INDAZOLE SULFONAMIDE DERIVATIVES AS INVERSE AGONISTS OF RETINOID-RELATED ORPHAN RECEPTOR GAMMA (ROR GAMMA (T))

Abstract

Indazole sulfonamide derivatives of formula (I), the pharmaceutically acceptable addition salts thereof, the hydrates and/or solvates thereof, and the use of same as inverse agonists of retinoid-related orphan receptor gamma RORγt are described.

Pharmaceutical compositions including such compounds, as well as the use thereof for the topical and/or oral treatment of RORγt receptor-mediated inflammatory diseases, in particular acne, psoriasis and/or atopic dermatitis are also described.

Claims

1. Compound of formula (Ia), pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof: ##STR00295## in which formula (I): L represents a single bond or a methylene group CH.sub.2, X represents a cyclic radical chosen from the radicals X.sub.1 and X.sub.2 below: ##STR00296## one or two of the elements Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 represent(s) a nitrogen atom and the other elements correspond to a group —CR.sup.2, or each of the elements Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 corresponds to a group —CR.sup.2, one or two of the elements Q.sup.1, Q.sup.2 and Q.sup.3 represent(s) a nitrogen atom and the other element(s) correspond(s) to a group —CR.sup.2a, or each of the elements Q.sup.1, Q.sup.2 and Q.sup.3 corresponds to a group —CR.sup.2a, R.sup.1 represents a linear or branched C.sub.3-C.sub.5 alkyl radical, optionally substituted with a hydroxyl group and/or a halogen atom, a C.sub.3-C.sub.5 cycloalkyl radical, a linear or branched C.sub.2-C.sub.5 alkenyl radical, a (C.sub.1)alkyl(C.sub.3-C.sub.5)cycloalkyl radical, a C.sub.4-C.sub.5 heterocycloalkyl radical, a (C.sub.1)alkyl(C.sub.4-C.sub.6)heterocycloalkyl radical, R.sup.2 represents a hydrogen atom or a halogen atom, a linear or branched C.sub.1-C.sub.5 alkyl radical, a linear or branched C.sub.2-C.sub.4 alkenyl radical, a C.sub.1-C.sub.4 alkoxy radical, a cyano group —CN, a radical —C(═O)R′.sup.2 with R′.sup.2 denoting a C.sub.1-C.sub.3 alkoxy radical, a —CF.sub.3 radical; said alkyl, alkenyl and alkoxy radicals possibly being substituted with one or more halogen atoms, R.sup.2a represents a hydrogen atom or a halogen atom, a linear or branched C.sub.1-C.sub.5 alkyl radical, a linear or branched C.sub.2-C.sub.4 alkenyl radical, a C.sub.1-C.sub.4 alkoxy radical, a —CN group, a hydroxyl group —OH, a group —CH(R.sup.3a)OH, a carboxylic group —COOH, a carbamoyl group —CONR.sup.2cR.sup.2d, an amido group —NR.sup.2cCOR.sup.2d, a group —SO.sub.2R.sup.2c, a group —SOR.sup.2c, a group —S(═O)(═NH—R.sup.2c), said alkyl, alkenyl and alkoxy radicals possibly being substituted with one or more halogen atoms, R.sup.2c and R.sup.2d, which may be identical or different, represent a hydrogen atom or a linear or branched C.sub.1-C.sub.5 alkyl radical; R.sup.3a represents a hydrogen atom or a linear or branched C.sub.1-C.sub.5 alkyl radical, R.sup.3 represents a hydrogen atom, a halogen atom, a group (CHR.sup.6).sub.n—(Z).sub.o—(CHR′.sup.6).sub.p—R.sup.7, a group CH═R.sup.7 or a group —C═CH—R.sup.7, n, o and p, which may be identical or different, represent zero or a natural integer ranging from 1 to 3, Z represents a divalent group chosen from a methylene group —CH.sub.2—, an amino group —NH— and an oxygen atom —O—, R.sup.6 and R′.sup.6, which may be identical or different, represent a hydrogen atom, a methyl group —CH.sub.3, a group —OH, a C.sub.1 hydroxyalkyl group, a carboxylic function —COOH, R.sup.7 represents: a hydrogen atom or a halogen atom, a group COOR′.sup.7 with R′.sup.7 denoting (C.sub.1)alkyl(C.sub.6)heterocycle, a non-cationic heterocyclic radical optionally substituted with one or more halogen atoms, one or more linear or branched C.sub.1-C.sub.3 alkyl groups, one or more —OH groups, one or more carbonyl functions, one or more linear or branched C.sub.1-C.sub.4 hydroxyalkyl groups, one or more amino groups, one or more groups-C(═O)R.sup.7a, one or more groups S(═O).sub.2R.sup.7a; R.sup.7a representing a linear or branched C.sub.1-C.sub.3 alkyl radical, a linear or branched C.sub.1-C.sub.3 alkoxy radical, or an amino radical N(R.sup.8a)(R.sup.8b), a non-cationic C.sub.3-C.sub.6 cycloalkyl radical optionally substituted with one or more C.sub.1 alkyl radicals, one or more halogen atoms, a cyano group —CN or one or more groups —COR.sup.9; R.sup.9 denoting a linear or branched C.sub.1-C.sub.3 alkoxy radical, or a hydroxyl group, an aromatic or heteroaromatic, non-cationic radical optionally substituted with one or more halogen atoms, one or more linear or branched C.sub.1-C.sub.3 alkyl groups optionally substituted with one or more halogen atoms, one or more C.sub.1-C.sub.3 alkoxy groups, one or more amino groups —NR.sup.11R.sup.12, one or more groups —COR.sup.11, one or more groups —COOR, one or more amido groups-CONR.sup.11R.sup.12, one or more groups —SOR.sup.11, one or more groups —SO.sub.2R.sup.11, one or more groups —NHCOR.sup.11, one or more groups —NHCOOR.sup.11, one or more groups —SO.sub.2NR.sup.11R.sup.12 or one or more —CN groups; R.sup.11 and R.sup.12, which may be identical or different, representing a hydrogen atom, a hydroxyl radical —OH, a linear or branched C.sub.1-C.sub.3 alkyl radical optionally substituted with one or more halogen atoms; when R.sup.3 represents a group —CH═R.sup.7 or a group —C═CH—R.sup.7, then R.sup.7 does not represent a hydrogen atom, a halogen atom or a group COOR′.sup.7, R.sup.5 represents a hydrogen atom or a halogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical optionally substituted with one or more halogen atoms; an amino radical —NH.sub.2, a C.sub.4-C.sub.5 heterocyclic radical, an OCH.sub.2—(C.sub.4-C.sub.5)heterocyclic radical, a radical CH.sub.2R′.sup.7a with R′.sup.7a denoting a C.sub.1 alkoxy radical, a hydroxyl group —OH, a —CH.sub.2COOH group, a group —CH(R.sup.5b)OH, an amino group —NH.sub.2, a carboxylic group —COOH, a —CN group, a thioxo function, R.sup.5b represents a hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical optionally substituted with one or more carboxylic functions; a cyclopropyl radical, R.sup.8a and R.sup.8b, which may be identical or different, denote a hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical or a cyclopropyl radical.

2. Compound of formula (I) as claimed in claim 1, characterized in that R.sup.7 represents a heterocyclic radical chosen from the following heterocycles: ##STR00297## in which: R.sub.7a represents a linear or branched C.sub.1-C.sub.3 alkyl radical, a linear or branched C.sub.1-C.sub.3 alkoxy radical or an amino radical N(R.sup.8a)(R.sup.8b), R.sup.8a and R.sup.8b, which may be identical or different, denote a hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical or a cyclopropyl radical, R.sub.8 and R.sub.9, which may be identical or different, represent a hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical, a hydroxyl group —OH, a carbonyl function ═O, a C.sub.1 hydroxyalkyl radical (—CH.sub.2OH), an amino group NH.sub.2, R.sub.8 and R.sub.9 can form, together with the carbon atoms to which they are attached, a 5- to 7-membered carbocyclic ring.

3. Compound of formula (I) as claimed in claim 1, characterized in that R.sup.7 represents an aromatic or heteroaromatic radical chosen from: ##STR00298## in which: R.sub.10 represents a hydrogen atom or a halogen atom, one linear or branched C.sub.1-C.sub.3 alkyl group optionally substituted with one or more halogen atoms, one C.sub.1-C.sub.3 alkoxy group, one amino group —NR.sup.11R.sup.12, one group —COR.sup.1, one group —COOR.sup.11, one amido group —CONR.sup.11R.sup.12, one group —SOR.sup.11, one group —SO.sub.2R.sup.11, one group —NHCOR.sup.11, one group —NHCOOR.sup.11, one group —SO.sub.2NR.sup.11R.sup.12 or one —CN group; R.sup.11 and R.sup.12, which may be identical or different, representing a hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl radical optionally substituted with one or more halogen atoms, m denotes zero or a natural integer ranging from 1 to 3.

4. Compound of formula (I) as claimed in claim 1, characterized in that it is chosen from the compound(s) of formula (II), and also the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof: ##STR00299## in which formula (II) R.sup.1, R.sup.3, R.sup.5 and Y.sup.1 to Y.sup.5 have the same meanings as in formula (I) as defined in claim 1.

5. Compound of formula (I) as claimed in claim 1, characterized in that it is chosen from the compound(s) of formula (III), and also the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof: ##STR00300## in which formula (III) R.sup.1, R.sup.3, R.sup.5 and Y.sup.1 to Y.sup.5 have the same meanings as in formula (I) as defined in claim 1.

6. Compound of formula (I) as claimed in any one of the preceding claims, characterized in that it is chosen from the following compounds: ##STR00301## ##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317## ##STR00318##

7. Compound as claimed in any one of the preceding claims, as a medicament.

8. Compound as claimed in any one of the preceding claims, for its use in the treatment of inflammatory disorders and/or autoimmune diseases mediated by the RORγt receptor.

9. Compound as claimed in claim 8, characterized for its use in the treatment of acne.

10. Compound as claimed in claim 8, characterized for its use in the treatment of psoriasis.

11. Pharmaceutical composition comprising one or more compounds as defined in any one of claims 1 to 6.

12. Pharmaceutical composition as defined in claim 11, for its use in the treatment of diseases mediated by the RORγt receptor, especially inflammatory disorders and/or autoimmune diseases, especially acne, atopic dermatitis and/or psoriasis.

Description

EXAMPLES

[0178] The standard LCMS method for analyzing the products is as follows: BEH C.sub.18 standard column (150×2.1 mm, 1.8 μm) solvent: water/acetonitrile 0.1% formic acid.

[0179] The preparative HPLC purifications were performed on a C.sub.18 column using, as eluent: 85% acetonitrile in water/0.1% formic acid.

