Isoxazoline derivative and herbicide comprising the same as active ingredient

[0001] BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to a novel isoxazoline derivative and a herbicide containing the isoxazoline derivative as the active ingredient.

[0004] 2. Description of the Prior Art

[0005] The herbicidal activity of isoxazoline derivatives are reported in, for example, JP-A-8-22558, JP-A-9-328477 and JP-A-9-328483. The compound of the present invention described in detail later, however, is not described in these literatures.

[0006] Herbicides applied to useful crops are desired to (a) be applicable to soil or foliage, (b) show a sufficient herbicidal effect at a low ingredient amount, and (c) show a high selectivity between crop and weed. In these respects, the compounds described in the above literatures are not fully satisfactory.

SUMMARY OF THE INVENTION

[0007] In view of the above situation, the present inventors made a study on the herbicidal effect and selectivity between crop and weed of various compounds. As a result, the present inventors found out that a novel isoxazoline derivative has an excellent herbicidal effect and an excellent selectivity between crop and weed. The above finding has led to the completion of the present invention.

[0008] The present invention provides the followings.

[0009] (1) An isoxazoline derivative represented by the following general formula [I] or a pharmaceutically acceptable salt thereof:

[0010] wherein R1 and R2 may be the same or different and are each a hydrogen atom, a C1 to C10 alkyl group, a C3 to C8 cycloalkyl group or a C3to C8 cycloalkyl C1 to C3 alkyl group, or R1 and R2 may be bonded to each other to form a C3 to C7 spiro ring together with the carbon atoms to which they bond;

[0011] R3 and R4 may be the same or different and are each a hydrogen atom, a C1 to C10 alkyl group or a C3 to C8 cycloalkyl group; or R3 and R4 may be bonded to each other to form a C3 to C7 spiro ring together with the carbon atoms to which they bond; or R1, R2, R3 and R4 may form a 5- to 8-membered ring together with the carbon atoms to which they bond;

[0012] R5 and R6 may be the same or different and are each a hydrogen atom or a C1 to C10 alkyl group;

[0013] Y is a 5- to 6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group having one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; the heterocyclic group may be substituted with 0 to 6 same or different groups selected from the following substituent group α; when the heterocyclic group is substituted at the two adjacent positions with two alkyl groups, two alkoxy groups, an alkyl group and an alkoxy group, an alkyl group and an alkylthio group, an alkyl group and an alkylsulfonyl group, an alkyl group and a monoalkylamino group, or an alkyl group and a dialkylamino group, all selected from the substituent group α, the two groups may form, together with the atoms to which they bond, a 5- to 8-membered ring which may be substituted with 1 to 4 halogen atoms; the hetero atom of the heterocyclic group, when it is a nitrogen atom, may be oxidized to become N-oxide;

[0014] n is an integer of 0 to 2.

[0015] [Substituent Group α]

[0016] Hydroxyl group; thiol group; halogen atoms; C1 to C10 alkyl groups; C1 to C10 alkyl groups each mono-substituted with a group selected from the following substituent group β, C1 to C4 haloalkyl groups; C3 to C8 cycloalkyl groups; C1 to C10 alkoxy groups; C1 to C10 alkoxy groups each mono-substituted with a group selected from the following substituent group γ; C1 to C4 haloalkoxy groups; C3 to C8 cycloalkyloxy groups; C3 to C8 cycloalkyl C1 to C3 alkyloxy groups; C1 to C10 alkylthio groups; C1 to C10 alkylthio groups each mono-substituted with a group selected from the substituent group γ; C1 to C4 haloalkylthio groups; C2 to C6 alkenyl groups; C2 to C6alkenyloxy groups; C2 to C6 alkynyl groups; C2 to C6 alkynyloxy groups; C1 to C10 alkylsulfinyl groups; C1 to C10 alkylsulfinyl groups each mono-substituted with a group selected from the substituent group γ; C1 to C10 alkylsulfonyl groups; C1 to C10 alkylsulfonyl groups each mono-substituted with a group selected from the substituent group γ; C1 to C4 haloalkylsulfinyl groups; C1 to C10 alkylsulfonyloxy groups each mono-substituted with a group selected from the substituent group γ; C1 to C4 haloalkylsulfonyl groups; C1 to C10 alkylsulfonyloxy groups; C1 to C4 haloalkylsulfonyloxy groups; optionally substituted phenyl group; optionally substituted phenoxy group; optionally substituted phenylthio group; optionally substituted aromatic heterocyclic groups; optionally substituted aromatic heterocyclic oxy groups; optionally substituted aromatic heterocyclic thio groups; optionally substituted phenylsulfinyl groups; optionally substituted phenylsulfonyl groups; optionally substituted aromatic heterocyclic sulfonyl groups; optionally substituted phenylsulfonyloxy groups; acyl groups; C1 to C4 haloalkylcarbonyl groups; optionally substituted benzylcarbonyl group; optionally substituted benzoyl group; carboxyl group; C1 to C10 alkoxycarbonyl groups; optionally substituted benzyloxycarbonyl group; optionally substituted phenoxycarbonyl group; cyano group; carbamoyl group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups and optionally substituted phenyl group); C1 to C6acyloxy groups; C1 to C4 haloalkylcarbonyloxy groups; optionally substituted benzylcarbonyloxy group; optionally substituted benzoyloxy group; nitro group; and amino group (its nitrogen atom may be substituted with same or different: groups selected from C1 to C10 alkyl groups, optionally substituted phenyl group, C1 to C6 acyl groups, C1 to C4 haloalkylcarbonyl groups, optionally substituted benzylcarbonyl group, optionally substituted benzoyl group, C1 to C10 alkylsulfonyl group, C1 to C4 haloalkylsulfonyl groups, optionally substituted benzylsulfonyl group, and optionally substituted phenylsulfonyl group).

[0017] [Substituent Group β]

[0018] Hydroxyl group; C3 to C8 cycloalkyl groups which may be substituted with halogen atom or alky group); C1 to C10 alkoxy groups; C1 to C10 alkylthio groups; C1 to C10 alkylsulfonyl groups; C1 to C10 alkoxycarbonyl groups; C2to C6 haloalkenyl groups; amino group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups, C1 to C6 acyl groups; C1 to C4 haloalkylcarbonyl groups, C1 to C10 alkylsulfonyl groups and C1 to C4 haloalkylsulfonyl groups); carbamoyl group (its nitrogen atom may be substituted with same or different C1 to C10 alkyl groups); C1 to C6 acyl groups; C1 to C4 haloalkylcarbonyl groups; C1 to C10 alkoxyimino groups; cyano group; optionally substituted phenyl group; and optionally substituted phenoxy group.

[0019] [Substituent Group γ]

[0020] C1 to C10 alkoxycarbonyl groups; optionally substituted phenyl group; optionally substituted aromatic heterocyclic groups; cyano group; and carbamoyl group (its nitrogen atom may be substituted with same or different C1 to C10 alkyl groups).

[0021] (2) An isoxazoline derivative-according to (1), wherein the substituent group a on the heterocycle which may be substituted with 0 to 6 same or different groups, includes hydroxyl group; halogen atoms; C1 to C10 alkyl groups; C1 to C10 alkyl groups each mono-substituted with a group selected from the substituent group β, C1 to C4 haloalkyl groups; C3 to C8 cycloalkyl groups; C1 to C10 alkoxy groups; C1 to C10 alkoxy groups each mono-substituted with a group selected from the substituent group γ; C1 to C4 haloalkoxy groups; C3 to C8 cycloalkyloxy groups; C3 to C8 cycloalkyl C1 to C3 alkyloxy groups; C1 to C10 alkylthio groups; C1 to C10 alkylthio groups each mono-substituted with a group selected from the substituent group γ; C1 to C4 haloalkylthio groups; C2 to C6 alkenyl groups; C2 to C6 alkenyloxy groups; C2 to C6 alkynyl groups; C2 to C6 alkynyloxy groups; C1 to C10 alkylsulfonyl groups; C1 to C4 haloalkylsulfonyl groups; optionally substituted phenyl group; optionally substituted phenoxy group; optionally substituted phenylthio group; optionally substituted aromatic heterocyclic groups; optionally substituted aromatic heterocyclic oxy groups; optionally substituted aromatic heterocyclic thio groups; optionally substituted phenylsulfonyl groups; optionally substituted aromatic heterocyclic sulfonyl groups; C1 to C6 acyl groups; C1 to C4 haloalkylcarbonyl groups; optionally substituted benzylcarbonyl group; optionally substituted benzoyl group; carboxyl group; C1 to C10 alkoxycarbonyl groups; cyano group; carbamoyl group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups and optionally substituted phenyl group); nitro group; and amino group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups, optionally substituted phenyl group, C1 to C6 acyl groups, C1 to C4 haloalkylcarbonyl groups, optionally substituted benzylcarbonyl group, optionally substituted benzoyl group, C1 to C10 alkylsulfonyl groups, C1 to C4 haloalkylsulfonyl groups, optionally substituted benzylsulfonyl group, and optionally substituted phenylsulfonyl group); when the heterocyclic group is substituted at the two adjacent positions with two alkyl groups, two alkoxy groups, an alkyl group and an alkoxy group, an alkyl group and an alkylthio group, an alkyl group and an alkylsulfonyl group, an alkyl group and a monoalkylamino group, or an alkyl group and a dialkylamino group, all selected from the substituent group α, the two groups may form, together with the atoms to which they bond, a 5- to 8-membered ring which may be substituted with 1 to 4 halogen atoms.

[0022] (3) An isoxazoline derivative according to (2), wherein the substituent group α on the heterocycle which may be substituted with 0 to 6 same or different groups, includes halogen atoms; C1 to C10 alkyl groups; C1 to C4 haloalkyl groups; C1 to C10 alkoxy C1 to C3 alkyl groups; C3 to C8 cycloalkyl groups which may be substituted with halogen atom or alkyl group; C1 to C10 alkoxy groups; C1 to C4 haloalkoxy groups; C3 to C8 cycloalkyl C1 to C3 alkyloxy groups; optionally substituted phenoxy group; C1 to C10 alkylthio groups; C1 to C10 alkylsulfonyl groups; acyl groups; C1 to C4 haloalkylcarbonyl groups; C1 to C10 alkoxycarbonyl groups; cyano group and carbamoyl group (its nitrogen atom may be substituted with same or different C1 to C10 alkyl groups).

[0023] (4) An isoxazoline derivative according to any of (1), (2) or (3), wherein R1 and R2 may be the same or different and are each a methyl group or an ethyl group; and R3, R4, R5 and R6 are each a hydrogen atom.

[0024] (5) An isoxazoline derivative according to any of (1), (2), (3) or (4) wherein Y is a 5- or 6-membered aromatic heterocyclic group having a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.

[0025] (6) An isoxazoline derivative according to (5), wherein Y is a thienyl group, a pyrazolyl group, an isoxazolyl group, an isothiazolyl group, a pyridyl group or a pyrimidinyl group.

[0026] (7) An isoxazoline derivative according to (6), wherein Y is a thiophen-3-yl group, a pyrazol-4-yl group, a pyrazol-5-yl group, an isoxazol-4-yl group, an isothiazol-4-yl group, a pyridyn-3-yl group or a pyrimidin-5-yl group.

[0027] (8) An isoxazoline derivative according to (7), wherein Y is a thiophen-3-yl group and the thiophene ring is substituted with the substituent group α at the 2- and 4-positions.

[0028] (9) An isoxazoline derivative according to (7), wherein Y is a pyrazol-4-yl group and the pyrazole ring is substituted at the 3- and 5-positions with the substituent group α and at the 1-position with a hydrogen atom, a C1 to C10 alkyl group, a C1 to C10 alkyl group mono-substituted with a group selected from the substituent group β, a C1 to C4 haloalkyl group, a C3 to C8 cycloalkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, a C1 to C10 alkylsulfinyl group, a C1 to C10 alkylsulfonyl group, a C1 to C10 alkylsulfonyl group mono-substituted with a group selected from the substituent group γ, a C1 to C4 haloalkylsulfonyl group, an optionally substituted phenyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted phenylsulfonyl group, an optionally substituted aromatic heterocyclic sulfonyl group, an acyl group, a C1 to C4 haloalkylcarbonyl group, an optionally substituted benzylcarbonyl group, an optionally substituted benzoyl group, a C1 to C10 alkoxycarbonyl group, an optionally substituted benzyloxycarbonyl group, an optionally substituted phenoxycarbonyl group, a carbamoyl group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups and optionally substituted phenyl group), or an amino group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups, optionally substituted phenyl group, acyl groups, C1 to C4 haloalkylcarbonyl groups, optionally substituted benzylcarbonyl group, optionally substituted benzoyl group, C1 to C10 alkylsulfonyl groups, C1 to C4 haloalkylsulfonyl groups, optionally substituted benzylsulfonyl group and optionally substituted phenylsulfonyl group).

[0029] (10) An isoxazoline derivative according to (7), wherein Y is a pyrazol-5-yl group and the pyrazole ring is substituted at the 4-position with the substituent group α and at the 1-position with a hydrogen atom, a C1 to C10 alkyl group, a C1 to C10 alkyl group mono-substituted with a group selected from the substituent group β, a C1 to C4 haloalkyl group, a C3 to C8 cycloalkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, a C1 to C10 alkylsulfinyl group, a C1 to C10 alkylsulfonyl group, a C1 to C10alkylsulfonyl group mono-substituted with a group selected from the substituent group γ, a C1 to C4 haloalkylsulfonyl group, an optionally substituted phenyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted phenylsulfonyl group, an optionally substituted aromatic heterocyclic sulfonyl group, an acyl group, a C1 to C4 haloalkylcarbonyl group, an optionally substituted benzylcarbonyl group, an optionally substituted benzoyl group, a C1 to C10 alkoxycarbonyl group, an optionally substituted benzyloxycarbonyl group, an optionally substituted phenoxycarbonyl group, a carbamoyl group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups and optionally substituted phenyl group), or an amino group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups, optionally substituted phenyl group; acyl groups, C1 to C4 haloalkylcarbonyl groups, optionally substituted benzylcarbonyl group, optionally substituted benzoyl group, C1 to C10 alkylsulfonyl groups, C1 to C4 haloalkylsulfonyl groups, optionally substituted benzylsulfonyl group and optionally substituted phenylsulfonyl group).

[0030] (11) An, isoxazoline derivative according to (7), wherein Y is an isoxazol-4-yl group and the isoxazole ring is substituted with the substituent group α at the 3- and 5-positions.

[0031] (12) An isoxazoline derivative according to (7), wherein Y is an isothiazol-4-yl group and the isothiazole ring is substituted with the substituent group α at the 3- and 5-positions.

[0032] (13) An isoxazoline derivative according to (7), wherein Y is a pyridin-3-yl group and the pyridine ring is substituted with the substituent group α at the 2- and 4-positions.

[0033] (14) An isoxazoline derivative according to (7), wherein Y is a pyrimidin-5-yl group and the pyrimidine ring is substituted with the substituent group α at the 4- and 6-positions.

[0034] (15) An isoxazoline derivative according to any of (1) to (14), wherein n is an integer of 2.

[0035] (16) An isoxazoline derivative according to any of (1) to (14)., wherein n is an integer of 1.

[0036] (17) An isoxazoline derivative according to any of (1) to (14), wherein n is an integer of 0.

[0037] (18) A herbicide containing, as the active ingredient, an isoxazoline derivative set forth in any of (1) to (17) or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0038] The definitions of the terms used in the present specification are given below.

[0039] The expression of “C1 to C10”, etc. indicates that the substituent appearing after the expression has 1 to 10 carbon atoms in the case of “C1 to C10”.

[0040] Halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0041] C1 to C10 alkyl group refers to a straight or branched chain alkyl group of 1 to 10 carbon atoms unless other wise specified; and there can be mentioned, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, isohexyl group, 3,3-dimethylbutyl group, heptyl group and octyl group.

[0042] C3 to C8 cycloalkyl group refers to a cycloalkyl group of 3 to 8 carbon atoms; and there can be mentioned, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group.

[0043] C3 to C8 cycloalkyl C1 to C3 alkyl group (which may be substituted with halogen atom or alkyl group) refers, unless otherwise specified, to a C1 to C3 alkyl group substituted with a C3 to C8 cycloalkyl group which may be substituted with 1 to 4 same or different halogen atoms or C1 to C3 alkyl group; and there can be mentioned, for example, cyclopropylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclopropylpropyl group, 2-cyclopropylpropyl group, 3-cyclopropylpropyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 2-chlorocyclopropylmethyl group, 2,2-dichlorocyclopropylmethyl group, 2-fluorocyclopropylmethyl group, 2,2-difluorocyclopropylmethyl group, 2-methylcyclopropylmethyl group, 2,2-dimethylcyclopropylmethyl group and 2-methylcyclopropylethyl group.

[0044] C3 to C8 cycloalkyl C1 to C3 alkyl group refers to a alkyl group of 1 to 3 carbon atoms, substituted with a cycloalkyl group of 3 to 8 carbon atoms; and there can be mentioned, for example, cyclopropylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclopropylpropyl group, 2-cyclopropylpropyl group, 3-cyclopropylpropyl group, cyclobutylmethyl group, cyclopentylmethyl group and cyclohexylmethyl group.

[0045] C1 to C4 haloalkyl group refers, unless otherwise specified, to a straight or branched chain alkyl group of 1 to 4 carbon atoms, substituted with 1 to 9 same or different halogen atoms; and there can be mentioned, for example, fluoromethyl group, chloromethyl group, bromomethyl group, difluoromethyl group, trifluoromethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group and pentafluoroethyl group.

[0046] C2 to C6 alkenyl group refers to a straight or branched chain alkenyl group of 2 to 6 carbon atoms; and there can be mentioned, for example, ethenyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group and 2-pentenyl group.

[0047] C2 to C6 alkynyl group refers to a straight or branched chain alkynyl group of 2 to 6 carbon atoms; and there can be mentioned, for example, ethynyl group, 2-propynyl group, 1-methyl-2-propynyl group, 2-butynyl group, 3-butynyl group and 2-methyl-3-butynyl group.

[0048] C2 to C6 haloalkenyl group refers, unless otherwise specified, to a straight or branched alkenyl group of 2 to 6 carbon atoms, substituted with 1 to 4 same or different halogen atoms; and there can be mentioned, for example, 3-chloro-2-propenyl group and, 2-chloro-2-propneyl group.

[0049] C1 to C10 alkoxy group refers to an (alkyl)-O— group wherein the alkyl moiety has the above definition; and there can be mentioned, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, tert-butoxy group, n-butoxy group, sec-butoxy group and isobutoxy group.

[0050] C1 to C4 haloalkoxy group refers to a (haloalkyl)-O— group wherein the haloalkyl moiety has the above definition; and there can be mentioned, for example, difluoromethoxy group, trifluoromethoxy group, 2,2-difluoroethoxy group and 2,2,2-trifluoroethoxy group.

[0051] C3 to C8 cycloalkyloxy group refers to a (cycloalkyl)-O— group wherein the cycloalkyl moiety has the above definition; and there can be mentioned, for example, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group and cyclohexyloxy group.

[0052] C3 to C8 cycloalkyl C1 to C3 alkyloxy group refers to a (cycloalkylalkyl)-O— group wherein the cycloalkylalkyl moiety has the above definition; and there can be mentioned, for example, cyclopropylmethoxy group, 1-cyclopropylethoxy group, 2-cyclopropylethoxy group, 1-cyclopropylpropoxy group, 2-chclopropylpropoxy group, 3-cyclopropylpropoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group and cyclohexylmethoxy group.

[0053] C2 to C6 alkenyloxy group and C2 to C6 alkynyloxy group refer, respectively, to an (alkenyl)-O— group and an (alkynyl)-O— group, in each of which the alkenyl or alkynyl moiety has the above definition; and there can be mentioned, for example, 2-propenyloxy group and 2-propynyloxy group.

[0054] C1 to C10 alkoxyimino group refers to an (alkoxy)-N═group wherein the alkoxy moiety has the above definition; and there can be mentioned, for example, methoxyimino group and ethoxyimino group.

[0055] C1 to C10 alkylthio group, C1 to C10 alkylsulfinyl group and C1 to C10 alkylsulfonyl group refer, respectively, to an (alkyl)-S— group, an (alkyl)-SO— group and an (alkyl)-SO2— group, in each of which the alkyl moiety has the above definition; and there can be mentioned, for example, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, methylsulfinyl, group, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group and isopropylsulfonyl group.

[0056] C1 to C10 alkylsulfonyloxy group refers to an (alkylsulfonyl)-O— group wherein the alkylsulfonyl moiety has the above definition, and there can be mentioned, for example, methylsulfonyloxy group and ethylsulfonyloxy group.

[0057] C1 to C10 alkoxycarbonyl group refers to an (alkoxy)-CO— group wherein the alkoxy moiety has the above definition, and there can be mentioned, for, example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group and isopropoxycarbonyl group.

[0058] C1 to C6 acryl group refers to a straight or branched chain aliphatic acyl group of 1 to 6 carbon atoms, and there can be mentioned, for example, formyl group, acetyl group, propionyl group, isopropionyl group, butyryl group and pivaloyl group.

[0059] C1 to C10 acyloxy group refers to an (acyl)-O— group wherein the acyl moiety has the above definition; and there can be mentioned, for example, acetoxy group, propionyloxy group, ispropionyloxy group and pivalolyoxy group.

[0060] C1 to C4 haloalkylcarbonyl group, C1 to C4 haloalkylthio group and C1 to C4 haloalkylsulfonyl group refers, respectively, to a (haloalkyl)-CO— group, a (haloalkyl)-S— group and a (haloalkyl)-SO2— group, in each of which the haloalkyl moiety has the above definition; and there can be mentioned, for example, chloroacetyl group, trifluoroacetyl group, pentafluoropropyl group, difluoromethylthio group, trifluoromethylthio group, chloromethylsulfonyl group, difluoromethylsulfonyl group and trifluoromethylsulfonyl group.

[0061] C1 to C4 haloalkylcarbonyloxy group and C1 to C4 haloalkylsulfonyloxy group refer, respectively, to a (haloalkylcarbonyl)-O— group and a (haloalkylsulfonyl)-O— group, in each of which the haloalkylcarbonyl moiety or the haloalkylsulfonyl moiety has the above definition; and there can be mentioned, for example, chloroacetyloxy group, trifluoroacetyloxy group, chloromethylsulfonyloxy group and trifluoromehtylsulfonyloxy group.

[0062] “Optionally substituted” in (optionally substituted) phenyl group, (optionally substituted) aromatic heterocyclic group, (optionally substituted) phenoxy group, (optionally substituted aromatic heterocyclic oxy group, (optionally substituted) phenylthio group, (optionally substituted) aromatic heterocyclic thio group, (optionally substituted) phenylsulfonyl group, (optionally substituted) phenylsulfonyloxi group, (optionally substituted) aromatic heterocyclic sulfonyl group, (optionally substituted) benzylcarbonyl group, (optionally substituted) benzylcarbonyloxy group, (optionally substituted) benzylsulfonyl group, (optionally substituted) benzoyl group, (optionally substituted) benzoyloxy group, (optionally substituted) benzyloxycarbonyl group and (optionally substituted) phenoxycarbonyl group, refers to being optionally substituted with, for example, halogen atom, C1 to C10 alkyl group, C1 to C4haloalkyl group, C1 to C10 alkoxyalkyl group, C1 to C10 alkoxy group, C1 to C10 alkylthio group, C1 to C10 alkylsulfonyl group, acyl group, C1 to C10 alkoxycarbonyl group, cyano group, carbamoyl group (its nitrogen atom may be substituted with same or different C1 to C10 alkyl groups) nitro group or amino group (its nitrogen atom may be substituted with same or different groups selected from C1 to C10 alkyl groups, C1 to C6 acyl groups, C1 to C4 haloalkylcarbonyl groups, C1 to C10 alkylsulfonyl groups and C1 to C4 haloalkylsulfonyl groups).

[0063] 5- to 6-membered aromatic heterocyclic group having a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom includes, for example, furyl group, thienyl group, pyrrolyl group, pyrazolyl group, isoxazolyl group, isothiazolyl group, oxazolyl group, thiazolyl group, imidazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, triazolyl group, oxadiazolyl group and thiadiazolyl group, each having 1 to 3 hetero atoms.

[0064] Fused aromatic heterocyclic group refers to a group having 1 to 3 hetero atoms randomly selected from nitrogen atom, oxygen atom and sulfur atom; and there can be mentioned, for example, benzofuryl group, benzothienyl group, indolyl group, benzoxazolyl group, benzothiazolyl group, benzimidazolyl group, benzisoxazolyl group, benzisothiazolyl group, indazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group and benzotriazolyl group.

[0065] Aromatic heterocycle in (optionally substituted) aromatic heterocyclic group, (optionally, substituted) aromatic heterocyclic oxy group, (optionally substituted) aromatic heterocyclic thio group and (optionally substituted) aromatic heterocyclic sulfonyl group, refers to a 5- to 6-membered group having 1 to 3 hetero atoms randomly selected from nitrogen atom, oxygen atom and sulfur atom; and there can be mentioned, for example, furyl group, thienyl group, pyrrolyl group, pyrazolyl group, isoxazolyl group, isothiazolyl group, oxazolyl group, thiazolyl group, imidazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, triazolyl group, oxadiazolyl group and thiadiazolyl group.

[0066] Pharmaceutically acceptable salt is a salt of a compound of the general formula [I]having, in the structure, hydroxyl group, carboxyl group, amino group or the like, with a metal or an organic base or with a mineral acid or an organic acid. As the metal, there can be mentioned alkali metals such as sodium, potassium and the like; and alkaline earth metals such as magnesium, calcium and the like. As the organic base, there can be mentioned triethylamine, diisopropylamine, etc. As the mineral acids, there can be mentioned hydrochloric acid, sulfuric acid, etc. As the organic acid, there can be mentioned acetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.

[0067] In the above-mentioned general formula [I], it is preferred that

[0068] R1 and R2 may be the same or different and are each a methyl group or an ethyl group;

[0069] R3; R4, R5 and R6 are each a hydrogen atom;

[0070] n is an integer of 2; and

[0071] Y is a thiophen-3-yl group [the 2- and 4-positions of the group are substituted with same or different groups selected from halogen atoms, alkyl groups, haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups, alkoxy groups, haloalkoxy groups, acyl groups, haloalkylcarbonyl groups, alkoxycarbonyl groups, cyano group and carbamoyl group (its nitrogen atom may be substituted with same or different alkyl groups)], or

[0072] a pyrazol-4-yl group [the 3- and 5-positions of the group are substituted with same or different groups selected from halogen atoms, alkyl groups, haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkylalkyloxy groups, optionally substituted phenoxy group, alkylthio groups, alkylsulfonyl groups, acyl groups, haloalkylcarbonyl groups, alkoxycarbonyl groups, cyano group and carbamoyl group (its nitrogen atom may be substituted with same or different alkyl groups); the 1-position is substituted with hydrogen atom, alkyl group, alkyl group mono-substituted with a group selected from the substituent group β, haloalkyl group, cycloalkyl group, alkenyl group, alkynyl group, alkylsulfonyl group, alkylsulfonyl group mono-substituted with a group selected from the substituent group γ, haloalkylsulfonyl group, optionally substituted phenyl group, optionally substituted aromatic heterocyclic group, optionally substituted phenylsulfonyl group, optionally substituted aromatic heterocyclicsulfonyl group, acyl group, haloalkylcarbonyl group, optionally substituted benzylcarbonyl group, optionally substituted benzoyl group, alkoxycarbonyl group, optionally substituted benzyloxycarbonyl group, optionally substituted phenoxycarbonyl group or carbamoyl group (its nitrogen atom may be substituted with same or different groups selected from alkyl groups and optionally substituted phenyl group)], or

[0073] a pyrazol-5-yl group [the 4-position of the group is substituted with halogen atom, alkyl group, haloalkyl group, alkoxyalkyl group, haloalkoxy group, acyl group, haloalkylcarbonyl group, alkoxycarbonyl group, cyano group or carbamoyl group (its nitrogen atom maybe substituted with same or different alkyl groups); the 1-position is substituted with hydrogen atom, alkyl group, alkyl group mono-substituted with a group selected from the substituent group β, haloalkyl group, cycloalkyl group; or optionally substituted phenyl group], or

[0074] an isoxazol-4-yl group [the 3- and 5-positions of the group are substituted with same or different groups selected from halogen atoms, alkyl groups, haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups, alkoxy groups, haloalkoxy groups, alkylthio groups, alkylsulfonyl groups, acyl groups, haloalkylcarbonyl groups, alkoxycarbonyl groups, cyano group and carbamoyl group (its nitrogen atom may be substituted with same or different alkyl groups)], or

[0075] an isothiazol-4-yl group -[the 3- and 5-positions of the group are substituted with same or different groups selected from halogen atoms, alkyl groups,haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups, alkoxy groups, haloalkoxy groups, optionally substituted phenoxy group, alkylthio groups, alkylsulfonyl groups, acyl groups, haloalkylcarbonyl groups, alkoxycarbonyl groups, cyano group and carbamoyl group (its nitrogen atom may be substituted with same or different alkyl groups)], or

[0076] a pyridin-3-yl group [the 2- and 4-positions of the group are substituted with same or different groups selected from halogen atoms, alkyl groups, haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups, alkoxy groups, haloalkoxy groups, alkylthio groups, alkylsulfonyl groups, acyl groups, haloalkylcarbonyl groups, alkoxycarbonyl groups, cyano group and carbamoyl group (its nitrogen atom may be substituted with same or different alkyl groups)], or

[0077] a pyrimidin-5-yl group [the 4- and 6-positions of the group are substituted with same or different groups selected from halogen atoms, alkyl groups, haloalkyl groups, alkoxyalkyl groups, cycloalkyl groups, alkoxy groups, haloalkoxy groups, alkylthio groups, alkylsulfonyl groups, acyl groups, haloalkylcarbonyl groups, alkoxycarbonyl groups, cyano group and carbamoyl group (its nitrogen atom may be substituted with same or different alkyl groups)].

[0078] Next, representative examples of the present compound represented by the general formula [I] are shown in Tables 1 to 10. However, the present compound is not restricted to these examples.

[0079] The following abbreviated expressions used in the Tables refer to the following groups.

1Me:methyl groupEt:ethyl groupPr:n-propyl groupPr-i:isopropyl groupPr-c:cyclopropyl roupBu:n-butyl groupBu-i:isobutyl groupBu-s:sec-butyl groupBu-t:tert-butyl groupBu-c:cyclobutyl groupPen:n-pentyl groupPen-c:cyclopentyl groupHex:n-hexyl groupHex-c:cyclohexyl groupPh:phenyl group

[0080] For example, (4-Cl)Ph indicates 4-chlorophenyl group, and 3-Hex indicates 3-hexyl group.

[0081] When the present compound contains hydroxyl group as a substituent, there may exist keto-enol tautomers. Any of these tautomers and any mixture of these tautomers are included in the present compound.

2TABLE 1

R1R2R3R4nR5R6Z1R22R23R24MeMeHH2HHSMeHHMeMeHH2HHSClMeHMeMeHH2HHSHHMeMeMeHH2HHSClHHMeMeHH2HHSHHClMeMeHH2HHSClClClMeMeHH2HHSOmeHHMeMeHH2HHSOEtHHMeMeHH2HHSOCHF2HHMeMeHH2HHSOCH2PhHHMeMeHH2HHOHHHMeMeHH2HHOHHC(═O)OmeMeMeHH2HHNMeMeHMeMeMeHH2HHNMeMeC(═O)OMeCH2C(═O)OMeMeMeHH2HHNMeMeC(═O)OEtCH2C(═O)OEtMeMeHH2HHNMeMeMeMeMeMeHH2HHNPhOMeHHMeMeHH2HHNPhOEtHHMeMeHH2HHNPhOCHF2HHHHHH2HHSOCHF2HHMeHHH2HHSOCHF2HHMeHMeH2HHSOCHF2HHMeMeHH2MeHSOCHF2HHMeMeHH2EtHSOCHF2HHMeMeHH2Pr-iHSOCHF2HHMeMeHH2MeMeSOCHF2HHMeEtHH2HHSOCHF2HHEtEtHH2HHSOCHF2HHMePr-iHH2HHSOCHF2HHMePrHH2HHSOCHF2HHMePr-cHH2HHSOCHF2HHMeCH2Pr-cHH2HHSOCHF2HH—(CH2)2—HH2HHSClClCl—(CH2)3—HH2HHSClClCl—(CH2)4—HH2HHSClClCl—(CH2)5—HH2HHSClClClH—(CH2)3—H2HHSClClClH—(CH2)4—H2HHSClClClH—(CH2)5—H2HHSClClClH—(CH2)6—H2HHSClClClMeMeHH1HHSMeHHMeMeHH1HHSClMeHMeMeHH1HHSHHMeMeMeHH1HHSClHHMeMeHH1HHSHHClMeMeHH1HHSClClClMeMeHH1HHSOMeHHMeMeHH1HHSOEtHHMeMeHH1HHSOCHF2HHMeMeHH1HHSOCH2PhHHMeMeHH1HHOHHHMeMeHH1HHOHHC(═O)OmeMeMeHH1HHNMeMeHMeMeMeHH1HHNMeMeC(═O)OMeCH2C(═O)OMeMeMeHH1HHNMeMeC(═O)OEtCH2C(═O)OEtMeMeHH1HHNMeMeMeMeMeMeHH1HHNPhOMeHHMeMeHH1HHNPhOEtHHMeMeHH1HHNPhOCHF2HHHHHH1HHSOCHF2HHMeHHH1HHSOCHF2HHMeHMeH1HHSOCHF2HHMeMeHH1MeHSOCHF2HHMeMeHH1EtHSOCHF2HHMeMeHH1Pr-iHSOCHF2HHMeMeHH1MeMeSOCHF2HHMeEtHH1HHSOCHF2HHEtEtHH1HHSOCHF2HHMePr-iHH1HHSOCHF2HHMePrHH1HHSOCHF2HHMePr-cHH1HHSOCHF2HHMeCH2Pr-cHH1HHSOCHF2HH—(CH2)2—HH1HHSClClCl—(CH2)3—HH1HHSClClCl—(CH2)4—HH1HHSClClCl—(CH2)5—HH1HHSClClClH—(CH2)3—H1HHSClClClH—(CH2)4—H1HHSClClClH—(CH2)5—H1HHSClClClH—(CH2)6—H1HHSClClClMeMeHH0HHSMeHHMeMeHH0HHSClMeHMeMeHH0HHSHHMeMeMeHH0HHSClHHMeMeHH0HHSHHClMeMeHH0HHSClClClMeMeHH0HHSOMeHHMeMeHH0HHSOEtHHMeMeHH0HHSOCHF2HHMeMeHH0HHSOCH2PhHHMeMeHH0HHOHHHMeMeHH0HHOHHC(═O)OmeMeMeHH0HHNMeMeHMeMeMeHH0HHNMeMeC(═O)OMeCH2C(═O)OMeMeMeHH0HHNMeMeC(═O)OEtCH2C(═O)OEtMeMeHH0HHNMeMeMeMeMeMeHH0HHNPhOMeHHMeMeHH0HHNPhOEtHHMeMeHH0HHNPhOCHF2HHHHHH0HHSOCHF2HHMeHHH0HHSOCHF2HHMeHMeH0HHSOCHF2HHMeMeHH0MeHSOCHF2HHMeMeHH0EtHSOCHF2HHMeMeHH0Pr-iHSOCHF2HHMeMeHH0MeMeSOCHF2HHMeEtHH0HHSOCHF2HHEtEtHH0HHSOCHF2HHMePr-iHH0HHSOCHF2HHMePrHH0HHSOCHF2HHMePr-cHH0HHSOCHF2HHMeCH2Pr-cHH0HHSOCHF2HH—(CH2)2—HH0HHSClClCl—(CH2)3—HH0HHSClClCl—(CH2)4—HH0HHSClClCl—(CH2)5—HH0HHSClClClH—(CH2)3—H0HHSClClClH—(CH2)4—H0HHSClClClH—(CH2)5—H0HHSClClClH—(CH2)6—H0HHSClClClMeEtHH2HHSHHHMeEtHH2HHOHHHMeEtHH2HHNHHHH

[0082]

3

TABLE 2

R1
R2
R3
R4
n
R5
R6
Z2
R25
R26
R27

Me
Me
H
H
2
H
H
S
H
H
H

Me
Me
H
H
2
H
H
S
H
OMe
H

Me
Me
H
H
2
H
H
S
Cl
H
Cl

Me
Me
H
H
2
H
H
S
Cl
Cl
Cl

Me
Me
H
H
2
H
H
S
Cl
Me
H

Me
Me
H
H
2
H
H
S
NHMe
Me
H

Me
Me
H
H
2
H
H
S
N(Me)2
Me
H

Me
Me
H
H
2
H
H
S
NHC(═O)Me
Me
H

Me
Me
H
H
2
H
H
S
NHC(═O)Ph
Me
H

Me
Me
H
H
2
H
H
S
NHSO2Me
Me
H

Me
Me
H
H
2
H
H
S
NHSO2Ph
Me
H

Me
Me
H
H
2
H
H
S
Me
Me
Me

Me
Me
H
H
2
H
H
S
Me
C(═O)OMe
Me

Me
Me
H
H
2
H
H
S
Me
C(═O)OEt
Me

Me
Me
H
H
2
H
H
S
Me
C(═O)OPh
Me

Me
Me
H
H
2
H
H
S
Me
CN
Me

Me
Me
H
H
2
H
H
S
Me
C(═O)NHMe
Me

Me
Me
H
H
2
H
H
S
Me
C(═O)Me
Me

Me
Me
H
H
2
H
H
S
Me
C(═O)Et
Me

Me
Me
H
H
2
H
H
S
Me
C(═O)Pr-i
Me

Me
Me
H
H
2
H
H
S
Me
C(═O)Pr
Me

Me
Me
H
H
2
H
H
S
Me
C(═O)CF3
Me

Me
Me
H
H
2
H
H
S
Me
C(NOMe)Me
Me

Me
Me
H
H
2
H
H
S
Ph
C(═O)Me
Me

Me
Me
H
H
2
H
H
S
Ph
C(═NOMe)Me
Me

Me
Me
H
H
2
H
H
S
CF3
OMe
H

Me
Me
H
H
2
H
H
S
CF3
OFt
H

Me
Me
H
H
2
H
H
S
CF3
OPr-i
H

Me
Me
H
H
2
H
H
S
CF3
OPr-i
H

Me
Me
H
H
2
H
H
S
CF3
OCHF2
H

Me
Me
H
H
2
H
H
S
Cl
Me
H

Me
Me
H
H
2
H
H
S
Cl
Me
Me

Me
Me
H
H
2
H
H
S
Cl
C(═O)OMe
Cl

Me
Me
H
H
2
H
H
S
Cl
CN
Cl

Me
Me
H
H
2
H
H
S
Cl
C(═O)NHMe
Cl

Me
Me
H
H
2
H
H
S
Cl
C(═O)N(Me)2
Cl

Me
Me
H
H
2
H
H
S
Cl
C(═O)Me
Cl

Me
Me
H
H
2
H
H
S
Cl
C(═O)Et
Cl

Me
Me
H
H
2
H
H
S
Cl
C(═O)Pr-i
Cl

Me
Me
H
H
2
H
H
S
Cl
C(═O)Pr
Cl

Me
Me
H
H
2
H
H
S
Cl
C(~O)CF3
Cl

Me
Me
H
H
2
H
H
S
Cl
C(~NOMe)Me
Cl

Me
Me
H
H
2
H
H
O
H
H
H

Me
Me
H
H
2
H
H
O
Me
H
Cl

H
H
H
H
2
H
H
S
Cl
Cl
Cl

Me
H
H
H
2
H
H
S
Cl
Cl
Cl

Me
H
Me
H
2
H
H
S
Cl
Cl
Cl

Me
Me
H
H
2
Me
H
S
Cl
Cl
Cl

Me
Me
H
H
2
Et
H
S
Cl
Cl
Cl

Me
Me
H
H
2
Pr-i
H
S
Cl
Cl
Cl

Me
Me
H
H
2
Me
Me
S
Cl
Cl
Cl

Me
Et
H
H
2
H
H
S
Cl
Cl
Cl

Et
Ft
H
H
2
H
H
S
Cl
Cl
Cl

Me
Pr-i
H
H
2
H
H
S
Cl
Cl
Cl

Me
Pr
H
H
2
H
H
S
Cl
Cl
Cl

Me
Pr-c
H
H
2
H
H
S
Cl
Cl
Cl

Me
CH2Pr-c
H
H
2
H
H
S
Cl
Cl
Cl

—(CH2)2—
H
H
2
H
H
S
Cl
Cl
Cl

—(CH2)3—
H
H
2
H
H
S
Cl
Cl
Cl

—(CH2)4—
H
H
2
H
H
S
Cl
Cl
Cl

—(CH2)5—
H
H
2
H
H
S
Cl
Cl
Cl

H
—(CH2)3—
H
2
H
H
S
Cl
Cl
Cl

H
—(CH2)4—
H
2
H
H
S
Cl
Cl
Cl

H
—(CH2)5—
H
2
H
H
S
Cl
Cl
Cl

H
—(CH2)6—
H
2
H
H
S
Cl
Cl
Cl

Me
Me
H
H
1
H
H
S
H
H
H

Me
Me
H
H
1
H
H
S
H
OMe
H

Me
Me
H
H
1
H
H
S
Cl
H
Cl

Me
Me
H
H
1
H
H
S
Cl
Cl
Cl

Me
Me
H
H
1
H
H
S
Cl
Me
H

Me
Me
H
H
1
H
H
S
NHMe
Me
H

Me
Me
H
H
1
H
H
S
N(Me)2
Me
H

Me
Me
H
H
1
H
H
S
NHC(═O)Me
Me
H

Me
Me
H
H
1
H
H
S
NHC(═O)Ph
Me
H

Me
Me
H
H
1
H
H
S
NHSO2Me
Me
H

Me
Me
H
H
1
H
H
S
NHSO2Ph
Me
H

Me
Me
H
H
1
H
H
S
Me
Me
Me

Me
Me
H
H
1
H
H
S
Me
C(═O)OMe
Me

Me
Me
H
H
1
H
H
S
Me
C(═O)OEt
Me

Me
Me
H
H
1
H
H
S
Me
C(═O)OPh
Me

Me
Me
H
H
1
H
H
S
Me
CN
Me

Me
Me
H
H
1
H
H
S
Me
C(═O)NHMe
Me

Me
Me
H
H
1
H
H
S
Me
C(═O)Me
Me

Me
Me
H
H
1
H
H
S
Me
C(═O)Et
Me

Me
Me
H
H
1
H
H
S
Me
C(═O)Pr-i
Me

Me
Me
H
H
1
H
H
S
Me
C(═O)Pr
Me

Me
Me
H
H
1
H
H
S
Me
C(═O)CF3
Me

Me
Me
H
H
1
H
H
S
Me
C(═NOMe)Me
Me

Me
Me
H
H
1
H
H
S
Ph
C(═O)Me
Me

Me
Me
H
H
1
H
H
S
Ph
C(═NOMe)Me
Me

Me
Me
H
H
1
H
H
S
CF3
OMe
H

Me
Me
H
H
1
H
H
S
CF3
OEt
H

Me
Me
H
H
1
H
H
S
CF3
OPr-i
H

Me
Me
H
H
1
H
H
S
CF3
OPr-i
H

Me
Me
H
H
1
H
H
S
CF3
OCHF2
H

Me
Me
H
H
1
H
H
S
Cl
Me
H

Me
Me
H
H
1
H
H
S
Cl
Me
Me

Me
Me
H
H
1
H
H
S
Cl
C(═O)OMe
Cl

Me
Me
H
H
1
H
H
S
Cl
CN
Cl

Me
Me
H
H
1
H
H
S
Cl
C(═O)NHMe
Cl

Me
Me
H
H
1
H
H
S
Cl
C(═O)N(Me)2
Cl

Me
Me
H
H
1
H
H
S
Cl
C(═O)Me
Cl

Me
Me
H
H
1
H
H
S
Cl
C(═O)Et
Cl

Me
Me
H
H
1
H
H
S
Cl
C(═O)Pr-i
Cl

Me
Me
H
H
1
H
H
S
Cl
C(═O)Pr
Cl

Me
Me
H
H
1
H
H
S
Cl
C(═O)CF3
Cl

Me
Me
H
H
1
H
H
S
Cl
C(═NOMe)Me
Cl

Me
Me
H
H
1
H
H
O
H
H
H

Me
Me
H
H
1
H
H
O
Me
H
Cl

H
H
H
H
1
H
H
S
Cl
Cl
Cl

Me
H
H
H
1
H
H
S
Cl
Cl
Cl

Me
H
Me
H
1
H
H
S
Cl
Cl
Cl

Me
Me
H
H
1
Me
H
S
Cl
Cl
Cl

Me
Me
H
H
1
Et
H
S
Cl
Cl
Cl

Me
Me
H
H
1
Pr-i
H
S
Cl
Cl
Cl

Me
Me
H
H
1
Me
Me
S
C1
Cl
Cl

Me
Et
H
H
1
H
H
S
Cl
Cl
Cl

Et
Et
H
H
1
H
H
S
Cl
Cl
Cl

Me
Pr-i
H
H
1
H
H
S
Cl
Cl
Cl

Me
Pr
H
H
1
H
H
S
Cl
Cl
Cl

Me
Pr-c
H
H
1
H
H
S
Cl
Cl
Cl

Me
CH2Pr-c
H
H
1
H
H
S
Cl
Cl
Cl

—(CH2)2—
H
H
1
H
H
S
Cl
Cl
Cl

—(CH2)3—
H
H
1
H
H
S
Cl
Cl
Cl

—(CH2)4—
H
H
1
H
H
S
Cl
Cl
Cl

—(CH2)5—
H
H
1
H
H
S
Cl
Cl
Cl

H
—(CH2)3—
H
1
H
H
S
Cl
Cl
Cl

H
—(CH2)4—
H
1
H
H
S
Cl
Cl
Cl

H
—(CH2)5—
H
1
H
H
S
Cl
Cl
Cl

H
—(CH2)6—
H
1
H
H
S
Cl
Cl
Cl

Me
Me
H
H
0
H
H
S
H
H
H

Me
Me
H
H
0
H
H
S
H
OMe
H

Me
Me
H
H
0
H
H
S
Cl
H
Cl

Me
Me
H
H
0
H
H
S
Cl
Cl
Cl

Me
Me
H
H
0
H
H
S
Cl
Me
H

Me
Me
H
H
0
H
H
S
NHMe
Me
H

Me
Me
H
H
0
H
H
S
N(Me)2
Me
H

Me
Me
H
H
0
H
H
S
NHC(═O)Me Me
Me
H

Me
Me
H
H
0
H
H
S
NHC(═O)Ph Me
Me
H

Me
Me
R
H
0
H
H
S
NHSO2Me
Me
H

Me
Me
H
H
0
H
H
S
NHSO2Ph
Me
H

Me
Me
H
H
0
H
H
S
Me
Me
Me

Me
Me
H
H
0
H
H
S
Me
C(═O)OMe
Me

Me
Me
H
H
0
H
H
S
Me
C(═O)OEt
Me

Me
Me
H
H
0
H
H
S
Me
C(═O)OPh
Me

Me
Me
H
H
0
H
H
S
Me
CN
Me

Me
Me
H
H
0
H
H
S
Me
C(═O)NHMe
Me

Me
Me
H
H
0
H
H
S
Me
C(═O)Me
Me

Me
Me
H
H
0
H
H
S
Me
C(═O)Et
Me

Me
Me
H
H
0
H
H
S
Me
C(═O)Pr-i
Me

Me
Me
H
H
0
H
H
S
Me
C(═O)Pr
Me

Me
Me
H
H
0
H
H
S
Me
C(═O)CF3
Me

Me
Me
H
H
0
H
H
S
Me
C(═NOMe)Me
Me

Me
Me
H
H
0
H
H
S
Ph
C(═O)Me
Me

Me
Me
H
H
0
H
H
S
Ph
C(═NOMe)Me
Me

Me
Me
H
H
0
H
H
S
CF3
OMe
H

Me
Me
H
H
0
H
H
S
CF3
OEt
H

Me
Me
H
H
0
H
H
S
CF3
OPr-i
H

Me
Me
H
H
0
H
H
S
CF3
OPr-i
H

Me
Me
H
H
0
H
H
S
CF3
OCHF2
H

Me
Me
H
H
0
H
H
S
Cl
Me
H

Me
Me
H
H
0
H
H
S
Cl
Me
Me

Me
Me
H
H
0
H
H
S
Cl
C(═O)OMe
Cl

Me
Me
H
H
0
H
H
S
Cl
CN
Cl

Me
Me
H
H
0
H
H
S
Cl
C(═O)NHMe
Cl

Me
Me
H
H
0
H
H
S
Cl
C(═O)N(Me)2
Cl

Me
Me
H
H
0
H
H
S
Cl
C(═O)Me
Cl

Me
Me
H
H
0
H
H
S
Cl
C(═O)Et
Cl

Me
Me
H
H
0
H
H
S
Cl
C(═O)Pr-i
Cl

Me
Me
H
H
0
H
H
S
Cl
C(═O)Pr
Cl

Me
Me
H
H
0
H
H
S
Cl
C(═O)CF3
Cl

Me
Me
H
H
0
H
H
S
Cl
C(═NOMe)Me
Cl

Me
Me
H
H
0
H
H
O
H
H
H

Me
Me
H
H
0
H
H
O
Me
H
Cl

H
H
H
H
0
H
H
S
Cl
Cl
Cl

Me
H
H
H
0
H
H
S
Cl
Cl
Cl

Me
H
Me
H
0
H
H
S
Cl
Cl
Cl

Me
Me
H
H
0
Me
H
S
Cl
Cl
Cl

Me
Me
H
H
0
Et
H
S
Cl
Cl
Cl

Me
Me
H
H
0
Pr-i
H
S
Cl
Cl
Cl

Me
Me
H
H
0
Me
Me
S
Cl
Cl
Cl

Me
Et
H
H
0
H
H
S
Cl
Cl
Cl

Et
Et
H
H
0
H
H
S
Cl
Cl
Cl

Me
Pr-i
H
H
0
H
H
S
Cl
Cl
Cl

Me
Pr
H
H
0
H
H
S
Cl
Cl
Cl

Me
Pr-c
H
H
0
H
H
S
Cl
Cl
Cl

Me
CH2Pr-c
H
H
0
H
H
S
Cl
Cl
Cl

—(CH2)2—
H
H
0
H
H
S
Cl
Cl
Cl

—(CH2)3—
H
H
0
H
H
S
Cl
Cl
Cl

—(CH2)4—
H
H
0
H
H
S
Cl
Cl
Cl

—(CH2)5—
H
H
0
H
H
S
Cl
Cl
Cl

H
—(CH2)3—
H
0
H
H
S
Cl
Cl
Cl

H
—(CH2)4—
H
0
H
H
S
Cl
Cl
Cl

H
—(CH2)5—
H
0
H
H
S
Cl
Cl
Cl

H
—(CH2)6—
H
0
H
H
S
Cl
Cl
Cl

[0083]

4

TABLE 3

R1
R2
R3
R4
n
R5
R6
R29
R28
R30

Me
Me
H
H
2
H
H
Cl
H
Cl

Me
Me
H
H
2
H
H
OCHF2
H
Cl

Me
Me
H
H
2
H
H
OCHF2
H
OCHF2

Me
Me
H
H
2
H
H
Me
H
Cl

Me
Me
H
H
2
H
H
Me
H
OCHF2

Me
Me
H
H
2
H
H
CHF2
H
Cl

Me
Me
H
H
2
H
H
CHF2
H
OCHF2

Me
Me
H
H
2
H
H
CF3
H
F

Me
Me
H
H
2
H
H
CF3
H
Cl

Me
Me
H
H
2
H
H
CF3
H
OMe

Me
Me
H
H
2
H
H
CF3
H
OEt

Me
Me
H
H
2
H
H
CF3
H
OCHF2

Me
Me
H
H
2
H
H
CF3
H
CN

Me
Me
H
H
2
H
H
CF3
H
Me

Me
Me
H
H
2
H
H
H
Me
Cl

Me
Me
H
H
2
H
H
Me
Me
Me

Me
Me
H
H
2
H
H
Me
Me
F

Me
Me
H
H
2
H
H
F
Me
Me

Me
Me
H
H
2
H
H
Me
Me
Cl

Me
Me
H
H
2
H
H
Cl
Me
Me

Me
Me
H
H
2
H
H
Me
Me
OMe

Me
Me
H
H
2
H
H
OMe
Me
Me

Me
Me
H
H
2
H
H
Me
Me
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Me
Me

Me
Me
H
H
2
H
H
Me
Me
CN

Me
Me
H
H
2
H
H
CN
Me
Me

Me
Me
H
H
2
H
H
Et
Me
F

Me
Me
H
H
2
H
H
F
Me
Et

Me
Me
H
H
2
H
H
Et
Me
Cl

Me
Me
H
H
2
H
H
Cl
Me
Et

Me
Me
H
H
2
H
H
Et
Me
OMe

Me
Me
H
H
2
H
H
OMe
Me
Et

Me
Me
H
H
2
H
H
Et
Me
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Me
Et

Me
Me
H
H
2
H
H
Et
Me
CN

Me
Me
H
H
2
H
H
CN
Me
Et

Me
Me
H
H
2
H
H
Pr-i
Me
F

Me
Me
H
H
2
H
H
F
Me
Pr-i

Me
Me
H
H
2
H
H
Pr-i
Me
Cl

Me
Me
H
H
2
H
H
Cl
Me
Pr-i

Me
Me
H
H
2
H
H
Pr-i
Me
OMe

Me
Me
H
H
2
H
H
OMe
Me
Pr-i

Me
Me
H
H
2
H
H
Pr-i
Me
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Me
Pr-i

Me
Me
H
H
2
H
H
Pr-i
Me
CN

Me
Me
H
H
2
H
H
CN
Me
Pr-i

Me
Me
H
H
2
H
H
Bu-t
Me
F

Me
Me
H
H
2
H
H
F
Me
Bu-t

Me
Me
H
H
2
H
H
Bu-t
Me
Cl

Me
Me
H
H
2
H
H
Cl
Me
Bu-t

Me
Me
H
H
2
H
H
Bu-t
Me
OMe

Me
Me
H
H
2
H
H
OMe
Me
Bu-t

Me
Me
H
H
2
H
H
Bu-t
Me
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Me
Bu-t

Me
Me
H
H
2
H
H
Bu-t
Me
CN

Me
Me
H
H
2
H
H
CN
Me
Bu-t

Me
Me
H
H
2
H
H
CH2OMe
Me
F

Me
Me
H
H
2
H
H
F
Me
CH2OMe

Me
Me
H
H
2
H
H
CH2OMe
Me
Cl

Me
Me
H
H
2
H
H
Cl
Me
CH2OMe

Me
Me
H
H
2
H
H
CH2OMe
Me
OMe

Me
Me
H
H
2
H
H
OMe
Me
CH2OMe

Me
Me
H
H
2
H
H
CH2OMe
Me
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Me
CH2OMe

Me
Me
H
H
2
H
H
CH2OMe
Me
CN

Me
Me
H
H
2
H
H
CN
Me
CH2OMe

Me
Me
H
H
2
H
H
Cl
Me
Cl

Me
Me
H
H
2
H
H
CHF2
Me
Cl

Me
Me
H
H
2
H
H
Cl
Me
CHF2

Me
Me
H
H
2
H
H
OCHF2
Me
H

Me
Me
H
H
2
H
H
OCHF2
Me
F

Me
Me
H
H
2
H
H
F
Me
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Me
Cl

Me
Me
H
H
2
H
H
Cl
Me
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Me
OMe

Me
Me
H
H
2
H
H
OMe
Me
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Me
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Me
CN

Me
Me
H
H
2
H
H
CN
Me
OCHF2

Me
Me
H
H
2
H
H
CF3
Me
H

Me
Me
H
H
2
H
H
CF3
Me
Cl

Me
Me
H
H
2
H
H
Cl
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
Br

Me
Me
H
H
2
H
H
Br
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
I

Me
Me
H
H
2
H
H
I
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
F

Me
Me
H
H
2
H
H
F
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
OH

Me
Me
H
H
2
H
H
OH
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
OMe

Me
Me
H
H
2
H
H
OMe
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
OEt

Me
Me
H
H
2
H
H
OEt
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
OPr-i

Me
Me
H
H
2
H
H
CF3
Me
OPr

Me
Me
H
H
2
H
H
CF3
Me
OBu-t

Me
Me
H
H
2
H
H
CF3
Me
OBu-s

Me
Me
H
H
2
H
H
CF3
Me
OBu-i

Me
Me
H
H
2
H
H
CF3
Me
OBu

Me
Me
H
H
2
H
H
CF3
Me
O(2-Pen)

Me
Me
H
H
2
H
H
CF3
Me
O(3-Pen)

Me
Me
H
H
2
H
H
CF3
Me
OPen-n

Me
Me
H
H
2
H
H
CF3
Me
O(2-Hex)

Me
Me
H
H
2
H
H
CF3
Me
O(3-Hex)

Me
Me
H
H
2
H
H
CF3
Me
OHex-n

Me
Me
H
H
2
H
H
CF3
Me
OPen-c

Me
Me
H
H
2
H
H
CF3
Me
OHex-c

Me
Me
H
H
2
H
H
CF3
Me
OCH2Pr-c

Me
Me
H
H
2
H
H
CF3
Me
OCH2Bu-c

Me
Me
H
H
2
H
H
CF3
Me
OCH2Pen-c

Me
Me
H
H
2
H
H
CF3
Me
OCH2Hex-c

Me
Me
H
H
2
H
H
CF3
Me
OCH2CH═CH2

Me
Me
H
H
2
H
H
CF3
Me
0CH2C≡CH

Me
Me
H
H
2
H
H
CF3
Me
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
OCH2CHF2

Me
Me
H
H
2
H
H
OCH2CHF2
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
OCH2CF3

Me
Me
H
H
2
H
H
OCH2CF3
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
OCH2CN

Me
Me
H
H
2
H
H
CF3
Me
OCH2C(═O)OEt

Me
Me
H
H
2
H
H
CF3
Me
OCH(Me)C(═O)OEt

Me
Me
H
H
2
H
H
CF3
Me
OCH2C(═O)NH2

Me
Me
H
H
2
H
H
CF3
Me
OCH2C(═O)NHMe

Me
Me
H
H
2
H
H
CF3
Me
OCH2C(═O)N(Me)2

Me
Me
H
H
2
H
H
CF3
Me
OCH2Ph

Me
Me
H
H
2
H
H
CF3
Me
OPh

Me
Me
H
H
2
H
H
CF3
Me
O(2-Cl)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(2-Br)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(2-F)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(2-Me)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(2-OMe)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(2-NO2)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(2-CN)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(2-C(═O)OMe)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(3-Cl)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(3-Br)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(3-F)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(3-Me)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(3-OMe)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(3-NO2)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(3-CN)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(3-C(═O)OMe)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(4-Cl)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(4-Br)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(4-F)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(4-Me)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(4-OMe)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(4-NO2)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(4-CN)Ph

Me
Me
H
H
2
H
H
CF3
Me
O(4-C(═O)OMe)Ph

Me
Me
H
H
2
H
H
CF3
Me
OC(═O)Me

Me
Me
H
H
2
H
H
CF3
Me
OC(═O)Et

Me
Me
H
H
2
H
H
CF3
Me
OC(═O)CH2Ph

Me
Me
H
H
2
H
H
CF3
Me
OC(═O)CF3

Me
Me
H
H
2
H
H
CF3
Me
OC(═O)Ph

Me
Me
H
H
2
H
H
CF3
Me
OSO2Me

Me
Me
H
H
2
H
H
CF3
Me
OSO2Et

Me
Me
H
H
2
H
H
CF3
Me
OSO2CH2Ph

Me
Me
H
H
2
H
H
CF3
Me
OSO2CF3

Me
Me
H
H
2
H
H
CF3
Me
OSO2Ph

Me
Me
H
H
2
H
H
CF3
Me
SMe

Me
Me
H
H
2
H
H
CF3
Me
SOMe

Me
Me
H
H
2
H
H
CF3
Me
SO2Me

Me
Me
H
H
2
H
H
CF3
Me
SEt

Me
Me
H
H
2
H
H
CF3
Me
SOEt

Me
Me
H
H
2
H
H
CF3
Me
SO2Et

Me
Me
H
H
2
H
H
CF3
Me
SPr

Me
Me
H
H
2
H
H
CF3
Me
SOPr

Me
Me
H
H
2
H
H
CF3
Me
SO2Pr

Me
Me
H
H
2
H
H
CF3
Me
SPr-i

Me
Me
H
H
2
H
H
CF3
Me
SOPr-i

Me
Me
H
H
2
H
H
CF3
Me
SO2Pr-i

Me
Me
H
H
2
H
H
CF3
Me
SBu-t

Me
Me
H
H
2
H
H
CF3
Me
SOBu-t

Me
Me
H
H
2
H
H
CF3
Me
SO2Bu-t

Me
Me
H
H
2
H
H
CF3
Me
SCHF2

Me
Me
H
H
2
H
H
CF3
Me
SOCHF2

Me
Me
H
H
2
H
H
CF3
Me
SO2CHF2

Me
Me
H
H
2
H
H
CF3
Me
SCF3

Me
Me
H
H
2
H
H
CF3
Me
SOCF3

Me
Me
H
H
2
H
H
CF3
Me
SO2CF3

Me
Me
H
H
2
H
H
CF3
Me
SPh

Me
Me
H
H
2
H
H
CF3
Me
SOh

Me
Me
H
H
2
H
H
CF3
Me
SO2Ph

Me
Me
H
H
2
H
H
CF3
Me
SCH2Ph

Me
Me
H
H
2
H
H
CF3
Me
SOCH2Ph

Me
Me
H
H
2
H
H
CF3
Me
SO2CH2Ph

Me
Me
H
H
2
H
H
CF3
Me
SCH2C(═O)OEt

Me
Me
H
H
2
H
H
CF3
Me
SOCH2C(═O)OEt

Me
Me
H
H
2
H
H
CF3
Me
SO2CH2C(═O)OEt

Me
Me
H
H
2
H
H
CF3
Me
SCH(Me)C(═O)OEt

Me
Me
H
H
2
H
H
CF3
Me
SOCH(Me)C(═O)OEt

Me
Me
H
H
2
H
H
CF3
Me
SO2CH(Me)C(═O)OEt

Me
Me
H
H
2
H
H
CF3
Me
SCH2C(═O)NH2

Me
Me
H
H
2
H
H
CF3
Me
SOCH2C(═O)NH2

Me
Me
H
H
2
H
H
CF3
Me
SO2CH2C(═O)NH2

Me
Me
H
H
2
H
H
CF3
Me
SCH2C(═O)NHMe

Me
Me
H
H
2
H
H
CF3
Me
SOCH2C(═O)NHMe

Me
Me
H
H
2
H
H
CF3
Me
SO2CH2C(═O)NHMe

Me
Me
H
H
2
H
H
CF3
Me
SCH2C(═O)N(Me)2

Me
Me
H
H
2
H
H
CF3
Me
SOCH2C(═O)N(Me)2

Me
Me
H
H
2
H
H
CF3
Me
SO2CH2C(═O)N(Me)2

Me
Me
H
H
2
H
H
CF3
Me
NH2

Me
Me
H
H
2
H
H
CF3
Me
NHMe

Me
Me
H
H
2
H
H
CF3
Me
N(Me)2

Me
Me
H
H
2
H
H
CF3
Me
NHC(═O)Me

Me
Me
H
H
2
H
H
CF3
Me
N(Me)C(═O)Me

Me
Me
H
H
2
H
H
CF3
Me
NHSO2Me

Me
Me
H
H
2
H
H
CF3
Me
N(Me)SO2Me

Me
Me
H
H
2
H
H
CF3
Me
NHSO2CHF2

Me
Me
H
H
2
H
H
CF3
Me
N(Me)SO2CHF2

Me
Me
H
H
2
H
H
CF3
Me
NHSO2CF3

Me
Me
H
H
2
H
H
CF3
Me
N(Me)SO2CF3

Me
Me
H
H
2
H
H
CF3
Me
NHPh

Me
Me
H
H
2
H
H
CF3
Me
N(Me)Ph

Me
Me
H
H
2
H
H
CF3
Me
CN

Me
Me
H
H
2
H
H
CN
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
C(═O)OMe

Me
Me
H
H
2
H
H
CF3
Me
C(═O)OPr-i

Me
Me
H
H
2
H
H
CF3
Me
C(═O)OCH2Ph

Me
Me
H
H
2
H
H
CF3
Me
C(═O)OPh

Me
Me
H
H
2
H
H
CF3
Me
C(═O)NH2

Me
Me
H
H
2
H
H
CF3
Me
C(═O)NHMe

Me
Me
H
H
2
H
H
CF3
Me
C(═O)N(Me)2

Me
Me
H
H
2
H
H
CF3
Me
C(═O)Me

Me
Me
H
H
2
H
H
CF3
Me
C(═O)CF3

Me
Me
H
H
2
H
H
CF3
Me
C(═O)CH2Ph

Me
Me
H
H
2
H
H
CF3
Me
C(═O)Ph

Me
Me
H
H
2
H
H
CF3
Me
Me

Me
Me
H
H
2
H
H
Me
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
Et

Me
Me
H
H
2
H
H
CF3
Me
Pr-i

Me
Me
H
H
2
H
H
CF3
Me
Pr

Me
Me
H
H
2
H
H
CF3
Me
CH2OMe

Me
Me
H
H
2
H
H
CF3
Me
CF3

Me
Me
H
H
2
H
H
CF3
Me
CHF2

Me
Me
H
H
2
H
H
CF3
Me
Ph

Me
Me
H
H
2
H
H
CF2CF3
Me
Cl

Me
Me
H
H
2
H
H
CN
Me
F

Me
Me
H
H
2
H
H
F
Me
CN

Me
Me
H
H
2
H
H
CN
Me
Cl

Me
Me
H
H
2
H
H
CL
Me
CN

Me
Me
H
H
2
H
H
CN
Me
CN

Me
Me
H
H
2
H
H
COOMe
Me
F

Me
Me
H
H
2
H
H
F
Me
COOMe

Me
Me
H
H
2
H
H
COOMe
Me
Cl

Me
Me
H
H
2
H
H
Cl
Me
COOMe

Me
Me
H
H
2
H
H
SO2Me
Me
Cl

Me
Me
H
H
2
H
H
Cl
Me
SO2Me

Me
Me
H
H
2
H
H
Ph
Me
Me

Me
Me
H
H
2
H
H
Ph
Me
Cl

Me
Me
H
H
2
H
H
Ph
Me
QEt

Me
Me
H
H
2
H
H
Ph
Me
CF3

Me
Me
H
H
2
H
H
Ph
Me
Ph

Me
Me
H
H
2
H
H
Me
Et
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Et
Me

Me
Me
H
H
2
H
H
Me
Et
CN

Me
Me
H
H
2
H
H
CN
Et
Me

Me
Me
H
H
2
H
H
Pr-i
Et
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Et
Pr-i

Me
Me
H
H
2
H
H
Pr-i
Et
CN

Me
Me
H
H
2
H
H
CN
Et
Pr-i

Me
Me
H
H
2
H
H
Cl
Et
Cl

Me
Me
H
H
2
H
H
OCHF2
Et
Cl

Me
Me
H
H
2
H
H
Cl
Et
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Et
OCHF2

Me
Me
H
H
2
H
H
CF3
Et
F

Me
Me
H
H
2
H
H
F
Et
CF3

Me
Me
H
H
2
H
H
CF3
Et
Cl

Me
Me
H
H
2
H
H
Cl
Et
CF3

Me
Me
H
H
2
H
H
CF3
Et
OMe

Me
Me
H
H
2
H
H
OMe
Et
CF3

Me
Me
H
H
2
H
H
CF3
Et
OEt

Me
Me
H
H
2
H
H
OEt
Et
CF3

Me
Me
H
H
2
H
H
CF3
Et
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Et
CF3

Me
Me
H
H
2
H
H
CF3
Et
CN

Me
Me
H
H
2
H
H
CN
Et
CF3

Me
Me
H
H
2
H
H
CF3
Et
Me

Me
Me
H
H
2
H
H
Me
Et
CF3

Me
Me
H
H
2
H
H
Me
Pr-i
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Pr-i
Me

Me
Me
H
H
2
H
H
Me
Pr-i
CN

Me
Me
H
H
2
H
H
CN
Pr-i
Me

Me
Me
H
H
2
H
H
Pr-i
Pr-i
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Pr-i
Pr-i

