 6.9036 (1.22); 6.4980 (4 , 40); 6.0822 (0.43); 6.0692 (0.96); 6.0560 (0.94); 6, 0428 (1.11); 6.0390 (0.59); 6.0298 (0.60); 6.0259 (1 , 19); 6.0128 (1.05); 5.9996 (1.20); 5.99866 (0.57); 5, 7179 (1.17); 5.6978 (1.40); 5.6911 (1.37); 5.6706 (1 , 21); 5.4168 (0.67); 5.4126 (1.94); 5.4082 (2.03); 5, 4039 (0.75); 5.3737 (0.62); 5.3694 (1.73); 5.3650 (1 , 80); 5.3607 (0.77); 5.3504 (0.89); 5.3076 (2.74); 5, 2632 (2.49); 5.2590 (4.21); 5.2407 (0.78); 5.2370 (1 , 73); 5.2328 (1.74); 5.2294 (0.81); 5.2153 (0.92); 5, 1968 (0.86); 4.5810 (2.25); 4.5772 (4.03); 4.5735 (2 , 51); 4.5680 (2.46); 4.5642 (4.01); 4.5606 (2.36); 4, 3853 (0.73); 4.3525 (0.77); 4.0377 (0.73); 4.0200 (0 , 78); 4.0021 (0.45); 3.9890 (0.69); 3.9532 (0.73); 3, 8941 (1.27); 3.8670 (1.46); 3.8512 (1.69); 3.8239 (1 , 42); 3.4095 (0.54); 3.3929 (1.96); 3.3809 (1.27); 3, 3725 (2.16); 3.3619 (0.42); 3.3500 (2.09); 3.3262 (194.10) ; 3.3243 (226, 61) ; 3.3220 (303.73) ; 3.2983 (3.23); 3, 2653 (1.26); 3.2367 (0.64); 3.2314 (0.57); 3.0428 (2 , 05); 2.8659 (0.53); 2.8544 (1.75); 2.8381 (0.92); 2, 8086 (0.52); 2.6792 (0.39); 2.6748 (0.88); 2.6702 (1 , 21); 2.6657 (0.89); 2.6612 (0.41); 2.5406 (0.42); 2, 5237 (2.26); 2.5188 (3.67); 2.5102 (61.32); 2.5057

Petition 870180056486, of 06/29/2018, p. 178/206

171/191

(131.73); 2.5011 (185.44); 2.4966 (139.12); 2.4921 (67.67); 2.3326 (0.93), : 2.3280 (1.24); 2.3234 (0.94); 2.3188 (0.50); 2.2068 (16.00); 2.1923 (1.83); 2.1313 (0.66); 2.1023 (1.37); 2.0736 (1.16); 1.9884 (3.47); 1.8230 (0.57); 1.8150 (0.63); 1.7916 (0.57); 1.7835 (0.54); 1.5831 (0.57); 1.5736 (0.63); 1.5521 (0.59); 1.5421 (0.57); 1.3976 (0.32); 1.2583 (0.39); 1.2493 (0.59); 1.2354 (0.71); 1.1922 (0.94); 1.1744 (1.90); 1.1566 (0.93); 0.0080 (2.08); - 0.0002 (68.81); -0.0085 (2.53); Ex. 42, solvent: DMSO, spectrometer: 601, 6 MHz 8.0198 (3.29); 7.9396 (10.59) ; 7.3640 (2.27) ; 7.3503 (4.58); 7.3366 (2.94); 7,1002 (2.64); 7.0987 (3.30); 7.0868 (2.70); 7.0852 (2.96); 7.0813 (2.45); 7.0671 (2.24); 7.0451 (2.24); 7.0324 (2.55); 6,9980 (2.70); 6.8566 (1.49); 6.8547 (1.50); 6.8439 (1.31); 6.8421 (1.31); 6.2494 (1.52); 6.2337 (1.82); 6.2287 (1.73); 6.2131 (1.56); 5.8156 (0.47); 5.8065 (0.92); 5.7978 (0.85); 5.7890 (1.03); 5.7869 (0.64); 5.7799 (0.59); 5.7777 (1.10); 5.7690 (0.94); 5.7602 (1.06); 5.7555 (1.13); 5.7512 (0.57); 5.2645 (0.67); 5.2618 (2.03); 5.2591 (2.05); 5.2564 (0.74); 5.2357 (0.62); 5.2331 (1.79); 5.2303 (1.85); 5.2277 (0.64); 5.0126 (0.70); 5.0104 (1.86); 5.0079 (1.83); 5.0057 (0.74); 4.9951 (0.68); 4.9929 (1.76); 4.9904 (1.76); 4.9882 (0.71); 4.5755 (0.35); 4.5732 (0.62); 4.5708 (0.38); 4.5667 (0.38); 4.5644 (0.63); 4.5621 (0.37); 4.5544 (0.78); 4.5521 (1.36); 4.5497 (0.85); 4.5456 (0.80); 4.5433 (1.33); 4.5410 (0.78); 4.5214 (0.78); 4.5192 (1.35); 4.5170 (0.83); 4.5120 (0.80); 4.5098 (1.34); 4.5077

Petition 870180056486, of 06/29/2018, p. 179/206

172/191

(0.79); 4,5004 (0.38); 4.4981 (0.66); 4.4958 (0.40); 4.4910 (0.37); 4.4887 (0.63); 4.4865 (0.37); 4.1690 (1.42); 4.1468 (1.48); 4.0466 (1.14); 4.0348 (3.48); 4.0229 (3.47); 4.0111 (1.16); 3.7493 (1.28); 3.7286 (1.61); 3.7214 (1.98); 3.7008 (1.62); 3.5691 (1.84); 3.5535 (1.86); 3.5413 (1.45); 3.5257 (1.45); 3.3579 (0.37); 3.3517 (0.85); 3.3481 (0.61); 3.3454 (0.84); 3.3251 (591.42); 3.3079 (1.11); 3.3012 (4.55); 3.0160 (0.87); 3.0123 (1.06); 2.9927 (1.95); 2.9738 (1.08); 2.9701 (0.92); 2.6190 (0.40); 2.6160 (0.88); 2.6130 (1.25); 2.6099 (0.90); 2.6069 (0.41); 2.5405 (0.37); 2.5223 (3.07); 2.5192 (3.82); 2.5161 (3.46); 2.5074 (64.00); 2.5043 (141, 18); 2, 5012 (196.75); 2.4981 (141.80) ; 2.4951 (65.39) ; 2.3915 (0.37); 2.3885 (0.85); 2.3854 (1.21); 2.3823 (0.86); 2.3793 (0.38); 2.2327 (12.96); 2.1103 (13.21); 2.0890 (1.16); 2.0837 (1.23); 2.0734 (1.26); 2.0670 (1.33); 1.9884 (16.00); 1.6966 (0.39); 1.6905 (0.47); 1.6763 (1.08); 1.6704 (1.18); 1.6561 (1.12); 1.6504 (1.09); 1.6365 (0.44); 1.6299 (0.37); 1.3976 (0.40); 1.1862 (4.45); 1.1744 (9.23); 1.1626 (4.25); 0 , 0053 ( 0.64); - 0.0002 (24.12); -0.0057 (0.68); Ex. 43, solvent: CD3CN, spectrometer: 399, 95 MHz 7.7017 (16.00); 7.5291 (2.62) ; 7.5095 (4.66); 7.4599 (1.87); 7.4556 (2.02); 7.4419 (3.09); 7.4379 (4.17); 7.4302 (2.69); 7.4189 (4.14); 7.4148 (6.16); 7.3934 (4.06); 7.3899 (3.96); 7.3753 (3.19); 7.3569 (1.29); 7.3536 (1.16); 6.4212 (7.95); 6.0279 (2.81); 6.0066 (3.23); 6,0002 (3.19); 5.9789 (2.93); 5.1548 (1.55); 5.1129 (7.73); 5.0841 (7.77); 5.0630 (0.76); 5.0419