Part I: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 1

[0180] ##STR00105##

Example 1: Synthesis of N-(4-ethylphenyl)-N-isobutyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide

[0181] ##STR00106##

1. Synthesis of Intermediate 1.1

[0182] ##STR00107##

[0183] Isobutyraldehyde (6.33 ml; 0.07 mol) in tetrahydrofuran (100 ml) is added to 4-ethylaniline (9.48 ml; 0.08 mol). The mixture is stirred for 2 hours at room temperature. Sodium triacetoxyborohydride (22.04 g; 0.10 mol) is then added. The mixture is stirred overnight at room temperature, water (100 ml) are added and the resulting mixture is extracted with ethyl acetate (2×100 ml). The organic phases are combined, washed with brine (100 ml), dried (Na.sub.2SO.sub.4) and concentrated.

[0184] The crude product is chromatographed on silica gel (eluent: heptane/dichloromethane from 0 to 50% of dichloromethane). The (4-ethylphenyl)isobutylamine is obtained in the form of an orange oil with a compliant .sup.1H NMR.

[0185] MS: [M+H]=179

2. Synthesis of Intermediate 1.2

[0186] ##STR00108##

[0187] 1H-Indazole-5-sulfonyl chloride (502 mg; 2.20 mmol) is added to (4-ethylphenyl)isobutylamine (300 mg; 1.69 mmol) and pyridine (820 μl; 10.15 mmol) in tetrahydrofuran (6 ml). The reaction medium is stirred for 7 hours at room temperature, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

[0188] The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 20 to 50% of ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (357 mg; 59%) is obtained in the form of a cream-colored solid with a compliant .sup.1H NMR.

[0189] MS: [M+H]=358

3. Synthesis of Compound 39 According to the Invention

[0190] ##STR00109##

[0191] 4-(Bromomethyl)tetrahydropyran (90 mg; 0.50 mmol) is added to N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (150 mg; 0.42 mmol) and cesium carbonate (137 mg; 0.42 mmol) in N,N-dimethylformamide (12 ml). The reaction medium is stirred for 30 minutes at a temperature of 100° C. under microwave irradiation, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

[0192] The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, 40% of ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide (97 mg; 50%) is obtained in the form of a white powder.

[0193] .sup.1H NMR (400 MHz, DMSO-d6) δ 0.85 (d, J=6.6 Hz, 7H), 1.17 (t, J=7.6 Hz, 4H), 1.22-1.53 (m, 6H), 2.16-2.31 (m, 1H), 2.59 (q, J=7.6 Hz, 2H), 3.15-3.44 (m, 6H), 3.83 (ddd, J=11.5, 4.4, 2.0 Hz, 3H), 4.39 (d, J=7.2 Hz, 3H), 6.92-7.05 (m, 3H), 7.10-7.21 (m, 3H), 7.26 (dd, J=9.1, 1.8 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H), 8.10 (d, J=1.7 Hz, 1H), 8.62 (s, 1H).

[0194] MS: [M+H]=456

[0195] With a procedure similar to that described for the synthesis of example 1, the compounds of the table below are obtained:

TABLE-US-00004 Example 2 [00110] N-(4-ethylphenyl)-N-isobutyl-1- ((tetrahydro-2H-pyran-3-yl)methyl)-1H- indazole-5-sulfonamide 1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.23-1.35 (m, 1H), 1.35-1.53 (m, 2H), 1.54-1.72 (m, 2H), 2.08-2.23 (m, 1H), 2.59 (q, J = 7.6 Hz, 2H), 3.21 (dd, J = 11.2, 8.9 Hz, 1H), 3.32- 3.40 (m, 3H), 3.57-3.65 (m, 1H), 3.70 (dt, J = 10.9, 3.9 Hz, 1H), 4.31-4.48 (m, 2H), 6.96 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 9.0, 1.8 Hz, 1H), 7.84- 7.89 (m, 1H), 8.09 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 0.8 Hz, 1H) MS: [M + H] = 456 Example 3 [00111] N-(4-ethylphenyl)-N-isobutyl-1- ((tetrahydrofuran-3-yl)methyl)-1H- indazole-5-sulfonamide 1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.7 Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.42 (hept, J = 6.8 Hz, 1H), 1.57-1.73 (m, 1H), 1.83-2.00 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 2.81 (hept, J = 7.1 Hz, 1H), 3.31-3.35 (m, 2H), 3.50 (dd, J = 8.6, 5.6 Hz, 1H), 3.60-3.71 (m, 2H), 3.81 (td, J = 8.1, 5.5 Hz, 1H), 4.36- 4.55 (m, 2H), 6.96 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.46 (dd, J = 8.8, 1.8 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H) MS: [M + H] = 442 Example 4 [00112] N-(4-ethylphenyl)-N-isobutyl-1-(oxetan-3- ylmethyl)-1H-indazole-5-sulfonamide 1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz. 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.41 (non, J = 6.8 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.32 (m, 2H), 3.52 (tt, J = 7.6, 6.1 Hz, 1H), 4.49 (t, J = 6.2 Hz, 2H), 4.67 (dd, J = 7.8, 6.1 Hz, 2H), 4.77 (d, J = 7.2 Hz, 2H), 6.96 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.47 (dd, J = 8.9, 1.7 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H), 8.29 (d. J = 0.9 Hz, 1H) MS: [M + H] = 428 Example 5 [00113] 1-((1-acetylpyrrolidin-3-yl)methyl)-N-(4- ethylphenyl)-N-isobutyl-1H-indazole-5- sulfonamide 1H NMR (DMSO-d6, 80° C.) δ: 0.86 (d, J = 6.6 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 1.44- 1.60 (m, 1H), 1.60-1.83 (m, 1H), 1.83- 2.07 (m, 4H), 2.61 (q, J = 7.6 Hz, 2H), 2.72- 2.94 (m, 1H), 3.09-3.61 (m, 6H), 4.51 (d, J = 7.1 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 8.10 (s, 1H). 8.28 (s, 1H) MS: [M + H] = 483 Example 6 [00114] 1-benzyl-N-(4-ethylphenvl)-N-isobutyl-1H- indazole-5-sulfonamide 1H NMR (DMSO-d6) δ: 0.84 (d. J = 6.7 Hz. 6H), 1.16 (t, J = 7.6 Hz, 3H), 1.41 (hept, J = 6.9 Hz, 1H), 2.59 (q, J = 7.6 Hz, 2H), 3.32 (m, 2H), 5.71 (s, 2H), 6.98 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.25 (dd, J = 9.2, 1.8 Hz, 1H), 7.31-7.43 (m, 5H), 7.73 (d, J = 9.1 Hz, 1H), 8.12 (dd, J = 1.9, 0.8 Hz, 1H), 8.75 (d, J = 1.0 Hz, 1H) MS: [M + H] = 448 Example 7 [00115] N-(4-ethylphenyl)-N-isobutyl-1-pyridin-4- ylmethyl)-1H-indazole-5-sulfonamide 1H NMR (DMSO-d6) δ: 0.85 (d. J = 6.6 Hz. 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.32-1.48 (m, 1H), 2.59 (q, J = 7.7 Hz. 2H), 3.33 (m, 2H), 5.82 (s, 2H), 6.96 (d, J = 7.9 Hz, 2H), 7.15 (dd, J = 11.8, 6.5 Hz, 4H), 7.48 (d, J = 8.9 Hz, 1H), 7.90 (d. J = 8.9 Hz, 1H), 8.14 (s, 1H), 8.39 (s, 1H), 8.52 (d, J = 5.1 Hz, 2H) MS: [M + H] = 449 Example 8 [00116] 1-((3,5-dimethylisoxazol-4-yl)methyl)-N- (4-ethylphenyl)-N-isobutyl-1H-indazole-5- sulfonamide 1H NMR (DMSO-d6) δ: 0.85 (d. J = 6.6 Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.41 (hept, J = 6.8 Hz, 1H), 2.11 (s, 3H), 2.44 (s, 3H), 2.59 (q, J = 7.6 Hz, 2H), 3.33 (s, 2H), 5.54 (s, 2H), 6.88-7.00 (m, 2H), 7.12-7.20 (m, 2H), 7.50 (dd, J = 8.9, 1.8 Hz, 1H), 7.88-8.01 (m, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H) MS: [M + H] = 467

Example 9: Synthesis of 1-((1-acetylazetidin-3-yl)methyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide

[0196] ##STR00117##

[0197] 1-(3-Hydroxymethylazetidin-1-yl)ethanone (0.27 g; 2.09 mmol) in toluene (1 ml) is added to a mixture of N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (0.20 g; 0.56 mmol) and (triphenyl-λ.sup.5-phosphanylidene)acetonitrile (0.51 g; 1.68 mmol) in anhydrous toluene (3 ml) under argon. The reaction medium is stirred for 3 days at a temperature of 95° C., hydrolyzed and extracted with ethyl acetate. The organic phase is washed, dried (Na.sub.2SO.sub.4), filtered and concentrated.

[0198] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(1-acetylazetidin-3-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (136 mg; 51%) is obtained in the form of a pale yellow solid.

[0199] .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.42 (hept, J=6.8 Hz, 1H), 1.73 (s, 3H), 2.59 (q, J=7.6 Hz, 2H), 3.07-3.20 (m, 1H), 3.30-3.36 (m, 2H), 3.69 (dd, J=9.6, 5.6 Hz, 1H), 3.89 (t, J=9.0 Hz, 1H), 3.98 (dd, J=8.5, 5.5 Hz, 1H), 4.18 (t, J=8.4 Hz, 1H), 4.71 (d, J=7.3 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.48 (dd, J=9.0, 1.7 Hz, 1H), 7.89-7.97 (m, 1H), 8.09 (d, J=1.7 Hz, 1H), 8.31 (d, J=0.9 Hz, 1H)

[0200] MS: [M+H]=469

Example 10: Synthesis of 1-(tetrahydropyran-4-yl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide

[0201] ##STR00118##

[0202] By following the same procedure as that for example 9, 1-(tetrahydropyran-4-yl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (22 mg; 36%) is obtained in the form of a white solid.

[0203] .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J=6.7 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.41 (non, J=6.5 Hz, 1H), 1.85-1.97 (m, 2H), 2.15 (qd, J=12.3, 4.6 Hz, 2H), 2.60 (q, J=7.6 Hz, 2H), 3.30-3.32 (m, 2H), 3.58 (td, J=11.9, 2.0 Hz, 2H), 3.98-4.07 (m, 2H), 4.99 (td, J=11.3, 5.7 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.44 (dd, J=8.9, 1.7 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 8.32 (s, 1H)

[0204] MS: [M+H]=442

Example 11: Synthesis of 1-(1-acetylpyrrolidin-3-yl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide

[0205] ##STR00119##

[0206] A mixture of N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (0.20 g; 0.56 mmol), cesium carbonate (0.27 g; 0.84 mmol) and 1-(3-bromopyrrolidin-1-yl)ethanone (0.13 g; 0.67 mmol) in 1-methyl-2-pyrrolidone (3 ml) is stirred for 5 hours at a temperature of 80° C., hydrolyzed and extracted with ethyl acetate. The organic phase is washed with water, dried (Na.sub.2SO.sub.4), filtered and concentrated.

[0207] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(1-acetylpyrrolidin-3-yl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (29 mg; 11%) is obtained in the form of a white solid.