Me
Me
H
H
2
H
H
Pr-i
Pr-i
CN

Me
Me
H
H
2
H
H
CN
Pr-i
Pr-i

Me
Me
H
H
2
H
H
Cl
Pr-i
Cl

Me
Me
H
H
2
H
H
OCHF2
Pr-i
Cl

Me
Me
H
H
2
H
H
Cl
Pr-i
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Pr-i
OCHF2

Me
Me
H
H
2
H
H
CF3
Pr-i
F

Me
Me
H
H
2
H
H
F
Pr-i
CF3

Me
Me
H
H
2
H
H
CF3
Pr-i
Cl

Me
Me
H
H
2
H
H
Cl
Pr-i
CF3

Me
Me
H
H
2
H
H
CF3
Pr-i
OMe

Me
Me
H
H
2
H
H
OMe
Pr-i
CF3

Me
Me
H
H
2
H
H
CF3
Pr-i
OEt

Me
Me
H
H
2
H
H
OEt
Pr-i
CF3

Me
Me
H
H
2
H
H
CF3
Pr-i
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Pr-i
CF3

Me
Me
H
H
2
H
H
CF3
Pr-i
CN

Me
Me
H
H
2
H
H
CN
Pr-i
CF3

Me
Me
H
H
2
H
H
CF3
Pr-i
Me

Me
Me
H
H
2
H
H
Me
Pr-i
CF3

Me
Me
H
H
2
H
H
Me
Pr
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Pr
Me

Me
Me
H
H
2
H
H
Me
Pr
CN

Me
Me
H
H
2
H
H
CN
Pr
Me

Me
Me
H
H
2
H
H
Pr-i
Pr
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Pr
Pr-i

Me
Me
H
H
2
H
H
Pr-i
Pr
CN

Me
Me
H
H
2
H
H
CN
Pr
Pr-i

Me
Me
H
H
2
H
H
Cl
Pr
Cl

Me
Me
H
H
2
H
H
OCHF2
Pr
Cl

Me
Me
H
H
2
H
H
Cl
Pr
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Pr
OCHF2

Me
Me
H
H
2
H
H
CF3
Pr
F

Me
Me
H
H
2
H
H
F
Pr
CF3

Me
Me
H
H
2
H
H
CF3
Pr
Cl

Me
Me
H
H
2
H
H
Cl
Pr
CF3

Me
Me
H
H
2
H
H
CF3
Pr
OMe

Me
Me
H
H
2
H
H
OMe
Pr
CF3

Me
Me
H
H
2
H
H
CF3
Pr
OEt

Me
Me
H
H
2
H
H
OEt
Pr
CF3

Me
Me
H
H
2
H
H
CF3
Pr
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Pr
CF3

Me
Me
H
H
2
H
H
CF3
Pr
CN

Me
Me
H
H
2
H
H
CN
Pr
CF3

Me
Me
H
H
2
H
H
CF3
Pr
Me

Me
Me
H
H
2
H
H
Me
Pr
CF3

Me
Me
H
H
2
H
H
Me
Bu-t
F

Me
Me
H
H
2
H
H
Me
Bu-t
Cl

Me
Me
H
H
2
H
H
Me
Bu-t
OCHF2

Me
Me
H
H
2
H
H
Me
Bu-t
CN

Me
Me
H
H
2
H
H
Cl
Bu-t
Cl

Me
Me
H
H
2
H
H
OCHF2
Bu-t
Cl

Me
Me
H
H
2
H
H
OCHF2
Bu-t
OCHF2

Me
Me
H
H
2
H
H
CF3
Bu-t
H

Me
Me
H
H
2
H
H
CF3
Bu-t
F

Me
Me
H
H
2
H
H
CF3
Bu-t
Cl

Me
Me
H
H
2
H
H
Cl
Bu-t
CF3

Me
Me
H
H
2
H
H
CF3
Bu-t
OMe

Me
Me
H
H
2
H
H
OMe
Bu-t
CF3

Me
Me
H
H
2
H
H
CF3
Bu-t
OEt

Me
Me
H
H
2
H
H
OEt
Bu-t
CF3

Me
Me
H
H
2
H
H
CF3
Bu-t
OCHF2

Me
Me
H
H
2
H
H
CF3
Bu-t
CN

Me
Me
H
H
2
H
H
CF3
Bu-t
Me

Me
Me
H
H
2
H
H
Me
Bu-t
CF3

Me
Me
H
H
2
H
H
CF3
Bu-s
Cl

Me
Me
H
H
2
H
H
Cl
Bu-s
CF3

Me
Me
H
H
2
H
H
CF3
Bu-i
Cl

Me
Me
H
H
2
H
H
Cl
Bu-i
CF3

Me
Me
H
H
2
H
H
CF3
Bu
Cl

Me
Me
H
H
2
H
H
Cl
Bu
CF3

Me
Me
H
H
2
H
H
CF3
1-Methylbutyl
Cl

Me
Me
H
H
2
H
H
Cl
1-Methylbutyl
CF3

Me
Me
H
H
2
H
H
CF3
1-Ethylpropyl
Cl

Me
Me
H
H
2
H
H
Cl
1-Ethylpropyl
CF3

Me
Me
H
H
2
H
H
CF3
1-Pentyl
Cl

Me
Me
H
H
2
H
H
Cl
1-Pentyl
CF3

Me
Me
H
H
2
H
H
CF3
1-Methylpentyl
Cl

Me
Me
H
H
2
H
H
Cl
1-Methylpentyl
CF3

Me
Me
H
H
2
H
H
CF3
2-Ethylbutyl
Cl

Me
Me
H
H
2
H
H
Cl
2-Ethylbutyl
CF3

Me
Me
H
H
2
H
H
CF3
3,3-Dimethylbutyl
Cl

Me
Me
H
H
2
H
H
Cl
3,3-Dimethylbutyl
CF3

Me
Me
H
H
2
H
H
CF3
1-Hexyl
Cl

Me
Me
H
H
2
H
H
Cl
1-Hexyl
CF3

Me
Me
H
H
2
H
H
CF3
1-Heptyl
Cl

Me
Me
H
H
2
H
H
Cl
1-Heptyl
CF3

Me
Me
H
H
2
H
H
CF3
1-Octyl
Cl

Me
Me
H
H
2
H
H
Cl
1-Octyl
CF3

Me
Me
H
H
2
H
H
CF3
CH2Ph
Cl

Me
Me
H
H
2
H
H
Cl
CH2Ph
CF3

Me
Me
H
H
2
H
H
CF3
Pr-c
F

Me
Me
H
H
2
H
H
CF3
Pr-c
Cl

Me
Me
H
H
2
H
H
CF3
Pr-c
OMe

Me
Me
H
H
2
H
H
CF3
Pr-c
OCHF2

Me
Me
H
H
2
H
H
CF3
Pr-c
CN

Me
Me
H
H
2
H
H
CF3
Pen-c
Cl

Me
Me
H
H
2
H
H
Cl
Pen-c
CF3

Me
Me
H
H
2
H
H
CF3
Hex-c
Cl

Me
Me
H
H
2
H
H
Cl
Hex-c
CF3

Me
Me
H
H
2
H
H
Me
CH2Pr-c
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CH2Pr-c
Me

Me
Me
H
H
2
H
H
Cl
CH2Pr-c
Cl

Me
Me
H
H
2
H
H
OCHF2
CH2Pr-c
Cl

Me
Me
H
H
2
H
H
Cl
CH2Pr-c
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CH2Pr-c
OCHF2

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
F

Me
Me
H
H
2
H
H
F
CH2Pr-c
CF3

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
Cl

Me
Me
H
H
2
H
H
Cl
CH2Pr-c
CF3

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
OH

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
OMe

Me
Me
H
H
2
H
H
OMe
CH2Pr-c
CF3

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
OEt

Me
Me
H
H
2
H
H
OEt
CH2Pr-c
CF3

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
OPr-i

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
OPr

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
OBu-t

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
OCH2Pr-c

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
OCH2Bu-c

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
OPen-c

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CH2Pr-c
CF3

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
CN

Me
Me
H
H
2
H
H
CN
CH2Pr-c
CF3

Me
Me
H
H
2
H
H
CF3
CH2Pr-c
Me

Me
Me
H
H
2
H
H
Me
CH2Pr-c
CF3

Me
Me
H
H
2
H
H
CF3
1-cyclopropylethyl
Cl

Me
Me
H
H
2
H
H
Cl
1-cyclopropylethyl
CF3

Me
Me
H
H
2
H
H
CF3
CH2(2-Methyl-cyclopropyl)
Cl

Me
Me
H
H
2
H
H
Cl
CH2(2-Methyl-cyclopropyl)
CF3

Me
Me
H
H
2
H
H
CF3
CH2(2,2-Dimethyl-cyclopropyl)
Cl

Me
Me
H
H
2
H
H
Cl
CH2(2,2-Dimethyl-cyclopropyl)
CF3

Me
Me
H
H
2
H
H
CF3
CH2(2-Chloro-cyclopropyl)
Cl

Me
Me
H
H
2
H
H
Cl
CH2(2-Chloro-cyclopropyl)
CF3

Me
Me
H
H
2
H
H
CF3
CH2(2,2-Dichloro-cyclopropyl)
Cl

Me
Me
H
H
2
H
H
Cl
CH2(2,2-Dichloro-cyclopropyl)
CF3

Me
Me
H
H
2
H
H
CF3
CH2(2-Fluoro-cyclopropyl)
Cl

Me
Me
H
H
2
H
H
Cl
CH2(2-Fluoro-cyclopropyl)
CF3

Me
Me
H
H
2
H
H
CF3
CH2(2,2-Difluoro-cyclopropyl)
Cl

Me
Me
H
H
2
H
H
Cl
CH2(2,2-Difluoro-cyclopropyl)
CF3

Me
Me
H
H
2
H
H
CF3
CH2Bu-c
Cl

Me
Me
H
H
2
H
H
Cl
CH2Bu-c
CF3

Me
Me
H
H
2
H
H
CF3
CH2Pen-c
Cl

Me
Me
H
H
2
H
H
Cl
CH2Pen-c
CF3

Me
Me
H
H
2
H
H
CF3
CH2Hex-c
Cl

Me
Me
H
H
2
H
H
Cl
CH2Hex-c
CF3

Me
Me
H
H
2
H
H
CF3
CH2CH2Pr-c
Cl

Me
Me
H
H
2
H
H
Cl
CH2CH2Pr-c
CF3

Me
Me
H
H
2
H
H
CF3
CH2CH═CH2
Cl

Me
Me
H
H
2
H
H
Cl
CH2CH═CH2
CF3

Me
Me
H
H
2
H
H
CF3
CH2CH═CHCl
Cl

Me
Me
H
H
2
H
H
Cl
CH2CH═CHCl
CF3

Me
Me
H
H
2
H
H
Me
CH2C≡CH
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CH2C═CH
Me

Me
Me
H
H
2
H
H
Cl
CH2C≡CH
Cl

Me
Me
H
H
2
H
H
OCHF2
CH2C≡CH
Cl

Me
Me
H
H
2
H
H
Cl
CH2C≡CH
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CH2C≡CH
OCHF2

Me
Me
H
H
2
H
H
CF3
CH2C≡CH
F

Me
Me
H
H
2
H
H
F
CH2C≡CH
CF3

Me
Me
H
H
2
H
H
CF3
CH2C≡CH
Cl

Me
Me
H
H
2
H
H
Cl
CH2C≡CH
CF3

Me
Me
H
H
2
H
H
CF3
CH2C≡CH
OMe

Me
Me
H
H
2
H
H
OMe
CH2C≡CH
CF3

Me
Me
H
H
2
H
H
CF3
CH2C≡CH
OEt

Me
Me
H
H
2
H
H
OEt
CH2C≡CH
CF3

Me
Me
H
H
2
H
H
CF3
CH2C≡CH
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CH2C≡CH
CF3

Me
Me
H
H
2
H
H
CF3
CH2C≡CH
CN

Me
Me
H
H
2
H
H
CN
CH2C≡CH
CF3

Me
Me
H
H
2
H
H
CF3
CH2C≡CH
Me

Me
Me
H
H
2
H
H
Me
CH2C≡CH
CF3

Me
Me
H
H
2
H
H
CF3
CHMeC≡CH
Cl

Me
Me
H
H
2
H
H
Cl
CHMeC≡CH
CF3

Me
Me
H
H
2
H
H
CF3
CH2C≡CMe
Cl

Me
Me
H
H
2
H
H
Cl
CH2C≡CMe
CF3

Me
Me
H
H
2
H
H
Me
CHF2
F

Me
Me
H
H
2
H
H
F
CHF2
Me

Me
Me
H
H
2
H
H
Me
CHF2
Cl

Me
Me
H
H
2
H
H
Cl
CHF2
Me

Me
Me
H
H
2
H
H
Me
CHF2
OMe

Me
Me
H
H
2
H
H
OMe
CHF2
Me

Me
Me
H
H
2
H
H
Me
CHF2
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CHF2
Me

Me
Me
H
H
2
H
H
Me
CHF2
CN

Me
Me
H
H
2
H
H
CN
CHF2
Me

Me
Me
H
H
2
H
H
Me
CHF2
Me

Me
Me
H
H
2
H
H
Et
CHF2
Cl

Me
Me
H
H
2
H
H
Cl
CHF2
Et

Me
Me
H
H
2
H
H
Et
CHF2
Et

Me
Me
H
H
2
H
H
Pr-i
CHF2
Cl

Me
Me
H
H
2
H
H
Cl
CHF2
Pr-i

Me
Me
H
H
2
H
H
Cl
CHF2
Cl

Me
Me
H
H
2
H
H
OCHF2
CHF2
Cl

Me
Me
H
H
2
H
H
Cl
CHF2
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CHF2
OCHF2

Me
Me
H
H
2
H
H
CF3
CHF2
Cl

Me
Me
H
H
2
H
H
Cl
CHF2
CF3

Me
Me
H
H
2
H
H
CF3
CHF2
F

Me
Me
H
H
2
H
H
F
CHF2
CF3

Me
Me
H
H
2
H
H
CF3
CHF2
OMe

Me
Me
H
H
2
H
H
OMe
CHF2
CF3

Me
Me
H
H
2
H
H
CF3
CHF2
OEt

Me
Me
H
H
2
H
H
OEt
CHF2
CF3

Me
Me
H
H
2
H
H
CF3
CHF2
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CHF2
CF3

Me
Me
H
H
2
H
H
CF3
CHF2
CN

Me
Me
H
H
2
H
H
CN
CHF2
CF3

Me
Me
H
H
2
H
H
CF3
CHF2
Me

Me
Me
H
H
2
H
H
Me
CHF2
CF3

Me
Me
H
H
2
H
H
CF3
CH2CHF2
Cl

Me
Me
H
H
2
H
H
Cl
CH2CHF2
CF3

Me
Me
H
H
2
H
H
CF3
CH2CF3
Cl

Me
Me
H
H
2
H
H
Cl
CH2CF3
CF3

Me
Me
H
H
2
H
H
CF3
CH2OH
Cl

Me
Me
H
H
2
H
H
Cl
CH2OH
CF3

Me
Me
H
H
2
H
H
Me
CH2OMe
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CH2OMe
Me

Me
Me
H
H
2
H
H
Cl
CH2OMe
Cl

Me
Me
H
H
2
H
H
OCHF2
CH2OMe
Cl

Me
Me
H
H
2
H
H
Cl
CH2OMe
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CH2OMe
OCHF2

Me
Me
H
H
2
H
H
CF3
CH2OMe
F

Me
Me
H
H
2
H
H
F
CH2OMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2OMe
Cl

Me
Me
H
H
2
H
H
Cl
CH2OMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2OMe
OMe

Me
Me
H
H
2
H
H
OMe
CH2OMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2OMe
OEt

Me
Me
H
H
2
H
H
OEt
CH2OMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2OMe
OCHF2

Me
Me
H
H
2
H
H
OCHF2
CH2OMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2OMe
CN

Me
Me
H
H
2
H
H
CN
CH2OMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2OMe
Me

Me
Me
H
H
2
H
H
Me
CH2OMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2OEt
Cl

Me
Me
H
H
2
H
H
Cl
CH2OEt
CF3

Me
Me
H
H
2
H
H
CF3
CH2CH2OH
Cl

Me
Me
H
H
2
H
H
Cl
CH2CH2OH
CF3

Me
Me
H
H
2
H
H
CF3
CH2CH2OMe
Cl

Me
Me
H
H
2
H
H
Cl
CH2CH2OMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2CH2OEt
Cl

Me
Me
H
H
2
H
H
Cl
CH2CH2OEt
CF3

Me
Me
H
H
2
H
H
CF3
CH2NHMe
Cl

Me
Me
H
H
2
H
H
Cl
CH2NHMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2N(Me)2
Cl

Me
Me
H
H
2
H
H
Cl
CH2N(Me)2
CF3

Me
Me
H
H
2
H
H
CF3
CH2N(Me)C(═O)Me
Cl

Me
Me
H
H
2
H
H
Cl
CH2N(Me)C(═O)Me
CF3

Me
Me
H
H
2
H
H
CF3
CH2N(Me)C(═O)CF3
Cl

Me
Me
H
H
2
H
H
Cl
CH2N(Me)C(═O)CF3CF3

Me
Me
H
H
2
H
H
CF3
CH2N(Me)SO2Me
Cl

Me
Me
H
H
2
H
H
Cl
CH2N(Me)SO2Me
CF3

Me
Me
H
H
2
H
H
CF3
CH2N(Me)SO2CHF2
Cl

Me
Me
H
H
2
H
H
Cl
CH2N(Me)SO2CHF2
CF3

Me
Me
H
H
2
H
H
CF3
CH2N(Me)SO2CF3
Cl

Me
Me
H
H
2
H
H
Cl
CH2N(Me)SO2CF3
CF3

Me
Me
H
H
2
H
H
CF3
CH2SMe
Cl

Me
Me
H
H
2
H
H
Cl
CH2SMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2SO2Me
Cl

Me
Me
H
H
2
H
H
Cl
CH2SO2Me
CF3

Me
Me
H
H
2
H
H
CF3
CH2CH2SMe
Cl

Me
Me
H
H
2
H
H
Cl
CH2CH2SMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2CH2SO2Me
Cl

Me
Me
H
H
2
H
H
Cl
CH2CH2SO2Me
CF3

Me
Me
H
H
2
H
H
CF3
CH2CN
Cl

Me
Me
H
H
2
H
H
Cl
CH2CN
CF3

Me
Me
H
H
2
H
H
CF3
CH2C(═O)OMe
Cl

Me
Me
H
H
2
H
H
Cl
CH2C(═O)OMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2C(═O)OEt
Cl

Me
Me
H
H
2
H
H
Cl
CH2C(═O)OEt
CF3

Me
Me
H
H
2
H
H
CF3
CH(Me)C(═O)OMe
Cl

Me
Me
H
H
2
H
H
Cl
CH(Me)C(═O)OMe
CF3

Me
Me
H
H
2
H
H
CF3
C(Me)2C(═O)OMe
Cl

Me
Me
H
H
2
H
H
Cl
C(Me)2C(═O)OMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2C(═O)NH2
Cl

Me
Me
H
H
2
H
H
Cl
CH2C(═O)NH2
CF3

Me
Me
H
H
2
H
H
CF3
CH2C(═O)NHMe
Cl

Me
Me
H
H
2
H
H
Cl
CH2C(═O)NHMe
CF3

Me
Me
H
H
2
H
H
CF3
CH2C(═O)N(Me)2
Cl

Me
Me
H
H
2
H
H
Cl
CH2C(═O)N(Me)2
CF3

Me
Me
H
H
2
H
H
CF3
CH2C(═O)Me
Cl

Me
Me
H
H
2
H
H
Cl
CH2C(═O)Me
CF3

Me
Me
H
H
2
H
H
CF3
CH2C(NOMe)Me
Cl

Me
Me
H
H
2
H
H
Cl
CH2C(═NOMe)Me
CF3

Me
Me
H
H
2
H
H
CF3
CH2C(═O)CF3
Cl

Me
Me
H
H
2
H
H
Cl
CH2C(═O)CF3
CF3

Me
Me
H
H
2
H
H
CF3
CH2CH2C(═O)Me
Cl

Me
Me
H
H
2
H
H
Cl
CH2CH2C(═O)Me
CF3

Me
Me
H
H
2
H
H
Me
Ph
Me

Me
Me
H
H
2
H
H
Me
Ph
F

Me
Me
H
H
2
H
H
Me
Ph
Cl

Me
Me
H
H
2
H
H
Me
Ph
OCHF2

Me
Me
H
H
2
H
H
Me
Ph
CN

Me
Me
H
H
2
H
H
Et
Ph
F

Me
Me
H
H
2
H
H
Et
Ph
Cl

Me
Me
H
H
2
H
H
Et
Ph
OCHF2

Me
Me
H
H
2
H
H
Et
Ph
CN

Me
Me
H
H
2
H
H
Pr
Ph
F

Me
Me
H
H
2
H
H
Pr
Ph
Cl

Me
Me
H
H
2
H
H
Pr
Ph
OCHF2

Me
Me
H
H
2
H
H
Pr
Ph
CN

Me
Me
H
H
2
H
H
Pr-i
Ph
F

Me
Me
H
H
2
H
H
Pr-i
Ph
Cl

Me
Me
H
H
2
H
H
Pr-i
Ph
OCHF2

Me
Me
H
H
2
H
H
Pr-i
Ph
CN

Me
Me
H
H
2
H
H
Bu-t
Ph
Cl

Me
Me
H
H
2
H
H
CH2OMe
Ph
Cl

Me
Me
H
H
2
H
H
Cl
Ph
Cl

Me
Me
H
H
2
H
H
OCHF2
Ph
Cl

Me
Me
H
H
2
H
H
OCHF2
Ph
OCHF2

Me
Me
H
H
2
H
H
CHF2
Ph
Cl

Me
Me
H
H
2
H
H
CF3
Ph
H

Me
Me
H
H
2
H
H
CF3
Ph
Me

Me
Me
H
H
2
H
H
Me
Ph
CF3

Me
Me
H
H
2
H
H
CF3
Ph
Et

Me
Me
H
H
2
H
H
CF3
Ph
Pr-i

Me
Me
H
H
2
H
H
CF3
Ph
CHF2

Me
Me
H
H
2
H
H
CF3
Ph
CF3

Me
Me
H
H
2
H
H
CF3
Ph
F

Me
Me
H
H
2
H
H
CF3
Ph
Cl

Me
Me
H
H
2
H
H
Cl
Ph
CF3

Me
Me
H
H
2
H
H
CF3
Ph
OH

Me
Me
H
H
2
H
H
OH
Ph
CF3

Me
Me
H
H
2
H
H
CF3
Ph
OMe

Me
Me
H
H
2
H
H
OMe
Ph
CF3

Me
Me
H
H
2
H
H
CF3
Ph
OEt

Me
Me
H
H
2
H
H
OEt
Ph
CF3

Me
Me
H
H
2
H
H
CF3
Ph
OPr-i

Me
Me
H
H
2
H
H
CF3
Ph
OPr

Me
Me
H
H
2
H
H
CF3
Ph
OBu-t

Me
Me
H
H
2
H
H
CF3
Ph
OCH2Pr-c

Me
Me
H
H
2
H
H
CF3
Ph
OCH2CH═CH2

Me
Me
H
H
2
H
H
CF3
Ph
OCH2C≡CH

Me
Me
H
H
2
H
H
CF3
Ph
OCHF2

Me
Me
H
H
2
H
H
OCHF2
Ph
CF3

Me
Me
H
H
2
H
H
CF3
Ph
OCH2CHF2

Me
Me
H
H
2
H
H
CF3
Ph
OCH2CF3

Me
Me
H
H
2
H
H
CF3
Ph
OCH2C(═O)OMe

Me
Me
H
H
2
H
H
CF3
Ph
OCH(Me)C(═O)OMe

Me
Me
H
H
2
H
H
CF3
Ph
OC(Me)2C(═O)OMe

Me
Me
H
H
2
H
H
CF3
Ph
OC(═O)Me

Me
Me
H
H
2
H
H
CF3
Ph
OC(═O)Et

Me
Me
H
H
2
H
H
CF3
Ph
OC(═O)CH2Ph

Me
Me
H
H
2
H
H
CF3
Ph
OC(═O)CF3

Me
Me
H
H
2
H
H
CF3
Ph
OC(═O)Ph

Me
Me
H
H
2
H
H
CF3
Ph
OSO2Me

Me
Me
H
H
2
H
H
CF3
Ph
OSO2Et

Me
Me
H
H
2
H
H
CF3
Ph
OSO2CH2Ph

Me
Me
H
H
2
H
H
CF3
Ph
OSO2CF3

Me
Me
H
H
2
H
H
CF3
Ph
OSO2Ph

Me
Me
H
H
2
H
H
CF3
Ph
SMe

Me
Me
H
H
2
H
H
CF3
Ph
SOMe

Me
Me
H
H
2
H
H
CF3
Ph
SO2Me

Me
Me
H
H
2
H
H
CF3
Ph
SEt

Me
Me
H
H
2
H
H
CF3
Ph
SOEt

Me
Me
H
H
2
H
H
CF3
Ph
SO2Et

Me
Me
H
H
2
H
H
CF3
Ph
SPr-i

Me
Me
H
H
2
H
H
CF3
Ph
SOPr-i

Me
Me
H
H
2
H
H
CF3
Ph
SO2Pr-i

Me
Me
H
H
2
H
H
CF3
Ph
SPr

Me
Me
H
H
2
H
H
CF3
Ph
SOPr

Me
Me
H
H
2
H
H
CF3
Ph
SO2Pr

Me
Me
H
H
2
H
H
CF3
Ph
SBu-t

Me
Me
H
H
2
H
H
CF3
Ph
SOBu-t

Me
Me
H
H
2
H
H
CF3
Ph
SO2Bu-t

Me
Me
H
H
2
H
H
CF3
Ph
SCHF2

Me
Me
H
H
2
H
H
CF3
Ph
SOCHF2

Me
Me
H
H
2
H
H
CF3
Ph
SO2CHF2

Me
Me
H
H
2
H
H
CF3
Ph
NH2

Me
Me
H
H
2
H
H
CF3
Ph
NHMe

Me
Me
H
H
2
H
H
CF3
Ph
N(Me)2

Me
Me
H
H
2
H
H
CF3
Ph
NHC(═O)Me

Me
Me
H
H
2
H
H
CF3
Ph
N(Me)C(═O)Me

Me
Me
H
H
2
H
H
CF3
Ph
NHSO2Me

Me
Me
H
H
2
H
H
CF3
Ph
N(Me)SO2Me

Me
Me
H
H
2
H
H
CF3
Ph
NHSO2CF3

Me
Me
H
H
2
H
H
CF3
Ph
N(Me)SO2CF3

Me
Me
H
H
2
H
H
CF3
Ph
NHPh

Me
Me
H
H
2
H
H
CF3
Ph
N(Me)Ph

Me
Me
H
H
2
H
H
CF3
Ph
CN

Me
Me
H
H
2
H
H
CF3
Ph
C(═O)Me

Me
Me
H
H
2
H
H
CF3
Ph
C(═O)OMe

Me
Me
H
H
2
H
H
CF3
Ph
C(═O)NH2

Me
Me
H
H
2
H
H
CF3
Ph
C(═O)NHMe

Me
Me
H
H
2
H
H
CF3
Ph
C(═O)N(Me)2

Me
Me
H
H
2
H
H
CF3
Ph
Imidazol-1-yl

Me
Me
H
H
2
H
H
CF3
Ph
Pyrazol-1-yl

Me
Me
H
H
2
H
H
CF3
Ph
1,2,4-Triazol-1-yl

Me
Me
H
H
2
H
H
CF3
Ph
1,2,4-Triazol-4-yI

Me
Me
H
H
2
H
H
CF3
Ph
Tetrazol-1-yl

Me
Me
H
H
2
H
H
CF3
Ph
Tetrazol-5-yl

Me
Me
H
H
2
H
H
CF3
Ph
(4,6-Dimethoxypyrimidin-2-yI)oxy

Me
Me
H
H
2
H
H
CF3
Ph
(4,6-Dimethoxypyrimidin-2-yl)

sulfonyl

Me
Me
H
H
2
H
H
CF2CF3
Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-C1)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-F)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-OMe)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-Me)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-NO2)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-CN)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-C(═O)Me)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-C(═O)OMe)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-C(═O)OEt)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-C(═O)OPr-i)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-C(═O)NH2)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-C(═O)NHMe)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(2-C(═O)NMe2)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-Cl)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-F)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-OMe)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-Me)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-NO2)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-CN)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-C(═O)Me)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-C(═O)OMe)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-C(═)OEt)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-C(═O)OPr-i)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-C(═O)NH2)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-C(═O)NHMe)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(3-C(═O)NMe)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-Cl)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-F)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-OMe)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-Me)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-NO2)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-CN)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-C(═O)MePh
Cl

Me
Me
H
H
2
H
H
CF3
(4-C(═O)OMe)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-C(═O)OEt)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-C(═O)OPr-i)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-C(═O)NH2)Ph
Cl

Me
Me
H
H
2
H
H
CF3
(4-C(═O)NHMe)Ph

Me
Me
H
H
2
H
H
CF3
(4-C(═O)NMe2)Ph
Cl

Me
Me
H
H
2
H
H
CF3
Pyrmidin-2-yl
Cl

Me
Me
H
H
2
H
H
CF3
4,6-Dimethoxypyrmidin-2-yl
Cl

Me
Me
H
H
2
H
H
CF3
Thiophen-2-yl
Cl

Me
Me
H
H
2
H
H
CF3
Furan-2-yl
Cl

Me
Me
H
H
2
H
H
CF3
SO2Me
Cl

Me
Me
H
H
2
H
H
CF3
SO2Et
Cl

Me
Me
H
H
2
H
H
CF3
SO2Pr-i
Cl

Me
Me
H
H
2
H
H
dF3
SO2CH2Ph
Cl

Me
Me
H
H
2
H
H
CF3
SO2CHF2
Cl

Me
Me
H
H
2
H
H
dF3
SO2CF3
Cl

Me
Me
H
H
2
H
H
CF3
SO2Ph
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)Me
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)Et
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)Pr-i
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)Bu-t
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)Ph
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)CH2Ph
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)CH2Cl
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)CHCl2
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)CF3
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)OMe
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)OPh
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)OCH2Ph
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)NHMe
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)N(Me)2
Cl

Me
Me
H
H
2
H
H
CF3
C(═O)NHPh
Cl

Me
Me
H
H
2
H
H
CF3
NH2
Cl

Me
Me
H
H
2
H
H
Cl
—(CH2)2O—

Me
Me
H
H
2
H
H
Cl
—(CH2)3O—

Me
Me
H
H
2
H
H
Cl
—(CH2)3S—

Me
Me
H
H
2
H
H
Cl
—(CH2)3SO2—

Me
Me
H
H
2
H
H
CF3
—(CH2)2O—

Me
Me
H
H
2
H
H
CF3
—(CH2)3O—

Me
Me
H
H
2
H
H
CF3
—(CH2)3S—

Me
Me
H
H
2
H
H
CF3
—(CH2)3SO2—

Me
Me
H
H
2
H
H
OMe
—(CH2)4—

Me
Me
H
H
2
H
H
OCHF2
—(CH2)4—

H
H
H
H
2
H
H
CF3
Me
Cl

Me
H
H
H
2
H
H
CF3
Me
Cl

Me
H
Me
H
2
H
H
CF3
Me
Cl

Me
Me
Me
H
2
H
H
CF3
Me
Cl

Me
Me
H
H
2
Me
H
CF3
Me
Cl

Me
Me
H
H
2
Et
H
CF3
Me
Cl

Me
Me
H
H
2
Pr-i
H
CF3
Me
Cl

Me
Me
H
H
2
Me
Me
CF3
Me
Cl

Me
Et
H
H
2
H
H
CF3
Me
Cl

Et
Et
H
H
2
H
H
CF3
Me
Cl

Me
Pr-i
H
H
2
H
H
CF3
Me
Cl

Me
Pr
H
H
2
H
H
CF3
Me
Cl

Me
Pr-c
H
H
2
H
H
CF3
Me
Cl

Me
CH2Pr-c
H
H
2
H
H
CF3
Me
Cl

—(CH2)2—
H
H
2
H
H
CF3
Me
Cl

—(CH2)3—
H
H
2
H
H
CF3
Me
Cl

—(CH2)4—
H
H
2
H
H
CF3
Me
Cl

—(CH2)5—
H
H
2
H
H
CF3
Me
Cl

H
—(CH2)3—
H
2
H
H
CF3
Me
Cl

H
—(CH2)4—
H
2
H
H
CF3
Me
Cl

H
—(CH2)5—
H
2
H
H
CF3
Me
Cl

H
—(CH2)6—
H
2
H
H
CF3
Me
Cl

Me
Me
H
H
1
H
H
Cl
H
Cl

Me
Me
H
H
1
H
H
OCHF2
H
Cl

Me
Me
H
H
1
H
H
OCHF2
H
OCHF2

Me
Me
H
H
1
H
H
CHF2
H
Cl

Me
Me
H
H
1
H
H
CF3
H
F

Me
Me
H
H
1
H
H
CF3
H
Cl

Me
Me
H
H
1
H
H
CF3
H
OMe

Me
Me
H
H
1
H
H
CF3
H
OEt

Me
Me
H
H
1
H
H
CF3
H
OCHF2

Me
Me
H
H
1
H
H
CF3
H
CN

Me
Me
H
H
1
H
H
CF3
H
Me

Me
Me
H
H
1
H
H
H
Me
Cl

Me
Me
H
H
1
H
H
Me
Me
Me

Me
Me
H
H
I
H
H
Me
Me
Cl

Me
Me
H
H
1
H
H
Cl
Me
Me

Me
Me
H
H
1
H
H
Et
Me
Cl

Me
Me
H
H
1
H
H
Cl
Me
Et

Me
Me
H
H
1
H
H
Pr-i
Me
Cl

Me
Me
H
H
1
H
H
Cl
Me
Pr-i

Me
Me
H
H
1
H
H
Bu-t
Me
Cl

Me
Me
H
H
1
H
H
Cl
Me
Bu-t

Me
Me
H
H
1
H
H
Cl
Me
Cl

Me
Me
H
H
1
H
H
CHF2
Me
Cl

Me
Me
H
H
L
H
H
Cl
Me
CHF2

Me
Me
H
H
1
H
H
OCHF2
Me
H

Me
Me
H
H
1
H
H
OCHF2
Me
Cl

Me
Me
H
H
1
H
H
Cl
Me
OCHF2

Me
Me
H
H
1
H
H
OCHF2
Me
OCHF2

Me
Me
H
H
1
H
H
CF3
Me
H

Me
Me
H
H
1
H
H
CF3
Me
Cl

Me
Me
H
H
1
H
H
Cl
Me
CF3

Me
Me
H
H
1
H
H
CF3
Me
F

Me
Me
H
H
1
H
H
F
Me
CF3

Me
Me
H
H
1
H
H
CF3
Me
OH

Me
Me
H
H
1
H
H
OH
Me
CF3

Me
Me
H
H
1
H
H
CF3
Me
OMe

Me
Me
H
H
1
H
H
OMe
Me
CF3

Me
Me
H
H
1
H
H
CF3
Me
OEt

Me
Me
H
H
1
H
H
OEt
Me
CF3

Me
Me
H
H
I
H
H
CF3
Me
OPr-i

Me
Me
H
H
1
H
H
CF3
Me
OPr

Me
Me
H
H
1
H
H
CF3
Me
OBu-t

Me
Me
H
H
1
H
H
CF3
Me
OBu-s

Me
Me
H
H
1
H
H
CF3
Me
OBu-i

Me
Me
H
H
1
H
H
CF3
Me
OBu

Me
Me
H
H
1
H
H
CF3
Me
O(2-Pen)

Me
Me
H
H
1
H
H
CF3
Me
O(3-Pen)

Me
Me
H
H
1
H
H
CF3
Me
OPen-n

Me
Me
H
H
1
H
H
CF3
Me
O(2-Hex)

Me
Me
H
H
1
H
H
CF3
Me
O(3-Hex)

Me
Me
H
H
1
H
H
CF3
Me
OHex-n

Me
Me
H
H
1
H
H
CF3
Me
OPen-c

Me
Me
H
H
1
H
H
CF3
Me
OHex-c

Me
Me
H
H
1
H
H
CF3
Me
OCH2Pr-c

Me
Me
H
H
1
H
H
CF3
Me
OCH2Bu-c

Me
Me
H
H
1
H
H
CF3
Me
OCH2Pen-c

Me
Me
H
H
1
H
H
CF3
Me
OCH2Hex-c

Me
Me
H
H
1
H
H
CF3
Me
OCH2CH═CH2

Me
Me
H
H
1
H
H
CF3
Me
0CH2C≡CH

Me
Me
H
H
1
H
H
CF3
Me
OCHF2

Me
Me
H
H
1
H
H
OCHF2
Me
CF3

Me
Me
H
H
1
H
H
CF3
Me
OCH2CHF2

Me
Me
H
H
1
H
H
OCH2CHF2
Me
CF3

Me
Me
H
H
1
H
H
CF3
Me
OCH2CF3

Me
Me
H
H
1
H
H
OCH2CF3
Me
CF3

Me
Me
H
H
1
H
H
CF3
Me
OCH2CN

Me
Me
H
H
1
H
H
CF3
Me
OCH2C(═O)OEt

Me
Me
H
H
1
H
H
CF3
Me
OCH(Me)C(═O)OEt

Me
Me
H
H
1
H
H
CF3
Me
OCH2C(═O)NH2

Me
Me
H
H
1
H
H
CF3
Me
OCH2C(═0)NHMe

Me
Me
H
H
1
H
H
CF3
Me
OCH2C(═O)N(Me)2

Me
Me
H
H
1
H
H
CF3
Me
OCH2Ph

Me
Me
H
H
1
H
H
CF3
Me
OPh

Me
Me
H
H
1
H
H
CF3
Me
O(2-Cl)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(2-Br)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(2-F)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(2-Me)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(2-OMe)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(2-NO2)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(2-CN)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(2-C(═O)OMe)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(3-Cl)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(3-Br)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(3-F)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(3-Me)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(3-OMe)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(3-NO2)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(3-CN)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(3-C(═O)OMe)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(4-Cl)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(4-Br)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(4-F)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(4-Me)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(4-OMe)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(4-NO2)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(4-CN)Ph

Me
Me
H
H
1
H
H
CF3
Me
O(4-C(-O)OMe)Ph

Me
Me
H
H
1
H
H
CF3
Me
OC(═O)Me

Me
Me
H
H
1
H
H
CF3
Me
OC(═O)Et

Me
Me
H
H
1
H
H
CF3
Me
OC(═O)CH2Ph

Me
Me
H
H
1
H
H
CF3
Me
OC(═O)CF3

Me
Me
H
H
1
H
H
CF3
Me
OC(═O)Ph

Me
Me
H
H
1
H
H
CF3
Me
OSO2Me

Me
Me
H
H
1
H
H
CF3
Me
OSO2Et

Me
Me
H
H
1
H
H
CF3
Me
OSO2CH2Ph

Me
Me
H
H
1
H
H
CF3
Me
OSO2CF3

Me
Me
H
H
1
H
H
CF3
Me
OSO2Ph

Me
Me
H
H
1
H
H
CF3
Me
SMe

Me
Me
H
H
1
H
H
CF3
Me
SO2Me

Me
Me
H
H
1
H
H
CF3
Me
SEt

Me
Me
H
H
1
H
H
CF3
Me
SO2Et

Me
Me
H
H
1
H
H
CF3
Me
SPr

Me
Me
H
H
1
H
H
CF3
Me
SO2Pr

Me
Me
H
H
1
H
H
CF3
Me
SPr-i

Me
Me
H
H
1
H
H
CF3
Me
SO2Pr-i

Me
Me
H
H
1
H
H
CF3
Me
SBu-t

Me
Me
H
H
1
H
H
CF3
Me
SO2Bu-t

Me
Me
H
H
1
H
H
CF3
Me
SCHF2

Me
Me
H
H
1
H
H
CF3
Me
SO2CHF2

Me
Me
H
H
1
H
H
CF3
Me
SCF3

Me
Me
H
H
1
H
H
CF3
Me
SO2CF3

Me
Me
H
H
1
H
H
CF3
Me
SPh

Me
Me
H
H
1
H
H
CF3
Me
SO2Ph

Me
Me
H
H
1
H
H
CF3
Me
SCH2Ph

Me
Me
H
H
1
H
H
CF3
Me
SO2CH2Ph

Me
Me
H
H
1
H
H
CF3
Me
SCH2C(═O)OEt

Me
Me
H
H
1
H
H
CF3
Me
SO2CH2C(═O)OEt

Me
Me
H
H
1
H
H
CF3
Me
SCH(Me)C(═O)OEt

Me
Me
H
H
1
H
H
CF3
Me
SO2CH(Me)C(═O)OEt

Me
Me
H
H
1
H
H
CF3
Me
SCH2C(═O)NH2

Me
Me
H
H
1
H
H
CF3
Me
SO2CH2C(═O)NH2

Me
Me
H
H
1
H
H
CF3
Me
SCH2C(═O)NHMe

Me
Me
H
H
1
H
H
CF3
Me
SO2CH2C(═O)NHMe

Me
Me
H
H
1
H
H
CF3
Me
SCH2C(═O)N(Me)2

Me
Me
H
H
1
H
H
CF3
Me
SO2CH2C(═O)N(Me)2

Me
Me
H
H
1
H
H
CF3
Me
NH2

Me
Me
H
H
1
H
H
CF3
Me
NHMe

Me
Me
H
H
1
H
H
CF3
Me
N(Me)2

Me
Me
H
H
1
H
H
CF3
Me
NI-IC(═O)Me

Me
Me
H
H
1
H
H
CF3
Me
N(Me)C(═O)Me

Me
Me
H
H
1
H
H
CF3
Me
NHSO2Me

Me
Me
H
H
1
H
H
CF3
Me
N(Me)SO2Me

Me
Me
H
H
1
H
H
CF3
Me
NHSO2CHF2

Me
Me
H
H
1
H
H
CF3
Me
N(Me)SO2CHF2

Me
Me
H
H
1
H
H
CF3
Me
NHSO2CF3

Me
Me
H
H
1
H
H
CF3
Me
N(Me)SO2CF3

Me
Me
H
H
1
H
H
CF3
Me
NHPh

Me
Me
H
H
1
H
H
CF3
Me
N(Me)Ph

Me
Me
H
H
1
H
H
CF3
Me
CN

Me
Me
H
H
1
H
H
CN
Me
CF3

Me
Me
H
H
1
H
H
CF3
Me
C(═O)OMe

Me
Me
H
H
1
H
H
CF3
Me
C(═O)OCH2Ph

Me
Me
H
H
1
H
H
CF3
Me
C(═O)OPh

Me
Me
H
H
1
H
H
CF3
Me
C(═O)NH2

Me
Me
H
H
1
H
H
CF3
Me
C(═O)NHMe

Me
Me
H
H
1
H
H
CF3
Me
C(═O)N(Me)2

Me
Me
H
H
1
H
H
CF3
Me
C(═O)Me

Me
Me
H
H
1
H
H
CF3
Me
C(═)CF3

Me
Me
H
H
1
H
H
CF3
Me
CC═O)CH2ph

Me
Me
H
H
1
H
H
CF3
Me
C(═O)Ph

Me
Me
H
H
1
H
H
CF3
Me
Me

Me
Me
H
H
1
H
H
Me
Me
CF3

Me
Me
H
H
1
H
H
CF3
Me
Et

Me
Me
H
H
I
H
H
CF3
Me
Pr-i

Me
Me
H
H
1
H
H
CF3
Me
Pr

Me
Me
H
H
1
H
H
CF3
Me
CH2OMe

Me
Me
H
H
1
H
H
CF3
Me
CF3

Me
Me
H
H
1
H
H
CF3
Me
CHF2

Me
Me
H
H
I
H
H
CF3
Me
Ph

Me
Me
H
H
1
H
H
CF2CF3
Me
Cl

Me
Me
H
H
1
H
H
Ph
Me
Me

Me
Me
H
H
1
H
H
Ph
Me
Cl

Me
Me
H
H
1
H
H
Ph
Me
OEt

Me
Me
H
H
1
H
H
Ph
Me
CF3

Me
Me
H
H
I
H
H
Ph
Me
Ph

Me
Me
H
H
1
H
H
Cl
Et
Cl

Me
Me
H
H
1
H
H
OCHF2
Et
Cl

Me
Me
H
H
1
H
H
Cl
Et
OCHF2

Me
Me
H
H
1
H
H
OCHF2
Et
OCHF2

Me
Me
H
H
1
H
H
CF3
Et
F

Me
Me
H
H
1
H
H
F
Et
CF3

Me
Me
H
H
1
H
H
CF3
Et
Cl

Me
Me
H
H
1
H
H
Cl
Et
CF3

Me
Me
H
H
1
H
H
CF3
Et
OMe

Me
Me
H
H
1
H
H
OMe
Et
CF3

Me
Me
H
H
1
H
H
CF3
Et
OEt

Me
Me
H
H
1
H
H
OEt
Et
CF3

Me
Me
H
H
1
H
H
CF3
Et
OCHF2

Me
Me
H
H
1
H
H
OCHF2
Et
CF3

Me
Me
H
H
1
H
H
CF3
Et
CN

Me
Me
H
H
1
H
H
CN
Et
CF3

Me
Me
H
H
1
H
H
CF3
Et
Me

Me
Me
H
H
1
H
H
Me
Et
CF3

Me
Me
H
H
1
H
H
Cl
Pr-i
Cl

Me
Me
H
H
1
H
H
OCHF2
Pr-i
Cl

Me
Me
H
H
1
H
H
Cl
Pr-i
OCHF2

Me
Me
H
H
1
H
H
OCHF2
Pr-i
QCHF2

Me
Me
H
H
1
H
H
CF3
Pr-i
F

Me
Me
H
H
1
H
H
F
Pr-i
CF3

Me
Me
H
H
1
H
H
CF3
Pr-i
Cl

Me
Me
H
H
1
H
H
Cl
Pr-i
CF3

Me
Me
H
H
1
H
H
CF3
Pr-i
OMe

Me
Me
H
H
1
H
H
OMe
Pr-i
CF3

Me
Me
H
H
1
H
H
CF3
Pr-i
OEt

Me
Me
H
H
1
H
H
OEt
Pr-i
CF3

Me
Me
H
H
1
H
H
CF3
Pr-i
OCHF2

Me
Me
H
H
1
H
H
OCHF2
Pr-i
CF3

Me
Me
H
H
1
H
H
CF3
Pr-i
CN

Me
Me
H
H
1
H
H
CN
Pr-i
CF3

Me
Me
H
H
1
H
H
CF3
Pr-i
Me

Me
Me
H
H
1
H
H
Me
Pr-i
CF3

Me
Me
H
H
1
H
H
Cl
Pr
Cl

Me
Me
H
H
1
H
H
OCHF2
Pr
Cl

Me
Me
H
H
1
H
H
Cl
Pr
OCHF2

Me
Me
H
H
1
H
H
OCHF2
Pr
OCHF2

Me
Me
H
H
1
H
H
CF3
Pr
F

Me
Me
H
H
1
H
H
F
Pr
CF3

Me
Me
H
H
1
H
H
CF3
Pr
Cl

Me
Me
H
H
1
H
H
Cl
Pr
CF3

Me
Me
H
H
1
H
H
CF3
Pr
OMe

Me
Me
H
H
1
H
H
OMe
Pr
CF3

Me
Me
H
H
1
H
H
CF3
Pr
OEt

Me
Me
H
H
1
H
H
OEt
Pr
CF3

Me
Me
H
H
1
H
H
CF3
Pr
OCHF2

Me
Me
H
H
1
H
H
OCHF2
Pr
CF3

Me
Me
H
H
1
H
H
CF3
Pr
CN

Me
Me
H
H
1
H
H
CN
Pr
CF3

Me
Me
H
H
1
H
H
CF3
Pr
Me

Me
Me
H
H
1
H
H
Me
Pr
CF3

Me
Me
H
H
1
H
H
Cl
Bu-t
Cl

Me
Me
H
H
1
H
H
OCHF2
Bu-t
Cl

Me
Me
H
H
1
H
H
OCHF2
Bu-t
OCHF2

Me
Me
H
H
1
H
H
CF3
Bu-t
H

Me
Me
H
H
1
H
H
CF3
Bu-t
F

Me
Me
H
H
1
H
H
CF3
Bu-t
Cl

Me
Me
H
H
1
H
H
Cl
Bu-t
CF3

Me
Me
H
H
1
H
H
CF3
Bu-t
OMe

Me
Me
H
H
1
H
H
OMe
Bu-t
CF3

Me
Me
H
H
1
H
H
CF3
Bu-t
OEt

Me
Me
H
H
1
H
H
OEt
Bu-t
CF3

Me
Me
H
H
1
H
H
CF3
Bu-t
OCHF2

Me
Me
H
H
1
H
H
CF3
Bu-t
CN

Me
Me
H
H
1
H
H
CF3
Bu-t
Me

Me
Me
H
H
1
H
H
Me
Bu-t
CF3

Me
Me
H
H
1
H
H
CF3
Bu-s
Cl

Me
Me
H
H
1
H
H
Cl
Bu-s
CF3

Me
Me
H
H
1
H
H
CF3
Bu-i
Cl

Me
Me
H
H
1
H
H
Cl
Bu-i
CF3

Me
Me
H
H
1
H
H
CF3
Bu
Cl

Me
Me
H
H
1
H
H
Cl
Bu
CF3

Me
Me
H
H
1
H
H
CF3
1-Methylbutyl
Cl

Me
Me
H
H
1
H
H
Cl
1-Methylbutyl
CF3

Me
Me
H
H
1
H
H
CF3
1-Ethylpropyl
Cl

Me
Me
H
H
1
H
H
Cl
1-Ethylpropyl
CF3

Me
Me
H
H
1
H
H
CF3
1-Pentyl
Cl

Me
Me
H
H
1
H
H
Cl
1-Pentyl
CF3

Me
Me
H
H
1
H
H
CF3
1-Methylpentyl
Cl

Me
Me
H
H
1
H
H
Cl
1-Methylpentyl
CF3

Me
Me
H
H
1
H
H
CF3
2-Ethylbutyl
Cl

Me
Me
H
H
1
H
H
Cl
2-Ethylbutyl
CF3

Me
Me
H
H
1
H
H
CF3
3,3-Dimethylbutyl
Cl

Me
Me
H
H
1
H
H
Cl
3,3-Diniethylbutyl
CF3

Me
Me
H
H
1
H
H
CF3
1-Hexyl
Cl

Me
Me
H
H
1
H
H
Cl
1-Hexyl
CF3

Me
Me
H
H
1
H
H
CF3
1-Heptyl
Cl

Me
Me
H
H
1
H
H
Cl
1-Heptyl
CF3

Me
Me
H
H
1
H
H
CF3
1-Octyl
Cl

Me
Me
H
H
1
H
H
Cl
1-Octyl
CF3

Me
Me
H
H
1
H
H
CF3
CH2Ph
Cl

Me
Me
H
H
1
H
H
Cl
CH2Ph
CF3

Me
Me
H
H
1
H
H
CF3
Pr-c
Cl

Me
Me
H
H
1
H
H
CF3
Pen-c
Cl

Me
Me
H
H
1
H
H
Cl
Pen-c
CF3

Me
Me
H
H
1
H
H
CF3
Hex-c
Cl

Me
Me
H
H
1
H
H
Cl
Hex-c
CF3

Me
Me
H
H
1
H
H
Cl
CH2Pr-c
Cl

Me
Me
H
H
1
H
H
OCHF2
CH2Pr-c
Cl

Me
Me
H
H
1
H
H
Cl
CH2Pr-c
OCHF2

Me
Me
H
H
1
H
H
OCHF2
CH2Pr-c
OCHF2

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
F

Me
Me
H
H
1
H
H
F
CH2Pr-c
CF3

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
Cl

Me
Me
H
H
1
H
H
Cl
CH2Pr-c
CF3

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
CN

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
OH

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
OMe

Me
Me
H
H
1
H
H
OMe
CH2Pr-c
CF3

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
OEt

Me
Me
H
H
1
H
H
OEt
CH2Pr-c
CF3

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
OPr-i

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
OPr

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
OBu-t

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
OCH2Pr-c

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
OCH2Bu-c

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
OPen-c

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
OCHF2

Me
Me
H
H
1
H
H
OCHF2
CH2Pr-c
CF3

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
CN

Me
Me
H
H
1
H
H
CN
CH2Pr-c
CF3

Me
Me
H
H
1
H
H
CF3
CH2Pr-c
Me

Me
Me
H
H
1
H
H
Me
CH2Pr-c
CF3

Me
Me
H
H
I
H
H
CF3
1-cyclopropylethyl
Cl

Me
Me
H
H
1
H
H
Cl
1-cyclopropylethyl
CF3

Me
Me
H
H
1
H
H
CF3
CH2(2-Methyl-cyclopropyl)
Cl

Me
Me
H
H
1
H
H
Cl
CH2(2-Methyl-cyclopropyl)
CF3

Me
Me
H
H
1
H
H
CF3
CH2(2,2-Dimethyl-cyclopropyl)
Cl

Me
Me
H
H
1
H
H
Cl
CH2(2,2-Dimethyl-cyclopropyl)
CF3

Me
Me
H
H
1
H
H
CF3
CH2(2-Chloro-cyclopropyl)
Cl

Me
Me
H
H
1
H
H
Cl
CH2(2-Chloro-cyclopropyl)
CF3

Me
Me
H
H
1
H
H
CF3
CH2(2,2-Dichloro-cyclopropyl)
Cl

Me
Me
H
H
1
H
H
Cl
CH2(2,2-Dichloro-cyclopropyl)
CF3

Me
Me
H
H
1
H
H
CF3
CH2(2-Fluoro-cyclopropyl)
Cl

Me
Me
H
H
1
H
H
Cl
CH2(2-Fluoro-cyclopropyl)
CF3

Me
Me
H
H
1
H
H
CF3
CH2C2,2-Difluoro-cyclopropyl)
Cl

Me
Me
H
H
1
H
H
Cl
CH2(2,2-Difluoro-cyclopropyl)
CF3

Me
Me
H
H
1
H
H
CF3
CH2Bu-c
Cl

Me
Me
H
H
1
H
H
Cl
CH2Bu-c
CF3

Me
Me
H
H
1
H
H
CF3
CH2Pen-c
Cl

Me
Me
H
H
1
H
H
Cl
CH2Pen-c
CF3

Me
Me
H
H
1
H
H
CF3
CH2Hex-c
Cl

Me
Me
H
H
1
H
H
Cl
CH2Hex-c
CF3

Me
Me
H
H
1
H
H
CF3
CH2CH2Pr-c
Cl

Me
Me
H
H
1
H
H
Cl
CH2CH2Pr-c
CF3

Me
Me
H
H
1
H
H
CF3
CH2CH═CH2
Cl

Me
Me
H
H
1
H
H
Cl
CH2CH═CH2
CF3

Me
Me
H
H
1
H
H
CF3
CH2CH═CH
Cl
Cl

Me
Me
H
H
1
H
H
Cl
CH2CH═CH
Cl
CF3

Me
Me
H
H
1
H
H
Cl
CH2C≡CH
Cl

Me
Me
H
H
1
H
H
OCHF2
CH2C≡CH
Cl

Me
Me
H
H
1
H
H
Cl
CH2C≡CH
OCHF2

Me
Me
H
H
1
H
H
OCHF2
CH2C≡CH
OCHF2

Me
Me
H
H
1
H
H
CF3
CH2C≡CH
F

Me
Me
H
H
1
H
H
F
CH2C≡CH
CF3

Me
Me
H
H
1
H
H
CF3
CH2C≡CH
Cl

Me
Me
H
H
1
H
H
Cl
CH2C≡CH
CF3

Me
Me
H
H
1
H
H
CF3
CH2C≡CH
OMe

Me
Me
H
H
1
H
H
OMe
CH2C≡CH
CF3

Me
Me
H
H
1
H
H
CF3
CH2C≡CH
OEt

Me
Me
H
H
1
H
H
OEt
CH2C≡CH
CF3

Me
Me
H
H
1
H
H
CF3
CH2C≡CH
OCHF2

Me
Me
H
H
1
H
H
OCHF2
CH2C≡CH
CF3

Me
Me
H
H
1
H
H
CF3
CH2C≡CH
CN

Me
Me
H
H
1
H
H
CN
CH2C≡CH
CF3

Me
Me
H
H
1
H
H
CF3
CH2C≡CH
Me

Me
Me
H
H
1
H
H
Me
CH2C≡CH
CF3

Me
Me
H
H
1
H
H
CF3
CHMeC≡CH
Cl

Me
Me
H
H
1
H
H
Cl
CHMeC≡CH
CF3

Me
Me
H
H
1
H
H
CF3
CH2C≡CMe
Cl

Me
Me
H
H
1
H
H
Cl
CH2C≡CMe
CF3

Me
Me
H
H
1
H
H
Cl
CHF2
Cl

Me
Me
H
H
1
H
H
OCHF2
CHF2
Cl

Me
Me
H
H
1
H
H
Cl
CHF2
OCHF2

Me
Me
H
H
1
H
H
OCHF2
CHF2
OCHF2

Me
Me
H
H
1
H
H
CF3
CHF2
Cl

Me
Me
H
H
1
H
H
Cl
CHF2
CF3

Me
Me
H
H
1
H
H
CF3
CHF2
F

Me
Me
H
H
1
H
H
F
CHF2
CF3

Me
Me
H
H
1
H
H
CF3
CHF2
OMe

Me
Me
H
H
1
H
H
OMe
CHF2
CF3

Me
Me
H
H
1
H
H
CF3
CHF2
OEt

Me
Me
H
H
1
H
H
OEt
CHF2
CF3

Me
Me
H
H
1
H
H
CF3
CHF2
OCHF2

Me
Me
H
H
1
H
H
OCHF2
CHF2
CF3

Me
Me
H
H
1
H
H
CF3
CHF2
CN

Me
Me
H
H
1
H
H
CN
CHF2
CF3

Me
Me
H
H
1
H
H
CF3
CHF2
Me

Me
Me
H
H
1
H
H
Me
CHF2
CF3

Me
Me
H
H
1
H
H
Me
CHF2
Cl

Me
Me
H
H
1
H
H
Cl
CHF2
Me

Me
Me
H
H
1
H
H
Et
CHF2
Cl

Me
Me
H
H
1
H
H
Cl
CHF2
Et

Me
Me
H
H
1
H
H
CF3
CH2CHF2
Cl

Me
Me
H
H
1
H
H
Cl
CH2CHF2
CF3

Me
Me
H
H
1
H
H
CF3
CH2CF3
Cl

Me
Me
H
H
1
H
H
Cl
CH2CF3
CF3

Me
Me
H
H
1
H
H
CF3
CH2OH
Cl

Me
Me
H
H
1
H
H
Cl
CH2OH
CF3

Me
Me
H
H
1
H
H
Cl
CH2OMe
Cl

Me
Me
H
H
1
H
H
OCHF2
CH2OMe
Cl

Me
Me
H
H
1
H
H
Cl
CH2OMe
OCHF2

Me
Me
H
H
1
H
H
OCHF2
CH2OMe
OCHF2

Me
Me
H
H
1
H
H
CF3
CH2OMe
F

Me
Me
H
H
1
H
H
F
CH2OMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2OMe
Cl

Me
Me
H
H
1
H
H
Cl
CH2OMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2OMe
OMe

Me
Me
H
H
1
H
H
OMe
CH2OMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2OMe
OEt

Me
Me
H
H
1
H
H
OEt
CH2OMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2OMe
OCHF2

Me
Me
H
H
1
H
H
OCHF2
CH2OMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2OMe
CN

Me
Me
H
H
1
H
H
CN
CH2OMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2OMe
Me

Me
Me
H
H
1
H
H
Me
CH2OMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2OEt
Cl

Me
Me
H
H
1
H
H
Cl
CH2OEt
CF3

Me
Me
H
H
1
H
H
CF3
CH2CH2OH
Cl

Me
Me
H
H
1
H
H
Cl
CH2CH2OH
CF3

Me
Me
H
H
1
H
H
CF3
CH2CH2OMe
Cl

Me
Me
H
H
1
H
H
Cl
CH2CH2OMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2CH2OEt
Cl

Me
Me
H
H
1
H
H
Cl
CH2CH2OEt
CF3

Me
Me
H
H
1
H
H
CF3
CH2NHMe
Cl

Me
Me
H
H
1
H
H
Cl
CH2NHMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2N(Me)2
Cl

Me
Me
H
H
1
H
H
Cl
CH2N(Me)2
CF3

Me
Me
H
H
1
H
H
CF3
CH2N(Me)C(═O)Me
Cl

Me
Me
H
H
1
H
H
Cl
CH2N(Me)C(═O)Me
CF3

Me
Me
H
H
1
H
H
CF3
CH2N(Me)C(═O)CF3
Cl

Me
Me
H
H
1
H
H
Cl
CH2N(Me)C(═O)CF3
CF3

Me
Me
H
H
1
H
H
CF3
CH2N(Me)SO2Me
Cl

Me
Me
H
H
1
H
H
Cl
CH2N(Me)SO2Me
CF3

Me
Me
H
H
1
H
H
CF3
CH2N(Me)SO2CHF2
Cl

Me
Me
H
H
1
H
H
Cl
CH2N(Me)SO2CHF2
CF3

Me
Me
H
H
1
H
H
CF3
CH2N(Me)SO2CF3
Cl

Me
Me
H
H
1
H
H
Cl
CH2N(Me)SO2CF3
CF3

Me
Me
H
H
1
H
H
CF3
CH2SMe
Cl

Me
Me
H
H
1
H
H
Cl
CH2SMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2SO2Me
Cl

Me
Me
H
H
1
H
H
Cl
CH2SO2Me
CF3

Me
Me
H
H
1
H
H
CF3
CH2CH2SMe
Cl

Me
Me
H
H
1
H
H
Cl
CH2CH2SMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2CH2SO2Me
Cl

Me
Me
H
H
1
H
H
Cl
CH2CH2SO2Me
CF3

Me
Me
H
H
1
H
H
CF3
CH2CN
Cl

Me
Me
H
H
1
H
H
Cl
CH2CN
CF3

Me
Me
H
H
1
H
H
CF3
CH2C(═O)OMe
Cl

Me
Me
H
H
1
H
H
Cl
CH2C(═O)OMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2C(═O)OEt
Cl

Me
Me
H
H
1
H
H
Cl
CH2C(═O)OEt
CF3

Me
Me
H
H
1
H
H
CF3
CH(Me)C(═O)OMe
Cl

Me
Me
H
H
1
H
H
Cl
CH(Me)C(═)OMe
CF3

Me
Me
H
H
1
H
H
CF3
C(Me)2C(═O)OMe
Cl

Me
Me
H
H
1
H
H
Cl
C(Me)2C(═O)OMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2C(═)NH2
Cl

Me
Me
H
H
1
H
H
Cl
CH2C(═O)NH2
CF3

Me
Me
H
H
1
H
H
CF3
CH2C(═O)NHMe
Cl

Me
Me
H
H
1
H
H
Cl
CH2C(═O)NHMe
CF3

Me
Me
H
H
1
H
H
CF3
CH2C(═O)N(Me)2
Cl

Me
Me
H
H
1
H
H
Cl
CH2C(═O)N(Me)2
CF3

Me
Me
H
H
1
H
H
CF3
CH2C(═O)Me
Cl

Me
Me
H
H
1
H
H
Cl
CH2C(═O)Me
CF3

Me
Me
H
H
1
H
H
CF3
CH2C(NOMe)Me
Cl

Me
Me
H
H
1
H
H
Cl
CH2C(NOMe)Me
CF3

Me
Me
H
H
1
H
H
CF3
CH2C(═O)CF3
Cl

Me
Me
H
H
1
H
H
Cl
CH2C(═O)CF3
CF3

Me
Me
H
H
1
H
H
CF3
CH2CH2C(═O)Me
Cl

Me
Me
H
H
1
H
H
Cl
CH2CH2C(═O)Me
CF3

Me
Me
H
H
1
H
H
Me
Ph
Me

Me
Me
H
H
1
H
H
Me
Ph
Cl

Me
Me
H
H
1
H
H
Et
Ph
Cl

Me
Me
H
H
1
H
H
Pr
Ph
Cl

Me
Me
H
H
1
H
H
Pr-i
Ph
Cl

Me
Me
H
H
1
H
H
Bu-t
Ph
Cl

Me
Me
H
H
1
H
H
CH2OMe
Ph
Cl

Me
Me
H
H
1
H
H
Cl
Ph
Cl

Me
Me
H
H
1
H
H
OCHF2
Ph
Cl

Me
Me
H
H
1
H
H
OCHF2
Ph
OCHF2

Me
Me
H
H
1
H
H
CHF2
Ph
Cl

Me
Me
H
H
1
H
H
CF3
Ph
H

Me
Me
H
H
1
H
H
CF3
Ph
Me

Me
Me
H
H
1
H
H
Me
Ph
CF3

Me
Me
H
H
1
H
H
CF3
Ph
Et

Me
Me
H
H
1
H
H
CF3
Ph
Pr-i

Me
Me
H
H
1
H
H
CF3
Ph
CHF2

Me
Me
H
H
1
H
H
CF3
Ph
CF3

Me
Me
H
H
1
H
H
CF3
Ph
F

Me
Me
H
H
1
H
H
CF3
Ph
Cl

Me
Me
H
H
1
H
H
Cl
Ph
CF3

Me
Me
H
H
1
H
H
CF3
Ph
OH

Me
Me
H
H
1
H
H
OH
Ph
CF3

Me
Me
H
H
1
H
H
CF3
Ph
OMe

Me
Me
H
H
1
H
H
OMe
Ph
CF3

Me
Me
H
H
1
H
H
CF3
Ph
OEt

Me
Me
H
H
1
H
H
OEt
Ph
CF3

Me
Me
H
H
1
H
H
CF3
Ph
OPr-i

Me
Me
H
H
1
H
H
CF3
Ph
OPr

Me
Me
H
H
1
H
H
CF3
Ph
OBu-t

Me
Me
H
H
1
H
H
CF3
Ph
OCH2Pr-c

Me
Me
H
H
1
H
H
CF3
Ph
OCH2CH═CH2

Me
Me
H
H
1
H
H
CF3
Ph
OCH2C≡CH

Me
Me
H
H
1
H
H
CF3
Ph
OCHF2

Me
Me
H
H
1
H
H
OCHF2
Ph
CF3

Me
Me
H
H
1
H
H
CF3
Ph
OCH2CHF2

Me
Me
H
H
1
H
H
CF3
Ph
OCH2CF3

Me
Me
H
H
1
H
H
CF3
Ph
OCH2C(═O)OMe

Me
Me
H
H
1
H
H
CF3
Ph
OCH(Me)C(═O)OMe

Me
Me
H
H
1
H
H
CF3
Ph
OC(Me)2C(═O)OMe

Me
Me
H
H
1
H
H
CF3
Ph
OC(═O)Me

Me
Me
H
H
1
H
H
CF3
Ph
OC(═O)Et

Me
Me
H
H
1
H
H
CF3
Ph
OC(═O)CH2Ph

Me
Me
H
H
1
H
H
CF3
Ph
OC(═O)CF3

Me
Me
H
H
1
H
H
CF3
Ph
OC(═O)Ph

Me
Me
H
H
1
H
H
CF3
Ph
OSO2Me

Me
Me
H
H
1
H
H
CF3
Ph
OSO2Et

Me
Me
H
H
1
H
H
CF3
Ph
OSO2CH2Ph

Me
Me
H
H
1
H
H
CF3
Ph
OSO2CF3

Me
Me
H
H
1
H
H
CF3
Ph
OSO2Ph

Me
Me
H
H
1
H
H
CF3
Ph
SMe

Me
Me
H
H
1
H
H
CF3
Ph
SO2Me

Me
Me
H
H
1
H
H
CF3
Ph
SEt

Me
Me
H
H
1
H
H
CF3
Ph
SO2Et

Me
Me
H
H
1
H
H
CF3
Ph
SPr-i

Me
Me
H
H
1
H
H
CF3
Ph
SO2Pr-i

Me
Me
H
H
1
H
H
CF3
Ph
SPr

Me
Me
H
H
1
H
H
CF3
Ph
SO2Pr

Me
Me
H
H
1
H
H
CF3
Ph
SBu-t

Me
Me
H
H
1
H
H
CF3
Ph
SO2Bu-t

Me
Me
H
H
1
H
H
CF3
Ph
SCHF2

Me
Me
H
H
1
H
H
CF3
Ph
SO2CHF2

Me
Me
H
H
1
H
H
CF3
Ph
NH2

Me
Me
H
H
1
H
H
CF3
Ph
NHMe

Me
Me
H
H
1
H
H
CF3
Ph
N(Me)2

Me
Me
H
H
1
H
H
CF3
Ph
NHC(═O)Me

Me
Me
H
H
1
H
H
CF3
Ph
N(Me)C(═O)Me

Me
Me
H
H
1
H
H
CF3
Ph
NHSO2Me

Me
Me
H
H
1
H
H
CF3
Ph
N(Me)SO2Me

Me
Me
H
H
1
H
H
CF3
Ph
NHSO2CF3

Me
Me
H
H
1
H
H
CF3
Ph
N(Me)SO2CF3

Me
Me
H
H
1
H
H
CF3
Ph
NHPh

Me
Me
H
H
1
H
H
CF3
Ph
N(Me)Ph

Me
Me
H
H
1
H
H
CF3
Ph
CN

Me
Me
H
H
1
H
H
CF3
Ph
C(═O)Me

Me
Me
H
H
1
H
H
CF3
Ph
C(═O)OMe

Me
Me
H
H
1
H
H
CF3
Ph
C(═O)NH2

Me
Me
H
H
1
H
H
CF3
Ph
C(═O)NHMe

Me
Me
H
H
1
H
H
CF3
Ph
C(═O)N(Me)2

Me
Me
H
H
1
H
H
CF3
Ph
Imidazol-1-yl

Me
Me
H
H
1
H
H
CF3
Ph
Pyrazol-1-yl

Me
Me
H
H
1
H
H
CF3
Ph
1,2,4-Triazoi-1-yl

Me
Me
H
H
1
H
H
CF3
Ph
1,2,4-Triazol-4-yl

Me
Me
H
H
1
H
H
CF3
Ph
Tetrazol-1-yl

Me
Me
H
H
1
H
H
CF3
Ph
Tetrazol-5-yl

Me
Me
H
H
1
H
H
CF3
Ph
(4,6-Dimethoxypyrimidin-2-yl)oxy

Me
Me
H
H
1
H
H
CF3
Ph
(4,6-Dimethoxypyrimidin-2-yl)

sulfonyl

Me
Me
H
H
1
H
H
CF2CF3
Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-Cl)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-F)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-OMe)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-Me)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-NO2)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-CN)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-C(═O)Me)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-C(═O)OMe)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-C(═O)OEt)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-C(═O)OPr-i)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-C(═O)NH2)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-C(═O)NHMe)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(2-C(═O)NMe2)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-Cl)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-F)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-OMe)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-Me)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-NO2)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-CN)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-C(═O)Me)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-C(═O)OMe)PhCl

