PARA-SUBSTITUTED INDANYL AND TETRALINYL DERIVATIVES

Abstract

Compounds of formula I and formula II

##STR00001##

their intermediates, as well as processes for the preparation of compounds of formula I and formula II, are disclosed. Use of compounds of formula I for the production of compounds of formula VI

##STR00002##

is also disclosed. Additionally, the use of compounds of formula I or formula II for the production of active compounds is disclosed.

Claims

1. Compounds of formula I ##STR00069## wherein the variables have the following meaning: X Cl, Br, or I; R.sup.1 H, OR.sup.11, or NR.sup.12R.sup.13; R.sup.11 a) H; b) C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.3-C.sub.8-cycloalkenyl, C.sub.2-C.sub.6-alkynyl; which groups are unsubstituted, or substituted by halogen, CN, NO.sub.2, phenyl, S(O).sub.mR.sup.A, OR.sup.B, NR.sup.BR.sup.C, S(O).sub.mNR.sup.BR.sup.C, Si(R.sup.B).sub.2R.sup.C, C(O)R.sup.B, C(O)NR.sup.BR.sup.C, C(O)OR.sup.B, C(S)R.sup.B, C(S)NR.sup.BR.sup.C, C(S)OR.sup.B, C(S)SR.sup.B, C(NR.sup.B)R.sup.C, C(NR.sup.B)NR.sup.CR.sup.D; c) phenyl, which is unsubstituted, or substituted by R.sup.A; or d) a 3-, 4-, 5-, 6-, or 7-membered saturated, partially unsaturated or fully unsaturated heterocycle, which heterocycle comprises one, or more, same, or different heteroatoms O, N(O).sub.n, or S(O).sub.m; wherein R.sup.A a) C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, phenyl; which groups are unsubstituted, or substituted by halogen, CN, OH, NO.sub.2, phenyl, or C.sub.1-C.sub.6-alkyl-phenyl; b) a 3-, 4-, 5-, 6-, or 7-membered saturated, partially unsaturated or fully unsaturated heterocycle, which heterocycle comprises one, or more, same, or different heteroatoms O, N(O).sub.n, and S(O).sub.m, wherein none, one, or more ring members are replaced by C(O), or C(S), and which heterocycle is unsubstituted, or substituted by halogen, CN, N.sub.3, NO.sub.2, SCN, SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, or C.sub.2-C.sub.6-haloalkynyl; R.sup.B, R.sup.C, R.sup.D are independently from one another, as defined for R.sup.A, or H; or two substituents R.sup.B, R.sup.C, or R.sup.D, together with the atom, or the atoms to which they are bound, form a 3, 4, 5, 6, or 7-membered saturated, partially unsaturated, or fully unsaturated carbocycle, or heterocycle, which cycles are unsubstituted, or substituted by R.sup.A, and wherein the heterocycle comprises one, or more, same, or different heteroatoms O, N(O).sub.n, or S(O).sub.m, and wherein none, one, or more ring members are replaced by C(O), or C(S); R.sup.12 H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, phenyl; which groups are unsubstituted, or substituted by R.sup.E; R.sup.13 a) H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.6-alkyl, phenyl; which groups are unsubstituted, or substituted by R.sup.E; b) a group Z-A, wherein Z is a chemical bond, CH.sub.2, CH.sub.2CH.sub.2 or CO; and A is a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or fully unsaturated heterocycle, which heterocycle is unsubstituted or substituted by R.sup.F and comprises one, or more, same, or different heteroatoms O, N(O).sub.n, and S(O).sub.m, and wherein none, one, or more ring members are replaced by C(O), or C(S), C(NR.sup.B), or C(NOR.sup.B); c) a group S(O).sub.mR.sup.A, S(O).sub.mN(R.sup.B)R.sup.C, N(R.sup.B)R.sup.C, N(R.sup.B)C(O)OR.sup.C, N(R.sup.B)C(O)N(R.sup.C)R.sup.D, N(R.sup.B)C(S)OR.sup.C, N(R.sup.B)C(S)N(R.sup.C)R.sup.D, C(O)N(R.sup.B)R.sup.C, C(S)N(R.sup.B)R.sup.C, C(O)OR.sup.A, CNOR.sup.A, CNR.sup.AR.sup.B, CNR.sup.BR.sup.C; or wherein R.sup.12 and R.sup.13, together with the N-atom to which they are bound, form a 3, 4, 5, 6, or 7-membered saturated, partially unsaturated, or fully unsaturated carbocycle, or heterocycle, which cycles are unsubstituted, or substituted by R.sup.F, and wherein the heterocycle comprises one, or more, same, or different heteroatoms O, N(O).sub.n, and S(O).sub.m, and wherein none, one, or more ring members are replaced by C(O), or C(S), C(NR.sup.B), or C(NOR.sup.B); or wherein R.sup.12 and R.sup.13, together with the N-atom to which they are bound, form a group S(R.sup.B)R.sup.C, NR.sup.B, NOR.sup.B, or NN(R.sup.B)R.sup.C; R.sup.E a) halogen, CN, N.sub.3, NO.sub.2, SCN, SF.sub.5, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, Si(R.sup.B).sub.2R.sup.C, OR.sup.11, OSO.sub.2R.sup.A, S(O).sub.mR.sup.A, S(O).sub.mN(R.sup.B)R.sup.C, N(R.sup.B)R.sup.C, C(O)N(R.sup.B)R.sup.C, C(O)N(R.sup.B)N(R.sup.C)R.sup.D, C(O)NOR.sup.B, C(S)N(R.sup.B)R.sup.C, C(O)OR.sup.A; b) phenyl, which is unsubstituted, or substituted by R.sup.A; or c) two substituents R.sup.E, together with the atom, or the atoms to which they are bound, form a 3, 4, 5, 6, or 7-membered saturated, partially unsaturated, or fully unsaturated carbocycle, or heterocycle, which cycles are unsubstituted, or substituted by R.sup.A, and wherein the heterocycle comprises one, or more, same, or different heteroatoms O, N(O).sub.n, or S(O).sub.m, and wherein none, one, or more ring members are replaced by C(O), or C(S), C(NR.sup.B), or C(NOR.sup.B); R.sup.F a) halogen, CN, N.sub.3, NO.sub.2, SCN, SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, Si(R.sup.B).sub.2R.sup.C, OR.sup.11, OSO.sub.2R.sup.A, S(O).sub.mR.sup.A, S(O).sub.mN(R.sup.B)R.sup.C, N(R.sup.B)R.sup.C, C(O)N(R.sup.B)R.sup.C, C(O)N(R.sup.B)N(R.sup.C)R.sup.D, C(O)NOR.sup.B, C(S)N(R.sup.B)R.sup.C, C(O)OR.sup.A; b) phenyl, which is unsubstituted, or substituted by R.sup.A; or c) two substituents R.sup.F, together with the atom, or the atoms to which they are bound, form a 3, 4, 5, 6, or 7-membered saturated, partially unsaturated, or fully unsaturated carbocycle, or heterocycle, which cycles are unsubstituted, or substituted by R.sup.A, and wherein the heterocycle comprises one, or more, same, or different heteroatoms O, N(O).sub.n, and S(O).sub.m, and wherein none, one, or more ring members are replaced by C(O), or C(S), C(NR.sup.B), or C(NOR.sup.B); k 1, or 2 m 0, 1, or 2; n 0, or 1.