[0208] Mixture of two conformers: .sup.1H NMR (DMSO-d6) δ: 0.85 (dd, J=6.7, 1.1 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.33-1.50 (m, 1H), 2.01 (s, 3H), 2.60 (q, J=7.6 Hz, 2H), 3.34 (d, J=2.4 Hz, 2H), 3.46-3.54 (m, 1H), 3.59-3.65 (m, 1H), 3.65-3.72 (m, 1H), 3.76-3.82 (m, 1H), 3.85 (dd, J=12.3, 6.8 Hz, 1H), 4.05 (dd, J=10.8, 7.0 Hz, 1H), 5.57 (ddt, J=27.8, 11.5, 6.2 Hz, 1H), 6.90-7.03 (m, 2H), 7.16-7.21 (m, 2H), 7.49 (ddd, J=8.8, 5.4, 1.7 Hz, 1H), 7.92 (t, J=9.0 Hz, 1H), 8.11 (dd, J=3.4, 1.6 Hz, 1H), 8.32-8.41 (m, 1H)

[0209] MS: [M+H]=469

[0210] With a procedure similar to that for intermediate 1.1, corresponding to a reductive amination between 1 equivalent of aldehyde and 1.15 equivalents of aniline in tetrahydrofuran in the presence of 1.45 equivalents of sodium triacetoxyborohydride, the anilines of the table below are obtained:

TABLE-US-00005 Inter- mediate 12.1 [00120] cyclopropylmethyl(4- ethylphenyl)amine (300 mg; 46%) obtained in the form of an orange oil with a compliant .sup.1H NMR. MS: [M + H] = 176 Inter- mediate 13.1 [00121] cyclobutylmethyl(4- ethylphenyl)amine (400 mg; 56%) obtained in the form of an orange oil with a compliant .sup.1H NMR. MS: [M + H] = 190 Inter- mediate 14.1 [00122] cyclopentylmethyl(4- ethylphenyl)amine (19.3 g; 56%) obtained in the form of an amber-colored oil with a compliant .sup.1H NMR. MS: [M + H] = 190 Inter- mediate 15.1 [00123] cyclobutylmethyl(4- ethylphenyl)amine (700 mg; 97%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 176 Inter- mediate 16.1 [00124] (tetrahydrofuran-3- ylmethyl)(4- ethylphenyl)amine (600 mg; 78%) obtained in the form of an orange oil with a compliant .sup.1H NMR. MS: [M + H] = 206 Inter- mediate 17.1 [00125] sec-butyl(4-ethylphenyl)amine (600 mg; 90%) obtained in the form of an orange oil with a compliant .sup.1H NMR. MS: [M + H] = 178 Inter- mediate 18.1 [00126] (4-ethylphenyl)(3- methylbutyl)amine (250 mg; 32%) obtained in the form of an orange oil with a compliant .sup.1H NMR. MS: [M + H] = 192 Inter- mediate 19.1 [00127] 4-ethyl-N-isopropylaniline (300 mg; 49%) obtained in the form of an orange oil with a compliant .sup.1H NMR. MS: [M + H] = 165 Inter- mediate 20.1 [00128] (4-ethylphenyl)(1- ethylpropyl)amine (700 mg; 98%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 192 Inter- mediate 21.1 [00129] ethyl(4-ethylphenyl)amine commercial Inter- mediate 22.1 [00130] propyl(4-ethylphenyl)amine (450 mg; 73%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 165 Inter- mediate 23.1 [00131] butyl(4-ethylphenyl)amine (650 mg; 98%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 178 Inter- mediate 24.1 [00132] (2,2,2-trifluoroethyl)(4- ethylphenyl)amine commercial Inter- mediate 25.1 [00133] isobutyl(4- isopropylphenyl)amine (600 mg; 93%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 193 Inter- mediate 26.1 [00134] (5-chloro-2- fluorophenyl)isobutylamine (350 mg; 56%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 202 Inter- mediate 27.1 [00135] (5-fluoro-2- methylphenyl)isobutylamine (802 mg; 61%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 182 Inter- mediate 28.1 [00136] (3-fluoro-2- methylphenyl)isobutylamine (408 mg; 31%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 182 Inter- mediate 29.1 [00137] (5-chlorophenyl)isobutylamine (655 mg; 100%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 185 Inter- mediate 30.1 [00138] (2-chlorophenyl)isobutylamine (655 mg; 100%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 183 Inter- mediate 31.1 [00139] (4-fluorophenyl)isobutylamine (684 mg; 100%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 169 Inter- mediate 32.1 [00140] (4-methylphenyl)isobutylamine (876 mg; 63%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 164 Inter- mediate 33.1 [00141] isobutyl-o-tolylamine (972.8 mg; 70%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 164 Inter- mediate 34.1 [00142] (2,5-dimethylphenyl) isobutylamine (700 mg; 97%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 179 Inter- mediate 35.1 [00143] (4-butyl-2- methylphenyl)isobutylamine (520 mg; 85%) obtained in the form of a clear yellow oil with a compliant .sup.1H NMR. MS: [M + H] = 220 Inter- mediate 36.1 [00144] (2,4-dimethylphenyl) isobutylamine (1.15 g; 83%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 179 Inter- mediate 37.1 [00145] (3,5-dimethylphenyl) isobutylamine (600 mg; 82%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 179 Inter- mediate 38.1 [00146] (3-methylphenyl)isobutylamine (600 mg; 79%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 164 Inter- mediate 39.1 [00147] (3-methoxyphenyl) isobutylamine (600 mg; 2%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 181 Inter- mediate 40.1 [00148] (4- trifluoromethoxyphenyl) isobutylamine (600 mg; 100%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 235 Inter- mediate 41.1 [00149] isobutyl(5-isopropylpyridin-2- yl)amine (600 mg; 93%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 193 Inter- mediate 42.1 [00150] (3-methoxypyridin-2- yl)isobutylamine (450 mg; 68%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 181 Inter- mediate 43.1 [00151] (3-chlorobenzyl)isobutylamine (500 mg; 68%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 198 Inter- mediate 44.1 [00152] (3-methoxypyridin-2- yl)isobutylamine (600 mg; 100%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 232 Inter- mediate 45.1 [00153] (2-fluoro-6- methylphenyl)isobutylamine (560 mg; 44%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 182 Inter- mediate 46.1 [00154] (4-chloro-2- methylphenyl)isobutylamine (892 mg; 71%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 182 Inter- mediate 47.1 [00155] isobutyl(4-methoxy-2- methylphenyl)amine (980 mg; 77%) obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 193

[0211] With a procedure similar to that for intermediate 1.2, by reacting 1 equivalent of N-substituted anilines (derived from the above table or corresponding commercial products) with 1.3 equivalents of 1H-indazole-5-sulfonyl chloride in tetrahydrofuran (20 vol) in the presence of 6 equivalents of pyridine, the intermediates of the table below are obtained:

TABLE-US-00006 Intermediate 12.2 [00156] 1H-indazole-5-sulfonic acid cyclopropylmethyl(4- ethylphenyl)amide (450 mg; 81%) is obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 356 Intermediate 13.2 [00157] 1H-indazole-5-sulfonic acid cyclobutylmethyl(4- ethylphenyl)amide (590 mg; 55%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 370 Intermediate 14.2 [00158] 1H-indazole-5-sulfonic acid cyclopentyl(4-ethylphenyl)amide (250 mg; 47%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 370 Intermediate 15.2 [00159] 1H-indazole-5-sulfonic acid cyclobutyl(4-ethylphenyl)amide (80 mg; 51%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 356 Intermediate 16.2 [00160] 1H-indazole-5-sulfonic acid (4- ethylphenyl)(tetrahydrofuran-3- ylmethyl)amide (800 mg; 78%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 386 Intermediate 17.2 [00161] 1H-indazole-5-sulfonic acid sec- butyl(4-ethylphenyl)amide (310 mg; 56%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 358 Intermediate 18.2 [00162] 1H-indazole-5-sulfonic acid (4- ethylphenyl)(3-methylbutyl)amide (220 mg; 50%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 372 Intermediate 19.2 [00163] 1H-indazole-5-sulfonic acid (4- ethylphenyl)isopropylamide (400 mg; 70%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 344 Intermediate 20.2 [00164] 1H-indazole-5-sulfonic acid (4- ethylphenyl)(1-ethylpropyl)amide (40 mg; 25%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 372 Intermediate 21.2 [00165] 1H-indazole-5-sulfonic acid ethyl(4- ethylphenyl)amide (160 mg; 55%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 330 Intermediate 22.2 [00166] 1H-indazole-5-sulfonic acid (4- ethylphenyl)propylamide (400 mg; 46%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 344 Intermediate 23.2 [00167] 1H-indazole-5-sulfonic acid (4- ethylphenyl)butylamide (800 mg; 67%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 358 Intermediate 25.2 [00168] 1H-indazole-5-sulfonic acid isobutyl(4-isopropylphenyl)amide (800 mg; 76%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 372 Intermediate 26.2 [00169] 1H-indazole-5-sulfonic acid (5- chloro-2-fluorophenyl)isobutylamide (120 mg; 20%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 381 Intermediate 27.2 [00170] 1H-indazole-5-sulfonic acid (5- fluoro-2-methylphenyl)isobutylamide (267 mg; 53%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 362 Intermediate 28.2 [00171] 1H-indazole-5-sulfonic acid (3- fluoro-2-methylphenyl)isobutylamide (137 mg; 38%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 362 Intermediate 29.2 [00172] 1H-indazole-5-sulfonic acid (5- chlorophenyl)isobutylamide (90 mg; 56%) obtained in the form of a white solid with a compliant .sup.1H NMR. MS: [M + H] = 364 Intermediate 31.2 [00173] 1H-indazole-5-sulfonic acid (4- fluorophenyl)isobutylamide (100 mg; 66%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 348 Intermediate 32.2 [00174] 1H-indazole-5-sulfonic acid isobutyl- p-tolylamide (770 mg; 81%) obtained in the form of a colorless oil with a compliant .sup.1H NMR MS: [M + H] = 344 Intermediate 33.2 [00175] 1H-indazole-5-sulfonic acid isobutyl- o-tolylamide (481 mg; 46%) obtained in the form of a white solid with a compliant .sup.1H NMR. MS: [M + H] = 344 Intermediate 34.2 [00176] 1H-indazole-5-sulfonic acid (2,5- dimethylphenyl)isobutylamide (540 mg; 59%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 358 Intermediate 35.2 [00177] 1H-indazole-5-sulfonic acid (4-butyl- 2-methylphenyl)isobutylamide (650 mg; 75%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 400 Intermediate 36.2 [00178] 1H-indazole-5-sulfonic acid (2,4- dimethylphenyl)isobutylamide (500 mg; 55%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 381 Intermediate 37.2 [00179] 1H-indazole-5-sulfonic acid (3,5- dimethylphenyl)isobutylamide (140 mg; 13%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 358 Intermediate 38.2 [00180] 1H-indazole-5-sulfonic acid (3- methylphenyl)isobutylamide (310 mg; 27%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 344 Intermediate 39.2 [00181] 1H-indazole-5-sulfonic acid (3- methoxyphenyl)isobutylamide (450 mg; 62%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 360 Intermediate 40.2 [00182] 1H-indazole-5-sulfonic acid (4- trifluoromethoxyphenyl)isobutylamide (100 mg; 55%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 414 Intermediate 42.2 [00183] 1H-indazole-5-sulfonic acid (3- methoxypyridin-2-yl)isobutylamide (300 mg; 37%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 361 Intermediate 43.2 [00184] 1H-indazole-5-sulfonic acid (3- chlorobenzyl)isobutylamide (50 mg; 30%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 378 Intermediate 44.2 [00185] 1H-indazole-5-sulfonic acid isobutyl(2- trifluoromethylbenzyl)amide (70 mg; 39%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 412 Intermediate 45.2 [00186] 1H-indazole-5-sulfonic acid (2- fluoro-6-methylphenyl)isobutylamide (305 mg; 65%) obtained in the form of a white solid with a compliant .sup.1H NMR. MS: [M + H] = 362 Intermediate 46.2 [00187] 1H-indazole-5-sulfonic acid (4- fluoro-2-methylphenyl)isobutylamide (307 mg; 65%) is obtained in the form of a yellowish solid with a compliant .sup.1H NMR. MS: [M − H] = 360 Intermediate 47.2 [00188] 1H-indazole-5-sulfonic acid isobutyl(4-methoxy-2- methylphenyl)amide (437 mg; 89%) obtained in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 374 Intermediate 48.1 [00189] methyl 4-(1H-indazole-5- sulfonylamino)-3-methylbenzoate Obtained from the commercial amine. (480 mg; 63%) obtained in the form of a white solid with a compliant .sup.1H NMR. MS: [M − H] = 346 Intermediate 49.1 [00190] 1H-indazole-5-sulfonic acid (4- cyano-2-methylphenyl)amide Obtained from the commercial amine. (330 mg; 80%) obtained in the form of a beige-colored solid with a compliant .sup.1H NMR. MS: [M − H] = 313