Me
Me
H
H
1
H
H
CF3
(3-C(═O)OEt)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-C(═O)OPr-i)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-C(═O)NH2)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-C(═O)NHMe)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(3-C(═O)NMe2)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-Cl)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-F)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-OMe)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-Me)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-NO2)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-CN)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-C(═O)Me)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-C(═O)OMe)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-C(═O)OEt)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-C(═O)OPr-i)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-C(═O)NH2)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-C(═O)NHMe)Ph
Cl

Me
Me
H
H
1
H
H
CF3
(4-C(═O)NMe2)Ph
Cl

Me
Me
H
H
1
H
H
CF3
Pyrmidin-2-yl
Cl

Me
Me
H
H
1
H
H
CF3
4,6-Dimethoxypyrmidin-2-yl
Cl

Me
Me
H
H
1
H
H
CF3
Thiophen-2-yl
Cl

Me
Me
H
H
1
H
H
CF3
Furan-2-yl
Cl

Me
Me
H
H
1
H
H
CF3
SO2Me
Cl

Me
Me
H
H
1
H
H
CF3
SO2Et
Cl

Me
Me
H
H
1
H
H
CF3
SO2Pr-i
Cl

Me
Me
H
H
1
H
H
CF3
SO2CH2Ph
Cl

Me
Me
H
H
1
H
H
CF3
SO2CHF2
Cl

Me
Me
H
H
1
H
H
CF3
SO2CF3
Cl

Me
Me
H
H
1
H
H
CF3
SO2Ph
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)Me
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)Et
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)Pr-i
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)Bu-t
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)Ph
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)CH2Ph
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)CH2Cl
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)CHCl2
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)CF3
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)OMe
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)OPh
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)OCH2Ph
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)NHMe
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)N(Me)2
Cl

Me
Me
H
H
1
H
H
CF3
C(═O)NHPh
Cl

Me
Me
H
H
1
H
H
CF3
NH2
Cl

Me
Me
H
H
1
H
H
Cl
—(CH2)2O—

Me
Me
H
H
1
H
H
Cl
—(CH2)3O—

Me
Me
H
H
1
H
H
Cl
—(CH2)3S—

Me
Me
H
H
1
H
H
Cl
—(CH2)3SO2—

Me
Me
H
H
1
H
H
CF3
—(CH2)2O—

Me
Me
H
H
1
H
H
CF3
—(CH2)3O—

Me
Me
H
H
1
H
H
CF3
—(CH2)3S—

Me
Me
H
H
1
H
H
CF3
—(CH2)3SO2—

Me
Me
H
H
1
H
H
OMe
—(CH2)4—

Me
Me
H
H
1
H
H
OCHF2
—(CH2)4—

H
H
H
H
1
H
H
CF3
Me
Cl

Me
H
H
H
1
H
H
CF3
Me
Cl

Me
H
Me
H
1
H
H
CF3
Me
Cl

Me
Me
Me
H
1
H
H
CF3
Me
Cl

Me
Me
H
H
1
Me
H
CF3
Me
Cl

Me
Me
H
H
1
Et
H
CF3
Me
Cl

Me
Me
H
H
1
Pr-i
H
CF3
Me
Cl

Me
Me
H
H
1
Me
Me
CF3
Me
Cl

Me
Et
H
H
1
H
H
CF3
Me
Cl

Et
Et
H
H
1
H
H
CF3
Me
Cl

Me
Pr-i
H
H
1
H
H
CF3
Me
Cl

Me
Pr
H
H
1
H
H
CF3
Me
Cl

Me
Pr-c
H
H
1
H
H
CF3
Me
Cl

Me
CH2Pr-c
H
H
1
H
H
CF3
Me
Cl

—(CH2)2—
H
H
1
H
H
CF3
Me
Cl

—(CH2)3—
H
H
1
H
H
CF3
Me
Cl

—(CH2)4—
H
H
1
H
H
CF3
Me
Cl

—(CH2)5—
H
H
1
H
H
CF3
Me
Cl

H
—(CH2)3—
H
1
H
H
CF3
Me
Cl

H
—(CH2)4—
H
1
H
H
CF3
Me
Cl

H
—(CH2)5—
H
1
H
H
CF3
Me
Cl

H
—(CH2)6—
H
1
H
H
CF3
Me
Cl

Me
Me
H
H
0
H
H
Cl
H
Cl

Me
Me
H
H
0
H
H
OCHF2
H
Cl

Me
Me
H
H
0
H
H
OCHF2
H
OCHF2

Me
Me
H
H
0
H
H
CHF2
H
Cl

Me
Me
H
H
0
H
H
CF3
H
F

Me
Me
H
H
0
H
H
CF3
H
Cl

Me
Me
H
H
0
H
H
CF3
H
OMe

Me
Me
H
H
0
H
H
CF3
H
OEt

Me
Me
H
H
0
H
H
CF3
H
OCHF2

Me
Me
H
H
0
H
H
CF3
H
CN

Me
Me
H
H
0
H
H
CF3
H
Me

Me
Me
H
H
0
H
H
H
Me
Cl

Me
Me
H
H
0
H
H
Me
Me
Me

Me
Me
H
H
0
H
H
Me
Me
Cl

Me
Me
H
H
0
H
H
CL
Me
Me

Me
Me
H
H
0
H
H
Et
Me
Cl

Me
Me
H
H
0
H
H
Cl
Me
Et

Me
Me
H
H
0
H
H
Pr-i
Me
Cl

Me
Me
H
H
0
H
H
Cl
Me
Pr-i

Me
Me
H
H
0
H
H
Bu-t
Me
Cl

Me
Me
H
H
0
H
H
Cl
Me
Bu-t

Me
Me
H
H
0
H
H
Cl
Me
Cl

Me
Me
H
H
0
H
H
CHF2
Me
Cl

Me
Me
H
H
0
H
H
Cl
Me
CHF2

Me
Me
H
H
0
H
H
OCHF2
Me
H

Me
Me
H
H
0
H
H
OCHF2
Me
Cl

Me
Me
H
H
0
H
H
Cl
Me
OCHF2

Me
Me
H
H
0
H
H
OCHF2
Me
OCHF2

Me
Me
H
H
0
H
H
CF3
Me
H

Me
Me
H
H
0
H
H
CF3
Me
Cl

Me
Me
H
H
0
H
H
Cl
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
F

Me
Me
H
H
0
H
H
F
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
OH

Me
Me
H
H
0
H
H
OH
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
OMe

Me
Me
H
H
0
H
H
OMe
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
OEt

Me
Me
H
H
0
H
H
OEt
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
OPr-i

Me
Me
H
H
0
H
H
CF3
Me
OPr

Me
Me
H
H
0
H
H
CF3
Me
OBu-t

Me
Me
H
H
0
H
H
CF3
Me
OBu-s

Me
Me
H
H
0
H
H
CF3
Me
OBu-i

Me
Me
H
H
0
H
H
CF3
Me
OBu

Me
Me
H
H
0
H
H
CF3
Me
O(2-Pen)

Me
Me
H
H
0
H
H
CF3
Me
O(3-Pen)

Me
Me
H
H
0
H
H
CF3
Me
OPen-n

Me
Me
H
H
0
H
H
CF3
Me
O(2-Hex)

Me
Me
H
H
0
H
H
CF3
Me
O(3-Hex)

Me
Me
H
H
0
H
H
CF3
Me
OHex-n

Me
Me
H
H
0
H
H
CF3
Me
OPen-c

Me
Me
H
H
0
H
H
CF3
Me
OHex-c

Me
Me
H
H
0
H
H
CF3
Me
OCH2Pr-c

Me
Me
H
H
0
H
H
CF3
Me
OCH2Bu-c

Me
Me
H
H
0
H
H
CF3
Me
OCH2Pen-c

Me
Me
H
H
0
H
H
CF3
Me
OCH2Hex-c

Me
Me
H
H
0
H
H
CF3
Me
OCH2CH═CH2

Me
Me
H
H
0
H
H
CF3
Me
OCH2C*CH

Me
Me
H
H
0
H
H
CF3
Me
OCHF2

Me
Me
H
H
0
H
H
OCHF2
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
OCH2CHF2

Me
Me
H
H
0
H
H
OCH2CHF2
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
OCH2CF3

Me
Me
H
H
0
H
H
OCH2CF3
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
OCH2CN

Me
Me
H
H
0
H
H
CF3
Me
OCH2C(═)OEt

Me
Me
H
H
0
H
H
CF3
Me
OCH(Me)C(═O)OEt

Me
Me
H
H
0
H
H
CF3
Me
OCH2C(═O)NH2

Me
Me
H
H
0
H
H
CF3
Me
OCH2C(═O)NHMe

Me
Me
H
H
0
H
H
CF3
Me
OCH2C(═O)N(Me)2

Me
Me
H
H
0
H
H
CF3
Me
OCH2Ph

Me
Me
H
H
0
H
H
CF3
Me
OPh

Me
Me
H
H
0
H
H
CF3
Me
O(2-CL)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(2-Br)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(2-F)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(2-Me)Ph

Me
Me
H
H
0
H
H
CF3
Me
0C2-OMe)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(2-NO2)Ph

Me
Me
H
H
0
H
H
CF3
Me
Q(2-CN)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(2-C(═O)OMe)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(3-Cl)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(3-Br)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(3-F)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(3-Me)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(3-OMe)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(3-NO2)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(3-CN)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(3-C(═O)OMe)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(4-Cl)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(4-Br)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(4-F)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(4-Me)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(4-OMe)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(4-NO2)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(4-CN)Ph

Me
Me
H
H
0
H
H
CF3
Me
O(4-C(═O)OMe)Ph

Me
Me
H
H
0
H
H
CF3
Me
OC(═O)Me

Me
Me
H
H
0
H
H
CF3
Me
OC(═O)Et

Me
Me
H
H
0
H
H
CF3
Me
OC(═O)CH2Ph

Me
Me
H
H
0
H
H
CF3
Me
OC(═O)CF3

Me
Me
H
H
0
H
H
CF3
Me
OC(═O)Ph

Me
Me
H
H
0
H
H
CF3
Me
OSO2Me

Me
Me
H
H
0
H
H
CF3
Me
OSO2Et

Me
Me
H
H
0
H
H
CF3
Me
OSO2CH2Ph

Me
Me
H
H
0
H
H
CF3
Me
OSO2CF3

Me
Me
H
H
0
H
H
CF3
Me
OSO2Ph

Me
Me
H
H
0
H
H
CF3
Me
SMe

Me
Me
H
H
0
H
H
CF3
Me
SO2Me

Me
Me
H
H
0
H
H
CF3
Me
SEt

Me
Me
H
H
0
H
H
CF3
Me
SO2Et

Me
Me
H
H
0
H
H
CF3
Me
SPr

Me
Me
H
H
0
H
H
CF3
Me
SO2Pr

Me
Me
H
H
0
H
H
CF3
Me
SPr-i

Me
Me
H
H
0
H
H
CF3
Me
SO2Pr-i

Me
Me
H
H
0
H
H
CF3
Me
SBu-t

Me
Me
H
H
0
H
H
CF3
Me
SO2Bu-t

Me
Me
H
H
0
H
H
CF3
Me
SCHF2

Me
Me
H
H
0
H
H
CF3
Me
SO2CHF2

Me
Me
H
H
0
H
H
CF3
Me
SCF3

Me
Me
H
H
0
H
H
CF3
Me
SO2CF3

Me
Me
H
H
0
H
H
CF3
Me
SPh

Me
Me
H
H
0
H
H
CF3
Me
SO2Ph

Me
Me
H
H
0
H
H
CF3
Me
SCH2Ph

Me
Me
H
H
0
H
H
CF3
Me
SO2CH2Ph

Me
Me
H
H
0
H
H
CF3
Me
SCH2C(═O)OEt

Me
Me
H
H
0
H
H
CF3
Me
SO2CH2C(═O)OEt

Me
Me
H
H
0
H
H
CF3
Me
SCH(Me)C(═O)OEt

Me
Me
H
H
0
H
H
CF3
Me
SO2CH(Me)C(═O)OEt

Me
Me
H
H
0
H
H
CF3
Me
SCH2C(═O)NH2

Me
Me
H
H
0
H
H
CF3
Me
SO2CH2C(═O)NH2

Me
Me
H
H
0
H
H
CF3
Me
SCH2C(═O)NHMe

Me
Me
H
H
0
H
H
CF3
Me
SO2CH2C(═O)NHMe

Me
Me
H
H
0
H
H
CF3
Me
SCH2C(═O)N(Me)2

Me
Me
H
H
0
H
H
CF3
Me
SO2CH2C(═O)N(Me)2

Me
Me
H
H
0
H
H
CF3
Me
NH2

Me
Me
H
H
0
H
H
CF3
Me
NHMe

Me
Me
H
H
0
H
H
CF3
Me
N(Me)2

Me
Me
H
H
0
H
H
CF3
Me
NHC(═O)Me

Me
Me
H
H
0
H
H
CF3
Me
N(Me)C(═O)Me

Me
Me
H
H
0
H
H
CF3
Me
NHSO2Me

Me
Me
H
H
0
H
H
CF3
Me
N(Me)SO2Me

Me
Me
H
H
0
H
H
CF3
Me
NHSO2CHF2

Me
Me
H
H
0
H
H
CF3
Me
N(Me)SO2CHF2

Me
Me
H
H
0
H
H
CF3
Me
NHSO2CF3

Me
Me
H
H
0
H
H
CF3
Me
N(Me)SO2CF3

Me
Me
H
H
0
H
H
CF3
Me
NHPh

Me
Me
H
H
0
H
H
CF3
Me
N(Me)Ph

Me
Me
H
H
0
H
H
CF3
Me
CN

Me
Me
H
H
0
H
H
CN
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
C(═O)OMe

Me
Me
H
H
0
H
H
CF3
Me
C(═O)OCH2Ph

Me
Me
H
H
0
H
H
CF3
Me
C(═O)OPh

Me
Me
H
H
0
H
H
CF3
Me
C(═O)NH2

Me
Me
H
H
0
H
H
CF3
Me
C(═O)NHMe

Me
Me
H
H
0
H
H
CF3
Me
C(═O)N(Me)2

Me
Me
H
H
0
H
H
CF3
Me
C(═O)Me

Me
Me
H
H
0
H
H
CF3
Me
C(═O)CF3

Me
Me
H
H
0
H
H
CF3
Me
C(═O)CH2Ph

Me
Me
H
H
0
H
H
CF3
Me
C(═O)Ph

Me
Me
H
H
0
H
H
CF3
Me
Me

Me
Me
H
H
0
H
H
Me
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
Et

Me
Me
H
H
0
H
H
CF3
Me
Pr-i

Me
Me
H
H
0
H
H
CF3
Me
Pr

Me
Me
H
H
0
H
H
CF3
Me
CH2OMe

Me
Me
H
H
0
H
H
CF3
Me
CF3

Me
Me
H
H
0
H
H
CF3
Me
CHF2

Me
Me
H
H
0
H
H
CF3
Me
Ph

Me
Me
H
H
0
H
H
CF2CF3
Me
Cl

Me
Me
H
H
0
H
H
Ph
Me
Me

Me
Me
H
H
0
H
H
Ph
Me
Cl

Me
Me
H
H
0
H
H
Ph
Me
OEt

Me
Me
H
H
0
H
H
Ph
Me
CF3

Me
Me
H
H
0
H
H
Ph
Me
Ph

Me
Me
H
H
0
H
H
Cl
Et
Cl

Me
Me
H
H
0
H
H
OCHF2
Et
Cl

Me
Me
H
H
0
H
H
Cl
Et
OCHF2

Me
Me
H
H
0
H
H
OCHF2
Et
OCHF2

Me
Me
H
H
0
H
H
CF3
Et
F

Me
Me
H
H
0
H
H
F
Et
CF3

Me
Me
H
H
0
H
H
CF3
Et
Cl

Me
Me
H
H
0
H
H
Cl
Et
CF3

Me
Me
H
H
0
H
H
CF3
Et
OMe

Me
Me
H
H
0
H
H
OMe
Et
CF3

Me
Me
H
H
0
H
H
CF3
Et
OEt

Me
Me
H
H
0
H
H
OEt
Et
CF3

Me
Me
H
H
0
H
H
CF3
Et
OCHF2

Me
Me
H
H
0
H
H
OCHF2
Et
CF3

Me
Me
H
H
0
H
H
CF3
Et
CN

Me
Me
H
H
0
H
H
CN
Et
CF3

Me
Me
H
H
0
H
H
CF3
Et
Me

Me
Me
H
H
0
H
H
Me
Et
CF3

Me
Me
H
H
0
H
H
Cl
Pr-i
Cl

Me
Me
H
H
0
H
H
OCHF2
Pr-i
Cl

Me
Me
H
H
0
H
H
Cl
Pr-i
OCHF2

Me
Me
H
H
0
H
H
OCHF2
Pr-i
OCHF2

Me
Me
H
H
0
H
H
CF3
Pr-i
F

Me
Me
H
H
0
H
H
F
Pr-i
CF3

Me
Me
H
H
0
H
H
CF3
Pr-i
Cl

Me
Me
H
H
0
H
H
Cl
Pr-i
CF3

Me
Me
H
H
0
H
H
CF3
Pr-i
OMe

Me
Me
H
H
0
H
H
OMe
Pr-i
CF3

Me
Me
H
H
0
H
H
CF3
Pr-i
OEt

Me
Me
H
H
0
H
H
OEt
Pr-i
CF3

Me
Me
H
H
0
H
H
CF3
Pr-i
OCHF2

Me
Me
H
H
0
H
H
OCHF2
Pr-i
CF3

Me
Me
H
H
0
H
H
CF3
Pr-i
CN

Me
Me
H
H
0
H
H
CN
Pr-i
CF3

Me
Me
H
H
0
H
H
CF3
Pr-i
Me

Me
Me
H
H
0
H
H
Me
Pr-i
CF3

Me
Me
H
H
0
H
H
Cl
Pr
Cl

Me
Me
H
H
0
H
H
OCHF2
Pr
Cl

Me
Me
H
H
0
H
H
Cl
Pr
OCHF2

Me
Me
H
H
0
H
H
OCHF2
Pr
OCHF2

Me
Me
H
H
0
H
H
CF3
Pr
F

Me
Me
H
H
0
H
H
F
Pr
CF3

Me
Me
H
H
0
H
H
CF3
Pr
Cl

Me
Me
H
H
0
H
H
Cl
Pr
CF3

Me
Me
H
H
0
H
H
CF3
Pr
OMe

Me
Me
H
H
0
H
H
OMe
Pr
CF3

Me
Me
H
H
0
H
H
CF3
Pr
OEt

Me
Me
H
H
0
H
H
OEt
Pr
CF3

Me
Me
H
H
0
H
H
CF3
Pr
OCHF2

Me
Me
H
H
0
H
H
OCHF2
Pr
CF3

Me
Me
H
H
0
H
H
CF3
Pr
CN

Me
Me
H
H
0
H
H
CN
Pr
CF3

Me
Me
H
H
0
H
H
CF3
Pr
Me

Me
Me
H
H
0
H
H
Me
Pr
CF3

Me
Me
H
H
0
H
H
Cl
Bu-t
Cl

Me
Me
H
H
0
H
H
OCHF2
Bu-t
Cl

Me
Me
H
H
0
H
H
OCHF2
Bu-t
OCHF2

Me
Me
H
H
0
H
H
CF3
Bu-t
H

Me
Me
H
H
0
H
H
CF3
Bu-t
F

Me
Me
H
H
0
H
H
CF3
Bu-t
Cl

Me
Me
H
H
0
H
H
Cl
Bu-t
CF3

Me
Me
H
H
0
H
H
CF3
Bu-t
OMe

Me
Me
H
H
0
H
H
OMe
Bu-t
CF3

Me
Me
H
H
0
H
H
CF3
Bu-t
OEt

Me
Me
H
H
0
H
H
OEt
Bu-t
CF3

Me
Me
H
H
0
H
H
CF3
Bu-t
OCHF2

Me
Me
H
H
0
H
H
CF3
Bu-t
CN

Me
Me
H
H
0
H
H
CF3
Bu-t
Me

Me
Me
H
H
0
H
H
Me
Bu-t
CF3

Me
Me
H
H
0
H
H
CF3
Bu-s
Cl

Me
Me
H
H
0
H
H
Cl
Bu-s
CF3

Me
Me
H
H
0
H
H
CF3
Bu-i
Cl

Me
Me
H
H
0
H
H
Cl
Bu-i
CF3

Me
Me
H
H
0
H
H
CF3
Bu
Cl

Me
Me
H
H
0
H
H
Cl
Bu
CF3

Me
Me
H
H
0
H
H
CF3
1-Methylbutyl
Cl

Me
Me
H
H
0
H
H
Cl
1-Methylbutyl
CF3

Me
Me
H
H
0
H
H
CF3
1-Ethylpropyl
Cl

Me
Me
H
H
0
H
H
Cl
1-Ethylpropyl
CF3

Me
Me
H
H
0
H
H
CF3
1-Pentyl
Cl

Me
Me
H
H
0
H
H
Cl
1-Pentyl
CF3

Me
Me
H
H
0
H
H
CF3
1-Methylpentyl
Cl

Me
Me
H
H
0
H
H
Cl
1-Methylpentyl
CF3

Me
Me
H
H
0
H
H
CF3
2-Ethylbutyl
Cl

Me
Me
H
H
0
H
H
Cl
2-Ethylbutyl
CF3

Me
Me
H
H
0
H
H
CF3
3,3-Dimethylbutyl
Cl

Me
Me
H
H
0
H
H
Cl
3,3-Dimethylbutyl
CF3

Me
Me
H
H
0
H
H
CF3
1-Hexyl
Cl

Me
Me
H
H
0
H
H
Cl
1-Hexyl
CF3

Me
Me
H
H
0
H
H
CF3
1-Heptyl
Cl

Me
Me
H
H
0
H
H
Cl
1-Heptyl
CF3

Me
Me
H
H
0
H
H
CF3
1-Octyl
Cl

Me
Me
H
H
0
H
H
Cl
1-Octyl
CF3

Me
Me
H
H
0
H
H
CF3
CH2Pb
Cl

Me
Me
H
H
0
H
H
Cl
CH2Ph
CF3

Me
Me
H
H
0
H
H
CF3
Pr-c
Cl

Me
Me
H
H
0
H
H
CF3
Pen-c
Cl

Me
Me
H
H
0
H
H
Cl
Pen-c
CF3

Me
Me
H
H
0
H
H
CF3
Hex-c
Cl

Me
Me
H
H
0
H
H
Cl
Hex-c
CF3

Me
Me
H
H
0
H
H
Cl
CH2Pr-c
Cl

Me
Me
H
H
0
H
H
OCHF2
CH2Pr-c
Cl

Me
Me
H
H
0
H
H
Cl
CH2Pr-c
OCHF2

Me
Me
H
H
0
H
H
OCHF2
CH2Pr-c
OCHF2

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
F

Me
Me
H
H
0
H
H
F
CH2Pr-c
CF3

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
Cl

Me
Me
H
H
0
H
H
Cl
CH2Pr-c
CF3

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
CN

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
OH

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
OMe

Me
Me
H
H
0
H
H
OMe
CH2Pr-c
CF3

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
OEt

Me
Me
H
H
0
H
H
OEt
CH2Pr-c
CF3

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
OPr-i

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
OPr

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
OBu-t

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
OCH2Pr-c

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
OCH2Bu-c

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
OPen-c

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
OCHF3

Me
Me
H
H
0
H
H
OCHF2
CH2Pr-c
CF3

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
CN

Me
Me
H
H
0
H
H
CN
CH2Pr-o
CF3

Me
Me
H
H
0
H
H
CF3
CH2Pr-c
Me

Me
Me
H
H
0
H
H
Me
CH2Pr-c
CF3

Me
Me
H
H
0
H
H
CF3
1-cyclopropylethyl
Cl

Me
Me
H
H
0
H
H
Cl
1-cyclopropylethyl
CF3

Me
Me
H
H
0
H
H
CF3
CH2(2-Methyl-cyclopropyl)
Cl

Me
Me
H
H
0
H
H
Cl
CH2(2-Methyl-cyclopropyl)
CF3

Me
Me
H
H
0
H
H
CF3
CH2(2,2-Dimethyl-cycloproppyl)
Cl

Me
Me
H
H
0
H
H
Cl
CH2(2,2-Dimethyl-cyclopropyl)
CF3

Me
Me
H
H
0
H
H
CF3
CH2(2-Chloro-cyclopropyl)
Cl

Me
Me
H
H
0
H
H
Cl
CH2(2-Chloro-cyclopropyl)
CF3

Me
Me
H
H
0
H
H
CF3
CH2(2,2-Dichloro-cyclopropyl)
Cl

Me
Me
H
H
0
H
H
Cl
CH2(2,2-Dichloro-cyclopropyl)
CF3

Me
Me
H
H
0
H
H
CF3
CH2(2-Fluoro-cyclopropyl)
Cl

Me
Me
H
H
0
H
H
Cl
CH2(2-Fluoro-cyclopropyl)
CF3

Me
Me
H
H
0
H
H
CF3
CH2(2,2-Difluoro-cyclopropyl)
Cl

Me
Me
H
H
0
H
H
Cl
CH2(2,2-Difluoro-cyclopropyl)
CF3

Me
Me
H
H
0
H
H
CF3
CH2Bu-c
Cl

Me
Me
H
H
0
H
H
Cl
CH2Bu-c
CF3

Me
Me
H
H
0
H
H
CF3
CH2Pen-c
Cl

Me
Me
H
H
0
H
H
Cl
CH2Pen-c
CF3

Me
Me
H
H
0
H
H
CF3
CH2Hex-c
Cl

Me
Me
H
H
0
H
H
Cl
CH2Hex-c
CF3

Me
Me
H
H
0
H
H
CF3
CH2CH2Pr-c
Cl

Me
Me
H
H
0
H
H
Cl
CH2CH2Pr-c
CF3

Me
Me
H
H
0
H
H
CF3
CH2CH═CH2
Cl

Me
Me
H
H
0
H
H
Cl
CH2CH═CH2
CF3

Me
Me
H
H
0
H
H
CF3
CH2CH═CHCl
Cl

Me
Me
H
H
0
H
H
Cl
CH2CH═CHCl
CF3

Me
Me
H
H
0
H
H
Cl
CH2C≡CH
Cl

Me
Me
H
H
0
H
H
OCHF2
CH2C≡CH
Cl

Me
Me
H
H
0
H
H
Cl
CH2C≡CH
OCHF2

Me
Me
H
H
0
H
H
OCHF2
CH2C≡CH
OCHF

Me
Me
H
H
0
H
H
CF3
CH2C≡CH
F

Me
Me
H
H
0
H
H
F
CH2C≡CH
CF3

Me
Me
H
H
0
H
H
CF3
CH2C≡CH
Cl

Me
Me
H
H
0
H
H
Cl
CH2C≡CH
CF3

Me
Me
H
H
0
H
H
CF3
CH2C≡CH
OMe

Me
Me
H
H
0
H
H
OMe
CH2C≡CH
CF3

Me
Me
H
H
0
H
H
CF3
CH2C≡CH
OEt

Me
Me
H
H
0
H
H
OEt
CH2C≡CH
CF3

Me
Me
H
H
0
H
H
CF3
CH2C≡CH
OCHF2

Me
Me
H
H
0
H
H
OCHF2
CH2C≡CH
CF3

Me
Me
H
H
0
H
H
CF3
CH2C≡CH
CN

Me
Me
H
H
0
H
H
CN
CH2C≡CH
CF3

Me
Me
H
H
0
H
H
CF3
CH2C≡CH
Me

Me
Me
H
H
0
H
H
Me
CH2C≡CH
CF3

Me
Me
H
H
0
H
H
CF3
CH2C≡CH
Cl

Me
Me
H
H
0
H
H
Cl
CH2C≡CH
CF3

Me
Me
H
H
0
H
H
CF3
CH2C≡Me
Cl

Me
Me
H
H
0
H
H
Cl
CH2C≡Me
CF3

Me
Me
H
H
0
H
H
Cl
CHF2
Cl

Me
Me
H
H
0
H
H
OCHF2
CHF2
Cl

Me
Me
H
H
0
H
H
Cl
CHF2
OCHF2

Me
Me
H
H
0
H
H
OCHF2
CHF2
OCHF2

Me
Me
H
H
0
H
H
CF3
CHF2
Cl

Me
Me
H
H
0
H
H
Cl
CHF2
CF3

Me
Me
H
H
0
H
H
CF3
CHF2
F

Me
Me
H
H
0
H
H
F
CHF2
CF3

Me
Me
H
H
0
H
H
CF3
CHF2
OMe

Me
Me
H
H
0
H
H
OMe
CHF2
CF3

Me
Me
H
H
0
H
H
CF3
CHF2
OEt

Me
Me
H
H
0
H
H
OEt
CHF2
CF3

Me
Me
H
H
0
H
H
CF3
CHF2
OCHF2

Me
Me
H
H
0
H
H
OCHF2
CHF2
CF3

Me
Me
H
H
0
H
H
CF3
CHF2
CN

Me
Me
H
H
0
H
H
CN
CHF2
CF3

Me
Me
H
H
0
H
H
CF3
CHF2
Me

Me
Me
H
H
0
H
H
Me
CHF2
CF3

Me
Me
H
H
0
H
H
Me
CHF2
Cl

Me
Me
H
H
0
H
H
Cl
CHF2
Me

Me
Me
H
H
0
H
H
Et
CHF2
Cl

Me
Me
H
H
0
H
H
Cl
CHF2
Et

Me
Me
H
H
0
H
H
CF3
CH2CHF2
Cl

Me
Me
H
H
0
H
H
Cl
CH2CHF2
CF3

Me
Me
H
H
0
H
H
CF3
CH2CF3
Cl

Me
Me
H
H
0
H
H
Cl
CH2CF3
CF3

Me
Me
H
H
0
H
H
CF3
CH2OH
Cl

Me
Me
H
H
0
H
H
Cl
CH2OH
CF3

Me
Me
H
H
0
H
H
Cl
CH2OMe
Cl

Me
Me
H
H
0
H
H
OCHF2
CH2OMe
Cl

Me
Me
H
H
0
H
H
Cl
CH2OMe
OCHF2

Me
Me
H
H
0
H
H
OCHF2
CH2OMe
OCHF2

Me
Me
H
H
0
H
H
CF3
CH2OMe
F

Me
Me
H
H
0
H
H
F
CH2OMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2OMe
Cl

Me
Me
H
H
0
H
H
Cl
CH2OMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2OMe
OMe

Me
Me
H
H
0
H
H
OMe
CH2OMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2OMe
OEt

Me
Me
H
H
0
H
H
OEt
CH2OMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2OMe
OCHF2

Me
Me
H
H
0
H
H
OCHF2
CH2OMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2OMe
CN

Me
Me
H
H
0
H
H
CN
CH2OMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2OMe
Me

Me
Me
H
H
0
H
H
Me
CH2OMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2OEt
Cl

Me
Me
H
H
0
H
H
Cl
CH2OEt
CF3

Me
Me
H
H
0
H
H
CF3
CH2CH2OH
Cl

Me
Me
H
H
0
H
H
Cl
CH2CH2OH
CF3

Me
Me
H
H
0
H
H
CF3
CH2CH2OMe
Cl

Me
Me
H
H
0
H
H
Cl
CH2CH2OMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2CH2OEt
Cl

Me
Me
H
H
0
H
H
Cl
CH2CH2OEt
CF3

Me
Me
H
H
0
H
H
CF3
CH2NHMe
Cl

Me
Me
H
H
0
H
H
Cl
CH2NHMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2N(Me)2
Cl

Me
Me
H
H
0
H
H
Cl
CH2N(Me)2
CF3

Me
Me
H
H
0
H
H
CF3
CH2N(Me)C(═O)Me
Cl

Me
Me
H
H
0
H
H
Cl
CH2N(Me)C(═O)Me
CF3

Me
Me
H
H
0
H
H
CF3
CH2N(Me)C(═O)CF3
Cl

Me
Me
H
H
0
H
H
Cl
CH2N(Me)C(═O)CF3
CF3

Me
Me
H
H
0
H
H
CF3
CH2N(Me)SO2Me
Cl

Me
Me
H
H
0
H
H
Cl
CH2N(Me)SO2Me
CF3

Me
Me
H
H
0
H
H
CF3
CH2N(Me)SO2CHF2
Cl

Me
Me
H
H
0
H
H
Cl
CH2N(Me)SO2CHF2
CF3

Me
Me
H
H
0
H
H
CF3
CH2N(Me)SO2CF3
Cl

Me
Me
H
H
0
H
H
Cl
CH2N(Me)SO2CF3
CF3

Me
Me
H
H
0
H
H
CF3
CH2SMe
Cl

Me
Me
H
H
0
H
H
Cl
CH2SMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2SO2Me
Cl

Me
Me
H
H
0
H
H
Cl
CH2SO2Me
CF3

Me
Me
H
H
0
H
H
CF3
CH2CH2SMe
Cl

Me
Me
H
H
0
H
H
Cl
CH2CH2SMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2CH2SO2Me
Cl

Me
Me
H
H
0
H
H
Cl
CH2CH2SO2Me
CF3

Me
Me
H
H
0
H
H
CF3
CH2CN
Cl

Me
Me
H
H
0
H
H
Cl
CH2CN
CF3

Me
Me
H
H
0
H
H
CF3
CH2C(═O)OMe
Cl

Me
Me
H
H
0
H
H
Cl
CH2C(═O)OMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2C(═O)OEt
Cl

Me
Me
H
H
0
H
H
Cl
CH2C(═O)OEt
CF3

Me
Me
H
H
0
H
H
CF3
CH(Me)C(═O)OMe
Cl

Me
Me
H
H
0
H
H
Cl
CH(Me)C(═O)OMe
CF3

Me
Me
H
H
0
H
H
CF3
C(Me)2C(═O)OMe
Cl

Me
Me
H
H
0
H
H
Cl
C(Me)2C(═O)OMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2C(═O)NH2
Cl

Me
Me
H
H
0
H
H
Cl
CH2C(═O)NH2
CF3

Me
Me
H
H
0
H
H
CF3
CH2C(═O)NHMe
Cl

Me
Me
H
H
0
H
H
Cl
CH2C(═O)NHMe
CF3

Me
Me
H
H
0
H
H
CF3
CH2C(═O)N(Me)2
Cl

Me
Me
H
H
0
H
H
Cl
CH2C(═O)N(Me)2
CF3

Me
Me
H
H
0
H
H
CF3
CH2C(═O)Me
Cl

Me
Me
H
H
0
H
H
Cl
CH2C(═O)Me
CF3

Me
Me
H
H
0
H
H
CF3
CH2C(═NOMe)Me
Cl

Me
Me
H
H
0
H
H
Cl
CH2C(═NOMe)Me
CF3

Me
Me
H
H
0
H
H
CF3
CH2C(═O)CF3
Cl

Me
Me
H
H
0
H
H
Cl
CH2C(═O)CF3
CF3

Me
Me
H
H
0
H
H
CF3
CH2CH2C(═O)Me
Cl

Me
Me
H
H
0
H
H
Cl
CH2CH2C(═O)Me
CF3

Me
Me
H
H
0
H
H
Me
Ph
Me

Me
Me
H
H
0
H
H
Me
Ph
Cl

Me
Me
H
H
0
H
H
Et
Ph
Cl

Me
Me
H
H
0
H
H
Pr
Ph
Cl

Me
Me
H
H
0
H
H
Pr-i
Ph
Cl

Me
Me
H
H
0
H
H
Bu-t
Ph
Cl

Me
Me
H
H
0
H
H
CH2OMe
Ph
Cl

Me
Me
H
H
0
H
H
Cl
Ph
Cl

Me
Me
H
H
0
H
H
OCHF2
Ph
Cl

Me
Me
H
H
0
H
H
OCHF2
Ph
OCHF2

Me
Me
H
H
0
H
H
CHF2
Ph
Cl

Me
Me
H
H
0
H
H
CF3
Ph
H

Me
Me
H
H
0
H
H
CF3
Ph
Me

Me
Me
H
H
0
H
H
Me
Ph
CF3

Me
Me
H
H
0
H
H
CF3
Ph
Et

Me
Me
H
H
0
H
H
CF3
Ph
Pr-i

Me
Me
H
H
0
H
H
CF3
Ph
CHF2

Me
Me
H
H
0
H
H
CF3
Ph
CF3

Me
Me
H
H
0
H
H
CF3
Ph
F

Me
Me
H
H
0
H
H
CF3
Ph
Cl

Me
Me
H
H
0
H
H
Cl
Ph
CF3

Me
Me
H
H
0
H
H
CF3
Ph
OH

Me
Me
H
H
0
H
H
OH
Ph
CF3

Me
Me
H
H
0
H
H
CF3
Ph
OMe

Me
Me
H
H
0
H
H
OMe
Ph
CF3

Me
Me
H
H
0
H
H
CF3
Ph
OEt

Me
Me
H
H
0
H
H
OEt
Ph
CF3

Me
Me
H
H
0
H
H
CF3
Ph
OPr-i

Me
Me
H
H
0
H
H
CF3
Ph
OPr

Me
Me
H
H
0
H
H
CF3
Ph
OBu-t

Me
Me
H
H
0
H
H
CF3
Ph
OCH2Pr-c

Me
Me
H
H
0
H
H
CF3
Ph
OCH2CH═CH2

Me
Me
H
H
0
H
H
CF3
Ph
OCH2C≡CH

Me
Me
H
H
0
H
H
CF3
Ph
OCHF2

Me
Me
H
H
0
H
H
OCHF2
Ph
CF3

Me
Me
H
H
0
H
H
CF3
Ph
OCH2CHF2

Me
Me
H
H
0
H
H
CF3
Ph
OCH2CF3

Me
Me
H
H
0
H
H
CF3
Ph
OCH2C(═O)OMe

Me
Me
H
H
0
H
H
CF3
Ph
OCH(Me)C(═O)OMe

Me
Me
H
H
0
H
H
CF3
Ph
OC(Me)2C(═O)OMe

Me
Me
H
H
0
H
H
CF3
Ph
OC(═O)Me

Me
Me
H
H
0
H
H
CF3
Ph
OC(═O)Et

Me
Me
H
H
0
H
H
CF3
Ph
OC(═O)CH2Ph

Me
Me
H
H
0
H
H
CF3
Ph
OC(═O)CF3

Me
Me
H
H
0
H
H
CF3
Ph
OC(═O)Ph

Me
Me
H
H
0
H
H
CF3
Ph
OSO2Me

Me
Me
H
H
0
H
H
CF3
Ph
OSO2Et

Me
Me
H
H
0
H
H
CF3
Ph
OSO2CH2Ph

Me
Me
H
H
0
H
H
CF3
Ph
OSO2CF3

Me
Me
H
H
0
H
H
CF3
Ph
OSO2Ph

Me
Me
H
H
0
H
H
CF3
Ph
SMe

Me
Me
H
H
0
H
H
CF3
Ph
SO2Me

Me
Me
H
H
0
H
H
CF3
Ph
SEt

Me
Me
H
H
0
H
H
CF3
Ph
SO2Et

Me
Me
H
H
0
H
H
CF3
Ph
SPr-i

Me
Me
H
H
0
H
H
CF3
Ph
SO2Pr-i

Me
Me
H
H
0
H
H
CF3
Ph
SPr

Me
Me
H
H
0
H
H
CF3
Ph
SO2Pr

Me
Me
H
H
0
H
H
CF3
Ph
SBu-t

Me
Me
H
H
0
H
H
CF3
Ph
SO2Bu-t

Me
Me
H
H
0
H
H
CF3
Ph
SCHF2

Me
Me
H
H
0
H
H
CF3
Ph
SO2CHF2

Me
Me
H
H
0
H
H
CF3
Ph
NH2

Me
Me
H
H
0
H
H
CF3
Ph
NHMe

Me
Me
H
H
0
H
H
CF3
Ph
N(Me)2

Me
Me
H
H
0
H
H
CF3
Ph
NHC(═O)Me

Me
Me
H
H
0
H
H
CF3
Ph
N(Me)C(═O)Me

Me
Me
H
H
0
H
H
CF3
Ph
NHSO2Me

Me
Me
H
H
0
H
H
CF3
Ph
N(Me)SO2Me

Me
Me
H
H
0
H
H
CF3
Ph
NHSO2CF3

Me
Me
H
H
0
H
H
CF3
Ph
N(Me)SO2CF3

Me
Me
H
H
0
H
H
CF3
Ph
NHPh

Me
Me
H
H
0
H
H
CF3
Ph
N(Me)Ph

Me
Me
H
H
0
H
H
CF3
Ph
CN

Me
Me
H
H
0
H
H
CF3
Ph
C(═O)Me

Me
Me
H
H
0
H
H
CF3
Ph
C(═O)OMe

Me
Me
H
H
0
H
H
CF3
Ph
C(═O)NH2

Me
Me
H
H
0
H
H
CF3
Ph
C(═O)NHMe

Me
Me
H
H
0
H
H
CF3
Ph
C(═O)N(Me)2

Me
Me
H
H
0
H
H
CF3
Ph
Imidazol-1-yl

Me
Me
H
H
0
H
H
CF3
Ph
Pyrazol-1-yl

Me
Me
H
H
0
H
H
CF3
Ph
1,2,4-Triazol-1-yl

Me
Me
H
H
0
H
H
CF3
Ph
1,2,4-Triazol-4-yl

Me
Me
H
H
0
H
H
CF3
Ph
Tetrazol-1-yl

Me
Me
H
H
0
H
H
CF3
Ph
Tetrazol-5-yl

Me
Me
H
H
0
H
H
CF3
Ph
(4,6-Dimethoxypyrimidin-2-yl)oxy

Me
Me
H
H
0
H
H
CF3
Ph
(4,6-Dimethoxypyrimidin-2-yl)

sulfonyl

Me
Me
H
H
0
H
H
CF2CF3
Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-Cl)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-F)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-OMe)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-Me)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-NO2)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-CN)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-C(═O)Me)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-C(═O)OMe)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-C(═O)OEt)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-C(═O)OPr-i)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-C(═O)NH2)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-C(═O)NHMe)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(2-C(═O)NMe2)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-Cl)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-F)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-OMe)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-Me)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-NO2)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-CN)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-C(═O)Me)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-C(═O)OMe)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-C(═O)OEt)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-C(═O)OPr-i)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-C(═O)NH2)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-C(═O)NHMe)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(3-C(═O)NMe2)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-Cl)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-F)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-OMe)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-Me)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-NO2)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-N)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-C(═O)Me)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-C(═O)OMe)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-C(═O)OEt)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-C(═O)OPr-i)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-C(═O)NH2)Ph
Cl

Me
Me
H
H
0
H
H
CF3
(4-C(═O)NHMe)Ph
Cl

Me
Me
H
H
0
H
H
CF3
C4-C(═O)NMe2)Ph
Cl

Me
Me
H
H
0
H
H
CF3
Pyrmidin-2-yl
Cl

Me
Me
H
H
0
H
H
CF3
4,6-Dimethoxypyrmidin-2-yl
Cl

Me
Me
H
H
0
H
H
CF3
Thiophen-2-yl
Cl

Me
Me
H
H
0
H
H
CF3
Furan-2-yl
Cl

Me
Me
H
H
0
H
H
CF3
SO2Me
Cl

Me
Me
H
H
0
H
H
CF3
SO2Et
Cl

Me
Me
H
H
0
H
H
CF3
SO2Pr-i
Cl

Me
Me
H
H
0
H
H
CF3
SO2CH2Ph
Cl

Me
Me
H
H
0
H
H
CF3
SO2CHF2
Cl

Me
Me
H
H
0
H
H
CF3
SO2CF3
Cl

Me
Me
H
H
0
H
H
CF3
SO2Ph
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)Me
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)Et
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)Pr-i
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)Bu-t
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)Ph
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)CH2Ph
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)CH2Cl
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)CHCl2
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)CF3
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)OMe
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)OPh
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)OCH2Ph
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)NHMe
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)N(Me)2
Cl

Me
Me
H
H
0
H
H
CF3
C(═O)NHPh
Cl

Me
Me
H
H
0
H
H
CF3
NH2
Cl

Me
Me
H
H
0
H
H
Cl
—(CH2)2O—

Me
Me
H
H
0
H
H
Cl
—(CH2)3O—

Me
Me
H
H
0
H
H
Cl
—(CH2)3S—

Me
Me
H
H
0
H
H
Cl
—(CH2)3SO2—

Me
Me
H
H
0
H
H
CF3
—(CH2)2O—

Me
Me
H
H
0
H
H
CF3
—(CH2)3O—

Me
Me
H
H
0
H
H
CF3
—(CH2)3S—

Me
Me
H
H
0
H
H
CF3
—(CH2)3SO2—

Me
Me
H
H
0
H
H
OMe
—(CH2)4—

Me
Me
H
H
0
H
H
OCHF2
—(CH2)4—

H
H
H
H
0
H
H
CF3
Me
Cl

Me
H
H
H
0
H
H
CF3
Me
Cl

Me
H
Me
H
0
H
H
CF3
Me
Cl

Me
Me
Me
H
0
H
H
CF3
Me
Cl

Me
Me
H
H
0
Me
H
CF3
Me
Cl

Me
Me
H
H
0
Et
H
CF3
Me
Cl

Me
Me
H
H
0
Pr-i
H
CF3
Me
Cl

Me
Me
H
H
0
Me
Me
CF3
Me
Cl

Me
Et
H
H
0
H
H
CF3
Me
Cl

Et
Et
H
H
0
H
H
CF3
Me
Cl

Me
Pr-i
H
H
0
H
H
CF3
Me
Cl

Me
Pr
H
H
0
H
H
CF3
Me
Cl

Me
Pr-c
H
H
0
H
H
CF3
Me
Cl

Me
CH2Pr-c
H
H
0
H
H
CF3
Me
Cl

—(CH2)2—
H
H
0
H
H
CF3
Me
Cl

—(CH2)3—
H
H
0
H
H
CF3
Me
Cl

—(CH2)4—
H
H
0
H
H
CF3
Me
Cl

—(CH2)5—
H
H
0
H
H
CF3
Me
Cl

H
—(CH2)3—
H
0
H
H
CF3
Me
Cl

H
—(CH2)4—
H
0
H
H
CF3
Me
Cl

H
—(CH2)5—
H
0
H
H
CF3
Me
Cl

H
—(CH2)6—
H
0
H
H
CF3
Me
Cl

Me
Et
H
H
2
H
H
H
H
H

[0084]