2. The compounds according to claim 1, wherein k is 1.

3. The compounds according to claim 1, wherein k is 2.

4. The compounds according to claim 1, wherein R.sup.1 is OR.sup.11, and R.sup.11 is H, C.sub.1-C.sub.6-alkyl, phenyl, or benzyl.

5. The compounds according to claim 4, wherein R.sup.11 is C.sub.1-C.sub.4-alkyl.

6. A process for the production of compounds I, as defined in claim 1, by reaction of compounds II with a reducing agent. ##STR00070##

7. The process according to claim 6, wherein compounds II are produced by reaction of compounds V ##STR00071## with H.sub.2O, R.sup.11OH, or NHR.sup.12R.sup.13; wherein X is Cl, Br, or I, and U is halogen; and wherein compounds V are produced by reaction of compounds III ##STR00072## with a halogenating agent, followed by cyclization in the presence of a Lewis acid.

8. The process according to claim 7, wherein compounds III are produced by reaction of compounds IV selected from IVa, IVb, or IVc ##STR00073## with hydrogen, followed by hydrolysis; wherein R.sup.2 is CN, or C(O)OR.sup.A.

9. The process according to claim 8, wherein the hydrogen is produced in situ from a) a metal selected from alkali metals, and alkaline earth metals, or b) a metal with a redox potential below 0 at a pH below 7.0.

10. (canceled)

11. Compounds of formula VI ##STR00074## produced from compounds of formula 1 as defined in claim 1, wherein R.sup.3 is H, or CH.sub.3, and k and R.sup.1 have a meaning as defined in claim 1.

12. Insecticidal compounds of formula XIV-A or XV-A ##STR00075## produced from compounds of formula 1 as defined in claim 1, wherein V is selected from CH, N, and NO, W is selected from O, S and CH.sub.2, and R.sup.7, R.sup.8, and R.sup.9 are independently hydrogen, halogen, halomethyl, or halomethoxy, wherein at most two substituents R.sup.7, R.sup.8, and R.sup.9 are H, and R.sup.1, R.sup.13, and k have a meaning as defined in claim 1.

13. (canceled)

14. (canceled)

15. (canceled)

16. The insecticidal compounds of claim 12, wherein the compounds of formula 1 are produced by reaction of compounds II with a reducing agent. ##STR00076##

Description

EXAMPLES

I. Characterization

[0432] The characterization can be done by coupled High Performance Liquid Chromato-graphy/mass spectrometry (HPLC/MS), by NMR or by their melting points.

[0433] HPLC/MS. The gradient was 5-95% B in 0.7 min, 95-95% B in 0.45 min, 95-5% B in 0.01 min, and then hold at 0% B for 0.44 min (1.5 mL/min flow rate). Mobile phase A was 0.0375% TFA in water, mobile phase B was 0.018% TFA (trifluoroacetic acid) in MeCN (acetonitrile). Column temperature was 40 C. The column used for the chromatography was a Chromolith Flash RP-18e 25-2 mm column. MS-method: ESI positive.

[0434] NMR data of compounds and intermediates are summarized in Table 2.

[0435] HPLC-MS data of compounds and intermediates are summarized in Table 3 to 5. HPLC devices, solvents, columns, and gradients are listed in Table 7.

[0436] .sup.1H-NMR: The signals are characterized by chemical shift (ppm) vs. tetramethylsilane, by their multiplicity and by their integral (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of the signals: m=multiplett, q=quartett, t=triplett, d=doublet and s=singlet.

[0437] Abbreviations used are: h for hour(s), min for minute(s), eq for equivalent(s).

Preparation Examples

Example 1: Production of ethyl (E)-3-(5-bromo-2-cyano-phenyl)prop-2-enoate (IVa.1)

[0438] A mixture of NaH (1.05 g/60 wt % in mineral oil) and DME (7 mL) was produced and cooled to 30 C. Subsequently, a solution of ethyl 2-diethoxyphosphorylacetate (5.9 g) in DME (47 mL) was added dropwise to the mixture over 15 minutes and stirred at 30 C. for further 35 minutes. Then, a solution of 4-bromo-2-formylbenzonitrile (5 g) in DME (43 mL) was added at about 30 C. dropwise over 20 minutes, and the mixture was stirred for additional 2 h. The reaction was quenched by addition of H.sub.2O (70 mL), which was extracted with ethyl acetate. The organic extracts were combined and the solvent was evaporated. Compound IVa.1 was isolated by silica chromatography, resulting in a final yield of 88%. No impurities were detectable by H-NMR.

Example 2: Production of 4-bromo-2-(2-carboxyethyl)benzoic acid (III.1)

[0439] A mixture of compound IVa (1 g) from Example 1 with 25 mL of acetic acid was produced. Subsequently Zn powder (2 g) was added and the mixture stirred for 3 h at 80 C. The mixture was filtrated and the filtrate concentrated by evaporation of the solvent. Ethyl 3-(5-bromo-2-cyano-phenyl)propanoate was obtained with a yield of 100%, no impurities were detectable by H-NMR.

[0440] In turn, a premix of H.sub.2SO.sub.4 (2.1 g) with 1 mL of H.sub.2O and 2.6 mL acetic acid was produced. Ethyl 3-(5-bromo-2-cyano-phenyl)propanoate (400 mg) was added to the premix and the resulting reaction mixture was stirred for 20 h at about 139 C. The reaction was then cooled by addition of 25 g of ice. The precipitated compound III.1 was filtrated, washed with H.sub.2O, and the resulting crystals were dried. The final yield was 75%.

Example 3: Production of methyl 7-bromo-1-oxo-indane-4-carboxylate (II.1)

[0441] Step 1: A mixture of compound III.1 (600 mg) from Example 2 with 26 mL of CH.sub.2Cl.sub.2 and a few drops of DMF was produced. Oxalylchloride (1.9 g) was added dropwise at about 25 C. and the mixture was stirred for 35 minutes. The solvent and remaining oxalylchloride were evaporated and 4-bromo-2-(3-chloro-3-oxo-propyl)benzoyl chloride (compound III.1) was instantly further converted by Friedel-Crafts acylation.

[0442] Step 2: A mixture of AlCl.sub.3 (469 mg) and CH.sub.2Cl.sub.2 (10 mL) was produced. A solution of compound III.1 (692 mg) in CH.sub.2Cl.sub.2 (20 mL) was added to the mixture at about 0 C. over 12 minutes. The mixture was then heated to about 40 C. and stirred under reflux.