1. Synthesis of Intermediate 24.2

[0212] ##STR00191##

[0213] A mixture of 1H-indazole-5-sulfonyl chloride (200 mg; 0.88 mmol), pyridine (3 ml), potassium iodide (7.3 mg; 0.04 mmol), 4-dimethylaminopyridine (5.4 mg; 0.04 mmol) and N-(4-ethylphenyl)-N-(2,2,2-trifluoroethyl)amine hydrochloride (231 mg; 0.96 mmol) is stirred for 16 hours at a temperature of 100° C.

[0214] Silver(I) fluoride (5.6 mg; 0.04 mmol) is added to the reaction medium, which is stirred for 3 days at a temperature of 80° C.

[0215] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1H-indazole-5-sulfonic acid (4-ethylphenyl)(2,2,2-trifluoroethyl)amide (20 mg; 6%) is obtained in the form of a clear yellow oil.

[0216] MS: [M+H]=384

2. Synthesis of Intermediate 30.2

[0217] ##STR00192##

[0218] A mixture of 1H-indazole-5-sulfonyl chloride (200 mg; 0.88 mmol), pyridine (3.0 ml), potassium iodide (14 mg; 0.08 mmol), 4-dimethylaminopyridine (5.4 mg; 0.04 mmol) and (2-chlorophenyl)isobutylamine (600 mg; 3.27 mmol) is stirred for 3 days at a temperature of 100° C.

[0219] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1H-indazole-5-sulfonic acid (2-chlorophenyl)isobutylamide (10 mg; 3%) is obtained in the form of a yellow oil with a compliant .sup.1H NMR.

[0220] MS: [M+H]=364

3. Synthesis of Intermediate 41.2

[0221] ##STR00193##

[0222] With the same procedure as that used for intermediate 30.2, 1H-indazole-5-sulfonic acid cyclopropylmethyl(4-ethylphenyl)amide (40 mg; 12%) is obtained in the form of a yellow oil with a compliant .sup.1H NMR.

[0223] MS: [M+H]=373

4. Synthesis of Intermediate 45.2

[0224] ##STR00194##

[0225] (2-Fluoro-6-methylphenyl)isobutylamine (520 mg; 2.87 mmol) is added to a solution of 1H-indazole-5-sulfonyl chloride (297.4 mg; 1.30 mmol) in acetonitrile (1.25 ml) and the reaction medium is stirred for 40 minutes with microwave irradiation at a temperature of 100° C. The reaction medium is treated with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water, dried (MgSO.sub.4), filtered and concentrated.

[0226] The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 60% of ethyl acetate). The 1H-indazole-5-sulfonic acid (2-fluoro-6-methylphenyl)isobutylamide (305 mg; 65%) is obtained in the form of a white solid with a compliant .sup.1H NMR.

[0227] MS: [M+H]=362

[0228] With a procedure similar to that described for the synthesis of example 1, the addition of 1.2 equivalents of 4-(bromomethyl)tetrahydropyran to 1 equivalent of N-substituted 1H-indazole-5-sulfonamide (prepared previously) in N,N-dimethylformamide in the presence of 1 equivalent of cesium carbonate under microwave irradiation at 100° C. leads to the compounds in the table below:

TABLE-US-00007 Example 12 [00195]   Compound 31 N-(cyclopropylmethyl)-N-(4- ethylphenyl)-1-((tetrahydro-2H-pyran- 4-yl)methyl)-1H-indazole-5- sulfonamide .sup.1H NMR (DMSO-d6) δ: 0.23-0.35 (m, 2H), 0.64-0.77 (m, 1H), 1.12 (t, J = 7.6 Hz, 3H), 1.19-1.37 (m, 4H), 2.10 (dtd, J = 11.1, 6.9, 3.4 Hz, 1H), 2.54 (q, J = 7.6 Hz, 2H), 3.17 (td, J = 11.3, 3.0 Hz, 2H), 3.38 (d, J = 7.0 Hz, 2H), 3.76 (ddd, J = 11.5, 4.4, 2.2 Hz, 2H), 4.32 (d, J = 7.1 Hz, 2H), 6.89-6.97 (m, 2H), 7.11 (d, J = 8.3 Hz, 2H), 7.45 (dd, J = 8.9, 1.7 Hz, 1H), 7.85 (dt, J = 8.8, 0.9 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 8.23 (d, J = 0.9 Hz, 1H). MS: [M + H] = 454 Example 13 [00196]   Compound 24 N-(cyclobutylmethyl)-N-(4- ethylphenyl)-1-((tetrahydro-2H-pyran- 4-yl)methyl)-1H-indazole-5- sulfonamide .sup.1H NMR (DMSO-d6) δ: 1.17 (t, J = 7.6 Hz, 3H), 1.24-1.45 (m, 4H), 1.54-1.66 (m, 2H), 1.69-1.89 (m, 4H), 2.10-2.30 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H), 3.27 (td, J = 11.6, 2.4 Hz, 2H), 3.56 (d, J = 7.5 Hz, 2H), 3.83 (ddd, 2H), 4.40 (d, J = 7.1 Hz, 2H), 6.88-6.96 (m, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.31 (dd, J = 9.1, 1.8 Hz, 1H), 7.75 (d, J = 9.1 Hz, 1H), 8.12-8.14 (m, 1H), 8.63 (d, J = 0.9 Hz, 1H) MS: [M + H] = 468 Example 14 [00197]   Compound 32 l-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid cyclopentyl(4- ethylphenyl)amide .sup.1H NMR (DMSO-d6) δ: 1.12-1.26 (m, 5H), 1.26-1.49 (m, 9H), 1.74 (dd, J = 12.2, 6.9 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.24 (td, J = 11.3, 2.9 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.2 Hz, 2H), 4.39 (d, J = 7.0 Hz, 2H), 4.46-4.57 (m, 1H), 6.87- 6.92 (m, 2H), 7.17-7.23 (m, 2H), 7.69 (dd, J = 9.0, 1.8 Hz, 1H), 7.91-7.96 (m, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H) MS: [M + H] = 468 Example 15 [00198]   Compound 41 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid cyclobutyl(4- ethylphenyl)amide .sup.1H NMR (DMSO-d6) δ: 1.18 (t, J = 7.6 Hz, 3H), 1.23-1.62 (m, 6H), 1.76 (dq, J = 12.0, 9.7 Hz, 2H), 2.05 (dddd, J = 9.4, 7.4, 5.1, 2.5 Hz, 2H), 2.10-2.26 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.24 (td, J = 11.3, 2.9 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.1 Hz, 2H), 4.38 (dd, J = 8.5, 6.5 Hz, 3H), 6.80 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.48 (dd, J = 9.0, 1.8 Hz, 1H), 7.90 (d, J = 9.1 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H) MS: [M + H] = 454 Example 16 [00199]   Compound 33 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4- ethylphenyl)(tetrahydrofuran-3- ylmethyl)amide .sup.1H NMR (DMSO-d6) δ: 1.18 (t, J = 7.6 Hz, 3H), 1.25-1.43 (m, 4H), 1.58 (dq, J = 13.2, 6.8 Hz, 1H), 1.76-1.90 (m, 1H), 2.06 (p, J = 5.9 Hz, 1H), 2.11-2.22 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.24 (td, J = 11.3, 3.0 Hz, 2H), 3.42 (dd, J = 8.6, 5.2 Hz, 1H), 3.48-3.62 (m, 4H), 3.71 (td, J = 8.1, 5.4 Hz, 1H), 3.76-3.89 (m, 2H), 4.39 (d, J = 7.0 Hz, 2H), 6.91-7.00 (m, 2H), 7.14-7.24 (m, 2H), 7.48 (dd, J = 9.0, 1.7 Hz, 1H), 7.87-7.95 (m, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 1.0 Hz, 1H) MS: [M + H] = 484 Example 17 [00200]   Compound 30 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid sec-butyl(4- ethylphenyl)amide .sup.1H NMR (DMSO-d6) δ: 0.85 (t, J = 7.3 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 1.12- 1.25 (m, 5H), 1.26-1.44 (m, 4H), 2.62 (q, J = 7.6 Hz, 2H), 3.24 (td, J = 11.3, 3.2 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.3 Hz, 2H), 4.19 (dt, J = 7.8, 6.4 Hz, 1H), 4.39 (d, J = 7.1 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.68 (dd, J = 8.9, 1.8 Hz, 1H), 7.94 (dt, J = 9.0, 0.9 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H) MS: [M + H] = 456 Example 18 [00201]   Compound 35 N-(4-ethylphenyl)-N-isopentyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)- 1H-indazole-5-sulfonamide .sup.1H NMR (DMSO-d6) δ: 0.80 (d, J = 6.6 Hz, 6H), 1.17 (t, J = 7.6 Hz, 5H), 1.25- 1.42 (m, 4H), 1.61 (hept, J = 6.7 Hz, 1H), 2.09-2.24 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.23 (td, J = 11.2, 3.1 Hz, 2H), 3.55 (t, J = 7.1 Hz, 2H), 3.81 (dt, J = 11.5, 3.3 Hz, 2H), 4.38 (d, J = 7.1 Hz, 2H), 6.90- 6.99 (m, 2H), 7.12-7.22 (m, 2H), 7.47 (dd, J = 9.0, 1.7 Hz, 1H), 7.87-7.96 (m, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 1.1 Hz, 1H) MS: [M + H] = 470 Example 19 [00202]   Compound 29 N-(4-ethylphenyl)-N-isopropyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)- 1H-indazole-5-sulfonamide .sup.1H NMR (DMSO-d6) δ: 0.95 (d, J = 6.7 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 1.26- 1.45 (m, 4H), 2.63 (q, J = 7.6 Hz, 2H), 3.24 (td, J = 11.3, 3.0 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.2 Hz, 2H), 4.39 (d, J = 7.1 Hz, 2H), 4.47 (p, J = 6.7 Hz, 1H), 6.90- 6.98 (m, 2H), 7.22 (d, J = 8.3 Hz, 2H), 7.70 (dd, J = 8.9, 1.8 Hz, 1H), 7.90-7.99 (m, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H). MS: [M + H] = 442 Example 20 [00203]   Compound 1 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4- ethylphenyl)(1-ethylpropyl)amide .sup.1H NMR (DMSO-d6) δ: 0.85 (t, J = 7.3 Hz, 6H), 1.07-1.22 (m, 5H), 1.30 (ddd, J = 20.0, 9.0, 5.7 Hz, 6H), 2.16 (s, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.23 (td, J = 11.2, 3.4 Hz, 2H), 3.81 (d, J = 11.1 Hz, 2H), 3.91 (q, J = 6.5 Hz, 1H), 4.39 (d, J = 7.2 Hz, 2H), 6.86-6.93 (m, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 9.0 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H). MS: [M + H] = 470 Example 22 [00204]   Compound 8 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4- ethylphenyl)propylamide .sup.1H NMR (DMSO-d6) δ: 0.83 (t, J = 7.3 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H), 1.25- 1.44 (m, 6H), 2.24 (ddt, J = 10.9, 7.5, 3.8 Hz, 1H), 2.60 (q, J = 7.5 Hz, 2H), 3.26 (td, J = 11.6, 2.5 Hz, 2H), 3.50 (t, J = 6.9 Hz, 2H), 3.83 (ddd, J = 11.5, 4.5, 2.0 Hz, 2H), 4.40 (d, J = 7.1 Hz, 2H), 6.93-7.02 (m, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.29 (dd, J = 9.1, 1.8 Hz, 1H), 7.70-7.80 (m, 1H), 8.12 (dd, J = 1.9, 0.8 Hz, 1H), 8.62 (d, J = 1.0 Hz, 1H) MS: [M + H] = 442 Example 23 [00205]   Compound 9 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid butyl(4- ethyl)phenyl)amide .sup.1H NMR (DMSO-d6) δ: 0.74-0.88 (m, 3H), 1.17 (t, J = 7.6 Hz, 3H), 1.23-1.45 (m, 8H), 2.24 (ddt, J = 11.0, 7.6, 3.8 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.26 (td, J = 11.5, 2.5 Hz, 2H), 3.54 (q, J = 4.4 Hz, 2H), 3.83 (ddd, J = 11.5, 4.3, 2.0 Hz, 2H), 4.40 (d, J = 7.2 Hz, 2H), 6.93-7.01 (m, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.28 (dd, J = 9.1, 1.8 Hz, 1H), 7.74 (dd, J = 9.0, 1.0 Hz, 1H), 8.11-8.14 (m, 1H), 8.62 (d, J = 0.9 Hz, 1H). MS: [M + H] = 456 Example 25 [00206]   Compound 7 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid butyl(4- isopropylphenyl)amide .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.7 Hz, 6H), 1.19 (d, J = 6.9 Hz, 6H), 1.25- 1.50 (m, 5H), 2.11-2.22 (m, 1H), 2.88 (hept, J = 6.8 Hz, 1H), 3.23 (td, J = 11.3, 2.9 Hz, 2H), 3.82 (ddd, J = 11.6, 4.4, 2.2 Hz, 2H), 4.38 (d, J = 7.1 Hz, 2H), 6.94- 7.03 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.44 (dd, J = 8.9, 1.8 Hz, 1H), 7.85-7.94 (m, 1H), 8.09 (d, J = 1.7 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H) MS: [M + H] = 470 Example 26 [00207]   Compound 10 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-chloro-2- fluorophenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H), 1.21-1.49 (m, 5H), 2.17 (dd, J = 10.5, 5.9 Hz, 1H), 3.23 (td, J = 11.1, 3.3 Hz, 2H), 3.76-3.87 (m, 2H), 4.40 (d, J = 7.0 Hz, 2H), 7.15 (dd, J = 6.5, 2.7 Hz, 1H), 7.35 (dd, J = 10.1, 8.9 Hz, 1H), 7.50 (ddd, J = 8.8, 4.1, 2.6 Hz, 1H), 7.56 (dd, J = 9.0, 1.8 Hz, 1H), 7.92-7.99 (m, 1H), 8.20 (d, J = 1.7 Hz, 1H), 8.33 (d, J = 1.0 Hz, 1H). MS: [M + H] = 480 Example 27 [00208]   Compound 42 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-fluoro-2- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.77 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.22- 1.49 (m, 5H), 2.07-2.25 (m, 1H), 2.27 (s, 3H), 3.13 (dd, J = 13.2, 4.7 Hz, 1H), 3.23 (td, J = 11.2, 3.4 Hz, 2H), 3.43 (dd, J = 13.2, 9.1 Hz, 1H), 3.81 (dt, J = 11.5, 3.2 Hz, 2H), 4.40 (d, J = 7.1 Hz, 2H), 6.45 (dd, J = 10.1, 2.7 Hz, 1H), 7.12 (td, J = 8.3, 2.7 Hz, 1H), 7.35 (dd, J = 8.6, 6.6 Hz, 1H), 7.51 (dd, J = 8.9, 1.8 Hz, 1H), 7.91- 7.99 (m, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.34 (d, J = 0.9 Hz, 1H). MS: [M + H] = 460 Example 28 [00209]   Compound 43 1-(tetrahydropyran-4-ylmethyl)-2H- indazole-5-sulfonic acid (3-fluoro-2- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.77 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H), 1.18- 1.52 (m, 5H), 2.08-2.27 (m, 4H), 3.13 (dd, J = 13.1, 4.8 Hz, 1H), 3.23 (td, J = 11.2, 3.1 Hz, 2H), 3.46 (dd, J = 13.2, 9.0 Hz, 1H), 3.73-3.88 (m, 2H), 4.39 (d, J = 7.1 Hz, 2H), 6.52 (d, J = 8.1 Hz, 1H), 7.06- 7.26 (m, 2H), 7.52 (dd, J = 8.9, 1.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 1.7 Hz, 1H), 8.32 (d, J = 1.0 Hz, 1H). MS: [M + H] = 460 Example 29 [00210]   Compound 44 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5- chlorophenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H), 1.21-1.50 (m, 5H), 3.23 (td, J = 11.2, 3.2 Hz, 2H), 3.38 (d, J = 7.3 Hz, 2H), 3.80 (s, 2H), 4.38 (d, J = 7.1 Hz, 2H), 7.08 (dt, J = 7.0, 2.0 Hz, 1H), 7.13 (t, J = 1.9 Hz, 1H), 7.34-7.40 (m, 2H), 7.41- 7.44 (m, 1H), 7.91 (d, J = 8.9 Hz, 1H), 8.11 (d, J = 1.7 Hz, 1H), 8.31 (d, J = 1.0 Hz, 1H). MS: [M + H] = 462 Example 30 [00211]   Compound 45 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2- chlorophenyl)isobutylamide .sup.1H NMR (400 MHz, CDCl3) δ 0.86 (t, J = 6.2 Hz, 6H), 1.37 (td, J = 10.9, 9.9, 4.0 Hz, 4H), 1.55 (dt, J = 13.5, 6.8 Hz, 2H), 2.22 (s, 1H), 3.28 (td, J = 11.1, 4.0 Hz, 2H), 3.36 (dd, J = 7.2, 1.8 Hz, 2H), 3.89 (dt, J = 11.6, 3.3 Hz, 2H), 4.22 (d, J = 7.1 Hz, 2H), 7.19 (m, 3H), 7.25-7.30 (m, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.9, 1.7 Hz, 1H), 8.03 (s, 1H), 8.07 (d, J = 1.6 Hz, 1H). MS: [M + H] = 462 Example 31 [00212]   Compound 46 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4- fluorophenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H), 1.23-1.48 (m, 5H), 2.16 (ddd, J = 11.0, 6.9, 4.2 Hz, 1H), 3.23 (td, J = 11.3, 2.9 Hz, 2H), 3.35 (s, 2H), 3.82 (ddd, J = 11.5, 4.5, 2.2 Hz, 2H), 4.38 (d, J = 7.0 Hz, 2H), 7.05-7.22 (m, 4H), 7.45 (dd, J = 8.9, 1.7 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 8.07 (d, J = 1.7 Hz, 1H), 8.30 (s, 1H). MS: [M + H] = 446 Example 32 [00213]   Compound 47 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl-p- tolylamide .