Anthelmintic agents and their use

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

SUMMARY OF THE INVENTION

[0007]

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

I. Compounds Of This Invention

[0027]
The substituents in Formula (I) are defined as follows:

A. Preferred Embodiments of R1, R2, R3, R4, and R5

B. Preferred Embodiments of X1

[0061]

[0063]
In other embodiments, for example, X¹ is —N(CH₃)—. Here, the compound is encompassed by the following formula:

[0064]

C. Preferred Embodiments of X2

[0069]

[0071]

[0079]

[0081]

[0083]

D. Preferred Embodiments of X3

[0087]

[0089]

E. Preferred Embodiments of X4

[0094]

[0096]
In other embodiments, X⁴ is —CH₂— substituted with two methyl groups. In such embodiments, the compound is encompassed by the following formula:

[0097]

[0099]
In other embodiments, X⁴ is —CH₂— substituted with two trifluoromethyl groups. In such embodiments, the compound is encompassed by the following formula:

[0100]

[0102]

[0104]

[0106]
In other embodiments, X³ is —C(O)—, and X⁴ is —NH— substituted with C₁-C₆-alkyl. For example, in some such embodiments, X⁴ is —N(CH₃)—. In those embodiments, the compound is encompassed by the following formula:

[0107]

F. Preferred Embodiments of X5

[0111]
In other embodiments, X⁵ is —C(S)—. In those embodiments, the compound is encompassed by the following formula:

[0112]
In still other embodiments, X⁵ is —S(O)₂—. In those embodiments, the compound is encompassed by the following formula:

[0113]
In still yet other embodiments, X⁵ is —CH₂—. In such embodiments, the compound is encompassed by the following formula:

[0114]

[0116]
In other embodiments, X⁵ is —C(O)—, and X⁴ is —NH— substituted with C₁-C₆-alkyl. For example, in some such embodiments, X⁴ is —N(CH₃)—. In those embodiments, the compound is encompassed by the following formula:

[0117]

G. Preferred Embodiments of X6

[0132]

TABLE I
Example of X6 Linkers

Any such group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C₁-C₆-alkyl, hydroxy, C₁-C₆-alkoxy, oxo, and thiocarbonyl.

[0134]

[0136]

[0138]

[0140]

[0143]
Any such group is optionally substituted with one or more substituents independently selected from the group consisting of C₁-C₆-alkyl and oxo.

[0149]
In those embodiments, the compound is encompassed by the following formula:

[0150]

[0152]
In such embodiments, the compound is encompassed by the following formula:

[0153]

[0155]
In such embodiments, the compound is encompassed by the following formula:

[0156]
In some such embodiments, X⁵ is —C(O)—, and the compound is encompassed by the following formula:

[0157]
In other embodiments, X⁵ is —C(O)—, X⁴ is —N(H)—, and the compound is encompassed by the following formula:

[0158]
In still other embodiments, X⁵ is —C(O)—, X⁴ is —N(CH₃)—, and the compound is encompassed by the following formula:

[0159]

[0161]
In such embodiments, the compound is encompassed by the following formula:

[0162]

[0164]
In such embodiments, the compound is encompassed by the following formula:

[0165]

[0167]
In such embodiments, the compound is encompassed by the following formula:

[0168]

[0170]
In such embodiments, the compound is encompassed by the following formula:

[0171]

[0173]
In such embodiments, the compound is encompassed by the following formula:

[0174]

[0178]
Here, the compound is encompassed by the following formula:

[0179]
In other embodiments, for example, one or two of the ring atoms are substituted with methyl. To illustrate, the linker in such an instance may be, for example:

[0180]
Here, the compound is encompassed by the following formula:

[0181]
To further illustrate, the linker may alternatively be, for example:

[0182]
Here, the compound is encompassed by the following formula:

[0183]
In some such embodiments, for example, X⁵ is —C(O)—. In those embodiments, the compound is encompassed by the following formula:

[0184]

H. Preferred Embodiments of X7

[0188]

I. Preferred Embodiments of Z1, Z2, Z3, Z4, and Z5

[0192]

[0196]

[0198]

[0200]

[0202]

[0204]

[0208]

[0211]

[0220]

J. Examples of Various Specific Preferred Embodiments

[0223]
In some such embodiments:

• • [0224] Two of R¹, R², R³, R⁴, and R⁵ are each hydrogen. The remaining three of R¹, R², R³, R⁴, and R⁵ are each independently selected from the group consisting of hydrogen, halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl, phenoxy, and benzyloxy. The C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl, phenoxy, and benzyloxy are optionally substituted with one or more substituents independently selected from the group consisting of halogen and halo-C₁-C₆-alkyl.
  • [0225] X¹ is selected from the group consisting of −0 and —NH—. The —NH— is optionally substituted with C₁-C₆-alkyl.
  • [0226] X² is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl.
  • [0227] X³ is selected from the group consisting of —CH₂—, —O—, and —C(O)—.
  • [0228] X⁴ is selected from the group consisting of —CH₂— and —NH—. The —CH₂— is optionally substituted with up to two independently selected C₁-C₆-alkyl. The —NH— is optionally substituted with C₁-C₆-alkyl.
  • [0229] X⁵ is selected from the group consisting of —CH₂—, —C(S)—, —C(O)—, and —S(O)₂—.
  • [0230] X⁶ is selected from the group of linkers consisting of:

[0231]

• • [0232] Here, any such group is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl and oxo.
  • [0233] Z¹ is CH substituted with a substituent selected from the group consisting of halogen, nitro, cyano, C₁-C₆-alkoxy, and C₁-C₆-alkylsulfanyl. The C₁-C₆-alkoxy and C₁-C₆-alkylsulfanyl are optionally substituted with one or more independently selected halogen.
  • [0234] Z² is CH optionally substituted with halo-C₁-C₆-alkyl.
  • [0235] One of Z³, Z⁴, and Z⁵ is CH. The remaining two of Z³, Z⁴, and Z⁵ are independently selected from the group consisting of N and CH, wherein the CH is optionally substituted with C₁-C₆-alkyl.
    Compounds encompassed by these embodiments include, for example:

[0236]

[0238]
In some such embodiments:

• • [0239] Two of R¹, R², R³, R⁴, and R⁵ are each hydrogen. The remaining three of R¹, R², R³, R⁴, and R⁵ are each independently selected from the group consisting of hydrogen, halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl, phenoxy, and benzyloxy. The C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl, phenoxy, and benzyloxy are optionally substituted with one or more substituents independently selected from the group consisting of halogen and halo-C₁-C₆-alkyl.
  • [0240] X¹ is —NH— optionally substituted with C₁-C₆-alkyl.
  • [0241] X³ is selected from the group consisting of —CH₂—, —O—, and —C(O)—.
  • [0242] X⁴ is selected from the group consisting of —CH₂— and —NH—. The —CH₂— is optionally substituted with up to two independently selected C₁-C₆-alkyl. The —NH— is optionally substituted with C₁-C₆-alkyl.
  • [0243] X⁵ is selected from the group consisting of —CH₂— and —C(O)—.
  • [0244] X⁶ is selected from the group of linkers consisting of:

[0245]

• • [0246] Any such group is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl and oxo.
  • [0247] Z¹ is CH substituted with a substituent selected from the group consisting of halogen, nitro, cyano, C₁-C₆-alkoxy, and C₁-C₆-alkylsulfanyl. The C₁-C₆-alkoxy and C₁-C₆-alkylsulfanyl are optionally substituted with one or more independently selected halogen.
  • [0248] Z² is CH optionally substituted with halo-C₁-C₆-alkyl.
  • [0249] Z³, Z⁴, and Z⁵ are each CH.
    In some of these embodiments, X⁷ is a bond such that the compound corresponds in structure to the following formula:

[0250]
Compounds encompassed by these embodiments include, for example:

[0251]

[0253]
In some such embodiments:

• • [0254] Three of R¹, R², R³, R⁴, and R⁵ are each independently selected from the group consisting of hydrogen, chloro, fluoro, cyano, nitro, methyl, tent-butyl, n-propyl, trifluoromethyl, ethyl, methoxy, ethoxy, trifluoromethoxy, trifluoromethylsulfanyl, iso-butoxy, phenyl, phenoxy, benzyloxy, and 4-trifluoromethylbenzyloxy. The remaining two of R¹, R², R³, R⁴, and R⁵ are each hydrogen.
  • [0255] X¹ is selected from the group consisting of —O—, —NH—, and —N(CH₃)—.
  • [0256] X² is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl.
  • [0257] X³ is selected from the group consisting of —CH₂—, —O—, and —C(O)—.
  • [0258] X⁴ is selected from the group consisting of —CH₂—, —C(H)(CH₃)—, —C(CH₃)₂—, —NH—, and —N(CH₃)—.
  • [0259] X⁵ is selected from the group consisting of —CH₂—, —C(S)—, —C(O)—, and —S(O)₂—.
  • [0260] X⁶ is selected from the group of linkers consisting of:

[0261]

• • [0262] Any such group is optionally substituted with up to two substituents independently selected from the group consisting of methyl and oxo.
  • [0263] Z¹ is CH substituted with a substituent selected from the group consisting of chloro, nitro, cyano, trifluoromethoxy, and trifluoromethylsulfanyl.
  • [0264] Z² is CH optionally substituted with trifluoromethyl.
  • [0265] Two of Z³, Z⁴, and Z⁵ are independently selected from the group consisting of N, CH, and C(CH₃). The remaining one of Z³, Z⁴, and Z⁵ is CH.