5

TABLE 4

R1
R2
R3
R4
n
R5
R6
Z3
R31
R32

Me
Me
H
H
2
H
H
O
Me
F

Me
Me
H
H
2
H
H
O
Me
Cl

Me
Me
H
H
2
H
H
O
Me
OMe

Me
Me
H
H
2
H
H
O
Me
OEt

Me
Me
H
H
2
H
H
O
Me
OPr-i

Me
Me
H
H
2
H
H
O
Me
OPh

Me
Me
H
H
2
H
H
O
Me
OCHF2

Me
Me
H
H
2
H
H
O
Me
Me

Me
Me
H
H
2
H
H
O
Me
CF3

Me
Me
H
H
2
H
H
O
Me
CN

Me
Me
H
H
2
H
H
O
OCHF2
F

Me
Me
H
H
2
H
H
O
OCHF2
Cl

Me
Me
H
H
2
H
H
O
OCHF2
Me

Me
Me
H
H
2
H
H
O
OCHF2
CF3

Me
Me
H
H
2
H
H
O
OCHF2
CN

Me
Me
H
H
2
H
H
O
CF3
F

Me
Me
H
H
2
H
H
O
CF3
Cl

Me
Me
H
H
2
H
H
O
CF3
OMe

Me
Me
H
H
2
H
H
O
CF3
OEt

Me
Me
H
H
2
H
H
O
CF3
OPr-i

Me
Me
H
H
2
H
H
O
CF3
OPh

Me
Me
H
H
2
H
H
O
CF3
OCHF2

Me
Me
H
H
2
H
H
O
CF3
SMe

Me
Me
H
H
2
H
H
O
CF3
SOMe

Me
Me
H
H
2
H
H
O
CF3
SO2Me

Me
Me
H
H
2
H
H
O
CF3
SEt

Me
Me
H
H
2
H
H
O
CF3
SOEt

Me
Me
H
H
2
H
H
O
CF3
SO2Et

Me
Me
H
H
2
H
H
O
CF3
SPr-i

Me
Me
H
H
2
H
H
O
CF3
SOPr-i

Me
Me
H
H
2
H
H
O
CF3
SO2Pr-i

Me
Me
H
H
2
H
H
O
CF3
SPh

Me
Me
H
H
2
H
H
O
CF3
SOPh

Me
Me
H
H
2
H
H
O
CF3
SO2Ph

Me
Me
H
H
2
H
H
O
CF3
SCHF2

Me
Me
H
H
2
H
H
O
CF3
SOCHF2

Me
Me
H
H
2
H
H
O
CF3
SO2CHF2

Me
Me
H
H
2
H
H
O
CF3
SCF3

Me
Me
H
H
2
H
H
O
CF3
SOCF3

Me
Me
H
H
2
H
H
O
CF3
SO2CF3

Me
Me
H
H
2
H
H
O
CF3
NH2

Me
Me
H
H
2
H
H
O
CF3
NHC(═O)Me

Me
Me
H
H
2
H
H
O
CF3
NHC(═O)Ph

Me
Me
H
H
2
H
H
O
CF3
NHC(═O)CH2Ph

Me
Me
H
H
2
H
H
O
CF3
NHC(═O)CF3

Me
Me
H
H
2
H
H
O
CF3
NHSO2Me

Me
Me
H
H
2
H
H
O
CF3
NHSO2Ph

Me
Me
H
H
2
H
H
O
CF3
NHSO2CHF2

Me
Me
H
H
2
H
H
O
CF3
NHSO2CF3

Me
Me
H
H
2
H
H
O
CF3
NHMe

Me
Me
H
H
2
H
H
O
CF3
NHPh

Me
Me
H
H
2
H
H
O
CF3
N(Me)C(═O)Me

Me
Me
H
H
2
H
H
O
CF3
N(Me)C(═O)Ph

Me
Me
H
H
2
H
H
O
CF3
N(Me)C(═O)CH2Ph

Me
Me
H
H
2
H
H
O
CF3
N(Me)C(═O)CF3

Me
Me
H
H
2
H
H
O
CF3
N(Me)SO2Me

Me
Me
H
H
2
H
H
O
CF3
N(Me)SO2Ph

Me
Me
H
H
2
H
H
O
CF3
N(Me)SO2CHF2

Me
Me
H
H
2
H
H
O
CF3
N(Me)SO2CF3

Me
Me
H
H
2
H
H
O
CF3
N(Me)2

Me
Me
H
H
2
H
H
O
CF3
N(Me)Ph

Me
Me
H
H
2
H
H
O
CF3
Me

Me
Me
H
H
2
H
H
O
CF3
CF3

Me
Me
H
H
2
H
H
O
CF3
CN

Me
Me
H
H
2
H
H
O
Ph
Me

H
H
H
H
2
H
H
O
CF3
Me

Me
H
H
H
2
H
H
O
CF3
Me

Me
H
Me
H
2
H
H
O
CF3
Me

Me
Me
Me
H
2
H
H
O
CF3
Me

Me
Me
H
H
2
Me
H
O
CF3
Me

Me
Me
H
H
2
Et
H
O
CF3
Me

Me
Me
H
H
2
Pr-i
H
O
CF3
Me

Me
Me
H
H
2
Me
Me
O
CF3
Me

Me
Et
H
H
2
H
H
O
CF3
Me

Et
Et
H
H
2
H
H
O
CF3
Me

Me
Pr-i
H
H
2
H
H
O
CF3
Me

Me
Pr
H
H
2
H
H
O
CF3
Me

Me
Pr-c
H
H
2
H
H
O
CF3
Me

Me
CH2Pr-c
H
H
2
H
H
O
CF3
Me

—(CH2)2—
H
H
2
H
H
O
CF3
Me

—(CH2)3—
H
H
2
H
H
O
CF3
Me

—(CH2)4—
H
H
2
H
H
O
CF3
Me

—(CH2)5—
H
H
2
H
H
O
CF3
Me

H
—(CH2)3—
H
2
H
H
O
CF3
Me

H
—(CH2)4—
H
2
H
H
O
CF3
Me

H
—(CH2)5—
H
2
H
H
O
CF3
Me

H
—(CH2)6—
H
2
H
H
O
CF3
Me

Me
Me
H
H
2
H
H
S
Me
F

Me
Me
H
H
2
H
H
S
Me
Cl

Me
Me
H
H
2
H
H
S
Me
OMe

Me
Me
H
H
2
H
H
S
Me
OEt

Me
Me
H
H
2
H
H
S
Me
OPr-i

Me
Me
H
H
2
H
H
S
Me
OPh

Me
Me
H
H
2
H
H
S
Me
OCHF2

Me
Me
H
H
2
H
H
S
OCHF2
F

Me
Me
H
H
2
H
H
S
OCHF2
Cl

Me
Me
H
H
2
H
H
S
OCHF2
Me

Me
Me
H
H
2
H
H
S
OCHF2
CF3

Me
Me
H
H
2
H
H
S
OCHF2
CN

Me
Me
H
H
2
H
H
S
CF3
F

Me
Me
H
H
2
H
H
S
CF3
Cl

Me
Me
H
H
2
H
H
S
CF3
OMe

Me
Me
H
H
2
H
H
S
CF3
OEt

Me
Me
H
H
2
H
H
S
CF3
OPh

Me
Me
H
H
2
H
H
S
CF3
OCHF2

Me
Me
H
H
2
H
H
S
CF3
SMe

Me
Me
H
H
2
H
H
S
CF3
SOMe

Me
Me
H
H
2
H
H
S
CF3
SO2Me

Me
Me
H
H
2
H
H
S
CF3
SEt

Me
Me
H
H
2
H
H
S
CF3
SOEt

Me
Me
H
H
2
H
H
S
CF3
SO2Et

Me
Me
H
H
2
H
H
S
CF3
SPr-i

Me
Me
H
H
2
H
H
S
CF3
SOPr-i

Me
Me
H
H
2
H
H
S
CF3
SO2Pr-i

Me
Me
H
H
2
H
H
S
CF3
SPh

Me
Me
H
H
2
H
H
S
CF3
SOPh

Me
Me
H
H
2
H
H
S
CF3
SO2Ph

Me
Me
H
H
2
H
H
S
CF3
SCHF2

Me
Me
H
H
2
H
H
S
CF3
SOCHF2

Me
Me
H
H
2
H
H
S
CF3
SO2CHF2

Me
Me
H
H
2
H
H
S
CF3
SCF3

Me
Me
H
H
2
H
H
S
CF3
SOCF3

Me
Me
H
H
2
H
H
S
CF3
SO2CF3

Me
Me
H
H
2
H
H
S
CF3
NH2

Me
Me
H
H
2
H
H
S
CF3
NHC(═O)Me

Me
Me
H
H
2
H
H
S
CF3
NHC(═O)Ph

Me
Me
H
H
2
H
H
S
CF3
NHC(═O)CH2Ph

Me
Me
H
H
2
H
H
S
CF3
NHC(═O)CF3

Me
Me
H
H
2
H
H
S
CF3
NHSO2Me

Me
Me
H
H
2
H
H
S
CF3
NHSO2Ph

Me
Me
H
H
2
H
H
S
CF3
NHSO2CHF2

Me
Me
H
H
2
H
H
S
CF3
NHSO2CF3

Me
Me
H
H
2
H
H
S
CF3
NHMe

Me
Me
H
H
2
H
H
S
CF3
NHPh

Me
Me
H
H
2
H
H
S
CF3
N(Me)C(═O)Me

Me
Me
H
H
2
H
H
S
CF3
N(Me)C(═O)Ph

Me
Me
H
H
2
H
H
S
CF3
N(Me)C(═O)CH2Ph

Me
Me
H
H
2
H
H
S
CF3
N(Me)C(═O)CF3

Me
Me
H
H
2
H
H
S
CF3
N(Me)SO2Me

Me
Me
H
H
2
H
H
S
CF3
N(Me)SO2Ph

Me
Me
H
H
2
H
H
S
CF3
N(Me)SO2CHF2

Me
Me
H
H
2
H
H
S
CF3
N(Me)SO2CF3

Me
Me
H
H
2
H
H
S
CF3
N(Me)2

Me
Me
H
H
2
H
H
S
CF3
N(Me)Ph

Me
Me
H
H
2
H
H
S
CF3
Me

Me
Me
H
H
2
H
H
S
CF3
CN

H
H
H
H
2
H
H
S
CF3
Cl

Me
H
H
H
2
H
H
S
CF3
Cl

Me
H
Me
H
2
H
H
S
CF3
Cl

Me
Me
Me
H
2
H
H
S
CF3
Cl

Me
Me
H
H
2
Me
H
S
CF3
Cl

Me
Me
H
H
2
Et
H
S
CF3
Cl

Me
Me
H
H
2
Pr-i
H
S
CF3
Cl

Me
Me
H
H
2
Me
Me
S
CF3
Cl

Me
Et
H
H
2
H
H
S
CF3
Cl

Et
Et
H
H
2
H
H
S
CF3
Cl

Me
Pr-i
H
H
2
H
H
S
CF3
Cl

Me
Pr
H
H
2
H
H
S
CF3
Cl

Me
Pr-c
H
H
2
H
H
S
CF3
Cl

Me
CH2Pr-c
H
H
2
H
H
S
CF3
Cl

—(CH2)2—
H
H
2
H
H
S
CF3
Cl

—(CH2)3—
H
H
2
H
H
S
CF3
Cl

—(CH2)4—
H
H
2
H
H
S
CF3
Cl

—(CH2)5—
H
H
2
H
H
S
CF3
Cl

H
—(CH2)3—
H
2
H
H
S
CF3
Cl

H
—(CH2)4—
H
2
H
H
S
CF3
Cl

H
—(CH2)5—
H
2
H
H
S
CF3
Cl

H
—(CH2)6—
H
2
H
H
S
CF3
Cl

Me
Me
H
H
1
H
H
O
Me
F

Me
Me
H
H
1
H
H
O
Me
Cl

Me
Me
H
H
1
H
H
O
Me
OMe

Me
Me
H
H
1
H
H
O
Me
OEt

Me
Me
H
H
1
H
H
O
Me
OPr-i

Me
Me
H
H
1
H
H
O
Me
OPh

Me
Me
H
H
1
H
H
O
Me
OCHF2

Me
Me
H
H
1
H
H
O
Me
Me

Me
Me
H
H
1
H
H
O
Me
CF3

Me
Me
H
H
1
H
H
O
Me
CN

Me
Me
H
H
1
H
H
O
OCHF2
F

Me
Me
H
H
1
H
H
O
OCHF2
Cl

Me
Me
H
H
1
H
H
O
OCHF2
Me

Me
Me
H
H
1
H
H
O
OCHF2
CF3

Me
Me
H
H
1
H
H
O
OCHF2
CN

Me
Me
H
H
1
H
H
O
CF3
F

Me
Me
H
H
1
H
H
O
CF3
Cl

Me
Me
H
H
1
H
H
O
CF3
OMe

Me
Me
H
H
1
H
H
O
CF3
OEt

Me
Me
H
H
1
H
H
O
CF3
OPr-i

Me
Me
H
H
1
H
H
O
CF3
OPh

Me
Me
H
H
1
H
H
O
CF3
OCHF2

Me
Me
H
H
1
H
H
O
CF3
SMe

Me
Me
H
H
1
H
H
O
CF3
SO2Me

Me
Me
H
H
1
H
H
O
CF3
SEt

Me
Me
H
H
1
H
H
O
CF3
SO2Et

Me
Me
H
H
1
H
H
O
CF3
SPr-i

Me
Me
H
H
1
H
H
O
CF3
SO2Pr-i

Me
Me
H
H
1
H
H
O
CF3
SPh

Me
Me
H
H
1
H
H
O
CF3
SO2Ph

Me
Me
H
H
1
H
H
O
CF3
SCHF2

Me
Me
H
H
1
H
H
O
CF3
SO2CHF2

Me
Me
H
H
1
H
H
O
CF3
SCF3

Me
Me
H
H
1
H
H
O
CF3
SO2CF3

Me
Me
H
H
1
H
H
O
CF3
NH2

Me
Me
H
H
1
H
H
O
CF3
NHC(═O)Me

Me
Me
H
H
1
H
H
O
CF3
NHC(═O)Ph

Me
Me
H
H
1
H
H
O
CF3
NHC(═O)CH2Ph

Me
Me
H
H
1
H
H
O
CF3
NHC(═O)CF3

Me
Me
H
H
1
H
H
O
CF3
NHSO2Me

Me
Me
H
H
1
H
H
O
CF3
NHSO2Ph

Me
Me
H
H
1
H
H
O
CF3
NHSO2CHF2

Me
Me
H
H
1
H
H
O
CF3
NHSO2CF3

Me
Me
H
H
1
H
H
O
CF3
NHMe

Me
Me
H
H
1
H
H
O
CF3
NHPh

Me
Me
H
H
1
H
H
O
CF3
N(Me)C(═O)Me

Me
Me
H
H
1
H
H
O
CF3
N(Me)C(═O)Ph

Me
Me
H
H
1
H
H
O
CF3
N(Me)C(═O)CH2Ph

Me
Me
H
H
1
H
H
O
CF3
N(Me)C(═O)CF3

Me
Me
H
H
1
H
H
O
CF3
N(Me)SO2Me

Me
Me
H
H
1
H
H
O
CF3
N(Me)SO2Ph

Me
Me
H
H
1
H
H
O
CF3
N(Me)SO2CHF2

Me
Me
H
H
1
H
H
O
CF3
N(Me)SO2CF3

Me
Me
H
H
1
H
H
O
CF3
N(Me)2

Me
Me
H
H
1
H
H
O
CF3
N(Me)Ph

Me
Me
H
H
1
H
H
O
CF3
Me

Me
Me
H
H
1
H
H
O
CF3
CF3

Me
Me
H
H
1
H
H
O
CF3
CN

Me
Me
H
H
1
H
H
O
Ph
Me

H
H
H
H
1
H
H
O
CF3
Me

Me
H
H
H
1
H
H
O
CF3
Me

Me
H
Me
H
1
H
H
O
CF3
Me

Me
Me
Me
H
1
H
H
O
CF3
Me

Me
Me
H
H
1
Me
H
O
CF3
Me

Me
Me
H
H
1
Et
H
O
CF3
Me

Me
Me
H
H
1
Pr-i
H
O
CF3
Me

Me
Me
H
H
1
Me
Me
O
CF3
Me

Me
Et
H
H
1
H
H
O
CF3
Me

Et
Et
H
H
1
H
H
O
CF3
Me

Me
Pr-i
H
H
1
H
H
O
CF3
Me

Me
Pr
H
H
1
H
H
O
CF3
Me

Me
Pr-c
H
H
1
H
H
O
CF3
Me

Me
CH2Pr-c
H
H
1
H
H
O
CF3
Me

—(CH2)2—
H
H
1
H
H
O
CF3
Me

—(CH2)3—
H
H
1
H
H
O
CF3
Me

—(CH2)4—
H
H
1
H
H
O
CF3
Me

—(CH2)5—
H
H
1
H
H
O
CF3
Me

H
—(CH2)3—
H
1
H
H
O
CF3
Me

H
—(CH2)4—
H
1
H
H
O
CF3
Me

H
—(CH2)5—
H
1
H
H
O
CF3
Me

H
—(CH2)6—
H
1
H
H
O
CF3
Me

Me
Me
H
H
1
H
H
S
Me
F

Me
Me
H
H
1
H
H
S
Me
Cl

Me
Me
H
H
1
H
H
S
Me
OMe

Me
Me
H
H
1
H
H
S
Me
OEt

Me
Me
H
H
1
H
H
S
Me
OPr-i

Me
Me
H
H
1
H
H
S
Me
OPh

Me
Me
H
H
1
H
H
S
Me
OCHF2

Me
Me
H
H
1
H
H
S
OCHF2
F

Me
Me
H
H
1
H
H
S
OCHF2
Cl

Me
Me
H
H
1
H
H
S
OCHF2
Me

Me
Me
H
H
1
H
H
S
OCHF2
CF3

Me
Me
H
H
1
H
H
S
OCHF2
CN

Me
Me
H
H
1
H
H
S
CF3
F

Me
Me
H
H
1
H
H
S
CF3
Cl

Me
Me
H
H
1
H
H
S
CF3
OMe

Me
Me
H
H
1
H
H
S
CF3
OEt

Me
Me
H
H
1
H
H
S
CF3
OPh

Me
Me
H
H
1
H
H
S
CF3
OCHF2

Me
Me
H
H
1
H
H
S
CF3
SMe

Me
Me
H
H
1
H
H
S
CF3
SO2Me

Me
Me
H
H
1
H
H
S
CF3
SEt

Me
Me
H
H
1
H
H
S
CF3
SO2Et

Me
Me
H
H
1
H
H
S
CF3
SPr-i

Me
Me
H
H
1
H
H
S
CF3
SO2Pr-i

Me
Me
H
H
1
H
H
S
CF3
SPh

Me
Me
H
H
1
H
H
S
CF3
SO2Ph

Me
Me
H
H
1
H
H
S
CF3
SCHF2

Me
Me
H
H
1
H
H
S
CF3
SO2CHF2

Me
Me
H
H
1
H
H
S
CF3
SCF3

Me
Me
H
H
1
H
H
S
CF3
SO2CF3

Me
Me
H
H
1
H
H
S
CF3
NH2

Me
Me
H
H
1
H
H
S
CF3
NHC(═O)Me

Me
Me
H
H
1
H
H
S
CF3
NHC(═O)Ph

Me
Me
H
H
1
H
H
S
CF3
NHC(═O)CH2Ph

Me
Me
H
H
1
H
H
S
CF3
NHC(═O)CF3

Me
Me
H
H
1
H
H
S
CF3
NHSO2Me

Me
Me
H
H
1
H
H
S
CF3
NHSO2Ph

Me
Me
H
H
1
H
H
S
CF3
NHSO2CHF2

Me
Me
H
H
1
H
H
S
CF3
NHSO2CF3

Me
Me
H
H
1
H
H
S
CF3
NHMe

Me
Me
H
H
1
H
H
S
CF3
NHPh

Me
Me
H
H
1
H
H
S
CF3
N(Me)C(═O)Me

Me
Me
H
H
1
H
H
S
CF3
N(Me)C(═O)Ph

Me
Me
H
H
1
H
H
S
CF3
N(Me)C(═O)CH2Ph

Me
Me
H
H
1
H
H
S
CF3
N(Me)C(═O)CF3

Me
Me
H
H
1
H
H
S
CF3
N(Me)SO2Me

Me
Me
H
H
1
H
H
S
CF3
N(Me)SO2Ph

Me
Me
H
H
1
H
H
S
CF3
N(Me)SO2CHF2

Me
Me
H
H
1
H
H
S
CF3
N(Me)SO2CF3

Me
Me
H
H
1
H
H
S
CF3
N(Me)2

Me
Me
H
H
1
H
H
S
CF3
N(Me)Ph

Me
Me
H
H
1
H
H
S
CF3
Me

Me
Me
H
H
1
H
H
S
CF3
CN

H
H
H
H
1
H
H
S
CF3
Cl

Me
H
H
H
1
H
H
S
CF3
Cl

Me
H
Me
H
1
H
H
S
CF3
Cl

Me
Me
Me
H
1
H
H
S
CF3
Cl

Me
Me
H
H
1
Me
H
S
CF3
Cl

Me
Me
H
H
1
Et
H
S
CF3
Cl

Me
Me
H
H
1
Pr-i
H
S
CF3
Cl

Me
Me
H
H
1
Me
Me
S
CF3
Cl

Me
Et
H
H
1
H
H
S
CF3
Cl

Et
Et
H
H
1
H
H
S
CF3
Cl

Me
Pr-i
H
H
1
H
H
S
CF3
Cl

Me
Pr
H
H
1
H
H
S
CF3
Cl

Me
Pr-c
H
H
1
H
H
S
CF3
Cl

Me
CH2Pr-c
H
H
1
H
H
S
CF3
Cl

—(CH2)2—
H
H
1
H
H
S
CF3
Cl

—(CH2)3—
H
H
1
H
H
S
CF3
Cl

—(CH2)4—
H
H
1
H
H
S
CF3
Cl

—(CH2)5—
H
H
1
H
H
S
CF3
Cl

H
—(CH2)3—
H
1
H
H
S
CF3
Cl

H
—(CH2)4—
H
1
H
H
S
CF3
Cl

H
—(CH2)5—
H
1
H
H
S
CF3
Cl

H
—(CH2)6—
H
1
H
H
S
CF3
Cl

Me
Me
H
H
0
H
H
O
Me
F

Me
Me
H
H
0
H
H
O
Me
Cl

Me
Me
H
H
0
H
H
O
Me
OMe

Me
Me
H
H
0
H
H
O
Me
OEt

Me
Me
H
H
0
H
H
O
Me
OPr-i

Me
Me
H
H
0
H
H
O
Me
OPh

Me
Me
H
H
0
H
H
O
Me
OCHF2

Me
Me
H
H
0
H
H
O
Me
Me

Me
Me
H
H
0
H
H
O
Me
CF3

Me
Me
H
H
0
H
H
O
Me
CN

Me
Me
H
H
0
H
H
O
OCHF2
F

Me
Me
H
H
0
H
H
O
OCHF2
Cl

Me
Me
H
H
0
H
H
O
OCHF2
Me

Me
Me
H
H
0
H
H
O
OCHF2
CF3

Me
Me
H
H
0
H
H
O
OCHF2
CN

Me
Me
H
H
0
H
H
O
CF3
F

Me
Me
H
H
0
H
H
O
CF3
Cl

Me
Me
H
H
0
H
H
O
CF3
OMe

Me
Me
H
H
0
H
H
O
CF3
OEt

Me
Me
H
H
0
H
H
O
CF3
OPr-i

Me
Me
H
H
0
H
H
O
CF3
OPh

Me
Me
H
H
0
H
H
O
CF3
OCHF2

Me
Me
H
H
0
H
H
O
CF3
SMe

Me
Me
H
H
0
H
H
O
CF3
SO2Me

Me
Me
H
H
0
H
H
O
CF3
SEt

Me
Me
H
H
0
H
H
O
CF3
SO2Et

Me
Me
H
H
0
H
H
O
CF3
SPr-i

Me
Me
H
H
0
H
H
O
CF3
SO2Pr-i

Me
Me
H
H
0
H
H
O
CF3
SPh

Me
Me
H
H
0
H
H
O
CF3
SO2Ph

Me
Me
H
H
0
H
H
O
CF3
SCHF2

Me
Me
H
H
0
H
H
O
CF3
SO2CHF2

Me
Me
H
H
0
H
H
O
CF3
SCF3

Me
Me
H
H
0
H
H
O
CF3
SO2CF3

Me
Me
H
H
0
H
H
O
CF3
NH2

Me
Me
H
H
0
H
H
O
CF3
NHC(═O)Me

Me
Me
H
H
0
H
H
O
CF3
NHC(═O)Ph

Me
Me
H
H
0
H
H
O
CF3
NHC(═O)CH2Ph

Me
Me
H
H
0
H
H
O
CF3
NHC(═O)CF3

Me
Me
H
H
0
H
H
O
CF3
NHSO2Me

Me
Me
H
H
0
H
H
O
CF3
NHSO2Ph

Me
Me
H
H
0
H
H
O
CF3
NHSO2CHF2

Me
Me
H
H
0
H
H
O
CF3
NHSO2CF3

Me
Me
H
H
0
H
H
O
CF3
NHMe

Me
Me
H
H
O
H
H
O
CF3
NHPh

Me
Me
H
H
0
H
H
O
CF3
N(Me)C(═0)Me

Me
Me
H
H
0
H
H
O
CF3
N(Me)C(═O)Ph

Me
Me
H
H
0
H
H
O
CF3
N(Me)C(═0)CH2Ph

Me
Me
H
H
0
H
H
O
CF3
N(Me)C(═O)CF3

Me
Me
H
H
0
H
H
O
CF3
N(Me)SO2Me

Me
Me
H
H
0
H
H
O
CF3
N(Me)SO2Ph

Me
Me
H
H
0
H
H
O
CF3
N(Me)SO2CHF2

Me
Me
H
H
0
H
H
O
CF3
N(Me)SO2CF3

Me
Me
H
H
0
H
H
O
CF3
N(Me)2

Me
Me
H
H
0
H
H
O
CF3
N(Me)Ph

Me
Me
H
H
0
H
H
O
CF3
Me

Me
Me
H
H
0
H
H
O
CF3
CF3

Me
Me
H
H
0
H
H
O
CF3
CN

Me
Me
H
H
0
H
H
O
Ph
Me

H
H
H
H
0
H
H
O
CF3
Me

Me
H
H
H
0
H
H
O
CF3
Me

Me
H
Me
H
0
H
H
O
CF3
Me

Me
Me
Me
H
0
H
H
O
CF3
Me

Me
Me
H
H
0
Me
H
O
CF3
Me

Me
Me
H
H
0
Et
H
O
CF3
Me

Me
Me
H
H
0
Pr-i
H
O
CF3
Me

Me
Me
H
H
0
Me
Me
O
CF3
Me

Me
Et
H
H
0
H
H
O
CF3
Me

Et
Et
H
H
0
H
H
O
CF3
Me

Me
Pr-i
H
H
0
H
H
O
CF3
Me

Me
Pr
H
H
0
H
H
O
CF3
Me

Me
Pr-c
H
H
0
H
H
O
CF3
Me

Me
CH2Pr-c
H
H
0
H
H
O
CF3
Me

—(CH2)2—
H
H
0
H
H
O
CF3
Me

—(CH2)3—
H
H
0
H
H
O
CF3
Me

—(CH2)4—
H
H
0
H
H
O
CF3
Me

—(CH2)5—
H
H
0
H
H
O
CF3
Me

H
—(CH2)3—
H
0
H
H
O
CF3
Me

H
—(CH2)4—
H
0
H
H
O
CF3
Me

H
—(CH2)5—
H
0
H
H
O
CF3
Me

H
—(CH2)6—
H
0
H
H
O
CF3
Me

Me
Me
H
H
0
H
H
S
Me
F

Me
Me
H
H
0
H
H
S
Me
Cl

Me
Me
H
H
0
H
H
S
Me
OMe

Me
Me
H
H
0
H
H
S
Me
OEt

Me
Me
H
H
0
H
H
S
Me
OPr-i

Me
Me
H
H
0
H
H
S
Me
OPh

Me
Me
H
H
0
H
H
S
Me
OCHF2

Me
Me
H
H
0
H
H
S
OCHF2
F

Me
Me
H
H
0
H
H
S
OCHF2
Cl

Me
Me
H
H
0
H
H
S
OCHF2
Me

Me
Me
H
H
0
H
H
S
OCHF2
CF3

Me
Me
H
H
0
H
H
S
OCHF2
CN

Me
Me
H
H
0
H
H
S
CF3
F

Me
Me
H
H
0
H
H
S
CF3
Cl

Me
Me
H
H
0
H
H
S
CF3
OMe

Me
Me
H
H
0
H
H
S
CF3
OEt

Me
Me
H
H
0
H
H
S
CF3
OPh

Me
Me
H
H
0
H
H
S
CF3
OCHF2

Me
Me
H
H
0
H
H
S
CF3
SMe

Me
Me
H
H
0
H
H
S
CF3
SO2Me

Me
Me
H
H
0
H
H
S
CF3
SEt

Me
Me
H
H
0
H
H
S
CF3
SO2Et

Me
Me
H
H
0
H
H
S
CF3
SPr-i

Me
Me
H
H
0
H
H
S
CF3
SO2Pr-i

Me
Me
H
H
0
H
H
S
CF3
SPh

Me
Me
H
H
0
H
H
S
CF3
SO2Ph

Me
Me
H
H
0
H
H
S
CF3
SCHF2

Me
Me
H
H
0
H
H
S
CF3
SO2CHF2

Me
Me
H
H
0
H
H
S
CF3
SCF3

Me
Me
H
H
0
H
H
S
CF3
SO2CF3

Me
Me
H
H
0
H
H
S
CF3
NH2

Me
Me
H
H
0
H
H
S
CF3
NHC(═O)Me

Me
Me
H
H
0
H
H
S
CF3
NHC(═O)Ph

Me
Me
H
H
0
H
H
S
CF3
NHC(═O)CH2Ph

Me
Me
H
H
0
H
H
S
CF3
NHC(═O)CF3

Me
Me
H
H
0
H
H
S
CF3
NHSO2Me

Me
Me
H
H
0
H
H
S
CF3
NHSO2Ph

Me
Me
H
H
0
H
H
S
CF3
NHSO2CHF2

Me
Me
H
H
0
H
H
S
CF3
NHSO2CF3

Me
Me
H
H
0
H
H
S
CF3
NHMe

Me
Me
H
H
0
H
H
S
CF3
NEPh

Me
Me
H
H
0
H
H
S
CF3
N(Me)C(═O)Me

Me
Me
H
H
0
H
H
S
CF3
N(Me)C(═O)Ph

Me
Me
H
H
0
H
H
S
CF3
N(Me)C(═O)CH2Ph

Me
Me
H
H
0
H
H
S
CF3
N(Me)C(═O)CF3

Me
Me
H
H
0
H
H
S
CF3
N(Me)SO2Me

Me
Me
H
H
0
H
H
S
CF3
N(Me)SO2Ph

Me
Me
H
H
0
H
H
S
CF3
N(Me)SO2CHF2

Me
Me
H
H
0
H
H
S
CF3
N(Me)SO2CF3

Me
Me
H
H
0
H
H
S
CF3
N(Me)2

Me
Me
H
H
0
H
H
S
CF3
N(Me)Ph

Me
Me
H
H
0
H
H
S
CF3
Me

Me
Me
H
H
0
H
H
S
CF3
CN

H
H
H
H
0
H
H
S
CF3
Cl

Me
H
H
H
0
H
H
S
CF3
Cl

Me
H
Me
H
0
H
H
S
CF3
Cl

Me
Me
Me
H
0
H
H
S
CF3
Cl

Me
Me
H
H
0
Me
H
S
CF3
Cl

Me
Me
H
H
0
Et
H
S
CF3
Cl

Me
Me
H
H
0
Pr-i
H
S
CF3
Cl

Me
Me
H
H
0
Me
Me
S
CF3
Cl

Me
Et
H
H
0
H
H
S
CF3
Cl

Et
Et
H
H
0
H
H
S
CF3
Cl

Me
Pr-i
H
H
0
H
H
S
CF3
Cl

Me
Pr
H
H
0
H
H
S
CF3
Cl

Me
Pr-c
H
H
0
H
H
S
CF3
Cl

Me
CH2Pr-c
H
H
0
H
H
S
CF3
Cl

—(CH2)2—
H
H
0
H
H
S
CF3
Cl

—(CH2)3—
H
H
0
H
H
S
CF3
Cl

—(CH2)4—
H
H
0
H
H
S
CF3
Cl

—(CH2)5—
H
H
0
H
H
S
CF3
Cl

H
—(CH2)3—
H
0
H
H
S
CF3
Cl

H
—(CH2)4—
H
0
H
H
S
CF3
Cl

H
—(CH2)5—
H
0
H
H
S
CF3
Cl

H
—(CH2)6—
H
0
H
H
S
CF3
Cl

[0085]

6

TABLE 5

R1
R2
R3
R4
n
R5
R6
Z4
R33
R34

Me
Me
H
H
2
H
H
NMe
Cl
H

Me
Me
H
H
2
H
H
NMe
Cl
Me

Me
Me
H
H
2
H
H
NMe
Cl
Et

Me
Me
H
H
2
H
H
NMe
Cl
CF3

Me
Me
H
H
2
H
H
NMe
CF3
H

Me
Me
H
H
2
H
H
NMe
CF3
Me

Me
Me
H
H
2
H
H
NMe
OCHF2
H

Me
Me
H
H
2
H
H
NMe
OCHF2
Me

Me
Me
H
H
2
H
H
NMe
C(═O)Me
H

Me
Me
H
H
2
H
H
NMe
C(═O)Me
Me

Me
Me
H
H
2
H
H
NMe
—(CH2)3—

Me
Me
H
H
2
H
H
NMe
—(CH2)4—

Me
Me
H
H
2
H
H
NEt
Cl
Me

Me
Me
H
H
2
H
H
NEt
CF3
H

Me
Me
H
H
2
H
H
NEt
CF3
Me

Me
Me
H
H
2
H
H
NEt
OCHF2
H

Me
Me
H
H
2
H
H
NEt
OCHF2
Me

Me
Me
H
H
2
H
H
NEt
—(CH2)3—

Me
Me
H
H
2
H
H
NEt
—(CH2)4—

Me
Me
H
H
2
H
H
NPr-i
Cl
Me

Me
Me
H
H
2
H
H
NPr-i
CF3
H

Me
Me
H
H
2
H
H
NPr-i
CF3
Me

Me
Me
H
H
2
H
H
NPr-i
OCHF2
H

Me
Me
H
H
2
H
H
NPr-i
OCHF2
Me

Me
Me
H
H
2
H
H
NPr-i
—(CH2)3—

Me
Me
H
H
2
H
H
NPr-i
—(CH2)4—

Me
Me
H
H
2
H
H
NPr
Cl
Me

Me
Me
H
H
2
H
H
NPr
CF3
H

Me
Me
H
H
2
H
H
NPr
CF3
Me

Me
Me
H
H
2
H
H
NPr
OCHF2
H

Me
Me
H
H
2
H
H
NPr
OCHF2
Me

Me
Me
H
H
2
H
H
NPr
—(CH2)3—

Me
Me
H
H
2
H
H
NPr
—(CH2)4—

Me
Me
H
H
2
H
H
NBu-t
Cl
Me

Me
Me
H
H
2
H
H
NBu-t
CF3
H

Me
Me
H
H
2
H
H
NBu-t
CF3
Me

Me
Me
H
H
2
H
H
NBu-t
OCHF2
H

Me
Me
H
H
2
H
H
NBu-t
OCHF2
Me

Me
Me
H
H
2
H
H
NBu-t
—(CH2)3—

Me
Me
H
H
2
H
H
NBu-t
—(CH2)4—

Me
Me
H
H
2
H
H
NCH2Ph
Cl
Me

Me
Me
H
H
2
H
H
NCH2Ph
CF3
H

Me
Me
H
H
2
H
H
NCH2Ph
OCHF2
H

Me
Me
H
H
2
H
H
NCH2OMe
Cl
Me

Me
Me
H
H
2
H
H
NCH2OMe
CF3
H

Me
Me
H
H
2
H
H
NCH2OMe
OCHF2
H

Me
Me
H
H
2
H
H
NCH2C≡CH
Cl
Me

Me
Me
H
H
2
H
H
NCH2C≡CH
CF3
H

Me
Me
H
H
2
H
H
NCH2C≡CH
OCHF2
H

Me
Me
H
H
2
H
H
NCH2CH═CH2
Cl
Me

Me
Me
H
H
2
H
H
NCH2CH═CH2
CF3
H

Me
Me
H
H
2
H
H
NCH2CH═CH2
OCHF2
H

Me
Me
H
H
2
H
H
NCHF2
Cl
Me

Me
Me
H
H
2
H
H
NCHF2
CF3
H

Me
Me
H
H
2
H
H
NCHF2
CF3
Me

Me
Me
H
H
2
H
H
NCHF2
OCHF2
H

Me
Me
H
H
2
H
H
NCHF2
OCHF2
Me

Me
Me
H
H
2
H
H
NCHF2
C(═O)Me
H

Me
Me
H
H
2
H
H
NCHF2
C(═O)Me
Me

Me
Me
H
H
2
H
H
NCHF2
—(CH2)3—

Me
Me
H
H
2
H
H
NCHF2
—(CH2)4—

Me
Me
H
H
2
H
H
NPh
OMe
Me

Me
Me
H
H
2
H
H
NPh
OEt
Me

Me
Me
H
H
2
H
H
NPh
OCHF2
Me

Me
Me
H
H
2
H
H
NPh
OCH2CF3
Me

Me
Me
H
H
2
H
H
NPh
CF3
H

Me
Me
H
H
2
H
H
NPh
OCH2CH═CH2
Me

Me
Me
H
H
2
H
H
NPh
OCH2CH≡CH
Me

Me
Me
H
H
2
H
H
NPh
Cl
Me

Me
Me
H
H
2
H
H
N(2-Cl)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(2-F)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(2-OMe)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(2-Me)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(3-Cl)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(3-F)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(3-OMe)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(3-Me)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(4-Cl)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(4-F)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(4-OMe)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(4-Me)Ph
Cl
Me

Me
Me
H
H
2
H
H
N(Thiophen-2-yl)
Cl
Me

Me
Me
H
H
2
H
H
N(Thiophen-2-yl)
CF3
H

Me
Me
H
H
2
H
H
N(Thiophen-2-yl)
OCHF2
H

Me
Me
H
H
2
H
H
NC(═O)Me
Cl
Me

Me
Me
H
H
2
H
H
NC(═O)Me
CF3
H

Me
Me
H
H
2
H
H
NC(═O)Me
OCHF2
H

Me
Me
H
H
2
H
H
NC(═O)CF3
Cl
Me

Me
Me
H
H
2
H
H
NC(═O)CF3
CF3
H

Me
Me
H
H
2
H
H
NC(═O)CF3
OCHF2
H

Me
Me
H
H
2
H
H
NC(═O)CH2Ph
Cl
Me

Me
Me
H
H
2
H
H
NC(═O)CH2Ph
CF3
H

Me
Me
H
H
2
H
H
NC(═O)CH2Ph
OCHF2
H

Me
Me
H
H
2
H
H
NC(═O)Ph
Cl
Me

Me
Me
H
H
2
H
H
NC(═O)Ph
CF3
H

Me
Me
H
H
2
H
H
NC(═O)Ph
OCHF2
H

Me
Me
H
H
2
H
H
NC(═O)OMe
Cl
Me

Me
Me
H
H
2
H
H
NC(═O)OMe
CF3
H

Me
Me
H
H
2
H
H
NC(═O)OMe
OCHF2
H

Me
Me
H
H
2
H
H
NC(═O)OCH2Ph
Cl
Me

Me
Me
H
H
2
H
H
NC(═O)OCH2Ph
CF3
H

Me
Me
H
H
2
H
H
NC(═O)OCH2Ph
OCHF2
H

Me
Me
H
H
2
H
H
NC(═O)OPh
Cl
Me

Me
Me
H
H
2
H
H
NC(═O)OPh
CF3
H

Me
Me
H
H
2
H
H
NC(═O)OPh
OCHF2
H

Me
Me
H
H
2
H
H
NC(═O)NHMe
Cl
Me

Me
Me
H
H
2
H
H
NC(═O)NHMe
CF3
H

Me
Me
H
H
2
H
H
NC(═O)NHMe
OCHF2
H

Me
Me
H
H
2
H
H
NC(═O)N(Me)2
Cl
Me

Me
Me
H
H
2
H
H
NC(═O)N(Me)2
CF3
H

Me
Me
H
H
2
H
H
NC(═O)N(Me)2
OCHF2
H

H
H
H
H
2
H
H
NPh
Cl
Me

Me
H
H
H
2
H
H
NPh
Cl
Me

Me
H
Me
H
2
H
H
NPh
Cl
Me

Me
Me
H
H
2
Me
H
NPh
Cl
Me

Me
Me
H
H
2
Et
H
NPh
Cl
Me

Me
Me
H
H
2
Pr-i
H
NPh
Cl
Me

Me
Me
H
H
2
Me
Me
NPh
Cl
Me

Me
Et
H
H
2
H
H
NPh
Cl
Me

Et
Et
H
H
2
H
H
NPh
Cl
Me

Me
Pr-i
H
H
2
H
H
NPh
Cl
Me

Me
Pr
H
H
2
H
H
NPh
Cl
Me

Me
Pr-c
H
H
2
H
H
NPh
Cl
Me

Me
CH2Pr-c
H
H
2
H
H
NPh
Cl
Me

—(CH2)2—
H
H
2
H
H
NPh
Cl
Me

—(CH2)3—
H
H
2
H
H
NPh
Cl
Me

—(CH2)4—
H
H
2
H
H
NPh
Cl
Me

—(CH2)5—
H
H
2
H
H
NPh
Cl
Me

H
—(CH2)3—
H
2
H
H
NPh
Cl
Me

H
—(CH2)4—
H
2
H
H
NPh
Cl
Me

H
—(CH2)5—
H
2
H
H
NPh
Cl
Me

H
—(CH2)6—
H
2
H
H
NPh
Cl
Me

Me
Me
H
H
2
H
H
O
H
Me

Me
Me
H
H
2
H
H
O
Cl
Me

Me
Me
H
H
2
H
H
S
H
Me

Me
Me
H
H
2
H
H
S
Cl
Me

Me
Me
H
H
1
H
H
NMe
Cl
H

Me
Me
H
H
1
H
H
NMe
Cl
Me

Me
Me
H
H
1
H
H
NMe
Cl
Et

Me
Me
H
H
1
H
H
NMe
Cl
CF3

Me
Me
H
H
1
H
H
MAe
CF3
H

Me
Me
H
H
1
H
H
NMe
CF3
Me

Me
Me
H
H
1
H
H
NMe
OCHF2
H

Me
Me
H
H
1
H
H
NMe
OCHF2
Me

Me
Me
H
H
1
H
H
NMe
C(═O)Me
H

Me
Me
H
H
1
H
H
NMe
C(═O)Me
Me

Me
Me
H
H
1
H
H
NMe
—(CH2)3—

Me
Me
H
H
1
H
H
NMe
—(CH2)4—

Me
Me
H
H
1
H
H
NEt
Cl
Me

Me
Me
H
H
1
H
H
NEt
CF3
H

Me
Me
H
H
1
H
H
NEt
CF3
Me

Me
Me
H
H
1
H
H
NEt
OCHF2
H

Me
Me
H
H
1
H
H
NEt
OCHF2
Me

Me
Me
H
H
1
H
H
NEt
—(CH2)3—

Me
Me
H
H
1
H
H
NEt
—(CH2)4—

Me
Me
H
H
1
H
H
NPr-i
Cl
Me

Me
Me
H
H
1
H
H
NPr-i
CF3
H

Me
Me
H
H
1
H
H
NPr-i
CF3
Me

Me
Me
H
H
1
H
H
NPr-i
OCHF2
H

Me
Me
H
H
1
H
H
NPr-i
OCHF2
Me

Me
Me
H
H
1
H
H
NPr-i
—(CH2)3—

Me
Me
H
H
1
H
H
NPr-i
—(CH2)4—

Me
Me
H
H
1
H
H
NPr
Cl
Me

Me
Me
H
H
1
H
H
NPr
CF3
H

Me
Me
H
H
I
H
H
NPr
CF3
Me

Me
Me
H
H
1
H
H
NPr
OCHF2
H

Me
Me
H
H
1
H
H
NPr
OCHF2
Me

Me
Me
H
H
1
H
H
NPr
—(CH2)3—

Me
Me
H
H
1
H
H
NPr
—(CH2)4—

Me
Me
H
H
1
H
H
NBu-t
Cl
Me

Me
Me
H
H
1
H
H
NBu-t
CF3
H

Me
Me
H
H
1
H
H
NBu-t
CF3
Me

Me
Me
H
H
1
H
H
NBu-t
OCHF2
H

Me
Me
H
H
1
H
H
NBu-t
OCHF2
Me

Me
Me
H
H
1
H
H
NBu-t
—(CH2)3—

Me
Me
H
H
1
H
H
NBu-t
—(CH2)4—

Me
Me
H
H
1
H
H
NCH2Ph
Cl
Me

Me
Me
H
H
1
H
H
NCH2Ph
CF3
H

Me
Me
H
H
1
H
H
NCH2Ph
OCHF2
H

Me
Me
H
H
1
H
H
NCH2OMe
Cl
Me

Me
Me
H
H
1
H
H
NCH2OMe
CF3
H

Me
Me
H
H
1
H
H
NCH2OMe
OCHF2
H

Me
Me
H
H
1
H
H
NCH2C≡CH
Cl
Me

Me
Me
H
H
1
H
H
NCH2C≡CH
CF3
H

Me
Me
H
H
1
H
H
NCH2C≡CH
OCHF2
H

Me
Me
H
H
1
H
H
NCH2CH═CH2
Cl
Me

Me
Me
H
H
1
H
H
NCH2CH═CH2
CF3
H

Me
Me
H
H
1
H
H
NCH2CH═CH2
OCHF2
H

Me
Me
H
H
1
H
H
NCHF2
Cl
Me

Me
Me
H
H
1
H
H
NCHF2
CF3
H

Me
Me
H
H
1
H
H
NCHF2
CF3
Me

Me
Me
H
H
1
H
H
NCHF2
OCHF2
H

Me
Me
H
H
1
H
H
NCHF2
OCHF2
Me

Me
Me
H
H
1
H
H
NCHF2
C(═O)Me
H

Me
Me
H
H
1
H
H
NCHF2
C(═O)Me
Me

Me
Me
H
H
1
H
H
NCHF2
—(CH2)3—

Me
Me
H
H
1
H
H
NCHF2
—(CH2)4—

Me
Me
H
H
1
H
H
NPh
OMe
Me

Me
Me
H
H
1
H
H
NPh
OEt
Me

Me
Me
H
H
1
H
H
NPh
OCHF2
Me

Me
Me
H
H
1
H
H
NPh
OCH2CF3
Me

Me
Me
H
H
1
H
H
NPh
CF3
H

Me
Me
H
H
1
H
H
NPh
OCH2CH═CH2
Me

Me
Me
H
H
1
H
H
NPh
OCH2CH═CH
Me

Me
Me
H
H
1
H
H
NPh
Cl
Me

Me
Me
H
H
1
H
H
N(2-Cl)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(2-F)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(2-OMe)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(2-Me)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(3-Cl)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(3-F)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(3-OMe)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(3-Me)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(4-Cl)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(4-F)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(4-OMe)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(4-Me)Ph
Cl
Me

Me
Me
H
H
1
H
H
N(Thiophen-2-yl)
Cl
Me

Me
Me
H
H
1
H
H
N(Thiophen-2-yl)
CF3
H

Me
Me
H
H
1
H
H
N(Thiophen-2-yl)
OCHF2
H

Me
Me
H
H
1
H
H
NC(═O)Me
Cl
Me

Me
Me
H
H
1
H
H
NC(═O)Me
CF3
H

Me
Me
H
H
1
H
H
NC(═O)Me
OCHF2
H

Me
Me
H
H
1
H
H
NC(═O)CF3
Cl
Me

Me
Me
H
H
1
H
H
NC(═O)CF3
CF3
H

Me
Me
H
H
1
H
H
NC(═O)CF3
OCHF2
H

Me
Me
H
H
1
H
H
NC(═O)CH2Ph
Cl
Me

Me
Me
H
H
1
H
H
NC(═O)CH2Ph
CF3
H

Me
Me
H
H
1
H
H
NC(═O)CH2Ph
OCHF2
H

Me
Me
H
H
1
H
H
NC(═O)Ph
Cl
Me

Me
Me
H
H
1
H
H
NC(═O)Ph
CF3
H

Me
Me
H
H
1
H
H
NC(═O)Ph
OCHF2
H

Me
Me
H
H
1
H
H
NC(═O)OMe
Cl
Me

Me
Me
H
H
1
H
H
NC(═O)OMe
CF3
H

Me
Me
H
H
1
H
H
NC(═O)OMe
OCHF2
H

Me
Me
H
H
1
H
H
NC(═O)OCH2Ph
Cl
Me

Me
Me
H
H
1
H
H
NC(═O)OCH2Ph
CF3
H

Me
Me
H
H
1
H
H
NC(═O)OCH2Ph
OCHF2
H

Me
Me
H
H
1
H
H
NC(═O)OPh
Cl
Me

Me
Me
H
H
1
H
H
NC(═O)OPh
CF3
H

Me
Me
H
H
1
H
H
NC(═O)OPh
OCHF2
H

Me
Me
H
H
1
H
H
NC(═O)NHMe
Cl
Me

Me
Me
H
H
1
H
H
NC(═O)NHMe
CF3
H

Me
Me
H
H
1
H
H
NC(═O)NHMe
OCHF2
H

Me
Me
H
H
1
H
H
NC(═O)N(Me)2
Cl
Me

Me
Me
H
H
1
H
H
NC(═O)N(Me)2
CF3
H

Me
Me
H
H
1
H
H
NC(═O)N(Me)2
OCHF2
H

H
H
H
H
1
H
H
NPh
Cl
Me

Me
H
H
H
1
H
H
NPh
Cl
Me

Me
H
Me
H
1
H
H
NPh
Cl
Me

Me
Me
H
H
1
Me
H
NPh
Cl
Me

Me
Me
H
H
1
Et
H
NPh
Cl
Me

Me
Me
H
H
1
Pr-i
H
NPh
Cl
Me

Me
Me
H
H
1
Me
Me
NPh
Cl
Me

Me
Et
H
H
1
H
H
NPh
Cl
Me

Et
Et
H
H
1
H
H
NPh
Cl
Me

Me
Pr-i
H
H
1
H
H
NPh
Cl
Me

Me
Pr
H
H
1
H
H
NPh
Cl
Me

Me
Pr-c
H
H
1
H
H
NPh
Cl
Me

Me
CH2Pr-c
H
H
1
H
H
NPh
Cl
Me

—(CH2)2—
H
H
1
H
H
NPh
Cl
Me

—(CH2)3—
H
H
1
H
H
NPh
Cl
Me

—(CH2)4—
H
H
1
H
H
NPh
Cl
Me

—(CH2)5—
H
H
1
H
H
NPh
Cl
Me

H
—(CH2)3—
H
1
H
H
NPh
Cl
Me

H
—(CH2)4—
H
1
H
H
NPh
Cl
Me

H
—(CH2)5—
H
1
H
H
NPh
Cl
Me

H
—(CH2)6—
H
1
H
H
NPh
Cl
Me

Me
Me
H
H
1
H
H
O
H
Me

Me
Me
H
H
1
H
H
O
Cl
Me

Me
Me
H
H
1
H
H
S
H
Me

Me
Me
H
H
1
H
H
S
Cl
Me

Me
Me
H
H
0
H
H
NMe
Cl
H

Me
Me
H
H
0
H
H
NMe
Cl
Me

Me
Me
H
H
0
H
H
NMe
Cl
Et

Me
Me
H
H
0
H
H
NMe
Cl
CF3

Me
Me
H
H
0
H
H
NMe
CF3
H

Me
Me
H
H
0
H
H
MAe
CF3
Me

Me
Me
H
H
0
H
H
NMe
OCHF2
H

Me
Me
H
H
0
H
H
NMe
OCHF2
Me

Me
Me
H
H
0
H
H
NMe
C(═O)Me
H

Me
Me
H
H
0
H
H
NMe
C(═O)Me
Me

Me
Me
H
H
0
H
H
NMe
—(CH2)3—

Me
Me
H
H
0
H
H
NMe
—(CH2)4—

Me
Me
H
H
0
H
H
NEt
Cl
Me

Me
Me
H
H
0
H
H
NEt
CF3
H

Me
Me
H
H
0
H
H
NEt
CF3
Me

Me
Me
H
H
0
H
H
NEt
OCHF2
H

Me
Me
H
H
0
H
H
NEt
OCHF2
Me

Me
Me
H
H
0
H
H
NEt
—(CH2)3—

Me
Me
H
H
0
H
H
NEt
—(CH2)4—

Me
Me
H
H
0
H
H
NPr-i
Cl
Me

Me
Me
H
H
0
H
H
NPr-i
CF3
H

Me
Me
H
H
0
H
H
NPr-i
CF3
Me

Me
Me
H
H
0
H
H
NPr-i
OCHF2
H

Me
Me
H
H
0
H
H
NPr-i
OCHF2
Me

Me
Me
H
H
0
H
H
NPr-i
—(CH2)3—

Me
Me
H
H
0
H
H
NPr-i
—(CH2)4—

Me
Me
H
H
0
H
H
NPr
Cl
Me

Me
Me
H
H
0
H
H
NPr
CF3
H

Me
Me
H
H
0
H
H
NPr
CF3
Me

Me
Me
H
H
0
H
H
NPr
OCHF2
H

Me
Me
H
H
0
H
H
NPr
OCHF2
Me

Me
Me
H
H
0
H
H
NPr
—(CH2)3—

Me
Me
H
H
0
H
H
NPr
—(CH2)4—

Me
Me
H
H
0
H
H
NBu-t
Cl
Me

Me
Me
H
H
0
H
H
NBu-t
CF3
H

Me
Me
H
H
0
H
H
NBu-t
CF3
Me

Me
Me
H
H
0
H
H
NBu-t
OCHF2
H

Me
Me
H
H
0
H
H
NBu-t
OCHF2
Me

Me
Me
H
H
0
H
H
NBu-t
—(CH2)3—

Me
Me
H
H
0
H
H
NBu-t
—(CH2)4—

Me
Me
H
H
0
H
H
NCH2Ph
Cl
Me

Me
Me
H
H
0
H
H
NCH2Ph
CF3
H

Me
Me
H
H
0
H
H
NCH2Ph
OCHF2
H

Me
Me
H
H
0
H
H
NCH2OMe
Cl
Me

Me
Me
H
H
0
H
H
NCH2OMe
CF3
H

Me
Me
H
H
0
H
H
NCH2OMe
OCHF2
H

Me
Me
H
H
0
H
H
NCH2C≡CH
Cl
Me

Me
Me
H
H
0
H
H
NCH2C≡CH
CF3
H

Me
Me
H
H
0
H
H
NCH2C≡CH
OCHF2
H

Me
Me
H
H
0
H
H
NCH2CH═CH2
Cl
Me

Me
Me
H
H
0
H
H
NCH2CH═CH2
CF3
H

Me
Me
H
H
0
H
H
NCH2CH═CH2
OCHF2
H

Me
Me
H
H
0
H
H
NCHF2
Cl
Me

Me
Me
H
H
0
H
H
NCHF2
CF3
H

Me
Me
H
H
0
H
H
NCHF2
CF3
Me

Me
Me
H
H
0
H
H
NCHF2
OCHF2
H

Me
Me
H
H
0
H
H
NCHF2
OCHF2
Me

Me
Me
H
H
0
H
H
NCHF2
C(═O)Me
H

Me
Me
H
H
0
H
H
NCHF2
C(═O)Me
Me

Me
Me
H
H
0
H
H
NCHF2
—(CH2)3—

Me
Me
H
H
0
H
H
NCHF2
—(CH2)4—

Me
Me
H
H
0
H
H
NPh
OMe
Me

Me
Me
H
H
0
H
H
NPh
OEt
Me

Me
Me
H
H
0
H
H
NPh
OCHF2
Me

Me
Me
H
H
0
H
H
NPh
OCH2CF3
Me

Me
Me
H
H
0
H
H
NPh
CF3
H

Me
Me
H
H
0
H
H
NPh
OCH2CH═CH2
Me

Me
Me
H
H
0
H
H
NPh
OCH2CH═CH
Me

Me
Me
H
H
0
H
H
NPh
Cl
Me

Me
Me
H
H
0
H
H
N(2-Cl)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(2-F)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(2-OMe)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(2-Me)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(3-Cl)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(3-F)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(3-OMe)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(3-Me)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(4-Cl)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(4-F)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(4-OMe)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(4-Me)Ph
Cl
Me

Me
Me
H
H
0
H
H
N(Thiophen-2-yl)
Cl
Me

Me
Me
H
H
0
H
H
N(Thiophen-2-yl)
CF3
H

Me
Me
H
H
0
H
H
N(Thiophen-2-yl)
OCHF2
H

Me
Me
H
H
0
H
H
NC(═O)Me
Cl
Me

Me
Me
H
H
0
H
H
NC(═O)Me
CF3
H

Me
Me
H
H
0
H
H
NC(═O)Me
OCHF2
H

Me
Me
H
H
0
H
H
NC(═O)CF3
Cl
Me

Me
Me
H
H
0
H
H
NC(═O)CF3
CF3
H

Me
Me
H
H
0
H
H
NC(═O)CF3
OCHF2
H

Me
Me
H
H
0
H
H
NC(═O)CH2Ph
Cl
Me

Me
Me
H
H
0
H
H
NC(═O)CH2Ph
CF3
H

Me
Me
H
H
0
H
H
NC(═O)CH2Ph
OCHF2
H

Me
Me
H
H
0
H
H
NC(═O)Ph
Cl
Me

Me
Me
H
H
0
H
H
NC(═O)Ph
CF3
H

Me
Me
H
H
0
H
H
NC(═O)Ph
OCHF2
H

Me
Me
H
H
0
H
H
NC(═O)OMe
Cl
Me

Me
Me
H
H
0
H
H
NC(═O)OMe
CF3
H

Me
Me
H
H
0
H
H
NC(═O)OMe
OCHF2
H

Me
Me
H
H
0
H
H
NC(═O)OCH2Ph
Cl
Me

Me
Me
H
H
0
H
H
NC(═O)OCH2Ph
CF3
H

Me
Me
H
H
0
H
H
NC(═O)OCH2Ph
OCHF2
H

Me
Me
H
H
0
H
H
NC(═O)OPh
Cl
Me

Me
Me
H
H
0
H
H
NC(═O)OPh
CF3
H

Me
Me
H
H
0
H
H
NC(═O)OPh
OCHF2
H

Me
Me
H
H
0
H
H
NC(═O)NHMe
Cl
Me

Me
Me
H
H
0
H
H
NC(═O)NHMe
CF3
H

Me
Me
H
H
0
H
H
NC(═O)NHMe
OCHF2
H

Me
Me
H
H
0
H
H
NC(═O)N(Me)2
Cl
Me

Me
Me
H
H
0
H
H
NC(═O)N(Me)2
CF3
H

Me
Me
H
H
0
H
H
NC(═O)N(Me)2
OCHF2
H

H
H
H
H
0
H
H
NPh
Cl
Me

Me
H
H
H
0
H
H
NPh
Cl
Me

Me
H
Me
H
0
H
H
NPh
Cl
Me

Me
Me
H
H
0
Me
H
NPh
Cl
Me

Me
Me
H
H
0
Et
H
NPh
Cl
Me

Me
Me
H
H
0
Pr-i
H
NPh
Cl
Me

Me
Me
H
H
0
Me
Me
NPh
Cl
Me

Me
Et
H
H
0
H
H
NPh
Cl
Me

Et
Et
H
H
0
H
H
NPh
Cl
Me

Me
Pr-i
H
H
0
H
H
NPh
Cl
Me

Me
Pr
H
H
0
H
H
NPh
Cl
Me

Me
Pr-c
H
H
0
H
H
NPh
Cl
Me

Me
CH2Pr-c
H
H
0
H
H
NPh
Cl
Me

—(CH2)2—
H
H
0
H
H
NPh
Cl
Me

—(CH2)3—
H
H
0
H
H
NPh
Cl
Me

—(CH2)4—
H
H
0
H
H
NPh
Cl
Me

—(CH2)5—
H
H
0
H
H
NPh
Cl
Me

H
—(CH2)3—
H
0
H
H
NPh
Cl
Me

H
—(CH2)4—
H
0
H
H
NPh
Cl
Me

H
—(CH2)5—
H
0
H
H
NPh
Cl
Me

H
—(CH2)6—
H
0
H
H
NPh
Cl
Me

Me
Me
H
H
0
H
H
O
H
Me

Me
Me
H
H
0
H
H
O
Cl
Me

Me
Me
H
H
0
H
H
S
H
Me

Me
Me
H
H
0
H
H
S
Cl
Me

Me
Et
H
H
2
H
H
NH
H
H

[0086]

7

TABLE 6

R1
R2
R3
R4
n
R5
R6
Z5
R35
R36

Me
Me
H
H
2
H
H
NMe
H
OMe

Me
Me
H
H
2
H
H
NMe
H
OEt

Me
Me
H
H
2
H
H
NMe
H
OCHF2

Me
Me
H
H
2
H
H
NMe
H
OCH2CF3

Me
Me
H
H
2
H
H
NMe
—(CH2)3—

Me
Me
H
H
2
H
H
NMe
—(CH2)4—

Me
Me
H
H
2
H
H
NEt
—(CH2)3—

Me
Me
H
H
2
H
H
NEt
—(CH2)4—

Me
Me
H
H
2
H
H
NPr-i
—(CH2)3—

Me
Me
H
H
2
H
H
NPr-i
—(CH2)4—

Me
Me
H
H
2
H
H
NCHF2
—(CH2)3—

Me
Me
H
H
2
H
H
NCHF2
—(CH2)4—

Me
Me
H
H
2
H
H
N(CH2)3O—
H

Me
Me
H
H
2
H
H
N(CH2)4O—
H

Me
Me
H
H
2
H
H
N(CH2)4—
H

Me
Me
H
H
2
H
H
N(CH2)5—
H

Me
Me
H
H
2
H
H
NPh
H
OMe

Me
Me
H
H
2
H
H
NPh
H
OEt

Me
Me
H
H
2
H
H
NPh
H
OCHF2

Me
Me
H
H
2
H
H
NPh
H
OCH2CF3

Me
Me
H
H
2
H
H
O
Me
H

Me
Me
H
H
2
H
H
S
Me
H

H
H
H
H
2
H
H
NPh
H
OMe

Me
H
H
H
2
H
H
NPh
H
OEt

Me
H
Me
H
2
H
H
NPh
H
OMe

Me
Me
H
H
2
Me
H
NPh
H
OEt

Me
Me
H
H
2
Et
H
NPh
H
OMe

Me
Me
H
H
2
Pr-i
H
NPh
H
OEt

Me
Me
H
H
2
Me
Me
NPh
H
OMe

Me
Et
H
H
2
H
H
NPh
H
OEt

Et
Et
H
H
2
H
H
NPh
H
OMe

Me
Pr-i
H
H
2
H
H
NPh
H
OEt

Me
Pr
H
H
2
H
H
NPh
H
OMe

Me
Pr-c
H
H
2
H
H
NPh
H
OEt

Me
CH2Pr-c
H
H
2
H
H
NPh
H
OMe

—(CH2)2—
H
H
2
H
H
NPh
H
OEt

—(CH2)3—
H
H
2
H
H
NPh
H
OMe

—(CH2)4—
H
H
2
H
H
NPh
H
OEt

—(CH2)5—
H
H
2
H
H
NPh
H
OMe

H
—(CH2)3—
H
2
H
H
NPh
H
OEt

H
—(CH2)4—
H
2
H
H
NPh
H
OMe

H
—(CH2)5—
H
2
H
H
NPh
H
OMe

H
—(CH2)6—
H
2
H
H
NPh
H
OEt

Me
Me
H
H
1
H
H
NMe
H
OMe

Me
Me
H
H
1
H
H
NMe
H
OEt

Me
Me
H
H
1
H
H
NMe
H
OCHF2

Me
Me
H
H
1
H
H
NMe
H
OCH2CF3

Me
Me
H
H
1
H
H
NMe
—(CH2)3—

Me
Me
H
H
1
H
H
NMe
—(CH2)4—

Me
Me
H
H
1
H
H
NEt
—(CH2)3—

Me
Me
H
H
1
H
H
NEt
—(CH2)4—

Me
Me
H
H
1
H
H
NPr-i
—(CH2)3—

Me
Me
H
H
1
H
H
NPr-i
—(CH2)4—

Me
Me
H
H
1
H
H
NCHF2
—(CH2)3—

Me
Me
H
H
1
H
H
NCHF2
—(CH2)4—

Me
Me
H
H
1
H
H
N(CH2)3O—
H

Me
Me
H
H
1
H
H
N(CH2)4O—
H

Me
Me
H
H
1
H
H
N(CH2)4—
H

Me
Me
H
H
1
H
H
N(CH2)5—
H

Me
Me
H
H
1
H
H
NPh
H
OMe

Me
Me
H
H
1
H
H
NPh
H
OEt

Me
Me
H
H
1
H
H
NPh
H
OCHF2

Me
Me
H
H
1
H
H
NPh
H
OCH2CF3

Me
Me
H
H
1
H
H
O
Me
H

Me
Me
H
H
1
H
H
S
Me
H

H
H
H
H
1
H
H
NPh
H
OMe

Me
H
H
H
1
H
H
NPh
H
OEt

Me
H
Me
H
1
H
H
NPh
H
OMe

Me
Me
H
H
1
Me
H
NPh
H
OEt

Me
Me
H
H
1
Et
H
NPh
H
OMe

Me
Me
H
H
1
Pr-i
H
NPh
H
OEt

Me
Me
H
H
1
Me
Me
NPh
H
OMe

Me
Et
H
H
1
H
H
NPh
H
OEt

Et
Et
H
H
1
H
H
NPh
H
OMe

Me
Pr-i
H
H
1
H
H
NPh
H
OEt

Me
Pr
H
H
1
H
H
NPh
H
OMe

Me
Pr-c
H
H
1
H
H
NPh
H
OEt

Me
CH2Pr-c
H
H
1
H
H
NPh
H
OMe

—(CH2)2—
H
H
1
H
H
NPh
H
OEt

—(CH2)3—
H
H
1
H
H
NPh
H
OMe

—(CH2)4—
H
H
1
H
H
NPh
H
OEt

—(CH2)5—
H
H
1
H
H
NPh
H
OMe

H
—(CH2)3—
H
1
H
H
NPh
H
OEt

H
—(CH2)4—
H
1
H
H
NPh
H
OMe

H
—(CH2)5—
H
1
H
H
NPh
H
OMe

H
—(CH2)6—
H
1
H
H
NPh
H
OEt

Me
Me
H
H
0
H
H
NMe
H
OMe

Me
Me
H
H
0
H
H
NMe
H
OEt

Me
Me
H
H
0
H
H
NMe
H
OCHF2

Me
Me
H
H
0
H
H
NMe
H
OCH2CF3

Me
Me
H
H
0
H
H
NMe
—(CH2)3—

Me
Me
H
H
0
H
H
NMe
—(CH2)4—

Me
Me
H
H
0
H
H
NEt
—(CH2)3—

Me
Me
H
H
0
H
H
NEt
—(CH2)4—

Me
Me
H
H
0
H
H
NPr-i
—(CH2)3—

Me
Me
H
H
0
H
H
NPr-i
—(CH2)4—

Me
Me
H
H
0
H
H
NCHF2
—(CH2)3—

Me
Me
H
H
0
H
H
NCHF2
—(CH2)4—

Me
Me
H
H
0
H
H
N(CH2)3O—
H

Me
Me
H
H
0
H
H
N(CH2)4O—
H

Me
Me
H
H
0
H
H
N(CH2)4—
H

Me
Me
H
H
0
H
H
N(CH2)5—
H

Me
Me
H
H
0
H
H
NPh
H
OMe

Me
Me
H
H
0
H
H
NPh
H
OEt

Me
Me
H
H
0
H
H
NPh
H
OCHF2

Me
Me
H
H
0
H
H
NPh
H
OCH2CF3

Me
Me
H
H
0
H
H
O
Me
H

Me
Me
H
H
0
H
H
S
Me
H

H
H
H
H
0
H
H
NPh
H
OMe

Me
H
H
H
0
H
H
NPh
H
OEt

Me
H
Me
H
0
H
H
NPh
H
OMe

Me
Me
H
H
0
Me
H
NPh
H
OEt

Me
Me
H
H
0
Et
H
NPh
H
OMe

Me
Me
H
H
0
Pr-i
H
NPh
H
OEt

Me
Me
H
H
0
Me
Me
NPh
H
OMe

Me
Et
H
H
0
H
H
NPh
H
OEt

Et
Et
H
H
0
H
H
NPh
H
OMe

Me
Pr-i
H
H
0
H
H
NPh
H
OEt

Me
Pr
H
H
0
H
H
NPh
H
OMe

Me
Pr-c
H
H
0
H
H
NPh
H
OEt

Me
CH2Pr-c
H
H
0
H
H
NPh
H
OMe

—(CH2)2—
H
H
0
H
H
NPh
H
OEt

—(CH2)3—
H
H
0
H
H
NPh
H
OMe

—(CH2)4—
H
H
0
H
H
NPh
H
OEt

—(CH2)5—
H
H
0
H
H
NPh
H
OMe

H
—(CH2)3—
H
0
H
H
NPh
H
OEt

H
—(CH2)4—
H
0
H
H
NPh
H
OMe

H
—(CH2)5—
H
0
H
H
NPh
H
OMe

H
—(CH2)6—
H
0
H
H
NPh
H
OEt

Me
Et
H
H
2
H
H
O
H
H

Me
Et
H
H
2
H
H
S
H
H

Me
Et
H
H
2
H
H
NH
H
H

[0087]

8

TABLE 7

R1
R2
R3
R4
n
R5
R6
R37
R38
R39
R40

Me
Me
H
H
2
H
H
H
H
H
H
—

Me
Me
H
H
2
H
H
H
H
H
H
N-oxide

Me
Me
H
H
2
H
H
Cl
Ph
H
H
—

Me
Me
H
H
2
H
H
OMe
Ph
H
H
—

Me
Me
H
H
2
H
H
Cl
Me
H
H
—

Me
Me
H
H
2
H
H
OMe
Me
H
H
—

Me
Me
H
H
2
H
H
H
CF3
H
H
—

Me
Me
H
H
2
H
H
H
CF3
H
H
N-oxide

Me
Me
H
H
2
H
H
Cl
CF3
H
H
—

Me
Me
H
H
2
H
H
CN
CF3
H
H
—

Me
Me
H
H
2
H
H
OMe
CF3
H
H
—

Me
Me
H
H
2
H
H
OEt
CF3
H
H
—

Me
Me
H
H
2
H
H
Me
Me
H
H
N-oxide

Me
Me
H
H
2
H
H
Ph
Ph
H
H
—

Me
Me
H
H
2
H
H
Cl
(4-Cl)Ph
H
Me
—

Me
Me
H
H
2
H
H
Cl
(4-Cl)Ph
H
H
—

Me
Me
H
H
2
H
H
OMe
Cl
H
H
—

Me
Me
H
H
2
H
H
Cl
(CH2)3
H
—

Me
Me
H
H
2
H
H
Me
(CH2)3
H
—

Me
Me
H
H
2
H
H
Cl
(CH2)4
H
—

Me
Me
H
H
2
H
H
Me
(CH2)4
H
—

Me
Me
H
H
2
H
H
Cl
H
(CH2)3
—

Me
Me
H
H
2
H
H
Me
H
(CH2)3
—

Me
Me
H
H
2
H
H
Cl
H
(CH2)4
—

Me
Me
H
H
2
H
H
Me
H
(CH2)4
—

H
H
H
H
2
H
H
H
CF3
H
H
—

Me
H
H
H
2
H
H
H
CF3
H
H
—

Me
H
Me
H
2
H
H
H
CF3
H
H
—

Me
Me
Me
H
2
H
H
H
CF3
H
H
—

Me
Me
H
H
2
Me
H
H
CF3
H
H
—

Me
Me
H
H
2
Et
H
H
CF3
H
H
—

Me
Me
H
H
2
Pr-i
H
H
CF3
H
H
—

Me
Me
H
H
2
Me
Me
H
CF3
H
H
—

Me
Et
H
H
2
H
H
H
CF3
H
H
—

Et
Et
H
H
2
H
H
H
CF3
H
H
—

Me
Pr-i
H
H
2
H
H
H
CF3
H
H
—

Me
Pr
H
H
2
H
H
H
CF3
H
H
—

Me
Pr-c
H
H
2
H
H
H
CF3
H
H
—

Me
CH2Pr-c
H
H
2
H
H
H
CF3
H
H
—

—(CH2)2—
H
H
2
H
H
H
CF3
H
H
—

—(CH2)3—
H
H
2
H
H
H
CF3
H
H
—

—(CH2)4—
H
H
2
H
H
H
CF3
H
H
—

—(CH2)5—
H
H
2
H
H
H
CF3
H
H
—

H
—(CH2)3—
H
2
H
H
H
CF3
H
H
—

H
—(CH2)4—
H
2
H
H
H
CF3
H
H
—

H
—(CH2)5—
H
2
H
H
H
CF3
H
H
—

H
—(CH2)6—
H
2
H
H
H
CF3
H
H
—

Me
Me
H
H
1
H
H
H
H
H
H
—

Me
Me
H
H
1
H
H
H
H
H
H
N-oxide

Me
Me
H
H
1
H
H
Cl
Ph
H
H
—

Me
Me
H
H
1
H
H
OMe
Ph
H
H
—

Me
Me
H
H
1
H
H
Cl
Me
H
H
—

Me
Me
H
H
1
H
H
OMe
Me
H
H
—

Me
Me
H
H
1
H
H
H
CF3
H
H
—

Me
Me
H
H
1
H
H
Cl
CF3
H
H
—

Me
Me
H
H
1
H
H
CN
CF3
H
H
—

Me
Me
H
H
1
H
H
OMe
CF3
H
H
—

Me
Me
H
H
1
H
H
OEt
CF3
H
H
—

Me
Me
H
H
1
H
H
Me
Me
H
H
N-oxide

Me
Me
H
H
1
H
H
Ph
Ph
H
H
—

Me
Me
H
H
1
H
H
Cl
(4-Cl)Ph
H
Me
—

Me
Me
H
H
1
H
H
Cl
(4-Cl)Ph
H
H
—

Me
Me
H
H
1
H
H
OMe
Cl
H
H
—

Me
Me
H
H
1
H
H
Cl
(CH2)3
H
—

Me
Me
H
H
1
H
H
Me
(CH2)3
H
—

Me
Me
H
H
1
H
H
Cl
(CH2)4
H
—

Me
Me
H
H
1
H
H
Me
(CH2)4
H
—

Me
Me
H
H
1
H
H
Cl
H
(CH2)3
—

Me
Me
H
H
1
H
H
Me
H
(CH2)3
—

Me
Me
H
H
1
H
H
Cl
H
(CH2)4
—

Me
Me
H
H
1
H
H
Me
H
(CH2)4
—

H
H
H
H
1
H
H
H
CF3
H
H
—

Me
H
H
H
1
H
H
H
CF3
H
H
—

Me
H
Me
H
1
H
H
H
CF3
H
H
—

Me
Me
Me
H
1
H
H
H
CF3
H
H
—

Me
Me
H
H
1
Me
H
H
CF3
H
H
—

Me
Me
H
H
1
Et
H
H
CF3
H
H
—

Me
Me
H
H
1
Pr-i
H
H
CF3
H
H
—

Me
Me
H
H
1
Me
Me
H
CF3
H
H
—

Me
Et
H
H
1
H
H
H
CF3
H
H
—

Et
Et
H
H
1
H
H
H
CF3
H
H
—

Me
Pr-i
H
H
1
H
H
H
CF3
H
H
—

Me
Pr
H
H
1
H
H
H
CF3
H
H
—

Me
Pr-c
H
H
1
H
H
H
CF3
H
H
—

Me
CH2Pr-c
H
H
1
H
H
H
CF3
H
H
—

—(CH2)2—
H
H
1
H
H
H
CF3
H
H
—

—(CH2)3—
H
H
1
H
H
H
CF3
H
H
—

—(CH2)4—
H
H
1
H
H
H
CF3
H
H
—

—(CH2)5—
H
H
1
H
H
H
CF3
H
H
—

H
—(CH2)3—
H
1
H
H
H
CF3
H
H
—

H
—(CH2)4—
H
1
H
H
H
CF3
H
H
—

H
—(CH2)5—
H
1
H
H
H
CF3
H
H
—

H
—(CH2)6—
H
1
H
H
H
CF3
H
H
—

Me
Me
H
H
0
H
H
H
H
H
H
—

Me
Me
H
H
0
H
H
H
H
H
H
N-oxide

Me
Me
H
H
0
H
H
Cl
Ph
H
H
—

Me
Me
H
H
0
H
H
OMe
Ph
H
H
—

Me
Me
H
H
0
H
H
Cl
Me
H
H
—

Me
Me
H
H
0
H
H
OMe
Me
H
H
—

Me
Me
H
H
0
H
H
H
CF3
H
H
—

Me
Me
H
H
0
H
H
Cl
CF3
H
H
—

Me
Me
H
H
0
H
H
CN
CF3
H
H
—

Me
Me
H
H
0
H
H
OMe
CF3
H
H
—

Me
Me
H
H
0
H
H
OEt
CF3
H
H
—

Me
Me
H
H
0
H
H
Me
Me
H
H
N-oxide

Me
Me
H
H
0
H
H
Ph
Ph
H
H
—

Me
Me
H
H
0
H
H
Cl
(4-Cl)Ph
H
Me
—

Me
Me
H
H
0
H
H
Cl
(4-Cl)Ph
H
H
—

Me
Me
H
H
0
H
H
OMe
Cl
H
H
—

Me
Me
H
H
0
H
H
Cl
(CH2)3
H
—

Me
Me
H
H
0
H
H
Me
(CH2)3
H
—

Me
Me
H
H
0
H
H
Cl
(CH2)4
H
—

Me
Me
H
H
0
H
H
Me
(CH2)4
H
—

Me
Me
H
H
0
H
H
Cl
H
(CH2)3
—

Me
Me
H
H
0
H
H
Me
H
(CH2)3
—

Me
Me
H
H
0
H
H
Cl
H
(CH2)4
—

Me
Me
H
H
0
H
H
Me
H
(CH2)4
—

Me
Me
H
H
0
H
H
(2-Chloropyridin-3-
H
H
H
—

yl)methylthio

H
H
H
H
0
H
H
H
CF3
H
H
—

Me
H
H
H
0
H
H
H
CF3
H
H
—

Me
Me
Me
H
0
H
H
H
CF3
H
H
—

Me
H
Me
H
0
H
H
H
CF3
H
H
—

Me
Me
H
H
0
Me
H
H
CF3
H
H
—

Me
Me
H
H
0
Et
H
H
CF3
H
H
—

Me
Me
H
H
0
Pr-i
H
H
CF3
H
H
—

Me
Me
H
H
0
Me
Me
H
CF3
H
H
—

Me
Et
H
H
0
H
H
H
CF3
H
H
—

Et
Et
H
H
0
H
H
H
CF3
H
H
—

Me
Pr-i
H
H
0
H
H
H
CF3
H
H
—

Me
Pr
H
H
0
H
H
H
CF3
H
H
—

Me
Pr-c
H
H
0
H
H
H
CF3
H
H
—

Me
CH2Pr-c
H
H
0
H
H
H
CF3
H
H
—

—(CH2)2—
H
H
0
H
H
H
CF3
H
H
—

—(CH2)3—
H
H
0
H
H
H
CF3
H
H
—

—(CH2)4—
H
H
0
H
H
H
CF3
H
H
—

—(CH2)5—
H
H
0
H
H
H
CF3
H
H
—

H
—(CH2)3—
H
0
H
H
H
CF3
H
H
—

H
—(CH2)4—
H
0
H
H
H
CF3
H
H
—

H
—(CH2)5—
H
0
H
H
H
CF3
H
H
—

H
—(CH2)6—
H
0
H
H
H
CF3
H
H
—

Me
Et
H
H
2
H
H
H
H
H
H
—

[0088]