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.7 Hz, 6H), 1.23-1.48 (m, 5H), 2.05-2.25 (m, 1H), 2.29 (s, 3H), 3.24 (td, J = 11.3, 2.8 Hz, 3H), 3.32 (td, 2H), 3.82 (dd, J = 11.3, 3.7 Hz, 2H), 4.38 (d, J = 7.1 Hz, 2H), 6.89-6.95 (m, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.45 (dd, J = 8.9, 1.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H). MS: [M + H] = 442 Example 33 [00214]   Compound 48 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl-o- tolylamide .sup.1H NMR (DMSO-d6) δ: 0.76 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.24- 1.50 (m, 5H), 2.07-2.26 (m, 1H), 2.30 (s, 3H), 3.13 (dd, J = 13.2, 4.9 Hz, 1H), 3.24 (td, J = 11.0, 2.9 Hz, 2H), 3.45 (dd, J = 13.1, 8.9 Hz, 1H), 3.82 (dd, J = 13.4, 2.4 Hz, 2H), 4.40 (d, J = 7.1 Hz, 2H), 6.62 (dd, J = 8.1, 1.3 Hz, 1H), 7.08 (td, J = 7.7, 1.7 Hz, 1H), 7.24 (td, J = 7.5, 1.3 Hz, 1H), 7.31 (dd, J = 7.8, 1.6 Hz, 1H), 7.53 (dd, J = 8.9, 1.8 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 8.13 (s, 1H), 8.32 (s, 1H). MS: [M + H] = 442 Example 34 [00215]   Compound 11 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,5- dimethylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.77 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.26- 1.38 (m, 4H), 1.44 (dtd, J = 8.9, 6.7, 4.8 Hz, 1H), 2.03 (s, 3H), 2.12-2.22 (m, 1H), 2.23 (s, 3H), 3.07 (dd, J = 13.1, 4.8 Hz, 1H), 3.19-3.27 (m, 2H), 3.43 (dd, J = 13.1, 8.9 Hz, 1H), 3.81 (dq, J = 10.8, 3.4 Hz, 2H), 4.41 (d, J = 7.0 Hz, 2H), 6.29 (d, J = 1.7 Hz, 1H), 7.04 (dd, J = 7.8, 1.8 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.49 (dd, J = 9.0, 1.7 Hz, 1H), 7.93 (dt, J = 9.0, 0.9 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H) MS: [M + H] = 456 Example 35 [00216]   Compound 13 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-butyl-2- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.75 (d, J = 6.6 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.24-1.47 (m, 8H), 1.48- 1.59 (m, 2H), 2.16 (s, 1H), 2.25 (s, 3H), 3.09 (dd, J = 13.1, 4.9 Hz, 1H), 3.24 (td, J = 11.1, 3.2 Hz, 2H), 3.37-3.46 (m, 1H), 3.77-3.88 (m, 2H), 4.39 (d, J = 7.0 Hz, 2H), 6.52 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.2, 2.2 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 7.52 (dd, J = 9.0, 1.7 Hz, 1H), 7.85- 7.98 (m, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 0.9 Hz, 1H) MS: [M + H] = 498 Example 36 [00217]   Compound 27 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,4- dimethylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.76 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H), 1.22- 1.48 (m, 5H), 2.09 (d, J = 4.8 Hz, 1H), 2.11-2.21 (m, 1H), 2.25 (d, J = 4.1 Hz, 6H), 3.08 (dd, J = 13.1, 4.8 Hz, 1H), 3.24 (td, J = 11.2, 3.2 Hz, 2H), 3.43 (dd, J = 13.1, 8.9 Hz, 1H), 3.76-3.87 (m, 2H), 4.40 (d, J = 7.0 Hz, 2H), 6.48 (d, J = 8.1 Hz, 1H), 6.87 (dd, J = 8.1, 2.1 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 7.53 (dd, J = 9.0, 1.7 Hz, 1H), 7.90-7.96 (m, 1H), 8.13 (d, J = 1.7 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H) MS: [M + H] = 456 Example 37 [00218]   Compound 28 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3,5- dimethylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H), 1.22-1.38 (m, 4H), 1.44 (hept, J = 6.8 Hz, 1H), 2.16 (s, 7H), 3.23 (td, J = 11.1, 3.6 Hz, 2H), 3.29 (d, J = 7.3 Hz, 2H), 3.76-3.85 (m, 2H), 4.39 (d, J = 7.0 Hz, 2H), 6.58-6.63 (m, 2H), 6.94 (s, 1H), 7.42 (dd, J = 8.8, 1.7 Hz, 1H), 7.87- 7.92 (m, 1H), 8.09 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 0.9 Hz, 1H) MS: [M + H] = 456 Example 38 [00219]   Compound 26 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H), 1.23-1.52 (m, 5H), 2.22 (s, 4H), 3.23 (td, J = 11.3, 3.2 Hz, 2H), 3.77- 3.87 (m, 2H), 4.38 (d, J = 7.1 Hz, 2H), 6.78-6.89 (m, 2H), 7.10-7.15 (m, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.85-7.93 (m, 1H), 8.08 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H) MS: [M + H] = 442 Example 39 [00220]   Compound 25 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3- methoxyphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.86 (d, J = 6.6 Hz, 6H), 1.21-1.38 (m, 4H), 1.45 (hept, J = 6.8 Hz, 1H), 3.23 (td, J = 11.3, 3.2 Hz, 2H), 3.61 (s, 3H), 3.81 (dt, J = 11.7, 2.7 Hz, 2H), 4.38 (d, J = 7.0 Hz, 2H), 6.53 (t, J = 2.3 Hz, 1H), 6.66 (ddd, J = 7.9, 2.0, 0.9 Hz, 1H), 6.89 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 7.24 (t, J = 8.1 Hz, 1H), 7.46 (dd, J = 8.9, 1.7 Hz, 1H), 7.88-7.94 (m, 1H), 8.10 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.8 Hz, 1H) MS: [M + H] = 458 Example 40 [00221]   Compound 49 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4- trifluoromethoxyphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H), 1.24-1.47 (m, 5H), 2.10-2.20 (m, 1H), 3.23 (td, J = 11.3, 2.9 Hz, 2H), 3.37 (d, J = 7.4 Hz, 2H), 3.80 (s, 2H), 4.38 (d, J = 7.1 Hz, 2H), 7.20-7.26 (m, 2H), 7.32-7.37 (m, 2H), 7.43 (dd, J = 9.0, 1.8 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H); MS: [M + H] = 512 Example 41 [00222]   Compound 50 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(5- isopropylpyridin-2-yl)amide .sup.1H NMR (Chloroform-d) δ: 0.82 (d, J = 6.7 Hz, 6H), 1.20 (s, 6H), 1.30-1.44 (m, 4H), 2.15-2.28 (m, 1H), 2.87 (p, J = 7.0 Hz, 1H), 3.28 (td, J = 11.5, 3.0 Hz, 2H), 3.42 (d, J = 7.3 Hz, 2H), 3.86-3.93 (m, 2H), 4.18 (d, J = 7.2 Hz, 2H), 7.29-7.33 (m, 1H), 7.40 (dd, J = 9.0, 1.7 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 8.3, 2.5 Hz, 1H), 8.01 (d, J = 0.8 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H). MS: [M + H] = 471 Example 42 [00223]   Compound 12 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3- methoxypyridin-2-yl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.86 (d, J = 6.6 Hz, 6H), 1.20-1.37 (m, 4H), 1.57 (hept, J = 6.9 Hz, 1H), 2.03-2.24 (m, 1H), 3.12- 3.26 (m, 3H), 3.42 (s, 3H), 3.53 (d, J = 7.1 Hz, 2H), 3.71-3.87 (m, 2H), 4.37 (d, J = 7.1 Hz, 2H), 6.69 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.46 (dd, J = 9.0, 1.8 Hz, 1H), 7.73-7.82 (m, 1H), 7.88 (dd, J = 9.0, 1.0 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H) MS: [M + H] = 459 Example 43 [00224]   Compound 51 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3- chlorobenzyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.70 (d, J = 6.6 Hz, 6H), 1.25-1.42 (m, 4H), 1.58 (dt, J = 13.6, 6.9 Hz, 1H), 2.92 (d, J = 7.6 Hz, 2H), 3.24 (td, J = 11.3, 3.2 Hz, 2H), 3.82 (d, J = 11.2 Hz, 2H), 4.33 (s, 2H), 4.40 (d, J = 7.1 Hz, 2H), 7.24-7.37 (m, 4H), 7.80 (dd, J = 9.0, 1.7 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 8.31 (d, J = 0.9 Hz, 1H), 8.37 (d, J = 1.7 Hz, 1H) MS: [M + H] = 476 Example 44 [00225]   Compound 52 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(2- trifluoromethylbenzyl)amide .sup.1H NMR (DMSO-d6) δ: 0.70 (d, J = 6.6 Hz, 6H), 1.23-1.43 (m, 5H), 2.97 (d, J = 7.2 Hz, 2H), 3.24 (td, J = 11.3, 3.0 Hz, 2H), 3.82 (d, J = 10.7 Hz, 2H), 4.40 (d, J = 7.1 Hz, 2H), 4.48 (s, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.70 (q, J = 7.6 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.83 (dd, J = 8.9, 1.8 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 8.39 (d, J = 1.7 Hz, 1H) MS: [M + H] = 510 Example 45 [00226]   Compound 53 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2-fluoro-6- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.77 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.21- 1.39 (m, 4H), 1.41-1.57 (m, 1H), 2.08- 2.25 (m, 1H), 2.28 (s, 3H), 3.15 (dd, J = 13.7, 5.8 Hz, 1H), 3.23 (td, J = 11.0, 3.7 Hz, 2H), 3.45 (dd, J = 13.6, 7.9 Hz, 1H), 3.81 (dt, J = 11.4, 3.3 Hz, 2H), 4.39 (d, J = 7.0 Hz, 2H), 7.00 (ddd, J = 10.2, 8.3, 1.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.23- 7.36 (m, 1H), 7.63 (dd, J = 8.9, 1.8 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 1.0 Hz, 1H) MS: [M + H] = 460 Example 46 [00227]   Compound 54 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-fluoro-2- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.77 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 1.24- 1.50 (m, 5H), 2.11-2.24 (m, 1H), 2.29 (s, 3H), 3.10 (dd, J = 13.1, 4.8 Hz, 1H), 3.23 (td, J = 11.2, 3.2 Hz, 2H), 3.45 (dd, J = 13.2, 8.9 Hz, 1H), 3.82 (dt, J = 11.6, 2.7 Hz, 2H), 4.39 (d, J = 7.1 Hz, 2H), 6.66 (dd, J = 8.9, 5.5 Hz, 1H), 6.92 (td, J = 8.4, 3.1 Hz, 1H), 7.18 (dd, J = 9.8, 3.0 Hz, 1H), 7.53 (dd, J = 8.9, 1.7 Hz, 1H), 7.93 (dd, J = 9.0, 0.9 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H) MS: [M + H] = 460 Example 47 [00228]   Compound 55 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(4- methoxy-2-methylphenyl)amide 1H NMR (DMSO-d6) δ: 0.76 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.23- 1.53 (m, 5H), 2.08-2.21 (m, 1H), 2.24 (s, 3H), 3.07 (dd, J = 13.0, 4.8 Hz, 1H), 3.24 (td, J = 11.2, 3.2 Hz, 2H), 3.43 (dd, J = 13.1, 8.9 Hz, 1H), 3.73 (s, 3H), 3.82 (dt, J = 11.4, 3.3 Hz, 2H), 4.39 (d, J = 7.1 Hz, 2H), 6.51 (d, J = 8.8 Hz, 1H), 6.61 (dd, J = 8.8, 3.0 Hz, 1H), 6.85 (d, J = 2.9 Hz, 1H), 7.53 (dd, J = 8.9, 1.7 Hz, 1H), 7.87- 7.96 (m, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 0.9 Hz, 1H) MS: [M + H] = 472 Example 48 [00229]   Compound 56 methyl 4-{isobutyl[1-(tetrahydropyran- 4-ylmethyl)-1H-indazole-5- sulfonyl]amino}-3-methylbenzoate .sup.1H NMR (DMSO-d6) δ: 0.76 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 1.23- 1.49 (m, 5H), 2.09-2.23 (m, 1H), 2.37 (s, 3H), 3.15 (dd, J = 13.2, 4.8 Hz, 1H), 3.24 (td, J = 11.2, 3.0 Hz, 2H), 3.46 (dd, J = 13.3, 8.9 Hz, 1H), 3.75-3.88 (m, 5H), 4.40 (d, J = 7.1 Hz, 2H), 6.80 (d, J = 8.3 Hz, 1H), 7.51 (dd, J = 8.9, 1.7 Hz, 1H), 7.65 (dd, J = 8.3, 2.2 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H) MS: [M + H] = 500 Example 49 [00230]   Compound 57 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-cyano-2- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) δ: 0.76 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H), 1.21- 1.48 (m, 5H), 2.06-2.25 (m, 1H), 2.35 (s, 3H), 3.07-3.29 (m, 3H), 3.45 (dd, J = 13.3, 9.0 Hz, 1H), 3.82 (dd, J = 10.1, 3.2 Hz, 2H), 4.40 (d, J = 7.0 Hz, 2H), 6.88 (d, J = 8.3 Hz, 1H), 7.52 (dd, J = 9.0, 1.8 Hz, 1H), 7.59 (dd, J = 8.2, 2.1 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 9.0, 0.9 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 1.0 Hz, 1H). MS: [M + H] = 467