[0267]
In some such embodiments:

• • [0268] Three of R¹, R², R³, R⁴, and R⁵ are each independently selected from the group consisting of hydrogen, chloro, fluoro, cyano, nitro, methyl, tent-butyl, n-propyl, trifluoromethyl, ethyl, methoxy, ethoxy, trifluoromethoxy, trifluoromethylsulfanyl, iso-butoxy, phenyl, phenoxy, benzyloxy, and 4-trifluoromethylbenzyloxy. The remaining two of R¹, R², R³, R⁴, and R⁵ are each hydrogen.
  • [0269] X¹ is selected from the group consisting of —NH— and —N(CH₃)—.
  • [0270] X³ is selected from the group consisting of —CH₂—, —O—, and —C(O)—.
  • [0271] X⁴ is selected from the group consisting of —CH₂, —C(H)(CH₃)—, —C(CH₃)₂—, —NH—, and —N(CH₃)—.
  • [0272] X⁵ is selected from the group consisting of —CH₂— and —C(O)—.
  • [0273] X⁶ is selected from the group of linkers consisting of:

[0274]

• • [0275] Any such group is optionally substituted with up to two methyl groups.
  • [0276] Z¹ is CH substituted with a substituent selected from the group consisting of chloro, nitro, cyano, trifluoromethoxy, and trifluoromethylsulfanyl.
  • [0277] Z² is CH optionally substituted with trifluoromethyl.

[0279]
In some such embodiments:

• • [0280] R³ is selected from the group consisting of halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl, phenoxy, and benzyloxy. The C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl, phenoxy, and benzyloxy are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, and halo-C₁-C₆-alkoxy.
  • [0281] At least two of R¹, R², R⁴, and R⁵ are each hydrogen. The remaining two of R¹, R², R⁴, and R⁵ are each independently selected from the group consisting of hydrogen, halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl, phenoxy, and benzyloxy. The C₁-C₆-alkyl, C₁-C₆-alkoxy, phenyl, phenoxy, and benzyloxy are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, and halo-C₁-C₆-alkoxy.

[0283]

[0285]

[0287]

[0289]

[0291]

[0293]

[0296]
These compounds exhibited a lack undesirable toxicity levels in at least one toxicity study conducted by Applicants. In some embodiments, the compound is selected from the group consisting of:

[0297]

K. Isomers

[0299]
In some embodiments, this compound has the trans configuration such that the compound is encompassed by following formula:

[0300]
In other embodiments, the compound has the cis configuration such that the compound is encompassed by the following formula:

[0301]
Unless otherwise stated, a compound structure that does not indicate a particular conformation is intended to encompass compositions of all the possible conformational isomers of the compound, as well as compositions comprising fewer than all the possible conformational isomers.

II. Salts of Compounds of this Invention

III. Treatment Methods Using Compounds and Salts of this Invention

EXAMPLES

Example 1

Protocols for Analyzing Compounds Prepared in Accordance with this Invention

System I

Protocol I-A

Protocol I-B

Protocol I-C

Protocol I-D

System II

Protocol II-A

Protocol II-B

Protocol II-C

Example 2

Preparation of 1-(4-trifluormethyl-phenyl)-2,5-dimethylpiperazine intermediate (also known as trans-2,5-dimethyl-1-(4-trifluoromethyl-phenyl)-piperazine)

[0335]
4-Bromobenzotrifluoride (1.35 g, 6.0 mmol), trans-2,5-dimethylpiperazine (582 mg, 5.1 mmol), tris-(dibenzylideneacetone)-dipalladium (240 mg, 0.26 mmol), 2-(dicyclohexylphosphino)-biphenyl (252 mg, 0.72 mmol) were dissolved in toluene (6 mL). A molar solution of lithium bis(trimethylsilyl)-amide (12 mL, 12 mmol) was then added. The resulting mixture was heated to 85° C. and stirred at that temperature for 6.5 hr. The mixture was then cooled to room temperature and diluted with diethyl ether (20 mL). The precipitate was separated by filtration, and the filtrate was concentrated under vacuum. Purification by column chromatography on silica gel (dichloromethane/methanol 1:0, 8:2) afforded the desired product as a brown oil (760 mg, 58% yield).

[0337]
Here, R¹, R², R³, R⁴, and R⁵ are as defined above for the compounds of this invention. R^a, R^b, R^c, R^d, R^e, R^f, R^g, and R^h are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, and alkoxy, with at least one of them being hydrogen Determining the suitability of the method (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 3

Preparation of 1-chloracetyl-4-(4-trifluormethyl-phenyl)-2,5-dimethylpiperazine intermediate (also known as 2-chloro-1-[trans-2,5-dimethyl-4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]ethanone)

[0338]
1-(4-Trifluormethyl-phenyl)-2,5-dimethylpiperazine (760 mg, 2.94 mmol, prepared in accordance with Example 2) and triethylamine (820 μL, 5.88 mmol) were dissolved in dichloromethane (5 mL). Chloroacetyl chloride (234 μL, 2.94 mmol) was then slowly added under stirring. After stirring for an additional 20 min at room temperature, the mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), and washed with saturated aqueous sodium hydrogencarbonate (10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a light yellow oil (340 mg, 35% yield).

Example 4

Preparation of 1-chloracetyl-4-(4-trifluoromethyl-phenyl)-piperazine intermediate (also known as 2-chloro-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]ethanone)

[0339]
1-(4-Trifluormethyl-phenyl)-piperazine (283 mg, 1 mmol) and triethylamine (220 μL, 2 mmol) were dissolved in dichloromethane (8 mL). Chloroacetyl chloride (110 μL, 1 mmol) was then slowly added under stirring. After stirring for an additional 10 min at room temperature, the mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), and washed with saturated aqueous sodium hydrogencarbonate (10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a light yellow oil (292 mg, 95% yield).

[0341]
Here, R¹, R², R³, R⁴, and R⁵ are as defined above for the compounds of this invention. R^a, R^b, R^c, R^d, R^e, R^f, R^g, and R^h are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, and alkoxy. And Rⁱ is either

[0342]
optionally substituted with halogen, hydroxy, alkyl, and alkoxy. Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 5

Preparation of trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol Intermediate

[0343]
5-Fluoro-2-nitrobenzotrifluoride (400 mg, 1.91 mmol) and trans-4-aminocyclohexanol (220 mg, 1.91 mmol) were dissolved in dimethylsulfoxide (10 mL). The resulting mixture was heated at 95° C. for 3.5 hr. After cooling at room temperature, the mixture was diluted with dichloromethane (15 mL) and washed with water (3×10 mL). The organic phase was collected and dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was re-crystallized from petrol ether. The desired product was then isolated as a yellow solid (490 mg, 84% yield).

[0345]
Here, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0346]
Determining the suitability of the method (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 6

Preparation of 4-(trans-4-hydroxy-cyclohexylamino)-2-trifluoromethyl-benzonitrile Intermediate

[0347]
Potassium carbonate (304 mg, 2.2 mmol) was dissolved in a minimum amount of water. Next, 4-fluoro-2-trifluoromethylbenzonitrile (378 mg, 2.0 mmol) and trans-4-aminocyclohexanol (460 mg, 4.0 mmol) dissolved in acetonitrile (10 mL) were added. The resulting mixture was then heated at 80° C. for 3 days. After cooling at room temperature, the mixture was concentrated under vacuum, taken up in ethyl acetate (15 mL), washed with saturated aqueous ammonium chloride (2×10 mL), and washed with water (10 mL). The organic phase was collected and dried over sodium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a colorless solid (456 mg, 80% yield).

Example 7

Preparation of 1-benzyl-4-(4-phenoxy-phenyl)-piperidin-4-ol Intermediate

[0348]
A 0.5 M solution of 4-phenoxy-phenylmagnesium bromide in tetrahydrofuran (30 mL, 15 mmol) was introduced into a flame-dried flask placed under an argon atmosphere. A solution of 1-benzyl-4-piperidone (2.84 g, 15 mmol) in dry tetrahydrofuran (12 mL) was then added dropwise, while the temperature was maintained at less than 20° C. with an ice bath. After completion of the addition, the mixture was allowed to reach room temperature and further stirred for 2 hr. Ice was then added to the mixture, and 1 N HCl was added until the resulting precipitate was completely dissolved. The reaction was then diluted with diethyl ether (100 mL) and washed with water (50 mL). The aqueous layer was extracted with diethyl ether (2×50 mL), and the combined organic layers were sequentially washed with saturated aqueous sodium hydrogencarbonate (2×50 mL) and water (50 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (dichloromethane and then diethyl ether). The desired product was then isolated as a colorless solid (1.74 g, 33% yield).

[0350]
Here, R¹, R², R³, R⁴, and R⁵ are as defined above for the compounds of this invention. And R^a, R^b, R^c, R^d, R^e, R^f, R^g, and R^h each are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, and alkoxy, with at least one of them being hydrogen. Another illustrative generic scheme is as follows:

[0351]
Here, Z may be, for example, halogen, such as bromo. Determining the suitability of the method (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 8

Preparation of 4-(4-phenoxy-phenyl)-piperidine Intermediate

[0352]
1-Benzyl-4-(4-phenoxy-phenyl)-piperidin-4-ol (3.47 g, 9.6 mmol, prepared in accordance with Example 7) was combined with trifluoroacetic acid (6 mL). The resulting mixture was irradiated at 130° C. in a mono-mode microwave oven for 15 min. The mixture was then concentrated under vacuum, and the obtained residue was triturated with diethyl ether (20 mL). After the solvent was removed under vacuum, the isolated product (6.6 g) was dissolved in methanol (350 mL). To this mixture was added 10% Pd/C was added (800 mg). The resulting suspension was reacted under H₂ pressure (4 bar) for 5 hr at 75° C. After removing the catalyst by filtration, the filtrate was concentrated under vacuum. The obtained residue was triturated with diethyl ether (50 mL), and the precipitate was filtered and dried under vacuum. The desired product was obtained as a light yellow solid (3.26 g, 92% yield).