[0443] Chemical shifts, multiplicity, and peak intensity for 7-bromo-1-oxo-indane-4-carbonyl chloride (compound V.1) are summarized in Table 2.

[0444] Compound V.1 was then esterified by addition of CH.sub.3OH (10 mL) to the mixture at about 15 C. The solvent was evaporated, 5 mL of H.sub.2O was added and the aqueous phase was extracted with CH.sub.2Cl.sub.2. The organic phases were combined and the solvent was evaporated. Compound II.1 was isolated from the reaction mixture via silica chromatography.

Example 4: Production of 7-bromo-N-(cyclopropylmethyl)-1-oxo-indane-4-carboxamide (II.2)

[0445] Compound III.1 was cyclized to compound V.1 as described in Example 3. Compound V.1 was then amidated by addition of 172 mg cyclopropylmethanamine to the mixture to yield compound II.2.

Example 5: Production of 7-bromo-1-oxo-indane-4-carboxylic acid (II.3)

[0446] Compound III.1 was cyclized to compound V.1 as described in Example 3. Compound V.1 was then treated with water to yield compound II.3.

Example 6: Production of methyl 7-bromoindane-4-carboxylate (I.1)

[0447] A mixture of HgCl.sub.2 (28 mg), H.sub.2O (3 mL), concentrated aqueous HCl (0.025 mL) and Zn powder (370 mg) was produced. The mixture was stirred for 5 minutes at about 20-25 C., the supernatant was decanted. A premix of 3 mL of H.sub.2O and 9 mL of concentrated aqueous HCl was added to the mixture, resulting in the production of gas. Compound II.1 (100 mg) from Example 3 was added to the mixture and stirred for 1.5 h under reflux. Workup was achieved by addition of brine and extraction with ethyl acetate. The organic phases were combined and the solvent was evaporated. Compound 1.1 was isolated by silica chromatography with a purity above 90% (determined by .sup.1H-NMR).

Example 7: Production of Compound 1.1 from Compound II.1 by Reduction with NaBH.SUB.4., Followed by Dehydroxylation

[0448] A mixture of compound II.1 (180 mg) from Example 3 with CH.sub.3OH (10 mL) was produced and cooled to 0 C. NaBH.sub.4 (28 mg) was added to the mixture and stirred for 40 minutes at about 0 C., followed by 40 minutes at 20-25 C. Aqueous HCl (1 M) was added to a final pH of 7.0 and the solvent was evaporated. Methyl 7-bromo-1-hydroxy-indane-4-carboxylate (IIa.1) was produced at high purity (95%, determined by .sup.1H-NMR) with a yield of 89%.

[0449] A mixture of compound IIa (65 mg) with CH.sub.2Cl.sub.2 and trifluoroacetic acid (160 mg) was produced.

[0450] The mixture was stirred at about 25 C. for 70 h. Methyl 7-bromo-1-(2,2,2-trifluoroacetyl)oxy-indane-4-carboxylate was isolated by silica chromatography.

[0451] A mixture of methyl 7-bromo-1-(2,2,2-trifluoroacetyl)oxy-indane-4-carboxylate with 3 mL of trifluoroacetic acid and triethyl silane (67 mg) was produced. The mixture was stirred at 20-25 C. for 64 h, upon which the solvent was evaporated. Compound 1.1 was produced in pure form with a yield of 92% (determined by .sup.1H-NMR).

Example 8: Characterization of Compound V.1 by NMR Spectroscopy

[0452] Compound V.1 was synthesized as described in Example 3. Before quenching, the reaction mixture was complemented with perdeuterated DMSO. The sample was measured by .sup.1H-NMR and .sup.1H-decoupled .sup.13C-NMR at 500 MHz.

[0453] The following peaks were detected in the

[0454] a).sup.13C-spectrum [ppm]: 27.58, 38.64, 162.27, 166.55, 223.00.

[0455] b).sup.1H-spectrum [ppm]: 3.02, 3.14, 7.49 (d), 8.07 (d).

[0456] The sample was also measured by .sup.1H-Correlation Spectroscopy (COSY) .sup.1H,.sup.13C-heteronuclear single quantum coherence (HSQC), and .sup.1H,.sup.1H-heteronuclear multiple bond correlation (HMBC), resulting in the following peaks and their structural correlation:

##STR00068##

[0457] Assignment: 1) (3.14/27.58); 2) (3.02/38.64); 3) (223.00), 4) (162); 5) (139.6), 6) (121.0); 7) (7.49/131.6); 8) (8.07/134.0); 9) (130.6), 10) (167.0).

Example 9: Production of methyl 7-acetylindane-4-carboxylate (VI.1)

[0458] A mixture of methyl 7-bromoindane-4-carboxylate (compound I.1, 46 mg), ethylene glycol vinyl ether (79.5 mg), Pd(OAc).sub.2 (1 mg), 1,3-bis(diphenylphosphino)propane (3.7 mg), K.sub.2CO.sub.3 (74.5 mg) and 1 mL of water was stirred at 90 C. for 80 minutes under reflux. The mixture was cooled to about 25 C. and concentrated aqueous HCl (0.3 mL) was added. The resulting mixture was stirred at about 25 C. for one hour. Workup was achieved by addition of K.sub.2CO.sub.3 (10 wt % aqueous solution) and extraction by ethyl acetate. Then the organic phase was dried and concentrated. Compound VI.1 was isolated from the extract by silica column chromatography.

Example 10: Production of methyl 7-[(Z)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]indane-4-carboxylate (XIX.1)

[0459] A solution of methyl 7-acetylindane-4-carboxylate (compound VI.1, 50.00 g) in 1 liter 1,2-dichloroethane (DCE) was added to a mixture of 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (119.59 g), K.sub.2CO.sub.3 (38.00 g), and triethylamine (27.82 g). Then the mixture was stirred at about 120 C. under nitrogen for 12 h. Water (500 mL) was added to the mixture, which was in turn extracted with dichloromethane (DCM). Then the organic phase was dried and concentrated. Compound IX.1 was isolated by from the residue by silica column chromatography.

Example 11: Production of methyl 7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indane-4-carboxylate (XIV.1)

[0460] A mixture of a solution of compound XIX.1 of example 10 (100.00 g) in two liters DCE, NH.sub.2OH/HCl (30.13 g), and tetra-n-butylammonium bromide (10.48 g) was produced. A solution of NaOH (34.69 g) in 400 mL water was admixed dropwise at about 25 C. Then the mixture was stirred at about 25 C. for 12 h. Water (200 mL) was added to the mixture, which was in turn extracted with DCM. The organic phase was washed with water, dried, filtered and concentrated by evaporation of the solvent. Compound XIV.1 was isolated from the residue by silica column chromatography with a yield of 96.8%.