Petition 870180056486, of 06/29/2018, p. 180/206

173/191

(1.47); 4.8696 (4.32); 4.8408 (6.69); 4.7412 (7.05); 4.7123 (4.54); 4.5215 (1.52); 4.4876 (1.67); 4.1447 (1.76); 4.0968 (5.36); 4.0790 (5.57); 4.0678 (1.89); 4.0612 (2.11); 4.0560 (2.15); 4.0534 (1.43); 4.0451 (5.27); 4.0334 (5.47); 4.0225 (5.45); 4.0107 (5.47); 4.0023 (1.59); 3.9998 (2.14); 3.9880 (2.51); 3.9798 (2.25); 3.9570 (0.81); 3.9327 (4.54); 3.9049 (3.73); 3.8896 (4.22); 3.8619 (4.00); 3.4070 (0.67); 3.3974 (1.35); 3.3878 (0.87); 3,3783 (1.53); 3.3687 (2.87); 3.3591 (1.67); 3.3494 (2.09); 3.3407 (2.44); 3.3303 (1.21); 3.3227 (4.99); 3.3136 (2.36); 3.3017 (4.58); 3,2797 (4.61); 3.2586 (3.78); 2.9157 (1.05); 2.9093 (1.15); 2.8782 (2.03); 2.8520 (1.17); 2.8454 (1.08); 2.4976 (0.34); 2 , 2545 (40.20); 2.2208 (828.11); • 2.2177 (745.43 ); 2.1997 (2.66) ; 2.1436 (2.69); 2.1474 (2.27); 2.1312 (1.52); 2.1250 (0.99); 2.0912 (0.59); 2.0015 (24.43) ; 1.9943 (7.48); 1.9880 (7.97); 1.9823 (68, 62); 1.9762 (130.30); 1.9700 (182.81); 1.9638 (126, 48) ; 1.9576 (65.15) ; 1.9303 (1.19); : 1.9197 (1.10); 1.8997 (1.68); 1.8900 (1.75); 1.8680 (1.55); 1.8584 (1.52); 1.8382 (0.87); 1.8278 (0.69); 1.8108 (0.60); 1.8046 (0.94); 1.7984 (1.25); 1.7922 (0.94); 1.7861 (0.56); 1.7660 (0.75); 1.7553 (0.82); 1.7355 (1.55); 1.7253 (1.60); 1.7042 (1.49); 1.6942 (1.45); 1.6744 (0.70); 1.6635 (0.66); 1.4653 (1.05); 1.3891 (0.33); 1.2986 (1.87); 1.2504 (6.62); 1, 2326 (12.99); 1, 2147 (6, 49);

Ex. 44, solvent: CD3CN, spectrometer: 399.95 MHz

7.6732 (4.41); 7.4745 (0.94); 7.4565 (1.13); 7.4523 (1.04); 7.3852 (0.53); 7.3812 (0.64); 7.3687 (1.08);

7.3640 (1.38); 7.3565 (1.61); 7.3526 (1.54); 7.3477

Petition 870180056486, of 06/29/2018, p. 181/206

174/191

(1.18); 7.3262 (1.14); 7.3226 (1.11); 7.3066 (0.84); 6.3930 (2.25); 6,0032 (0.78); 5.99814 (0.93); 5.9756 (0.90); 5.9538 (0.80); 5.1262 (0.46); 5.0841 (2.18); 5.0558 (2.16); 5.0139 (0.41); 4.6676 (1.34); 4.6387 (2.06); 4.5397 (2.16); 4.5108 (1.47); 4.4929 (0.48); 4.4592 (0.51); 4.0683 (0.55); 4.0504 (0.54); 3.9493 (1.39); 3.9217 (1.31); 3.9062 (1.51); 3.8785 (1.11); 3.6257 (0.85); 3.6130 (1.73); 3.6025 (3.17); 3.5924 (1.34); 3.5316 (2.71); 3.5217 (2.79); 3.5177 (1.62); 3.5106 (1.21); 3.5076 (1.14); 3.3701 (0.38); 3.3510 (0.45); 3.3413 (0.82); 3.3317 (0.51); 3.3194 (0.56); 3.3126 (0.88); 3.2965 (16.00); 3.2833 (1.32); 3.2790 (1.78); 3.2675 (0.34); 3.2573 (1.34); 3.2482 (0.40); 3.2357 (1.04); 3.2141 (1.01); 2.8782 (0.34); 2.8476 (0.60); 2.8214 (0.34); 2.8155 (0.32); 2.4691 (0.44); 2.2258 12.47); 2.2245 (12.61); 2.2048 (274.24); : 2,1995 (217.79) ; 2.1214 (0.81) ; 2,1153 (0.79); 2.1091 (0.70); 2.1029 (0.44); 1.9729 (2.73); 1.9659 (2.55); 1.9540 (26, 83); 1.9478 (51.05); 1.9417 (70.86); 1.9355 (49.44); 1.9293 (25.39); 1.9048 (0.46); 1.8942 (0.37); 1.8736 (0.51); 1.8642 (0.53); 1.8424 (0.46); 1.8331 (0.47); 1.7763 (0.36); 1.7701 (0.48); 1.7639 (0.36); 1.7087 (0.45); 1.6988 (0.48); 1.6775 (0.44); 1.6675 (0.44); 1.2699 (0.61); 1.2218 (0.68); 1.2040 (1.33); 1.1862 (0.67); -0,0002 (0.39); Ex. 45, solvent: DMSO, spectrometer: 399, 95 MHz 8.0061 (9.48 ); 7.9826 (0.77) ; 7.6598 (0.38); : 7.3440 (1.15); 7.3246 (5.02); 7.3058 (4.59); 7.1517 (2.63); 7.1318 (2.19); 7.0473 (2.59); 7.0283 (2.99); 7.0207 (2.26); 7,0000 (4.37); 6.9832 (1.47); 6.8561 (1.85);