9

TABLE 8

R1
R2
R3
R4
n
R5
R6
R41
R42
R43

Me
Me
H
H
2
H
H
H
Cl
Cl

Me
Me
H
H
2
H
H
H
OH
Cl

Me
Me
H
H
2
H
H
H
OMe
Cl

Me
Me
H
H
2
H
H
H
OEt
Cl

Me
Me
H
H
2
H
H
H
OPr-i
Cl

Me
Me
H
H
2
H
H
H
OPr
Cl

Me
Me
H
H
2
H
H
H
OBu-t
Cl

Me
Me
H
H
2
H
H
H
OCH2Pr-c
Cl

Me
Me
H
H
2
H
H
H
OCH2Bu-c
Cl

Me
Me
H
H
2
H
H
H
OCH2Pen-c
Cl

Me
Me
H
H
2
H
H
H
OCH2Hex-c
Cl

Me
Me
H
H
2
H
H
H
OPen-c
Cl

Me
Me
H
H
2
H
H
H
OHex-c
Cl

Me
Me
H
H
2
H
H
H
OCH2Ph
Cl

Me
Me
H
H
2
H
H
H
OPh
Cl

Me
Me
H
H
2
H
H
H
OCHF2
Cl

Me
Me
H
H
2
H
H
H
SH
Cl

Me
Me
H
H
2
H
H
H
SMe
Cl

Me
Me
H
H
2
H
H
H
SO2Me
Cl

Me
Me
H
H
2
H
H
H
SEt
Cl

Me
Me
H
H
2
H
H
H
SO2Et
Cl

Me
Me
H
H
2
H
H
H
SPr-i
Cl

Me
Me
H
H
2
H
H
H
SO2Pr-i
Cl

Me
Me
H
H
2
H
H
H
SPh
Cl

Me
Me
H
H
2
H
H
H
SO2Ph
Cl

Me
Me
H
H
2
H
H
H
SCHF2
Cl

Me
Me
H
H
2
H
H
H
SO2CHF2
Cl

Me
Me
H
H
2
H
H
H
NH2
Cl

Me
Me
H
H
2
H
H
H
NHMe
Cl

Me
Me
H
H
2
H
H
H
NMe2
Cl

Me
Me
H
H
2
H
H
H
NHEt
Cl

Me
Me
H
H
2
H
H
H
NEt2
Cl

Me
Me
H
H
2
H
H
H
NHPh
Cl

Me
Me
H
H
2
H
H
H
N(Me)Ph
Cl

Me
Me
H
H
2
H
H
H
CN
Cl

Me
Me
H
H
2
H
H
H
F
Me

Me
Me
H
H
2
H
H
H
Cl
Me

Me
Me
H
H
2
H
H
H
OH
Me

Me
Me
H
H
2
H
H
H
OMe
Me

Me
Me
H
H
2
H
H
H
OEt
Me

Me
Me
H
H
2
H
H
H
OPr-i
Me

Me
Me
H
H
2
H
H
H
OPr
Me

Me
Me
H
H
2
H
H
H
OBu-t
Me

Me
Me
H
H
2
H
H
H
OCH2Pr-c
Me

Me
Me
H
H
2
H
H
H
OCH2Bu-c
Me

Me
Me
H
H
2
H
H
H
OCH2Pen-c
Me

Me
Me
H
H
2
H
H
H
OCH2Hex-c
Me

Me
Me
H
H
2
H
H
H
OPen-c
Me

Me
Me
H
H
2
H
H
H
OHex-c
Me

Me
Me
H
H
2
H
H
H
OCH2Ph
Me

Me
Me
H
H
2
H
H
H
OPh
Me

Me
Me
H
H
2
H
H
H
OCHF2
Me

Me
Me
H
H
2
H
H
H
SH
Me

Me
Me
H
H
2
H
H
H
SMe
Me

Me
Me
H
H
2
H
H
H
SO2Me
Me

Me
Me
H
H
2
H
H
H
SEt
Me

Me
Me
H
H
2
H
H
H
SO2Et
Me

Me
Me
H
H
2
H
H
H
SPr-i
Me

Me
Me
H
H
2
H
H
H
SO2Pr-i
Me

Me
Me
H
H
2
H
H
H
SPh
Me

Me
Me
H
H
2
H
H
H
SO2Ph
Me

Me
Me
H
H
2
H
H
H
SCHF2
Me

Me
Me
H
H
2
H
H
H
SO2CHF2
Me

Me
Me
H
H
2
H
H
H
NH2
Me

Me
Me
H
H
2
H
H
H
NHMe
Me

Me
Me
H
H
2
H
H
H
NMe2
Me

Me
Me
H
H
2
H
H
H
NHEt
Me

Me
Me
H
H
2
H
H
H
NEt2
Me

Me
Me
H
H
2
H
H
H
NHPh
Me

Me
Me
H
H
2
H
H
H
N(Me)Ph
Me

Me
Me
H
H
2
H
H
H
CN
Me

Me
Me
H
H
2
H
H
H
F
Pr-i

Me
Me
H
H
2
H
H
H
Cl
Pr-i

Me
Me
H
H
2
H
H
H
OH
Pr-i

Me
Me
H
H
2
H
H
H
OMe
Pr-i

Me
Me
H
H
2
H
H
H
OEt
Pr-i

Me
Me
H
H
2
H
H
H
OPr-i
Pr-i

Me
Me
H
H
2
H
H
H
OPr
Pr-i

Me
Me
H
H
2
H
H
H
OBu-t
Pr-i

Me
Me
H
H
2
H
H
H
OCH2Pr-c
Pr-i

Me
Me
H
H
2
H
H
H
OCH2Bu-c
Pr-i

Me
Me
H
H
2
H
H
H
OCH2Pen-c
Pr-i

Me
Me
H
H
2
H
H
H
OCH2Hex-c
Pr-i

Me
Me
H
H
2
H
H
H
OPen-c
Pr-i

Me
Me
H
H
2
H
H
H
OHex-c
Pr-i

Me
Me
H
H
2
H
H
H
OCH2Ph
Pr-i

Me
Me
H
H
2
H
H
H
OPh
Pr-i

Me
Me
H
H
2
H
H
H
OCHF2
Pr-i

Me
Me
H
H
2
H
H
H
SH
Pr-i

Me
Me
H
H
2
H
H
H
SMe
Pr-i

Me
Me
H
H
2
H
H
H
SO2Me
Pr-i

Me
Me
H
H
2
H
H
H
SEt
Pr-i

Me
Me
H
H
2
H
H
H
SO2Et
Pr-i

Me
Me
H
H
2
H
H
H
SPr-i
Pr-i

Me
Me
H
H
2
H
H
H
SO2Pr-i
Pr-i

Me
Me
H
H
2
H
H
H
SPh
Pr-i

Me
Me
H
H
2
H
H
H
SO2Ph
Pr-i

Me
Me
H
H
2
H
H
H
SCHF2
Pr-i

Me
Me
H
H
2
H
H
H
SO2CHF2
Pr-i

Me
Me
H
H
2
H
H
H
NH2
Pr-i

Me
Me
H
H
2
H
H
H
NHMe
Pr-i

Me
Me
H
H
2
H
H
H
NMe2
Pr-i

Me
Me
H
H
2
H
H
H
NHEt
Pr-i

Me
Me
H
H
2
H
H
H
NEt2
Pr-i

Me
Me
H
H
2
H
H
H
NHPh
Pr-i

Me
Me
H
H
2
H
H
H
N(Me)Ph
Pr-i

Me
Me
H
H
2
H
H
H
CN
Pr-i

Me
Me
H
H
2
H
H
H
F
Pr-c

Me
Me
H
H
2
H
H
H
Cl
Pr-c

Me
Me
H
H
2
H
H
H
OH
Pr-c

Me
Me
H
H
2
H
H
H
OMe
Pr-c

Me
Me
H
H
2
H
H
H
OEt
Pr-c

Me
Me
H
H
2
H
H
H
OPr-i
Pr-c

Me
Me
H
H
2
H
H
H
OPr
Pr-c

Me
Me
H
H
2
H
H
H
OBu-t
Pr-c

Me
Me
H
H
2
H
H
H
OCH2Pr-c
Pr-c

Me
Me
H
H
2
H
H
H
OCH2Bu-c
Pr-c

Me
Me
H
H
2
H
H
H
OCH2Pen-c
Pr-c

Me
Me
H
H
2
H
H
H
OCH2Hex-c
Pr-c

Me
Me
H
H
2
H
H
H
OPen-c
Pr-c

Me
Me
H
H
2
H
H
H
OHex-c
Pr-c

Me
Me
H
H
2
H
H
H
OCH2Ph
Pr-c

Me
Me
H
H
2
H
H
H
OPh
Pr-c

Me
Me
H
H
2
H
H
H
OCHF2
Pr-c

Me
Me
H
H
2
H
H
H
SH
Pr-c

Me
Me
H
H
2
H
H
H
SMe
Pr-c

Me
Me
H
H
2
H
H
H
SO2Me
Pr-c

Me
Me
H
H
2
H
H
H
SEt
Pr-c

Me
Me
H
H
2
H
H
H
SO2Et
Pr-c

Me
Me
H
H
2
H
H
H
SPr-i
Pr-c

Me
Me
H
H
2
H
H
H
SO2Pr-i
Pr-c

Me
Me
H
H
2
H
H
H
SPh
Pr-c

Me
Me
H
H
2
H
H
H
SO2Ph
Pr-c

Me
Me
H
H
2
H
H
H
SCHF2
Pr-c

Me
Me
H
H
2
H
H
H
SO2CHF2
Pr-c

Me
Me
H
H
2
H
H
H
NH2
Pr-c

Me
Me
H
H
2
H
H
H
NHMe
Pr-c

Me
Me
H
H
2
H
H
H
NMe2
Pr-c

Me
Me
H
H
2
H
H
H
NHEt
Pr-c

Me
Me
H
H
2
H
H
H
NEt2
Pr-c

Me
Me
H
H
2
H
H
H
NHPh
Pr-c

Me
Me
H
H
2
H
H
H
N(Me)Ph
Pr-c

Me
Me
H
H
2
H
H
H
CN
Pr-c

Me
Me
H
H
2
H
H
H
F
CHF2

Me
Me
H
H
2
H
H
H
Cl
CHF2

Me
Me
H
H
2
H
H
H
OH
CHF2

Me
Me
H
H
2
H
H
H
OMe
CHF2

Me
Me
H
H
2
H
H
H
OEt
CHF2

Me
Me
H
H
2
H
H
H
OPr-i
CHF2

Me
Me
H
H
2
H
H
H
OPr
CHF2

Me
Me
H
H
2
H
H
H
OBu-t
CHF2

Me
Me
H
H
2
H
H
H
OCH2Pr-c
CHF2

Me
Me
H
H
2
H
H
H
OCH2Bu-c
CHF2

Me
Me
H
H
2
H
H
H
OCH2Pen-c
CHF2

Me
Me
H
H
2
H
H
H
OCH2Hex-c
CHF2

Me
Me
H
H
2
H
H
H
OPen-c
CHF2

Me
Me
H
H
2
H
H
H
OHex-c
CHF2

Me
Me
H
H
2
H
H
H
OCH2Ph
CHF2

Me
Me
H
H
2
H
H
H
OPh
CHF2

Me
Me
H
H
2
H
H
H
OCHF2
CHF2

Me
Me
H
H
2
H
H
H
SH
CHF2

Me
Me
H
H
2
H
H
H
SMe
CHF2

Me
Me
H
H
2
H
H
H
SO2Me
CHF2

Me
Me
H
H
2
H
H
H
SEt
CHF2

Me
Me
H
H
2
H
H
H
SO2Et
CHF2

Me
Me
H
H
2
H
H
H
SPr-i
CHF2

Me
Me
H
H
2
H
H
H
SO2Pr-i
CHF2

Me
Me
H
H
2
H
H
H
SPh
CHF2

Me
Me
H
H
2
H
H
H
SO2Ph
CHF2

Me
Me
H
H
2
H
H
H
SCHF2
CHF2

Me
Me
H
H
2
H
H
H
SO2CHF2
CHF2

Me
Me
H
H
2
H
H
H
NH2
CHF2

Me
Me
H
H
2
H
H
H
NHMe
CHF2

Me
Me
H
H
2
H
H
H
NMe2
CHF2

Me
Me
H
H
2
H
H
H
NHEt
CHF2

Me
Me
H
H
2
H
H
H
NEt2
CHF2

Me
Me
H
H
2
H
H
H
NHPh
CHF2

Me
Me
H
H
2
H
H
H
N(Me)Ph
CHF2

Me
Me
H
H
2
H
H
H
CN
CHF2

Me
Me
H
H
2
H
H
H
F
CF3

Me
Me
H
H
2
H
H
H
Cl
CF3

Me
Me
H
H
2
H
H
H
OH
CF3

Me
Me
H
H
2
H
H
H
OMe
CF3

Me
Me
H
H
2
H
H
H
OEt
CF3

Me
Me
H
H
2
H
H
H
OPr-i
CF3

Me
Me
H
H
2
H
H
H
OPr
CF3

Me
Me
H
H
2
H
H
H
OBu-t
CF3

Me
Me
H
H
2
H
H
H
OCH2Pr-c
CF3

Me
Me
H
H
2
H
H
H
OCH2Bu-c
CF3

Me
Me
H
H
2
H
H
H
OCH2Pen-c
CF3

Me
Me
H
H
2
H
H
H
OCH2Hex-c
CF3

Me
Me
H
H
2
H
H
H
OPen-c
CF3

Me
Me
H
H
2
H
H
H
OHex-c
CF3

Me
Me
H
H
2
H
H
H
OCH2Ph
CF3

Me
Me
H
H
2
H
H
H
OPh
CF3

Me
Me
H
H
2
H
H
H
OCHF2
CF3

Me
Me
H
H
2
H
H
H
SH
CF3

Me
Me
H
H
2
H
H
H
SMe
CF3

Me
Me
H
H
2
H
H
H
SO2Me
CF3

Me
Me
H
H
2
H
H
H
SEt
CF3

Me
Me
H
H
2
H
H
H
SO2Et
CF3

Me
Me
H
H
2
H
H
H
SPr-i
CF3

Me
Me
H
H
2
H
H
H
SO2Pr-i
CF3

Me
Me
H
H
2
H
H
H
SPh
CF3

Me
Me
H
H
2
H
H
H
SO2Ph
CF3

Me
Me
H
H
2
H
H
H
SCHF2
CF3

Me
Me
H
H
2
H
H
H
SO2CHF2
CF3

Me
Me
H
H
2
H
H
H
NH2
CF3

Me
Me
H
H
2
H
H
H
NHMe
CF3

Me
Me
H
H
2
H
H
H
NMe2
CF3

Me
Me
H
H
2
H
H
H
NHEt
CF3

Me
Me
H
H
2
H
H
H
NEt2
CF3

Me
Me
H
H
2
H
H
H
NHPh
CF3

Me
Me
H
H
2
H
H
H
N(Me)Ph
CF3

Me
Me
H
H
2
H
H
H
CN
CF3

Me
Me
H
H
2
H
H
H
F
OMe

Me
Me
H
H
2
H
H
H
OH
OMe

Me
Me
H
H
2
H
H
H
OMe
OMe

Me
Me
H
H
2
H
H
H
OEt
OMe

Me
Me
H
H
2
H
H
H
OPr-i
OMe

Me
Me
H
H
2
H
H
H
OPr
OMe

Me
Me
H
H
2
H
H
H
OBu-t
OMe

Me
Me
H
H
2
H
H
H
OCH2Pr-c
OMe

Me
Me
H
H
2
H
H
H
OCH2Bu-c
OMe

Me
Me
H
H
2
H
H
H
OCH2Pen-c
OMe

Me
Me
H
H
2
H
H
H
OCH2Hex-c
OMe

Me
Me
H
H
2
H
H
H
OPen-c
OMe

Me
Me
H
H
2
H
H
H
OHex-c
OMe

Me
Me
H
H
2
H
H
H
OCH2Ph
OMe

Me
Me
H
H
2
H
H
H
OPh
OMe

Me
Me
H
H
2
H
H
H
OCHF2
OMe

Me
Me
H
H
2
H
H
H
SH
OMe

Me
Me
H
H
2
H
H
H
SMe
OMe

Me
Me
H
H
2
H
H
H
SO2Me
OMe

Me
Me
H
H
2
H
H
H
SEt
OMe

Me
Me
H
H
2
H
H
H
SO2Et
OMe

Me
Me
H
H
2
H
H
H
SPr-i
OMe

Me
Me
H
H
2
H
H
H
SO2Pr-i
OMe

Me
Me
H
H
2
H
H
H
SPh
OMe

Me
Me
H
H
2
H
H
H
SO2Ph
OMe

Me
Me
H
H
2
H
H
H
SCHF2
OMe

Me
Me
H
H
2
H
H
H
SO2CHF2
OMe

Me
Me
H
H
2
H
H
H
NH2
OMe

Me
Me
H
H
2
H
H
H
NHMe
OMe

Me
Me
H
H
2
H
H
H
NMe2
OMe

Me
Me
H
H
2
H
H
H
NHEt
OMe

Me
Me
H
H
2
H
H
H
NEt2
OMe

Me
Me
H
H
2
H
H
H
NHPh
OMe

Me
Me
H
H
2
H
H
H
N(Me)Ph
OMe

Me
Me
H
H
2
H
H
H
CN
OMe

Me
Me
H
H
2
H
H
H
F
OPh

Me
Me
H
H
2
H
H
H
OH
OPh

Me
Me
H
H
2
H
H
H
OMe
OPh

Me
Me
H
H
2
H
H
H
OEt
OPh

Me
Me
H
H
2
H
H
H
OPr-i
OPh

Me
Me
H
H
2
H
H
H
OPr
OPh

Me
Me
H
H
2
H
H
H
OBu-t
OPh

Me
Me
H
H
2
H
H
H
OCH2Pr-c
OPh

Me
Me
H
H
2
H
H
H
OCH2Bu-c
OPh

Me
Me
H
H
2
H
H
H
OCH2Pen-c
OPh

Me
Me
H
H
2
H
H
H
OCH2Hex-c
OPh

Me
Me
H
H
2
H
H
H
OPen-c
OPh

Me
Me
H
H
2
H
H
H
OHex-c
OPh

Me
Me
H
H
2
H
H
H
OCH2Ph
OPh

Me
Me
H
H
2
H
H
H
OPh
OPh

Me
Me
H
H
2
H
H
H
OCHF2
OPh

Me
Me
H
H
2
H
H
H
SH
OPh

Me
Me
H
H
2
H
H
H
SMe
OPh

Me
Me
H
H
2
H
H
H
SO2Me
OPh

Me
Me
H
H
2
H
H
H
SEt
OPh

Me
Me
H
H
2
H
H
H
SO2Et
OPh

Me
Me
H
H
2
H
H
H
SPr-i
OPh

Me
Me
H
H
2
H
H
H
SO2Pr-i
OPh

Me
Me
H
H
2
H
H
H
SPh
OPh

Me
Me
H
H
2
H
H
H
SO2Ph
OPh

Me
Me
H
H
2
H
H
H
SCHF2
OPh

Me
Me
H
H
2
H
H
H
SO2CHF2
OPh

Me
Me
H
H
2
H
H
H
NH2
OPh

Me
Me
H
H
2
H
H
H
NHMe
OPh

Me
Me
H
H
2
H
H
H
NMe2
OPh

Me
Me
H
H
2
H
H
H
NHEt
OPh

Me
Me
H
H
2
H
H
H
NEt2
OPh

Me
Me
H
H
2
H
H
H
NHPh
OPh

Me
Me
H
H
2
H
H
H
N(Me)Ph
OPh

Me
Me
H
H
2
H
H
H
CN
OPh

Me
Me
H
H
2
H
H
H
F
OCHF2

Me
Me
H
H
2
H
H
H
OH
OCHF2

Me
Me
H
H
2
H
H
H
OMe
OCHF2

Me
Me
H
H
2
H
H
H
OEt
OCHF2

Me
Me
H
H
2
H
H
H
OPr-i
OCHF2

Me
Me
H
H
2
H
H
H
OPr
OCHF2

Me
Me
H
H
2
H
H
H
OBu-t
OCHF2

Me
Me
H
H
2
H
H
H
OCH2Pr-c
OCHF2

Me
Me
H
H
2
H
H
H
OCH2Bu-c
OCHF2

Me
Me
H
H
2
H
H
H
OCH2Pen-c
OCHF2

Me
Me
H
H
2
H
H
H
OCH2Hex-c
OCHF2

Me
Me
H
H
2
H
H
H
OPen-c
OCHF2

Me
Me
H
H
2
H
H
H
OHex-c
OCHF2

Me
Me
H
H
2
H
H
H
OCH2Ph
OCHF2

Me
Me
H
H
2
H
H
H
OPh
OCHF2

Me
Me
H
H
2
H
H
H
OCHF2
OCHF2

Me
Me
H
H
2
H
H
H
SH
OCHF2

Me
Me
H
H
2
H
H
H
SMe
OCHF2

Me
Me
H
H
2
H
H
H
SO2Me
OCHF2

Me
Me
H
H
2
H
H
H
SEt
OCHF2

Me
Me
H
H
2
H
H
H
SO2Et
OCHF2

Me
Me
H
H
2
H
H
H
SPr-i
OCHF2

Me
Me
H
H
2
H
H
H
SO2Pr-i
OCHF2

Me
Me
H
H
2
H
H
H
SPh
OCHF2

Me
Me
H
H
2
H
H
H
SO2Ph
OCHF2

Me
Me
H
H
2
H
H
H
SCHF2
OCHF2

Me
Me
H
H
2
H
H
H
SO2CHF2
OCHF2

Me
Me
H
H
2
H
H
H
NH2
OCHF2

Me
Me
H
H
2
H
H
H
NHMe
OCHF2

Me
Me
H
H
2
H
H
H
NMe2
OCHF2

Me
Me
H
H
2
H
H
H
NHEt
OCHF2

Me
Me
H
H
2
H
H
H
NEt2
OCHF2

Me
Me
H
H
2
H
H
H
NHPh
OCHF2

Me
Me
H
H
2
H
H
H
N(Me)Ph
OCHF2

Me
Me
H
H
2
H
H
H
CN
OCHF2

Me
Me
H
H
2
H
H
Me
F
CF3

Me
Me
H
H
2
H
H
Me
Cl
CF3

Me
Me
H
H
2
H
H
Me
OH
CF3

Me
Me
H
H
2
H
H
Me
OMe
CF3

Me
Me
H
H
2
H
H
Me
OEt
CF3

Me
Me
H
H
2
H
H
Me
OPr-i
CF3

Me
Me
H
H
2
H
H
Me
OPr
CF3

Me
Me
H
H
2
H
H
Me
OBu-t
CF3

Me
Me
H
H
2
H
H
Me
OCH2Pr-c
CF3

Me
Me
H
H
2
H
H
Me
OCH2Bu-c
CF3

Me
Me
H
H
2
H
H
Me
OCH2Pen-c
CF3

Me
Me
H
H
2
H
H
Me
OCH2Hex-c
CF3

Me
Me
H
H
2
H
H
Me
OPen-c
CF3

Me
Me
H
H
2
H
H
Me
OHex-c
CF3

Me
Me
H
H
2
H
H
Me
OCH2Ph
CF3

Me
Me
H
H
2
H
H
Me
OPh
CF3

Me
Me
H
H
2
H
H
Me
OCHF2
CF3

Me
Me
H
H
2
H
H
Me
SH
CF3

Me
Me
H
H
2
H
H
Me
SMe
CF3

Me
Me
H
H
2
H
H
Me
SO2Me
CF3

Me
Me
H
H
2
H
H
Me
SEt
CF3

Me
Me
H
H
2
H
H
Me
SO2Et
CF3

Me
Me
H
H
2
H
H
Me
SPr-i
CF3

Me
Me
H
H
2
H
H
Me
SO2Pr-i
CF3

Me
Me
H
H
2
H
H
Me
SPh
CF3

Me
Me
H
H
2
H
H
Me
SO2Ph
CF3

Me
Me
H
H
2
H
H
Me
SCHF2
CF3

Me
Me
H
H
2
H
H
Me
SO2CHF2
CF3

Me
Me
H
H
2
H
H
Me
NH2
CF3

Me
Me
H
H
2
H
H
Me
NHMe
CF3

Me
Me
H
H
2
H
H
Me
NMe2
CF3

Me
Me
H
H
2
H
H
Me
NHEt
CF3

Me
Me
H
H
2
H
H
Me
NEt2
CF3

Me
Me
H
H
2
H
H
Me
NHPh
CF3

Me
Me
H
H
2
H
H
Me
N(Me)Ph
CF3

Me
Me
H
H
2
H
H
Me
CN
CF3

Me
Me
H
H
2
H
H
OMe
F
CF3

Me
Me
H
H
2
H
H
OMe
Cl
CF3

Me
Me
H
H
2
H
H
OMe
OH
CF3

Me
Me
H
H
2
H
H
OMe
OMe
CF3

Me
Me
H
H
2
H
H
OMe
OEt
CF3

Me
Me
H
H
2
H
H
OMe
OPr-i
CF3

Me
Me
H
H
2
H
H
OMe
OPr
CF3

Me
Me
H
H
2
H
H
OMe
OBu-t
CF3

Me
Me
H
H
2
H
H
OMe
OCH2Pr-c
CF3

Me
Me
H
H
2
H
H
OMe
OCH2Bu-c
CF3

Me
Me
H
H
2
H
H
OMe
OCH2Pen-c
CF3

Me
Me
H
H
2
H
H
OMe
OCH2Hex-c
CF3

Me
Me
H
H
2
H
H
OMe
OPen-c
CF3

Me
Me
H
H
2
H
H
OMe
OHex-c
CF3

Me
Me
H
H
2
H
H
OMe
OCH2Ph
CF3

Me
Me
H
H
2
H
H
OMe
OPh
CF3

Me
Me
H
H
2
H
H
OMe
OCHF2
CF3

Me
Me
H
H
2
H
H
OMe
SH
CF3

Me
Me
H
H
2
H
H
OMe
SMe
CF3

Me
Me
H
H
2
H
H
OMe
SO2Me
CF3

Me
Me
H
H
2
H
H
OMe
SEt
CF3

Me
Me
H
H
2
H
H
OMe
SO2Et
CF3

Me
Me
H
H
2
H
H
OMe
SPr-i
CF3

Me
Me
H
H
2
H
H
OMe
SO2Pr-i
CF3

Me
Me
H
H
2
H
H
OMe
SPh
CF3

Me
Me
H
H
2
H
H
OMe
SO2Ph
CF3

Me
Me
H
H
2
H
H
OMe
SCHF2
CF3

Me
Me
H
H
2
H
H
OMe
SO2CHF2
CF3

Me
Me
H
H
2
H
H
OMe
NH2
CF3

Me
Me
H
H
2
H
H
OMe
NHMe
CF3

Me
Me
H
H
2
H
H
OMe
NMe2
CF3

Me
Me
H
H
2
H
H
OMe
NHEt
CF3

Me
Me
H
H
2
H
H
OMe
NEt2
CF3

Me
Me
H
H
2
H
H
OMe
NHPh
CF3

Me
Me
H
H
2
H
H
OMe
N(Me)Ph
CF3

Me
Me
H
H
2
H
H
OMe
CN
CF3

Me
Me
H
H
2
H
H
SMe
F
CF3

Me
Me
H
H
2
H
H
SMe
Cl
CF3

Me
Me
H
H
2
H
H
SMe
OH
CF3

Me
Me
H
H
2
H
H
SMe
OMe
CF3

Me
Me
H
H
2
H
H
SMe
OEt
CF3

Me
Me
H
H
2
H
H
SMe
OPr-i
CF3

Me
Me
H
H
2
H
H
SMe
OPr
CF3

Me
Me
H
H
2
H
H
SMe
OBu-t
CF3

Me
Me
H
H
2
H
H
SMe
OCH2Pr-c
CF3

Me
Me
H
H
2
H
H
SMe
OCH2Bu-c
CF3

Me
Me
H
H
2
H
H
SMe
OCH2Pen-c
CF3

Me
Me
H
H
2
H
H
SMe
OCH2Hex-c
CF3

Me
Me
H
H
2
H
H
SMe
OPen-c
CF3

Me
Me
H
H
2
H
H
SMe
OHex-c
CF3

Me
Me
H
H
2
H
H
SMe
OCH2Ph
CF3

Me
Me
H
H
2
H
H
SMe
OPh
CF3

Me
Me
H
H
2
H
H
SMe
OCHF2
CF3

Me
Me
H
H
2
H
H
SMe
SH
CF3

Me
Me
H
H
2
H
H
SMe
SMe
CF3

Me
Me
H
H
2
H
H
SMe
SO2Me
CF3

Me
Me
H
H
2
H
H
SMe
SEt
CF3

Me
Me
H
H
2
H
H
SMe
SO2Et
CF3

Me
Me
H
H
2
H
H
SMe
SPr-i
CF3

Me
Me
H
H
2
H
H
SMe
SO2Pr-i
CF3

Me
Me
H
H
2
H
H
SMe
SPh
CF3

Me
Me
H
H
2
H
H
SMe
SO2Ph
CF3

Me
Me
H
H
2
H
H
SMe
SCHF2
CF3

Me
Me
H
H
2
H
H
SMe
SO2CHF2
CF3

Me
Me
H
H
2
H
H
SMe
NH2
CF3

Me
Me
H
H
2
H
H
SMe
NHMe
CF3

Me
Me
H
H
2
H
H
SMe
NMe2
CF3

Me
Me
H
H
2
H
H
SMe
NHEt
CF3

Me
Me
H
H
2
H
H
SMe
NEt2
CF3

Me
Me
H
H
2
H
H
SMe
NHPh
CF3

Me
Me
H
H
2
H
H
SMe
N(Me)Ph
CF3

Me
Me
H
H
2
H
H
SMe
CN
CF3

Me
Me
H
H
2
H
H
SO2Me
F
CF3

Me
Me
H
H
2
H
H
SO2Me
Cl
CF3

Me
Me
H
H
2
H
H
SO2Me
OH
CF3

Me
Me
H
H
2
H
H
SO2Me
OMe
CF3

Me
Me
H
H
2
H
H
SO2Me
OEt
CF3

Me
Me
H
H
2
H
H
SO2Me
OPr-i
CF3

Me
Me
H
H
2
H
H
SO2Me
OPr
CF3

Me
Me
H
H
2
H
H
SO2Me
OBu-t
CF3

Me
Me
H
H
2
H
H
SO2Me
OCH2Pr-c
CF3

Me
Me
H
H
2
H
H
SO2Me
OCH2Bu-c
CF3

Me
Me
H
H
2
H
H
SO2Me
OCH2Pen-c
CF3

Me
Me
H
H
2
H
H
SO2Me
OCH2Hex-c
CF3

Me
Me
H
H
2
H
H
SO2Me
OPen-c
CF3

Me
Me
H
H
2
H
H
SO2Me
OHex-c
CF3

Me
Me
H
H
2
H
H
SO2Me
OCH2Ph
CF3

Me
Me
H
H
2
H
H
SO2Me
OPh
CF3

Me
Me
H
H
2
H
H
SO2Me
OCHF2
CF3

Me
Me
H
H
2
H
H
SO2Me
SH
CF3

Me
Me
H
H
2
H
H
SO2Me
SMe
CF3

Me
Me
H
H
2
H
H
SO2Me
SO2Me
CF3

Me
Me
H
H
2
H
H
SO2Me
SEt
CF3

Me
Me
H
H
2
H
H
SO2Me
SO2Et
CF3

Me
Me
H
H
2
H
H
SO2Me
SPr-i
CF3

Me
Me
H
H
2
H
H
SO2Me
SO2Pr-i
CF3

Me
Me
H
H
2
H
H
SO2Me
SPh
CF3

Me
Me
H
H
2
H
H
SO2Me
SO2Ph
CF3

Me
Me
H
H
2
H
H
SO2Me
SCHF2
CF3

Me
Me
H
H
2
H
H
SO2Me
SO2CHF2
CF3

Me
Me
H
H
2
H
H
SO2Me
NH2
CF3

Me
Me
H
H
2
H
H
SO2Me
NHMe
CF3

Me
Me
H
H
2
H
H
SO2Me
NMe2
CF3

Me
Me
H
H
2
H
H
SO2Me
NHEt
CF3

Me
Me
H
H
2
H
H
SO2Me
NEt2
CF3

Me
Me
H
H
2
H
H
SO2Me
NHPh
CF3

Me
Me
H
H
2
H
H
SO2Me
N(Me)Ph
CF3

Me
Me
H
H
2
H
H
SO2Me
CN
CF3

Me
Me
H
H
2
H
H
NH2
F
CF3

Me
Me
H
H
2
H
H
NH2
Cl
CF3

Me
Me
H
H
2
H
H
NH2
OH
CF3

Me
Me
H
H
2
H
H
NH2
OMe
CF3

Me
Me
H
H
2
H
H
NH2
OEt
CF3

Me
Me
H
H
2
H
H
NH2
OPr-i
CF3

Me
Me
H
H
2
H
H
NH2
OPr
CF3

Me
Me
H
H
2
H
H
NH2
OBu-t
CF3

Me
Me
H
H
2
H
H
NH2
OCH2Pr-c
CF3

Me
Me
H
H
2
H
H
NH2
OCH2Bu-c
CF3

Me
Me
H
H
2
H
H
NH2
OCH2Pen-c
CF3

Me
Me
H
H
2
H
H
NH2
OCH2Hex-c
CF3

Me
Me
H
H
2
H
H
NH2
OPen-c
CF3

Me
Me
H
H
2
H
H
NH2
OHex-c
CF3

Me
Me
H
H
2
H
H
NH2
OCH2Ph
CF3

Me
Me
H
H
2
H
H
NH2
OPh
CF3

Me
Me
H
H
2
H
H
NH2
OCHF2
CF3

Me
Me
H
H
2
H
H
NH2
SH
CF3

Me
Me
H
H
2
H
H
NH2
SMe
CF3

Me
Me
H
H
2
H
H
NH2
SO2Me
CF3

Me
Me
H
H
2
H
H
NH2
SEt
CF3

Me
Me
H
H
2
H
H
NH2
SO2Et
CF3

Me
Me
H
H
2
H
H
NH2
SPr-i
CF3

Me
Me
H
H
2
H
H
NH2
SO2Pr-i
CF3

Me
Me
H
H
2
H
H
NH2
SPh
CF3

Me
Me
H
H
2
H
H
NH2
SO2Ph
CF3

Me
Me
H
H
2
H
H
NH2
SCHF2
CF3

Me
Me
H
H
2
H
H
NH2
SO2CHF2
CF3

Me
Me
H
H
2
H
H
NH2
NH2
CF3

Me
Me
H
H
2
H
H
NH2
NHMe
CF3

Me
Me
H
H
2
H
H
NH2
NMe2
CF3

Me
Me
H
H
2
H
H
NH2
NHEt
CF3

Me
Me
H
H
2
H
H
NH2
NEt2
CF3

Me
Me
H
H
2
H
H
NH2
NHPh
CF3

Me
Me
H
H
2
H
H
NH2
N(Me)Ph
CF3

Me
Me
H
H
2
H
H
NH2
CN
CF3

H
H
H
H
2
H
H
H
OMe
CF3

H
H
H
H
2
H
H
H
OEt
CF3

Me
H
H
H
2
H
H
H
OMe
CF3

Me
H
H
H
2
H
H
H
OEt
CF3

Me
H
Me
H
2
H
H
H
OMe
CF3

Me
H
Me
H
2
H
H
H
OEt
CF3

Me
Me
H
H
2
Me
H
H
OMe
CF3

Me
Me
H
H
2
Me
H
H
OEt
CF3

Me
Me
H
H
2
Et
H
H
OMe
CF3

Me
Me
H
H
2
Et
H
H
OEt
CF3

Me
Me
H
H
2
Pr-i
H
H
H
CF3

Me
Me
H
H
2
Pr-i
H
H
OMe
CF3

Me
Me
H
H
2
Pr-i
H
H
OEt
CF3

Me
Me
H
H
2
Me
Me
H
OMe
CF3

Me
Me
H
H
2
Me
Me
H
OEt
CF3

Me
Et
H
H
2
H
H
H
OMe
CF3

Me
Et
H
H
2
H
H
H
OEt
CF3

Et
Et
H
H
2
H
H
H
OMe
CF3

Et
Et
H
H
2
H
H
H
OEt
CF3

Me
Pr-i
H
H
2
H
H
H
OMe
CF3

Me
Pr-i
H
H
2
H
H
H
OEt
CF3

Me
Pr
H
H
2
H
H
H
OMe
CF3

Me
Pr
H
H
2
H
H
H
OEt
CF3

Me
Pr-c
H
H
2
H
H
H
OMe
CF3

Me
Pr-c
H
H
2
H
H
H
OEt
CF3

Me
CH2Pr-c
H
H
2
H
H
H
OMe
CF3

Me
CH2Pr-c
H
H
2
H
H
H
OEt
CF3

—(CH2)2—
H
H
2
H
H
H
OMe
CF3

—(CH2)2—
H
H
2
H
H
H
OEt
CF3

—(CH2)3—
H
H
2
H
H
H
OMe
CF3

—(CH2)3—
H
H
2
H
H
H
OEt
CF3

—(CH2)4—
H
H
2
H
H
H
OMe
CF3

—(CH2)4—
H
H
2
H
H
H
OEt
CF3

—(CH2)5—
H
H
2
H
H
H
OMe
CF3

—(CH2)5—
H
H
2
H
H
H
OEt
CF3

H
—(CH2)3—
H
2
H
H
H
OMe
CF3

H
—(CH2)3—
H
2
H
H
H
OEt
CF3

H
—(CH2)4—
H
2
H
H
H
OMe
CF3

H
—(CH2)4—
H
2
H
H
H
OEt
CF3

H
—(CH2)5—
H
2
H
H
H
OMe
CF3

H
—(CH2)5—
H
2
H
H
H
OEt
CF3

H
—(CH2)6—
H
2
H
H
H
OMe
CF3

H
—(CH2)6—
H
2
H
H
H
OEt
CF3

Me
Me
H
H
1
H
H
H
Cl
Cl

Me
Me
H
H
1
H
H
H
OH
Cl

Me
Me
H
H
1
H
H
H
OMe
Cl

Me
Me
H
H
1
H
H
H
OEt
Cl

Me
Me
H
H
1
H
H
H
OPr-i
Cl

Me
Me
H
H
1
H
H
H
OPr
Cl

Me
Me
H
H
1
H
H
H
OBu-t
Cl

Me
Me
H
H
1
H
H
H
OCH2Pr-c
Cl

Me
Me
H
H
1
H
H
H
OCH2Bu-c
Cl

Me
Me
H
H
1
H
H
H
OCH2Pen-c
Cl

Me
Me
H
H
1
H
H
H
OCH2Hex-c
Cl

Me
Me
H
H
1
H
H
H
OPen-c
Cl

Me
Me
H
H
1
H
H
H
OHex-c
Cl

Me
Me
H
H
1
H
H
H
OCH2Ph
Cl

Me
Me
H
H
1
H
H
H
OPh
Cl

Me
Me
H
H
1
H
H
H
OCHF2
Cl

Me
Me
H
H
1
H
H
H
SH
Cl

Me
Me
H
H
1
H
H
H
SMe
Cl

Me
Me
H
H
1
H
H
H
SO2Me
Cl

Me
Me
H
H
1
H
H
H
SEt
Cl

Me
Me
H
H
1
H
H
H
SO2Et
Cl

Me
Me
H
H
1
H
H
H
SPr-i
Cl

Me
Me
H
H
1
H
H
H
SO2Pr-i
Cl

Me
Me
H
H
1
H
H
H
SPh
Cl

Me
Me
H
H
1
H
H
H
SO2Ph
Cl

Me
Me
H
H
1
H
H
H
SCHF2
Cl

Me
Me
H
H
1
H
H
H
SO2CHF2
Cl

Me
Me
H
H
1
H
H
H
NH2
Cl

Me
Me
H
H
1
H
H
H
NHMe
Cl

Me
Me
H
H
1
H
H
H
NMe2
Cl

Me
Me
H
H
1
H
H
H
NHEt
Cl

Me
Me
H
H
1
H
H
H
NEt2
Cl

Me
Me
H
H
1
H
H
H
NHPh
Cl

Me
Me
H
H
1
H
H
H
N(Me)Ph
Cl

Me
Me
H
H
1
H
H
H
CN
Cl

Me
Me
H
H
1
H
H
H
F
Me

Me
Me
H
H
1
H
H
H
Cl
Me

Me
Me
H
H
1
H
H
H
OH
Me

Me
Me
H
H
1
H
H
H
OMe
Me

Me
Me
H
H
1
H
H
H
OEt
Me

Me
Me
H
H
1
H
H
H
OPr-i
Me

Me
Me
H
H
1
H
H
H
OPr
Me

Me
Me
H
H
1
H
H
H
OBu-t
Me

Me
Me
H
H
1
H
H
H
OCH2Pr-c
Me

Me
Me
H
H
1
H
H
H
OCH2Bu-c
Me

Me
Me
H
H
1
H
H
H
OCH2Pen-c
Me

Me
Me
H
H
1
H
H
H
OCH2Hex-c
Me

Me
Me
H
H
1
H
H
H
OPen-c
Me

Me
Me
H
H
1
H
H
H
OHex-c
Me

Me
Me
H
H
1
H
H
H
OCH2Ph
Me

Me
Me
H
H
1
H
H
H
OPh
Me

Me
Me
H
H
1
H
H
H
OCHF2
Me

Me
Me
H
H
1
H
H
H
SH
Me

Me
Me
H
H
1
H
H
H
SMe
Me

Me
Me
H
H
1
H
H
H
SO2Me
Me

Me
Me
H
H
1
H
H
H
SEt
Me

Me
Me
H
H
1
H
H
H
SO2Et
Me

Me
Me
H
H
1
H
H
H
SPr-i
Me

Me
Me
H
H
1
H
H
H
SO2Pr-i
Me

Me
Me
H
H
1
H
H
H
SPh
Me

Me
Me
H
H
1
H
H
H
SO2Ph
Me

Me
Me
H
H
1
H
H
H
SCHF2
Me

Me
Me
H
H
1
H
H
H
SO2CHF2
Me

Me
Me
H
H
1
H
H
H
NH2
Me

Me
Me
H
H
1
H
H
H
NHMe
Me

Me
Me
H
H
1
H
H
H
NMe2
Me

Me
Me
H
H
1
H
H
H
NHEt
Me

Me
Me
H
H
1
H
H
H
NEt2
Me

Me
Me
H
H
1
H
H
H
NHPh
Me

Me
Me
H
H
1
H
H
H
N(Me)Ph
Me

Me
Me
H
H
1
H
H
H
CN
Me

Me
Me
H
H
1
H
H
H
F
Pr-i

Me
Me
H
H
1
H
H
H
Cl
Pr-i

Me
Me
H
H
1
H
H
H
OH
Pr-i

Me
Me
H
H
1
H
H
H
OMe
Pr-i

Me
Me
H
H
1
H
H
H
OEt
Pr-i

Me
Me
H
H
1
H
H
H
OPr-i
Pr-i

Me
Me
H
H
1
H
H
H
OPr
Pr-i

Me
Me
H
H
1
H
H
H
OBu-t
Pr-i

Me
Me
H
H
1
H
H
H
OCH2Pr-c
Pr-i

Me
Me
H
H
1
H
H
H
OCH2Bu-c
Pr-i

Me
Me
H
H
1
H
H
H
OCH2Pen-c
Pr-i

Me
Me
H
H
1
H
H
H
OCH2Hex-c
Pr-i

Me
Me
H
H
1
H
H
H
OPen-c
Pr-i

Me
Me
H
H
1
H
H
H
OHex-c
Pr-i

Me
Me
H
H
1
H
H
H
OCH2Ph
Pr-i

Me
Me
H
H
1
H
H
H
OPh
Pr-i

Me
Me
H
H
1
H
H
H
OCHF2
Pr-i

Me
Me
H
H
1
H
H
H
SH
Pr-i

Me
Me
H
H
1
H
H
H
SMe
Pr-i

Me
Me
H
H
1
H
H
H
SO2Me
Pr-i

Me
Me
H
H
1
H
H
H
SEt
Pr-i

Me
Me
H
H
1
H
H
H
SO2Et
Pr-i

Me
Me
H
H
1
H
H
H
SPr-i
Pr-i

Me
Me
H
H
1
H
H
H
SO2Pr-i
Pr-i

Me
Me
H
H
1
H
H
H
SPh
Pr-i

Me
Me
H
H
1
H
H
H
SO2Ph
Pr-i

Me
Me
H
H
1
H
H
H
SCHF2
Pr-i

Me
Me
H
H
1
H
H
H
SO2CHF2
Pr-i

Me
Me
H
H
1
H
H
H
NH2
Pr-i

Me
Me
H
H
1
H
H
H
NHMe
Pr-i

Me
Me
H
H
1
H
H
H
NMe2
Pr-i

Me
Me
H
H
1
H
H
H
NHEt
Pr-i

Me
Me
H
H
1
H
H
H
NEt2
Pr-i

Me
Me
H
H
1
H
H
H
NHPh
Pr-i

Me
Me
H
H
1
H
H
H
N(Me)Ph
Pr-i

Me
Me
H
H
1
H
H
H
CN
Pr-i

Me
Me
H
H
1
H
H
H
F
Pr-c

Me
Me
H
H
1
H
H
H
Cl
Pr-c

Me
Me
H
H
1
H
H
H
OH
Pr-c

Me
Me
H
H
1
H
H
H
OMe
Pr-c

Me
Me
H
H
1
H
H
H
OEt
Pr-c

Me
Me
H
H
1
H
H
H
OPr-i
Pr-c

Me
Me
H
H
1
H
H
H
OPr
Pr-c

Me
Me
H
H
1
H
H
H
OBu-t
Pr-c

Me
Me
H
H
1
H
H
H
OCH2Pr-c
Pr-c

Me
Me
H
H
1
H
H
H
OCH2Bu-c
Pr-c

Me
Me
H
H
1
H
H
H
OCH2Pen-c
Pr-c

Me
Me
H
H
1
H
H
H
OCH2Hex-c
Pr-c

Me
Me
H
H
1
H
H
H
OPen-c
Pr-c

Me
Me
H
H
1
H
H
H
OHex-c
Pr-c

Me
Me
H
H
1
H
H
H
OCH2Ph
Pr-c

Me
Me
H
H
1
H
H
H
OPh
Pr-c

Me
Me
H
H
1
H
H
H
OCHF2
Pr-c

Me
Me
H
H
1
H
H
H
SH
Pr-c

Me
Me
H
H
1
H
H
H
SMe
Pr-c

Me
Me
H
H
1
H
H
H
SO2Me
Pr-c

Me
Me
H
H
1
H
H
H
SEt
Pr-c

Me
Me
H
H
1
H
H
H
SO2Et
Pr-c

Me
Me
H
H
1
H
H
H
SPr-i
Pr-c

Me
Me
H
H
1
H
H
H
SO2Pr-i
Pr-c

Me
Me
H
H
1
H
H
H
SPh
Pr-c

Me
Me
H
H
1
H
H
H
SO2Ph
Pr-c

Me
Me
H
H
1
H
H
H
SCHF2
Pr-c

Me
Me
H
H
1
H
H
H
SO2CHF2
Pr-c

Me
Me
H
H
1
H
H
H
NH2
Pr-c

Me
Me
H
H
1
H
H
H
NHMe
Pr-c

Me
Me
H
H
1
H
H
H
NMe2
Pr-c

Me
Me
H
H
1
H
H
H
NHEt
Pr-c

Me
Me
H
H
1
H
H
H
NEt2
Pr-c

Me
Me
H
H
1
H
H
H
NHPh
Pr-c

Me
Me
H
H
1
H
H
H
N(Me)Ph
Pr-c

Me
Me
H
H
1
H
H
H
CN
Pr-c

Me
Me
H
H
1
H
H
H
F
CHF2

Me
Me
H
H
1
H
H
H
Cl
CHF2

Me
Me
H
H
1
H
H
H
OH
CHF2

Me
Me
H
H
1
H
H
H
OMe
CHF2

Me
Me
H
H
1
H
H
H
OEt
CHF2

Me
Me
H
H
1
H
H
H
OPr-i
CHF2

Me
Me
H
H
1
H
H
H
OPr
CHF2

Me
Me
H
H
1
H
H
H
OBu-t
CHF2

Me
Me
H
H
1
H
H
H
OCH2Pr-c
CHF2

Me
Me
H
H
1
H
H
H
OCH2Bu-c
CHF2

Me
Me
H
H
1
H
H
H
OCH2Pen-c
CHF2

Me
Me
H
H
1
H
H
H
OCH2Hex-c
CHF2

Me
Me
H
H
1
H
H
H
OPen-c
CHF2

Me
Me
H
H
1
H
H
H
OHex-c
CHF2

Me
Me
H
H
1
H
H
H
OCH2Ph
CHF2

Me
Me
H
H
1
H
H
H
OPh
CHF2

Me
Me
H
H
1
H
H
H
OCHF2
CHF2

Me
Me
H
H
1
H
H
H
SH
CHF2

Me
Me
H
H
1
H
H
H
SMe
CHF2

Me
Me
H
H
1
H
H
H
SO2Me
CHF2

Me
Me
H
H
1
H
H
H
SEt
CHF2

Me
Me
H
H
1
H
H
H
SO2Et
CHF2

Me
Me
H
H
1
H
H
H
SPr-i
CHF2

Me
Me
H
H
1
H
H
H
SO2Pr-i
CHF2

Me
Me
H
H
1
H
H
H
SPh
CHF2

Me
Me
H
H
1
H
H
H
SO2Ph
CHF2

Me
Me
H
H
1
H
H
H
SCHF2
CHF2

Me
Me
H
H
1
H
H
H
SO2CHF2
CHF2

Me
Me
H
H
1
H
H
H
NH2
CHF2

Me
Me
H
H
1
H
H
H
NHMe
CHF2

Me
Me
H
H
1
H
H
H
NMe2
CHF2

Me
Me
H
H
1
H
H
H
NHEt
CHF2

Me
Me
H
H
1
H
H
H
NEt2
CHF2

Me
Me
H
H
1
H
H
H
NHPh
CHF2

Me
Me
H
H
1
H
H
H
N(Me)Ph
CHF2

Me
Me
H
H
1
H
H
H
CN
CHF2

Me
Me
H
H
1
H
H
H
F
CF3

Me
Me
H
H
1
H
H
H
Cl
CF3

Me
Me
H
H
1
H
H
H
OH
CF3

Me
Me
H
H
1
H
H
H
OMe
CF3

Me
Me
H
H
1
H
H
H
OEt
CF3

Me
Me
H
H
1
H
H
H
OPr-i
CF3

Me
Me
H
H
1
H
H
H
OPr
CF3

Me
Me
H
H
1
H
H
H
OBu-t
CF3

Me
Me
H
H
1
H
H
H
OCH2Pr-c
CF3

Me
Me
H
H
1
H
H
H
OCH2Bu-c
CF3

Me
Me
H
H
1
H
H
H
OCH2Pen-c
CF3

Me
Me
H
H
1
H
H
H
OCH2Hex-c
CF3

Me
Me
H
H
1
H
H
H
OPen-c
CF3

Me
Me
H
H
1
H
H
H
OHex-c
CF3

Me
Me
H
H
1
H
H
H
OCH2Ph
CF3

Me
Me
H
H
1
H
H
H
OPh
CF3

Me
Me
H
H
1
H
H
H
OCHF2
CF3

Me
Me
H
H
1
H
H
H
SH
CF3

Me
Me
H
H
1
H
H
H
SMe
CF3

Me
Me
H
H
1
H
H
H
SO2Me
CF3

Me
Me
H
H
1
H
H
H
SEt
CF3

Me
Me
H
H
1
H
H
H
SO2Et
CF3

Me
Me
H
H
1
H
H
H
SPr-i
CF3

Me
Me
H
H
1
H
H
H
SO2Pr-i
CF3

Me
Me
H
H
1
H
H
H
SPh
CF3

Me
Me
H
H
1
H
H
H
SO2Ph
CF3

Me
Me
H
H
1
H
H
H
SCHF2
CF3

Me
Me
H
H
1
H
H
H
SO2CHF2
CF3

Me
Me
H
H
1
H
H
H
NH2
CF3

Me
Me
H
H
1
H
H
H
NHMe
CF3

Me
Me
H
H
1
H
H
H
NMe2
CF3

Me
Me
H
H
1
H
H
H
NHEt
CF3

Me
Me
H
H
1
H
H
H
NEt2
CF3

Me
Me
H
H
1
H
H
H
NHPh
CF3

Me
Me
H
H
1
H
H
H
N(Me)Ph
CF3

Me
Me
H
H
1
H
H
H
CN
CF3

Me
Me
H
H
1
H
H
H
F
OMe

Me
Me
H
H
1
H
H
H
OH
OMe

Me
Me
H
H
1
H
H
H
OMe
OMe

Me
Me
H
H
1
H
H
H
OEt
OMe

Me
Me
H
H
1
H
H
H
OPr-i
OMe

Me
Me
H
H
1
H
H
H
OPr
OMe

Me
Me
H
H
1
H
H
H
OBu-t
OMe

Me
Me
H
H
1
H
H
H
OCH2Pr-c
OMe

Me
Me
H
H
1
H
H
H
OCH2Bu-c
OMe

Me
Me
H
H
1
H
H
H
OCH2Pen-c
OMe

Me
Me
H
H
1
H
H
H
OCH2Hex-c
OMe

Me
Me
H
H
1
H
H
H
OPen-c
OMe

Me
Me
H
H
1
H
H
H
OHex-c
OMe

Me
Me
H
H
1
H
H
H
OCH2Ph
OMe

Me
Me
H
H
1
H
H
H
OPh
OMe

Me
Me
H
H
1
H
H
H
OCHF2
OMe

Me
Me
H
H
1
H
H
H
SH
OMe

Me
Me
H
H
1
H
H
H
SMe
OMe

Me
Me
H
H
1
H
H
H
SO2Me
OMe

Me
Me
H
H
1
H
H
H
SEt
OMe

Me
Me
H
H
1
H
H
H
SO2Et
OMe

Me
Me
H
H
1
H
H
H
SPr-i
OMe

Me
Me
H
H
1
H
H
H
SO2Pr-i
OMe

Me
Me
H
H
1
H
H
H
SPh
OMe

Me
Me
H
H
1
H
H
H
SO2Ph
OMe

Me
Me
H
H
1
H
H
H
SCHF2
OMe

Me
Me
H
H
1
H
H
H
SO2CHF2
OMe

Me
Me
H
H
1
H
H
H
NH2
OMe

Me
Me
H
H
1
H
H
H
NHMe
OMe

Me
Me
H
H
1
H
H
H
NMe2
OMe

Me
Me
H
H
1
H
H
H
NHEt
OMe

Me
Me
H
H
1
H
H
H
NEt2
OMe

Me
Me
H
H
1
H
H
H
NHPh
OMe

Me
Me
H
H
1
H
H
H
N(Me)Ph
OMe

Me
Me
H
H
1
H
H
H
CN
OMe

Me
Me
H
H
1
H
H
H
F
OPh

Me
Me
H
H
1
H
H
H
OH
OPh

Me
Me
H
H
1
H
H
H
OMe
OPh

Me
Me
H
H
1
H
H
H
OEt
OPh

Me
Me
H
H
1
H
H
H
OPr-i
OPh

Me
Me
H
H
1
H
H
H
OPr
OPh

Me
Me
H
H
1
H
H
H
OBu-t
OPh

Me
Me
H
H
1
H
H
H
OCH2Pr-c
OPh

Me
Me
H
H
1
H
H
H
OCH2Bu-c
OPh

Me
Me
H
H
1
H
H
H
OCH2Pen-c
OPh

Me
Me
H
H
1
H
H
H
OCH2Hex-c
OPh

Me
Me
H
H
1
H
H
H
OPen-c
OPh

Me
Me
H
H
1
H
H
H
OHex-c
OPh

Me
Me
H
H
1
H
H
H
OCH2Ph
OPh

Me
Me
H
H
1
H
H
H
OPh
OPh

Me
Me
H
H
1
H
H
H
OCHF2
OPh

Me
Me
H
H
1
H
H
H
SH
OPh

Me
Me
H
H
1
H
H
H
SMe
OPh

Me
Me
H
H
1
H
H
H
SO2Me
OPh

Me
Me
H
H
1
H
H
H
SEt
OPh

Me
Me
H
H
1
H
H
H
SO2Et
OPh

Me
Me
H
H
1
H
H
H
SPr-i
OPh

Me
Me
H
H
1
H
H
H
SO2Pr-i
OPh

Me
Me
H
H
1
H
H
H
SPh
OPh

Me
Me
H
H
1
H
H
H
SO2Ph
OPh

Me
Me
H
H
1
H
H
H
SCHF2
OPh

Me
Me
H
H
1
H
H
H
SO2CHF2
OPh

Me
Me
H
H
1
H
H
H
NH2
OPh

Me
Me
H
H
1
H
H
H
NHMe
OPh

Me
Me
H
H
1
H
H
H
NMe2
OPh

Me
Me
H
H
1
H
H
H
NHEt
OPh

Me
Me
H
H
1
H
H
H
NEt2
OPh

Me
Me
H
H
1
H
H
H
NHPh
OPh

Me
Me
H
H
1
H
H
H
N(Me)Ph
OPh

Me
Me
H
H
1
H
H
H
CN
OPh

Me
Me
H
H
1
H
H
H
F
OCHF2

Me
Me
H
H
1
H
H
H
OH
OCHF2

Me
Me
H
H
1
H
H
H
OMe
OCHF2

Me
Me
H
H
1
H
H
H
OEt
OCHF2

Me
Me
H
H
1
H
H
H
OPr-i
OCHF2

Me
Me
H
H
1
H
H
H
OPr
OCHF2

Me
Me
H
H
1
H
H
H
OBu-t
OCHF2

Me
Me
H
H
1
H
H
H
OCH2Pr-c
OCHF2

Me
Me
H
H
1
H
H
H
OCH2Bu-c
OCHF2

Me
Me
H
H
1
H
H
H
OCH2Pen-c
OCHF2

Me
Me
H
H
1
H
H
H
OCH2Hex-c
OCHF2

Me
Me
H
H
1
H
H
H
OPen-c
OCHF2

Me
Me
H
H
1
H
H
H
OHex-c
OCHF2

Me
Me
H
H
1
H
H
H
OCH2Ph
OCHF2

Me
Me
H
H
1
H
H
H
OPh
OCHF2

Me
Me
H
H
1
H
H
H
OCHF2
OCHF2

Me
Me
H
H
1
H
H
H
SH
OCHF2

Me
Me
H
H
1
H
H
H
SMe
OCHF2

Me
Me
H
H
1
H
H
H
SO2Me
OCHF2

Me
Me
H
H
1
H
H
H
SEt
OCHF2

Me
Me
H
H
1
H
H
H
SO2Et
OCHF2

Me
Me
H
H
1
H
H
H
SPr-i
OCHF2

Me
Me
H
H
1
H
H
H
SO2Pr-i
OCHF2

Me
Me
H
H
1
H
H
H
SPh
OCHF2

Me
Me
H
H
1
H
H
H
SO2Ph
OCHF2

Me
Me
H
H
1
H
H
H
SCHF2
OCHF2

Me
Me
H
H
1
H
H
H
SO2CHF2
OCHF2

Me
Me
H
H
1
H
H
H
NH2
OCHF2

Me
Me
H
H
1
H
H
H
NHMe
OCHF2

Me
Me
H
H
1
H
H
H
NMe2
OCHF2

Me
Me
H
H
1
H
H
H
NHEt
OCHF2

Me
Me
H
H
1
H
H
H
NEt2
OCHF2

Me
Me
H
H
1
H
H
H
NHPh
OCHF2

Me
Me
H
H
1
H
H
H
N(Me)Ph
OCHF2

Me
Me
H
H
1
H
H
H
CN
OCHF2

Me
Me
H
H
1
H
H
Me
F
CF3

Me
Me
H
H
1
H
H
Me
Cl
CF3

Me
Me
H
H
1
H
H
Me
OH
CF3

Me
Me
H
H
1
H
H
Me
OMe
CF3

Me
Me
H
H
1
H
H
Me
OEt
CF3

Me
Me
H
H
1
H
H
Me
OPr-i
CF3

Me
Me
H
H
1
H
H
Me
OPr
CF3

Me
Me
H
H
1
H
H
Me
OBu-t
CF3

Me
Me
H
H
1
H
H
Me
OCH2Pr-c
CF3

Me
Me
H
H
1
H
H
Me
OCH2Bu-c
CF3

Me
Me
H
H
1
H
H
Me
OCH2Pen-c
CF3

Me
Me
H
H
1
H
H
Me
OCH2Hex-c
CF3

Me
Me
H
H
1
H
H
Me
OPen-c
CF3

Me
Me
H
H
1
H
H
Me
OHex-c
CF3

Me
Me
H
H
1
H
H
Me
OCH2Ph
CF3

Me
Me
H
H
1
H
H
Me
OPh
CF3

Me
Me
H
H
1
H
H
Me
OCHF2
CF3

Me
Me
H
H
1
H
H
Me
SH
CF3

Me
Me
H
H
1
H
H
Me
SMe
CF3

Me
Me
H
H
1
H
H
Me
SO2Me
CF3

Me
Me
H
H
1
H
H
Me
SEt
CF3

Me
Me
H
H
1
H
H
Me
SO2Et
CF3

Me
Me
H
H
1
H
H
Me
SPr-i
CF3

Me
Me
H
H
1
H
H
Me
SO2Pr-i
CF3

Me
Me
H
H
1
H
H
Me
SPh
CF3

Me
Me
H
H
1
H
H
Me
SO2Ph
CF3

Me
Me
H
H
1
H
H
Me
SCHF2
CF3

Me
Me
H
H
1
H
H
Me
SO2CHF2
CF3

Me
Me
H
H
1
H
H
Me
NH2
CF3

Me
Me
H
H
1
H
H
Me
NHMe
CF3

Me
Me
H
H
1
H
H
Me
NMe2
CF3

Me
Me
H
H
1
H
H
Me
NHEt
CF3

Me
Me
H
H
1
H
H
Me
NEt2
CF3

Me
Me
H
H
1
H
H
Me
NHPh
CF3

Me
Me
H
H
1
H
H
Me
N(Me)Ph
CF3

Me
Me
H
H
1
H
H
Me
CN
CF3

Me
Me
H
H
1
H
H
OMe
F
CF3

Me
Me
H
H
1
H
H
OMe
Cl
CF3

Me
Me
H
H
1
H
H
OMe
OH
CF3

Me
Me
H
H
1
H
H
OMe
OMe
CF3

Me
Me
H
H
1
H
H
OMe
GEt
CF3

Me
Me
H
H
1
H
H
OMe
OPr-i
CF3

Me
Me
H
H
1
H
H
OMe
OPr
CF3

Me
Me
H
H
1
H
H
OMe
OBu-t
CF3

Me
Me
H
H
1
H
H
OMe
OCH2Pr-c
CF3

Me
Me
H
H
1
H
H
OMe
OCH2Bu-c
CF3

Me
Me
H
H
1
H
H
OMe
OCH2Pen-c
CF3

Me
Me
H
H
1
H
H
OMe
OCH2Hex-c
CF3

Me
Me
H
H
1
H
H
OMe
OPen-c
CF3

Me
Me
H
H
1
H
H
OMe
OHex-c
CF3

Me
Me
H
H
1
H
H
OMe
OCH2Ph
CF3

Me
Me
H
H
1
H
H
OMe
OPh
CF3

Me
Me
H
H
1
H
H
OMe
OCHF2
CF3

Me
Me
H
H
1
H
H
OMe
SH
CF3

Me
Me
H
H
1
H
H
OMe
SMe
CF3

Me
Me
H
H
1
H
H
OMe
SO2Me
CF3

Me
Me
H
H
1
H
H
OMe
SEt
CF3

Me
Me
H
H
1
H
H
OMe
SO2Et
CF3

Me
Me
H
H
1
H
H
OMe
SPr-i
CF3

Me
Me
H
H
1
H
H
OMe
SO2Pr-i
CF3

Me
Me
H
H
1
H
H
OMe
SPh
CF3

Me
Me
H
H
1
H
H
OMe
SO2Ph
CF3

Me
Me
H
H
1
H
H
OMe
SCHF2
CF3

Me
Me
H
H
1
H
H
OMe
SO2CHF2
CF3

Me
Me
H
H
1
H
H
OMe
NH2
CF3

Me
Me
H
H
1
H
H
OMe
NHMe
CF3

Me
Me
H
H
1
H
H
OMe
NMe2
CF3

Me
Me
H
H
1
H
H
OMe
NHEt
CF3

Me
Me
H
H
1
H
H
OMe
NEt2
CF3

Me
Me
H
H
1
H
H
OMe
NHPh
CF3

Me
Me
H
H
1
H
H
OMe
N(Me)Ph
CF3

Me
Me
H
H
1
H
H
OMe
CN
CF3

Me
Me
H
H
1
H
H
SMe
F
CF3

Me
Me
H
H
1
H
H
SMe
Cl
CF3

Me
Me
H
H
1
H
H
SMe
OH
CF3

Me
Me
H
H
1
H
H
SMe
OMe
CF3

Me
Me
H
H
1
H
H
SMe
OEt
CF3

Me
Me
H
H
1
H
H
SMe
OPr-i
CF3

Me
Me
H
H
1
H
H
SMe
OPr
CF3

Me
Me
H
H
1
H
H
SMe
OBu-t
CF3

Me
Me
H
H
1
H
H
SMe
OCH2Pr-c
CF3

Me
Me
H
H
1
H
H
SMe
OCH2Bu-c
CF3

Me
Me
H
H
1
H
H
SMe
OCH2Pen-c
CF3

Me
Me
H
H
1
H
H
SMe
OCH2Hex-c
CF3

Me
Me
H
H
1
H
H
SMe
OPen-c
CF3

Me
Me
H
H
1
H
H
SMe
OHex-c
CF3

Me
Me
H
H
1
H
H
SMe
OCH2Ph
CF3

Me
Me
H
H
1
H
H
SMe
OPh
CF3

Me
Me
H
H
1
H
H
SMe
OCHF2
CF3

Me
Me
H
H
1
H
H
SMe
SH
CF3

Me
Me
H
H
1
H
H
SMe
SMe
CF3

Me
Me
H
H
1
H
H
SMe
SO2Me
CF3

Me
Me
H
H
1
H
H
SMe
SEt
CF3

Me
Me
H
H
1
H
H
SMe
SO2Et
CF3

Me
Me
H
H
1
H
H
SMe
SPr-i
CF3

Me
Me
H
H
1
H
H
SMe
SO2Pr-i
CF3

Me
Me
H
H
1
H
H
SMe
SPh
CF3

Me
Me
H
H
1
H
H
SMe
SO2Ph
CF3

Me
Me
H
H
1
H
H
SMe
SCHF2
CF3

Me
Me
H
H
1
H
H
SMe
SO2CHF2
CF3

Me
Me
H
H
1
H
H
SMe
NH2
CF3

Me
Me
H
H
1
H
H
SMe
NHMe
CF3

Me
Me
H
H
1
H
H
SMe
NMe2
CF3

Me
Me
H
H
1
H
H
SMe
NHEt
CF3

Me
Me
H
H
1
H
H
SMe
NEt2
CF3

Me
Me
H
H
1
H
H
SMe
NHPh
CF3

Me
Me
H
H
1
H
H
SMe
N(Me)Ph
CF3

Me
Me
H
H
1
H
H
SMe
CN
CF3

Me
Me
H
H
1
H
H
SO2Me
F
CF3

Me
Me
H
H
1
H
H
SO2Me
Cl
CF3

Me
Me
H
H
1
H
H
SO2Me
OH
CF3

Me
Me
H
H
1
H
H
SO2Me
OMe
CF3

Me
Me
H
H
1
H
H
SO2Me
OEt
CF3

Me
Me
H
H
1
H
H
SO2Me
OPr-i
CF3

Me
Me
H
H
1
H
H
SO2Me
OPr
CF3

Me
Me
H
H
1
H
H
SO2Me
OBu-t
CF3

Me
Me
H
H
1
H
H
SO2Me
OCH2Pr-c
CF3

Me
Me
H
H
1
H
H
SO2Me
OCH2Bu-c
CF3

Me
Me
H
H
1
H
H
SO2Me
OCH2Pen-c
CF3

Me
Me
H
H
1
H
H
SO2Me
OCH2Hex-c
CF3

Me
Me
H
H
1
H
H
SO2Me
OPen-c
CF3

Me
Me
H
H
1
H
H
SO2Me
OHex-c
CF3

Me
Me
H
H
1
H
H
SO2Me
OCH2Ph
CF3

Me
Me
H
H
1
H
H
SO2Me
OPh
CF3

Me
Me
H
H
1
H
H
SO2Me
OCHF2
CF3

Me
Me
H
H
1
H
H
SO2Me
SH
CF3

Me
Me
H
H
1
H
H
SO2Me
SMe
CF3

Me
Me
H
H
1
H
H
SO2Me
SO2Me
CF3

Me
Me
H
H
1
H
H
SO2Me
SEt
CF3

Me
Me
H
H
1
H
H
SO2Me
SO2Et
CF3

Me
Me
H
H
1
H
H
SO2Me
SPr-i
CF3

Me
Me
H
H
1
H
H
SO2Me
SO2Pr-i
CF3

Me
Me
H
H
1
H
H
SO2Me
SPh
CF3

Me
Me
H
H
1
H
H
SO2Me
SO2Ph
CF3

Me
Me
H
H
1
H
H
SO2Me
SCHF2
CF3

Me
Me
H
H
1
H
H
SO2Me
SO2CHF2
CF3

Me
Me
H
H
1
H
H
SO2Me
NH2
CF3

Me
Me
H
H
1
H
H
SO2Me
NHMe
CF3

Me
Me
H
H
1
H
H
SO2Me
NMe2
CF3

Me
Me
H
H
1
H
H
SO2Me
NHEt
CF3

Me
Me
H
H
1
H
H
SO2Me
NEt2
CF3

Me
Me
H
H
1
H
H
SO2Me
NHPh
CF3

Me
Me
H
H
1
H
H
SO2Me
N(Me)Ph
CF3

Me
Me
H
H
1
H
H
SO2Me
CN
CF3

Me
Me
H
H
1
H
H
NH2
F
CF3

Me
Me
H
H
1
H
H
NH2
Cl
CF3

Me
Me
H
H
1
H
H
NH2
OH
CF3

Me
Me
H
H
1
H
H
NH2
OMe
CF3

Me
Me
H
H
1
H
H
NH2
OEt
CF3

Me
Me
H
H
1
H
H
NH2
OPr-i
CF3

Me
Me
H
H
1
H
H
NH2
OPr
CF3

Me
Me
H
H
1
H
H
NH2
OBu-t
CF3

Me
Me
H
H
1
H
H
NH2
OCH2Pr-c
CF3

Me
Me
H
H
1
H
H
NH2
OCH2Bu-c
CF3

Me
Me
H
H
1
H
H
NH2
OCH2Pen-c
CF3

Me
Me
H
H
1
H
H
NH2
OCH2Hex-c
CF3

Me
Me
H
H
1
H
H
NH2
OPen-c
CF3

Me
Me
H
H
1
H
H
NH2
OHex-c
CF3

Me
Me
H
H
1
H
H
NH2
OCH2Ph
CF3

Me
Me
H
H
1
H
H
NH2
OPh
CF3

Me
Me
H
H
1
H
H
NH2
OCHF2
CF3

Me
Me
H
H
1
H
H
NH2
SH
CF3

Me
Me
H
H
1
H
H
NH2
SMe
CF3

Me
Me
H
H
1
H
H
NH2
SO2Me
CF3

Me
Me
H
H
1
H
H
NH2
SEt
CF3

Me
Me
H
H
1
H
H
NH2
SO2Et
CF3

Me
Me
H
H
1
H
H
NH2
SPr-i
CF3

Me
Me
H
H
1
H
H
NH2
SO2Pr-i
CF3

Me
Me
H
H
1
H
H
NH2
SPh
CF3

Me
Me
H
H
1
H
H
NH2
SO2Ph
CF3

Me
Me
H
H
1
H
H
NH2
SCHF2
CF3

Me
Me
H
H
1
H
H
NH2
SO2CHF
CF3

Me
Me
H
H
1
H
H
NH2
NH2
CF3

Me
Me
H
H
1
H
H
NH2
NHMe
CF3

Me
Me
H
H
1
H
H
NH2
NMe2
CF3

Me
Me
H
H
1
H
H
NH2
NHEt
CF3

Me
Me
H
H
1
H
H
NH2
NEt2
CF3

Me
Me
H
H
1
H
H
NH2
NHPh
CF3

Me
Me
H
H
1
H
H
NH2
N(Me)Ph
CF3

Me
Me
H
H
1
H
H
NH2
CN
CF3

H
H
H
H
1
H
H
H
OMe
CF3

H
H
H
H
1
H
H
H
OEt
CF3

Me
H
H
H
1
H
H
H
OMe
CF3

Me
H
H
H
1
H
H
H
OEt
CF3

Me
H
Me
H
1
H
H
H
OMe
CF3

Me
H
Me
H
1
H
H
H
OEt
CF3

Me
Me
H
H
1
Me
H
H
OMe
CF3

Me
Me
H
H
1
Me
H
H
OEt
CF3

Me
Me
H
H
1
Et
H
H
OMe
CF3

Me
Me
H
H
1
Et
H
H
OEt
CF3

Me
Me
H
H
1
Pr-i
H
H
H
CF3

Me
Me
H
H
1
Pr-i
H
H
OMe
CF3

Me
Me
H
H
1
Pr-i
H
H
OEt
CF3

Me
Me
H
H
1
Me
Me
H
OMe
CF3

Me
Me
H
H
1
Me
Me
H
OEt
CF3

Me
Et
H
H
1
H
H
H
OMe
CF3

Me
Et
H
H
1
H
H
H
OEt
CF3

Et
Et
H
H
1
H
H
H
OMe
CF3

Et
Et
H
H
1
H
H
H
OEt
CF3

Me
Pr-i
H
H
1
H
H
H
OMe
CF3

Me
Pr-i
H
H
1
H
H
H
OEt
CF3

Me
Pr
H
H
1
H
H
H
OMe
CF3

Me
Pr
H
H
1
H
H
H
OEt
CF3

Me
Pr-c
H
H
1
H
H
H
OMe
CF3

Me
Pr-c
H
H
1
H
H
H
OEt
CF3

Me
CH2Pr-c
H
H
1
H
H
H
OMe
CF3

Me
CH2Pr-c
H
H
1
H
H
H
OEt
CF3

—(CH2)2—
H
H
1
H
H
H
OMe
CF3

—(CH2)2—
H
H
1
H
H
H
OEt
CF3

—(CH2)3—
H
H
1
H
H
H
OMe
CF3

—(CH2)3—
H
H
1
H
H
H
OEt
CF3

—(CH2)4—
H
H
1
H
H
H
OMe
CF3

—(CH2)4—
H
H
1
H
H
H
OEt
CF3

—(CH2)5—
H
H
1
H
H
H
OMe
CF3

—(CH2)5—
H
H
1
H
H
H
OEt
CF3

H
—(CH2)3—
H
1
H
H
H
OMe
CF3

H
—(CH2)3—
H
1
H
H
H
OEt
CF3

H
—(CH2)4—
H
1
H
H
H
OMe
CF3

H
—(CH2)4—
H
1
H
H
H
OEt
CF3

H
—(CH2)5—
H
1
H
H
H
OMe
CF3

H
—(CH2)5—
H
1
H
H
H
OEt
CF3

H
—(CH2)6—
H
1
H
H
H
OMe
CF3

H
—(CH2)6—
H
1
H
H
H
OEt
CF3

Me
Me
H
H
0
H
H
H
Cl
Cl

Me
Me
H
H
0
H
H
H
OH
Cl

Me
Me
H
H
0
H
H
H
OMe
Cl

Me
Me
H
H
0
H
H
H
OEt
Cl

Me
Me
H
H
0
H
H
H
OPr-i
Cl

Me
Me
H
H
0
H
H
H
OPr
Cl

Me
Me
H
H
0
H
H
H
OBu-t
Cl

Me
Me
H
H
0
H
H
H
OCH2Pr-c
Cl

Me
Me
H
H
0
H
H
H
OCH2Bu-c
Cl

Me
Me
H
H
0
H
H
H
OCH2Pen-c
Cl

Me
Me
H
H
0
H
H
H
OCH2Hex-c
Cl

Me
Me
H
H
0
H
H
H
OPen-c
Cl

Me
Me
H
H
0
H
H
H
OHex-c
Cl

Me
Me
H
H
0
H
H
H
OCH2Ph
Cl

Me
Me
H
H
0
H
H
H
OPh
Cl

Me
Me
H
H
0
H
H
H
OCHF2
Cl

Me
Me
H
H
0
H
H
H
SH
Cl

Me
Me
H
H
0
H
H
H
SMe
Cl

Me
Me
H
H
0
H
H
H
SO2Me
Cl

Me
Me
H
H
0
H
H
H
SEt
Cl

Me
Me
H
H
0
H
H
H
SO2Et
Cl

Me
Me
H
H
0
H
H
H
SPr-i
Cl

Me
Me
H
H
0
H
H
H
SO2Pr-i
Cl

Me
Me
H
H
0
H
H
H
SPh
Cl

Me
Me
H
H
0
H
H
H
SO2Ph
Cl

Me
Me
H
H
0
H
H
H
SCHF2
Cl

Me
Me
H
H
0
H
H
H
SO2CHF2
Cl

Me
Me
H
H
0
H
H
H
NH2
Cl

Me
Me
H
H
0
H
H
H
NHMe
Cl

Me
Me
H
H
0
H
H
H
NMe2
Cl

Me
Me
H
H
0
H
H
H
NHEt
Cl

Me
Me
H
H
0
H
H
H
NEt2
Cl

Me
Me
H
H
0
H
H
H
NHPh
Cl

Me
Me
H
H
0
H
H
H
N(Me)Ph
Cl

Me
Me
H
H
0
H
H
H
CN
Cl

Me
Me
H
H
0
H
H
H
F
Me

Me
Me
H
H
0
H
H
H
Cl
Me

Me
Me
H
H
0
H
H
H
OH
Me

Me
Me
H
H
0
H
H
H
OMe
Me

Me
Me
H
H
0
H
H
H
OEt
Me

Me
Me
H
H
0
H
H
H
OPr-i
Me

Me
Me
H
H
0
H
H
H
OPr
Me

Me
Me
H
H
0
H
H
H
OBu-t
Me

Me
Me
H
H
0
H
H
H
OCH2Pr-c
Me

Me
Me
H
H
0
H
H
H
OCH2Bu-c
Me

Me
Me
H
H
0
H
H
H
OCH2Pen-c
Me

Me
Me
H
H
0
H
H
H
OCH2Hex-c
Me

Me
Me
H
H
0
H
H
H
OPen-c
Me

Me
Me
H
H
0
H
H
H
OHex-c
Me

Me
Me
H
H
0
H
H
H
OCH2Ph
Me

Me
Me
H
H
0
H
H
H
OPh
Me

Me
Me
H
H
0
H
H
H
OCHF2
Me

Me
Me
H
H
0
H
H
H
SH
Me

Me
Me
H
H
0
H
H
H
SMe
Me

Me
Me
H
H
0
H
H
H
SO2Me
Me

Me
Me
H
H
0
H
H
H
SEt
Me

Me
Me
H
H
0
H
H
H
SO2Et
Me

Me
Me
H
H
0
H
H
H
SPr-i
Me

Me
Me
H
H
0
H
H
H
SO2Pr-i
Me

Me
Me
H
H
0
H
H
H
SPh
Me

Me
Me
H
H
0
H
H
H
SO2Ph
Me

Me
Me
H
H
0
H
H
H
SCHF2
Me

Me
Me
H
H
0
H
H
H
SO2CHF2
Me

Me
Me
H
H
0
H
H
H
NH2
Me

Me
Me
H
H
0
H
H
H
NHMe
Me

Me
Me
H
H
0
H
H
H
NMe2
Me

Me
Me
H
H
0
H
H
H
NHEt
Me

Me
Me
H
H
0
H
H
H
NEt2
Me

Me
Me
H
H
0
H
H
H
NHPh
Me

Me
Me
H
H
0
H
H
H
N(Me)Ph
Me

Me
Me
H
H
0
H
H
H
CN
Me

Me
Me
H
H
0
H
H
H
F
Pr-i

Me
Me
H
H
0
H
H
H
Cl
Pr-i

Me
Me
H
H
0
H
H
H
OH
Pr-i

Me
Me
H
H
0
H
H
H
OMe
Pr-i

Me
Me
H
H
0
H
H
H
OEt
Pr-i

Me
Me
H
H
0
H
H
H
OPr-i
Pr-i

Me
Me
H
H
0
H
H
H
OPr
Pr-i

Me
Me
H
H
0
H
H
H
OBu-t
Pr-i

Me
Me
H
H
0
H
H
H
OCH2Pr-c
Pr-i

Me
Me
H
H
0
H
H
H
OCH2Bu-c
Pr-i

Me
Me
H
H
0
H
H
H
OCH2Pen-c
Pr-i

Me
Me
H
H
0
H
H
H
OCH2Hex-c
Pr-i

Me
Me
H
H
0
H
H
H
OPen-c
Pr-i

Me
Me
H
H
0
H
H
H
OHex-c
Pr-i

Me
Me
H
H
0
H
H
H
OCH2Ph
Pr-i

Me
Me
H
H
0
H
H
H
OPh
Pr-i

Me
Me
H
H
0
H
H
H
OCHF2
Pr-i

Me
Me
H
H
0
H
H
H
SH
Pr-i

Me
Me
H
H
0
H
H
H
SMe
Pr-i

Me
Me
H
H
0
H
H
H
SO2Me
Pr-i

Me
Me
H
H
0
H
H
H
SEt
Pr-i

Me
Me
H
H
0
H
H
H
SO2Et
Pr-i

Me
Me
H
H
0
H
H
H
SPr-i
Pr-i

Me
Me
H
H
0
H
H
H
SO2Pr-i
Pr-i

Me
Me
H
H
0
H
H
H
SPh
Pr-i

Me
Me
H
H
0
H
H
H
SO2Ph
Pr-i

Me
Me
H
H
0
H
H
H
SCHF2
Pr-i

Me
Me
H
H
0
H
H
H
SO2CHF2
Pr-i

Me
Me
H
H
0
H
H
H
NH2
Pr-i

Me
Me
H
H
0
H
H
H
NHMe
Pr-i

Me
Me
H
H
0
H
H
H
NMe2
Pr-i

Me
Me
H
H
0
H
H
H
NHEt
Pr-i

Me
Me
H
H
0
H
H
H
NEt2
Pr-i

Me
Me
H
H
0
H
H
H
NHPh
Pr-i

Me
Me
H
H
0
H
H
H
N(Me)Ph
Pr-i

Me
Me
H
H
0
H
H
H
CN
Pr-i

Me
Me
H
H
0
H
H
H
F
Pr-c

Me
Me
H
H
0
H
H
H
Cl
Pr-c

Me
Me
H
H
0
H
H
H
OH
Pr-c

Me
Me
H
H
0
H
H
H
OMe
Pr-c

Me
Me
H
H
0
H
H
H
OEt
Pr-c

Me
Me
H
H
0
H
H
H
OPr-i
Pr-c

Me
Me
H
H
0
H
H
H
OPr
Pr-c

Me
Me
H
H
0
H
H
H
OBu-t
Pr-c

Me
Me
H
H
0
H
H
H
OCH2Pr-c
Pr-c

Me
Me
H
H
0
H
H
H
OCH2Bu-c
Pr-c

Me
Me
H
H
0
H
H
H
OCH2Pen-c
Pr-c

Me
Me
H
H
0
H
H
H
OCH2Hex-c
Pr-c

Me
Me
H
H
0
H
H
H
OPen-c
Pr-c

Me
Me
H
H
0
H
H
H
OHex-c
Pr-c

Me
Me
H
H
0
H
H
H
OCH2Ph
Pr-c

Me
Me
H
H
0
H
H
H
OPh
Pr-c

Me
Me
H
H
0
H
H
H
OCHF2
Pr-c

Me
Me
H
H
0
H
H
H
SH
Pr-c

Me
Me
H
H
0
H
H
H
SMe
Pr-c

Me
Me
H
H
0
H
H
H
SO2Me
Pr-c

Me
Me
H
H
0
H
H
H
SEt
Pr-c

Me
Me
H
H
0
H
H
H
SO2Et
Pr-c

Me
Me
H
H
0
H
H
H
SPr-i
Pr-c

Me
Me
H
H
0
H
H
H
SO2Pr-i
Pr-c

Me
Me
H
H
0
H
H
H
SPh
Pr-c

Me
Me
H
H
0
H
H
H
SO2Ph
Pr-c

Me
Me
H
H
0
H
H
H
SCHF2
Pr-c

Me
Me
H
H
0
H
H
H
SO2CHF2
Pr-c

Me
Me
H
H
0
H
H
H
NH2
Pr-c

Me
Me
H
H
0
H
H
H
NHMe
Pr-c

Me
Me
H
H
0
H
H
H
NMe2
Pr-c

Me
Me
H
H
0
H
H
H
NHEt
Pr-c

Me
Me
H
H
0
H
H
H
NEt2
Pr-c

Me
Me
H
H
0
H
H
H
NHPh
Pr-c

Me
Me
H
H
0
H
H
H
N(Me)Ph
Pr-c

Me
Me
H
H
0
H
H
H
CN
Pr-c

Me
Me
H
H
0
H
H
H
F
CHF2

Me
Me
H
H
0
H
H
H
Cl
CHF2

Me
Me
H
H
0
H
H
H
OH
CHF2

Me
Me
H
H
0
H
H
H
OMe
CHF2

Me
Me
H
H
0
H
H
H
OEt
CHF2

Me
Me
H
H
0
H
H
H
OPr-i
CHF2

Me
Me
H
H
0
H
H
H
OPr
CHF2

Me
Me
H
H
0
H
H
H
OBu-t
CHF2

Me
Me
H
H
0
H
H
H
OCH2Pr-c
CHF2

Me
Me
H
H
0
H
H
H
OCH2Bu-c
CHF2

Me
Me
H
H
0
H
H
H
OCH2Pen-c
CHF2

Me
Me
H
H
0
H
H
H
OCH2Hex-c
CHF2

Me
Me
H
H
0
H
H
H
OPen-c
CHF2

Me
Me
H
H
0
H
H
H
OHex-c
CHF2

Me
Me
H
H
0
H
H
H
OCH2Ph
CHF2

Me
Me
H
H
0
H
H
H
OPh
CHF2

Me
Me
H
H
0
H
H
H
OCHF2
CHF2

Me
Me
H
H
0
H
H
H
SH
CHF2

Me
Me
H
H
0
H
H
H
SMe
CHF2

Me
Me
H
H
0
H
H
H
SO2Me
CHF2

Me
Me
H
H
0
H
H
H
SEt
CHF2

Me
Me
H
H
0
H
H
H
SO2Et
CHF2

Me
Me
H
H
0
H
H
H
SPr-i
CHF2

Me
Me
H
H
0
H
H
H
SO2Pr-i
CHF2

Me
Me
H
H
0
H
H
H
SPh
CHF2

Me
Me
H
H
0
H
H
H
SO2Ph
CHF2

Me
Me
H
H
0
H
H
H
SCHF2
CHF2

Me
Me
H
H
0
H
H
H
SO2CHF2
CHF2

Me
Me
H
H
0
H
H
H
NH2
CHF2

Me
Me
H
H
0
H
H
H
NHMe
CHF2

Me
Me
H
H
0
H
H
H
NMe2
CHF2

Me
Me
H
H
0
H
H
H
NHEt
CHF2

Me
Me
H
H
0
H
H
H
NEt2
CHF2

Me
Me
H
H
0
H
H
H
NHPh
CHF2

Me
Me
H
H
0
H
H
H
N(Me)Ph
CHF2

Me
Me
H
H
0
H
H
H
CN
CHF2

Me
Me
H
H
0
H
H
H
F
CF3

Me
Me
H
H
0
H
H
H
Cl
CF3

Me
Me
H
H
0
H
H
H
OH
CF3

Me
Me
H
H
0
H
H
H
OMe
CF3

Me
Me
H
H
0
H
H
H
OEt
CF3

Me
Me
H
H
0
H
H
H
OPr-i
CF3

Me
Me
H
H
0
H
H
H
OPr
CF3

Me
Me
H
H
0
H
H
H
OBu-t
CF3

Me
Me
H
H
0
H
H
H
OCH2Pr-c
CF3

Me
Me
H
H
0
H
H
H
OCH2Bu-c
CF3

Me
Me
H
H
0
H
H
H
OCH2Pen-c
CF3

Me
Me
H
H
0
H
H
H
OCH2Hex-c
CF3

Me
Me
H
H
0
H
H
H
OPen-c
CF3

Me
Me
H
H
0
H
H
H
OHex-c
CF3

Me
Me
H
H
0
H
H
H
OCH2Ph
CF3

Me
Me
H
H
0
H
H
H
OPh
CF3

Me
Me
H
H
0
H
H
H
OCHF2
CF3

Me
Me
H
H
0
H
H
H
SH
CF3

Me
Me
H
H
0
H
H
H
SMe
CF3

Me
Me
H
H
0
H
H
H
SO2Me
CF3

Me
Me
H
H
0
H
H
H
SEt
CF3

Me
Me
H
H
0
H
H
H
SO2Et
CF3

Me
Me
H
H
0
H
H
H
SPr-i
CF3

Me
Me
H
H
0
H
H
H
SO2Pr-i
CF3

Me
Me
H
H
0
H
H
H
SPh
CF3

Me
Me
H
H
0
H
H
H
SO2Ph
CF3

Me
Me
H
H
0
H
H
H
SCHF2
CF3

Me
Me
H
H
0
H
H
H
SO2CHF2
CF3

Me
Me
H
H
0
H
H
H
NH2
CF3

Me
Me
H
H
0
H
H
H
NHMe
CF3

Me
Me
H
H
0
H
H