Example 12: Production of 7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indane-4-carboxylic acid (XIV.2)

[0461] A solution of compound XIV.1 of example 11 (110.00 g) in THF/dioxane (500 mL/500 mL), and a solution of LiOH.H.sub.2O (48.46 g) in 150 mL water was mixed at about 25 C. Then the mixture was stirred at about 80 C. for 18 h, cooled to about 25 C., and concentrated under reduced pressure at about 50 C. Water (400 mL) was added to the mixture, which was subsequently extracted with petroleum ether (400 mL). The pH of the aqueous phase was then adjusted to about 2.0 with aqueous HCl. The aqueous phase was subsequently extracted with ethyl acetate. The ethyl acetate extract was dried, and concentrated in vacuo. The residue was washed with hexane (600 mL), resulting in compound XIV.2 with a yield of 93.7% as a white solid.

Example 13: Production of 7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-(pyrimidin-2-ylmethyl)indane-4-carboxamide (XIV.3)

[0462] A solution of compound XIV.2 of example 12 (230 mg), the HCl salt of pyrimidin-2-ylmethanamine (65 mg), and PyBrop (279 mg), in DCM (15 mL) was produced. Di-isopropyl ethyl amine (258 mg) was admixed at 20 to 25 C. The mixture was stirred overnight under nitrogen. The reaction was extracted with water, and the organic phase was concentrated in vacuo. Compound XIV.3 was isolated from the residue via silica column chromatography.

Example 14: Production of methyl 7-[(Z)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl]indane-4-carboxylate (XIX.2)

[0463] A mixture of 1-[7-(1-methoxyvinyl)indan-4-yl]ethanone (27 g), 1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethanone (60 g), K.sub.2CO.sub.3 (22 g), triethylamine (16 g) and dichloroethane (600 mLl) was produced. The mixture was stirred at 110 C. under nitrogen for 12 h. Water (500 mL) was added to the mixture. The mixture was subsequently extracted with DCM. The organic phase was dried over N.sub.2SO.sub.4 and concentrated in vacuo. Compound XIX.2 was isolated from the residue via silica column chromatography with a yield of 87.8%.

Example 15: Production of methyl 7-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-(nitromethyl)butanoyl]indane-4-carboxylate

[0464] A mixture of compound XIX.2 of example 14 (40 g), MeCN (400 mL), 1,8-diazabicyclo[5.4.0]un-dec-7-ene (41 g) and nitromethane (27 g) was produced. The mixture was stirred for 40 min at 20 C. and subsequently adjusted to pH 5-6 with aqueous HCl. The mixture was then extracted with ethyl acetate. The organic phase was concentrated in vacuo. Methyl 7-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-(nitromethyl)butanoyl]indane-4-carboxylate was isolated from the residue via silica column chromatography with a yield of 80%.

Example 16: Production of Methyl 7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5-yl]indane-4-carboxylate (XIV.4)

[0465] Iron powder (10.4 g) was added at about 25 C. to a mixture of methyl 7-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-(nitromethyl)butanoyl]indane-4-carboxylate of example 15, CH.sub.3OH (300 mL), and CH.sub.3COOH (300 mL). The mixture was stirred at 80 C. for 12 h. The mixture was concentrated in vacuo and subsequently poured into a saturated solution of aqueous NaHCO.sub.3. The resulting mixture was extracted with ethyl acetate. The organic phase was concentrated in vacuo. Compound XIV.4 was isolated from the residue via silica column chromatography.

Example 17: Production of 7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5-yl]indane-4-carboxylic acid (XIV.5)

[0466] A mixture of compound XIV.4 of example 16 (19 g), THF (200 mL) and CH.sub.3OH (100 mL) was produced. A solution of LiOH.H.sub.2O (8.4 g) in water (100 mL) was added to the mixture at 25 C., which was subsequently stirred at 20 C. for 12 h. The pH of the mixture was then adjusted to pH 9 with aqueous HCl. The mixture was subsequently reduced in vacuo, upon which the pH was again adjusted to pH 5 with aqueous HCl. The resulting mixture was then extracted with ethyl acetate. The organic phase was concentrated in vacuo. Compound XIV.5 was isolated from the residue via silica column chromatography.

Example 18: Production of 7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5-yl]-N-(pyrimidin-2-ylmethyl)indane-4-carboxamide (XIV.6)

[0467] A solution of compound XIV.5 (1.0 eq), pyrimidin-2-ylmethanammoniumchloride (1.2 eq), PyBrOP (1.2 eq) in DCM (10 mL) was produced. Diisopropylethylamine (3-4 eq) was added to the mixture at 20 to 25 C. The mixture was stirred under nitrogen for several hours. The mixture was extracted with water, and the organic phase was reduced in vacuo. Compound XIV.6 was isolated from the residue via silica column chromatography.

Example 19: Production of 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5-yl]-N-(pyrimidin-2-ylmethyl)indane-4-carboxamide (XIV.7)

[0468] Compound 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5-yl]indane-4-carboxylic acid was produced in analogy to examples 14 to 17. A solution of 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5-yl]indane-4-carboxylic acid (2.5 g), pyrimidin-2-ylmethanammoniumchloride (0.95 g), PyBrOP (3.04 g) in DCM (100 mL) was produced. Diisopropylethylamine (2.25 g) was added to the mixture at 20 to 25 C. The mixture was stirred under nitrogen for several hours. The mixture was extracted with water, and the organic phase was reduced in vacuo. Compound XIV.7 was isolated from the residue via silica column chromatography.

Example 20: Production of 5-(3,5-dichlorophenyl)-3-hydroxy-3-(7-methoxycarbonylindan-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid

[0469] 2-sulfanylacetic acid (2.2 g) and triethylamine (2.4 g) were added to a mixture of compound XIX.2 of example 14 (2.2 g) and THF (35 mL). The resulting mixture was stirred at 20 C. for 16 h and reduced in vacuo. Subsequently, the pH was adjusted to pH 2 with aqueous HCl. The mixture was extracted with methyl-tert-butyl-ether (50 mL). Subsequently, the pH of the aqueous phase was adjusted to pH 8 with a saturated solution of NaHCO.sub.3. The aqueous phase was then extracted with ethyl acetate and reduced in vacuo to dryness, thereby yielding 3-(7-carboxyindan-4-yl)-5-(3,5-dichlorophenyl)-3-hydroxy-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid.

Example 21: Production of methyl 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-thiophen-4-yl]indane-4-carboxylate (XIV.8)

[0470] Mesyl chloride (3 g) was added to a mixture of 5-(3,5-dichlorophenyl)-3-hydroxy-3-(7-methoxycarbonylindan-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid of example 20 (6.2 g) and pyridine (60 mL) at 0 C. The mixture was subsequently stirred at 20 C. for 16 h, then poured into H.sub.2O (100 mL) and extracted with ethyl acetate. The organic phase was washed with brine, dried, and reduced in vacuo. DMF (20 mL) was added to the residue, and the resulting mixture was stirred at 120 C. for 1 h. The mixture was reduced in vacuo and then poured into H.sub.2O (100 mL) and extracted with methyl tert-butyl ether. The organic phase was reduced in vacuo. Compound XIV.8 was isolated from the residue via silica column chromatography.