Petition 870180056486, of 06/29/2018, p. 182/206

175/191

6, 8393 (1.79); 5.8864 (1.24); 5.8686 (1.50); 5.8588 (1 , 54); 5.8407 (1.30); 5.7552 (11.14); 4.8813 (6.84); 4, 8756 (7.31); 4.1688 (1.86); 4.1351 (1.96); 4.0375 (0 , 44); 4.0198 (0.43); 3.9005 (1.28); 3.8727 (1.45); 3, 8576 (1.70); 3.8298 (1.38); 3.5843 (1.93); 3.5785 (3 , 88); 3.5727 (1.85); 3 , 3549 (49.56); 3 , 3360 (230.21); 3, 3284 (217.08) ; 3.3256 (287.42) ; 3.2867 (2.54);  3.2724 (2 , 74); 3.2544 (2.19); 3.2403 (0.76); 3.2293 (1.76); 3, 2115 (1.70); 3.1978 (0.45); 3.1549 (0.35); 3.1491 (0 , 47); 2.9978 (1.36); 2.9676 (2.48); 2.9391 (1.36); 2, 9078 (7.08); 2.6750 (0.71); 2.6706 (0.96); 2.6662 (0 , 71); 2.5408 (0.63); 2, 5060 (108.78); 2 , 5015 (142.02); 2, 4971 (107.62) ; 2.3326 (0.81); 2.3282 (1.05); 2.3239 (0 , 84); 2.2620 (0.49); 2.2319 (14.26); 2.1266 (0.83); 2, 1063 (16.00); 2.0734 (2.22); 2.0429 (2.16); 1.9884 (1 , 83); 1.6864 (0.67); 1.6787 (0.78); 1.6565 (1.51); 1, 6485 (1.61); 1.6261 (1.49); 1.6187 (1.39); 1.5966 (0 , 58); 1.5873 (0.47); 1.2581 (0.37); 1.2346 (1.05); 1, 1923 (0.52); 1.1745 (0.99); 1.1567 (0.51); 0.0079 (1 , 58); -0,0002 (26.90); -0.0083 (1.28); Ex. 46, solvent: DMSO, spectrometer: 399, 95 MHz 8.0114 (3.98); 8.0029 (11.23) ; 7.3168 (0.64), ; 7.3102 (2 , 52); 7.3057 (2.06); 7.2948 (3.13); 7.2911 (3.67); 7, 2869 (2.38); 7.2770 (1.89); 7.2727 (1.12); 7.0621 (2 , 97); 7.0470 (3.07); 7.0424 (2.86); 7.0400 (2.62); 7, 0278 (3.25); 6,9937 (3.44); 6.9741 (1.81); 6.9554 (2 , 92); 6.9385 (1.31); 6.9367 (1.32); 6.8563 (1.94); 6, 8404 (1.62); 6.8372 (1.60); 6.0807 (0.50); 6.0682 (1 , 08); 6, 0546 (0.80); 6.0417 (1.23); 6.0374 (0.69); 6, 0293 (0.63); 6.0249 (1.34); 6.0114 (0.91); 5,9984

Petition 870180056486, of 06/29/2018, p. 183/206

176/191

(1 , 32); 5.99860 (0.64); 5.9166 (1.45); 5.8987 (1.67); 5, 8889 (1.66); 5.8708 (1.52); 5.4429 (0.74); 5.4386 (2 , 25); 5.4343 (2.36); 5,4300 (0.91); 5.3996 (0.64); 5, 3953 (1.95); 5.3910 (2.07); 5.3867 (0.80); 5.2483 (0 , 83); 5.2445 (2.18); 5.2405 (2.21); 5.2369 (0.89); 5, 2218 (0.75); 5.2180 (2.01); 5.2140 (2.08); 5.2104 (0 , 84); 4.6375 (1.28); 4.6331 (2, 95); 4.6284 (3.27); 4, 6249 (2.68); 4.6210 (3.20); 4.6161 (3.05); 4.1680 (1 , 90); 4.1345 (1.99); 4.0556 (1.04); 4.0378 (3.12); 4, 0200 (3.15); 4.0022 (1.05); 3.8925 (1.59); 3.8645 (1 , 82); 3.8497 (2.08); 3.8218 (1.73); 3.3907 (0.37); 3, 3748 (0.51); 3.3267 (710.58) ; 3.2892 (3.58); 3,2791 (1 , 56); 3.2711 (2.91); 3.2574 (0.53); 3.2464 (2.07); 3, 2284 (2.00); 3,0001 (1.35); 2.9703 (2.48); 2.9418 (1 , 39); 2.6795 (0.44); 2.6752 (0.98); 2.6706 (1.42); 2, 6660 (1.05); 2.6614 (0.52); 2.5408 (0.73); 2.5240 (2 , 28); 2.5193 (3.48); 2.5105 ( 71.10); 2 , 5060 (152.70); 2, 5014 (209, 79) ; 2.4969 (155, 79) ; 2.4924 (77.49); 2.3373 (0 , 50); 2.3328 (1.07); 2.3282 (1.49); 2.3237 (1.12); 2, 3191 (0.57); 2.2321 (15.82); 2.1056 (16.00); 2.0735 (3 , 20); 2.0413 (1.86); 1.9885 (13.82); 1.6890 (0.55); 1, 6799 (0.66); 1,6586 (1.41); 1.6501 (1.59); 1.6278 (1 , 45); 1.6193 (1.40); 1.5978 (0.57); 1.5879 (0.48); 1, 3976 (1.15); 1.2978 (0.39); 1.2583 (0.59); 1.2348 (1 , 38); 1.1923 (3.77); 1.1745 (7.51); 1, 1567 (3 , 71); - 0, 0002 (6.96);

Ex. 47, solvent: DMSO, spectrometer: 399.95 MHz

8.7845 (0.35); 8.0356 (1.18); 8.0319 (7.37); 8.0173 (0.49); 7.5869 (0.42); 7.4420 (0.59); 7.4347 (3.88);

7.4182 (1.40); 7.4133 (4.68); 7.3994 (0.34); 7.3507

Petition 870180056486, of 06/29/2018, p. 184/206

177/191

(0.44); 7.1707 (0.68); 7.1642 (5.09); 7.1593 (1.82); 7.1477 (1.45); 7.1427 (4.51); 7.1361 (0.67); 6.4984 (4.27); 5.7729 (1.07); 5.7530 (1.32); 5.7460 (1.23); 5.7256 (1.00); 5.3488 (0.82); 5.3061 (2.51); 5.2560 (2.62); 5.2135 (0.86); 4.3851 (0.72); 4.3514 (0.78); 4.0558 (0.62); 4.0380 (1.84); 4.0202 (1.89); 4.0024 (0.80); 3.9879 (0.71); 3.9524 (0.75); 3.9109 (1.03); 3.8837 (1.26); 3.8679 (1.39); 3.8406 (1.14); 3.4604 (0.37); 3,4400 (0.63); 3.4132 (2.35); 3.3927 (3.49); 3.3525 (353.69) ; 3.3485 (459.15); 3.3461 (516.01); 3.3421 (735.82 ); 3.2661 (2.04) ; 3.2380 (1.15); 3.2318 (1.10); 3.1922 (0.43); 2.8668 (0.59); 2.8363 (0.98); 2.8095 (0.58); 2.6807 (0.41); 2.6763 (0.84); 2.6717 (1.18); 2.6672 (0.88); 2.6628 (0.45); 2.5419 (0.62); 2.5251 (2.21); 2.5204 (3.20); 2.5117 (56.02); 2.5072 (119.61); 2.5027 (163.85) ; 2.4981 (121.68); 2.4936 (60, 83); 2.3385 (0.42); 2.3340 (0.83); 2.3294 (1.15); 2.3249 (0.87); 2.3202 (0.44); 2.2069 (16.00); 2.1340 (0.75); 2.1017 (1.45); 2.0861 (1.25); 2.0729 (1.73); 1.9886 (8.30); 1.9241 (0.45); 1,9123 (0.85); 1.9045 (0.99); 1.9016 (0.74); 1.8929 (1.48); 1.8887 (0.92); 1.8812 (0.96); 1.8732 (0.96); 1.8615 (0.56); 1.8252 (0.61); 1.8148 (0.66); 1.7924 (0.59); 1.7839 (0.57); 1.7603 (0.33); 1.6043 (0.33); 1.5838 (0.59); 1.5743 (0.65); 1.5525 (0.63); 1.5443 (0.61); 1.3976 (1.15); 1.2349 (0.77); 1.1925 (2.26); 1.1747 (4.49); 1.1569 (2.23); 1,1158 (0.39); 1.0957 (0.36); 1.0830 (0.77); 1.0704 (1.81); 1.0631 (3.57); 1.0553 (2.15); 1.0505 (1.85); 1.0431 (2.83); 1.0368 (1.75); 1.0246 (1.74); 1.0175 (3.08); 1.0106 (3.01); 1.0063 (3.12); 0.9984 (2.10); 0.9854