[0354]
Here, R¹, R², R³, R⁴, and R⁵ are as defined above for the compounds of this invention.
And R^a, R^b, R^c, R^d, R^e, R^f, R^g, and R^h are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, and alkoxy. An illustrative generic scheme is as follows:

[0355]
Determining the suitability of the method (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 9

Preparation of 4-(4-butyl-phenyl)-piperidine Intermediate

[0356]
4-(4-Butyl-phenyl)-piperidine was prepared using a two-step procedure. In the first step, 1-benzyl-4-(4-butyl-phenyl)-piperidin-4-ol was prepared from (4-butyl-phenyl)magnesium bromide and 1-benzyl-4-piperidone using the procedure illustrated in Example 7, and in the second step, the 1-benzyl-4-(4-butyl-phenyl)-piperidin-4-ol was converted to 4-(4-butyl-phenyl)-piperidine using the procedure illustrated in Example 8. This afforded a quantitative yield of the product as a yellow oil.

Example 10

Preparation of 1-[trans-2,5-dimethyl-4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

[0357]
Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (118 mg, 0.39 mmol, prepared in accordance with Example 5) was placed under an inert atmosphere, dissolved in dry dimethylformamide (2 mL). A molar solution of lithium bis(trimethylsilyl)-amide (774 μL, 0.77 mmol) was added to the resulting mixture. The mixture was then stirred for 15 min at room temperature. Afterward, a solution of 2-chloro-1-[trans-2,5-dimethyl-4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (130 mg, 0.39 mmol, prepared in accordance with Example 3) in tetrahydrofuran (1 mL) was added. The resulting mixture was stirred at room temperature until the conversion stopped. Next, the mixture was diluted with diethylether (10 mL). The mixture was then washed with water (5 mL), and then saturated aqueous sodium hydrogencarbonate (5 mL). The organic phase was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product isolated was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (24 mg, 10% yield). The structure was confirmed using Protocol II-A. Calculated mass=603; observed mass=603; HPLC retention time=4.69 min.

Example 11

Preparation of 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone

[0358]
2-Chloro-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (26 mg, 0.09 mmol, prepared in accordance with Example 4), trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (26 mg, 0.09 mmol, prepare in accordance with Example 5), and sodium hydride (10 mg, 60% in oil, 0.26 mmol) were placed under an inert atmosphere. Tetrahydrofuran (1 mL) was added under stirring. Next, dimethylformamide (300 μL) was added under stirring. The resulting mixture was stirred for 40 min at room temperature and then diluted with dichloromethane (5 mL). The mixture was washed with water (5 mL) and then washed with saturated aqueous sodium hydrogencarbonate (5 mL). The organic phase was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (21 mg, 43% yield). The structure was confirmed using Protocol II-A. Calculated mass=575; observed mass=575; HPLC retention time=4.51 min.

[0360]
Here, R¹, R², R³, R⁴, R⁵, X¹, X², X⁶, X⁷, Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0361]
Here, R^a, R^b, R^c, R^d, R^e, R^f, R^g, and R^h are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, and alkoxy. And Rⁱ is either

[0362]
optionally substituted with halogen, hydroxy, alkyl, and alkoxy. Another illustrative generic scheme is as follows:

[0363]
Still another illustrative generic scheme is as follows:

[0364]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular compound (or salt thereof) is generally within the skill of those in the art after reading this patent.

Example 12

Preparation of 2-{trans-4-[methyl(4-nitro-3-trifluoromethyl-phenyl)-amino]-cyclohexyloxy}-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone

[0365]
2-[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (172 mg, 0.30 mmol, prepared in accordance with Example 11) and sodium hydride (12 mg, 0.30 mmol) were placed under an inert atmosphere. Dry tetrahydrofuran (3 mL) was then added. After gas evolution ceased, methyl iodide (20 μL, 0.31 mmol) was added under stirring to the dark orange colored solution. The resulting mixture was stirred at room temperature. After an hour, HPLC-MS monitoring of the reaction showed about 75% conversion to the desired product. More methyl iodide was added (5 μL, 0.08 mmol), and the mixture was stirred for an additional 30 min. HPLC-MS showed 85% conversion. The mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (25 mL). The organic layer was separated, washed with water (10 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. A yellow oil was isolated. The oil was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (106 mg, 59% yield). The structure was confirmed using Protocol I-A. Calculated mass=589; observed mass=589; HPLC retention time=4.69 min.

[0367]
Here, R¹, R², R³, R⁴, R⁵, X², X³, X⁴, X⁵, X⁶, X⁷, Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Determining the suitability of the method (and any necessary routine adaptations) for making a particular compound (or salt thereof) is generally within the skill of those in the art after reading this patent.

Example 13

Preparation of 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propan-1-one

[0368]
To a solution of diisopropylamine (0.28 mL, 2.0 mmol) in dry tetrahydrofuran (3 mL) at 5° C. was added n-butyllithium (2.5 M solution in hexanes, 1 mL, 2.5 mmol). The resulting mixture was allowed to stir for 30 min. Meanwhile, 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (287 mg, 0.5 mmol, prepared in accordance with Example 11) was dissolved in dry tetrahydrofuran (2 mL). The solution was then cooled to −35° C. To the cooled solution was added an aliquot from the freshly prepared lithium diisopropylamide solution (1.8 mL). Stirring was continued for another 30 min. Methyliodide (37 μL, 0.6 mmol) was then added, and the mixture was allowed to attain −10° C. over 1 hr. Saturated ammonium chloride solution was then added (3 mL), and the mixture warmed to room temperature and acidified to a pH of 3 with 1 N HCl. The aqueous solution was then extracted with ethyl acetate (2×15 mL), and the combined organic layers were washed with brine (2×5 mL), dried over magnesium sulfate, and concentrated. Purification by column chromatography (Ethyl acetate/cyclohexanes, 4:1) afforded the desired product as an orange solid (152 mg, 52% yield). The structure was confirmed using Protocol I-B. Calculated mass=589; observed mass=589; HPLC retention time=5.82 min.

[0370]
Here, R¹, R², R³, R⁴, R⁵, X¹, X², X⁶, X⁷, Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Determining the suitability of the method (and any necessary routine adaptations) for making a particular compound (or salt thereof) is generally within the skill of those in the art after reading this patent.

Example 14

Preparation of 2-methyl-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propan-1-one

[0371]
To a solution of diisopropylamine (1.12 mL, 8.0 mmol) in dry tetrahydrofuran (12 mL) at 5° C. was added n-butyllithium (2.5 M solution in hexanes, 3.2 mL, 8.0 mmol). The resulting mixture was allowed to stir for 30 min. Meanwhile, 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (574 mg, 1.0 mmol, prepared in accordance with Example 11) was dissolved in dry tetrahydrofuran (16 mL), and the solution was cooled to −35° C. To this solution was added an aliquot from the freshly prepared lithium diisopropylamide solution (4.5 mL). Stirring was then continued for another 30 min. Next, methyliodide (75 μL, 1.2 mmol) was added, and the mixture was allowed to attain −10° C. over 1 hr. The mixture was then re-cooled to −35° C., and another aliquot from the lithium diisopropylamide solution (4.5 mL) was added. After stirring was for an additional 30 min, methyliodide (75 μL, 1.2 mmol) was added, and the mixture was allowed to attain −10° C. over 1 hr. Afterward, the mixture was acidified to a pH of 3 with the aid of 1 N HCl. The mixture was then diluted with water (4 mL). The aqueous solution was extracted with ethyl acetate (2×20 mL), and the combined organic layers were washed with brine (2×5 mL), dried over magnesium sulfate, and concentrated. Purification by column chromatography (ethyl acetate/cyclohexanes, 1:1, 21:1, and, finally, 3:1) afforded the desired product as a yellow solid (376 mg, 62% yield). The structure was confirmed using Protocol I-B. Calculated mass=603; observed mass=603; HPLC retention time=5.94 min.

[0373]
Here, R¹, R², R³, R⁴, R⁵, X¹, X², X⁶, X⁷, Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Determining the suitability of the method (and any necessary routine adaptations) for making a particular compound (or salt thereof) is generally within the skill of those in the art after reading this patent.

Example 15

Preparation of 1-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

[0374]
1-[4-(4-Tert-butyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-Tert-butyl-phenyl)-piperazine was prepared with a 92% yield from 1-(4-Tert-butyl-phenyl)-piperazine and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (32% yield). The structure was confirmed using Protocol II-A. Calculated mass=563; observed mass=563; HPLC retention time=4.79 min.

Example 16

Preparation of 4-(4-{2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetyl}-piperazin-1-yl)-benzonitrile

[0375]
4-(4-{2-[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetyl}-piperazin-1-yl)-benzonitrile was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-benzonitrile)-piperazine (also known as 4-[4-(2-chloroacetyl)-piperazin-1-yl]-benzonitrile) was prepared from 4-(piperazin-1-yl)-benzonitrile and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 4-(4-{2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetyl]-piperazin-1-yl)-benzonitrile was prepared from the 1-chloracetyl-4-(4-benzonitrile)-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (39% yield). The structure was confirmed using Protocol II-A. Calculated mass=532; observed mass=532; HPLC retention time=4.14 min.

Example 17

Preparation of 1-[4-(4-methoxy-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

[0376]
1-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-methoxy-phenyl)-piperazine (also known as 2-chloro-1-[4-(4-methoxy-phenyl)-piperazin-1-yl)-ethanone) was prepared with a 78% yield from 1-(4-methoxy-phenyl)-piperazine and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(4-methoxy-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(4-methoxy-phenyl)-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (24% yield). The structure was confirmed using Protocol II-A. Calculated mass=537; observed mass=537; HPLC retention time=4.05 min.

Example 18

Preparation of 1-[4-(4-chloro-2-fluoro-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

[0377]
1-[4-(4-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-chloro-2-fluoro-phenyl)-piperazine (also known as 2-chloro-1-[4-(4-chloro-2-fluoro-phenyl)-piperazin-1-yl]-ethanone) was prepared from 1-(4-chloro-2-fluoro-phenyl)-piperazine and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(4-chloro-2-fluoro-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(4-chloro-2-fluoro-phenyl)-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (13% yield). The structure was confirmed using Protocol II-A. Calculated mass=559; observed mass=559; HPLC retention time=4.57 min.