Example 22: Production of 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-thiophen-4-yl]indane-4-carboxylic acid (XIV.9)

[0471] A mixture of compound XIV.8 of example 21 (1.1 g), and THF (15 mL) was produced. A solution of LiOH.H.sub.2O (0.3 g) in water (1 mL) was added to the mixture, which was subsequently stirred at 20 C. for 16 h. The pH of the mixture was then adjusted to pH 2 with aqueous HCl. The resulting mixture was then extracted with ethyl acetate. The organic phase was washed with brine, dried, and concentrated in vacuo. Compound XIV.9 was isolated from the residue via silica column chromatography.

Example 23: Production of Dihydrothiophene Compounds XIV.10 to XIV.13

[0472] A solution comprising compound XIV.9 of example 22 (1.0 eq), PyBrOP (1.2 eq), DCM (10 mL), and an ammonium chloride compound selected from pyrimidin-2-ylmethanammonium chloride, 2-pyridylmethanammonium chloride, 2-ammonium-N-(2,2,2-trifluoroethyl)acetamide chloride, or 1,1-dioxothietan-3-ammonium chloride (1.2 eq) was produced. Diisopropylethylamine (3-4 eq) was added to the mixture at 20 to 25 C. The mixture was stirred under nitrogen for several hours. The mixture was extracted with water, and the organic phase was reduced in vacuo. Depending on the ammonium chloride compound used, a compound XIV.10 to XIV.13 was isolated from the residue via silica column chromatography.

Example 24: Production of Dihydrothiophene Compounds XIV.15 to XIV.20

[0473] 7-[2-(3,5-dichloro-4-fluoro-phenyl)-2-(trifluoromethyl)-3H-thiophen-4-yl]indane-4-carboxylic acid (XIV.14) was produced in analogy to compound XIV.9 in examples 20 to 22. A solution comprising compound XIV.14 (1.0 eq), PyBrOP (1.2 eq), DCM (10 mL), and an ammonium chloride compound selected from 1,1-dioxothietan-3-ammonium chloride, (4R)-4-ammonium-2-ethyl-isoxazolidin-3-one chloride, pyrimidin-2-ylmethanammonium chloride, 2-ammonium-N-(2,2,2-trifluoroethyl)acetamide chloride, thietan-3-ammonium chloride, and 2-methylsulfanylethanammonium chloride (1.2 eq) was produced. Diisopropylethylamine (3-4 eq) was added to the mixture at 20 to 25 C. The mixture was stirred under nitrogen for several hours. The mixture was extracted with water, and the organic phase was reduced in vacuo. Depending on the ammonium chloride compound used, a compound XIV.15 to XIV.20 was isolated from the residue via silica column chromatography.

Example 25: Production of [7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indan-4-yl]methanol

[0474] LiBH.sub.4 (0.44 g) was added to a mixture of compound XIV.1 of example 11 (2 g), and THF (50 mL) at 25 C. The mixture was stirred at 70 C. for 15 h and subsequently diluted with a saturated aqueous solution of NH.sub.4Cl. The mixture was extracted with ethyl acetate. The organic phases were dried, reduced in vacuo. [7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indan-4-yl]methanol was isolated from the residue by silica column chromatography.

Example 26: Production of 3-[7-(chloromethyl)indan-4-yl]-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoro-methyl)-4H-isoxazole

[0475] To a solution of [7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indan-4-yl]methanol (2.0 g) in DCM (60 mL) was admixed triethylamine (3 mL) and mesylchloride (1 g) at 0 C. The mixture was stirred at 25 C. for 10 h. The mixture was subsequently diluted with a saturated aqueous solution of NH.sub.4Cl. The mixture was extracted with ethyl acetate. The organic phases were dried, reduced in vacuo. [7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indan-4-yl]methanol was isolated from the residue by silica column chromatography with a yield of 94%.

Example 27: Production of [7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indan-4-yl]methanamine

[0476] A mixture of 3-[7-(chloromethyl)indan-4-yl]-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoro-methyl)-4H-isoxazole of example 26 (3.8 g), NaN.sub.3 (0.95 g), and DMF (50 mL) was stirred at 25 C. under nitrogen for 13 h. The mixture was diluted with water (100 mL) and extracted with methyl tert-butyl ether. The organic phases were dried and reduced in vacuo. The residue was dissolved in THF (80 mL) and H.sub.2O (80 mL). Triphenylphosphine (2 g) was added, and the mixture was stirred at 85 C. under nitrogen for 2 h. The mixture was extracted with ethyl acetate and the organic phases were dried and concentrated. [7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indan-4-yl]methanamine was isolated from the residue by silica column chromatography.

Example 27: Production of Inverted Amides XV.1 to XV.6

[0477] A mixture of [7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indan-4-yl]methanamine of example 26 (1.0 eq) in THF (10 mL) and TEA (3.0 eq.) was stirred at 20 to 25 C. An acid chloride (1.2 eq.) selected from 2-methylsulfonylacetyl chloride, propanoyl chloride, 3,3,3-trifluoropropanoyl chloride, acetyl chloride, cyclopropanecarbonyl chloride was added dropwise. The reaction mixture was stirred at 20 to 25 C., followed by dilution with H.sub.2O and extraction with ethyl acetate. The organic phases were dried and reduced in vacuo. Depending on the acid chloride compound used, a compound XV.1 to XIV.6 was isolated from the residue via silica column chromatography.

Example 28: Production of Inverted Amides XV.7 to XV.8

[0478] Compound [7-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indan-4-yl]methanamine was produced in analogy to [7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indan-4-yl]methanamine in examples 25 to 27.

[0479] A mixture of [7-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indan-4-yl]methanamine (1.0 eq) in THF (10 mL) and TEA (3.0 eq.) was stirred at 20 to 25 C.

[0480] An acid chloride (1.2 eq.) selected from 2-methylsulfonylacetyl chloride, and propanoyl chloride, was added dropwise. The reaction mixture was stirred at 20 to 25 C., followed by dilution with H.sub.2O and extraction with ethyl acetate. The organic phases were dried and reduced in vacuo. Depending on the acid chloride compound used, a compound XV.7 or XIV.8 was isolated from the residue via silica column chromatography.

Example 29: Production of Further Compounds XIV-A and XV-A

[0481] Tables 3, 4, 5 and 6 list further compounds XIV-A and XV-A from the classes of isoxazazoles, pyrrolines, dihydrothophenes, and dihydrofuranes. These were produced in analogy to examples 1 to 28, or in accordance to the general description of the reactions above from compounds I.1 and VI.1 with the respective amines, acid chlorides, 2,2,2-trifluoroacetophenone, and 4-halogen-2-phenyl-2-(trifluoromethyl)-3H-furan derivatives.