Petition 870180056486, of 06/29/2018, p. 185/206

178/191 (0.50); 0.0080 (0.33); -0.0002 (11, 67); -0.0084 (0.46);

Ex. 48, solvent: DMSO, spectrometer: 399.95 MHz

8.0329 (7.22); 7.4658 (0.49); 7.4552 (8.31); 7.4454 (4 , 85); 7.4417 (4.76); 7.4214 (0.51); 7.2027 (0.35); 7, 1921 (2.05); 7.1817 (1.81); 7.1789 (1.98); 7.1687 (1 , 79); 6.5052 (4.35); 6.1109 (1.31); 6.0867 (1.67); 6, 0798 (1.60); 6.0555 (1.36); 5.7630 (9.67); 5.3651 (0 , 98); 5.3226 (2.46); 5.2634 (2.42); 5.2208 (0.98); 4, 3907 (0.71); 4.3580 (0.75); 4.0544 (0.35); 4.0367 (1 , 07); 4.0189 (1.11); 4.0010 (0.69); 3.9922 (0.67); 3, 9571 (0.72); 3.9209 (1.11); 3.8896 (1.34); 3, 8776 (1 , 54); 3.8464 (1.23); 3.4331 (1.62); 3.4211 (0.73); 3, 4089 (1.99); 3.4016 (1.17); 3.3900 (3.25); 3.3692 (105.50) ; 3.3662 (108 , 97); 3, 3627 (125.98); 3.3557 (125.25) ; 3.3535 (153.94); 3.3133 (0.59); 3.2996 (0.80); 3, 2691 (1.11); 3.2411 (0.58); 3.0424 (0.57); 2.8682 (0 , 53); 2.8540 (0.58); 2.8380 (0.90); 2.8106 (0.52); 2, 6772 (0.44); 2.6726 (0.62); 2.6680 (0.44); 2.5261 (1 , 16); 2.5214 (1.66); 2.5126 ( 31.65); 2.5081 (69.43); 2, 5035 (94.42); 2.4989 (67.38); 2.4944 (31.70); 2.3347 (0 , 46); 2.3303 (0.64); 2.3257 (0.48); 2.2067 (16.00); 2, 1915 (0.73); 2.1337 (0.69); 2.1264 (0.52); 2.1033 (1 , 36); 2.0774 (1.16); 1.9902 (4.94); 1.8206 (0.56); 1, 8121 (0.62); 1.7897 (0.56); 1.7816 (0.52); 1.6306 (0 , 37); 1.6183 (0.69); 1.6112 (0.91); 1.6056 (0.71); 1, 5993 (1.52); 1.5876 (1.00); 1.5796 (1.26); 1.5678 (1 , 05); 1.5464 (0.60); 1.5370 (0.58); 1.1920 (1.38); 1, 1742 (2.75); 1.1564 (1.35); 0.9614 (0.64); 0.9531 (0 , 62); 0.9425 (2.08); 0.9294 (1.10); 0.9219 (2.04); 0, 9102 (0.90); 0.9030 (0.72); 0.8210 (0.39); 0.8110

Petition 870180056486, of 06/29/2018, p. 186/206

179/191

(0 , 77); 0.8005 (0.70); 0.7932 (0.89); 0.7835 (0.72); 0, 7686 (0.74); 0.75586 (0.60); 0.7470 (0.93); 0.7375 (0 , 80); 0.7268 (0.86); 0.7176 (0.60); 0.0080 (0.72); - 0, 0002 (27.69); -0.0085 (1.03);

Ex. 49, solvent: DMSO, spectrometer: 399.95 MHz

7.9775 (7.21); 7.9529 (0.74); 7.3985 (0.59); 7.38 (0.71); 7.3775 (1.25); 7.3604 (1.27) 7.3567 (0.82); 7.33 (0.66); 6.9326 (1.66); 6.9116 (1.52) 6.8657 (0.89); 6.84 (1.10); 6,8200 (0.86); 6.5035 (3.21) 6.0604 (0.81); 6.03 (1.02); 6.0299 (0.96); 6,0070 (0.85) 5.3679 (0.77); 5.32 (1.93); 5.2637 (1.85); 5.2211 (0.75) 4.3962 (0.51); 4.36 (0.54); 4.1114 (1.81); 4,1006 (2.89) 4.0887 (1.95); 4.05 (0.57); 4.0370 (1.71); 4.0192 (1.75) 4.0013 (0.96); 3.96 (0.51); 3.7633 (0.56); 3.7322 (0.67) 3.7208 (0.99); 3.69 (0.88); 3.5957 (1.03); 3.5730 (1.06) 3.5536 (0.67); 3.53 (0.66); 3.4820 (1.31); 3,4783 (1.25) 3.4727 (2.14); 3.46 (2.14); 3.4542 (1.04); 3.4264 (0.43) 3.4069 (0.40); 3.39 (0.75); 3.3870 (0.38); 3.3688 (0.48) 3.3607 (0.74); 3.34 (218.73 ); 3.3183 (1.43); 3, 3079 (0.72); 3.3033 (0.71 3.2721 (0.80); 3.2654 (0.64); 3.2445 (0.46); 3.0407 (0.36 3.0169 (16.00); 2.8906 (6.62); 2.8700 (0.39); 2.8386 (0.74 2.8125 (0.39); 2.7310 (5.14); 2.6763 (0.36); 2.6718 (0.52 2.6673 (0.37); 2.5252 (0.78); 2.5206 (1.20); 2.5118 (26.94 2.5073 (58.44) ; 2.5028 (78, 90); 2 , 4982 ( 55.83); 2.49 (26.07) ; 2.3342 (0.39); 2.3295 (0.54) ; 2.3249 (0.40); 2.20 (12.09) ; 2.1993 (0.48); 2.1331 (0.49) ; 2.1257 (0.45); 2.11 (0.99); 2.0768 (0.66); 1.9899 (7.95) 1.9076 (0.84); 1.82 (0.44); 1.8211 (0.47); 1.7982 (0.43), 1.7900 (0.40); 1.58 (0.41); 1.5753 (0.46); 1.5538 (0.44), 1.5450 (0.43); 1.19 (2.10); 1.1742 (4.23); 1.1564 (2.04); 0.0080 (0.40); -0.00

Petition 870180056486, of 06/29/2018, p. 187/206

180/191 (14.85); -0.0085 (0.51);