Example 19

Preparation of 1-(4-(4-trifluoromethyl-benzyloxy)-phenyl)-piperazine Intermediate

[0378]
A solution of 4-(4-hydroxy-phenyl)-piperazine-1-carboxylic acid tent-butyl ester (1.5 g, 5.4 mmol) in dry tetrahydrofuran (5 mL) was added to a suspension of sodium hydride (431 mg, 60% in oil, 10.8 mmol) in dry tetrahydrofuran (35 mL). After 15 min, a solution of 1-bromomethyl-4-trifluoromethyl-benzene (1.9 g, 8.1 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred for 16 hr at room temperature, filtered, and concentrated under vacuum. The resulting residue was diluted in ethyl acetate (40 mL), and the organic layer was washed with water (3×20 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid (30 mL). The mixture was then stirred for 30 min. Afterward, the mixture was concentrated under vacuum, taken up in dichloromethane (30 mL), and evaporated to dryness. The resulting residue was diluted in diethylether (5 mL) and then combined with a molar solution of HCl in diethylether (10 mL, 1M). A precipitate formed, which was filtered, washed with diethylether (10 mL), and dried under vacuum. The desired product was isolated as a hydrochloride salt with traces of solvent.

Example 20

Preparation of 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-{4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-ethanone

[0379]
2-[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-{4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazine (also known as 2-chloro-1-{4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-ethanone) was prepared with a 46% yield from 1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazine (prepared in accordance with Example 19) and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-{4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-ethanone was prepared from the 1-chloracetyl-4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (10% yield). The structure was confirmed using Protocol II-A. Calculated mass=681; observed mass=681; HPLC retention time=4.75 min.

Example 21

Preparation of 1-[4-(4-butyl-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

[0380]
1-[4-(4-Butyl-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-butyl-phenyl)-piperidine (also known as 1-[4-(4-butyl-phenyl)-piperidin-1-yl]-2-chloroethanone) was prepared with a 72% yield from 4-(4-butyl-phenyl)-piperidine (prepared in accordance with Example 9) and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(4-butyl-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(4-butyl-phenyl)-piperidine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (36% yield). The structure was confirmed using Protocol II-A. Calculated mass=548; observed mass=548; HPLC retention time=4.92 min.

Example 22

Preparation of 1-[4-(2,4-difluoro-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

[0381]
1-[4-(2,4-Difluoro-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(2,4-difluoro-phenyl)-piperidine (also known as 2-chloro-1-[4-(2,4-difluoro-phenyl)-piperidin-1-yl]-ethanone) was prepared from 4-(2,4-difluoro-phenyl)-piperidine and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(2,4-difluoro-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(2,4-difluoro-phenyl)-piperidine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (16% yield). The structure was confirmed using Protocol II-A. Calculated mass=542; observed mass=543; HPLC retention time=4.36 min.

Example 23

Preparation of 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-phenoxy-phenyl)-piperidin-1-yl]-ethanone

[0382]

Example 24

Preparation of 1-chloracetyl-4-(4-benzyloxy-phenyl)-piperazine Intermediate

[0384]
Crude 1-chloracetyl-4-(4-benzyloxy-phenyl)-piperazine (also known as 1-[4-(4-benzyloxy-phenyl)-piperazin-1-yl]-2-chloroethanone) was prepared from 1-(4-benzyloxy-phenyl)-piperazine and chloroacetyl chloride using the procedure illustrated in Example 4.

Example 25

Preparation of 4-(trans-4-{2-[4-(4-benzyloxy-phenyl)-piperazin-1-yl]-2-oxoethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

[0385]
4-(Trans-4-{2-[4-(4-benzyloxy-phenyl)-piperazin-1-yl]-2-oxoethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile was prepared from 1-chloracetyl-4-(4-benzyloxy-phenyl)-piperazine (prepared in accordance with Example 24) and 4-(trans-4-hydroxy-cyclohexylamino)-2-trifluoromethyl-benzonitrile (prepared in accordance with Example 6) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (51% yield). The structure was confirmed using Protocol II-A. Calculated mass=593; observed mass=593; HPLC retention time=4.41 min.

Example 26

Preparation of 1-chloracetyl-4-(4-tert-butyl-phenyl)-piperazine Intermediate

[0386]
1-Chloracetyl-4-(4-Tert-butyl-phenyl)-piperazine (also known as 1-[4-(4-Tert-butyl-phenyl)-piperazin-1-yl]-2-chloroethanone) was prepared with a 92% yield from 1-(4-tert-butyl-phenyl)-piperazine and chloroacetyl chloride using the procedure illustrated in Example 4.

Example 27

Preparation of 4-(trans-4-{2-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

[0387]
4-(Trans-4-{2-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile was prepared from 1-chloracetyl-4-(4-tert-butyl-phenyl)-piperazine (prepared in accordance with Example 26) and 4-(trans-4-hydroxy-cyclohexylamino)-2-trifluoromethyl-benzonitrile (prepared in accordance with Example 6) using the procedure illustrated in Example 11. This afforded the product as a colorless solid (39% yield). The structure was confirmed using Protocol II-A. Calculated mass=543; observed mass=543; HPLC retention time=4.68 min.

Example 28

Preparation of [trans-4-(tert-butyl-dimethyl-silyloxy)-cyclohexyl]-(4-trifluoromethylsulfanyl-phenyl)-amine Intermediate

[0388]
(4-Trifluoromethylsulfanyl-phenyl)-amine (386 mg, 2 mmol) and 4-Tert-butyl-dimethyl-silyloxy-cyclohexanone (457 mg, 2 mmol) were dissolved in acetonitrile (5 mL), and the resulting solution was refluxed for 1 hr. After cooling the mixture to room temperature, sodium triacetoxyborohydride (848 mg, 4 mmol) was added. The mixture was then stirred at room temperature for 18 hr. Afterward, the mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium hydrogencarbonate (10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. An oily residue was obtained. This residue was purified by column chromatography on silica gel (cyclohexane/diethylether, 98:2). The trans isomer was isolated as a colorless oil (180 mg, 22% yield).

[0390]
Here, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0391]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 29

Preparation of trans-4-(4-trifluoromethylsulfanyl-phenylamino)-cyclohexanol Intermediate

[0392]
[Trans-4-(tert-butyl-dimethyl-silyloxy)-cyclohexyl]-(4-trifluoromethylsulfanyl-phenyl)-amine (180 mg, 0.44 mmol, prepared in accordance with Example 28) was dissolved in tetrahydrofuran (3 mL). A molar solution of tetrabutylammonium fluoride (500 μL, 5 mmol) was then added. The resulting mixture was heated to 40° C. and then maintained at that temperature for 4 hr. After cooling to room temperature, the mixture was diluted with diethylether (20 mL), washed with water (10 mL), and washed with saturated aqueous hydrogencarbonate (10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The oily residue obtained was purified by column chromatography on silica gel (dichloromethane and then dichloromethane/methanol, 95:5). The desired product was isolated as a colorless oil with traces of tetrabutylammonium fluoride.

[0394]
Here, X¹, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0395]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 30

Preparation of [trans-4-(4-(trifluoromethylsulfanyl)-phenylamino)-cyclohexyloxy]-acetic acid Intermediate

[0396]
Trans-4-(4-trifluoromethylsulfanyl-phenylamino)-cyclohexanol (160 mg, 0.55 mmol, prepared in accordance with Example 29) was placed under an inert atmosphere and dissolved in dry tetrahydrofuran (2 mL). A molar solution of lithium bis(trimethylsilyl)-amide (1 mL, 1.0 mmol) was added. After 15 min, tert-butyl-bromoacetate (75 μL, 0.55 mmol) was added. After two additional hours, more lithium bis-(trimethylsilyl)-amide solution (500 μL, 0.50 mmol) and tert-butyl-bromoacetate (37 μL, 0.28 mmol) was added. After 4 hr, the mixture was diluted with diethylether (20 mL), washed with water (10 mL), and washed with saturated aqueous hydrogencarbonate (10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum to afford an oil. This crude product was diluted in dichloromethane (4 mL) and treated with trifluoroacetic acid (3 mL) at room temperature. After 3 hr, the mixture was diluted with diethylether (20 mL) and washed with water (3×10 mL), and washed with aqueous saturated hydrogencarbonate (2×10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The oily residue obtained was purified by column chromatography on silica gel (dichloromethane followed by dichloromethane/methanol, 95:5). The desired product was isolated as a yellow solid (68 mg, 35% yield).

[0398]
Here, X¹, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0399]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 31

Preparation of 1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-trifluoromethylsulfanyl-phenylamino)-cyclohexyloxy]-ethanone

[0400]
2-[Trans-4-(4-trifluoromethylsulfanyl-phenylamino)-cyclohexyloxy]-acetic acid (18 mg, 0.05 mmol, prepared in accordance with Example 30) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (19 mg, 0.05 mmol) were dissolved in dry tetrahydrofuran (2 mL) and stirred at room temperature for 10 min. 1-(4-Trifluormethyl-phenyl)-piperazine (12 mg, 0.05 mmol) and diisopropylethylamine (18 μL, 0.10 mmol) were then added, and the solution was stirred at room temperature for 1.5 hr. Aluminium oxide was then added (1 spatula). Afterward, the mixture was diluted with diethylether (10 mL) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a solid (16 mg, 57% yield). The structure was confirmed using Protocol I-B. Calculated mass=562; observed mass=562; HPLC retention time=6.03 min.

[0402]
Here, R¹, R², R³, R⁴, R⁵, X¹, X², X³, Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. R^a, R^b, R^c, R^d, R^e, R^f, R^g, and R^h are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, and alkoxy. And Rⁱ is either

[0403]
optionally substituted with halogen, hydroxy, alkyl, and alkoxy. Another illustrative generic scheme is as follows:

[0404]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular compound (or salt thereof) is generally within the skill of those in the art after reading this patent.