Example 50: Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)(tetrahydropvran-4-ylmethyl)amide

[0229] ##STR00231##

1. Synthesis of Intermediate 50.1

[0230] ##STR00232##

[0231] A mixture of 1H-indazole-5-sulfonyl chloride (1.00 g; 4.39 mmol), pyridine (5.0 ml) and 4-ethylaniline (603 μl; 4.82 mmol) is stirred for 4 hours at 50° C. The reaction medium is diluted with ethyl acetate and extracted. The organic phase is washed with saturated ammonium chloride solution, with saturated sodium hydrogen carbonate solution and with water. It is dried (MgSO.sub.4), filtered and concentrated to dryness.

[0232] The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The 1H-indazole-5-sulfonic acid (4-ethylphenyl)amide (1.32 g; 100%) is obtained in the form of an orange oil with a compliant .sup.1H NMR.

[0233] MS: [M+H]=302

2. Synthesis of Compound 5 According to the Invention

[0234] ##STR00233##

[0235] A mixture of 1H-indazole-5-sulfonic acid (4-ethylphenyl)amide (1.30 g; 4.31 mmol), cesium carbonate (2.11 g; 6.47 mmol) and 4-(bromomethyl)tetrahydropyran (680 μl; 5.18 mmol; 1.20 eq.) in N-methyl-2-pyrrolidone (10 ml) is stirred for 16 hours at a temperature of 50° C. The reaction medium is diluted with ethyl acetate (30 ml). The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml). The organic phase is dried (MgSO.sub.4), filtered and concentrated.

[0236] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)(tetrahydropyran-4-ylmethyl)amide (360 mg; 17%) is obtained in the form of a white solid.

[0237] .sup.1H NMR (DMSO-d6) δ: 1.08-1.23 (m, 5H), 1.25-1.47 (m, 5H), 1.52-1.62 (m, 2H), 2.60 (q, J=7.5 Hz, 2H), 3.13 (td, J=11.6, 2.2 Hz, 2H), 3.23 (td, J=11.3, 3.0 Hz, 2H), 3.43 (d, J=7.2 Hz, 2H), 3.72-3.87 (m, 4H), 4.38 (d, J=7.1 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.46 (dd, J=9.0, 1.7 Hz, 1H), 7.84-7.98 (m, 1H), 8.10 (d, J=1.7 Hz, 1H), 8.29 (d, J=0.9 Hz, 1H)

[0238] MS: [M+H]=498 [0239] Another fraction is obtained corresponding to the mixture below:

##STR00234##

Intermediate 51.1: Mixture of N-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide and N-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulfonamide

[0240] The mixture of N-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide and N-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulfonamide (170.00 mg; 10%) is obtained in the form of a solid with a compliant .sup.1H NMR.

[0241] MS: [M+H]=400

Example 51: Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid cyclopropyl(4-ethylphenyl)amide

[0242] ##STR00235##

[0243] A spatulaful of molecular sieves is added to a mixture of N-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide and N-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulfonamide (170 mg; 0.43 mmol), triethylamine (180 μl; 1.28 mmol), copper(II) acetate (232 mg; 1.28 mmol) and cyclopropylboronic acid (220 mg; 2.55 mmol) in dichloromethane (3 ml).

[0244] The reaction medium is stirred for 16 hours at room temperature under 1 atmosphere of oxygen and filtered through Celite, which is rinsed with dichloromethane (50 ml) and with water (20 ml). The organic phase is extracted, washed with a mixture (1/1) of aqueous ammonia and saturated NH.sub.4Cl solution (2×50 ml) and then with water (50 ml), dried (MgSO.sub.4), filtered and concentrated.

[0245] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid cyclopropyl(4-ethylphenyl)amide 002 (40 mg; 21%) is obtained in the form of a white solid.

[0246] .sup.1H NMR (DMSO-d6) δ: 0.62 (t, J=3.2 Hz, 2H), 0.76 (dt, J=7.1, 3.6 Hz, 2H), 1.14-1.22 (m, 4H), 1.23-1.42 (m, 4H), 2.16 (dd, J=10.8, 5.1 Hz, 1H), 2.58-2.71 (m, 3H), 3.17-3.29 (m, 3H), 3.76-3.89 (m, 2H), 4.38 (d, J=7.1 Hz, 2H), 6.87-7.02 (m, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.46 (dd, J=8.8, 1.7 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.33 (d, J=0.9 Hz, 1H)

[0247] MS: [M+H]=440

Example 52: Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid isobutyl(2-trifluoromethylphenyl)amide

[0248] ##STR00236##

1. Synthesis of Intermediate 52.1

[0249] ##STR00237##

[0250] A mixture of 1H-indazole-5-sulfonyl chloride (500.0 mg; 2.19 mmol), pyridine (3.0 ml) and 2-(trifluoromethyl)aniline (306.18 μl; 2.41 mmol) is stirred for 16 hours at a temperature of 40° C. The reaction medium is diluted with ethyl acetate and extracted. The organic phase is washed with saturated ammonium chloride solution, with saturated sodium hydrogen carbonate solution and with water. It is dried (MgSO.sub.4), filtered and concentrated to dryness.

[0251] The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate).

[0252] The 1H-indazole-5-sulfonic acid (2-trifluoromethylphenyl)amide (300 mg; 40%) is obtained in the form of a white solid with a compliant .sup.1H NMR.

[0253] MS: [M+H]=342

2. Synthesis of Compound 58 According to the Invention

[0254] ##STR00238##

[0255] Cesium carbonate (30 mg; 1.32 mmol) and 4-(bromomethyl)tetrahydropyran (127 μl; 0.97 mmol) are added to a solution of 1H-indazole-5-sulfonic acid (2-trifluoromethylphenyl)amide (300 mg; 0.88 mmol) in 1-methyl-2-pyrrolidone (3 ml). The reaction medium is stirred for 16 hours at room temperature. 1-Bromo-2-methylpropane (287 μl; 2.64 mmol) is added and the reaction medium is stirred for 6 hours at 80° C. The reaction medium is diluted with ethyl acetate, washed with saturated ammonium chloride solution and then with saturated sodium hydrogen carbonate solution and with water. The organic phase is dried (MgSO.sub.4), filtered and concentrated to dryness.

[0256] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid isobutyl(2-trifluoromethylphenyl)amide (80 mg; 16%) is obtained in the form of a beige-colored solid.

[0257] .sup.1H NMR (DMSO-d6) δ: 0.71 (d, J=6.7 Hz, 3H), 0.85-0.93 (m, 3H), 1.25-1.43 (m, 4H), 1.48 (dtd, J=8.8, 6.6, 4.6 Hz, 1H), 2.12-2.25 (m, 1H), 3.15 (dd, J=13.4, 4.6 Hz, 1H), 3.24 (td, J=10.8, 10.4, 2.2 Hz, 2H), 3.46 (dd, J=13.4, 8.8 Hz, 1H), 3.78-3.86 (m, 2H), 4.41 (d, J=7.1 Hz, 2H), 6.99 (dd, J=5.7, 3.7 Hz, 1H), 7.56 (dd, J=9.0, 1.7 Hz, 1H), 7.58-7.64 (m, 2H), 7.85 (dt, J=5.6, 3.7 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 8.18-8.24 (m, 1H), 8.35 (s, 1H).

[0258] MS: [M+H]=496

Example 53: Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid isobutyl(4-trifluoromethylphenyl)amide

[0259] ##STR00239##

1. Synthesis of Intermediate 53.1

[0260] ##STR00240##

[0261] A mixture of 1H-indazole-5-sulfonyl chloride (250.0 mg; 1.10 mmol) and 4-(trifluoromethyl)aniline (388.6 μl; 2.41 mmol) in acetonitrile (1.7 ml) is stirred for 40 minutes at a temperature of 100° C. under microwave irradiation. The reaction medium is diluted with ethyl acetate and extracted.

[0262] The organic phase is washed with saturated ammonium chloride solution, with saturated sodium hydrogen carbonate solution and with water. It is dried (MgSO.sub.4), filtered and concentrated to dryness.

[0263] The 1H-indazole-5-sulfonic acid (4-trifluoromethylphenyl)amide (297 mg; 79%) is obtained in the form of a yellowish solid with a compliant .sup.1H NMR.

[0264] MS: [M+H]=342

2. Synthesis of Compound 59 According to the Invention

[0265] ##STR00241##

[0266] With a procedure similar to that described for example 52, 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid isobutyl(4-trifluoromethylphenyl)amide (178 mg; 40%) is obtained in the form of a white solid.

[0267] .sup.1H NMR (DMSO-d6) δ: 0.84 (d, J=6.6 Hz, 6H), 1.22-1.51 (m, 5H), 2.07-2.24 (m, 1H), 3.23 (td, J=11.4, 2.9 Hz, 2H), 3.42 (d, J=7.3 Hz, 2H), 3.81 (ddd, J=11.6, 4.2, 2.1 Hz, 2H), 4.37 (d, J=7.1 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.43 (dd, J=8.9, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.91 (d, 1H), 8.13 (d, J=1.6 Hz, 1H), 8.31 (d, J=1.0 Hz, 1H).

[0268] MS: [M+H]=496

Example 54: Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (2-cyano-4-methylphenyl)isobutylamide

[0269] ##STR00242##

1. Synthesis of Intermediate 54.1

[0270] ##STR00243##

[0271] With a procedure similar to that described for intermediate 53.1, 1H-indazole-5-sulfonic acid (2-cyano-4-methylphenyl)amide (342.4 mg; 100%) is obtained in the form of a yellowish solid with a compliant .sup.1H NMR.

[0272] MS: [M+H]=313

2. Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (2-cyano-4-methylphenyl)isobutylamide (Compound 70)

[0273] With a procedure similar to that described for example 52, 1-(tetrahydropyran-4-ylmethyl)-2H-indazole-5-sulfonic acid (2-cyano-4-methylphenyl)isobutylamide (129.7 mg; 20%) is obtained in the form of a white solid.

[0274] .sup.1H NMR (Chloroform-d) δ: 0.93 (d, J=6.7 Hz, 6H), 1.42-1.53 (m, 4H), 1.54-1.67 (m, 1H), 2.21-2.39 (m, 1H), 2.42 (s, 3H), 3.37 (td, J=11.3, 3.5 Hz, 2H), 3.45 (d, J=7.2 Hz, 2H), 3.98 (dt, J=11.7, 2.6 Hz, 2H), 4.32 (d, J=7.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 1H), 7.41 (dd, J=8.2, 2.1 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.78 (dd, J=8.9, 1.6 Hz, 1H), 8.15 (d, J=1.0 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H).