Ex. 50, solvent: DMSO, spectrometer: 399.95 MHz

7.9530 (8.91); 7.3744 (1.93); 7.3538 (4.10); 7.3332

(2.69); 7.1062 (2.47); 7.1041 (3.28); 7.0859 (4.76); 7.0839 (4.63); 7.0648 (2.13); 6,5062 (4.45); 6.2598 (1.34); 6.2363 (1.75); 6.2289 (1.61); 6.2053 (1.41); 5.8253 (0.33); 5.8117 (0.67); 5.7985 (0.66); 5.7852 (0.82); 5.7684 (0.90); 5.7616 (0.80); 5.7552 (0.78); 5.7420 (0.86); 5.7285 (0.44); 5.3676 (1.03); 5.3250 (2.60); 5.2642 (3.94); 5.2243 (2.34); 5.2207 (2.27); 5.0140 (1.59); 5.0105 (1.62); 4.9877 (1.50); 4.9843 (1.52); 4.5816 (0.47); 4.5687 (0.49); 4.5500 (1.39); 4.5367 (1.37); 4.5208 (1.37); 4.5066 (1.34); 4.4889 (0.48); 4.4748 (0.47); 4.3923 (0.71); 4.3596 (0.76); 4.0547 (0.87); 4.0369 (2.63); 4.0191 (2.70); 4.0012 (1.40); 3.9622 (0.72); 3.7620 (1.05); 3.7309 (1.29); 3.7201 (1.84); 3.6890 (1.47); 3.5752 (1.59); 3.5516 (1.58); 3.5332 (1.13); 3.5097 (1.10); 3.4242 (0.83); 3.3788 (2 55, 26); 3.3768 (255.06); 3.3727 (209, 45) ; 3.3699 (232.41 ); 3.3125 (1.04) ; 3.3074 (1.07); 3,2773 (1.18); 3.2489 (0.69); 3.2435 (0.63); 2.8774 (0.54); 2.8465 (0.94); 2.8206 (0.55); 2,6783 (0.38); 2.6737 (0.53); 2.6691 (0.39); 2.5271 (0.84); 2.5224 (1.36); 2.5136 (27.60) ; 2.5092 (60.18); 2.5046 (80, 99); 2.5000 (57.47); 2.4955 (26.85); 2.3358 (0.40); 2.3313 (0.55); 2.3267 (0.40); 2.2088 (16.00); 2.1502 (0.67); 2,1123 (1.37); 2.0865 (0.77); 2.0771 (0.87); 1.9903 (12.30); 1.8314 (0.58); 1.8229 (0.64); 1.8004 (0.59); 1.7919 (0.55); 1.5907 (0.55); 1.5814 (0.64); 1.5603 (0.59); 1.5511 (0.58); 1.1921 (3.28); 1.1743 (6.54); 1 , 1565 (3 , 22); -

Petition 870180056486, of 06/29/2018, p. 188/206

181/191

0.0002 (4.51);

Ex. 51, solvent: DMSO, spectrometer: 399.95 MHz

7.9706 (8.74); 7.3989 (0.78) ; 7.3817 (0.97); 7.3779 (1.64); 7.3609 (1.66); 7.3571 (1.04); 7.3400 (0.84); 6.9372 (2.31); 6.9160 (2.12); 6.8675 (1.21); 6.8422 (1.42); 6.8207 (1.13); 6.5037 (4.21); 6.1077 (1.07); 6.0857 (1.30); 6.0770 (1.24); 6.0548 (1.13); 5.9293 (0.34); 5.9160 (0.74); 5.9029 (0.73); 5.8895 (0.86); 5.8864 (0.53); 5.8729 (0.95); 5.8559 (0.86); 5.8465 (0.92); 5.8334 (0.45); 5.3659 (1.00); 5.3406 (1.76); 5.3366 (1.84); 5.3327 (0.85); 5.3235 (2.65); 5.3012 (0.59); 5.2974 (1.51); 5.2933 (1.53); 5.2895 (0.62); 5.2665 (2.53); 5.2239 (0.98); 5.2032 (0.61); 5.1221 (1.65); 5.1185 (1.63); 5.0957 (1.55); 5.0922 (1.53); 4.5906 (1.63); 4.5869 (1.21); 4.5786 (2.74); 4.5662 (1.56); 4.3942 (0.70); 4.3609 (0.75); 4.0550 (1.00); 4.0372 (3.03); 4.0194 (3.09); 4.0015 (1.49); 3.9625 (0.71); 3.8005 (0.77); 3.7702 (0.88); 3.7578 (1.10); 3.7280 (1.01); 3.5352 (1.27); 3.5132 (1.28); 3.4928 (0.96); 3.4709 (0.98); 3.4237 (0.44); 3.4120 (0.35); 3.4037 (0.62); 3.3943 (1.11); 3,3854 (0.68); 3.3772 (0.39); 3.3744 (0.40); 3.3657 (0.78); 3.3620 (0.95); 3.3602 (0.99); 3.356 (1.40); 3.3418 (302.46); 3.3264 (1.23); 3.3180 (1.55); 3.3079 (0.78); 3.3038 (0.71); 3.2744 (0.93); 3.2461 (0.52); 3.2401 (0.47); 3.0429 (1.33); 2.8736 (0.50); 2.8543 (1.43); 2.8467 (0.90); 2.8166 (0.51); 2.6763 (0.42); 2.6719 (0.59); 2.6673 (0.42); 2.5253 (0.96); 2.5206 (1.55); 2.5119 (31.01); 2.5074 (66.11); 2.5029 (88.42); 2.48984 (62.76); 2.4940 (29.40) ; 2.3344 (0.41); 2.3297 (0.58); 2.3251 (0.42);

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2.2091 (16.00); 2.1913 (1.25) ; 2.1998 (0.67); 2.1466 (0.63); 2,1125 (1.31); 2.0862 (0.71); 2.0776 (0.71); 1.9900 (13.71); 1.8331 (0.55) ; 1.8264 (0.66); 1.8031 (0.54); 1.7952 (0.52); 1.5914 (0.55); 1.5826 (0.61); 1.5608 (0.58); 1.5508 (0.56); 1.2349 (0.34); 1.1921 (3.53); 1.1743 (7.13); 1.1564 (3.43); 0, 0081 (0.47); - 0.0002 (15.63); -0.0084 (0.51);

Ex. 52, solvent: DMSO, spectrometer: 601.6 MHz

8.0358 (7.61); 7.2774 (0.74); 7.2742 (0.77); 7.2644

(0 , 94); 7.2612 (1.03); 7.2580 (0.86); 7.2551 (0.81); 7, 2446 (0.93); 7.2418 (0.95); 7.1645 (0.94); 7.1617 (1 , 01); 7.11515 (2.51); 7.1487 (1.98); 7.1409 (1.34); 7, 1331 (1.26); 7.1279 (1.36); 7,1200 (1.37); 7.1150 (0 , 49); 7.1069 (0.50); 6.5053 (4.35); 6.0851 (0.60); 6, 0763 (0.47); 6.0669 (0.85); 6.0568 (0.89); 6, 0476 (0 , 52); 6.0393 (0.68); 6, 0293 (0.35); 5.9261 (1.26); 5, 9136 (1.43); 5.9074 (1.36); 5.8949 (1.27); 5.3966 (1 , 73); 5.3940 (1.69); 5.3915 (0.67); 5.3681 (1.60); 5, 3654 (1.56); 5.3630 (0.64); 5.3509 (1.29); 5.3225 (2 , 53); 5.2618 (2.61); 5.2407 (1.82); 5.2382 (1.83); 5, 2361 (1.33); 5.2336 (1.44); 5.2235 (1.62); 4.6113 (2 , 93); 4.6016 (2.75); 4.3806 (0.76); 4.3588 (0.79); 4, 0335 (0.46); 4.0217 (0.46); 3.9801 (0.75); 3.9567 (0 , 77); 3.9224 (1.21); 3.9035 (1.38); 3.8938 (1.51); 3, 8750 (1.27); 3.3986 (0.64); 3.3926 (0.49); 3.3855 (0 , 79); 3,3793 (1.41); 3.3493 ( 580.12); 3.3257 (12.73); 3, 3089 (1.64); 3.2826 (0.66); 3.2634 (1.08); 3.2439 (0 , 62); 3,2396 (0.52); 2.8516 (0.54); 2.8309 (0.97); 2, 8134 (0.56); 2.6178 (1.20); 2.6149 (1.62); 2.6119 (1 , 14); 2.5426 (0.65); 2.5241 (2.96); 2.5211 (4.06);