Example 32

Preparation of [4-(tert-butyl-dimethyl-silyloxy)-cyclohexyl]-(4-chloro-3-trifluoromethyl-phenyl)-amine Intermediate

[0405]
(4-Chloro-3-trifluoromethyl-phenyl)-amine (782 mg, 4 mmol) and 4-(tent-butyl-dimethyl-silyloxy)-cyclohexanone (913 mg, 4 mmol) were dissolved in dichloromethane (35 mL). Next, sodium triacetoxyborohydride (1.69 g, 8 mmol) was added, and the mixture was stirred at room temperature for 6 days. The mixture was then diluted with dichloromethane (35 mL), washed with water (25 mL), washed with HCl 1N (25 mL), washed with water (25 mL), and washed with brine (25 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. This afforded an oily residue, which was purified by column chromatography on silica gel (pentane/ether gradient). The desired product was isolated as a yellow oil (1.3 g of 1:1 mixtures of cis and trans isomers, 80% yield).

Example 33

Preparation of trans-4-(4-chloro-3-trifluoromethyl-phenylamino)-cyclohexanol and cis-4-(4-chloro-3-trifluoromethyl-phenylamino)-cyclohexanol Intermediates

[0406]
[4-(Tert-butyl-dimethyl-silyloxy)-cyclohexyl]-(4-chloro-3-trifluoromethyl-phenyl)-amine (1.3 g, 3.2 mmol, prepared in accordance with Example 32) was dissolved in tetrahydrofuran (25 mL). Next, a molar solution of tetrabutylammonium fluoride was added (3.2 mL, 3.2 mmol). The resulting mixture was heated to 40° C., and then maintained at this temperature for 8 hr. Afterward, the mixture was cooled to room temperature and then stirred at room temperature for 3 days. The resulting solution was concentrated under vacuum and purified by preparative HPLC. The fractions corresponding to the cis and trans isomers were isolated separately, partly evaporated under vacuum, and lyophilized.

[0408]
Here, X¹, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 34

Preparation of [4-(tert-butyl-dimethyl-silyloxy)-cyclohexyl]-(4-trifluoromethoxy-3-trifluoromethyl-phenyl)-amine Intermediate

[0409]
(4-Trifluoromethoxy-3-trifluoromethyl-phenyl)-amine (735 mg, 3 mmol) and 4-(tert-butyl-dimethyl-silyloxy)-cyclohexanone (685 mg, 3 mmol) were dissolved in dichloromethane (25 mL). Next, sodium triacetoxyborohydride (1.27 g, 6 mmol) was added. The resulting mixture was stirred at room temperature for 6 days. Afterward, the mixture was diluted with dichloromethane (25 mL), washed with water (20 mL), washed with HCl 1N (20 mL), washed with water (20 mL), and washed with brine (20 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum to afford an oily residue. The residue was purified by column chromatography on silica gel (pentane/ether gradient). The desired product was isolated as a colorless oil (900 mg of 1:1 mixtures of cis and trans isomers, 66% yield).

Example 35

Preparation of cis-4-(4-trifluoromethoxy-3-trifluoromethyl-phenylamino)-cyclohexanol and trans-4-(4-trifluoromethoxy-3-trifluoromethyl-phenylamino)-cyclohexanol Intermediates

[0410]
[4-(Tert-butyl-dimethyl-silyloxy)-cyclohexyl]-(4-trifluoromethoxy-3-trifluoromethyl-phenyl)-amine (1.3 g, 3.2 mmol, prepared in accordance with Example 34) was dissolved in tetrahydrofuran (25 mL). Next, a molar solution of tetrabutylammonium fluoride was added (3.2 mL, 3.2 mmol). The resulting mixture was heated to 40° C., and then maintained at that temperature for 8 hr. Afterward, the mixture was cooled to room temperature and then stirred at that temperature for 3 days. The resulting solution was concentrated under vacuum and purified by preparative HPLC. The fractions corresponding to the cis and trans isomers were isolated separately, partly evaporated under vacuum, and lyophilized.

Example 36

Preparation of 1-[4-(4-benzyloxy-phenyl)-piperazin-1-yl]-2-[trans-4-(4-trifluoromethoxy-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

[0411]
1-[4-(4-Benzyloxy-phenyl)-piperazin-1-yl]-2-[trans-4-(4-trifluoromethoxy-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from crude 1-chloracetyl-4-(4-benzyloxy-phenyl)-piperazine (prepared in accordance with Example 24) and trans-4-(4-trifluoromethoxy-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 35) using the procedure illustrated in Example 11. This afforded the desired product as a colorless solid with a 37% yield. The structure was confirmed using Protocol I-B. Calculated mass=652; observed mass=652; HPLC retention time=6.17 min.

Example 37

Preparation of 1-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-trifluoromethoxy-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

[0412]
1-[4-(4-Tert-butyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-trifluoromethoxy-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from 1-chloracetyl-4-(4-tert-butyl-phenyl)-piperazine (prepared in accordance with Example 26) and trans-4-(4-trifluoromethoxy-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 35) using the procedure illustrated in Example 11. This afforded the desired product as a colorless solid with a 39% yield. The structure was confirmed using Protocol I-B. Calculated mass=602; observed mass=602; HPLC retention time=6.35 min.

Example 38

Preparation of 1-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-chloro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

[0413]
1-[4-(4-Tert-butyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-chloro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from 1-chloracetyl-4-(4-tert-butyl-phenyl)-piperazine (prepared in accordance with Example 26) and trans-4-(4-chloro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 35) using the procedure illustrated in Example 11. This afforded the desired product as a colorless solid with a 47% yield. The structure was confirmed using Protocol I-B. Calculated mass=552; observed mass=552; HPLC retention time=6.26 min.

Example 39

Preparation of 1-[4-(4-benzyloxy-phenyl)-piperazin-1-yl]-2-[trans-4-(4-chloro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

[0414]
1-[4-(4-Benzyloxy-phenyl)-piperazin-1-yl]-2-[trans-4-(4-chloro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from crude 1-chloracetyl-4-(4-tert-butyl-phenyl)-piperazine (prepared in accordance with Example 24) and trans-4-(4-chloro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 35) using the procedure illustrated in Example 11. This afforded the desired product as a colorless solid with a 45% yield. The structure was confirmed using Protocol I-B. Calculated mass=602; observed mass=602; HPLC retention time=6.12 min.

Example 40

Preparation of (trans-4-{3-oxo-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propyl}-cyclohexyl)-carbamic acid tent-butyl ester Intermediate

[0415]
3-(Trans-4-tert-butoxycarbonylamino-cyclohexyl)-propanoic acid (50 mg, 0.18 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (140 mg, 0.37 mmol) were dissolved in a mixture of dimethylacetamide (1.2 mL) and dichloromethane (0.3 mL). Next, diisopropylethylamine (100 μL, 0.55 mmol) was added. After 5 min, a solution of 1-(4-trifluormethyl-phenyl)-piperazine (50 mg, 0.22 mmol) in dimethylacetamide (1.2 mL) and dichloromethane (0.3 mL) was added, and the resulting mixture was stirred at room temperature for 30 min. The mixture was then diluted with dichloromethane (40 mL), and the organic layer was washed with water (2×20 mL), washed with saturated aqueous ammonium chloride (20 mL), washed with water (10 mL), washed with saturated aqueous hydrogencarbonate (2×20 mL), and washed with water (10 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (pentane/ethyl acetate, 5:1), and the desired product was isolated as a light yellow solid (68 mg, 76% yield).

[0417]
Here, R¹, R², R³, R⁴, R⁵, and X² are as defined above for the compounds of this invention. R^a, R^b, R^c, R^d, R^e, R^f, R^g, and R^h are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, and alkoxy. And Rⁱ is either

[0418]
optionally substituted with halogen, hydroxy, alkyl, and alkoxy. Another illustrative generic scheme is as follows:

[0419]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 41

Preparation of 3-(trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyl)-1-(4-(4-trifluoromethyl-phenyl)-piperazin-1-yl)-propan-1-one

[0420]
(Trans-4-{3-oxo-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propyl}-cyclohexyl)-carbamic acid tert-butyl ester (23 mg, 0.06 mmol, prepared in accordance with Example 40) was combined with a 50% (vol/vol) solution of trifluoroacetic acid and dichloromethane (3 mL). The resulting mixture was stirred for 30 min at room temperature. The mixture was then concentrated under vacuum to form a crude residue. The crude residue was dissolved in dimethylsulfoxide (3 mL). Afterward, potassium carbonate was added (17 mg, 0.12 mmol). 5-Fluoro-2-nitrobenzotrifluoride (15 mg, 0.07 mmol) was then added. The resulting mixture was reacted at 120° C. for 18 hr. The mixture was then cooled to room temperature, diluted with dichloromethane (15 mL), washed with water (4×8 mL), washed with saturated aqueous ammonium chloride (8 mL), washed with water (8 mL), washed with saturated aqueous hydrogencarbonate (2×8 mL), and washed with water (2×8 mL). The organic phase was collected, dried over magnesium sulfate, and concentrated under vacuum to form a crude residue. The crude residue was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a solid (17 mg, 48% yield). The structure was confirmed using Protocol I-A. Calculated mass=573; observed mass=553; HPLC retention time=4.98 min. It is believed that the discrepancy between the actual and observed masses stems from a loss of HF upon ionization.

[0422]
Here, R¹, R², R³, R⁴, R⁵, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. R^a, R^b, R^c, R^d, R^e, R^f, R^g, and R^h are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, and alkoxy. And Rⁱ is either

[0423]
optionally substituted with halogen, hydroxy, alkyl, and alkoxy. Another illustrative generic scheme is as follows:

[0424]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular compound (or salt thereof) is generally within the skill of those in the art after reading this patent.