TABLE-US-00002 TABLE 2 Characterization of compounds by NMR spectroscopy Compound Solvent/frequency Chemical shift .sup.1H-NMR (ppm) Chemical shift .sup.13C-NMR (ppm) I.1 DMSO-d6/500 2.04 (m, 2H), 2.9 (t, 2H), 3.3 (t, 2H), 3.8 (s, 23.3, 33.9, 34.77, 52.04, 124.36, MHz 3H), 7.52 (d, 1H), 7.64 (d, 1H) 125.36, 129.65, 129.68, 145.68, 147.9, 166.12. II.1 DMSO-d6/500 2.71 (m, 2H), 3.34 (m, 2H), 3.9 (s, 3H), 25.82, 36.44, 52.21, 123.48, 126.29, MHz 7.78 (d, 1H), 8.06 (d, 1H). 132.66, 134.58, 136.14, 159.27, 165.06, 203.05. II.2 CDCl.sub.3/500 0.31 (q, 4H), 1.06 (m, 1H), 2.77 (m, 2H), 3.60 (2C), 10.70, 24.94, 36.94, 44.90, MHz 3.3 (m, 4H), 6.22 (t, 1H), 7.59 (d, 1H), 7.60 122.21, 132.42, 132.62, 132.75, 134.97, (d, 1H) 156.89, 166.38, 203.68 II.3 DMSO-d6/500 2.69(m, 2H), 3.35 (m, 2H), 7.74 (d, 1H), 26.09, 36.63, 123.14, 128.20, 132.66, MHz 8.04 (d, 1H), 13.4 (s, broad, 1H) 134.59, 136.61, 159.56, 166.42, 203.36 III.1 DMSO-d6/500 2.51 (t, 2H), 3.12 (t, 2H), 7.5 (s, 1H), 7.6 28.59, 34.84, 125.26, 129.24, 129.42, MHz (d, 1H), 7.7 (d, 1H), 12.5 (s, broad, 2H) 132.27, 133.33, 144.39, 167.72, 173.46 V.1 DMSO-d6/500 3.02 (m, 2H), 3.14 (m, 2H), 7.49 (d, 1H), 27.58, 38.64, 121.0, 130.6, 131.6, MHz 8.07 (d, 1H) 134.0, 139.6, 162.27, 167.0, 223.00 VI.1 CDCl.sub.3/500 2.09 (m, J = 7.7 Hz, 2 H) 2.62 (s, 3 H) 3.26 24.85, 28.74, 33.36, 33.64, 52.07, MHz (m, 4 H) 3.93 (s, 3 H) 7.7 (d, J = 8.1 Hz, 1 127.11, 128.15, 129.47, 136.65, 146.96, H) 7.90 (d, J = 8.1 Hz, 1 H) 148.77, 166.95, 199.85 XIV.1 CDCl.sub.3/400 7.809-7.789 (d, J = 8 Hz, 1 H) 7.527-7.513 MHz (d, J = 5.6 Hz, 1 H) 7.187-7.141 (t, J = 9.2 Hz, 1H) 4.099-4.056 (d, J = 17.2 Hz, 1H) 3.84 (s, 3H), 3.704-3.662 (d, J = 16.8 Hz), 3.264-3.226 (m, 2H), 3.137-3.120 (m, 2 H) 2.068-2.030 (m, 2 H). XIV.2 DMSO-d6/500 13.10 (s, 1H, very broad), 7.84 (d, 2H, 167.60, 157.84, 153.74, 146.97, 144.57, MHz J = 6 Hz), 7.81 (d, 1H, J = 8 Hz), 7.50 (d, 1H, 132.95, 129.69, 128.05, 128.05, 128.05, J = 8 Hz), 4.41 (d, 1H, J = 18.3 Hz), 4.33 (d, 126.88, 126.34, 123.68, 121.59, 121.59, 1H, J = 18.3 Hz), 3.23 (t, 2H, J = 7.7 Hz), 3.09 85.63, 43.95, 34.05, 33.25, 24.01 (m 2H), 2.03 (m, 2H) XIV.3 DMSO-d6/500 8.75 (d, 2H, J = 4.9 Hz), 7.65 (d, 1H, 167.74, 165.55, 157.29, 157.29, 156.32, MHz J = 8 Hz), 7.61 (d, 2H, J = 6 Hz), 7.45 (t, 1H, 154.76, 145.91, 144.94, 133.55, 133.08, J = 4.5 Hz), 7.27 (m, 2H), 4.91 (d, 2H, 127.57, 127.57, 126.32, 125.91, 125.79, J = 4.5 Hz), 4.17 (d, 1H, J = 17 Hz), 3.79 (d, 123.77, 123.06, 123.06, 119.73, 86.14, 1H, J = 17 Hz), 3.28 (t, 2H, J = 7.7 Hz), 3.22 45.68, 45.29, 34.93, 33.03, 25.00 (q, 2H, J = 7.7 Hz), 2.15 (m, 2H) XIV.4 CDCl.sub.3/400 7.82 (d, J = 8.38 Hz, 1 H), 7.39 (d, J = 7.94 MHz Hz, 1 H), 7.31 (t, J = 1.54 Hz, 1 H), 7.19 (d, J = 1.32 Hz, 2 H), 4.87 (dd, J = 17.20, 1.32 Hz, 1 H), 4.40 (d, J = 17.20 Hz, 1H), 3.85 (s, 3 H), 3.73 (dd, J = 17.42, 1.54 Hz, 1 H), 3.42 (d, J = 17.20 Hz, 1H), 3.12-3.29 (m, 4 H), 2.03 (t, J = 7.28 Hz, 2H) XIV.5 DMSO-d6/500 13.0 (s, 1H, broad), 7.82 (d, 1H, J = 8 Hz), 171.09, 167.52, 147.14, 145.16, 141.08, MHz 7.69 (m, 2H), 7.60 (d, 2H, J = 1.4 Hz), 4.91 134.15, 134.15, 132.62, 128.33, 128.1, (d, 1H, J = 17.3 Hz), 4.45 (d, 1H, J = 17.3 Hz), 127.9, 127.9, 127.9, 127.36, 127.18, 3.88 (d, 1H, J = 17.9 Hz), 3.77 (d, 1H, 67.22, 54.81, 43.78, 33.62, 33.12, 24.21 J = 17.9 Hz), 3.21 (m, 2H), 2.01 (m, 2H) XIV.6 DMSO-d6/500 8.75 (d, 2H, J = 5 Hz), 7.66 (d, 1H, J = 8 Hz), 135.29, 135.29, 133.3, 131.57, 128.57, MHz 7.51 (d, 1H, J = 8 Hz), 7.45 (t, 1H, J = 4.3 Hz), 127.15, 127.13, 127.13, 126.88, 125.52, 7.38 (t, 1H, J = 1.7 Hz), 7.27 (m, 3H), 4.94 119.63, 68.43, 55.12, 45.61, 45.05, (d, 1H, J = 17.3 Hz), 4.92 (d, 2H, J = 4.3 Hz), 34.24, 32.78, 25.23 4.47 (d, 1H, J = 17.3 Hz), 3.81 (d, 1H, J = 17.3 Hz), 3.51 (d, 1H, J = 17.3 Hz), 3.26 (m, 4H), 2.13 (m, 2H) XIV.8 CDCl.sub.3/400 7.84 (d, J = 8.03 Hz, 1H) 7.37-7.46 (m, MHz 3H) 7.11 (d, J = 8.28 Hz, 1H) 6.45 (s, 1H) 3.87-3.94 (m, 4H) 3.70-3.77 (m, 1H) 3.29-3.36 (m, 2H) 2.96-3.02 (m, 2H) 2.08-2.16 (m, 2H) XIV.9 CDCl.sub.3/400 7.94 (d, J = 8.38 Hz, 1H) 7.38-7.45 (m, 3 MHz H) 7.15 (d, J = 7.94 Hz, 1H) 3.87-3.97 (m, 1H), 3.68-3.80 (m, 2H) 3.32-3.42 (m, 2H) 3.01 (td, J = 7.39, 2.43 Hz, 2H) 2.06- 2.19 (m, 3H) XIV.56 DMSO-d6/500 7.6 (d, 2H, J = 6 Hz), 7.44 (d, 1H, J = 8 Hz), 168.17, 156.11, 154.73, 146.15, 145.47, MHz 7.2 (d, 1H, J = 8 Hz), 7.11 (d, 1H, J = 6.7 Hz), 132.84, 131.68, 127.5, 127.5, 126.22, 4.86 (m, 1H), 4.59 (m, 2H), 4.11 (m, 3H), 126.5, 125.33, 123.66, 123.02, 123.02, 3.77 (d, 1H, J = 17.3 Hz), 3.15 (m, 4H), 2.1 86.24, 71.48, 71.48, 45.08, 34.74, (m, 2H) 32.83, 32.25, 24.79 XIX.1 DMSO-d6/500 7.86 (d, 1H, J = 8 Hz), 7.49 (d, 1H, J = 8 Hz), 192.26, 166.51, 154.67, 149.11, 147.63, MHz 7.32 (q, 1H, J = 1.1 Hz), 7.19 (d, 2H, 135.88, 135.23, 133.35, 130.46, 129.64, J = 6 Hz), 3.92 (s, 3H,), 3.24 (t, 2H, 129.64, 128.25, 127.63, 127.16, 122.63, J = 7.6 Hz), 3.1 (t, 2H, J = 7.6 Hz), 2.07 (quin- 122.63, 122.18, 52.22, 33.33, 32.25, tet, 2H, J = 7.6 Hz) 24.86 XIX.2 CDCl.sub.3/400 7.81 (d, 1H, J = 8.38 Hz), 7.44 (d, 1H, MHz J = 7.94 Hz), 7.25 (d, 2H, 7.06 Hz), 7.07 (d, 2H, 0.88 Hz), 3.89 (s, 3H), 3.21 (t, 2H, J = 7.72 Hz), 3.06 (t, 2H, J = 7.5 Hz), 2.05 (d, 2H, J = 7.5 Hz)