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2.5179 (4.89); 2.5087 (96.04); 2.5061 (192.28); 2.5031 (255, 09) ; 2.5002 (185.23) ; 2.4804 (1.02) ; 2.4773 (0.92); 2.3903 (1.26); 2.3873 (1.66); 2.3843 (1.20); 2.2055 (16.00); 2.1928 (0.47); 2.1259 (0.69); 2.0981 (1.15); 2.0783 (2.81); 1.9905 (2.01); 1.8291 (0.33); 1.8150 (0.64); 1.8090 (0.69); 1.7944 (0.66); 1.7890 (0.62); 1.5684 (0.65); 1.5622 (0.69); 1.5482 (0.67); 1.5419 (0.64); 1.3969 (0.47); 1.2337 (1.34); 1.1860 (0.57); 1.1741 (1.09); 1.1623 (0.56); 1.1365 (0.56); 0.0052 (2.96); -0,0002 (72.51); -0.0057 (2.46);

Ex. 53, solvent: DMSO, spectrometer: 601.6 MHz

10.2595 (5.04); 8.0507 (7.33); 7.7701 (1.91); 7.7685

(2.00); 7,7574 (2.47); 7.7558 (2.50); 7.6824 (0.70); 7.6738 (0.84); 7.6690 (1.38); 7.6607 (1.40); 7.6562 (0.94); 7.6476 (0.77); 7.6120 (1.19); 7.5949 (1.38); 7.5811 (0.83); 6.5807 (1.13); 6.5629 (1.65); 6.5441 (1.15); 6,5072 (4.42); 5.3547 (1.33); 5.3263 (2.70); 5.2687 (2.59); 5.2404 (1.30); 4.3893 (0.87); 4.3673 (0.90); 3.9893 (0.85); 3.9787 (1.05); 3.9761 (1.10); 3.9663 (0.96); 3.9589 (1.23); 3.9501 (1.01); 3.9476 (0.99); 3.9280 (0.85); 3.5858 (1.07); 3.5688 (1.10); 3.5567 (0.95); 3.5400 (0.94); 3.4250 (0.34); 3.4189 (0.62); 3.4124 (0.47); 3.4059 (0.76); 3.3998 (1.23); 3.3935 (0.82); 3.3865 (0.63); 3.3799 (1.01); 3.3550 (256.99) ; 3.3314 (3.80) ; 3.2926 (0.68); 3.2728 (1.16); 3.2537 (0.62); 3.2502 (0.55); 2.8615 (0.60); 2.8411 (1.10); 2.8235 (0.61); 2.6182 (0.47); 2.6154 (0.64); 2.6125 (0.50); 2.5244 (1.20); 2.5214 (1.70); 2.5065 (75, 93); 2.5036 (101.45) ; 2.5007 (79.23) ; 2.3906 (0.48); 2.3877 (0.64); 2.3850 (0.50); 2.2082 (16.00); 2,1456

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184/191 (0.76); 2,1201 (1.12); 2.0913 (0.88); 2.0788 (6.21);

1.8307 (0.72); 1.8107 (0.69); 1.5836 (0.67); 1.5643 (0.66); 0.0049 (0.68); -0.0002 (13, 17);

Ex. 54, solvent: DMSO, spectrometer: 601.6 MHz

8.7986 (0.80); 8.0657 (0.34) ; 8.0560 (7.35); 7.3883 (0.52); 7.3857 (0.58); 7.3745 (1.21); 7.3720 (1.50); 7.3582 (1.39); 7.3556 (1.99); 7.3466 (1.11); 7.3429 (1.41); 7.3341 (1.38); 7.3293 (0.67); 7.3204 (0.56); 7.2762 (1.73); 7.2643 (1.25); 6.5057 (4.67); 5.8076 (1.23); 5.7950 (1.39); 5.7886 (1.33); 5.7758 (1.19); 5.3525 (1.24); 5.3241 (2.42); 5.2606 (2.46); 5.2323 (1.29); 4.3835 (0.74); 4.3617 (0.79); 4.0454 (0.50); 4.0336 (1.54); 4.0217 (1.56); 4,0099 (0.53); 3.9806 (0.75); 3.9577 (0.78); 3.9189 (1.07); 3.8997 (1.30); 3.8902 (1.38); 3.8711 (1.15); 3.4091 (0.41); 3.4028 (0.65); 3.3964 (0.51); 3.3889 (0.91); 3.3834 (1.46); 3.3753 (1.49); 3.3504 (474.54); 3.3268 (8.13); 3,3000 (1.54); 3.2873 (1.89); 3.2713 (1.56); 3.2588 (1.98); 3.2438 (0.60); 3,2396 (0.53); 2.8542 (0.55); 2.8505 (0.58); 2.8296 (1.00); 2.8122 (0.55); 2.8083 (0.49); 2.6209 (0.40); 2.6179 (0.83); 2.6150 (1.11); 2.6120 (0.79); 2.6090 (0.36); 2.5427 (0.68); 2.5242 (2.84); 2.5212 (3.66); 2.5180 (4.29); 2.5092 (64.10); 2.5062 (130.48) ; 2.5032 (174 , 29); 2, 5002 (125.86); 2.4973 (57.51); 2.4799 (0.46); 2.4766 (0.46); 2.4738 (0.44); 2.3933 (0.43); 2.3904 (0.86); 2.3874 (1.12); 2.3844 (0.81); 2.3814 (0.39); 2.2201 (0.42); 2.2057 (16.00); 2,1901 (0.44); 2.1246 (0.69); 2.0965 (1.20); 2.0782 (2.29); 2.0713 (0.77); 1.9905 (6.90); 1.8821 (0.38); 1.8742 (0.72); 1.8695 (0.72); 1.8640 (0.95); 1.8612

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(1.12); 1.8566 (0.62); 1.8537 (0.68); 1.8502 (0.75); 1.8406 (0.54); 1.8104 (0.60); 1.8039 (0.62); 1.7922 (0.72); 1.7867 (0.78); 1.7849 (0.70); 1.7792 (0.77); 1.7736 (0.34); 1.7716 (0.49); 1.7660 (0.46); 1.7354 (1.68); 1.5793 (0.35); 1.5662 (0.72); 1.5589 (0.80); 1.5456 (0.75); 1.5391 (0.65); 1.3969 (0.44); 1.2338 (0.92); 1.1860 (1.90); 1.1741 (3.78); 1.1623 (1.83); 1.0889 (0.49); 1.0841 (0.52); 1.0818 (1.11); 1.0767 (1.64); 1.0716 (0.99); 1.0687 (1.20); 1.0636 (1.59); 1.0587 (1.07); 1.0513 (0.99); 1.0481 (0.88); 1.0438 (1.23); 1.0381 (1.09); 1.0305 (0.91); 1.0247 (0.56); 1.0183 (0.45); 1.0128 (1.07); 1.0103 (0.64); 1.0053 (2.12); 1,0003 (1.42); 0.9975 (0.90); 0.9918 (2.06); 0.9789 (1.26); 0.9693 (0.47); 0.9641 (0.41); 0.0052 (1.72); -0,0002 (43.02); -0.0057 (1.34);