Example 42

Preparation of trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanecarboxylic acid Intermediate

[0425]
5-Fluoro-2-nitrobenzotrifluoride (1.46 g, 7.0 mmol) and trans-4-aminocyclohexane carboxylic acid (1.0 g, 7.0 mmol) were dissolved in a mixture of acetonitrile (42 mL), dimethylformamide (21 mL), and water (7 mL). The resulting solution was heated to 85° C. and then maintained at this temperature overnight. After cooling to room temperature, the mixture was partly concentrated under vacuum, diluted with ethyl acetate (50 mL), and washed with water (30 mL). The aqueous phase was acidified to pH 4 by the addition of 1 M HCl. This formed a precipitate, which was isolated by filtration. The filtrate was extracted with ethyl acetate (2×10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under vacuum to afford a solid. Both solids were combined and dried under vacuum. The desired product was isolated as a yellow solid (2.4 g, quantitative yield).

[0427]
Here, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0428]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 43

Preparation of [trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyl]-methanol Intermediate

[0429]
Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanecarboxylic acid (1.63 g, 4.9 mmol, prepared in accordance with Example 42) was suspended in tetrahydrofuran (40 mL). The resulting suspension was cooled to 0° C. with an ice bath. Afterward, a solution of lithium aluminium hydride in tetrahydrofuran (4.9 mL, 1 M in THF) was added under stirring. The resulting solution was allowed to reach room temperature, and then sonicated for 3 hr. After allowing the mixture to react overnight at room temperature, the mixture was heated to 60° C. to ensure complete conversion of the starting material. After cooling to room temperature, the mixture was acidified with 1M HCl and then diluted with ethyl acetate (50 mL). This formed a precipitate. The suspension was centrifuged, and the supernatant was collected and washed with water (10 mL). The organic layer was washed with saturated aqueous ammonium chloride (20 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was obtained as a solid (1.3 g, 83% yield).

[0431]
Here, X¹, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0432]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 44

Preparation of trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexylmethyl toluene-4-sulfonic acid ester Intermediate

[0433]
[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyl]-methanol (700 mg, 2.2 mmol, prepared in accordance with Example 43 without any further purification) was diluted in dichloromethane (20 mL). Triethylamine (1.11 mL, 11.0 mmol) was then added, and the resulting mixture was cooled to 0° C. Para-toluenesulfonyl chloride (719 mg, 2.2 mmol) was then added. The mixture was stirred overnight at room temperature, and then diluted with dichloromethane (20 mL). The resulting mixture was treated with a half-saturated aqueous hydrogencarbonate (25 mL) solution. The two phases were stirred for one hr and then separated. The organic phase was washed with saturated aqueous ammonium chloride (20 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue obtained was purified by chromatography on a short silica gel column (dichloromethane) to afford the desired product as a yellow solid (517 mg, 50% yield).

[0435]
Here, X¹, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0436]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 45

Preparation of (trans-4-aminomethyl-cyclohexyl)-4-nitro-3-trifluoromethyl-phenyl)-amine Intermediate

[0437]
Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexylmethyl toluene-4-sulfonic acid ester (715 mg, 1.51 mmol, prepared in accordance with Example 44) was dissolved in tetrahydrofuran (25 mL). An aqueous ammonia solution (1.5 mL, 25% wt/wt, 9.63 mmol) was then added. The resulting mixture was irradiated for 30 min at 150° C. in a microwave oven. After cooling to room temperature, the mixture was diluted with ethyl acetate (25 mL) and washed with water (30 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was diluted in dioxane (5 mL). Afterward, a concentrated solution of HCl in dioxane was added (10 mL, 4N). A precipitate formed. The precipitate was triturated for 10 min in the solution, filtered, washed with diethylether (2×10 mL), and dried under vacuum. The desired product was isolated as a dihydrochloride (650 mg, quantitative yield).

[0439]
Here, X¹, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0440]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 46

Preparation of trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanecarboxilic acid methylamide Intermediate

[0441]
Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanecarboxylic acid (500 mg, 1.50 mmol, prepared in accordance with Example 42), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (570 mg, 1.5 mmol), and diisopropylethylamine (600 μL, 3.30 mmol) were dissolved in dry tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature for 10 min, and then cooled to 0° C. A solution of methylamine in tetrahydrofuran (750 μL, 2M, 1.50 mmol) and dimethylformamide (1 mL) was added, and the resulting mixture was stirred at room temperature for 3 hr. The mixture was then concentrated under vacuum. The resulting residue was taken up in dichloromethane (25 mL), and the organic phase was washed with water (10 mL), and then with aqueous saturated hydrogencarbonate (3×10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was diluted in dioxane (5 mL), and a concentrated solution of HCl in dioxane was added (10 mL, 4N). A precipitate formed, which was then washed with diethylether (10 mL) and dried under vacuum. The desired product was isolated as a yellow solid (498 mg, 87% yield).

[0443]
Here, X¹, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0444]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 47

Preparation of (trans-4-methylaminomethyl-cyclohexyl)-4-nitro-3-trifluoromethyl-phenyl)-amine Intermediate

[0445]
Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanecarboxilic acid methylamide (690 mg, 2.00 mmol, prepared in accordance with Example 46) was diluted in tetrahydrofuran (2 mL). The resulting solution was heated to reflux. A solution of borane-dimethylsulfide complex in tetrahydrofuran (4 mL, 2M, 8.00 mmol) was added. The mixture was then stirred for 10 min, acidified with 0.5 M HCl, and extracted with dichloromethane (10 mL). The aqueous phase was neutralized with aqueous saturated hydrogencarbonate, and extracted with dichloromethane (2×15 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was diluted in diethylether (5 mL) and then combined with a molar solution of HCl in diethylether (10 mL, 1M). A precipitate formed, which was filtered, washed with diethylether (10 mL), and dried under vacuum. The desired product was isolated as a yellow solid (256 mg, 35% yield).

[0447]
Here, X¹, X², Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0448]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 48

Preparation of 1-(4-Tert-butyl-phenyl)-piperidine-4-carboxylic acid ethyl ester Intermediate

[0449]
4-Bromobenzotrifluoride (572 μL, 3.30 mmol), piperidine-4-carboxylic acid ethyl ester (985 μL, 6.00 mmol), tris-(dibenzylideneacetone)-dipalladium (62 mg, 0.07 mmol), 2,2′-bis-(diphenylphosphino)-1,1′-binaphthalin (121 mg, 0.19 mmol), and sodium tert-butoxide (576 mg, 6.0 mmol) were dissolved in toluene (5 mL). The resulting mixture was irradiated at 120° C. for 30 min in a microwave oven. The mixture was then cooled to room temperature and diluted with ethyl acetate (20 mL). This resulted in a precipitate. The precipitate was separated by filtration, and the filtrate was concentrated under vacuum. Purification by column chromatography on silica gel (dichloromethane/diethylether; first eluting with a 1:0 mixture (i.e., all dichloromethane), and then with a 6:1 mixture) afforded the desired product as an oil (110 mg, 12% yield).

[0451]
Here, R¹, R², R³, R⁴, and R⁵ are as defined above for the compounds of this invention. R^a, R^b, R^c, R^d, R^e, R^f, R^g, and R^h are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, and alkoxy. Another illustrative generic scheme is as follows:

[0452]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 49

Preparation of 1-(4-Tert-butyl-phenyl)-piperidine-4-carboxylic acid Intermediate

[0453]
1-(4-Tert-butyl-phenyl)-piperidine-4-carboxylic acid ethyl ester (120 mg, 0.41 mmol, prepared in accordance with Example 48) was diluted in methanol (4 mL). An aqueous solution of sodium hydroxide (2 mL, 4M, 8.00 mmol) was then added. The resulting mixture was heated to 90° C., and then maintained at that temperature for 3 hr. After cooling to room temperature, the mixture was filtered. The filtrate was diluted with water (10 mL), and the aqueous phase was washed with ethyl acetate (10 mL). The aqueous phase was then acidified to a pH of 4 with 1 M HCl and then extracted with ethyl acetate (2×10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a solid (28 mg, 26% yield).

[0455]
Here, R¹, R², R³, R⁴, R⁵, X⁶, and X⁷ are as defined above for the compounds of this invention. Another illustrative generic scheme is as follows:

[0456]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 50

Preparation of 1-(4-Tert-butyl-phenyl)-4-methyl-piperidine-4-carboxylic acid ethyl ester Intermediate

[0457]
Diisopropylamine (113 μL, 0.81 mmol) was diluted with tetrahydrofuran (1 mL). The resulting solution was cooled to 0° C., and a solution of n-butyllithium in cyclohexane (400 μL, 2M, 0.80 mmol) was then added. The mixture was stirred at 0° C. for 30 min. The mixture was then cooled to −78° C., and a solution of the 1-(4-Tert-butyl-phenyl)-piperidine-4-carboxylic acid ethyl ester (118 mg, 0.41 mmol, prepared in accordance with Example 48) in tetrahydrofuran (3 mL) was added. After 30 min, methyl iodide (57 μL, 0.41 mmol) was added. Afterward, the mixture was maintained at −78° C. for 1 hr. The mixture was then allowed to increase to room temperature, and maintained at that temperature for 1 hr. The mixture was then quenched with saturated aqueous ammonium chloride (15 mL). The organic phase was extracted with ethyl acetate (20 mL). The organic phase was then dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as an oil (155 mg, quantitative yield).

[0459]
Here, R¹, R², R³, R⁴, and R⁵ are as defined above for the compounds of this invention. R^a, R^b, R^c, R^d, R^e, R^f, R^g, and R^h are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, and alkoxy. Another illustrative generic scheme is as follows:

[0460]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular intermediate is generally within the skill of those in the art after reading this patent.

Example 51

Preparation of 1-(4-tert-butyl-phenyl)-4-methylpiperidine-4-carboxylic acid Intermediate

[0461]
1-(4-Tert-butyl-phenyl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (155 mg, 0.62 mmol, prepared in accordance with Example 50 without any further purification) was diluted in methanol (4 mL). An aqueous sodium hydroxide solution was then added (2 mL, 4M, 8.00 mmol). The resulting mixture was heated to 90° C. and then maintained at that temperature for 1 hr. After cooling to room temperature, the mixture was filtered. The filtrate was diluted with water (10 mL), and the aqueous phase was washed with ethyl acetate (10 mL). The aqueous phase was then acidified to a pH of 4 with 1 M HCl and extracted with ethyl acetate (2×10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a solid (81 mg, 48% yield).