H
NMe2
CF3

Me
Me
H
H
0
H
H
H
NHEt
CF3

Me
Me
H
H
0
H
H
H
NEt2
CF3

Me
Me
H
H
0
H
H
H
NHPh
CF3

Me
Me
H
H
0
H
H
H
N(Me)Ph
CF3

Me
Me
H
H
0
H
H
H
CN
CF3

Me
Me
H
H
0
H
H
H
F
OMe

Me
Me
H
H
0
H
H
H
OH
OMe

Me
Me
H
H
0
H
H
H
OMe
OMe

Me
Me
H
H
0
H
H
H
OEt
OMe

Me
Me
H
H
0
H
H
H
OPr-i
OMe

Me
Me
H
H
0
H
H
H
OPr
OMe

Me
Me
H
H
0
H
H
H
OBu-t
OMe

Me
Me
H
H
0
H
H
H
OCH2Pr-c
OMe

Me
Me
H
H
0
H
H
H
OCH2Bu-c
OMe

Me
Me
H
H
0
H
H
H
OCH2Pen-c
OMe

Me
Me
H
H
0
H
H
H
OCH2Hex-c
OMe

Me
Me
H
H
0
H
H
H
OPen-c
OMe

Me
Me
H
H
0
H
H
H
OHex-c
OMe

Me
Me
H
H
0
H
H
H
OCH2Ph
OMe

Me
Me
H
H
0
H
H
H
OPh
OMe

Me
Me
H
H
0
H
H
H
OCHF2
OMe

Me
Me
H
H
0
H
H
H
SH
OMe

Me
Me
H
H
0
H
H
H
SMe
OMe

Me
Me
H
H
0
H
H
H
SO2Me
OMe

Me
Me
H
H
0
H
H
H
SEt
OMe

Me
Me
H
H
0
H
H
H
SO2Et
OMe

Me
Me
H
H
0
H
H
H
SPr-i
OMe

Me
Me
H
H
0
H
H
H
SO2Pr-i
OMe

Me
Me
H
H
0
H
H
H
SPh
OMe

Me
Me
H
H
0
H
H
H
SO2Ph
OMe

Me
Me
H
H
0
H
H
H
SCHF2
OMe

Me
Me
H
H
0
H
H
H
SO2CHF2
OMe

Me
Me
H
H
0
H
H
H
NH2
OMe

Me
Me
H
H
0
H
H
H
NHMe
OMe

Me
Me
H
H
0
H
H
H
NMe2
OMe

Me
Me
H
H
0
H
H
H
NHEt
OMe

Me
Me
H
H
0
H
H
H
NEt2
OMe

Me
Me
H
H
0
H
H
H
NHPh
OMe

Me
Me
H
H
0
H
H
H
N(Me)Ph
OMe

Me
Me
H
H
0
H
H
H
CN
OMe

Me
Me
H
H
0
H
H
H
F
OPh

Me
Me
H
H
0
H
H
H
OH
OPh

Me
Me
H
H
0
H
H
H
OMe
OPh

Me
Me
H
H
0
H
H
H
OEt
OPh

Me
Me
H
H
0
H
H
H
OPr-i
OPh

Me
Me
H
H
0
H
H
H
OPr
OPh

Me
Me
H
H
0
H
H
H
OBu-t
OPh

Me
Me
H
H
0
H
H
H
OCH2Pr-c
OPh

Me
Me
H
H
0
H
H
H
OCH2Bu-c
OPh

Me
Me
H
H
0
H
H
H
OCH2Pen-c
OPh

Me
Me
H
H
0
H
H
H
OCH2Hex-c
OPh

Me
Me
H
H
0
H
H
H
OPen-c
OPh

Me
Me
H
H
0
H
H
H
OHex-c
OPh

Me
Me
H
H
0
H
H
H
OCH2Ph
OPh

Me
Me
H
H
0
H
H
H
OPh
OPh

Me
Me
H
H
0
H
H
H
OCHF2
OPh

Me
Me
H
H
0
H
H
H
SH
OPh

Me
Me
H
H
0
H
H
H
SMe
OPh

Me
Me
H
H
0
H
H
H
SO2Me
OPh

Me
Me
H
H
0
H
H
H
SEt
OPh

Me
Me
H
H
0
H
H
H
SO2Et
OPh

Me
Me
H
H
0
H
H
H
SPr-i
OPh

Me
Me
H
H
0
H
H
H
SO2Pr-i
OPh

Me
Me
H
H
0
H
H
H
SPh
OPh

Me
Me
H
H
0
H
H
H
SO2Ph
OPh

Me
Me
H
H
0
H
H
H
SCHF2
OPh

Me
Me
H
H
0
H
H
H
SO2CHF2
OPh

Me
Me
H
H
0
H
H
H
NH2
OPh

Me
Me
H
H
0
H
H
H
NHMe
OPh

Me
Me
H
H
0
H
H
H
NMe2
OPh

Me
Me
H
H
0
H
H
H
NHEt
OPh

Me
Me
H
H
0
H
H
H
NEt2
OPh

Me
Me
H
H
0
H
H
H
NHPh
OPh

Me
Me
H
H
0
H
H
H
N(Me)Ph
OPh

Me
Me
H
H
0
H
H
H
CN
OPh

Me
Me
H
H
0
H
H
H
F
OCHF2

Me
Me
H
H
0
H
H
H
OH
OCHF2

Me
Me
H
H
0
H
H
H
OMe
OCHF2

Me
Me
H
H
0
H
H
H
OEt
OCHF2

Me
Me
H
H
0
H
H
H
OPr-i
OCHF2

Me
Me
H
H
0
H
H
H
OPr
OCHF2

Me
Me
H
H
0
H
H
H
OBu-t
OCHF2

Me
Me
H
H
0
H
H
H
OCH2Pr-c
OCHF2

Me
Me
H
H
0
H
H
H
OCH2Bu-c
OCHF2

Me
Me
H
H
0
H
H
H
OCH2Pen-c
OCHF2

Me
Me
H
H
0
H
H
H
OCH2Hex-c
OCHF2

Me
Me
H
H
0
H
H
H
OPen-c
OCHF2

Me
Me
H
H
0
H
H
H
OHex-c
OCHF2

Me
Me
H
H
0
H
H
H
OCH2Ph
OCHF2

Me
Me
H
H
0
H
H
H
OPh
OCHF2

Me
Me
H
H
0
H
H
H
OCHF2
OCHF2

Me
Me
H
H
0
H
H
H
SH
OCHF2

Me
Me
H
H
0
H
H
H
SMe
OCHF2

Me
Me
H
H
0
H
H
H
SO2Me
OCHF2

Me
Me
H
H
0
H
H
H
SEt
OCHF2

Me
Me
H
H
0
H
H
H
SO2Et
OCHF2

Me
Me
H
H
0
H
H
H
SPr-i
OCHF2

Me
Me
H
H
0
H
H
H
SO2Pr-i
OCHF2

Me
Me
H
H
0
H
H
H
SPh
OCHF2

Me
Me
H
H
0
H
H
H
SO2Ph
OCHF2

Me
Me
H
H
0
H
H
H
SCHF2
OCHF2

Me
Me
H
H
0
H
H
H
SO2CHF2
OCHF2

Me
Me
H
H
0
H
H
H
NH2
OCHF2

Me
Me
H
H
0
H
H
H
NHMe
OCHF2

Me
Me
H
H
0
H
H
H
NMe2
OCHF2

Me
Me
H
H
0
H
H
H
NHEt
OCHF2

Me
Me
H
H
0
H
H
H
NEt2
OCHF2

Me
Me
H
H
0
H
H
H
NHPh
OCHF2

Me
Me
H
H
0
H
H
H
N(Me)Ph
OCHF2

Me
Me
H
H
0
H
H
H
CN
OCHF2

Me
Me
H
H
0
H
H
Me
F
CF3

Me
Me
H
H
0
H
H
Me
Cl
CF3

Me
Me
H
H
0
H
H
Me
OH
CF3

Me
Me
H
H
0
H
H
Me
OMe
CF3

Me
Me
H
H
0
H
H
Me
OEt
CF3

Me
Me
H
H
0
H
H
Me
OPr-i
CF3

Me
Me
H
H
0
H
H
Me
OPr
CF3

Me
Me
H
H
0
H
H
Me
OBu-t
CF3

Me
Me
H
H
0
H
H
Me
OCH2Pr-c
CF3

Me
Me
H
H
0
H
H
Me
OCH2Bu-c
CF3

Me
Me
H
H
0
H
H
Me
OCH2Pen-c
CF3

Me
Me
H
H
0
H
H
Me
OCH2Hex-c
CF3

Me
Me
H
H
0
H
H
Me
OPen-c
CF3

Me
Me
H
H
0
H
H
Me
OHex-c
CF3

Me
Me
H
H
0
H
H
Me
OCH2Ph
CF3

Me
Me
H
H
0
H
H
Me
OPh
CF3

Me
Me
H
H
0
H
H
Me
OCHF2
CF3

Me
Me
H
H
0
H
H
Me
SH
CF3

Me
Me
H
H
0
H
H
Me
SMe
CF3

Me
Me
H
H
0
H
H
Me
SO2Me
CF3

Me
Me
H
H
0
H
H
Me
SEt
CF3

Me
Me
H
H
0
H
H
Me
SO2Et
CF3

Me
Me
H
H
0
H
H
Me
SPr-i
CF3

Me
Me
H
H
0
H
H
Me
SO2Pr-i
CF3

Me
Me
H
H
0
H
H
Me
SPh
CF3

Me
Me
H
H
0
H
H
Me
SO2Ph
CF3

Me
Me
H
H
0
H
H
Me
SCHF2
CF3

Me
Me
H
H
0
H
H
Me
SO2CHF2
CF3

Me
Me
H
H
0
H
H
Me
NH2
CF3

Me
Me
H
H
0
H
H
Me
NHMe
CF3

Me
Me
H
H
0
H
H
Me
NMe2
CF3

Me
Me
H
H
0
H
H
Me
NHEt
CF3

Me
Me
H
H
0
H
H
Me
NEt2
CF3

Me
Me
H
H
0
H
H
Me
NHPh
CF3

Me
Me
H
H
0
H
H
Me
N(Me)Ph
CF3

Me
Me
H
H
0
H
H
Me
CN
CF3

Me
Me
H
H
0
H
H
OMe
F
CF3

Me
Me
H
H
0
H
H
OMe
Cl
CF3

Me
Me
H
H
0
H
H
OMe
OH
CF3

Me
Me
H
H
0
H
H
OMe
OMe
CF3

Me
Me
H
H
0
H
H
OMe
OEt
CF3

Me
Me
H
H
0
H
H
OMe
OPr-i
CF3

Me
Me
H
H
0
H
H
OMe
OPr
CF3

Me
Me
H
H
0
H
H
OMe
OBu-t
CF3

Me
Me
H
H
0
H
H
OMe
OCH2Pr-c
CF3

Me
Me
H
H
0
H
H
OMe
OCH2Bu-c
CF3

Me
Me
H
H
0
H
H
OMe
OCH2Pen-c
CF3

Me
Me
H
H
0
H
H
OMe
OCH2Hex-c
CF3

Me
Me
H
H
0
H
H
OMe
OPen-c
CF3

Me
Me
H
H
0
H
H
OMe
OHex-c
CF3

Me
Me
H
H
0
H
H
OMe
OCH2Ph
CF3

Me
Me
H
H
0
H
H
OMe
OPh
CF3

Me
Me
H
H
0
H
H
OMe
OCHF2
CF3

Me
Me
H
H
0
H
H
OMe
SH
CF3

Me
Me
H
H
0
H
H
OMe
SMe
CF3

Me
Me
H
H
0
H
H
OMe
SO2Me
CF3

Me
Me
H
H
0
H
H
OMe
SEt
CF3

Me
Me
H
H
0
H
H
OMe
SO2Et
CF3

Me
Me
H
H
0
H
H
OMe
SPr-i
CF3

Me
Me
H
H
0
H
H
OMe
SO2Pr-i
CF3

Me
Me
H
H
0
H
H
OMe
SPh
CF3

Me
Me
H
H
0
H
H
OMe
SO2Ph
CF3

Me
Me
H
H
0
H
H
OMe
SCHF2
CF3

Me
Me
H
H
0
H
H
OMe
SO2CHF2
CF3

Me
Me
H
H
0
H
H
OMe
NH2
CF3

Me
Me
H
H
0
H
H
OMe
NHMe
CF3

Me
Me
H
H
0
H
H
OMe
NMe2
CF3

Me
Me
H
H
0
H
H
OMe
NHEt
CF3

Me
Me
H
H
0
H
H
OMe
NEt2
CF3

Me
Me
H
H
0
H
H
OMe
NHPh
CF3

Me
Me
H
H
0
H
H
OMe
N(Me)Ph
CF3

Me
Me
H
H
0
H
H
OMe
CN
CF3

Me
Me
H
H
0
H
H
SMe
F
CF3

Me
Me
H
H
0
H
H
SMe
Cl
CF3

Me
Me
H
H
0
H
H
SMe
OH
CF3

Me
Me
H
H
0
H
H
SMe
OMe
CF3

Me
Me
H
H
0
H
H
SMe
OEt
CF3

Me
Me
H
H
0
H
H
SMe
OPr-i
CF3

Me
Me
H
H
0
H
H
SMe
OPr
CF3

Me
Me
H
H
0
H
H
SMe
OBu-t
CF3

Me
Me
H
H
0
H
H
SMe
OCH2Pr-c
CF3

Me
Me
H
H
0
H
H
SMe
OCH2Bu-c
CF3

Me
Me
H
H
0
H
H
SMe
OCH2Pen-c
CF3

Me
Me
H
H
0
H
H
SMe
OCH2Hex-c
CF3

Me
Me
H
H
0
H
H
SMe
OPen-c
CF3

Me
Me
H
H
0
H
H
SMe
OHex-c
CF3

Me
Me
H
H
0
H
H
SMe
OCH2Ph
CF3

Me
Me
H
H
0
H
H
SMe
OPh
CF3

Me
Me
H
H
0
H
H
SMe
OCHF2
CF3

Me
Me
H
H
0
H
H
SMe
SH
CF3

Me
Me
H
H
0
H
H
SMe
SMe
CF3

Me
Me
H
H
0
H
H
SMe
SO2Me
CF3

Me
Me
H
H
0
H
H
SMe
SEt
CF3

Me
Me
H
H
0
H
H
SMe
SO2Et
CF3

Me
Me
H
H
0
H
H
SMe
SPr-i
CF3

Me
Me
H
H
0
H
H
SMe
SO2Pr-i
CF3

Me
Me
H
H
0
H
H
SMe
SPh
CF3

Me
Me
H
H
0
H
H
SMe
SO2Ph
CF3

Me
Me
H
H
0
H
H
SMe
SCHF2
CF3

Me
Me
H
H
0
H
H
SMe
SO2CHF2
CF3

Me
Me
H
H
0
H
H
SMe
NH2
CF3

Me
Me
H
H
0
H
H
SMe
NHMe
CF3

Me
Me
H
H
0
H
H
SMe
NMe2
CF3

Me
Me
H
H
0
H
H
SMe
NHEt
CF3

Me
Me
H
H
0
H
H
SMe
NEt2
CF3

Me
Me
H
H
0
H
H
SMe
NHPh
CF3

Me
Me
H
H
0
H
H
SMe
N(Me)Ph
CF3

Me
Me
H
H
0
H
H
SMe
CN
CF3

Me
Me
H
H
0
H
H
SO2Me
F
CF3

Me
Me
H
H
0
H
H
SO2Me
Cl
CF3

Me
Me
H
H
0
H
H
SO2Me
OH
CF3

Me
Me
H
H
0
H
H
SO2Me
OMe
CF3

Me
Me
H
H
0
H
H
SO2Me
OEt
CF3

Me
Me
H
H
0
H
H
SO2Me
OPr-i
CF3

Me
Me
H
H
0
H
H
SO2Me
OPr
CF3

Me
Me
H
H
0
H
H
SO2Me
OBu-t
CF3

Me
Me
H
H
0
H
H
SO2Me
OCH2Pr-c
CF3

Me
Me
H
H
0
H
H
SO2Me
OCH2Bu-c
CF3

Me
Me
H
H
0
H
H
SO2Me
OCH2Pen-c
CF3

Me
Me
H
H
0
H
H
SO2Me
OCH2Hex-c
CF3

Me
Me
H
H
0
H
H
SO2Me
OPen-c
CF3

Me
Me
H
H
0
H
H
SO2Me
OHex-c
CF3

Me
Me
H
H
0
H
H
SO2Me
OCH2Ph
CF3

Me
Me
H
H
0
H
H
SO2Me
OPh
CF3

Me
Me
H
H
0
H
H
SO2Me
OCHF2
CF3

Me
Me
H
H
0
H
H
SO2Me
SH
CF3

Me
Me
H
H
0
H
H
SO2Me
SMe
CF3

Me
Me
H
H
0
H
H
SO2Me
SO2Me
CF3

Me
Me
H
H
0
H
H
SO2Me
SEt
CF3

Me
Me
H
H
0
H
H
SO2Me
SO2Et
CF3

Me
Me
H
H
0
H
H
SO2Me
SPr-i
CF3

Me
Me
H
H
0
H
H
SO2Me
SO2Pr-i
CF3

Me
Me
H
H
0
H
H
SO2Me
SPh
CF3

Me
Me
H
H
0
H
H
SO2Me
SO2Ph
CF3

Me
Me
H
H
0
H
H
SO2Me
SCHF2
CF3

Me
Me
H
H
0
H
H
SO2Me
SO2CHF2
CF3

Me
Me
H
H
0
H
H
SO2Me
NH2
CF3

Me
Me
H
H
0
H
H
SO2Me
NHMe
CF3

Me
Me
H
H
0
H
H
SO2Me
NMe2
CF3

Me
Me
H
H
0
H
H
SO2Me
NHEt
CF3

Me
Me
H
H
0
H
H
SO2Me
NEt2
CF3

Me
Me
H
H
0
H
H
SO2Me
NHPh
CF3

Me
Me
H
H
0
H
H
SO2Me
N(Me)Ph
CF3

Me
Me
H
H
0
H
H
SO2Me
CN
CF3

Me
Me
H
H
0
H
H
NH2
F
CF3

Me
Me
H
H
0
H
H
NH2
Cl
CF3

Me
Me
H
H
0
H
H
NH2
OH
CF3

Me
Me
H
H
0
H
H
NH2
OMe
CF3

Me
Me
H
H
0
H
H
NH2
OEt
CF3

Me
Me
H
H
0
H
H
NH2
OPr-i
CF3

Me
Me
H
H
0
H
H
NH2
OPr
CF3

Me
Me
H
H
0
H
H
NH2
OBu-t
CF3

Me
Me
H
H
0
H
H
NH2
OCH2Pr-c
CF3

Me
Me
H
H
0
H
H
NH2
OCH2Bu-c
CF3

Me
Me
H
H
0
H
H
NH2
OCH2Pen-c
CF3

Me
Me
H
H
0
H
H
NH2
OCH2Hex-c
CF3

Me
Me
H
H
0
H
H
NH2
OPen-c
CF3

Me
Me
H
H
0
H
H
NH2
OHex-c
CF3

Me
Me
H
H
0
H
H
NH2
OCH2Ph
CF3

Me
Me
H
H
0
H
H
NH2
OPh
CF3

Me
Me
H
H
0
H
H
NH2
OCHF2
CF3

Me
Me
H
H
0
H
H
NH2
SH
CF3

Me
Me
H
H
0
H
H
NH2
SMe
CF3

Me
Me
H
H
0
H
H
NH2
SO2Me
CF3

Me
Me
H
H
0
H
H
NH2
SEt
CF3

Me
Me
H
H
0
H
H
NH2
SO2Et
CF3

Me
Me
H
H
0
H
H
NH2
SPr-i
CF3

Me
Me
H
H
0
H
H
NH2
SO2Pr-i
CF3

Me
Me
H
H
0
H
H
NH2
SPh
CF3

Me
Me
H
H
0
H
H
NH2
SO2Ph
CF3

Me
Me
H
H
0
H
H
NH2
SCHF2
CF3

Me
Me
H
H
0
H
H
NH2
SO2CHF2
CF3

Me
Me
H
H
0
H
H
NH2
NH2
CF3

Me
Me
H
H
0
H
H
NH2
NHMe
CF3

Me
Me
H
H
0
H
H
NH2
NMe2
CF3

Me
Me
H
H
0
H
H
NH2
NHEt
CF3

Me
Me
H
H
0
H
H
NH2
NEt2
CF3

Me
Me
H
H
0
H
H
NH2
NHPh
CF3

Me
Me
H
H
0
H
H
NH2
N(Me)Ph
CF3

Me
Me
H
H
0
H
H
NH2
CN
CF3

H
H
H
H
0
H
H
H
OMe
CF3

H
H
H
H
0
H
H
H
OEt
CF3

Me
H
H
H
0
H
H
H
OMe
CF3

Me
H
H
H
0
H
H
H
OEt
CF3

Me
H
Me
H
0
H
H
H
OMe
CF3

Me
H
Me
H
0
H
H
H
OEt
CF3

Me
Me
H
H
0
Me
H
H
OMe
CF3

Me
Me
H
H
0
Me
H
H
OEt
CF3

Me
Me
H
H
0
Et
H
H
OMe
CF3

Me
Me
H
H
0
Et
H
H
OEt
CF3

Me
Me
H
H
0
Pr-i
H
H
H
CF3

Me
Me
H
H
0
Pr-i
H
H
OMe
CF3

Me
Me
H
H
0
Pr-i
H
H
OEt
CF3

Me
Me
H
H
0
Me
Me
H
OMe
CF3

Me
Me
H
H
0
Me
Me
H
OEt
CF3

Me
Et
H
H
0
H
H
H
OMe
CF3

Me
Et
H
H
0
H
H
H
OEt
CF3

Et
Et
H
H
0
H
H
H
OMe
CF3

Et
Et
H
H
0
H
H
H
OEt
CF3

Me
Pr-i
H
H
0
H
H
H
OMe
CF3

Me
Pr-i
H
H
0
H
H
H
OEt
CF3

Me
Pr
H
H
0
H
H
H
OMe
CF3

Me
Pr
H
H
0
H
H
H
OEt
CF3

Me
Pr-c
H
H
0
H
H
H
OMe
CF3

Me
Pr-c
H
H
0
H
H
H
OEt
CF3

Me
CH2Pr-c
H
H
0
H
H
H
OMe
CF3

Me
CH2Pr-c
H
H
0
H
H
H
OEt
CF3

—(CH2)2—
H
H
0
H
H
H
OMe
CF3

—(CH2)2—
H
H
0
H
H
H
OEt
CF3

—(CH2)3—
H
H
0
H
H
H
OMe
CF3

—(CH2)3—
H
H
0
H
H
H
OEt
CF3

—(CH2)4—
H
H
0
H
H
H
OMe
CF3

—(CH2)4—
H
H
0
H
H
H
OEt
CF3

—(CH2)5—
H
H
0
H
H
H
OMe
CF3

—(CH2)5—
H
H
0
H
H
H
OEt
CF3

H
—(CH2)3—
H
0
H
H
H
OMe
CF3

H
—(CH2)3—
H
0
H
H
H
OEt
CF3

H
—(CH2)4—
H
0
H
H
H
OMe
CF3

H
—(CH2)4—
H
0
H
H
H
OEt
CF3

H
—(CH2)5—
H
0
H
H
H
OMe
CF3

H
—(CH2)5—
H
0
H
H
H
OEt
CF3

H
—(CH2)6—
H
0
H
H
H
OMe
CF3

H
—(CH2)6—
H
0
H
H
H
OEt
CF3

[0089]

10

TABLE 9

R1
R2
R3
R4
n
R5
R6
Y1

Me
Me
H
H
2
H
H
Pyridin-2-yl

Me
Me
H
H
2
H
H
Pyridin-2-yl 1-oxide

Me
Me
H
H
2
H
H
Pyridin-4-yl

Me
Me
H
H
2
H
H
Pyridin-4-yl 1-oxide.

Me
Me
H
H
2
H
H
1,2,4-Oxadiazol-3-yl

Me
Me
H
H
2
H
H
3-Phenyl-1,2,4-oxadiazol-5-yl

Me
Me
H
H
2
H
H
3-Benzyl-1,2,4-oxadiazol-5-yl

Me
Me
H
H
2
H
H
2-Chlorothiazol-4-yl

Me
Me
H
H
2
H
H
5-Trifluoromethyl-1,3,4-thiadiazol-2-yl

Me
Me
H
H
2
H
H
1,4-Dimethylimidazol-5-yl

Me
Me
H
H
2
H
H
1-Phenyl-4-methoxycarbonyl-1,2,3-triazol-5-yl

Me
Me
H
H
2
H
H
1-Diflluoromethyl-1,2,4-triazol-3-yl

Me
Me
H
H
2
H
H
1-Diflluoromethyl-1,2,4-triazol-5-yl

Me
Me
H
H
2
H
H
4-Diflluoromethyl-1,2,4-triazo1-3-yl

Me
Me
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
2
H
H
4,6-Diethoxypyrimidin-2-yl

Me
Me
H
H
2
H
H
4,6-Dimethylpyrimidin-2-yl

Me
Me
H
H
2
H
H
4-Chloro-6-methylpyrimidin-2-yl

Me
Me
H
H
2
H
H
4-Methoxy-6-methylpyrimidin-2-yl

Me
Me
H
H
2
H
H
4-Difluoromethoxy-6-metbylpyrimidin-2-yl

Me
Me
H
H
2
H
H
4-Phenoxy-6-methylpyrimidin-2-yl

Me
Me
H
H
2
H
H
4-Chloro-6-trifluoromethylpyrimidin-2-yl

Me
Me
H
H
2
H
H
4-Methoxy-6-trifluoromethylpyrimidin-2-yl

Me
Me
H
H
2
H
H
4-Difluoromethoxy-6-trifluoromethylpyrimidin-2-yl

Me
Me
H
H
2
H
H
4-Phenoxy-6-trifluoromethylpyrimidin-2-yl

H
H
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
H
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
H
Me
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
2
Me
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
2
Et
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
2
Pr-i
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
2
Me
Me
4,6-Dirnetboxypyrimidin-2-yl

Me
Et
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

Et
Et
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Pr-i
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Pr
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Pr-c
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
CH2Pr-c
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)2—
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)3—
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)4—
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)5—
H
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)3—
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)4—
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)5—
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)6—
H
2
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
1
H
H
Pyridin-2-yl

Me
Me
H
H
1
H
H
Pyridin-2-yl 1-oxide

Me
Me
H
H
1
H
H
Pyridin-4-yl

Me
Me
H
H
1
H
H
Pyridin-4-yl 1-oxide

Me
Me
H
H
1
H
H
1,2,4-Oxadiazol-3-yl

Me
Me
H
H
1
H
H
3-Phenyl-1,2,4-oxadiazol-5-yl

Me
Me
H
H
1
H
H
3-Benzyl-1,2,4-oxadiazol-5-yl

Me
Me
H
H
1
H
H
2-Chlorothiazol-4-yl

Me
Me
H
H
1
H
H
5-Trifluoromethyl-1,3,4-thiadiazol-2-yl

Me
Me
H
H
1
H
H
1,4-Dimethylimidazol-5-yl

Me
Me
H
H
1
H
H
1-Phenyl-4-methoxycarbonyl-1,2,3-triazol-5-yl

Me
Me
H
H
1
H
H
1-Diflluoromethyl-1,2,4-triazol-3-yl

Me
Me
H
H
1
H
H
1-Diflluoromethyl-1,2,4-triazol-5-yl

Me
Me
H
H
1
H
H
4-Diflluoromethyl-1,2,4-triazol-3-yl

Me
Me
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
1
H
H
4,6-Diethoxypyrimidin-2-yl

Me
Me
H
H
1
H
H
4,6-Dimethylpyrimidin-2-yl

Me
Me
H
H
1
H
H
4-Chloro-6-methylpyrimidin-2-yl

Me
Me
H
H
1
H
H
4-Methoxy-6-methylpyrimidin-2-yl

Me
Me
H
H
1
H
H
4-Difluoromethoxy-6-methylpyrimidin-2-yl

Me
Me
H
H
1
H
H
4-Phenoxy-6-methylpyrimidin-2-yl

Me
Me
H
H
1
H
H
4-Chloro-6-trifluoromethylpyrimidin-2-yl

Me
Me
H
H
1
H
H
4-Methoxy-6-trifluoromethylpyrimidin-2-yl

Me
Me
H
H
1
H
H
4-Difluoromethoxy-6-trifluoromethylpyrimidin-2-yl

Me
Me
H
H
1
H
H
4-Phenoxy-6-trifluoromethylpyrimidin-2-yl

H
H
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
H
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
H
Me
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
1
Me
H
4,6-Dimethokypyrimidin-2-yl

Me
Me
H
H
1
Et
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
1
Pr-i
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
1
Me
Me
4,6-Dimethoxypyrimidin-2-yl

Me
Et
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

Et
Et
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Pr-i
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Pr
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Pr-c
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
CH2Pr-c
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)2—
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)3—
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)4—
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)5—
H
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)3—
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)4—
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)5—
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)6—
H
1
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
0
H
H
Pyridin-2-yl

Me
Me
H
H
0
H
H
Pyridin-2-yl 1-oxide

Me
Me
H
H
0
H
H
Pyridin-4-yl

Me
Me
H
H
0
H
H
Pyridin-4-yl 1-oxide

Me
Me
H
H
0
H
H
1,2,4-Oxadiazol-3-yl

Me
Me
H
H
0
H
H
3-Phenyl-1,2,4-oxadiazol-5-yl

Me
Me
H
H
0
H
H
3-Benzyl-1,2,4-oxadiazol-5-yl

Me
Me
H
H
0
H
H
2-Chlorothiazol-4-yl

Me
Me
H
H
0
H
H
5-Trifluoromethyl-1,3,4-thiadiazol-2-yl

Me
Me
H
H
0
H
H
1,4-Dimethylimidazol-5-yl

Me
Me
H
H
0
H
H
1-Phenyl-4-methoxycarbonyl-1,2,3-triazol-5-yl

Me
Me
H
H
0
H
H
1-Diflluoromethyl-1,2,4-triazol-3-yl

Me
Me
H
H
0
H
H
1-Diflluoromethyl-1,2,4-triazol-5-yl

Me
Me
H
H
0
H
H
4-Diflluoromethyl-1,2,4-triazol-3-yl

Me
Me
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
0
H
H
4,6-Diethoxypyrimidin-2-yl

Me
Me
H
H
0
H
H
4,6-Dimethylpyrimidin-2-yl

Me
Me
H
H
0
H
H
4-Chloro-6-methylpyrimidin-2-yl

Me
Me
H
H
0
H
H
4-Methoxy-6-methylpyrimidin-2-yl

Me
Me
H
H
0
H
H
4-Difluoromethoxy-6-methylpyrimidin-2-yl

Me
Me
H
H
0
H
H
4-Phenoxy-6-methylpyrimidin-2-yl

Me
Me
H
H
0
H
H
4-Chloro-6-trifluoromethylpyrimidin-2-yl

Me
Me
H
H
0
H
H
4-Methoxy-6-trifluoromethylpyrimidin-2-yl

Me
Me
H
H
0
H
H
4-Difluoromethoxy-6-trifluoromethylpyrimidin-2-yl

Me
Me
H
H
0
H
H
4-Phenoxy-6-trifluoromethylpyrimidin-2-yl

H
H
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
H
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
H
Me
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
0
Me
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
0
Et
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
0
Pr-i
H
4,6-Dimethoxypyrimidin-2-yl

Me
Me
H
H
0
Me
Me
4,6-Dimethoxypyrimidin-2-yl

Me
Et
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

Et
Et
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Pr-i
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Pr
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Pr-c
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
CH2Pr-c
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)2—
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)2—
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)2—
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

—(CH2)2—
H
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)2—
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)2—
H
0
H
H
4,6-Dimethoxypyrimidin-2-y1

H
—(CH2)2—
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

H
—(CH2)2—
H
0
H
H
4,6-Dimethoxypyrimidin-2-yl

Me
Et
H
H
2
H
H
Pirrol-1-yl

Me
Et
H
H
2
H
H
Oxazol-2-yl

Me
Et
H
H
2
H
H
Thiazol-2-yl

Me
Et
H
H
2
H
H
Thiazol-4-yl

Me
Et
H
H
2
H
H
1,2,3-Thiadiazol-4-yl

Me
Et
H
H
2
H
H
1,2,3-Thiadiazol-5-yl

Me
Et
H
H
2
H
H
1,2,4-Thiadiazol-3-yl

Me
Et
H
H
2
H
H
1,2,4-Thiadiazol-5-yl

Me
Et
H
H
2
H
H
1,3,4-Thiadiazol-2-yl

Me
Et
H
H
2
H
H
1,3,4-Thiadiazol-5-yl

Me
Et
H
H
2
H
H
Pyridin-2-yl

Me
Et
H
H
2
H
H
Pyridin-3-yl

Me
Et
H
H
2
H
H
Pyridin-4-yl

Me
Et
H
H
2
H
H
1H-Imidazol-2-yl

Me
Et
H
H
2
H
H
1H-Imidazol-4-yl

Me
Et
H
H
2
H
H
1H-Imidazol-5-yl

Me
Et
H
H
2
H
H
1H-1,3,4-Triazol-2-yl

Me
Et
H
H
2
H
H
1H-1,3,4-Triazol-5-yl

[0090]

11

TABLE 10

R1
R2
R3
R4
n
R5
R6
Y1

Me
Me
H
H
2
H
H
Benzimidazol-2-yl

Me
Me
H
H
2
H
H
Benzothiophen-2-yl

Me
Me
H
H
2
H
H
3-Chlorobenzothiophen-2-yl

Me
Me
H
H
2
H
H
Benzotriazol-1-yl

Me
Me
H
H
2
H
H
1-Methylindazol-4-yl

Me
Me
H
H
2
H
H
Benzothiazol-2-yl

Me
Me
H
H
2
H
H
Benzothiophen-3-yl

Me
Me
H
H
2
H
H
5-Chlorobenzothiophen-3-yl

Me
Me
H
H
2
H
H
Benzoxazol-2-yl

Me
Me
H
H
2
H
H
3-Methylbenzothiophen-2-yl

Me
Me
H
H
2
H
H
3-Bromobenzothiophen-2-yl

Me
Me
H
H
2
H
H
Benzofuran-2-yl

Me
Me
H
H
2
H
H
2-Methylbenzofuran-7-yl

Me
Me
H
H
2
H
H
3-Bromobenzofuran-2-yl

Me
Me
H
H
2
H
H
Benzothiophen-7-yl

Me
Me
H
H
2
H
H
1-Methylindazol-7-yl

Me
Me
H
H
2
H
H
1-Difluoromethylindazol-7-yl

Me
Me
H
H
2
H
H
3-Methylbenzofuran-2-yl

Me
Me
H
H
2
H
H
3-Chloro-1-methylindol-2-yl

Me
Me
H
H
1
H
H
Benzimidazol-2-yl

Me
Me
H
H
1
H
H
Benzothiophen-2-yl

Me
Me
H
H
1
H
H
3-Chlorobenzothiophen-2-yl

Me
Me
H
H
1
H
H
Benzotriazol-1-yl

Me
Me
H
H
1
H
H
1-Methylindazol-4-yi

Me
Me
H
H
1
H
H
Benzothiazol-2-yl

Me
Me
H
H
1
H
H
Benzothiophen-3-yl

Me
Me
H
H
1
H
H
5-Chlorobenzothiophen-3-yl

Me
Me
H
H
1
H
H
Benzoxazol-2-yl

Me
Me
H
H
1
H
H
3-Methylbenzothiophen-2-yl

Me
Me
H
H
1
H
H
3-Bromobenzothiophen-2-yl

Me
Me
H
H
1
H
H
Benzofuran-2-yl

Me
Me
H
H
1
H
H
2-Methylbenzofuran-7-yl

Me
Me
H
H
1
H
H
3-Bromobenzofuran-2-yl

Me
Me
H
H
1
H
H
Benzothiophen-7-yl

Me
Me
H
H
1
H
H
1-Methylindazol-7-yl

Me
Me
H
H
1
H
H
3-Methylbenzofuran-2-yl

Me
Me
H
H
1
H
H
3-Chloro-1-methylindol-2-yl

Me
Me
H
H
0
H
H
Benzimidazol-2-yl

Me
Me
H
H
0
H
H
Benzothiophen-2-yl

Me
Me
H
H
0
H
H
3-Chlorobenzothiophen-2-yl

Me
Me
H
H
0
H
H
Benzotriazol-1-yl

Me
Me
H
H
0
H
H
1 -Methylindazol-4-yl

Me
Me
H
H
0
H
H
Benzothiazol-2-yl

Me
Me
H
H
0
H
H
Benzothiophen-3-yl

Me
Me
H
H
0
H
H
5-Chlorobenzothiophen-3-yl

Me
Me
H
H
0
H
H
Benzoxazol-2-yl

Me
Me
H
H
0
H
H
3-Methylbenzothiophen-2-yl

Me
Me
H
H
0
H
H
3-Bromobenzothiophen-2-yl

Me
Me
H
H
0
H
H
Benzofuran-2-yl

Me
Me
H
H
0
H
H
2-Methylbenzofuran-7-yl

Me
Me
H
H
0
H
H
3-Bromobenzofuran-2-yl

Me
Me
H
H
0
H
H
Benzothiophen-7-yl

Me
Me
H
H
0
H
H
1-Methylindazol-7-yl

Me
Me
H
H
0
H
H
3-Methylbenzofuran-2-yl

Me
Me
H
H
0
H
H
3-Chloro-1-methylindol-2-yl

Me
Et
H
H
2
H
H
Benzoxazol-2-yl

Me
Et
H
H
2
H
H
4-Chlorobenzoxazol-2-yl

Me
Et
H
H
2
H
H
5-Chlorobenzoxazol-2-yl

Me
Et
H
H
2
H
H
6-Chlorobenzoxazol-2-yl

Me
Et
H
H
2
H
H
7-Chlorobenzoxazol-2-yl

Me
Et
H
H
2
H
H
4-Fluorobenzoxazol-2-yl

Me
Et
H
H
2
H
H
5-Fluorobenzoxazol-2-yl

Me
Et
H
H
2
H
H
6-Fluorobenzoxazol-2-yl

Me
Et
H
H
2
H
H
7-Fluorobenzoxazol-2-yl

Me
Et
H
H
2
H
H
4-Methylbenzoxazol-2-yl

Me
Et
H
H
2
H
H
5-Methylbenzoxazol-2-yl

Me
Et
H
H
2
H
H
6-Methylbenzoxazol-2-yl

Me
Et
H
H
2
H
H
7-Methylbenzoxazol-2-yl

Me
Et
H
H
2
H
H
4-Methoxybenzoxazol-2-yl

Me
Et
H
H
2
H
H
5-Methoxybenzoxazol-2-yl

Me
Et
H
H
2
H
H
6-Methoxybenzoxazol-2-yl

Me
Et
H
H
2
H
H
7-Methoxybenzoxazol-2-yl

Me
Et
H
H
2
H
H
Benzothiazol-2-yl

Me
Et
H
H
2
H
H
4-Chlorobenzothiazol-2-yl

Me
Et
H
H
2
H
H
5-Chlorobenzothiazol-2-yl

Me
Et
H
H
2
H
H
6-Chlorobenzothiazol-2-yl

Me
Et
H
H
2
H
H
7-Chlorobenzothiazol-2-yl

Me
Et
H
H
2
H
H
4-Fluorobenzothiazol-2-yl

Me
Et
H
H
2
H
H
5-Fluorobenzothiazol-2-yl

Me
Et
H
H
2
H
H
6-Fluorobenzothiazol-2-yl

Me
Et
H
H
2
H
H
7-Fluorobenzothiazol-2-yl

Me
Et
H
H
2
H
H
4-Methylbenzothiazol-2-yl

Me
Et
H
H
2
H
H
5-Methylbenzothiazol-2-yl

Me
Et
H
H
2
H
H
6-Methylbenzothiazol-2-yl

Me
Et
H
H
2
H
H
7-Methylbenzothiazol-2-yl

Me
Et
H
H
2
H
H
4-Methoxybenzothiazol-2-yl

Me
Et
H
H
2
H
H
5-Methoxybenzothiazol-2-yl

Me
Et
H
H
2
H
H
6-Methoxybenzothiazol-2-yl

Me
Et
H
H
2
H
H
7-Methoxybenzothiazol-2-yl

Me
Et
H
H
2
H
H
Qnolin-2-yl

Me
Et
H
H
2
H
H
Qinolin-6-yl

Me
Et
H
H
2
H
H
Quinoxalin-2-yl

Me
Et
H
H
2
H
H
Benzofuran-2-yl

Me
Et
H
H
2
H
H
3-Chlorobenzofuran-2-yl

Me
Et
H
H
2
H
H
4-Chlorobenzofuran-2-yl

Me
Et
H
H
2
H
H
5-Chlorobenzofuran-2-yl

Me
Et
H
H
2
H
H
6-Chlorobenzofuran-2-yl

Me
Et
H
H
2
H
H
7-Chlorobenzofuran-2-yl

Me
Et
H
H
2
H
H
3-Methylbenzofuran-2-yl

Me
Et
H
H
2
H
H
4-Methylbenzofuran-2-yl

Me
Et
H
H
2
H
H
5-Methylbenzofuran-2-yl

Me
Et
H
H
2
H
H
6-Methylbenzofuran-2-yl

Me
Et
H
H
2
H
H
7-Methylbenzofuran-2-yl

Me
Et
H
H
2
H
H
3-Methoxybenzofuran-2-yl

Me
Et
H
H
2
H
H
4-Methoxybenzofuran-2-yl

Me
Et
H
H
2
H
H
5-Methoxybenzofuran-2-yl

Me
Et
H
H
2
H
H
6-Methoxybenzofuran-2-yl

Me
Et
H
H
2
H
H
7-Methoxybenzofuran-2-yl

[0091] The present compound represented by the general formula [I] can be produced according to the processes shown below; however, the compound can be produced also by other processes.

[0092] <Production Process 1> Step 1 to Step 5

[0093] In the above production scheme, R1, R27 R3, R4, R5, R6 and Y have the same definitions as given above; X1 is a halogen atom; R7 is a C1 to C4 alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group; L is a leaving group such as halogen atom, C1 to C4 alkylsulfonyl group, optionally substituted phenylsulfonyl group, optionally substituted benzylsulfonyl group or the like; and x is an integer of 1 or more.

[0094] The above production process is described below in detail on each step.

[0095] (Step 1)

[0096] A sulfide derivative represented by the general formula [5] can be produced by reacting a compound represented by the general formula [1] with a sodium hydrosulfide hydrate represented by the general formula [2] in the presence or absence of a solvent (preferably in an appropriate solvent) in the presence of a salt to produce a base of a mercaptan, represented by the general formula [3] in the reaction system, and then, without isolating the salt of a mercaptan [3], reacting the salt [3] with a halogen derivative represented by the general formula [4] [in this case, a radical-generating agent, for example, Rongalit (trade name): CH2(OH)SO2Na·2H2O may be added].

[0097] The reaction temperature in each reaction is any temperature between 0° C. and the reflux temperature of each reaction system and is preferably 10 to 100° C. The reaction time varies depending upon the compounds used, but is 0.5 to 24 hours.

[0098] With respect to the amounts of the reagents used in each reaction, each of the compound represented by the general formula [2] and the compound represented by the general formula [4] is used in an amount of 1 to 3 equivalents relative to one equivalent of the compound represented by the general formula [1] and, when a base is used, the base is used in an amount of 0.5 to 3 equivalents.

[0099] As the solvent, there can be mentioned, for example, ethers such as dioxane, tetrahydrofuran (THF) and the like; halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethyl sulfoxide, sulfolane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and the like; ketones such as acetone, 2-butanone and the like; nitriles such as acetonitrile and the like; water; and mixtures thereof.

[0100] As the base, there can be mentioned, for example, metal hydrides such as sodium hydride and the like; alkali metal amides such as sodium amide, lithium diisopropylamide and the like; organic bases such as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and the like; alkali metal hydroxides such as sodium; hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as calcium hydroxide, magnesium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate and the like; and metal alcholates such as sodium methoxide, potassium tertbutoxide and the like.

[0101] (Step 2)

[0102] A sulfoxide derivative represented by the general formula [6] can be produced by reacting the sulfide derivative represented by the general formula [5] with an oxidizing agent in an appropriate solvent.

[0103] The reaction temperature is any temperature between 0° C. and the reflux temperature of the reaction system and is preferably 0 to 60° C. The reaction time varies depending upon the compounds used, but is 1 to 72 hours.

[0104] With respect to the amounts of the reagents used in the reaction, the oxidizing agent is used in an amount of 1 to 3 equivalents per equivalent of the compound represented by the general formula [5].

[0105] As the solvent, there can be mentioned, for example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like; ethers such as dioxane, tetrahydrofuran (THF), dimethoxyethane, diethyl ether and the like; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tertbutanol and the like; ketones such as acetone, 2-butanone and the like; nitrites such as acetonitrile and the like; acetic acid; water; and mixtures thereof.

[0106] As the oxidizing agent, there can be mentioned, for example, organic peroxides such as m-chloroperbenzoic acid, performic acid, peracetic acid and the like; and inorganic peroxides such as hydrogen peroxide, potassium permanganate, sodium periodate and the like.

[0107] (Step 3)

[0108] A sulfone derivative represented by the general formula [7] can be produced by reacting the sulfoxide derivative represented by the general formula [6] with an oxidizing agent in an appropriate solvent.

[0109] The reaction temperature is any temperature between 0° C. and the reflux temperature of the reaction system and is preferably 0 to 60° C. The reaction time varies depending upon the compounds used, but is 1 to 72 hours.

[0110] With respect to the amounts of the reagents used in the reaction, the oxidizing agent is used in an amount of 1 to 3 equivalents per equivalent of the compound represented by the general formula [6].

[0111] As the solvent and the oxidizing agent, there can be mentioned the same solvents and oxidizing agents as in the step 2.

[0112] (Step 4)

[0113] The sulfone derivative represented by the general formula [7] can also be produced by reacting the sulfide derivative represented by the general formula [5] with an oxidizing agent of appropriate amount in an appropriate solvent without isolating the sulfoxide derivative represented by the general formula [6].

[0114] The reaction temperature is any temperature between 0° C. and the reflux temperature of the reaction system and is preferably 0 to 60° C. The reaction time varies depending upon the compounds used, but is 1 to 72 hours.

[0115] With respect to the amounts of the reagents used in the reaction, the oxidizing agent is used in an amount of 1 to 3 equivalents per equivalent of the compound represented by the general formula [5].

[0116] As the solvent and the oxidizing agent, there can be mentioned the same solvents and oxidizing agents as in the step 2.

[0117] (Step 5)

[0118] The sulfide derivative represented by the general formula [5] can also be produced by reacting a compound represented by the general formula [8] with a mercaptan derivative represented by the general formula [9] in the presence or absence of a solvent (preferably in an appropriate solvent) in the presence of a base.

[0119] The reaction temperature is any temperature between 0° C. and the reflux temperature of the reaction system and is preferably 10 to 100° C. The reaction time varies depending upon the compounds used, but is 0.5 to 24 hours.

[0120] With respect to the amounts of the reagents used in the reaction, the compound represented by the general formula [9] is used in an amount of 1 to 3 equivalents per-equivalent of the compound represented by the general formula [8], and the base is used in an amount of 0.5 to 3 equivalents.

[0121] As the solvent, there can be mentioned, for example, ethers such as diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran (THF) and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene and the like; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethyl sulfoxide, sulfolane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol-and the like; ketones such as acetone, 2-butanone and the like; nitriles such as acetonitrile and the like; water; and mixtures thereof.

[0122] As the base, there can be mentioned, for example, metal hydrides such as sodium hydride and the like; alkali metal amides such as sodium amide, lithium diisopropylamide and the like; organic bases such as, pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as calcium hydroxide, magnesium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate and the like; and metal alcholates such as sodium methoxide, potassium tertbutoxide and the like.

[0123] A compound of the general formula [8] wherein L is a halogen atom, i.e. a compound [12] can be produced by a process shown by the following step 6. As necessary, a mixture of the compound [12] and a compound [13] is subjected to a separation and purification procedure to isolate the compound [12].

[0124] (Step 6)

[0125] In the above reaction, X1, R1, R2, R3 and R4 have the same definitions as given above.

[0126] The isoxazoline compounds represented by the general formulas [12] and [13] can be produced by reacting an olefin derivative represented by the general formula [10] with an oxime derivative represented by the general formula [11] in the presence or absence of a solvent (preferably in an appropriate solvent) in the presence of a base. When R3 and R4 are each a hydrogen atom, the isoxazoline compound represented by the general formula [12] can be obtained preferentially.

[0127] The reaction temperature is any temperature between 0° C. and the reflux temperature of the reaction system and is preferably 10 to 80° C. The reaction time varies depending upon the compounds used, but is 0.5 hours to 2 weeks.

[0128] With respect to the amounts of the reagents used in the reaction, the compound represented by the general formula [10] is used in an amount of 1 to 3 equivalents per equivalent of the compound represented by the general formula [11].

[0129] As the solvent, there can be mentioned, for example, ethers such as ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethyl ether, dioxane, tetrahydrofuran and the like; halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; acetic acid esters such as ethyl acetate, butyl acetate and the like; water; and mixtures thereof.

[0130] As the base, there can be mentioned, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as calcium hydroxide, magnesium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate and the like; alkali metal acetates such as sodium acetate, potassium acetate and the like; alkali metal fluorides such as sodium fluoride, potassium fluoride and the like; and organic bases such as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and the like.

[0131] In the above production process, the compound represented by the general formula [10], used as an intermediate can be a commercial product or can be produced by a known reaction such as Wittig reaction or the like. The compound represented by the general formula [11] can be produced, for example, by a process described in Liebigs Annalen der Chemie, 985 (1989).

[0132] The compound represented by the general formula [1] can be produced from the above-shown compound represented by the general formula [12] by the following process.

[0133] In the above reaction, X1, R1, R2, R3, R4 and R7 have the same definitions as given above.

[0134] A compound represented by the general formula [15] can be produced by the above-described step 5; a compound represented by the general formula [16] can be produced by the above-described step 2; and the compound represented by the general formula [1] can be produced from the compound [15] by the above-described step 4 or from the compound [16] by the above-described step 3.

[0135] As the solvent, base and oxidizing agent, there can be mentioned the same solvents, bases and oxidizing agents as mentioned in the step 2, 3, 4 or 5.

[0136] A compound represented by the general formula [4] wherein R6 is a hydrogen atom, i.e. a compound represented by the general formula [21] can be produced by the following process.

[0137] In the above reaction, R5, X1 and Y have the same definitions as given above; and R8 is an alkyl group.

[0138] (Step 11)

[0139] A compound represented by the general formula [20] can be produced by reacting a compound [17], [18] or [19] with a reducing agent in a solvent.

[0140] This reaction is conducted ordinarily at −60 to 150° C. for 10 minutes to 24 hours.

[0141] With respect to the amounts of the reagents used in the reaction, the reducing agent is used in an amount of desirably 0.5 to 2 equivalents per equivalent of the compound [17], [18] or [19]; however, the amount can be varied appropriately depending upon the condition of the reaction.

[0142] As the reducing agent, there can be mentioned, for example, metal hydrides (e.g. diisobutyl aluminum hydride) and metal hydrogen complex compounds (e.g. sodium borohydride and lithium aluminum hydride) in production of [20] from [17]; and metal hydrides (e.g. diisobutyl aluminum hydride), metal hydrogen complex compounds (e.g. sodium borohydride and lithium aluminum hydride) and diborane in production of [20] from [18] or [19].

[0143] As the solvent, there can be mentioned, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene and the like; and alcohols such as methanol, ethanol and the like.

[0144] (Step 12)

[0145] A compound represented by the general formula [21] can be produced by reacting the compound [20] with a halogenating agent in a solvent.

[0146] This reaction is conducted ordinarily at −50 to 100° C. for 10 minutes to 24, hours.

[0147] With respect to the amounts of the reagents used in the reaction, the halogenating agent is used in an amount of desirably 1 to 3 equivalents per equivalent of the compound [20]; however, the amount can be varied appropriately depending upon the condition of the reaction.

[0148] As the halogenating agent, there can be mentioned, for example, hydrogen chloride, hydrogen bromide, phosphorus trichloride, phosphorus tribromide and thionyl chloride.

[0149] As the solvent, there can be mentioned, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride and the like; acids such as acetic acid and the like; and ethers such as tetrahydrofuran and the like.

[0150] The compound represented by the general formula [4] can be produced by the following process.

[0151] In the above reaction, R5, R6, X1 and Y have the same definitions as given above.

[0152] The compound represented by the general formula [4] can be produced by reacting a compound [22] with a halogenating agent in a solvent in the presence or absence of a catalyst.

[0153] This reaction is conducted ordinarily at 30 to 150° C. for 10 minutes to 24 hours.

[0154] With respect to the amounts of the reagents used in the reaction, the halogenating agent is used in an amount of desirably 1 to 10 equivalents relative to one equivalent of the compound [22]; however, the amount of the halogenating agent can be varied appropriately depending upon the condition of the reaction. The catalyst is used in an amount of 0.01 to 0.5 equivalent.

[0155] As the halogenating agent, there can be mentioned, for example, halogens such as bromine, chlorine and the like; N-halosuccinimides such as N-bromosuccinimide and the like; and pyridine salts such as pyridinium perbromide and the like.

[0156] As the solvent, there can be mentioned, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethyl sulfoxide, sulfolane and the like; and carboxylic acids such as formic acid, acetic acid and the like.

[0157] As the catalyst, there can be mentioned, for example, benzoyl peroxide, α, α-azobisisobutyronitrile and a mixture thereof.

[0158] A compound represented by the general formula [4] wherein R5 and R6 are each a hydrogen atom, i.e. a compound represented by the general formula [24] can be produced by the following process.

[0159] In the above reaction, X1 and Y have the same definitions as given above.

[0160] The compound represented by the general formula [24] can be produced by reacting a compound [23], hydrogen halide, and formaldehyde or paraformaldehyde in a solvent in the presence or absence of a Lewis acid according to the method described in Org. Synth., III, 557 (1955) or J. Am. Chem. Soc., 72, 2216 (1950), or by reacting the compound [23] with a halogenomethyl ether in a solvent in the presence of a Lewis acid according to the method described in J. Am. Chem. Soc., 97, 6155 (1975).

[0161] This reaction is conducted ordinarily at −40 to 150° C. for 10 minutes to 24 hours.