Ex. 55, solvent: DMSO, spectrometer: 399.95 MHz

7,9900 (5.11); 7.9528 (0.50) ; 7.3211 (0.55); 7.3176 (0 , 67); 7.2998 (3.31); 7.2812 (2.93); 7.0705 (1.58); 7, 0499 (1.35); 6.9729 (0.99); 6.9546 (1.73); 6.9355 (0 , 83); 6.4972 (3.18); 5.8503 (0.83); 5.8310 (0.97); 5, 8223 (0.94); 5.8027 (0.85); 5.7551 (4.32); 5.3500 (0 , 66); 5.3070 (1.88); 5.2535 (1.78); 5.2112 (0.63); 4, 3837 (0.53); 4.3514 (0.57); 4.1549 (1.74); 4.1435 (2 , 88); 4.1318 (1.83); 3.9877 (0.51); 3.9499 (0.57); 3, 8507 (0.85); 3.8225 (0.88); 3.8079 (1.06); 3.7800 (0 , 93); 3.6311 (1.80); 3.6195 (2.15); 3.6085 (1.44); 3, 4026 (0.53); 3.3942 (0.34); 3.3750 (0.87); 3.3652 (0 , 66); 3.3274 (220.17) ; 3.2923 (1.45); 3.2735 (1.17); 3, 2628 (0.82); 3.2288 (16.00); 2.8907 (2.87); 2.8654 (0 , 38); 2.8617 (0.39); 2.8323 (0.69); 2.8040 (0.40);

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2.7315 (2.65); 2.6709 (0.42); 2.5018 (70.79); 2.3284 (0.42); 2.2064 (11.12); 2.1227 (0.49); 2.0958 (1.01); 2.0736 (0.61); 2.0630 (0.58); 1.9887 (0.52); 1.8156 (0.47); 1.8063 (0.47); 1.7840 (0.43); 1.7776 (0.42); 1.5733 (0.45); 1.5657 (0.46); 1.5433 (0.45); 1.5368 (0.43); 1.2357 (0.62); - 0.0002 (10.11); - 0.0082 (0 , 34);

Ex. 56, solvent: DMSO, spectrometer: 399.95 MHz

8.7868 (0.75); 8.0463 (0.81); 8.0388 (8.80); 7.4462

(1.28); 7.4419 (1.52); 7.4270 (1.61); 7.4229 (2.06); 7.4147 (0.94); 7.4104 (0.83); 7.3957 (1.69); 7.3911 (1.41); 7.3761 (1.48); 7.3717 (1.20); 7.3397 (0.34); 7.3110 (1.23); 7.3082 (1.42); 7.2922 (1.83); 7.2893 (1.97); 7.2736 (0.78); 7.2706 (0.76); 7.1763 (2.17); 7.1735 (2.19); 7.1562 (1.87); 7.1534 (1.78); 6.4972 (4.64); 5.7554 (11.20); 5.7402 (1.29); 5.7311 (1.31); 5.7115 (1.10); 5.3515 (0.79); 5.3091 (2.37); 5.2551 (2.53); 5.2130 (0.86); 4.3857 (0.69); 4.3536 (0.72); 4.0558 (0.33); 4.0379 (1.00); 4.0201 (1.05); 4.0023 (0.53); 3.9867 (0.68); 3.9522 (0.71); 3.8958 (1.11); 3.8672 (1.30); 3.8526 (1.44); 3.8241 (1.19); 3.4178 (0.34); 3.4083 (0.53); 3.3985 (0.40); 3.3893 (0.64); 3,3796 (1.07); 3.3705 (0.66); 3.3608 (0.54); 3.3515 (0.79); 3.3267 (95.06); 3.3230 (198.62); 3.2903 (1.88); 3.2705 (1.95); 3,2471 (1.43); 3.2359 (0.69); 3.2276 (1.64); 2.8628 (0.55); 2.8356 (0.90); 2.8060 (0.51); 2.6750 (0.40); 2.6705 (0.54); 2.6658 (0.41); 2.5406 (0.34); 2.5238 (0.95); 2.5191 (1.43); 2.5098 (30, 88); 2.5057 (60.00); 2.5013 (83.80); 2.4971 (58.45); 2.4928 (29.21) ; 2.3329 (0.41); 2.3281 (0.52); 2.3236 (0.39); 2.2066 (16.00); 2.1936 (0.85); 2.1291 (0.65); 2.0990

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(1.32); 2.0734 (1.01); 1.9884 (4.67); 1, 8725 (0, 41); 1.8566 (0.73); 1.8468 (0.87); 1.8412 (1 , 36); 1, 8356 (0.87); 1.8301 (0.85); 1.8223 (0.97); 1, 8105 (0, 93); 1.7848 (0.54); 1.5759 (0.57); 1.5668 (0 , 59); 1, 5442 (0.58); 1.5355 (0.54); 1.2344 (0.35); 1, 1923 (1, 29); 1.1745 (2.61); 1.1567 (1.28); 1.0728 (0 , 54); 1, 0647 (0.67); 1.0578 (0.73); 1.0521 (1.19); 1, 0467 (1, 39); 1.0304 (2.30); 1.0194 (1.51); 1.0140 (2 , 46); 1, 0076 (1.75); 1.0021 (1.05); 0.9962 (0.99); 0, 9871 (1, 16); 0.9824 (0.83); 0.9742 (0.89); 0.9631 (1 , 22); 0, 9488 (0.63); 0.9430 0.61); - 0.0002 ( 3.06);

[0267] The intensity of the clear signals is correlated with the height of the signals in a printed example of an NMR spectrum in cm and shows the true proportions between the signal intensities. In the case of wide signals, several peaks or the medium of the signal and their relative intensities can be displayed compared to the most intense signal in the spectrum.

[0268] For the calibration of the chemical deviation from the 1H NMR spectrum, tetramethylsilane and / or the chemical deviation of the solvent were used, particularly in the case of the spectrum measured in DMSO. Therefore, the peak of tetramethylsilane can occur, although not necessary, in the NMR peak listings.

[0269] The 1H NMR peak listings are similar to conventional 1H NMR impressions, thus normally containing all the peaks shown in conventional NMR interpretations.

[0270] In addition, as with conventional 1H NMR prints, they show solvent signals,

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stereoisomers of compounds target, which do equally part the subject of invention and / or spikes in impurities. [0271] No record of signs of compounds at the delta range of solvents and / or of water, the s listings From 1H NMR peaks show the peaks usual solvents, per

for example, DMSO peaks in DMSO-d6 and the water peak, which normally has a high intensity on average.

[0272] The peaks of the stereoisomers of the target compounds and / or the peaks of the impurities normally have a lower intensity on average than the peaks of the target compounds (for example, with a purity> 90%).