Example 52

Preparation of 1-(4-tert-butyl-phenyl)-N-methyl-N-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexylmethyl]-piperidine-4-carboxamide

[0462]
1-(4-Tert-butyl-phenyl)-piperidine-4-carboxylic acid (29 mg, 0.11 mmol, prepared in accordance with Example 49), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (38 mg, 0.11 mmol), and diisopropylethylamine (87 μL, 0.50 mmol) were dissolved in a 1:1 mixture of dry tetrahydrofuran (0.5 mL) and dry dimethylformamide (0.5 mL). The resulting mixture was stirred at room temperature for 5 min. A solution of (trans-4-methylaminomethyl-cyclohexyl)-4-nitro-3-trifluoromethyl-phenyl)-amine (35 mg, 0.10 mmol, prepared in accordance with Example 47) in a 1:1 mixture of dry tetrahydrofuran (0.5 mL) and dry dimethylformamide (0.5 mL) was then added. The resulting mixture was stirred at room temperature for 3 hr. The mixture was then diluted with dichloromethane (10 mL), and the organic phase was washed with water (5 mL), and then aqueous saturated hydrogencarbonate (2×5 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue obtained was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (40 mg, 63% yield). The structure was confirmed using Protocol II-A. Calculated mass=575; observed mass=575; HPLC retention time=4.32 min.

Example 53

Preparation of 1-(4-tert-butyl-phenyl)-N-dimethyl-N-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexylmethyl]-4-methyl-piperidine-4-carboxamide

[0463]
1-(4-Tert-butyl-phenyl)-4-methylpiperidine-4-carboxylic acid (30 mg, 0.11 mmol, prepared in accordance with Example 51), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (38 mg, 0.11 mmol), and diisopropylethylamine (87 μL, 0.50 mmol) were dissolved in a 1:1 mixture of dry tetrahydrofuran (0.5 mL) and dry dimethylformamide (0.5 mL). The resulting mixture was stirred at room temperature for 5 min. A solution of (trans-4-methylaminomethyl-cyclohexyl)-4-nitro-3-trifluoromethyl-phenyl)-amine (35 mg, 0.10 mmol, prepared in accordance with Example 47) in a 1:1 mixture of dry tetrahydrofuran (0.5 mL) and dry dimethylformamide (0.5 mL) was then added. The mixture was then stirred at room temperature for 3 hr. Afterward, the mixture was diluted with dichloromethane (10 mL), and the organic phase was washed with water (5 mL), and then aqueous saturated hydrogencarbonate (2×5 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (10 mg, 15% yield). The structure was confirmed using Protocol II-A. Calculated mass=589; observed mass=589; HPLC retention time=4.59 min.

Example 54

Preparation of 1-(4-tert-butyl-phenyl)-N-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexylmethyl]-piperidine-4-carboxamide

[0464]
1-(4-Tert-butyl-phenyl)-piperidine-4-carboxylic acid (29 mg, 0.11 mmol, prepared in accordance with Example 49), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (38 mg, 0.11 mmol), and diisopropylethylamine (87 μL, 0.50 mmol) were dissolved in a 1:1 mixture of dry tetrahydrofuran (0.5 mL) and dry dimethylformamide (0.5 mL). The resulting mixture was stirred at room temperature for 5 min. A solution of (trans-4-aminomethyl-cyclohexyl)-4-nitro-3-trifluoromethyl-phenyl)-amine (35 mg, 0.11 mmol, prepared in accordance with Example 45) in a 1:1 mixture of dry tetrahydrofuran (0.5 mL) and dry dimethylformamide (0.5 mL) was then added. The resulting mixture was stirred at room temperature for 3 hr. The mixture was then diluted with dichloromethane (10 mL), and the organic phase was washed with water (5 mL) and then aqueous saturated hydrogencarbonate (2×5 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (4 mg, 9% yield). The structure was confirmed using Protocol II-B. Calculated mass=561; observed mass=561; HPLC retention time=5.21 min.

[0466]
Here, R¹, R², R³, R⁴, R⁵, X¹, X², X⁶, X⁷, Z¹, Z², Z³, Z⁴, and Z⁵ are as defined above for the compounds of this invention. And R^k is selected from the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, and C₂-C₆-alkynyl. The C₁-C₆-alkyl, C₂-C₆-alkenyl, and C₂-C₆-alkynyl are optionally substituted with one or more independently selected halogen. Another illustrative generic scheme is as follows:

[0467]
Determining the suitability of the methods (and any necessary routine adaptations) for making a particular compound (or salt thereof) is generally within the skill of those in the art after reading this patent.

Example 55

Preparation of [1-(4-trifluoromethyl-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester

[0468]
A solution of 1-bromo-4-trifluoromethyl-benzene (50.0 g; 220 mmol) and piperidin-4-ylmethyl-carbamic acid tert-butyl ester (48.1 g; 220 mmol) in dioxane (1 L) was added to a suspension of palladium (II) acetate (7.41 g; 33 mmol), cesium carbonate (144.8 g; 440 mmol), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (31.8 g; 45 mmol) in dioxane (1 L). The resulting mixture was heated to 110° C., and then maintained at that temperature for 28 hr with stirring. The mixture was then allowed to cool to room temperature. Afterward, the reaction mixture was treated with water (2 L) and extracted with dichloromethane (2×1 L). The combined organic phases were dried over sodium sulfate and filtered, and then the solvents were removed under reduced pressure. The resulting residue was dissolved in acetonitrile (1.5 L). Water (1.5 L) was then added with stirring. This resulting in a precipitate, which was filtered and then dried overnight at 40° C. at a pressure of 3 mbar to afford the desired product (48.9 g; 136 mmol).

Example 56

Preparation of methyl-[1-(4-trifluoromethyl-phenyl)-piperidin-4-ylmethyl]-amine

[0469]
A solution of [1-(4-trifluoromethyl-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester (45 g; 126 mmol, prepared in accordance with Example 55) in tetrahydrofuran (450 mL) was added over 7 min to a molar solution of lithium aluminium hydride in tetrahydrofuran (377 mL). The resulting mixture was heated to 100° C., and then maintained at that temperature for 195 min. Afterward, the mixture was allowed to cool to room temperature and then poured onto a mixture of ice (500 g) and of 2 N aqueous HCl (350 mL). The organic solvents were removed by evaporation under reduced pressure, and the aqueous phase was basified to a pH of 11 by adding 2 N aqueous NaOH. This resulting in a precipitate, which was filtered and dried at 40° C. under a pressure of 3 mbar to afford the desired product (17.7 g; 65 mmol).

Example 57

Preparation of trans-N-methyl-4-(4-nitro-3-(trifluoromethyl)phenylamino)-N-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)cyclohexanecarboxamide

[0470]
A suspension of trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanecarboxylic acid (7.88 g; 23.7 mmol, prepared in accordance with Example 42), diisopropylethyl amine (8.56 mL; 47.4 mmol), and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (8.74 g; 22.6 mmol) in a mixture of dichloromethane (300 mL) and dimethylsulfoxide (5 mL) was stirred for 20 min. Afterward, methyl-[1-(4-trifluoromethyl-phenyl)-piperidin-4-ylmethyl]-amine (6.15 g; 22.6 mmol, prepared in accordance with Example 56) was added. The resulting suspension was stirred for 15.5 hr at room temperature. This resulted in a clear solution, which was extracted with water (1 L). The organic phase was dried over sodium sulfate. After concentrating under reduced pressure, the resulting residue obtained was dissolved in a small volume of acetonitrile and filtered over a silica gel pad. The solvent was removed under reduced pressure, and the resulting solid was dried at 40° C. under a pressure of 3 mbar to afford the desired product (12.9; 22.0 mmol).

Examples 58-265

Examples of Additional Compounds Prepared by Applicants in Accordance with this Invention

[0472]