[0162] With respect to the amounts of the reagents used in the reaction, the hydrogen halide, formaldehyde, paraformaldehyde, Lewis acid or halogenomethyl ether is used in an amount of desirably 1 to 2 equivalents per equivalent of the compound [23]; however, the amount of the former can be varied appropriately depending upon the condition of the reaction.

[0163] As the Lewis acid, there can be mentioned, for example, titanium tetrachloride, zinc chloride, aluminum chloride and zinc bromide.

[0164] As the hydrogen halide, there can be mentioned hydrogen chloride, hydrogen bromide and hydrogen iodide.

[0165] As the solvent, there can be mentioned, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chloroform and the like; aliphatic hydrocarbons such as hexane, heptane and the like; ethers such as dioxane, tetrahydrofuran and the like; carboxylic acids such as acetic acid and the like; carbon disulfide; and mixtures thereof.

[0166] A compound represented by the general formula [19] wherein R5 is a hydrogen atom, i.e. a compound represented by the general formula [25] can be produced by the following process.

[0167] In the above reaction, Y has the same definition as given above.

[0168] The compound represented by the general formula [25] can be produced by reacting the compound [23] with N,N-dimethylformamide in the presence of phosphoryl chloride, phosgene or thionyl chloride in the presence or absence of a solvent according to the Vilsmeier method described in Org. Synth., IV, 831 (1963), or by reacting the compound [23] with a dihalogenomethyl ether in a solvent in the presence of a Lewis acid and then giving rise to hydrolysis according to the method described in Chem. Ber., 93, 88 (1960).

[0169] This reaction is conducted ordinarily at −40 to 150° C. for 10 minutes to 24 hours.

[0170] With respect to the amounts of the reagents used in the reaction, the phosphoryl chloride, phosgene, thionyl chloride, N,N-dimethylformamide, Lewis acid or dihalogenomethyl ether is used in an amount of desirably 1 to 2 equivalents per equivalent of the compound [23]; however, the amount of the former can be varied appropriately depending upon the condition of the reaction.

[0171] As the Lewis acid, there can be mentioned, for example, titanium tetrachloride, tin tetrachloride, zinc chloride, aluminum chloride and zinc bromide.

[0172] As the solvent, there can be mentioned, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chloroform and the like; aliphatic hydrocarbons such as hexane, heptane and the like; ethers such as dioxane, tetrahydrofuran and the like; carboxylic acids such as acetic acid and the like; amides such as N,N-dimethylformamide and the like; carbon disulfide; and mixtures thereof.

[0173] The compounds represented by the general formulas [17], [18], [19] and [20] can be produced by the following process.

[0174] In the above reaction, R5, R8 and Y have the same definitions as given above; and X2 is a chlorine atom, a bromine atom or an iodine atom.

[0175] The compounds represented by the general formulas [17], [18], [19] and [20] can be produced by reacting a compound [26] with a magnesium reagent in the presence or absence of a solvent to obtain a compound [27] and then reacting the compound [27] with an electrophilic reagent according to the method described in J. Org. Chem., 65, 4618 (2000), or by reacting the compound [26] with n-butyl lithium in a solvent to obtain a compound [28] and then reacting the compound [28] with an electrophilic reagent according to the method described in Synth. Commun., 24 (2), 253 (1994).

[0176] This reaction is conducted ordinarily at −100 to 150° C. for 10 minutes to 24 hours.

[0177] With respect to the amounts of the reagents used in the reaction, the amount of the magnesium reagent or the lithium reagent is desirably 1to 5 equivalents per equivalent of the compound [26], and the amount of the electrophilic reagent is desirably 1 to 5 equivalents; however, these amounts can be varied appropriately depending upon the condition of the reaction.

[0178] As the magnesium reagent, there can be mentioned, for example, metal magnesium, isopropyl magnesium bromide and diisopropyl magnesium.

[0179] As the lithium reagent, there can be mentioned, for example, n-butyl lithium, sec-butyl lithium and tert-butyl lithium.

[0180] As the electrophilic reagent, there can be mentioned, for example, esters such as ethyl formate, ethyl cyanoformate, ethyl acetate and the like; acid halides such as acetyl chloride, methyl chloroformate and the like; amides such as N,N-dimethylformamide and the like; aldehydes such as paraformaldehyde and the like; and carbon dioxide.

[0181] As the solvent, there can be mentioned, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chloroform and the like; aliphatic hydrocarbons such as hexane, pentane and the like; ethers such as dioxane, tetrahydrofuran and the like; and mixtures thereof.

[0182] Among compounds represented by the general formulas [4], [17], [18], [19], [20], [22], [23], [26], [29] or [34], a compound represented by the general formula [31] can be produced by the following process.

[0183] In the above reaction, Y has the same definition as given above; R9 is an alkyl group, a haloalkyl group, a cycloalkyl gorup, a cycloalkylalkyl group, an alkoxycarbonylalkyl group, an optionally substituted, benzyl group, an optionally substituted heterocyclic alkyl group, an alkenyl tionally substituted heterocyclic alkyl group, an alkenyl group, an alkynyl group, an alkylsulfonyl group, a haloalkylsulfonyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted phenylsulfonyl group, an acyl group, a haloalkylcabonyl group, an optionally substituted benzylcarbonyl group or an optionally substituted benzoyl group; and L1 is a leaving group such as halogen atom, C1 to C4 alkylsulfonate group, C1 to C4 alkylsulfonyl group, optionally substituted benzylsulfonyl group, optionally substituted phenylsulfonate group, optionally substituted benzylsulfonate group or the like. When R9 is a haloalkyl group, L1 is a leaving group having a higher reactivity than the halogen atom remaining after haloalkylation. For example, when R9 is a CHF2 group, L1 is a chlorine atom or a bromine atom; and when R9 is a CH2CF3 group, L1 is a chlorine atom, a bromine atom, a p-toluenesulfonyloxy group or a methylsulfonyloxy group.

[0184] The compound represented by the general formula [31] can be produced by reacting a compound [29] with a compound [30] in a solvent in the presence of a base.

[0185] This reaction is conducted ordinarily at 0 to 120° C. for 10 minutes to 24 hours.

[0186] With respect to the amounts of the reagents used in the reaction, the amount of the compound [30] is 1 to 20 equivalents per equivalent of the compound [29], and the amount of the base is 1 to 3 equivalents.

[0187] As the base, there can be mentioned, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkali metal hydrides such as potassium hydride, sodium hydride and the like; alkali metal alcoholates such as sodium ethoxide, sodium methoxide and the like; and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene and the like.

[0188] As the solvent, there can be mentioned, for example, halogenated hydrocarbons such as dichloromethane, chloroform and the like; ethers such as diethyl ether, tetrahydrofuran and the like; aromatic hydrocarbons such as benzene, toluene and the like; aliphatic hydrocarbons such as hexane, heptane and the like; ketones such as acetone, methyl isobutyl ketone and the like; esters such as ethyl acetate, methyl acetate and the like; amides such as N-methylpyrrolidone, N,N-dimethylformamide and the like; sulfur compounds such as dimethyl sulfoxide, sulfolane and the like; nitriles such as acetonitrile and the like; and mixtures thereof.

[0189] Among compounds represented by the general formulas [4], [17], [18], [19], [20], [22], [23], [26], [29] or [31], a compound represented by the general formula [34] can be produced by the following process,

[0190] In the above reaction, L1 has the same definition as given above; and R10 is an alkyl group, an alkyl group mono-substituted with a group selected from the substituent group β, a haloalkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an alkylsulfinyl group, an alkylsulfonyl group, an alkylsulfonyl group mono-substituted with a group selected from the substituent group γ, a haloalkylsulfonyl group, an optionally substituted phenyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted phenylsulfonyl group, an optionally substituted aromatic heterocyclicsulfonyl group, an acyl group, a haloalkylcarbonyl group, an optionally substituted benzylcarbonyl group, an optionally substituted benzoyl group, an alkoxycarbonyl group, an optionally substituted benzyloxycarbonyl group, an optionally substituted phenoxycarbonyl group, or a carbamoyl group (its nitrogen atom may be substituted with same or different groups selected from alkyl groups and optionally substituted phenyl group). The carbon atoms of the pyrazole ring may be substituted with 1 to 2 same or different groups selected from the substituent group α.

[0191] The compound represented by the general formula [34] can be produced by reacting a compound [32] with a compound [33] in a solvent in the presence of a base.

[0192] This reaction is conducted ordinarily at 0 to 120° C. for 10 minutes to 24 hours.

[0193] With respect to the amounts of the reagents used in the reaction, the amount of the compound [33] is 1 to 20 equivalents per equivalent of the compound [32], and the amount of the base is 1 to 3 equivalents.

[0194] As the base and the solvent, there can be mentioned, for example, the same bases and solvents as mentioned in production of the compound [31] from the compound [29].

[0195] Introduction of a trifluoromethyl group into Y can be conducted according to or based on, for example, the methods described in J. Chem. Soc. Perkin Trans. 1, 8, 2293-2299 (1990); J. Fluorine Chem., 50 (3), 411-426 (1990); J. Chem. Soc. Chem. Commun., 18, 1389-1391 (1993); J. Chem. Soc. Chem. Commun., 1, 53-54 (1992); Chem. Lett., 1719-1720 (1981); Chem. Pharm. Bull., 38 (9), 2446-2458 (1990); J. Chem. Soc. Perkin Trans. 1, 921-926 (1988); Heterocycles, 37 (2), 775-782 (1994); Tetrahedron Lett., 30 (16), 2133-2136 (1989); J. Chem. Soc. Perkin Trans. 1, 2755-2761 (1980); Hetrocycles, 22 (1), 117-124 (1984); Eur. J. Med. Chem. Chim. Ther., 24, 249-258 (1989); Acta Chem. Scand. Ser. B, 38 (6), 505-508 (1984); J. Fluorine Chem., 21, 495-514 (1982); J. Chem. Soc. Chem. Commun., 10, 638-639 (1988); J. Fluorine Chem., 67 (1), 5-6 (1994); J. Heterocycl. Chem., 31 (6), 1413-1416 (1994); Chem. Heterocycl. Compd., 30 (5), 576-578 (1994); J. Fluorine Chem., 78 (2), 177-182 (1996); J. Heterocycl. Chem., 34 (2), 551-556 (1997); Tetrahedron, 55 (52), 15067-15070 (1999); and Synthesis, 11, 932-933 (1980).

[0196] The compounds represented by the general formulas [4], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [29] and [31] can be produced according to or based on, for example, the methods described in Methoden der Organischen Chemie, E6a, 16-185 (1994) when Y is a furyl group; Methoden der Organischen Chemie, E6a, 186-555 (1994) when Y is a thienyl group; Methoden der Organischen Chemie, E6a, 556-798 (1994) when Y is a pyrrolyl group; Methoden der Organischen Chemie, E8b, 399-763 (1994) and JP-A-2000-219679 when Y is a pyrazolyl group; Methoden der Organischen Chemie, E8a, 45-225 (1993) when Y is an isoxazolyl group; Methoden der Organischen Chemie, E8a, 668-798 (1993) when Y is an isothiazolyl group; Methoden der Organischen Chemie, E8a, 891-1019 (1993) when Y is an oxazolyl group; Methoden der Organischen Chemie, E8b, 1-398 (1994) when Y is a thiazolyl group; Methoden der Organischen Chemie, E8c, 1-215 (1994) when Y is an imidazolyl group; Methoden der Organischen Chemie, E7a, 286-686 (1992) when Y is a pyridyl group; Methoden der Organischen Chemie, E9a, 557-682 (1997) when Y is a pyridazinyl group; Methoden der Organischen Chemie, E9b/1, 1-249 (1998) when Y is a pyrimidinyl group; Methoden der Organischen Chemie, E9b/1, 250-372 (1998) when Y is a pyrazinyl group; Methoden der Organischen Chemie, E9c, 530-796 (1998) when Y is a triazinyl group; Methoden der Organischen Chemie, E8d, 305-405 and 479-598 (1994) when Y is a triazolyl group; Methoden der Organischen Chemie, E8c, 397-818 (1994) when Y is an oxadiazolyl group; Methoden der Organischeh Chemie, E8d, 59-304 (1994) when Y is a thiadiazolyl group; Methoden der Organischen Chemie, E6b1, 33-216 (1994) and Published International Patent Application WO-1997/29105 when Y is a benzofuryl group; Methoden der Organischen Chemie, E6b1, 217-322 (1994) when Y is a benzothienyl group; Methoden der Organischen Chemie, E6b1,546-848 (1994), Methoden der Organischen Chemie, E6b2, 849-1336 (1994) and Published International Patent Application WO-1997/42188-A1 when Y is an indolyl group; Methoden der Organischen Chemie, E8a, 1020-1194 (1993) when Y is a benzoxazolyl group; Methoden der Organischen Chemie, E8b, 865-1062 (1994) when Y is a benzothiazolyl group; Methoden der Organischen Chemie, E8c, 216-391 (1994) when Y is a benzimidazolyl group; Methoden der Organischen Chemie, E8a, 226-348 (1993) when Y is a benzisoxazolyl group; Methoden der Organischen Chemie, E8a, 799-852 (1993) when Y is a benzisothiazolyl group; Methoden der Organischen Chemie, E8b, 764-864 (1994) when Y is an indazolyl group; Methoden der Organischen Chemie, E7a, 290-570 (1991) when Y is a quinolyl group; Methoden der Organischen Chemie, E7a, 571-758 (1991) when Y is an isoquinolyl group; Methoden der Organischen Chemie, E9a, 744-789 (1997) when Y is a phthalazinyl group; Methoden der Organischen Chemie, E9b/2, 93-265 (1998) when Y is a quinoxalinyl group; Methoden der Organischen Chemie, E9b/2, 1-192 (1998) when Y is a quinazolinyl group; Methoden der Organischen Chemie, E9a, 683-743 (1997) when Y is a cinnolinyl group; and Methoden der Organischen Chemie, E8d, 406-478 (1994) when Y is a benzotriazolyl group.

[0197] <Production Process 2>

[0198] In the above reaction, R1, R2, R3, R4, R5 and R6 have the same definitions as given above. The carbon atoms of the pyrazole ring may be substituted with 1 to 2 same or different groups selected from the substituent group α.

[0199] A compound of the present invention represented by the general formula [36] can be produced by reacting a compound [35] of the present invention, produced by the Production Process 1, with an acid in a solvent.

[0200] This reaction is conducted ordinarily at 0 to 120° C. for 10 minutes to 24 hours.

[0201] With respect to the amounts of the reagents used in the reaction, the amount of the acid is 1 to 10 equivalents per equivalent of the compound [35]; however, the amount can be varied appropriately depending upon the condition of the reaction.

[0202] As the acid, there can be mentioned, for example, hydrochloric acid, hydrobromic acid and trifluoroacetic acid.

[0203] As the solvent, there can be mentioned, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethyl sulfoxide, sulfolane and the like; carboxylic acids such as formic acid, acetic acid and the like; and water.

[0204] <Production Process 3>

[0205] In the above reaction, n, L1, R1, R2, R3, R4, R5, R6 and R10 have the same definitions as given above. The carbon atoms of the pyrazole ring may be substituted with 1 to 2 same or different groups selected from the substituent group α.

[0206] A compound of the present invention represented by the general formula [37] can be produced by reacting the compound [36] of the present invention with the compound [33] in a solvent in the presence of a base.

[0207] With respect to the amounts of the reagents used in the reaction, the amount of the compound [33] is 1 to 3 equivalents per equivalent of the compound represented by the general formula [36] and the amount of the base is 1 to 3 equivalents.

[0208] As the solvent, there can be mentioned, for example, ethers such as dioxane, tetrahydrofuran (THF) and the like; halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethyl sulfoxide, sulfolane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; alcohols such as methanol, ethanol propanol, isopropanol, butanol, tert-butanol and the like; ketones such as acetone, 2-butanone and the like; nitrites such as acetonitrile and the like; water; and mixtures thereof.

[0209] As the base, there can be mentioned, for example, metal hydrides such as sodium hydride and the like; alkali metal amides such as sodium amide, lithium diisopropylamide and the like; organic bases such as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as calcium hydroxide, magnesium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate and the like; and metal alcoholates such as sodium methoxide, potassium tert-butoxide and the like.

[0210] <Production Process 4>

[0211] In the above reaction, R1, R2, R3, R4, R5 and R6 have the same definitions as given above; R11 is a hydrogen atom or substituent group α as mentioned above; X3 is a chlorine atom, a fluorine atom, an alkylsulfonyl group or an optionally substituted benzylsulfonyl group; R12 is an alkyl group, a haloalkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, an alkynyl group, an optionally substituted phenyl group, an optionally substituted aromatic heterocyclic group, an alkoxycarbonylalkyl group, an optionally substituted heterocyclic alkyl group or an optionally substituted benzyl group; R13 is an alkyl group, a haloalkyl group, an optionally substituted phenyl group, an optionally substituted aromatic heterocyclic group, an alkoxycarbonylalkyl group or an optionally substituted benzyl group; R14 and R15 may be the same or different and are each a hydrogen atom, an alkyl group, an optionally substituted phenyl group; an acyl group, a haloalkylcarbonyl group, an optionally substituted benzylcarbonyl group, an optionally substituted benzoyl group, an alkylsulfonyl group, a haloalkylsulfonyl group, an optionally substituted benzylsulfonyl group or an optionally substituted phenylsulfonyl group; and Z is an oxygen atom, a sulfur atom, N═CR11a, CR11a═N, CR11a═CR11b or N—R16 (wherein R16 is a hydrogen atom or has the same definition as R10, and R11a and R11b have the same definition as R11.).

[0212] Compounds of the present invention represented by the general formulas [40], [42] and [44] can be produced by reacting a compound of the present invention represented by the general formula [38] with a compound [39], a compound [41] and a compound [43], respectively, in the presence or absence of a solvent and, as necessary, in the presence of a base.

[0213] This reaction is conducted ordinarily,at 20 to 200° C., preferably 30 to 180° C. for 10 minutes to 48 hours and, as necessary, under pressure.

[0214] With respect to the amounts of the reagents used in the reaction, the amount of the compound [39], the compound [41] or the compound [43] is 1 to 20 equivalents per equivalent of the compound [38].

[0215] As the base used as necessary, there can be mentioned, for example, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and the like; alkali metal hydrides such as potassium hydride, sodium hydride and the like; alkali metal alcoholates such as sodium ethoxide, sodium methoxide and the like; and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene and the like.

[0216] As the solvent, there can be mentioned, for example, halogenated hydrocarbons such as chloroform and the like; ethers such as diethyl ether, tetrahydrofuran and the like; aromatic hydrocarbons such as benzene, toluene and the like; aliphatic hydrocarbons such as hexane, heptane and the like; ketones such as acetone, methyl isobutyl ketone and the like; esters such as ethyl acetate and the like; amides such as N-methylpyrrolidone, N,N-dimethylformamide and the like; sulfur compounds such as dimethyl sulfoxide, sulfolane and the like; acetonitrile; and mixtures thereof.

[0217] <Production Process 5>

[0218] In the above reaction, R1, R2, R3, R4, R5, R6, R8, R11 and Z have the same definitions as given above.

[0219] A compound of the present invention represented by the general formula [46] can be produced by reacting a compound [45] of the present invention with an acid in a solvent.

[0220] This reaction is conducted ordinarily at 0 to 120° C. for 10 minutes to 24 hours.

[0221] With respect to the amounts of the reagents used in the reaction, the amount of the acid is desirably 1 to 10 equivalents per equivalent of the compound [45]; however, the amount can be varied appropriately depending upon the condition of the reaction.

[0222] As the acid and the solvent, there can be mentioned the same acids and solvents as mentioned in the Production Process 2.

[0223] <Production Process 6>

[0224] In the above reaction, Y, R1, R2, R3, R4, R5, R6, R9 and L1 have the same definitions as given above. Y may be substituted with 1 to 5 same or different groups selected from the substituent group α.

[0225] A compound represented by the general formula [48] according to the present invention can be produced by reacting a compound [47] of the present invention with the compound [30] in a solvent in the presence of a base.

[0226] This reaction is conducted ordinarily at 0 to 150° C. for 10 minutes to 24 hours.

[0227] With respect to the amounts of the reagents used in the reaction, the amount of the acid is desirably 1 to 1.2 equivalents per equivalent of the compound [47]; however, the amount can be varied appropriately depending upon the condition of the reaction.

[0228] As the base and the solvent, there can be mentioned the same bases and solvents as mentioned in the Production Process 3.

[0229] <Production Process 7>

[0230] In the above reaction, Y, R1, R2, R3, R4, R5 and R6 have the same definitions as given above; and R17 is an alkyl group, an optionally substituted benzyl group or an optionally substituted phenyl group. Y may be substituted with 1 to 5 same or different groups selected from the substituent group α.

[0231] A compound represented by the general formula [50] according to the present invention can be produced by hydrolyzing a compound [49] of the present invention in water or a mixed solvent of water and other solvent in the presence or absence of a base.

[0232] This reaction is conducted ordinarily at 0 to 100° C. for 10 minutes to 24 hours.

[0233] With respect to the amounts of the reagents used in the reaction, the amount of the base, when used, is desirably 1 to 2 equivalents per equivalent of the compound [49]; however, the amount can be varied appropriately depending upon the condition of the reaction.

[0234] As the base, there can be mentioned, for example, inorganic bases such as potassium carbonate, sodium hydride, sodium hydroxide and the like; and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene and the like.

[0235] As the other solvent mixed with water, there can be mentioned, for example, alcohols such as methanol, ethanol and the like; ethers such as tetrahydrofuran and the like; ketones such as acetone, methyl isobutyl ketone and the like; amides such as N,N-dimethylformamide and the like; sulfur compounds such as dimethyl sulfoxide, sulfolane and the like; acetonitrile; and mixtures thereof.

[0236] <Production Process 8>

[0237] In the above reaction, Y, R1, R2, R3, R4, R5, R6 and R8 have the same definitions as given above; and R18 is an alkyl group. Y may be substituted with 1 to 5 same or different groups selected from the substituent group α.

[0238] A compound represented by the general formula [53] according to the present invention can be produced by reacting a compound [51] of the present invention with a compound [52] in a solvent in the presence of a base.

[0239] This reaction is conducted ordinarily at 0 to 100° C. for 10minutes to 24 hours.

[0240] With respect to the amounts of the reagents used in the reaction, the amount of the hydrochloride or sulfate of the compound [52] is desirably 1 to 5 equivalents per equivalent of the compound [51] and the amount of the base is desirably 1 to 10 equivalents; however, these amounts can be varied, appropriately depending upon the condition of the reaction.

[0241] As the base, there can be mentioned, for example, metal carbonates such as potassium carbonate, sodium carbonate and the like; metal acetates such as potassium acetate, sodium acetate and the like; and organic bases such as triethylamine, dimethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and the like.

[0242] As the solvent, there can be mentioned, for example, alcohols such as methanol, ethanol and the like; ethers such as tetrahydrofuran and the like; amides such as N,N-dimethylformamide and the like; water; and mixtures thereof.

[0243] <Production Process 9>

[0244] In the above reaction, Y, R1, R2, R3, R4, R5 and R6 have the same definitions as given above; and R19 and R20 are each a hydrogen atom or an alkyl group. Y may be substituted with 1 to 5 same or different groups selected from the substituent group α.

[0245] A compound represented by the general formula [57] according to the present invention can be produced by reacting the compound [50] of the present invention with thionyl chloride in the presence or absence of a solvent to obtain a compound [55] and then reacting the compound [55] with a compound [56] in the presence or absence of a solvent.

[0246] The reaction from the compound [50] to the compound [55] is conducted ordinarily at 0 to 100° C. for 10 minutes to 24 hours.

[0247] With respect to the amounts of the reagents used in the reaction, the amount of thionyl chloride [54] is desirably 1 to 100 equivalents per equivalent of the compound [50] but it can be varied appropriately depending upon the condition of the reaction.

[0248] As the solvent, there can be mentioned, for example, halogenated hydrocarbons such as dichloromethane, chloroform and the like; ethers such as diethyl ether, tetrahydrofuran and the like; and aromatic hydrocarbons such as benzene, toluene and the like.

[0249] The reaction from the compound [55] to the compound [57] is conducted ordinarily at 0 to 100° C. for 10 minutes to 24 hours.

[0250] With respect to the amounts of the reagents used in the reaction, the amount of the compound [56] is desirably 1 to 100 equivalents per equivalent of the compound [55] but it can be varied appropriately depending upon the condition of the reaction.

[0251] As the solvent, there can be mentioned, for example, the same solvents as used in the reaction from the compound [50] to the compound [55].

[0252] <Production Process 10>

[0253] In the above reaction, Z, R1, R2, R3, R4, R5, R6, R11 and X3 have the same definitions as given above.

[0254] A compound represented by the general formula [59] according to the present invention can be produced by reacting the compound [38] of the present invention with a compound [58] in a solvent.

[0255] This reaction is conducted ordinarily at 0 to 100° C. for 10 minutes to 24 hours.

[0256] With respect to the amounts of the reagents used in the reaction, the amount of the compound [58] is desirably 1 to 2 equivalents per equivalent of the compound [38] but it can be varied appropriately depending upon the condition of the reaction.

[0257] As the solvent, there can be mentioned, for example, ethers such as dioxane, tetrahydrofuran (THF) and the like; halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethyl sulfoxide, sulfolane and the like; ketones such as acetone, 2-butanone and the like; nitriles such as acetonitrile and the like; water; and mixtures thereof.

[0258] <Production Process 11>

[0259] In the above reaction, Y, R1, R2, R3, R4, R5 and R6 have the same definitions as given above; and R21 is an alkyl group, a haloalkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, an alkynyl group, an alkoxycarbonylalkyl group, an optionally substituted heteroalkyl group or an optionally substituted benzyl group. Y may be substituted with 1 to 5 same or different groups selected from the substituent group α.

[0260] A compound represented by the general formula [61] according to the present invention can be produced by reacting the compound [47] of the present invention with a compound [60] in the presence of an azo compound and triphenylphosphine in a solvent according to a known method [Synthesis, 1-28 (1981)].

[0261] This reaction is conducted ordinarily at 0 to 100° C. for 10 minutes to 24 hours.

[0262] With respect to the amounts of the reagents used in the reaction, the amounts of the compound [60], the azo compound and triphenylphosphine are desirably each 1 to 1.5 equivalents per equivalent of the compound [47] but the amounts can be varied appropriately depending upon the condition of the reaction.

[0263] As the solvent, there can be mentioned, for example, ethers such as dioxane, tetrahydrofuran (THF) and the like; halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethyl sulfoxide, sulfolane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; acetonitrile; and mixtures thereof.

[0264] As the azo compound, there can be mentioned, for example, diethyl azodicarboxylate and diisopropyl azodicarboxylate.

[0265] <Production Process 12>

[0266] In the above reaction, X3, n, R1, R2, R3, R4, R5, R6 and Z have the same definitions as given above; and m is an integer of 1 to 4. The carbon atom of the 3-position of the pyrazole ring may be substituted with a group selected from the substituent group α.

[0267] A compound represented by the general formula [63] according to the present invention can be produced by reacting a compound [62] of the present invention in the presence of a base in a solvent.

[0268] This reaction is conducted ordinarily at 0 to 120° C. for 10 minutes to 24 hours.

[0269] With respect to the amounts of the reagents used in the reaction, the amount of the base is desirably 1 to 3 equivalents per equivalent of the compound represented by the general formula [62] but the amount can be varied appropriately depending upon the condition of the reaction.

[0270] As the base and the solvent, there can be mentioned the same bases and solvents as mentioned in the Production Process 3.

[0271] Incidentally, the sulfide compound mentioned in the Production Process 2 or the Production Processes 4 to 11 can be converted into a sulfoxide compound or a sulfone compound by oxidation according to the method described in the Production Process 1. Furthermore, the sulfide compound mentioned in the Production Process 2 or the Production Processes 4 to 11 wherein substituent Y is substituted by C1 to C10 alkylthio group, C1 to C10 alkylthio group mono-substituted with a group selected from the substituent group γ or C1 to C4 haloalkylthio group, can be converted into a sulfoxide compound or a sulfone compound according to the method described in the Production Process 1, by adding equi-molar to excess amount of an oxidizing agent to the sulfide compound; oxidizing the substituent substituted to substituent Y (C1 to C10 alkylthio group, C1 to C10 alkylthio group mono-substituted with a group selected from the substituent group γ or C1 to C4 haloalkylthio group) at the same time, and convert these substituent into a sulfoxide group or a sulfone group.

[0272] Then, specific description is made on the production process of the present compound, the production method of the present herbicide and the application of the present herbicide by way of Examples. Description is also made on the production process of each intermediate of the present compound.

EXAMPLE 1

Production of 3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0001)

[0273] 2.1 g of sodium hydrosulfide hydrate (purity: 70%, 26.2 mmoles) was added to a solution of 2.3 g (13.1 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 20 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto were added 1.8 g (13.1 mmoles) of anhydrous potassium carbonate, 2.0 g (13.1 mmoles) of Rongalit and 3.6 g (10.5 mmoles) of 4-bromomethyl-5-chloro-1-phenyl-3-trifluoromethyl-1R-pyrazole. The resulting mixture was stirred at room temperature for 15 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.7 g (yield: 65.5%) of 3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as white crystals (melting point: 89 to 90° C.).

[0274]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.55-7.50 (5H,m), 4.33 (2H,s), 2.83 (2H,s), 1.45 (6H,s)

EXAMPLE 2

Production of 3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0002)

[0275] 0.63 g of m-chloroperbenzoic acid (purity: 70%, 2.6 mmoles) was added, with ice-cooling, to a solution of 0.4 g (1.0 mmoles) of 3-(5-chloro-1-phenyl-3-trifluoromethyl-1-H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 15 ml of chloroform. The mixture was stirred at room temperature for 22 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting crystals were washed with hexane to obtain 0.4 g (yield: 83.2%) of 3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as white crystals (melting point: 132 to 133° C.).

[0276]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.60-7.51 (5H,m), 4.37 (2H,s), 3.14 (2H,s) 1.53 (6H,s)

EXAMPLE 3

Production of 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0003)

[0277] 0.87 g of m-chloroperbenzoic acid (purity: 70%, 3.54 mmoles) was added, with ice-cooling, to a solution of 0.85 g (2.53 mmoles) of 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 30 ml of chloroform. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.48 g (yield: 53.9%) of 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfinyl)-5,5-dimethyl-2-isoxazoline as a transparent viscous substance.

[0278]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.63-7.60 (2H,m), 7.48-7.37 (3H,m), 4.29 (2H,q), 3.91 (3H,s), 3.12 (1H,d), 2.79 (1H,d), 1.41 (3H,s), 1.35 (3H,s)

Example 4

Production of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline (Present Compound No. 3-0021)

[0279] 9.3 g of sodium hydrosulfide hydrate (purity: 70%, 116.3 mmoles) was added to a solution of 18.7 g (105.7 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline (present compound No. 2-1) dissolved in 300 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. The reaction system was ice-cooled. Thereto was added a solution of 30.3 g (93.8 mmoles) of 4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole dissolved in 200 ml of N,N-dimethylformamide. The mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 13.11 g (yield: 37.4%) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline as a yellow oily substance.

[0280]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.65-7.39 (5H,m), 4.24 (2H,s), 2.81 (2H,s), 1.43 (6H,s)

Example 5

Production of 5,5-dimethyl-3-(5-ehtylthio-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline (Present Compound No. 3-0022)

[0281] 0.2 g (4.0 mmoles) of sodium hydroxide and 1 ml of water were added to a solution of 0.25 g (4.0 mmoles) of ethanethiol dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes. Thereto was added a solution of 0.5 g (1.4 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 5 ml of N,N-dimethylformamide. The resulting mixture was stirred for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.6 g (yield: 100%) of 5,5-dimethyl-3-(5-ethylthio-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.

[0282]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.62-7.47 (5H,m), 4.44 (2H,s), 2.83 (2H,s), 2.50 (2H,q), 1.45 (6H,s), 1.02 (3H,t)

Example 6

Production of 5,5-dimethyl-3-(5-ethylsulfonyl-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline (Present Compound No. 3-0004)

[0283] 1.7 g of m-chloroperbenzoic acid (purity: 70%, 6.7 mmoles) was added, with ice-cooling, to a solution of 0.6 g (1.3 mmoles) of 5,5-dimethyl-3-(5-ethylthio-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of chloroform. The mixture was stirred at room temperature for 16 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting crystals were washed with hexane to obtain 0.6 g (yield: 93.0%) of 5,5-dimethyl-3-(5-ethylsulfonyl-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline as light yellow crystals (melting point: 158 to 160° C.).

[0284]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.58-7.54 (5H,m), 5.16 (2H,s), 3.18 (2H,s), 3.15 (2H,q), 1.55 (6H,s), 1.24 (3H,t)

Example 7

Production of 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline (Present Compound 3-0023)

[0285] 0.8 g (6.7 mmoles) of a 40% aqueous dimethylamine solution was added to a solution of 0.5 g (1.3 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at 100° C. for 9 hours in a sealed tube. Thereto was added 3.0 g (26.6 mmoles) of a 40% aqueous dimethylamine solution, and the resulting mixture was stirred for 9 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g (yield: 80.6%) of 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.

[0286]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.58-7.38 (5H,m), 4.35 (2H,s), 2.82 (2H,s), 2.77 (6H,s), 1.45 (6H,s)

Example 8

Production of 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline (Present Compound 3-0005)

[0287] 0.7 g of m-chloroperbenzoic acid (purity: 70%, 2.7 mmoles) was added, with ice-cooling, to a solution of 0.4 g (1.1 mmoles) of 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of chloroform. The mixture was stirred at room temperature for 20 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting crystals were washed with hexane to obtain 0.2 g (yield: 52.0%) of 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline as a white powder (melting point: 150 to 151° C.).

[0288]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.61-7.38 (5H,m), 4.75 (2H,s), 3.13 (2H,s), 2.76 (6H,s), 1.53 (6H,s)

Example 9

Production of 3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0006)

[0289] 21.8 g of sodium hydrosulfide (purity: 70%, 272.5 mmoles) was added to a solution of 24.1 g (136.0 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 200 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto were added 18.8 g (136.2 mmoles) of anhydrous potassium carbonate and 21.0 g (136.2 mmoles) of Rongalit. The resulting mixture was stirred for 2 hours. Thereto was added, with ice-cooling, 40 g (125 mmoles) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 23.0 g (yield: 57.1%) of 3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as light pink crystals (melting point: 79.0 to 81.0° C.).

[0290]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.24 (2H,s), 2.80 (2H,s), 1.71 (9H,s), 1.43 (6H,s)

Example 10

Production of 3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0007)

[0291] 19.8 g (53.4 mmoles) of 3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline was added to 170 ml of a 25% hydrogen bromide-acetic acid solution. The mixture was stirred at 40 to 50° C. for 2 hours to give rise to a reaction. After the completion of the reaction was confirmed, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 12.0 g (yield: 60.6%) of 3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as light yellow crystals (melting point: 120.0 to 122.0° C.)

[0292]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.26 (2H,s), 2.81 (2H,s), 1.44 (6H,s)

Example 11

Production of 3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0008) and 3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (Present Compound 3-0009)

[0293] 3.1 g (22.5 mmoles) of anhydrous potassium carbonate was added to a solution of 2.3 g (7.3 mmoles) of 3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 50 ml of N,N-dimethylformamide. Thereinto was blown chlorodifluoromethane. The resulting mixture was stirred at 130 to 140° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was pored into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.69 g (yield: 25.8%) of 3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as light yellow crystals (melting point: 41.0 to 42.0° C.) and 0.54 g (yield: 20.2%) of 3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 89.0 to 90.0° C.). 3-(5-Chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline

[0294]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.22 (1H,t), 4.25 (2H,s), 2.80 (2H,s), 0.44 (6H,s) 3-(3-Chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline

[0295]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.19 (1H,t), 4.28 (2H,s), 2.80 (2H,s), 1.44 (6H,s)

Example 12

Production of 3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0010)

[0296] 1.4 g of m-chloroperbenzoic acid (purity: 70%, 8.1 mmoles) was added, with ice-cooling, to a solution of 0.69 g (1.9 mmoles) of 3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed with n-hexane to obtain 0.4 g (yield: 53.3%) of 3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 126.0 to 127.0° C.).

[0297]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.26 (1H,t), 4.68 (2H,s), 3.11 (2H,s), 1.53 (6H,s)

Example 13

Production of 3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0011)

[0298] 1.1 g of m-chloroperbenzoic acid (purity: 70%, 6.4 mmoles) was added, with ice-cooling, to a solution of 0.54 g (1.5 mmoles) of 3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed, with n-hexane to obtain 0.47 g (yield: 79.7%) of 3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 136.0 to 137.0° C.).

[0299]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.23 (1H,t), 4.71 (2H,s), 3.11 (2H,s), 1.53 (6H,s)

Example 14

Production of 5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline (Present Compound No. 3-0024)

[0300] 3.1 g of sodium hydrosulfide hydrate (purity: 70%, 22.0 mmoles) was added to a solution of 3.3 g (17.3 mmoles) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto were added 3.1 g (22.0 mmoles) of anhydrous potassium carbonate, 2.7 g (17.5 mmoles) of Rongalit and 4.0 g (17.5 mmoles) of 4-chloromethyl-3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.8 g (yield: 52.0%) of 5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.

Example 15

Production of 5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline (Present Compound No. 3-0025)

[0301] To 20 ml of a 25% hydrogen bromide acetic acid solution was added 3.3 g (10.6 mmoles) of 5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline. The mixture was stirred at 50° C. for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water. The resulting crystals were collected by filtration, washed with water and dried to obtain 3.1 g (yield: 96.0%) of intended 5,5-dimethyl-3-(3-hydroxy-1-methyl-.5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.

Example 16

Production of 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline (Present Compound No. 3-0026)

[0302] 0.20 g (1.3 mmoles) of anhydrous potassium carbonate and 0.20 g (1.5 mmoles) of ethyl iodide were added to a solution of 0.30 g (1.0 mmoles) of 5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at 50° C. for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.30g (yield: 92.0%) of intended 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.

Example 17

Production of 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline (Present Compound No. 3-0012)

[0303] 0.68 g of m-chloroperbenzoic acid (purity: 70%, 2.76 mmoles) was added, with ice-cooling, to a solution of 0.30 g (0.92 mmoles) of 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of chloroform. The mixture was stirred at room temperature for 5 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting crystals were washed with hexane to obtain 0.24 g (yield: 73.0%) of 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline as white crystals (melting point: 124 to 125° C.).

[0304]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.50 (2H,s), 4.27 (2H,q), 3.86 (3H,s), 3.04 (2H,s), 1.49 (6H,s), 1.39 (3H,t)

EXAMPLE 18

Production of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline (Present Compound No. 3-0027)

[0305] 19.3 g of sodium hydrosulfide (purity: 70%, 344.6 mmoles) was added to a solution of 21.3 g (120.3 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 200 ml of N,N-dimethyl-formamide. The mixture was stirred for 1 hour. Thereto were added 16.7 g (121.0 mmoles) of anhydrous potassium carbonate and 18.6 g (120.7 mmoles) of Rongalit. The resulting mixture was stirred for 2 hours. Thereto was added, with ice-cooling, 31.4 g (120.3 mmoles) of 4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove-the solvent contained therein, to obtain 29.0 g (yield: 90.3%) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylyhio)-2-isoxazoline as a yellow oily substance.

[0306]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.24 (2H,s), 3.90 (3H,s), 2.78 (2H,s), 1.42 (6H,s)

EXAMPLE 19

Production of 5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline (Present Compound No. 3-0028)

[0307] 0.77 g (4.0 mmoles) of sodium methoxide (a 28% methanol solution) was added to a solution of 0.5 g (1.6 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 20 ml of methanol. The mixture was stirred for 4 hours under refluxing, to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.5 g (yield: 96.7%) of 5,5-dimethyl-3-(5-methoxy-2-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline as a yellow oily substance.

[0308]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.26 (2H,s), 4.07 (3H,s), 3.72 (3H,s), 2.80 (2H,s), 1.43 (6H,s)

EXAMPLE 20

Production of 5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline (Present Compound No. 3-0013)

[0309] 1.3 g of m-chloroperbenzoic acid (purity: 70%, 7.5 mmoles) was added, with ice-cooling, to a solution of 0.5 g (1.5 mmoles) of 5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed with n-hexane to obtain 0.31 g (yield: 58.2%). of 5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-2-isoxazoline as a white powder (melting point: 113.0 to 114.0° C.).

[0310]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.60 (2H,s), 4.11 (3H,s), 3.79 (3H,s), 3.10 (2H,s), 1.51(6H,s)

EXAMPLE 21

Production of 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyraxzol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0029)

[0311] 0.2 g (8.3 mmoles) of sodium hydride (purity: 60%) was added, with ice-cooling, to a solution of 0.44 g (3.4 mmoles) of 2-chlorophenol dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto was added 0.7 g (2.2 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline The resulting mixture was stirred at 120 to 130° C. for 5 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.63 g (yield: 66.7%) of 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyraxzol-4-ylmethylthio)-2-isoxazoline-5,5-dimethyl-2-isoxazoline as a yellow oily substance.

EXAMPLE 22

Production of 3-(5-(2-chlorophenoxy)-17-methyl-3trifluoromethyl-1H-pyraxzol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0014)

[0312] 1.0 g of m-chloroperbenzoic acid (purity: 70%, 5.8 mmoles) was added, with ice-cooling, to a solution of 0.63 g (1.5 mmoles) of 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride: solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed with n-hexane to obtain 0.31 g (yield: 45.7%) of 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 67.0 to 70.0° C.).

[0313]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.50-6.91 (4H,m), 4.45 (2H,s), 3.71 (3H,s), 3.03 (2H,s), 1.47 (6H,s)

EXAMPLE 23

Production of 3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0030)

[0314] To a solution of 0.43 g (1.6 mmoles) of triphenylphosphine dissolved in 10 ml of benzene were added 0.14 g (1.6 mmoles) of cyclopentanol, 0.5 g (1.6 mmoles) of 5,5dimethyl-3-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline and 0.7 g (1.6 mmoles) of di-ethyl azodicarboxylate (a 40%, toluene solution). The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting organic layer was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica, gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.52 g (yield: 85.2%) of 3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a colorless transparent oily substance.

EXAMPLE 24

Production of 3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0015)

[0315] 0.85 g of m-chloroperbenzoic acid (purity: 70%, 4.9 mmoles) was added, with ice-cooling, to a solution of 0.52 g (1.4 mmoles) of 3-(5-(cyclopentyloxy-1-methyl-3trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed with n-hexane to obtain 0.2 g (yield: 35.5%) of 3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 113.0 to 114.0° C.).

[0316]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 5.03 (1H,br), 4.60 (2H,s), 3.73 (3H,s), 3.05 (2H,s), 1.88-1.70 (8H,m), 1.50 (6H,s)

EXAMPLE 25

Production of 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0031)

[0317] 0.2 g (4.0 mmoles) of sodium cyanide was added to a solution of 0.5 g (1.6 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred at 40° C. for 1 hour to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.9 g of crude 3-(5cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a yellow oily substance.

[0318]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.30 (2H,s), 4.08 (3H,s), 2.81 (2H,s), 1.43 (6H,s)

EXAMPLE 26

Production of 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0016)

[0319] 2.1 g of m-chloroperbenzoic acid (purity: 70%, 12.2 mmoles) was added, with ice-cooling, to a solution of 0.9 g of 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4ylmethylthio)-5,5-dimethyl-2-isoxazoline (crude compound) dissolved in 50 ml of chloroform. The mixture was stirred for 1 hour and then-at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed with n-hexane to obtain 0.43 g (yield: 76.4%) of 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as a white, powder (melting point: 105.0 to 108.0° C.).

[0320]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.73 (2H,s), 4.16 (3H,s), 3.14 (2H,s), 1.53 (6H,s)

EXAMPLE 27

Production of 3-(3,5-dichloro-1-ethyl-1H-pyrazol-4ylmethylthio)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0032)

[0321] 0.6 g of sodium hydrosulfide (purity: 70%, 10.7 mmoles) was added to a solution of 0.7 g (3.7 mmoles) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto were added 0.51 g (3.7 mmoles) of anhydrous potassium carbonate and 0.56 g (3.6 mmoles) of Rongalit. The resulting mixture was stirred for 2 hours. Thereto was added, with ice-cooling, 0.9 g (3.5 mmoles) of 4-bromomethyl-3,5-dichloro-1-ethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.8 g (yield: 70.8%) of 3-(3,5-dichloro-1-ethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a colorless transparent oily substance.

[0322]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.14 (2H,s), 4.14 (2H, q), 2.81 (2H,s), 1.43 (6H,s), 1.42 (3H,t)

EXAMPLE 28

Production of 3-(3,5-dichloro-1-ethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline (present compound No. 3-0017)

[0323] 2.0 g of m-chloroperbenzoic acid (purity: 70%, 11.6 mmoles) was added, with ice-cooling, to a solution of 0.8 g (2.6 mmoles) of 3-(3,5-dichloro-1-ethyl1H-pyrazol-4ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed with n-hexane to obtain 0.41 g (yield: 46.6%) of 3-(3,5-dichloro-1-ethyl-1H-pyrazol-4ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 105.0 to 107.0° C.)

[0324]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.48 (2H,s), 4.19 (2H,q), 3.05 (2H,s), 1.51 (6H,s), 1.45 (3H,t)

EXAMPLE 29

Production of 3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0020)

[0325] 1.2 g of sodium hydrosulfide hydrate (purity: 70%, 15.0 mmoles) was added to a solution of 1.9 g (10.0 mmoles) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto were added 2.1 g (15.0 mmoles) of anhydrous potassium carbonate, 2.3 g (15.0 mmoles) of Rongalit and 2.6 g (10.0 mmoles) of 4-bromomethyl-5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 15 hours to give, rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.1 g (yield: 68.0%) of 3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a colorless viscous liquid (nD20 =1.5183).

[0326]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 6.70 (1H,t, J=54.2 Hz), 4.24 (2H,s), 3.86 (3H,s) 2.80 (2H,s), 1.42 (6H,-s)

EXAMPLE 30

Production of 3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline (Present Compound No. 3-0018)

[0327] 3.6 g of m-chloroperbenzoic acid (purity:, 70%, 14.5 mmoles) was added, with ice-cooling, to a solution of 1.8 g (5.8 mmoles) of 3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved 30 in 15 ml of chloroform. The mixture was stirred at room temperature for 22 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting crystals were washed with hexane to obtain 1.7 g (yield: 85.9%) of 3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as white crystals (melting point: 78 to 79° C.).

[0328]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 6.80 (1H,t, J=54.8 Hz), 4.60 (2H,s), 3.91 (3H,s), 3.08 (2H,s), 1.51 (6H,s)

EXAMPLE 31

Production of 5,5-dimethyl-3-(5-methyl-3-trifluoromethylisoxazol-4-ylmethylthio)-2-isoxazoline (Present Compound No. 4-0003)

[0329] 0.4 g of sodium hydrosulfide hydrate (purity: 70%, 4.6 mmoles) was added to a solution of 0.4 g (2.3 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto were added 0.3 g (2.3 mmoles) of potassium carbonate, 0.4 g (2.3 mmoles) of Rongalit and 0.5 g (1.8 mmoles) of 4bromomethyl-5-methyl-3-trifluoromethylisoxazole. The resulting mixture was stirred at room temperature for 14 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g (yield: 70.0%) of 5,5-dimethyl-3-(5-methyl-3-trifluoromethylisoxazol-4-ylmethylthio)-2-isoxazoline.

[0330]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.11 (2H,s), 2.77 (2H,s), 2.54 (3H,s), 1.42 (6H,s)

EXAMPLE 32

Production of 5,5-dimethyl-3-(5-methyl-3trifluoromethylisoxazol-4-ylmehtylsulfonyl)-2-isoxazoline (Present Compound No. 4-0001)

[0331] 0.8 g of m-chloroperbenzoic acid (purity: 70%, 3.2 mmoles) was added, with ice-cooling, to a solution of 0.4 g (1.3 mmoles) of 5,5-dimethyl-3-(5-methyl-3-trifluoromethylisoxazol-4-ylmehtylthio)-2-isoxazoline dissolved in 10 ml of chloroform. The mixture was stirred at room temperature for 4 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous-sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting crystals were washed with hexane to obtain 0.4 g (yield: 95.0%) of 5,5-dimethyl-3-(5-methyl-3-trifluoromethylisoxazol-4-ylmehtylsulfonyl)-2-isoxazoline as white crystals (melting point: 135 to 136° C.).

[0332]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.54 (2H,s), 3.11 (2H,s), 2.61 (3H,s), 1.52 (6H,s)

EXAMPLE 33

Production of [(5-chloro-3-methyl-isothiazol-4-yl)methylthio]-5,5-dimethyl-2-isoxazoline (Present Compound No. 4-0004)

[0333] 0.82 g of sodium hydrosulfide (purity: 70%, 10.00 mmoles) was added at the room temperature to a solution of 0.89 g (5.00 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto were added 0.70 g (5.00 mmoles) of anhydrous potassium carbonate, 0.78 g (5.00 mmoles) of Rongalit and 0.91 g (5.00 mmoles) of 5-chloro-4-chloromethyl-3-methylisothiazole. The resulting mixture was stirred at room temperature overnight to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.38 g (yield: quantitative) of [(5-chloro-3-methyl-isothiazol-4-yl)methylthio]-5,5-dimethyl-2-isoxazoline.

EXAMPLE 34

Production of [(5-chloro-3-methyl-isothiazol-4-yl)-methylsulfonyl]-5,5-dimethyl-2-isoxazoline (Present Compound No. 4-0002)

[0334] 2.96 g of m-chloroperbenzoic acid (purity: 70%, 12.00 mmoles) was added, with ice-cooling, to a solution of 1.38 g (5.00 mmoles) of [(5-chloro-3-methyl-isothiazol-4-yl)-methylthio]-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The reside was purified by silica gel column chromatography to obtain 0.65 g (yield: 47.0%) of [(5-chloro-3-methyl-isothiazol-4-yl)-methylsulfonyl]-5,5-dimethyl-2-isoxazoline as a light yellow powder (melting point: 113 to 114° C.)

[0335]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.89 (1H,s), 4.67 (2H,s), 3.05 (2H,s), 2.59 (3H,s) 1.51 (6H,s)

EXAMPLE 35

Production of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylthio]-2-isoxazoline (Present Compound No. 2-0002)

[0336] 0.57 g (6.8 mmoles) of O-methylhydroxylamine hydrochloride and 0.56 g (6.8 mmoles) of sodium acetate were added to a solution of 1.0 g (3.4 mmoles) of 3-(4-acetyl-2,5-dimethylthiophen-3-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 50 ml of ethanol. The mixture was stirred for 5 hours under refluxing, to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g (36.4%) of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-2-ylmethylthio]-2-isoxazoline as a yellow oily substance.

[0337]

1
H-NMR [CDC13/TMS, (ppm)]: 4.21 (2H,s), 3.95 (3H,s), 2.76 (2H,s), 2.38 (3H,s), 2.34 (3H,s), 2.13 (3H,s), 1.42 (6H,s)

EXAMPLE 36

Production of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylsulfonyl]-2-isoxazoline (Present Compound No. 2-0001)

[0338] 0.61 g of m-chloroperbenzoic acid (purity: 70%, 3.5 mmoles) was added, with ice-cooling, to a solution of 0.4 g (1.2 mmoles) of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylthio]-2-isoxazoline dissolved in 30 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.35 g (80%) of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylsulfonyl]-2-isoxazoline as white crystals (melting point: 95.0 to 96.0° C.).

[0339]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.79 (2H,s), 3.95 (3H,s), 2.93 (2H,s), 2.42 (3H,s), 2.37 (3H,s), 2.17 (3H,s), 1.47 (6H,s)

EXAMPLE 37

Production of 5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylthio)-2-isoxazoline (Present Compound No. 7-0003)

[0340] 0.26 g of sodium hydrosulfide (purity: 70%, 4.6 mmoles) was added to a solution of 0.3 g (1.6 mmoles) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 20 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto were added 0.22 g (1.6 mmoles) of anhydrous potassium carbonate and 0.25 g (1.6 mmoles) of Rongalit. The resulting mixture was stirred for 2 hours. Thereto was added, with ice-cooling, 0.3 g (1.3 mmoles) of 3-bromomethyl-4-trifluoromethyl-pyridine. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.45 g (yield: 98.9%) of 5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylthio)-2isoxazoline as a yellow oily substance.

[0341]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.98 (1H,s), 8.70 (1H,d), 7.51 (1H,d), 4.47 (2H,s), 2.79 (2H,s), 1.43 (6H,s)

EXAMPLE 38

Production of 5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylsulfonyl)-2-isoxazoline (Present Compound No. 7-0001) and 5,5-dimethyl-3-(4-trifluoromethyl-pyridine-N-oxide-3-ylmethylsulfonyl)-2-isoxazoline (Present Compound No. 7-0002)

[0342] 0.77 g of m-chloroperbenzoic acid (purity: 70%, 4.5 mmoles) was added, with ice-cooling, to a solution of 0.45 g (1.6 mmoles) of 5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylthio)-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.06 g (yield: 12.0%) of 5,5-dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylsulfonyl)-2-isoxazoline as light yellow crystals (melting point: 77.0 to 80.0° C.) and 0.12 g (yield: 23.1%) of 5,5-dimethyl-3-(4-trifluoromethyl-pyridin-N-oxide-3-ylmethylsulfonyl)-2-isoxazoline as white crystals (melting point: 114.0 to 116.0° C.).

5,5-Dimethyl-3-(4-trifluoromethyl-pyridin-3-ylmethylsulfonyl)-2-isoxazoline

[0343]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.98 (1H,s), 8.84 (1H,d), 7.64 (1H,d), 4.92 (2H,s), 3.09 (2H,s), 1.52 (6H,s)

5,5-Dimethyl-3-(4-trifluoromethyl-pyridin-N-oxide-3ylmethylsulfonyl)-2-isoxazoline

[0344]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.50 (1H,s), 8.25 (1H,d), 7.59 (1H,d), 4.81 (2H,s), 3.12 (2H,s), 1.53 (6H,s)

EXAMPLE 39

Production of 5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylthio]-2-isoxazoline (Present Compound No. 8-0002)

[0345] 0.32 g of sodium hydrosulfide (purity: 70%, 4.00 mmoles) was added, at room temperature, to a solution of 0.35 g (2.00 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 10 ml of dimethylformamide. The mixture was stirred for 2 hours. To the reaction mixture were added 0.28 g (2.00 mmoles) of anhydrous potassium carbonate, 0.31 g (2.00 mmoles) of Rongalit and 0.45 g (2.00 mmoles) of 5-chloromethyl-4-methoxy-6-trifluoromethylpyrimidine. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.55 g (yield: 85.9%) of 5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylthio]-2-isoxazoline.

[0346]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.81 (1H,s), 4.44 (2H,d), 4.12 (3H,s), 2.81 (2H,s), 1.45 (6H,s)

EXAMPLE 40

Production of 5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylsulfonyl]-2-isoxazoline (Present Compound No. 8-0001)

[0347] 1.05 g of m-chloroperbenzoic acid (purity: 70%, 4.28 mmoles) was added, with ice-cooling, to a solution of 0.55 g (1.71 mmoles) of 5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylthio]-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 4 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.45 g (yield: 75.0%) of 5,5-dimethyl-[(4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methylsulfonyl]-2-isoxazoline as white feather-like crystals (melting point: 175 to 176° C.).

[0348]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.89 (1H,s), 5.00 (2H,d), 4.11 (3H,s), 3.11 (2H,s), 1.53 (6H,s)

EXAMPLE 41

Production of 3-(5,5-dimethyl-2-isoxazolin-3-ylthiomethyl)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (Present Compound No. 3-0033)

[0349] A solution of 0.82 g (2.3 mmoles) of 3-[5-chloro-1-(3-hydroxypropyl)-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio]-5,5-dimethyl-2-isoxazole dissolved in 5 ml of N,N-dimethylformamide was dropwise added to a suspension of 0.11 g (2.8 mmoles) of sodium hydride in 15 ml of N,N-dimethylformamide. After the completion of the dropwise addition, the resulting mixture was stirred at room temperature for 30 minutes, then heated to 100° C., and stirred for 1 hour to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous citric acid solution and an aqueous sodium chloride solution, and then dried over magnesium sulfate. The resulting solution was subjected to vacuum distillation to obtain 0.77 g (yield: 100%) of 3-(5,5-dimethyl-2-isoxazolin-3-ylthiomethyl)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine.

[0350]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.37 (2H,t), 4.19 (2H,t), 4.15 (2H,s), 2.80 (2H,s), 2.31 (2H,m), 1.42 (6H,s)

EXAMPLE 42

Production of 3-(5,5-dimethyl-2-isoxazolin-3-ylsulfonylmethyl)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (Present Compound No. 3-0019)

[0351] 1.25 g of m-chloroperbenzoic acid (purity: 70%, 5.1 mmoles) was added, with ice-cooling, to a solution of 0.77 g (2.3 mmoles) of 3-(6,7-dihydro-3-trifluoromethyl-5H-pyrazolo[5,1-b][1,3]oxazin-4yl-methylthio)-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.36 g (yield: 43%) of 3-(5,5-dimethyl-2-isoxazolin-3-ylsulfonylmethyl)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine as a white powder (melting point: 151.0 to 152.0° C.).

[0352]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.47 (2H,s), 4.40 (2H,t), 4.23 (2H,t), 3.09 (2H,s), 2.34 (2H,m), 1.50 (6H,s)

[0353] Compound numbers shown in Tables 11 to 20 are referred to in the Examples.

12TABLE 11

Meltingpoint(° C.)orCom-refractivepoundindexNo.R1R2R3R4nR5R6Z1R22R23R24(n D20)1-0001MeMeHH2HHSMeHH66-681-0002MeMeHH2HHSClMeH87-881-00Q3MeMeHH2HHSHHMe95-971-0004MeMeHH2HHSClHH70-721-0005MeMeHH2HHSHHCl118-1191-0006MeMeHH2HHOHHHImpossible tomeasure1-0007MeMeHH2HHOHHC(=O)OMe124-125

[0354]

13

TABLE 12

Melting point(° C.)

Com-

or

pound

refractive index

No.
R1
R2
R3
R4
n
R5
R6
Z2
R25
R26
R27
(n D20)

2-0001
Me
Me
H
H
2
H
H
S
Me
C(=NOMe)Me
Me
95-96

2-0002
Me
Me
H
H
0
H
H
S
Me
C(=NOMe)Me
Me

2-0003
Me
Me
H
H
2
H
H
S
H
H
H
99-101

2-0004
Me
Me
H
H
2
H
H
S
H
Ome
H
96-97

2-0005
Me
Me
H
H
2
H
H
S
Cl
H
Cl
125-127

2-0006
Me
Me
H
H
2
H
H
S
Cl
Cl
Cl
158-160

2-0007
Me
Me
H
H
2
H
H
S
Me
Me
Me
117-117

2-0008
Me
Me
H
H
2
H
H
S
Me
C(=O)Me
Me
146-148

2-0009
Me
Me
H
H
2
H
H
S
Ph
C(=O)Me
Me
1.5730

2-0010
Me
Me
H
H
2
H
H
S
Ph
C(=NOMe)Me
Me
129-131

2-0011
Me
Me
H
H
2
H
H
S
Cl
C(=O)Ome
Cl
157-158

2-0012
Me
Me
H
H
2
H
H
S
Cl
C(=O)NHMe
Cl
178-180

2-0013
Me
Me
H
H
2
H
H
O
H
H
H
58-61

2-0014
Me
Me
H
H
2
H
H
O
Me
H
Cl
180-181

[0355]

14

TABLE 13

Melting

point(° C.)

or

Com-

refractive

pound

index

No.
R1
R2
R3
R4
n
R5
R6
R29
R28
R30
(n D20)

3-0001
Me
Me
H
H
0
H
H
CF3
Ph
Cl
89-90

3-0002
Me
Me
H
H
2
H
H
CF3
Ph
Cl
132-133

3-0003
Me
Me
H
H
1
H
H
Ph
Me
Cl
Impossible to

measure

3-0004
Me
Me
H
H
2
H
H
CF3
Ph
SO2Et
158-160

3-0005
Me
Me
H
H
2
H
H
CF3
Ph
N(Me)2
150-151

3-0006
Me
Me
H
H
0
H
H
CF3
Bu-t
Cl
79-81

3-0007
Me
Me
H
H
0
H
H
CF3
H
Cl
120-122

3-0008
Me
Me
H
H
0
H
H
CF3
CHF2
Cl
41-42

3-0009
Me
Me
H
H
0
H
H
Cl
CHF2
CF3
89-90

3-0010
Me
Me
H
H
2
H
H
CF3
CHF2
Cl
126-127

3-0011
Me
Me
H
H
2
H
H
Cl
CHF2
CF3
136-137

3-0012
Me
Me
H
H
2
H
H
OEt
Me
CF3
124-125

3-0013
Me
Me
H
H
2
H
H
CF3
Me
OMe
113-114

3-0014
Me
Me
H
H
2
H
H
CF3
Me
O(2-Cl)Ph
67-70

3-0015
Me
Me
H
H
2
H
H
CF3
Me
OPen-c
113-114

3-0016
Me
Me
H
H
2
H
H
CF3
Me
CN
105-108

3-0017
Me
Me
H
H
2
H
H
Cl
Et
Cl
105-107

3-0018
Me
Me
H
H
2
H
H
CHF2
Me
Cl
78-79

3-0019
Me
Me
H
H
2
H
H
CF3
—(CH2)3O—
151-152

3-0020
Me
Me
H
H
0
H
H
CHF2
Me
Cl
1.5183

3-0021
Me
Me
H
H
0
H
H
CF3
Ph
F

3-0022
Me
Me
H
H
0
H
H
CF3
Ph
SEt

3-0023
Me
Me
H
H
0
H
H
CF3
Ph
N(Me)2

3-0024
Me
Me
H
H
0
H
H
OMe
Me
CF3

3-0025
Me
Me
H
H
0
H
H
OH
Me
CF3

3-0026
Me
Me
H
H
0
H
H
OEt
Me
CF3

3-0027
Me
Me
H
H
0
H
H
CF3
Me
F

3-0028
Me
Me
H
H
0
H
H
CF3
Me
OMe

3-0029
Me
Me
H
H
0
H
H
CF3
Me
O(2-Cl)Ph

3-0030
Me
Me
H
H
0
H
H
CF3
Me
OPen-c

3-0031
Me
Me
H
H
0
H
H
CF3
Me
CN

3-0032
Me
Me
H
H
0
H
H
Cl
Et
Cl

3-0033
Me
Me
H
H
0
H
H
CF3
—(CH2)3O—

3-0034
Me
Me
H
H
2
H
H
CF3
H
Cl
138-140

3-0035
Me
Me
H
H
2
H
H
H
Me
Cl
105-106

3-0036
Me
Me
H
H
2
H
H
Me
Me
Me
148-150

3-0037
Me
Me
H
H
2
H
H
Me
Me
Cl
99-101

3-0038
Me
Me
H
H
2
H
H
Cl
Me
Cl
143-145

3-0039
Me
Me
H
H
2
H
H
CF3
Me
Cl
115-116

3-0040
Me
Me
H
H
2
H
H
Cl
Me
CF3
120-122

3-0041
Me
Me
H
H
2
H
H
CF3
Me
F
79-82

3-0042
Me
Me
H
H
2
H
H
CF3
Me
OH
90-92

3-0043
Me
Me
H
H
2
H
H
OMe
Me
CF3
125-126

3-0044
Me
Me
H
H
2
H
H
CF3
Me
OEt
92-94

3-0045
Me
Me
H
H
2
H
H
CF3
Me
OPr-i
69-71

3-0046
Me
Me
H
H
2
H
H
CF3
Me
OPr
82-83

3-0047
Me
Me
H
H
2
H
H
CF3
Me
OBu-t
86-89

3-0048
Me
Me
H
H
2
H
H
CF3
Me
OBu
61-62

3-0049
Me
Me
H
H
2
H
H
CF3
Me
OHex-c
124-125

3-0050
Me
Me
H
H
2
H
H
CF3
Me
OCH2Pr-c
93-94

3-0051
Me
Me
H
H
2
H
H
CF3
Me
OCH2Pen-c
112-113

3-0052
Me
Me
H
H
2
H
H
CF3
Me
OCH2Hex-c
56-59

3-0053
Me
Me
H
H
2
H
H
CF3
Me
OCH2C≡CH
92-93

3-0054
Me
Me
H
H
2
H
H
CF3
Me
OCHF2
129-130

3-0055
Me
Me
H
H
2
H
H
OCHF2
Me
CF3
Impossible to

measure

3-0056
Me
Me
H
H
2
H
H
CF3
Me
OCH2CHF2
89-91

3-0057
Me
Me
H
H
2
H
H
CF3
Me
OCH2CF3
93-95

3-0058
Me
Me
H
H
2
H
H
CF3
Me
OCH2CN
1.4872

3-0059
Me
Me
H
H
2
H
H
CF3
Me
OCH2Ph
79-81

3-0060
Me
Me
H
H
2
H
H
CF3
Me
OPh
122-123

3-0061
Me
Me
H
H
2
H
H
CF3
Me
O(3-Cl)Ph
Impossible to

measure

3-0062
Me
Me
H
H
2
H
H
CF3
Me
O(3-OMe)Ph
1.5059

3-0063
Me
Me
H
H
2
H
H
CF3
Me
O(4-Cl)Ph
68-69

3-0064
Me
Me
H
H
2
H
H
CF3
Me
O(4-Me)Ph
132-133

3-0065
Me
Me
H
H
2
H
H
CF3
Me
O(4-OMe)Ph
115-117

3-0066
Me
Me
H
H
2
H
H
CF3
Me
OC(═O)Me
130-131

3-0067
Me
Me
H
H
2
H
H
CF3
Me
SO2Me
168-169

3-0068
Me
Me
H
H
2
H
H
CF3
Me
SEt
100-102

3-0069
Me
Me
H
H
2
H
H
CF3
Me
SO2Et
107-108

3-0070
Me
Me
H
H
2
H
H
CF3
Me
SO2Ph
166-168

3-0071
Me
Me
H
H
2
H
H
CF3
Me
Me
105-107

3-0072
Me
Me
H
H
2
H
H
Ph
Me
Cl
127-129

3-0073
Me
Me
H
H
2
H
H
CF3
Et
Cl
111-112

3-0074
Me
Me
H
H
2
H
H
Cl
Et
CF3
112-114

3-0075
Me
Me
H
H
2
H
H
CF3
Pr-i
Cl
157-158

3-0076
Me
Me
H
H
2
H
H
Cl
Pr-i
CF3
135-136

3-0077
Me
Me
H
H
2
H
H
CF3
Pr
Cl
89-90

3-0078
Me
Me
H
H
2
H
H
Cl
Pr
CF3
111-113

3-0079
Me
Me
H
H
2
H
H
CF3
Bu-t
H
101-103

3-0080
Me
Me
H
H
2
H
H
CF3
Bu-t
Cl
118-119

3-0081
Me
Me
H
H
2
H
H
CF3
Bu-s
Cl
110-112

3-0082
Me
Me
H
H
2
H
H
Cl
Bu-s
CF3
110-111

3-0083
Me
Me
H
H
2
H
H
CF3
Bu-i
Cl
96-98

3-0084
Me
Me
H
H
2
H
H
Cl
Bu-i
CF3
140-141

3-0085
Me
Me
H
H
2
H
H
CF3
Bu
Cl
89-90

3-0086
Me
Me
H
H
2
H
H
Cl
Bu
CF3
108-110

3-0087
Me
Me
H
H
2
H
H
CF3
CH2Ph
Cl
132-133

3-0088
Me
Me
H
H
2
H
H
Cl
CH2Ph
CF3
118-120

3-0089
Me
Me
H
H
2
H
H
CF3
Pen-c
Cl
130-131

3-0090
Me
Me
H
H
2
H
H
Cl
Pen-c
CF3
147-148

3-0091
Me
Me
H
H
2
H
H
CF3
Hex-c
Cl
151-152

3-0092
Me
Me
H
H
2
H
H
CF3
CH2Pr-c
Cl
93-95

3-0093
Me
Me
H
H
2
H
H
Cl
CH2Pr-c
CF3
129-130

3-0094
Me
Me
H
H
2
H
H
CF3
1-cyclopropylethyl
Cl
87-89

3-0095
Me
Me
H
H
2
H
H
Cl
1-cyclopropylethyl
CF3
121-123

3-0096
Me
Me
H
H
2
H
H
CF3
CH2(2-Methylcyclopropyl)
Cl
102-103

3-0097
Me
Me
H
H
2
H
H
Cl
CH2(2-Methylcyclopropyl)
CF3
118-119

3-0098
Me
Me
H
H
2
H
H
CF3
CH2Bu-c
Cl
94-96

3-0099
Me
Me
H
H
2
H
H
Cl
CH2Bu-c
CF3
141-142

3-0100
Me
Me
H
H
2
H
H
CF3
CH2Pen-c
Cl
127-129

3-0101
Me
Me
H
H
2
H
H
Cl
CH2Pen-c
CF3
146-149

3-0102
Me
Me
H
H
2
H
H
CF3
CH2Hex-c
Cl
152-154

3-0103
Me
Me
H
H
2
H
H
Cl
CH2Hex-c
CF3
115-117

3-0104
Me
Me
H
H
2
H
H
CF3
CH2CH≡CH2
Cl
78-80

3-0105
Me
Me
H
H
2
H
H
Cl
CH2CH≡CH2
CF3
105-106

3-0106
Me
Me
H
H
2
H
H
CF3
CH2C≡CH
Cl
73-74

3-0107
Me
Me
H
H
2
H
H
Cl
CH2C≡CH
CF3
108-109

3-0108
Me
Me
H
H
2
H
H
CF3
CHMeC≡CH
Cl
95-96

3-0109
Me
Me
H
H
2
H
H
Cl
CHMeC≡CH
CF3
116-118

3-0110
Me
Me
H
H
2
H
H
CF3
CH2C≡CMe
Cl
114-115

3-0111
Me
Me
H
H
2
H
H
Cl
CH2C≡CMe
CF3
115-116

3-0112
Me
Me
H
H
2
H
H
CF3
CHF2
OMe
72-74

3-0113
Me
Me
H
H
2
H
H
OMe
CHF2
CF3
108-109

3-0114
Me
Me
H
H
2
H
H
CF3
CH2CHF2
Cl
99-100

3-0115
Me
Me
H
H
2
H
H
Cl
CH2CHF2
CF3
107-109

3-0116
Me
Me
H
H
2
H
H
CF3
CH2CF3
Cl
135-136

3-0117
Me
Me
H
H
2
H
H
Cl
CH2CF3
CF3
112-115

3-0118
Me
Me
H
H
2
H
H
CF3
CH2OMe
Cl
87-89

3-0119
Me
Me
H
H
2
H
H
Cl
CH2OMe
CF3
125-128

3-0120
Me
Me
H
H
2
H
H
CF3
CH2OEt
Cl
97-98

3-0121
Me
Me
H
H
2
H
H
Cl
CH2OEt
CF3
128-129

3-0122
Me
Me
H
H
2
H
H
CF3
CH2CH2OH
Cl
79-81

3-0123
Me
Me
H
H
2
H
H
Cl
CH2CH2OH
CF3
93-94

3-0124
Me
Me
H
H
2
H
H
CF3
CH2CH2OMe
Cl
102-104

3-0125
Me
Me
H
H
2
H
H
Cl
CH2CH2OMe
CF3
118-119

3-0126
Me
Me
H
H
2
H
H
CF3
CH2CH2OEt
Cl
56-59

3-0127
Me
Me
H
H
2
H
H
Cl
CH2CH2OEt
CF3
118-119

3-0128
Me
Me
H
H
2
H
H
CF3
CH2SMe
Cl
103-105

3-0129
Me
Me
H
H
2
H
H
Cl
CH2SMe
CF3
128-129

3-0130
Me
Me
H
H
2
H
H
CF3
CH2SO2Me
Cl
157-159

3-0131
Me
Me
H
H
2
H
H
Cl
CH2SO2Me
CF3
165-166

3-0132
Me
Me
H
H
2
H
H
CF3
CH2CH2SO2Me
Cl
155-157

3-0133
Me
Me
H
H
2
H
H
Cl
CH2CH2SO2Me
CF3
166-168

3-0134
Me
Me
H
H
2
H
H
CF3
CH2CN
Cl
128-129

3-0135
Me
Me
H
H
2
H
H
Cl
CH2CN
CF3
117-118

3-0136
Me
Me
H
H
2
H
H
CF3
CH2C(═O)OEt
Cl
127-129

3-0137
Me
Me
H
H
2
H
H
Cl
CH2C(═O)OEt
CF3
143-145

3-0138
Me
Me
H
H
2
H
H
CF3
CH2C(═O)NH2
Cl
173-174

3-0139
Me
Me
H
H
2
H
H
Cl
CH2C(═O)NH2
CF3
182-183

3-0140
Me
Me
H
H
2
H
H
CF3
CH2C(═O)N(Me)2
Cl
142-143

3-0141
Me
Me
H
H
2
H
H
Cl
CH2C(═O)N(Me)2
CF3
181-182

3-0142
Me
Me
H
H
2
H
H
CF3
CH2C(═O)Me
Cl
148-149

3-0143
Me
Me
H
H
2
H
H
Cl
CH2C(═O)Me
CF3
163-164

3-0144
Me
Me
H
H
2
H
H
CF3
CH2CH2C(=O)Me
Cl
89-91

3-0145
Me
Me
H
H
2
H
H
Me
Ph
Me
140-141

3-0146
Me
Me
H
H
2
H
H
Me
Ph
Cl
124-125

3-0147
Me
Me
H
H
2
H
H
Et
Ph
Cl
112-113

3-0148
Me
Me
H
H
2
H
H
Pr
Ph
Cl
122-123

3-0149
Me
Me
H
H
2
H
H
Pr-i
Ph
Cl
116-117

3-0150
Me
Me
H
H
2
H
H
Bu-t
Ph
Cl
100-102

3-0151
Me
Me
H
H
2
H
H
CF3
Ph
H
111-112

3-0152
Me
Me
H
H
2
H
H
CF3
Ph
Me
129-132

3-0153
Me
Me
H
H
2
H
H
CF3
Ph
CF3
112-113

3-9154
Me
Me
H
H
2
H
H
CF3
Ph
F
90-91

3-0155
Me
Me
H
H
2
H
H
CF3
Ph
OMe
104-106

3-0156
Me
Me
H
H
2
H
H
CF3
Ph
OEt
129-131

3-0157
Me
Me
H
H
2
H
H
CF3
Ph
OPr-i
86-88

3-0158
Me
Me
H
H
2
H
H
CF3
Ph
OPr
117-118

3-0159
Me
Me
H
H
2
H
H
CF3
Ph
OBu-t
105-108

3-0160
Me
Me
H
H
2
H
H
CF3
Ph
OCHF2
90-92

3-0161
Me
Me
H
H
2
H
H
CF3
Ph
SO2Me
167-168

3-0162
Me
Me
H
H
2
H
H
CF3
Ph
CN
113-115

3-0163
Me
Me
H
H
2
H
H
CF3
(2-Cl)Ph
Cl
153-154

3-0164
Me
Me
H
H
2
H
H
CF3
(3-Cl)Ph
Cl
106-107

3-0165
Me
Me
H
H
2
H
H
CF3
(4-Cl)Ph
Cl
142-143

3-0166
Me
Me
H
H
2
H
H
CF3
(4-F)Ph
Cl
135-138

3-0167
Me
Me
H
H
2
H
H
CF3
(4-OMe)Ph
Cl
136-138

3-0168
Me
Me
H
H
2
H
H
CF3
(4-Me)Ph
Cl
129-130

3-0169
Me
Me
H
H
2
H
H
CF3
(4-NO2)Ph
Cl
145-147

3-0170
Me
Me
H
H
2
H
H
CF3
(4-CN)Ph
Cl
91-93

3-0171
Me
Me
H
H
2
H
H
CF3
(4-C(═O)Me)Ph
Cl
133-135

3-0172
Me
Me
H
H
2
H
H
CF3
(4-C(═O)OMe)Ph
Cl
121-124

3-0173
Me
Me
H
H
2
H
H
CF3
Pyrmidin-2-yl
Cl
148-150

3-0174
Me
Me
H
H
2
H
H
CF3
4,6-Dimethoxypyrmidin-
Cl
117-118

2-yl

3-0175
Me
Me
H
H
2
H
H
CF3
SO2Me
Cl
146-148

3-0176
Me
Me
H
H
2
H
H
CF3
SO2Ph
Cl
145-148

3-0177
Me
Me
H
H
2
H
H
CF3
C(═O)Me
Cl
139-131

3-0178
Me
Me
H
H
2
H
H
CF3
C(═O)Ph
Cl
114-117

3-0179
Me
Me
H
H
2
H
H
CF3
C(═O)OMe
Cl
104-106

3-0180
Me
Et
H
H
2
H
H
CF3
Me
Cl
108-110

3-0181
Me
Me
H
H
0
H
H
CHF2
Me
Cl
1.5183

3-0182
Me
Me
H
H
0
H
H
Ph
Me
Cl
76-77

3-0183
Me
Me
H
H
0
H
H
CF3
Bu-t
OMe
1.4831

3-0184
Me
Me
H
H
0
H
H
CF3
CH2C(═O)NH2
Cl
179-180

3-0185
Me
Me
H
H
0
H
H
Me
Ph
Cl
58-60

[0356]

15

TABLE 14

Melting

point(° C.)

or

refractive

index

R2
R3
R4
n
R5
R6
Z3
R31
R32
(n D20 )

Me
H
H
2
H
H
O
CF3
Me
135-136

Me
H
H
2
H
H
S
Me
Cl
113-114

Me
H
H
0
H
H
O
CF3
Me

Me
H
H
0
H
H
S
Me
Cl

Me
H
H
2
H
H
O
Me
Me
178-179

Me
H
H
2
H
H
O
CF3
OEt
89-91

Me
H
H
2
H
H
O
Ph
Me
81-83

Me
H
H
2
H
H
S
Me
OEt
109-111

[0357]

16

TABLE 15

Melting

point(° C.)