[0273] Such stereoisomers and / or impurities may be typical of the particular preparation process. Its peaks can thus help to identify the reproduction of our preparation process by reference to secondary fingerprints.

[0274] The calculation of the peaks of the target compounds by known methods (MestreC, ACD simulation, but also with empirically calculated expected values) can, if necessary, isolate the peaks of the target compounds, optionally using supplementary intensity filters. This isolation would be similar to the selection of the relevant peak in conventional 1H NMR interpretation.

[0275] More details of the 1H NMR peak listings can be found in the 'Research Disclosure' database number 564025.

Usage examples

Example A

Phytophthora (tomato) / protective test

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Solvent: 49 parts by weight of N, N-dimethylformamide

Emulsifier: 1 part by weight of polyglycyl alkylaryl ether [0276] To obtain a suitable formulation of active ingredient, 1 part by weight of active substance is mixed with the indicated amounts of solvent and emulsifier and then the concentrate is diluted with water to the desired concentration.

[0277] To test for protective activity, spray young tomatoes with the preparation of active ingredient, at the indicated application rate. After 1 day after treatment, the plants are inoculated with a spore suspension of Phytophthora infestans and then maintained at 100% relative humidity and 22 ° C for 24 hours. Then, the plants are placed in an air-conditioned chamber at about 96% relative humidity and at a temperature of approximately 20 ° C.

[0278] Evaluation is carried out 7 days after inoculation. A value of 0% means an efficacy corresponding to that of the control, whereas a value of 100% efficacy means that no infection is observed.

[0279] In this test, the following compounds of the invention demonstrated an efficiency of 70% or greater, for an active ingredient concentration of 100 p.p.m .:

Table 2:

Ex. % Effectiveness 1 100 2 100 3 100 4 95

Ex. % Effectiveness 5 95 6 95 7 100 8 100

Ex. % Effectiveness 9 94 11 85 12 75 13 89

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Ex. % Effectiveness 18 100 19 98 25 100 26 100 29 100 30 97 34 100 35 100 36 100 37 94

Ex. % Effectiveness 38 94 39 94 40 100 41 98 41 97 42 94 43 97 44 94 45 100 46 100

Ex. % Effectiveness 47 100 48 70 49 90 50 70 51 85 52 97 53 98 54 94 55 92 56 89

Example B

Plasmopara (vines) / protective test

Solvent:

24.5 parts by weight of acetone

24.5 parts by weight of dimethylacetamide

Emulsifier:

part by weight of polyaryl alkylaryl ether [0280]

To obtain a suitable formulation of active ingredient, part by weight of active substance is mixed with the indicated amounts of solvent and emulsifier and then the concentrate is diluted with water to the desired concentration.

[0281]

To test for protective activity, young plants are sprayed with the active ingredient formulation at the indicated application rate.

After the spray coating has dried, the plants are inoculated with an aqueous spore suspension of Plasmopara viticola and then kept in an incubator at approximately 20 ° C and

100% relative humidity for 1 day. Subsequently,

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[0282] The evaluation is carried out 6 days after inoculation. A value of 0% means an efficacy corresponding to that of the control, whereas a value of 100% efficacy means that no infection is observed.

[0283] In this test, the following compounds of the invention demonstrated an efficacy of 70% or greater, for an active ingredient concentration of 10 p.p.m .:

Claims (10)

1. Compound, characterized by the fact that it presents structural formula (I) R ² \ / 2 X - G — Q — L — R A — L where each radical has the meanings defined below: is phenyl which can contain up to two substituents, each of which is independently selected from the following listing: halogen, cyan, hydroxyl, -NR ³ R ⁴ , -C (= O) NR ³ R ⁴ , Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, cycloalkyl, Ci-Ce-haloalkyl, C2-C6-haloalkenyl, haloalkynyl, Ca-Ce-halocycloalkyl, C1-C4-alkoxy, haloalkoxy, C1-C4-alkenyloxy, C1-C4-alkynyloxy, alkylthio, C1-C4-alkylsulfonyl, C1-C4-haloalkylthio, haloalkylsulfonyl, C1-C4-alkoxy-C1- C6-alkyl, hydroxy-C1-C4 alkyl, Ci-Ce-alkylcarbonyl, Ci-Ce-alkoxycarbonyl, Ci-Ce alkylcarbonyloxy or -C (= O) H, L ¹ -NH-, carbon, R ² hydrogen, 0, r ^g1 where G ¹ the link identified by is linked directly to where the link identified by w is linked directly to Q, Petition 870190061172, of 7/1/2019, p. 10/13 2/3 R ^G1 is hydrogen, R ⁵ / y Γ The Q is Q ²⁴ -3 = , Where the call identified by “x is connected directly to G, and where the identified link by “y  it's on directly to L ² , R ⁵ is hydrogen, L ² is a direct link, R ¹ is phenyl which is substituted once by the Z4 substituent and may additionally have additional substitution, where the additional substituents are each independently selected from Z4 and Z ^1-1 , Z4 is C2-C6-alkenyloxy, Z ^1-1 is halogen, C1-C6-alkyl, or C1-C6-haloalkyl; and / or a salt, metal complex and / or an N-oxide thereof. 2. Composed of structural formula (I) and / or a salt, metal complex and / or N-oxide thereof according to claim 1, characterized by the fact that the definitions of radicals are as follows: A is phenyl, which can contain up to two substituents, where the substituents are each independently selected from the following list: methyl, ethyl, iodine, chlorine, bromine, fluorine, methoxy, ethoxy, difluoromethyl or trifluoromethyl. 3. Composed of structural formula (I) and / or a salt, metal complex and / or N-oxide thereof according to claim 1, characterized by the fact that A is 2,5-bis (difluoromethyl) phenyl, 2,5-dimethylphenyl or 5-chloro-2-methylphenyl. Petition 870190061172, of 7/1/2019, p. 11/13 3/3 4. Compound of structural formula (I) and / or a salt, metal complex and / or N-oxide thereof according to claim 1, characterized by the fact that Z ^1-1 is selected from halogen and C1-C6-alkyl. 5. Composed of structural formula (I) and / or a salt, metal complex and / or N-oxide thereof according to claim 1, characterized by the fact that R ¹ is 2- (allyloxy) phenyl, 3- (allyloxy) phenyl, 3 (allyloxy) -2,6-difluorophenyl, 2- (allyloxy) -4-methylphenyl, 2 (allyloxy) -4,6-dichlorophenyl, 2 - (allyloxy) -6-fluorophenyl, 2 (allyloxy) -6-chlorophenyl or 2- (allyloxy) -3-fluorophenyl. 6. Method for the control of harmful phytopathogenic fungi, characterized by the fact that it comprises applying a compound as defined in claim 1 to harmful phytopathogenic fungi and / or their habitat. 7. Composition for the control of harmful phytopathogenic fungi, characterized by the fact that it comprises at least one compound as defined in claim 1, and one or more fillers and / or surfactants. 8. Compound according to claim 1, characterized by the fact that it is capable of being used to control harmful phytopathogenic fungi. 9. Process for the production of compositions for the control of harmful phytopathogenic fungi, characterized by the fact that it comprises mixing a compound as defined in claim 1, with one or more fillers and / or surfactants. 10. Use of compounds as defined in claim 1, characterized by the fact that it is for the treatment of transgenic plants.