TABLE-US-00003 TABLE 3 Characterization of dihydrothiophene compounds by HPLC-MS Mass over HPLC Retention charge Compound set-up time (m/z) 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-thiophen-4- A 1.440 550.0 yl]-N-(pyrimidin-2-ylmethyl)indane-4-carboxamide (XIV.10) 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-thiophen-4- A 1.267 549.0 yl]-N-(2-pyridylmethyl)indane-4-carboxamide (XIV.11) 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-thiophen-4- A 1.432 596.9 yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]indane- 4-carboxamide (XIV.12) 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-thiophen-4- A 1.416 561.9 yl]-N-(1,1-dioxothietan-3-yl)indane-4-carboxamide (XIV.13) 7-[2-(3,5-dichloro-4-fluoro-phenyl)-2-(trifluoromethyl)-3H- B 1.428 579.6 thiophen-4-yl]-N-(1,1-dioxothietan-3-yl)indane-4-carboxamide (XIV.15) 7-[2-(3,5-dichloro-4-fluoro-phenyl)-2-(trifluoromethyl)-3H- A 1.464 590.4 thiophen-4-yl]-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4- yl]indane-4-carboxamide (XIV.16) 7-[2-(3,5-dichloro-4-fluoro-phenyl)-2-(trifluoromethyl)-3H- A 1.429 568.0 thiophen-4-yl]-N-(pyrimidin-2-ylmethyl)indane-4- carboxamide (XIV.17) 7-[2-(3,5-dichloro-4-fluoro-phenyl)-2-(trifluoromethyl)-3H- A 1.451 614.6 thiophen-4-yl]-N-[2-oxo-2-(2,2,2- trifluoroethylamino)ethyl]indane-4-carboxamide (XIV.18) 7-[2-(3,5-dichloro-4-fluoro-phenyl)-2-(trifluoromethyl)-3H- B 1.467 548.0 thiophen-4-yl]-N-(thietan-3-yl)indane-4-carboxamide (XIV.19) 7-[2-(3,5-dichloro-4-fluoro-phenyl)-2-(trifluoromethyl)-3H- A 1.462 550.0 thiophen-4-yl]-N-(2-methylsulfanylethyl)indane-4-carboxamide (XIV.20)

TABLE-US-00004 TABLE 4 Characterization of inverted amide compounds by HPLC-MS Mass over HPLC Retention charge Compound set-up time (m/z) N-[[7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- A 1.367 567.0 isoxazol-3-yl]indan-4-yl]methyl]-2-methylsulfonyl-acetamide (XV.1) N-[[7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- A 1.421 503.0 isoxazol-3-yl]indan-4-yl]methyl]propanamide (XV.2) N-[[7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- A 1.455 557.0 isoxazol-3-yl]indan-4-yl]methyl]-3,3,3-trifluoro-propanamide (XV.3) N-[[7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- A 1.384 488.9 isoxazol-3-yl]indan-4-yl]methyl]acetamide (XV.4) N-[[7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- A 1.423 514.9 isoxazol-3-yl]indan-4-yl]methyl]cyclopropanecarboxamide (XV.5) N-[[7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- A 1.421 503.0 isoxazol-3-yl]indan-4-yl]methyl]propanamide (XV.6) N-[[7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol- A 1.270 483.1 5-yl]indan-4-yl]methyl]propanamide (XV.7) N-[[7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol- C 1.222 547.1 5-yl]indan-4-yl]methyl]-2-methylsulfonyl-acetamide (XV.8)