TABLE II
Additional Compounds Prepared by Applicants in Accordance with this Invention
Compound	Analysis	Retention	Calc.	Obs.
Structure	Method	Time (min)	Mass	Mass
	Protocol II-A	4.57	575	575
	Protocol II-A	4.70	609	609
	Protocol II-A	4.70	575	575
	Protocol II-A	4.53	541	541
	Protocol II-A	4.64	575	575
	Protocol II-A	4.45	541	541
	Protocol II-A	4.35	600	600
	Protocol II-A	4.64	591	591
	Protocol I-C	3.45	507	507
	Protocol II-A	4.71	535	535
	Protocol II-A	4.89	549	549
	Protocol II-A	4.67	583	583
	Protocol II-A	4.36	521	521
	Protocol II-A	4.36	543	543
	Protocol II-A	4.60	520	520
	Protocol II-A	4.61	540	540
	Protocol II-A	4.37	536	536
	Protocol II-A	4.83	582	582
	Protocol II-A	4.97	562	562
	Protocol II-A	4.56	613	613
	Protocol II-A	3.89	567	567
	Protocol II-A	4.71	535	535
	Protocol II-A	4.62	575	575
	Protocol II-A	4.85	583	583
	Protocol II-A	4.67	579	579
	Protocol II-A	3.93	567	567
	Protocol I-A	5.21	561	561
	Protocol I-A	4.97	539	539
	Protocol I-C	3.65	519	519
	Protocol I-A	4.74	505	505
	Protocol II-A	4.38	521	521
	Protocol II-A	4.46	555	555
	Protocol I-B	6.13	580	580
	Protocol I-B	6.14	614	614
	Protocol I-B	6.07	580	580
	Protocol I-B	6.09	614	614
	Protocol I-B	6.30	602	602
	Protocol I-B	6.02	530	530
	Protocol I-B	6.04	564	564
	Protocol I-B	6.05	602	602
	Protocol I-B	6.07	530	530
	Protocol I-B	6.09	564	564
	Protocol I-B	6.32	552	552
	Protocol I-B	6.02	528	528
	Protocol I-B	5.76	524	524
	Protocol I-B	6.27	550	550
	Protocol II-B	4.90	573	573
	Protocol II-B	5.11	587	587
	Protocol II-B	5.02	553	553
	Protocol II-B	4.79	539	539
	Protocol I-A	4.80	567	567
	Protocol I-A	4.52	553	553
	Protocol I-A	4.99	601	601
	Protocol I-A	4.75	587	587
	Protocol I-A	4.00	537	537
	Protocol I-A	3.75	523	523
	Protocol II-A	4.28	551	551
	Protocol II-A	3.99	537	537
	Protocol I-C	3.21	549	549
	Protocol I-C	3.06	527	527
	Protocol I-C	3.04	507	507
	Protocol I-A	4.15	561	561
	Protocol II-A	4.47	572.5	572.8
	Protocol II-A	4.12	539.0	538.8
	Protocol II-A	3.69	560.7	560.9
	Protocol II-A	3.36	518.6	518.9
	Protocol II-A	3.24	504.5	504.9
	Protocol II-A	3.42	548.6	549.3
	Protocol II-C	3.75	504.5	505.2
	Protocol II-C	3.55	518.6	519.2
	Protocol II-C	4.10	560.7	561.2
	Protocol II-C	4.89	572.5	573.2
	Protocol II-C	4.78	539.0	539.2
	Protocol II-C	3.31	548.6	549.2
	Protocol II-A	3.88	574.7	574.9
	Protocol II-A	3.38	562.6	562.9
	Protocol II-A	4.01	518.6	518.7
	Protocol II-A	4.74	532.6	532.9
	Protocol I-B	5.48	553.0	553.1
	Protocol II-B	4.32	530.5	531.3
	Protocol I-B	5.96	587.6	588.2
	Protocol I-B	5.95	554.0	554.2
	Protocol I-B	5.78	537.6	538.2
	Protocol I-B	6.18	575.7	576.3
	Protocol I-B	5.54	523.5	524.2
	Protocol I-B	5.88	561.6	562.3
	Protocol I-B	5.70	540.0	540.2
	Protocol I-B	5.73	573.5	574.2
	Protocol I-B	5.91	586.5	587.2
	Protocol I-B	5.88	553.0	553.2
	Protocol I-B	5.73	518.5	519.2
	Protocol I-B	5.95	588.5	589.2
	Protocol I-B	5.94	555.0	555.2
	Protocol I-B	5.80	520.5	521.2
	Protocol I-B	5.89	562.5	563.2
	Protocol I-B	5.81	529.0	529.2
	Protocol I-B	5.77	514.9	515.2
	Protocol I-B	5.82	548.5	549.2
	Protocol I-B	5.57	480.5	481.2
	Protocol I-B	5.51	555.0	555.2
	Protocol I-B	5.60	588.5	589.2
	Protocol I-B	5.33	520.5	521.2
	Protocol I-B	6.08	600.6	601.2
	Protocol I-B	5.74	613.6	614.2
	Protocol I-B	5.68	593.6	594.2
	Protocol I-B	5.86	613.6	614.2
	Protocol I-B	5.80	593.6	594.2
	Protocol I-B	6.04	582.6	583.2
	Protocol I-B	6.33	541.7	542.3
	Protocol I-B	6.22	561.6	562.3
	Protocol I-B	6.29	527.6	528.3
	Protocol I-B	6.19	577.6	578.3
	Protocol I-B	5.48	582.6	583.3
	Protocol I-B	5.72	572.6	572.1
	Protocol I-B	5.59	589.6	590.3
	Protocol I-B	5.97	614.7	615.2
	Protocol I-B	5.77	613.6	614.2
	Protocol I-B	5.86	617.7	618.3
	Protocol I-B	5.45	575.6	576.2
	Protocol I-B	6.19	635.1	635.2
	Protocol I-B	5.71	593.6	594.2
	Protocol I-B	5.92	584.6	585.2
	Protocol I-B	6.13	620.6	621.2
	Protocol I-B	5.75	613.6	614.2
	Protocol I-B	5.91	633.5	634.2
	Protocol I-B	5.86	613.6	614.2
	Protocol I-B	6.10	602.6	603.2
	Protocol I-B	5.56	602.6	603.2
	Protocol I-B	5.78	592.6	547.2 (it is believed that this compound fragmented during analysis)
	Protocol I-B	5.66	609.6	610.2
	Protocol I-B	6.02	634.6	635.2
	Protocol I-B	5.83	633.5	634.2
	Protocol I-B	5.92	637.7	638.3
	Protocol I-B	5.53	595.6	596.2
	Protocol I-B	6.23	655.1	655.1
	Protocol I-B	5.77	613.6	614.2
	Protocol I-B	5.98	604.5	605.2
	Protocol II-A	4.85	590.6	590.8
	Protocol II-A	4.85	557.0	556.8
	Protocol II-A	4.50	547.6	547.9
	Protocol II-A	4.96	556.0	555.8
	Protocol II-A	4.76	551.6	551.9
	Protocol II-A	5.20	563.7	563.9
	Protocol II-A	4.99	591.5	590.8
	Protocol II-A	5.50	617.7	618.1
	Protocol II-A	5.15	546.5	545.9
	Protocol II-A	5.15	580.0	579.8
	Protocol II-A	5.18	596.0	595.9
	Protocol II-A	5.45	617.7	618.0
	Protocol II-A	4.48	582.6	582.9
	Protocol II-A	5.06	550.6	550.9
	Protocol II-A	4.80	537.0	536.8
	Protocol II-A	4.82	570.6	570.8
	Protocol II-A	5.47	568.1	567.9
	Protocol II-A	4.71	522.6	522.9
	Protocol II-A	4.97	588.6	588.9
	Protocol II-A	5.14	558.7	559.0
	Protocol II-A	5.42	568.1	567.9
	Protocol I-D	3.90	546.5	545.9
	Protocol II-A	5.04	618.6	619.0
	Protocol II-A	4.99	604.6	604.9
	Protocol II-A	5.12	618.6	618.8
	Protocol II-A	4.88	590.6	591.0
	Protocol II-A	4.99	625.0	624.9
	Protocol II-A	4.85	536.6	537.1
	Protocol II-A	4.65	552.6	553.1
	Protocol II-A	4.78	604.6	559.0
	Protocol II-A	4.77	614.6	615.2
	Protocol II-A	4.74	602.6	602.8
	Protocol I-B	6.14	568.5	569.2
	Protocol I-B	6.07	569.5	570.2
	Protocol I-B	5.79	531.5	532.2
	Protocol I-B	5.69	531.5	532.2
	Protocol I-B	6.08	574.5	575.2
	Protocol I-B	5.84	520.5	521.2
	Protocol I-B	5.90	520.5	521.2
	Protocol I-B	5.61	536.5	537.2
	Protocol I-B	5.58	452.6	453.2
	Protocol I-B	5.40	463.5	464.2
	Protocol I-B	5.30	468.6	469.2
	Protocol I-B	5.64	452.6	453.3
	Protocol I-B	5.51	463.5	464.2
	Protocol I-B	5.86	506.5	507.2
	Protocol I-B	5.80	487.0	487.2
	Protocol I-B	5.62	498.0	4.98
	Protocol I-B	5.54	503.0	530.2
	Protocol I-B	5.85	487.0	487.2
	Protocol I-B	5.73	498.0	498.2
	Protocol I-B	6.04	541.0	541.2
	Protocol I-B	6.10	508.7	509.3
	Protocol I-B	5.91	519.6	520.3
	Protocol I-B	5.84	524.7	525.3
	Protocol I-B	6.15	508.7	509.3
	Protocol I-B	6.02	519.6	520.3
	Protocol I-B	6.32	562.6	563.3
	Protocol I-B	5.97	574.5	575.2
	Protocol I-B	5.88	575.5	576.1
	Protocol I-B	5.08	542.0	542.0
	Protocol I-B	5.88	560.5	561.2
	Protocol I-B	6.18	548.6	549.3
	Protocol I-B	5.87	526.9	527.2
	Protocol I-B	6.11	546.6	547.3
	Protocol I-B	6.38	563.6	564.3
	Protocol I-B	6.28	588.7	589.3
	Protocol I-B	5.96	567.0	567.2
	Protocol I-B	5.80	534.5	535.1
	Protocol I-B	6.06	522.6	523.2
	Protocol I-B	5.76	500.9	501.1

Example 266

Determining Activity Against Ascaridia galli and Oesophagostomum dentatum

Example 267

Determining Resistance-Breaking Activity Against Haemonchus contortus

Example 268

Determining Efficacy Against Haemonchus contortus in Jirds

Example 269

Determining Efficacy Against Haemonchus contortus in Sheep

Example 270

Determining Efficacy Against Haemonchus contortus and Trichostrongylus colubriformis in Cattle

DEFINITIONS

[0491]

[0493]

[0495]

[0502]
This term also is intended to encompass a hydrated carbonyl substituent, i.e., —C(OH)₂—.

[0504]

[0508]

[0510]

[0512]
Similarly, the term “heterocyclylcarbonyl” (alone or in combination with another term(s)) means —C(O)-heterocyclyl.

[0516]

[0518]
Thus, for example, “alkyl-sulfonyl-alkyl” means alkyl-S(O)₂-alkyl.

[0520]

[0522]
Thus, for example, “alkyl-sulfinyl-alkyl” means alkyl-S(O)-alkyl.

[0534]
As can be seen, the ethyl is bound to the benzene, and the methoxy is the component of the substituent that is the component furthest from the benzene. As further illustration, benzene substituted with cyclohexanylsulfanylbutoxy has the following structure:

[0535]

[0537]

[0539]

* * *