Com-

or

pound

refractive index

No.
R1
R2
R3
R4
n
R5
R6
Z4
R33
R34
(n D20)

5-0001
Me
Me
H
H
2
H
H
NMe
Cl
Me
114-115

5-0002
Me
Me
H
H
2
H
H
NMe
Cl
Et
107-108

5-0003
Me
Me
H
H
2
H
H
NMe
CF3
H
142-143

5-0004
Me
Me
H
H
2
H
H
NCHF2
—(CH2)4—
123-125

5-0005
Me
Me
H
H
2
H
H
NPh
Oet
Me
1.5397

5-0006
Me
Me
H
H
2
H
H
NPh
OCHF2
Me
1.5339

5-0007
Me
Me
H
H
2
H
H
NPh
CF3
H
99-101

5-0008
Me
Me
H
H
2
H
H
NPh
OCH2CH═CH2
Me
87-90

5-0009
Me
Me
H
H
1
H
H
NPh
OCH2CH═CH2
Me
1.5702

[0358]

17

TABLE 16

Melting

point(° C.)

Com-

or

pound

refractive index

No.
R1
R2
R3
R4
n
R5
R6
Z5
R35
R36
(n D20)

6-0001
Me
Me
H
H
2
H
H
NCHF2
—(CH2)4—
Impossible to

measure

6-0002
Me
Me
H
H
2
H
H
NPh
H
Oet
107-108

6-0003
Me
Me
H
H
2
H
H
NPh
H
OCHF2
1.5383

6-0004
Me
Me
H
H
2
H
H
O
Me
H
100-102

6-0005
Me
Me
H
H
0
H
H
NCHF2
—(CH2)4—
1.5264

[0359]

18

TABLE 17

Melting

point(° C.)

or

Com-

refractive

pound

index

No.
R1
R2
R3
R4
n
R5
R6
R37
R38
R39
R40

(n D20)

7-0001
Me
Me
H
H
2
H
H
H
CF3
H
H
—
77-80

7-0002
Me
Me
H
H
2
H
H
H
CF3
H
H
N-oxide
114-116

7-0003
Me
Me
H
H
0
H
H
H
CF3
H
H
—

7-0004
Me
Me
H
H
2
H
H
H
H
H
H
—
130-131

7-0005
Me
Me
H
H
2
H
H
H
H
H
H
N-oxide
166-168

7-0006
Me
Me
H
H
2
H
H
Cl
Ph
H
H
—
118-120

7-0007
Me
Me
H
H
2
H
H
OMe
Ph
H
H
—
105-106

7-0008
Me
Me
H
H
2
H
H
Cl
Me
H
H
—
115-116

7-0009
Me
Me
H
H
2
H
H
OMe
Me
H
H
—
134-135

7-0010
Me
Me
H
H
2
H
H
Me
Me
H
H
N-oxide
198-199

7-0011
Me
Me
H
H
2
H
H
Ph
Ph
H
H
—
161-162

7-0012
Me
Me
H
H
1
H
H
H
H
H
H
—
97-99

7-0013
Me
Me
H
H
0
H
H
(2-Chloropyridin-
H
H
H
—
154-155

3-yl)methylthio

[0360]

19

TABLE 18

Melting

point(° C.)

or

refractive

index

R1
R2
R3
R4
n
R5
R6
R41
R42
R43
(n D20)

Me
Me
H
H
2
H
H
H
OMe
CF3
175-176

Me
Me
H
H
0
H
H
H
OMe
CF3

Me
Me
H
H
2
H
H
H
Cl
Cl
119-120

Me
Me
H
H
2
H
H
H
OEt
CF3
94-95

Me
Me
H
H
2
H
H
H
OMe
OMe
186-187

Me
Me
H
H
2
H
H
Me
OMe
CF3
143-144

Me
Me
H
H
2
H
H
OMe
OMe
CF3
144-145

Me
Me
H
H
2
H
H
SMe
OMe
CF3
160-162

Me
Me
H
H
2
H
H
SO2Me
OMe
CF3
144-146

Me
Me
H
H
2
H
H
NH2
OMe
CF3
208-209

Me
Me
H
H
2
Pr-i
H
H
H
CF3
112-113

Me
Me
H
H
0
Pr-i
H
H
H
CF3
1.4986

[0361]

20

TABLE 19

Melting

point(° C.)

or

Com-

refractive

pound

index

No.
R1
R2
R3
R4
n
R5
R6
Y1
(n D20)

9-0001
Me
Me
H
H
2
H
H
Pyridin-2-yl
116-118

9-0002
Me
Me
H
H
2
H
H
Pyridin-2-yl 1-oxide
140-143

9-0003
Me
Me
H
H
2
H
H
Pyridin-4-yl
133-136

9-0004
Me
Me
H
H
2
H
H
Pyridin-4-yl 1-oxide
110-113

9-0005
Me
Me
H
H
2
H
H
1,2,4-Oxadiazol-3-yl
Impossible to

measure

9-0006
Me
Me
H
H
2
H
H
3-Phenyl-1,2,4-oxadiazol-5-yl
153-454

9-0007
Me
Me
H
H
2
H
H
3-Benzyl-1,2,4-oxadiazol-5-yl
108-109

9-0008
Me
Me
H
H
2
H
H
2-Chlorothiazol-4-yl
110-112

9-0009
Me
Me
H
H
2
H
H
1,4-Dimethylimidazol-5-yl
163-164

9-0010
Me
Me
H
H
1
H
H
Pyridin-2-yl
81-82

9-0011
Me
Me
H
H
1
H
H
Pyridin-4-yl
94-96

9-0012
Me
Me
H
H
1
H
H
1,4-Dimethylimidazol-5-yl
138-140

9-0013
Me
Me
H
H
0
H
H
1,4-Dimethylimidazol-5-yl
1.5427

[0362]

21

TABLE 20

Melting

point(° C.)

or

Com-

refractive

pound

index

No.
R1
R2
R3
R4
n
R5
R6
Y1
(n D20)

10-0001
Me
Me
H
H
2
H
H
Benzimidazol-2-yl
171-174

10-0002
Me
Me
H
H
2
H
H
Benzothiophen-2-yl
181-183

10-0003
Me
Me
H
H
2
H
H
3-Chlorobenzothiophen-2-yl
109-112

10-0004
Me
Me
H
H
2
H
H
Benzotriazol-1-yl
206-207

10-0005
Me
Me
H
H
2
H
H
1-Methylindazol-4-yl
128-130

10-0006
Me
Me
H
H
2
H
H
Benzothiazol-2-yl
142-143

10-0007
Me
Me
H
H
2
H
H
Benzothiophen-3-yl
188-191

10-0008
Me
Me
H
H
2
H
H
5-Chlorobenzothiophen-3-yl
129-130

10-0009
Me
Me
H
H
2
H
H
Benzoxazol-2-yl
127-129

10-0010
Me
Me
H
H
2
H
H
3-Methylbenzothiophen-2-yl
161-163

10-0011
Me
Me
H
H
2
H
H
3-Bromobenzothiophen-2-yl
118-119

10-0012
Me
Me
H
H
2
H
H
Benzofuran-2-yl
123-124

10-0013
Me
Me
H
H
2
H
H
2-Methylbenzofuran-7-yl
135-137

10-0014
Me
Me
H
H
2
H
H
3-Bromobenzofuran-2-yl
107-108

10-0015
Me
Me
H
H
2
H
H
Benzothiophen-7-yl
95-97

10-0016
Me
Me
H
H
2
H
H
1-Methylindazol-7-yl
89-90

10-0017
Me
Me
H
H
2
H
H
3-Methylbenzofuran-2-yl
111-112

10-0018
Me
Me
H
H
2
H
H
3-Chloro-1-methylindol-2-yl
162-165

PRODUCTION EXAMPLES OF INTERMEDIATES

Reference Example 1

Production of 3-chloro-5,5-7dimethyl-2-isoxazoline

[0363] 534.0 g (4.0 moles) of N-chlorosuccinimide was gradually added, at 65 to 70° C., to a solution of 182.7 g (2.05 moles) of glyoxylic acid aldoxime dissolved in 2 liters of 1,2-dimethoxyethane. The mixture was refluxed for 1 hour with heating. Thereto were added, with ice-cooling, 1,440.0 g (14.4 moles) of potassium hydrogencarbonate and 10 ml of water. Then, 360.0 g (6.4 moles) of 2-methylpropene was added. The resulting mixture was stirred at room temperature for 24 hours to give rise to a reaction. The reaction mixture was poured into water, followed by extraction with diisopropyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 107.7 g (yield: 40.0%) of 3-chloro-5,5-dimethyl-2-isoxazoline as a yellow viscous liquid.

[0364]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 2.93 (2H,s), 1.47 (6H,s)

Reference Example 2

Production of 3-chloro-5-ethyl-5-methyl-2-isoxazoline.

[0365] 61.9 g (463.4 mmoles) of N-chlorosuccinimide was gradually added, at 60° C., to a solution of 20.6 g (231.7 mmoles) of glyoxylic acid aldoxime dissolved in 500 ml of 1,2-dimethoxyethane. After the addition, the mixture was refluxed for 10 minutes with heating. Thereto were added, with ice-cooling, 50 ml (463.4 mmoles) of 2-methyl-1-butene, 98.9 g (1,622 mmoles) of potassium hydrogencarbonate and 10 ml of water. The resulting mixture was stirred for 12 hours to give rise to a reaction. The reaction mixture was poured into water, followed by extraction with n-hexane. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum-distillation to remove the solvent contained therein, to obtain 13.9 g (yield: 40.6%) of 3-chloro-5-ethyl-5-methyl-2-isoxazoline as a yellow viscous liquid.

[0366]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 2.91 (2H, ABq, J=17.0, Δv=46.1 Hz), 1.73 (2H,q) 1.42 (3H,s), 0.96 (3H,t)

Reference Example 3

Production of 3-benzylthio-5,5-dimethyl-2-isoxazoline

[0367] 3.2 g (23.2 mmoles) of anhydrous potassium carbonate and 3.0 g (22.5 mmoles) of 3-chloro-5,5-dimethyl-2-isoxazoline were added, in a nitrogen atmosphere, to a solution of 2.8 g (22.5 mmoles) of benzylmercaptan dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 3.1 g (yield: 62.0%) of 3-benzylthio-5,5-dimethyl-2-isoxazoline as a yellow oily substance (nD20=1.5521).

[0368]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.24-7.39 (5H,m), 4.26 (2H,s), 2.77 (2H,s), 1.40 (6H,s)

Reference Example 4

Production of 3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline

[0369] 4.6 g of m-chloroperbenzoic acid (purity: 70%, 18.8 mmoles) was added, with ice-cooling, to a solution of 4.1 g (15.0 mmoles) of 3-(2,6-difluorobenzylthio)-5-ethyl-5-methyl-2-isoxazoline dissolved in 50 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.5 g (yield: 34.8%) of 3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline as a white powder (melting point: 30° C. or less).

[0370]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.39-7.28 (1H,m), 7.03-6.94 (2H,m), 4.38 (2H,s), 3.04 (1H, ABq, J=17.2, Δν=85.7 Hz), 3.12 (1H,s), 1.75 (2H,m), 1.44 (3H,S)+1.41 (3H,s), 0.97 (3H,m)

Reference Example 5

Production of 3-(2,6-difluorobenzylsulfonyl)-5-ethyl-5-methyl-2-isoxazoline

[0371] 1.0 g of m-chloroperbenzoic acid (purity: 70%, 4.1 mmoles) was added, with ice-cooling, to a solution of 0.8 g (2.8 mmoles) of 3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline dissolved in 50 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g (yield: 75.0%) of 3-(2,6-difluorobenzylsulfonyl)-5-ethyl-5-methyl-2-isoxazoline as a white powder (melting point: 64 to 65° C.).

[0372]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.36-7.46 (1H,m), 6.98-7.04 (2H,m), 4.73 (2H,s) 3.04 (2H, ABq, J=17.2, Δν=51.1 Hz), 1.77 (2H,q) 1.46 (3H,s), 0.97 (3H,t).

Reference Example 6

Production of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline

[0373] 1.0 kg of an aqueous sodium methanethiolate solution (content: 15%, 2.14 mmoles) was dropwise added, with ice-cooling, to a solution of 143.0 g (1.07 moles) of 3-chloro-5,5-dimethyl-2-isoxazoline dissolved in 500 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 115.0 g (yield: 74.1%) of 5,5-dimethyl-3-methylthio-2-isoxazoline. This residue (741.2 mmoles) was dissolved in 1 liter of chloroform. Thereto was added, with ice-cooling, 392.0 g of m-chloroperbenzoic acid (purity: 70%, 1.59 moles). The resulting mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction, the separated m-chloroperbenzoic acid was removed by filtration. The resulting filtrate was washed with an aqueous sodium hydrogensulfite solution, water, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with diisopropyl ether to obtain 77.6 g (yield: 59.1%) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline as a white powder (melting point: 82 to 84° C.).

[0374]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 3.26 (3H,s), 3.12-(2H,s), 1.51 (6H,s)

Reference Example 7

Production of 5,5-dimethyl-3-ethylthio-2-isoxazoline

[0375] 1,500 ml of an aqueous solution containing 560.0 g (9.0 moles) of ethyl mercaptan and 360.0 g (9.0 moles) of sodium hydroxide was added to a solution containing 3-chloro-5,5dimethyl-2-isoxazoline. The mixture was stirred at 60 to 70° C. for 16 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 270.0 g of crude 5,5-dimethyl-3-ethylthio-2-isoxazoline as a dark red oily substance.

Reference Example 8

Production of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline

[0376] 270.0 g (1.7 moles) of crude oily 5,5-dimethyl-3-ethylthio-2-isoxazoline was dissolved in 1.0 liter of chloroform. Thereto was added, with ice-cooling, 1,050 g of m-chloroperbenzoic acid (purity: 70%, 6.1 moles). The resulting mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the separated m-chloroperbenzoic acid was removed by filtration. The resulting filtrate was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with n-hexane to obtain 133.6 g (yield: 65.4%) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline as a white powder.

Reference Example 9

Production of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol

[0377] 20 g (184.9 mmoles) of phenylhydrazine and 4 ml of concentrated hydrochloric acid were added to a solution of 34.1 g (184.9 mmoles) of ethyl trifluoroacetoacetate dissolved in 500 ml of ethanol. The mixture was refluxed for 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was mixed with water to precipitate crystals. The crystals were collected by filtration, washed with water until the filtrate became neutral, and dried to obtain 37.1 g (yield: 87.9%) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol as ocherous crystals.

[0378]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.68-7.41 (5H,m), 5.86 (1H,s), 3.71 (1H,s)

Reference Example 10

[0379] Production of 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

[0380] 33.6 g (219.1 mmoles) of phosphorus oxychloride was added to 7.7 g (105.2 mmoles) of N,N-dimethylformamide with ice-cooling. Thereto was added, at room temperature, 20 g (87.7 mmoles) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol. The resulting mixture was refluxed for: 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water with ice-cooling, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 19.1 g (yield: 79.1%) of 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde as white crystals.

[0381]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 10.06 (1H,s), 7.57 (5H,s)

Reference Example 11

Production of (5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

[0382] A solution of 0.21 g (5.5 mmoles) of lithium aluminum hydride dissolved in 70 ml of THF was cooled to -30° C. Thereto was gradually added a solution of 3 g (10.9 mmoles) of 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4carboaldehyde dissolved in 30 ml of tetrahydrofuran. The resulting mixture was stirred at −30° C. for 30 minutes to give rise to a reaction. After the completion of the reaction, ethyl acetate was added, followed by stirring. Then, water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.0 g (yield: 99.9%) of (5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol as white crystals.

[0383]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.54-7.51 (5H,m), 4-71 (2H,d) 1.79 (1H,b)

Reference Example 12

Production of 4-bromomethyl-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole

[0384] A solution of 3.0 g (10.9 mmoles) of (5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 60 ml of diethyl ether was cooled to −10° C. Thereto was added 1.0 g (3.8 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.6 g (yield: 95.8%) of 4-bromomethyl-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole as white crystals.

[0385]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.58-7.48 (5H,m), 4.48 (2H,s)

Reference Example 13

Production of 5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

[0386] 10.5 g (180.2 mmoles) of potassium fluoride was added to a solution of 33.0 g (120.1 mmoles) of 5-chloro1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 500 ml of dimethyl sulfoxide. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 26.5 g (yield: 85.0%) of 5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.

[0387]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 9.96 (1H,s), 7.68-7.51 (5H,m)

Reference Example 14

Production of (5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

[0388] To a solution of 1.6 g (41.0 mmoles) of sodium borohydride dissolved in 300 ml of methanol was added, with ice-cooling, a solution of 26.5 g (102.5 mmoles) of 5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 200 ml of methanol. The resulting mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 28.5 g (yield: 100%) of (5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

[0389]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.65-7.41-(5H,m), 4.68 (2H,d), 1.73 (1H,t)

Reference Example 15

Production of 4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole

[0390] A solution of 27.5 g (105.7 mmoles) of (5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 300 ml of diethyl ether was cooled to 0° C. Thereto was added 10.0 g (37.0 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 30.3 g (yield: 88.8%) of 4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole.

[0391]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.66-7.42 (5H,m), 4.44 (2H,s)

Reference Example 16

Production of 1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol

[0392] 373.8 g (3.0 moles) of tert-butylhydrazine hydrochloride and 50 ml of concentrated hydrochloric acid were added to a solution of 552.3 g (3.0 moles) of ethyl trifluoroacetoacetate dissolved in 1,500 ml of ethanol. The mixture was refluxed for 2 days with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with n-hexane to obtain 369.0 g (yield: 59.1%) of 1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol as a white powder.

Reference Example 17

[0393] Production of 1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

[0394] 462.0 g (3.0 moles) of phosphorus oxychloride was added to 87.7 g (1.2 moles) of N,N-dimethylformamide with ice-cooling. Thereto was added, at room temperature, 208.2 g (1.0 moles) of 1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol. The resulting mixture was refluxed for 10 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water, a 5% aqueous sodium hydroxide solution and water in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 131.5 g (yield: 21.7%) of 1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde as white crystals.

[0395]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 9.97 (1H,d), 1.76 (9H,s)

Reference Example 18

Production of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

[0396] A solution of 39.9 g (156.9 mmoles) of (1-tert-butyl-5chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 300 ml of methanol was cooled to 0° C. Thereto was gradually added 6.5 g (172.6 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 37.7 g (yield: 93.6%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

[0397]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.60 (2H,d), 1.72 (9H,s), 1.58 (1H,t)

Reference Example 19

Production of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole

[0398] A solution of 9.2 g (35.7 mmoles) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto was added 11.6 g (42.9 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 10.0 g (yield: 87.3%) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole.

Reference Example 20

Production of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanethiol

[0399] 43.5 g (136.1 mmoles) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole was added to a solution of 21.8 g of sodium hydrosulfide hydrate (purity: 70%, 272.2 mmoles) dissolved in 300 ml of N,N-dimethylformamide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 32.3 g (yield: 87.0%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanethiol.

[0400]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 3.65 (2H,d), 1.90 (1H,t), 1.70 (9H,s)

Reference Example 21

Production of 1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazole

[0401] 15.0 g (108.4 mmoles) of anhydrous potassium carbonate and 19.3 g (135.5 mmoles) of methyl iodide were added, at room temperature, to a solution of 18.8 g (90.3 mmoles) of 1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol dissolved in 100 ml of N,N-dimethylformamide. The mixture was stirred for 15 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 20.0 g (yield: 99.8%) of 1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazole.

Reference Example 22

Production of 1-tert-butyl-4-chloromethyl-5-methoxy-3-trifluoromethyl-1H-pyrazole

[0402] 5.4 g of paraformaldehyde (180.2 mmoles in terms of formaldehyde) and 20 ml of concentrated hydrochloric acid were added to a solution of 20.0 g (90.1 mmoles) of 1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazole dissolved in 90 ml of acetic acid. The mixture was stirred at 60° C. for 30 minutes to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diisopropyl ether. The resulting organic layer was washed with water and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 21.7 g (yield: 89.0%) of 1-tert-butyl-4-chloromethyl-5-methoxy-3-trifluoromethyl-1H-pyrazole.

Reference Example 23

Production of 3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole

[0403] 10.0 g (72.3 mmoles) of anhydrous potassium carbonate and 12.8 g (90.3 mmoles) of methyl iodide were added, at room temperature, to a solution of 10.0 g (60.2 mmoles) of 3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazole dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred for 15 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 9.8 g (yield: 90.7%) of 3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole.

Reference Example 24

Production of 4-chloromethyl-3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole

[0404] 0.45 g of paraformaldehyde (15.0 mmoles in terms of formaldehyde) and 5 ml of concentrated hydrochloric acid were added to a solution of 1.00 g (5.6 mmoles) of 3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole dissolved in 25 ml of acetic acid. The mixture was stirred at 80° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and neutralized with potassium carbonate, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.83 g (yield: 65.0%) of 4-chloromethyl-3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole.

Reference Example 25

Production of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

[0405] 42.0 g (711.9 mmoles) of potassium fluoride was added to a solution of 60.4 g (282.7 mmoles) of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 700 ml of dimethyl sulfoxide. The mixture was stirred at 120 to 140° C. for 5 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 36.8 g (yield: 66.0%) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.

Reference Example 26

Production of (5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

[0406] To a solution of 3.9 g (102.6 mmoles) of sodium borohydride dissolved in 500 ml of methanol was added, with ice-cooling, a solution of 36.8 g (187.6 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 200 ml of methanol. The resulting mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 35.4 g (yield: 95.4%) of (5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

Reference Example 27

Production of 4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole

[0407] A solution of 35.4 g (178.7 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-methanol dissolved in 500 ml of diethyl ether was cooled to −30° C. Thereto was added 54.0 g (199.5 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 31.4 g (yield: 80.8%) of 4-bromomethyl-5-fluoro1-methyl-3-trifluoromethyl-1H-pyrazole.

Reference Example 28

Production of (ethoxycarbonyl)malondialdehyde

[0408] 12.6 g of sodium hydride (purity: 60%, 525.0 mmoles) was washed with diethyl ether by decantation several times and then made into a solution; in 500 ml of diethyl ether. Thereto were added, in a nitrogen current at 0 to 10° C., 194 g (2.6 moles) of ethyl formate and 50 g (262.0 mmoles) of ethyl 3,3-diethoxy-propionate. The resulting mixture was stirred at room temperature for 15 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by washing with diethyl ether. The resulting aqueous layer was allowed to have a pH of 1 with hydrochloric acid, followed by extraction with dichloromethane. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 37.6 g (yield: 100%) of crude (ethoxycarbonyl)malondialdehyde as a dark red oily substance.

[0409]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 9.09 (2H,s), 5.26 (1H,s), 4.27 (2H,q), 1.28 (3H,t)

Reference Example 29

Production of ethyl 1H-pyrazole-4-carboxylate

[0410] 6.2 g (193 mmoles) of hydrazine was added, with ice-cooling, to a solution of 27.6 g (192 mmoles) of (ethoxycarbonyl)malondialdehyde dissolved in 150 ml of ethanol. The mixture was stirred at room temperature for 17 hours to give rise to a reaction. The reaction mixture was subjected to vacuum distillation to remove the ethanol contained therein. The residue was purified by silica gel column chromatography (developing solvent: dichloromethane-ethyl acetate mixed solvent) to obtain 19.4 g (72.4%) of ethyl 1H-pyrazole-4-carboxylate as yellow crystals.

[0411]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.08 (2H,s), 5.30 (1H s), 4.31 (2H,q), 1.36 (3H,t)

Reference Example 30

Production of ethyl 1-ethyl-1H-pyrazole-4-carboxylate

[0412] 3.7 g (26.8 mmoles) of anhydrous potassium carbonate and 4.2 g (26.6 mmoles) of ethyl iodide were added to a solution of 1.5 g (10.7 mmoles) of ethyl 1H-pyrazole-4-carboxylate dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 20hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.6 g (yield: 88.9%) of ethyl 1-ethyl-1H-pyrazole-4-carboxylate as a yellow oily substance.

[0413]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 7.90 (2H,s), 4.28 (2H,q), 4.18 (2H,q), 1.51 (3H,t), 1.35 (3H,t)

Reference Example 31

Production of ethyl 3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate

[0414] In a glass sealed tube were placed 1.6 g (9.5 mmoles) of ethyl 1-ethyl-1H-pyrazole-4-carboxylate and 5.1 g (38.3 mmoles) of N-chlorosuccinimide. There were allowed to react at 160° C. for 6 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, washed with carbon tetrachloride and chloroform, and filtered under vacuum. The resulting filtrate (organic layer) was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.0 g (yield: 44.2%) of ethyl 3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate as a yellow oily substance.

[0415]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.36 (2H,q), 4.21 (2H,q), 1.44 (3H,t), 1.38 (3H,t)

Reference Example 32

Production of (3,5-dichloro-1-ethyl-1H-pyrazol-4-yl)methanol

[0416] A solution of 0.16 g (4.2 mmoles) of lithium aluminum hydride dissolved in 70 ml of tetrahydrofuran was cooled to −50° C. Thereto was gradually added dropwise a solution of 1.0 g (4.2 mmoles) of ethyl 3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate dissolved in 30 ml of tetrahydrofuran. The mixture was stirred at −50° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The resulting mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.82 g (yield: 100%) of (3,5-dichloro-1-ethyl-1H-pyrazol-4-yl)methanol as a brown oily substance.

[0417]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.52 (2H,s), 4.16 (2H,q), 1.43, (3H,t)

Reference Example 33

Production of 4-bromomethyl-3,5-dichloro-1-ethyl-1H-pyrazole

[0418] A solution of 0.82 g (4.2 mmoles) of (3,5-dichloro-1-ethyl-1H-pyrazol-4-yl)methanol dissolved in 50 ml of diethyl ether was cooled to −30° C. Thereto was added 1.3 g (4.8 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.9 g (yield: 81.8%) of 4-bromomethyl-3,5-dichloro-1-ethyl-1H-pyrazole as a yellow oily substance.

[0419]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.33 (2H,s), 4.13 (2H,q), 1.43 (3H,t)

Reference Example 34

Production of 3-difluoromethyl-1-methyl-1H-pyrazol-5-ol

[0420] 8.3 g (180.6 mmoles) of methylhydrazine and 5 ml of concentrated hydrochloric acid were added to a solution of 30.0 g (180.6 mmoles) of ethyl difluoroacetoacetate dissolved in 200 ml of ethanol. The mixture was refluxed for 2 days with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was poured into water. The mixture was allowed to have a pH of 4 using citric acid and extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 8.9 g (yield: 33.3) of 3-difluoromethyl-1-methyl-1H-pyrazol-5-ol.

Reference Example 35

Production of 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde

[0421] 41.6 g (270.1 mmoles) of phosphorus oxychloride was added, with ice-cooling, to 7.9 g (108.0 mmoles) of N,N-dimethylformamide. Thereto was added, at room temperature, 8.0 g (54.0 mmoles) of 3-difluoromethyl-1-methyl-1H-pyrazol-5-ol. The mixture was refluxed for 4 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water, a 5% aqueous sodium hydroxide solution and water in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 7.7 g (yield: 73.3%) of 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde as white crystals.

[0422]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 9.96 (1H,s), 6.90 (1H,t, J=53.6 Hz), 3.93 (3H,s)

Reference Example 36

Production of (5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanol

[0423] A solution of 7.2 g (37.0 mmoles) of 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde dissolved in 100 ml of methanol was cooled to 0° C. Thereto was gradually added 2.1 g (55.5 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.8 g (yield: 52.1%) of (5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanol.

[0424]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 6.70 (1H,t, J=40.8 Hz), 4.63 (2H,s), 3.86 (3H,s), 1.79 (1H,br)

Reference Example 37

Production of 4-bromomethyl-5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole

[0425] A solution of 2.0 g (10.0 mmoles) of (5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanol dissolved in 50 ml of diethyl ether was cooled to −10° C. Thereto was added 1.0 g (3.5 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 2.6 g (yield: 100.0%) of 4-bromomethyl-5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole.

Reference Example 38

Production of Trifluoroacetaldehyde Oxime Etherate

[0426] 24.1 g (347.0 mmoles) of hydroxylamine hydrochloride and 160 ml of water were added to a solution of 50.0 g (347.0 mmoles) of trifluoroacetaldehyde hemiethyl acetal dissolved in 80ml of methanol. Thereto was dropwise added, with ice-cooling, 80.0 g of a 50% aqueous sodium hydroxide solution (1.7 moles). After the completion of the dropwise addition, the resulting mixture was stirred at room temperature for 6 hours to give rise to a reaction. After the completion of the reaction, 10% hydrochloric acid was added for pH adjustment to 6. The resulting mixture was extracted with diethyl ether. The extract was subjected to vacuum distillation to remove the solvent contained therein. The residue was subjected to distillation to obtain 24.7 g (yield: 38.0%) of trifluoroacetaldehyde oxime etherate.

Reference Example 39

Production of Trifluoroacetohydroximoyl Bromide Etherate

[0427] A solution of 38.8 g (218.0 mmoles) of N-bromosuccinimide dissolved in 125 ml of N,N-dimethylformamide was added, with ice-cooling, to a solution of.24.7 g (131.7 mmoles) of trifluoroacetaldehyde oxime etherate dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was subjected to distillation to obtain 33.3 g (yield: 95.0%) of trifluoroacetohydroximoyl bromide etherate as a brown oily substance.

[0428]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 9.30 (1H,s)

Reference Example 40

Production of 4-ethoxycarbonyl-5-methyl-3-trifluoromethylisoxazole

[0429] 2.8 g (51.3 mmoles) of sodium methoxide was added to a solution of 6.7 g (51.3 mmoles) of ethyl acetoacetate dissolved in 80 ml of methanol. Thereto was added, with ice-cooling, a solution of 5.0 g (18.8 mmoles) of trifluorohydroximoyl bromide etherate dissolved in 20 ml of methanol. The resulting mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. Water was added to the residue, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.9 g (yield: 69.0%) of 4-ethoxycarbonyl--5-methyl-3-trifluoromethylisoxazole as a colorless oily substance.

[0430]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.36 (2H,q), 2;77 (3H,s), 1.37 (3H,t)

Reference Example 41

Production of (5-methyl-3-trifluoromethylisoxazol-4-yl)-methanol

[0431] A solution of 0. 16 g (4.2 mmoles) of lithium aluminum hydride dissolved in 15 ml of THF was cooled to 0° C. Thereto was gradually added a solution of 0.93 g (4.2 mmoles) of 4-ethoxycarbonyl-5-methyl-3-trifluoromethylisoxazole dissolved in 15 ml of THF. The mixture was stirred at 0° C. for 1 hour to give rise to a reaction. After the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.5 g (yield: 60.0%) of (5-methyl-3-trifluoromethylisoxazol-4-yl)-methanol.

[0432]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.60 (2H,d), 2.54 (3H,s), 1.66 (1H, br)

Reference Example 42

Production of 4-bromomethyl-5-methyl-3-trifluoromethylisoxazole

[0433] A solution of 0.45 g (2.5 mmoles) of (5-methyl-3-trifluoromethylisoxazol-4-yl)-methanol dissolved in 10 ml of diethyl ether was cooed to 0° C. Thereto was added 0.2 g (8.9 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.5 g (yield: 74.0%) of 4-bromomethyl-5-methyl-3-trifluoromethylisoxazole.

[0434]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.31 (2H,d), 2.51 (3H,s)

Reference Example 43

Production of (5-chloro-3-methyl-isothiazol-4-yl)-methanol

[0435] A solution of 2.06 g (10.0 mmoles) of ethyl 5-chloro-3-methyl-isothiazole-4-carboxylate dissolved in 10 ml of THF was dropwise added at −30° C., to. a solution of 0.42 g (11.0 mmoles) of lithium aluminum hydride dissolved in 10 ml of THF. The mixture was stirred at the same temperature for 1 hour to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added to the reaction mixture. The resulting mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.50 g (yield: 91.5%) of (5-chloro-3-methyl-isothiazol-4-yl)-methanol.

Reference Example 44

Production of 4-chloromethyl-5-chloro-3-methylisothiazole

[0436] 3.26 g (27.44 mmoles) of thionyl chloride was added, at room temperature, to a solution of 1.50 g (9.15 mmoles) of (5-chloro-3-methyl-isothiazol-4-yl)-methanol dissolved in 10 ml of chloroform. The mixture was stirred for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein, to obtain 1.67 g (yield: quantitative) of 4-chloromethyl-5-chloro-3-methylisothiazole.

Reference Example 45

Production of Methyl 4-trifluoromethylnicotinate

[0437] 6.7 g (48.6 mmoles) of anhydrous potassium carbonate and 6.9 g (48.6 mmoles) of methyl iodide were added to a solution of 4.6 g (24.1 mmoles) of 4-trifluoromethylnicotinic acid dissolved in 70 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.77 g (yield: 56.1%) of methyl 4-trifluoromethylnicotinate as a yellow oily substance.

[0438]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 9.11 (1H,s), 8.92 (1H,d), 7.64 (1H,d), 3.99 (3H,s)

Reference Example 46

Production of (4 trifluoromethylpyridin-3-yl)-methanol

[0439] A solution of 0.37 g (9.7 mmoles) of lithium aluminum hydride dissolved in 100 ml of THF was cooled to −50° C. Thereto was gradually added dropwise a solution of 2.0 g (9.8 mmoles) of methyl 4-trifluoromethylnicotinate dissolved in 30 ml of THF. The mixture was stirred at −50° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g (yield: 35.3%) of (4-trifluoromethylpyridin-3-yl)-methanol as a yellow oily substance.

[0440]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 9.00 (1H,s), 8.73 (1H,d), 7.51 (1H,d), 4.95 (2H,s)

Reference Example 47

Production of 3-bromomethyl-4-trifluoromethylpyridine

[0441] A solution of 0.6 g (3.4. mmoles) of (4-trifluoromethylpyridin-3-yl)-methanol dissolved in 50 ml of diethyl ether was cooed to −30° C. Thereto was added 1.4 g (5.2 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.61 g (yield: 75.3%) of 3-bromomethyl-4-trifluoromethylpyridine as a yellow oily substance.

[0442]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.88 (1H,s), 8.73 (1H,d), 7.54 (1H,d), 4.63 (2H,s)

Reference Example 48

Production of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine

[0443] 77.5 g (945.0 mmoles) of anhydrous sodium acetate was added, at room temperature, to a solution of 49.2 g (300.0 mmoles) of 4-hydroxy-6-trifluoromethylpyrimidine dissolved in 600 ml of acetic acid. Thereto was gradually added 50.3 g (315 mmoles) of bromine at 45° C. The resulting mixture was stirred at the same temperature for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with n-hexane to obtain 38.9 g (yield: 53.4%) of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine.

Reference Example 49

Production of 5-bromo-4-chloro-6-trifluoromethylpyrimidine

[0444] 24.3 g (100.0 mmoles) of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine was suspended in 18.5 g (120.0 mmoles) of phosphorus oxychloride. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water gradually, followed by extraction with chloroform. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 21.5 g (yield: 82.4%) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine.

Reference Example 50

Production of 5-bromo-4-methoxy-6-trifluoromethylpyrimidine

[0445] 16.7 ml of sodium methoxide (a 28% methanol solution, 86.4 mmoles) was added, at room temperature, to a solution of 21.5 g (82.2 mmoles) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine dissolved in 100 ml of methanol. The mixture was stirred to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with n-hexane to obtain 19.2 g (yield: 91.0%) of 5-bromo-4-methoxy-6-trifluoromethylpyrimidine.

Reference Example 51

Production of 5-bromo-4-ethoxy-6-trifluoromethylpyrimidine

[0446] 0.94 g (13.77 mmoles) of sodium ethoxide was added, at room temperature, to a solution of 3.00 g (11.48 mmoles) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine dissolved in 50 ml of ethanol. The mixture was stirred to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 2.44 g (yield: 82.9%) of 5-bromo-4-ethoxy-6-trifluoromethylpyrimidine.

Reference Example 52

Production of 4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde

[0447] 30.0 ml of n-butyllithium (a 1.6 moles/liter n-hexane solution, 48.0 mmoles) was gradually added, at −65 to −60° C., to a solution of 10.3 g (40.0 mmoles) of 5-bromo-4-methoxy-6-trifluoromethylpyrimidine dissolved in 100 ml of tetrahydrofuran. The mixture was stirred for 30 minutes. Thereto was added 3.6 g (48.0 mmoles) of ethyl formate at the same temperature. The resulting mixture was stirred at the same temperature for 3 hours to give rise to a reaction. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.3 g (yield: 15.8%) of 4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.

[0448]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 10.41 (1H,q), 8.91 (1H,s), 4.18 (3H,s)

Reference Example 53

Production of 4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde

[0449] A solution of 5.76 g (21.3 mmoles) of 5-bromo-4-ethoxy-6-trifluoromethylpyrimidine dissolved in 250 ml of THF was cooled to −78° C. Thereto was dropwise added 22.6 ml of n-butyllithium (a 1.6 moles/liter n-hexane solution, 36.1 mmoles). The mixture was stirred for 40 minutes. Thereto was added 2.7 g (45.1 mmoles) of methyl formate. The resulting mixture was stirred for 1.5 hours to give rise to a reaction. After the completion of the reaction, an aqueous ammonium chloride solution was added. The mixture was extracted with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 3.82 g (yield:. 81.6%) of 4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.

[0450]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 10.41 (1H,s), 8.95 (1H,s), 4.63 (2H,q), 1.48 (3H,t)

Reference Example 54

Production of (4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methanol

[0451] 0.24 g (6.3 mmoles) of sodium borohydride was gradually added, at room temperature, to a solution of 1.3 g (6.3 mmoles) of 4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde dissolved in 30 ml of methanol. The mixture was stirred for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.42 g (yield: 32.1%) of (4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methanol

[0452]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.93 (1H,s), 4.81 (2H,s), 4.13 (3H,s), 2.26 (1H,br)

Reference Example 55

Production of (4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol

[0453] A solution of 3.82 g (17.2 mmoles) of 4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde dissolved in 50 ml of methanol was added, with ice-cooling, to a solution of 1.7 g (45.7 mmoles) of sodium borohydride dissolved in 50 ml of methanol. The mixture was stirred at 0° C. for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.77 g (yield: 97.8%) of (4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol

[0454]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.80 (1H,s), 4.81 (2H,s), 4.59 (2H,q), 2.28 (1H,b), 1.48 (3H,t)

Reference Example 56

Production of 5-chloromethyl-4-methoxy-6-trifluoromethylpyrimidine

[0455] 1.19 g (10.1 mmoles) of thionyl chloride was added, at room temperature, to a solution of 0.42 g (2.02 mmoles) of (4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methanol. The mixture was stirred for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.45 g (yield: quantitative) of 5-chloromethyl-4-methoxy-6-trifluoromethylpyrimidine.

Reference Example 57

Production of 5-bromomethyl-4-ethoxy-6-trifluoromethylpyrimidine

[0456] A solution of 3.77 g (17.0 mmoles) of (4-ethoxy-6-trifluoromethylpyrimidine-5-yl)-methanol dissolved in 50 ml of diethyl ether was cooled to 0° C. Thereto was added 2.0 g (7.2 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour. The resulting salt was dissolved using methanol. The resulting mixture was stirred for 1 hour to give rise to a reaction. The reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain crude 5-bromomethyl-4-ethoxy-6-trifluoromethylpyrimidine.

[0457]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.79 (1H,s), 4.61 (2H,q), 4.55 (2H,s), 1.49 (3H,t)

Reference Example 58

Production of (2-chloro-4-methylpyridin-3-yl)methanol

[0458] A solution of 1.9 g (10.0 mmoles) of methyl 2-chloro-4-methylnicotinate dissolved in 5.0 ml of THF was gradually added, at −65 to −60° C., to a suspension of 0.4 g (10.0 mmoles) of lithium aluminum hydride in 30 ml of tetrahydrofuran. The mixture was stirred for 30 minutes and at −20° C. for 1 hour to give rise to a reaction. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.6 g (yield: 38.2%) of (2-chloro-4-methylpyridin-3-yl)methanol.

[0459]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.19 (1H,d), 7.08 (1h,d), 4.85 (2H,s), 2.49 (3H,s)

Reference Example 59

Production of 3-acetyl-4-chloromethyl-2,5-dichlorothiophene

[0460] 33 ml of titanium tetrachloride (a 2 moles/liter dichloromethane solution, 66.0 mmoles) was dropwise added, at 10° C. with ice-cooling, to a solution of 5.0 g (32;4 mmoles) of 3-acetyl-2,5-dichlorothiophene dissolved in 26 ml (323.0 mmoles) of chloromethyl methyl ether. The mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction action. After the completion of the reaction, the reaction mixture was poured into ice water, followed by extraction with chloroform. The resulting organic layer was washed with sodium bicarbonate, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1) to obtain 2.6 g (yield: 39.7%) of 3-acetyl-4-chloromethyl-2,5-dichlorothiophene as yellow crystals.

[0461]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 4.70 (2H,s), 2.56 (3H,s), 2.54 (3H,s), 2.39 (3H,s)

Reference Example 60

Production of 3-bromo-2-bromomethylbenzofuran

[0462] 2.7 g (15.3 mmoles) of N-bromosuccinimide and 0.4 g (2.7 mmoles) of azobisisobutyronitrile were added to a solution of 2.8 g (13.3 mmoles) of 3-bromo-2-mehtylbenzofuran dissolved in 30 ml of monochlorobenzene. The mixture was stirred at 80° C. for 30 minutes to give rise to a reaction. After confirmation of the disappearance of the raw materials, the reaction mixture was cooled to room temperature. The insolubles were removed by filtration. The filtrate was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.0 g (yield: 79.0%) of 3-bromo-2-bromomethylbenzofuran.

Reference Example 61

Production of ethyl 1-difluoromethyl-1H-pyrazole-4-carboxylate

[0463] 6.0 g (43.5 mmoles) of anhydrous potassium carbonate was added to a solution of 3.0 g (21.4 mmoles) of ethyl 1H-pyrazole-4-carboxylate dissolved in 100 ml of N,N-dimethylformamide. Thereinto was blown chlorodifluoromethane. The resulting mixture was stirred at 130 to 140° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.67 g (yield: 41.0%) of ethyl 1-difluoromethyl-1H-pyrazole-4-carboxylate as a colorless transparent oily substance.

[0464]

1
H-NMR [CDCl3/TMS, δ (ppm)]: 8.32 (1H,s), 8.04 (1H,s), 7.20 (1H,t), 4.32 (2H,q), 1.37 (3H,t)

[0465] The herbicide of the present invention contains, as the active ingredient, an isoxazoline derivative represented by the genera formula [I] or a salt thereof.

[0466] In using the compound of the present invention as a herbicide, the present compound may be used by itself. It can also be used in the form of a powder, a wettable powder, an emulsifiable concentrate, a flowable, fine granules, granules, etc. by mixing with a carrier, a surfactant, a dispersant, a adjuvant, etc. all generally used in formulation.

[0467] As the carrier used in formulation, there can be mentioned, for example, solid carriers such as talc, bentonite, clay, kaolin, diatomaceous earth, white carbon, vermiculite, calcium carbonate, slaked lime, siliceous sand, ammonium sulfate, urea and the like; and liquid carriers such as isopropyl alcohol, xylene, cyclohexane, methylnaphthalene and the like.

[0468] As the surfactant and the dispersant, there can be mentioned, for example, metal salts of alkylbenzenesulfonic acids, metal salts of dinaphthylmethanedisulfonic acid, salts of alcohol sulfates, alkylarylsulfonic acid salts, ligninsulfonic acid salts, polyoxyethylene glycol ether, polyoxyethylene alkyl aryl ethers, monoalkylates of polyoxyethylene sorbitan and the like. As the adjuvant, there can be mentioned, for example, carboxymethyl cellulose, polyethylene glycol and gum arabic. The present herbicide, when used, is diluted to an appropriate concentration and sprayed or applied directly.

[0469] The herbicide of the present invention can be used by spraying on foliage, application to soil, application on water surface, etc. The amount of the active ingredient used is determined appropriately so as to meet the application purpose. The content of the active ingredient is appropriately determined according to the purpose. When the present compound is formulated as a powder or granules, the content is in a range of 0.01% to 10% by weight, preferably 0.05% to 5% by weight. When the present compound is made into an emulsifiable concentrate or a wettable powder, the amount is appropriately determined in a range of 1 to 50% by weight, 5 to 30% by weight. When the present compound is made into a flowable, the amount is appropriately determined in a range of 1 to 40% by weight, preferably 5 to 30% by weight.

[0470] The amount of the present herbicide used varies depending upon the kind of the compound used, the target weed, the tendency of weed emergence, the environmental conditions, the type of the herbicide used, etc. When the present herbicide is used per se as in the case of a powder or granules, the amount is appropriately selected in a range of 1 g to 50 kg, preferably 10 g to 10 kg per 1 hectare in terms of the active ingredient. When the present herbicide is used in a liquid form as in the case of an emulsifiable concentrate, a wettable powder or a flowable, the amount is appropriately selected in a range of 0.1 to 50,000 ppm, preferably 10 to 10,000 ppm.

[0471] The compound of the present invention may be mixed as necessary with an insecticide, a fungicide, other herbicide, a plant growth-regulating agent, a fertilizer, etc.

[0472] Next, formulation from the present compound is described specifically by showing typical examples of formulation. The kinds of compounds and additives and their compounding ratios are not restricted to those shown below and can be varied widely. In the following description, “parts” refer to parts by weight.

[0473] <Formulation 1> Wettable Powder

[0474] 10 parts of a compound (3-0006) were mixed with 0.5 part of polyoxyethylene octylphenyl ether, 0.5 part of a sodium salt of a β-naphthalenesulfonic acid-formalin condensate, 20 parts of diatomaceous earth and 69 parts of clay. The mixture was mixed and pulverlized to obtain a wettable powder.

[0475] <Formulation 2> Flowable

[0476] 20 parts of a coarsely ground compound (3-0006) were dispersed in 69 parts of water. Thereto were added 4 parts of a polyoxyethylene styryl phenylether sulfate, 7 parts of ethylene glycol and 200 ppm, relative to the herbicide produced, of Silicone AF-118N (a product of Asahi Chemical Industry, Co. Ltd.). The resulting mixture was stirred for 30 minutes using a high-speed stirrer and then ground using a wet grinder to obtain a flowable.

[0477] <Formulation 3> Emulsion

[0478] To 30 parts of a compound (3-0006) were added 60 parts of an equal volume mixture of xylene and isophorone and 10 parts of a surfactant mixture of a polyoxyethylene sorbitan alkylate, a polyoxyethylene alkylaryl polymer and an alkylaryl sulfonate. The resulting mixture was stirred sufficiently to obtain an emulsifiable concentrate.

[0479] <Formulation 4> Granules

[0480] There were mixed 10 parts of a compound (3-0006), 80 parts of an extender which was a 1:3 mixture of talc and bentonite, 5 parts of white carbon and 5 parts of a surfactant mixture of a polyoxyethylene sorbitan alkylate, a polyoxyethylene alkylaryl polymer and an alkylaryl sulfonate. To the mixture were added 10 parts of water. The resulting mixture was kneaded sufficiently to form a paste. The paste was extruded through the eyes (diameter: 0.7 mm) of a sieve. The extrudate was dried and cut into a length of 0.5 to 1 mm to obtain granules.

[0481] Next, Application Examples of the present compound are described to show the effect of the present compound.

Application Example 1

[0482] Test for Herbicidal Effect by Paddy Field Soil Treatment

[0483] A paddy field soil was filled in a plastic pot of 100 cm2 and subjected to puddling. Then, seeds of Echinochloa oryzicola Vasing and Monochoria vaginalis (Murm. f.) Presl var. plantaginea (Roxb.) Solms-Laub. were sowed and water was filled in a depth of 3 cm. Next day, wettable powders produced in accordance with the Formulation 1 were diluted with water and dropped on the water surface. The application amount of each wettable powder was 1,000 g per 1 hectare in terms of the active ingredient. Then, breeding was made in a greenhouse, and the herbicidal effect of each wettable powder was examined at the 21st day from the treatment in accordance with the standard shown in Table 21. The results are shown in Table 22.

22TABLE 21Herbicidal effect (extent of growth inhibition) orIndexphytotoxicity5A herbicidal effect or phytotoxicity of 90%4A herbicidal effect or phytotoxicity of 70% to lessthan 90%3A herbicidal effect or phytotoxicity of 50% to lessthan 70%2A herbicidal effect or phytotoxicity of 30% to lessthan 50%1A herbicidal effect or phytotoxicity of 10% to lessthan 30%0A herbicidal effect or phytotoxicity of 0% to lessthan 10%

[0484]

23

TABLE 22

Monochoria vaginalis

Echinochloa

(Burm. F.) Presl var.

Active ingredient

oryzicola

plantaginea (Roxb.)

Compound No.
(g/ha)
Vasing
Solms-Laub.

1-0001
1000
5
5

1-0002
1000
5
5

1-0003
1000
5
5

1-0004
1000
5
5

1-0005
1000
5
5

2-0001
1000
5
5

2-0003
1000
5
5

2-0004
1000
5
5

2-0005
1000
5
5

2-0006
1000
5
5

2-0008
1000
5
5

2-0011
1000
5
5

2-0012
1000
5
5

3-0002
1000
5
5

3-0004
1000
5
5

3-0009
1000
5
5

3-0013
1000
5
5

3-0014
1000
5
5

3-0015
1000
5
5

3-0016
1000
5
5

3-0034
1000
5
5

3-0035
1000
5
5

3-0037
1000
5
5

3-0038
1000
5
5

3-0039
1000
5
5

3-0040
1000
5
5

3-0041
1000
5
5

3-0044
1000
5
5

3-0047
1000
5
5

3-0049
1000
5
5

3-0051
1000
5
5

3-0054
1000
5
5

3-0059
1000
5
5

3-0060
1000
5
5

3-0061
1000
5
5

3-0070
1000
5
5

3-0072
1000
5
5

3-0073
1000
5
5

3-0074
1000
5
5

3-0081
1000
5
5

3-0082
1000
5
5

3-0083
1000
5
5

3-0084
1000
5
5

3-0085
1000
5
5

3-0086
1000
5
5

3-0087
1000
5
5

3-0088
1000
5
5

3-0089
1000
5
5

3-0090
1000
5
5

3-0091
1000
5
5

3-0100
1000
5
5

3-0101
1000
5
5

3-0102
1000
5
5

3-0103
1000
5
5

3-0114
1000
5
5

3-0115
1000
5
5

3-0117
1000
5
5

3-0118
1000
5
5

3-0119
1000
5
5

3-0120
1000
5
5

3-0121
1000
5
5

3-0124
1000
5
5

3-0125
1000
5
5

3-0126
1000
5
5

3-0127
1000
5
5

3-0128
1000
5
5

3-0129
1000
5
5

3-0130
1000
5
5

3-0131
1000
5
5

3-0134
1000
5
5

3-0135
1000
5
5

3-0137
1000
5
5

3-0139
1000
5
5

3-0144
1000
5
5

3-0153
1000
5
5

3-0156
1000
5
5

3-0160
1000
5
5

3-0173
1000
5
5

3-0174
1000
5
5

3-0176
1000
5
5

3-0177
1000
5
5

3-0178
1000
5
5

3-0180
1000
5
5

4-0001
1000
5
5

4-0002
1000
5
5

4-0005
1000
5
5

4-0007
1000
5
5

4-0008
1000
5
5

5-0001
1000
5
5

5-0002
1000
5
5

5-0003
1000
5
5

5-0005
1000
5
5

5-0006
1000
5
5

5-0007
1000
5
5

6-0003
1000
5
5

6-0004
1000
5
5

7-0004
1000
5
5

7-0006
1000
5
5

7-0008
1000
5
5

7-0009
1000
5
5

8-0001
1000
5
5

8-0012
1000
5
5

9-0001
1000
5
5

9-0003
1000
5
5

9-0005
1000
5
5

9-0006
1000
5
5

9-0008
1000
5
5

10-0002
1000
5
4

10-0003
1000
5
5

10-0004
1000
5
5

10-0005
1000
5
5

10-0006
1000
5
5

10-0008
1000
5
5

10-0009
1000
5
5

10-0011
1000
5
5

10-0012
1000
5
5

10-0013
1000
5
5

10-0014
1000
5
5

10-0015
1000
5
5

10-0016
1000
5
5

10-0017
1000
5
5

10-0018
1000
5
5

Application Example 2

[0485] Test for Herbicidal Effect by Upland Field Soil Treatment

[0486] An upland field soil was filled in a plastic pot of 80 cm2. Seeds of Echinochloa crus-galli (L.) Beauv. var. crusgalli and Setaria viridis (L.) Beauv. were sowed, followed by covering with the same soil. Wettable powders produced in accordance with the Formulation 1 were diluted with water and sprayed uniformly on the soil surface using a small sprayer, in an amount of 1,000 liters per 1 hectare so that the amount of each active ingredient became 1,000 g per 1 hectare. Then, breeding was made in a greenhouse, and the herbicidal effect of each wettable powder was examined at the 21st day from the treatment in accordance with the standard shown in Table 21. The results are shown in Table 23.

24TABLE 23Echinochloacurs-galli (L.)Active ingredientBeauv. Var.Setaria viridisCompound No.(g/ha)crus-galli(L.) Beauv. 1-0001100055 1-0002100055 1-0003100055 1-0004100055 1-0005100055 1-0006100054 2-0001100055 2-0003100055 2-0004100055 2-0005100055 2-0006100054 2-0007100044 2-0008100055 2-0011100054 2-0012100055 3-0002100055 3-0004100055 3-0006100044 3-0008100055 3-0009100055 3-0012100055 3-0013100055 3-0015100055 3-0016100055 3-0017100055 3-0018100055 3-0019100055 3-0020100055 3-0034100055 3-0035100055 3-0036100055 3-0037100055 3-0038100055 3-0039100055 3-0040100055 3-0041100055 3-0043100055 3-0044100055 3-0047100055 3-0048100055 3-0049100055 3-0050100055 3-0053100055 3-0054100055 3-0054100055 3-0056100055 3-0059100055 3-0060100055 3-0063100055 3-0070100044 3-0072100055 3-0073100055 3-0074100055 3-0081100055 3-0082100055 3-0083100055 3-0084100055 3-0085100055 3-0086100055 3-0087100055 3-0088100054 3-0091100055 3-0114100055 3-0115100055 3-0117100055 3-0118100055 3-0119100055 3-0120100055 3-0121100055 3-0124100055 3-0125100055 3-0126100055 3-0127100055 3-0128100055 3-0129100055 3-0130100055 3-0131100055 3-0134100055 3-0135100055 3-0136100055 3-0137100055 3-0138100045 3-0139100055 3-0142100055 3-0143100055 3-0144100055 3-0153100055 3-0156100055 3-0173100055 3-0174100055 3-0180100055 4-0001100055 4-0001100043 4-0002100055 4-0005100055 4-0006100055 4-0007100055 4-0008100055 5-0001100055 5-0002100055 5-0003100055 5-0005100054 5-0006100055 5-0007100055 6-0001100055 6-0003100055 6-0004100055 7-0002100055 7-0004100054 7-0006100055 7-0007100054 7-0008100055 7-0009100055 8-0001100055 8-0004100055 8-0005100054 8-0007100055 9-0001100055 9-0005100054 9-0006100054 9-0007100044 9-000810005510-000310005510-000410005510-000510005510-000610005410-000910005510-001210005410-001310005510-001410005510-001510005510-001610005410-001710005510-0018100055

Application Example 3

[0487] Test for Herbicidal Effect by Upland Foliage Treatment

[0488] A sand was filled in a plastic pot of 80 cm2. Seeds of Echinochloa crus-galli (L.) Beauv. var. crus-galli and Setaria viridis (L.) Beauv. were sowed. Breeding was made in a greenhouse for 2 weeks. Wettable powders produced in accordance with the Formulation 1 were diluted with water and sprayed on the whole foliage of plants from above the plants using a small sprayer in an amount of 1,000 liters per 1 hectare so that the amount of each active ingredient became 1,000 g per 1 hectare. Then, breeding was made in the greenhouse, and the herbicidal effect of each wettable powder was examined at the 14th day from the treatment in accordance with the standard shown in Table 21. The results are shown in Table 24.

25TABLE 24Echinochloacurs-galli (L.)Active ingredientBeauv. Var.Setaria viridisCompound No.(g/ha)crus-galli(L.) Beauv.1-00011000541-00041000542-00011000542-00031000542-00041000542-00081000552-00111000543-00081000443-00101000543-00111000543-00131000553-00151000543-00351000443-00361000443-00371000543-00381000553-00391000553-00441000543-00491000443-00731000543-00741000543-00761000543-00771000543-00811000443-00821000443-00831000443-00841000443-00851000443-00861000443-00921000443-01041000543-01051000543-01061000543-01071000553-01151000543-01181000543-01191000543-01201000553-01441000554-00021000544-00051000545-00011000545-00021000555-00031000545-00071000556-00041000547-00081000557-00091000448-00011000549-00011000449-00051000449-0008100044

Industrial Applicability

[0489] The compound represented by the general formula [I] according to the present invention shows an excellent herbicidal effect over a wide period from before germination to growth, to various weeds causing problems in upland fields, for example, broadleaf weeds [e.g. Polygonum lapathifolium L. subsp. nodosum (Pers.) Kitam., Amaranthus viridis L., Chenopodium album L., Stellaria media (L.) Villars, Abutilon theophrasti Medik., Sida spinosa, Sesbaria exaltata, ipomoea spp. and Xanthium strumarium L.], perennial or annual cyperaceous weeds [e.g. Cyperus rotundus L., Cyperus esculentus, Kyllinga brevifolia Rottb. subsp. leiolepis (Fraxch. et Savat.) T. Koyama, Cyperus microiria Steud., and Cyperus iria L.], and Gramineae weeds [e.g. Echinochloa crus-galli (L.) Beauv. var. crus-galli, Digitaria ciliaris (Retz.) Koeler, Setaria viridis (L.) Beauv., Poa annua L., Sorghum halepense (L.) Pers., Alopecurus aequalis Sobol. var. amurensis (Komar.) Ohwi, and Avena fatua L.]. Further, the present compound shows a herbicidal effect also to weeds emerging in paddy fields, i.e. annual weeds [e.g. Echinochloa oryzicola Vasing., Cyperus difformis L., Mohochoria vaginalis (Burm. f.) Presl. var. plantaginea (Roxb.) Solms-Laub., and Lindernia procumbens] and perennial weeds [e.g. Sagittaria trifolia L., Sagittaria pygmaea Miq., Cyperus serotinus Rottb., Eleocharis kuroguwai Ohwi, and Scirpus juncoides Roxb. subsp. hotarui (Ohwi) T. Koyama, Alisma canaliculatum].

[0490] The herbicide of the present invention has high safety to crops, particularly to. rice, wheat, barley, corn, grain sorghum, soybean, cotton, sugar beat, etc.

Isoxazoline derivative and herbicide comprising the same as active ingredient

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