TABLE-US-00005 TABLE 5 Characterization of amide compounds by HPLC-MS Mass over HPLC Retention charge Compound set-up time (m/z) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.284 550.9 dihydropyrrol-5-yl]-N-(pyrimidin-2-ylmethyl)indane-4- carboxamide (XIV.7) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.405 535.0 dihydropyrrol-5-yl]-N-(2-methylsulfanylethyl)indane-4- carboxamide (XIV.21) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.284 550.9 dihydropyrrol-5-yl]-N-(pyrimidin-2-ylmethyl)indane-4- carboxamide (XIV.22) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.527 544.8 dihydropyrrol-5-yl]-N-(thietan-3-ylmethyl)indane-4-carboxamide (XIV.23) N-(cyclopropylmethyl)-7-[3-(3,5-dichloro-4-fluoro-phenyl)-3- A 1.393 514.6 (trifluoromethyl)-2,4-dihydropyrrol-5-yl]indane-4-carboxamide (XIV.24) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.265 576.9 dihydropyrrol-5-yl]-N-[(1,1-dioxothietan-3-yl)methyl]indane- 4-carboxamide (XIV.25) N-cyclopropyl-7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4- A 1.347 481.0 dihydropyrrol-5-yl]indane-4-carboxamide (XIV.26) 7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol- A 1.319 538.0 5-yl]-N-(thiazol-4-ylmethyl)indane-4-carboxamide (XIV.27) 7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol- A 1.357 594.0 5-yl]-N-[1-methyl-2-oxo-2-(2,2,2- trifluoroethylamino)ethyl]indane-4-carboxamide (XIV.28) 7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol- A 1.232 529.0 5-yl]-N-(1-oxothietan-3-yl)indane-4-carboxamide (XIV.29) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.468 515.8 dihydropyrrol-5-yl]-N-[(E)-methoxyiminomethyl]indane-4- carboxamide (XIV.30) 1-[[7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4- A 1.286 581.3 dihydropyrrol-5-yl]indane-4-carbonyl]amino]-3-(2,2,2- trifluoroethyl)urea (XIV.31) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.271 565.3 dihydropyrrol-5-yl]-N-(2-methylsulfonylethyl)indane-4- carboxamide (XIV.32) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.433 565.0 dihydropyrrol-5-yl]-N-[[1- (difluoromethyl)cyclopropyl]methyl]indane-4-carboxamide (XIV.33) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.358 498.9 dihydropyrrol-5-yl]-N-prop-2-ynyl-indane-4-carboxamide (XIV.34) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.411 549.3 dihydropyrrol-5-yl]-N-[(2,2- difluorocyclopropyl)methyl]indane-4-carboxamide (XIV.35) 7-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5- A 1.308 583.1 yl]-N-[[5-(difluoromethyl)pyrimidin-2-yl]methyl]indane-4- carboxamide (XIV.36) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.269 577.2 dihydropyrrol-5-yl]-N-(1,1-dioxothiolan-3-yl)indane-4- carboxamide (XIV.37) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.324 543.1 dihydropyrrol-5-yl]-N-(2-oxotetrahydrofuran-3-yl)indane- 4-carboxamide (XIV.38) 7-[3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)-2,4- A 1.510 546.0 dihydropyrrol-5-yl]-N-tetrahydrothiophen-3-yl-indane-4- carboxamide (XIV.39) N-allyl-7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)- A 1.440 500.8 4H-isoxazol-3-yl]indane-4-carboxamide (XIV.40) 7-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3- A 1.317 535.9 yl]-N-pyrimidin-2-yl-indane-4-carbohydrazide (XIV.41) 7-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3- A 1.396 556.0 yl]-N-[(4S)-2-ethyl-3-oxo-isoxazolidin-4-yl]indane-4- carboxamide (XIV.42) 7-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3- A 1.446 529.0 yl]-N-(thietan-3-ylmethyl)indane-4-carboxamide (XIV.43) N-[(2,2-dichlorocyclopropyl)methyl]-7-[5-(3,5-dichloro- A 1.526 584.9 4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]indane- 4-carboxamide (XIV.44) 7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- A 1.373 557.0 isoxazol-3-yl]-N-[(2-methyltetrazol-5-yl)methyl]indane-4- carboxamide (XIV.45) 7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- A 1.375 542.9 isoxazol-3-yl]-N-(1,2,4-oxadiazol-3-ylmethyl)indane-4- carboxamide (XIV.46) 7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- A 1.399 547.1 isoxazol-3-yl]-N-(1,3-dioxolan-2-ylmethyl)indane-4-carboxamide (XIV.47) 7-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- A 1.349 549.0 isoxazol-3-yl]-N-(diethyl-.sup.4-sulfanylidene)indane-4-carboxamide (XIV.48) 7-[2-(3,5-dichloro-4-fluoro-phenyl)-2-(trifluoromethyl)-3H- A 1.464 590.4 thiophen-4-yl]-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]indane- 4-carboxamide (XIV.49) 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-thiophen-4- A 1.461 561.9 yl]-N-(1,1-dioxothietan-3-yl)indane-4-carboxamide (XIV.50) 7-[2-(3,5-dichloro-4-fluoro-phenyl)-2-(trifluoromethyl)-3H- B 1.428 579.6 thiophen-4-yl]-N-(1,1-dioxothietan-3-yl)indane-4-carboxamide (XIV.51)

TABLE-US-00006 TABLE 6 Characterization of dihydrofurane compounds by HPLC-MS Mass over HPLC Retention charge Compound set-up time (m/z) 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-furan-4- A 1.388 555.1 yl]-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]indane-4- carboxamide (XIV.52) 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-furan-4- A 1.370 581.0 yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]indane-4- carboxamide (XIV.53) 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-furan-4- A 1.451 516.0 yl]-N-(2-methylsulfanylethyl)indane-4-carboxamide (XIV.54) 7-[2-(3,5-dichlorophenyl)-2-(trifluoromethyl)-3H-furan-4- A 1.378 534.0 yl]-N-(pyrimidin-2-ylmethyl)indane-4-carboxamide (XIV.55)

TABLE-US-00007 TABLE 7 HPLC set-up and equipment Code used in Tables 3, 4, and 5 HPLC set-up Equipment A Mobile phase A: water + 0.1% TFA; mobile MSD4/5: Shimadzu Nexera UHPLC and phase B: MeCN; gradient: 5% B to 100% B in Shimadzu LCMS 20-20, ESI; 1.50 min, 100% B for 0.25 min; flow 0.8 mL/min Column: Phenomenex Kinetex 1.7 m XB- to 1 mL/min in 1.51 min; temperature 60 C.; ESI C18 100A, 50 2.1 mm positive; range (m/z) 100-700 B Mobile phase A: water + 0.1% TFA; mobile phase B: MeCN; gradient: 5% B to 100% B in 1.50 min, 100% B for 0.25 min; flow 0.8 mL/min to 1 mL/min in 1.51 min; temperature 60 C.; ESI positive; range (m/z) 50-700 C Mobile phase A: water + 0.1% TFA; mobile phase B: MeCN; gradient: 5% B to 100% B in 1.50 min, 100% B for 0.25 min; flow 0.8 mL/min to 1 mL/min in 1.51 min; temperature 60 C.; ESI positive; range (m/z) 100-1400