[0275] MS: [M+H]=467

Example 55: Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4,6-dimethylpyridin-3-yl)isobutylamide

[0276] ##STR00244##

1. Synthesis of Intermediate 55.1

[0277] ##STR00245##

[0278] With a procedure similar to that described for intermediate 53.1, 1H-indazole-5-sulfonic acid (4,6-dimethylpyridin-3-yl)amide (151 mg; 46%) is obtained in the form of a yellowish solid with a compliant .sup.1H NMR.

[0279] MS: [M+H]=303

2. Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4,6-dimethylpyridin-3-yl)isobutylamide

[0280] With a procedure similar to that described for example 52, 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4,6-dimethylpyridin-3-yl)isobutylamide (17 mg; 7%) is obtained in the form of a white solid.

[0281] .sup.1H NMR (DMSO-d6) δ: 0.78 (d, J=6.7 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.18-1.56 (m, 5H), 2.13-2.27 (m, 4H), 2.41 (s, 3H), 3.19-3.29 (m, 3H), 3.44 (dd, J=13.3, 8.6 Hz, 1H), 3.78-3.89 (m, 2H), 4.40 (d, J=7.0 Hz, 2H), 7.21 (s, 1H), 7.56 (dd, J=8.9, 1.8 Hz, 1H), 7.68 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 8.33 (s, 1H).

[0282] MS: [M+H]=457

Example 56: Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-dimethylaminophenyl)isobutylamide

[0283] ##STR00246##

1. Synthesis of Intermediate 56.1

[0284] ##STR00247##

[0285] With a procedure similar to that described for intermediate 53.1, 1H-indazole-5-sulfonic acid (4-dimethylaminophenyl)amide (281 mg; 81%) is obtained in the form of a fluffy white solid with a compliant .sup.1H NMR.

[0286] MS: [M+H]=317

2. Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-dimethylaminophenyl)isobutylamide (Compound 72)

[0287] ##STR00248##

[0288] With a procedure similar to that described for example 52, 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-dimethylaminophenyl)isobutylamide (19 mg; 4%) is obtained in the form of a white solid.

[0289] .sup.1H 1H NMR (Chloroform-d) δ: 0.94 (d, J=6.7 Hz, 6H), 1.38-1.55 (m, 3H), 1.62 (dd, J=13.2, 6.3 Hz, 2H), 2.31 (dt, J=11.0, 5.6 Hz, 1H), 2.97 (s, 6H), 3.30 (d, J=7.3 Hz, 2H), 3.38 (td, J=11.3, 3.1 Hz, 2H), 3.99 (ddd, J=11.7, 4.4, 2.1 Hz, 2H), 4.31 (d, J=7.1 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 6.84-6.91 (m, 2H), 7.41-7.46 (m, 1H), 7.60 (dd, J=8.9, 1.6 Hz, 1H), 8.08 (d, J=1.7 Hz, 1H), 8.11 (d, J=0.9 Hz, 1H).

[0290] MS: [M+H]=471

Example 57: Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (2-fluoro-4-methylphenyl)isobutylamide

[0291] ##STR00249##

1. Synthesis of Intermediate 57.1

[0292] ##STR00250##

[0293] With a procedure similar to that described for intermediate 53.1, 1H-indazole-5-sulfonic acid (2-fluoro-4-methylphenyl)amide (189 mg; 94%) is obtained in the form of a yellowish solid with a compliant .sup.1H NMR.

[0294] MS: [M+H]=306

2. Synthesis of 1-(tetrahydropvran-4-ylmethyl)-1H-indazole-5-sulfonic acid (2-fluoro-4-methylphenyl)isobutylamide

[0295] With a procedure similar to that described for example 52, 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (2-fluoro-4-methylphenyl)isobutylamide (19 mg; 4%) is obtained in the form of a white solid.

[0296] .sup.1H 1H NMR (Chloroform-d) δ: 0.93 (d, J=6.6 Hz, 6H), 1.47 (td, J=11.2, 10.7, 4.2 Hz, 3H), 1.54-1.69 (m, 2H), 2.30 (dd, J=10.7, 4.6 Hz, 1H), 2.36 (s, 3H), 3.24-3.47 (m, 5H), 3.95-4.03 (m, 2H), 4.31 (d, J=7.1 Hz, 2H), 6.82 (dd, J=11.5, 1.8 Hz, 1H), 6.94 (dd, J=8.2, 1.8 Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 7.45 (dt, J=9.0, 0.9 Hz, 1H), 7.67 (dd, J=8.9, 1.6 Hz, 1H), 8.13 (dd, J=9.3, 1.2 Hz, 2H).

[0297] MS: [M+H]=460

Part II: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 2

[0298] ##STR00251##

Example 58: Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)oxetan-3-ylmethylamide

[0299] ##STR00252##

1. Synthesis of Intermediate 58.1

[0300] ##STR00253##

[0301] A mixture of 4-ethylaniline (513 μl; 4.13 mmol), oxetane-3-carbaldehyde (807.3 mg; 3.75 mmol) and tetrahydrofuran (2.5 ml) is stirred for 2 hours at room temperature. Sodium triacetoxyborohydride (1.19 g; 5.63 mmol) is added and the reaction medium is stirred for 16 hours at room temperature, hydrolyzed and extracted with ethyl acetate.

[0302] The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

[0303] The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The 2-chloromethyl-3-(4-ethylphenylamino)propan-1-ol (340 mg; 40%) is obtained in the form of an orange oil with a .sup.1H NMR showing the opening of the oxetane.

[0304] MS: [M+H]=228

2. Synthesis of Intermediate 58.2

[0305] ##STR00254##

[0306] A mixture of 1H-indazole-5-sulfonyl chloride (368.5 mg; 1.62 mmol), pyridine (3.0 ml; 37.17 mmol) and (4-ethylphenyl)oxetan-3-ylmethylamine (340 mg; 1.78 mmol) is stirred for 30 minutes at a temperature of 100° C. under microwave irradiation.

[0307] The reaction medium is diluted with ethyl acetate. The organic phase is washed with saturated ammonium chloride solution, with saturated sodium hydrogen carbonate solution and with water. It is dried (MgSO.sub.4), filtered and concentrated to dryness.

[0308] The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The 1H-indazole-5-sulfonic acid (2-chloromethyl-3-hydroxypropyl)(4-ethylphenyl)amide (260 mg; 39%) is obtained in the form of a colorless oil with a compliant .sup.1H NMR.

[0309] MS: [M+H]=408

3. Synthesis of Intermediate 58.3

[0310] ##STR00255##

[0311] A mixture of 1H-indazole-5-sulfonic acid (2-chloromethyl-3-hydroxypropyl)(4-ethylphenyl)amide (1.26 g; 0.64 mmol), cesium carbonate (0.31 mg; 0.96 mmol) and 4-(bromomethyl)tetrahydropyran (100 μl; 0.76 mmol) in N-methyl-2-pyrrolidone (4 ml) is stirred for 1 hour at a temperature of 80° C. The reaction medium is diluted with ethyl acetate (20 ml).

[0312] The organic phase is washed with saturated NH.sub.4Cl solution, with saturated NaHCO.sub.3 solution and with water. The organic phase is dried (MgSO.sub.4), filtered and concentrated.

[0313] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (3-chloro-2-hydroxymethylpropyl)(4-ethylphenyl)amide (100 mg; 31%) is obtained in the form of a colorless oil.

[0314] .sup.1H NMR (DMSO-d6) δ: 1.18 (t, J=7.6 Hz, 3H), 1.25-1.43 (m, 4H), 1.73 (p, J=6.4 Hz, 1H), 2.61 (q, J=7.6 Hz, 2H), 3.23 (td, J=11.3, 3.0 Hz, 2H), 3.35-3.41 (m, 1H), 3.46-3.52 (m, 1H), 3.52-3.63 (m, 2H), 3.69 (qd, J=10.8, 4.9 Hz, 2H), 3.82 (ddd, J=11.4, 4.3, 2.2 Hz, 2H), 4.39 (d, J=7.0 Hz, 2H), 4.69 (t, J=5.1 Hz, 1H), 6.95-7.02 (m, 2H), 7.16-7.22 (m, 2H), 7.44 (dd, J=9.0, 1.8 Hz, 1H), 7.92 (d, J=8.9 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.31 (s, 1H)

[0315] MS: [M+H]=506

4. Synthesis of Compound 16 According to the Invention

[0316] ##STR00256##

[0317] 60% sodium hydride (17.4 mg; 0.43 mmol) is added to a solution of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (3-chloro-2-hydroxymethylpropyl)(4-ethylphenyl)amide (100 mg; 0.20 mmol) in tetrahydrofuran (3 ml). The reaction medium is stirred for 1 hour at a temperature of 80° C. and then for 16 hours at a temperature of 30° C.

[0318] The reaction medium is diluted with ethyl acetate (20 ml). The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml). The organic phase is dried (MgSO.sub.4), filtered and concentrated.

[0319] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)oxetan-3-ylmethylamide (35.0 mg; 33%) is obtained in the form of a white solid.

[0320] .sup.1H NMR (Methanol-d4) δ: 1.20 (t, J=7.6 Hz, 3H), 1.31-1.51 (m, 5H), 2.27 (tq, J=10.6, 6.2, 5.6 Hz, 1H), 2.62 (q, J=7.6 Hz, 2H), 3.01 (hept, J=7.3 Hz, 1H), 3.31-3.43 (m, 2H), 3.92 (d, J=7.7 Hz, 3H), 4.33-4.42 (m, 3H), 4.56-4.66 (m, 2H), 6.88 (d, J=8.2 Hz, 2H), 6.93-7.03 (m, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.58 (dd, J=8.9, 1.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 8.13 (s, 1H)

[0321] MS: [M+H]=470

Part III: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 3

[0322] ##STR00257##

Example 59: Synthesis of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropvran-4-ylmethyl)-1H-indazole-7-carboxylate

[0323] ##STR00258##

1. Synthesis of Intermediate 59.1

[0324] ##STR00259##

[0325] (4-Ethylphenyl)isobutylamine (417.5 mg; 2.35 mmol) is added to methyl 5-chlorosulfonyl-1H-indazole-7-carboxylate (300 mg; 1.07 mmol) in acetonitrile (4 ml). The reaction medium is stirred for 1 hour 20 minutes at a temperature of 100° C. under microwave irradiation.

[0326] The reaction medium is diluted with ethyl acetate, washed with 1N hydrochloric acid solution, and then with saturated sodium hydrogen carbonate solution and with water, dried (MgSO.sub.4), filtered and concentrated.

[0327] The methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1H-indazole-7-carboxylate (429.8 mg; 97%) is obtained in the form of a white solid with a compliant .sup.1H NMR.

[0328] MS: [M+H]=416

2. Synthesis of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylate (Compound 74)

[0329] ##STR00260##

[0330] 4-(Bromomethyl)tetrahydropyran (97.6 μl; 0.74 mmol) is added to a mixture of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1H-indazole-7-carboxylate (280.0 mg; 0.67 mmol) and cesium carbonate (329 mg; 1 mmol) in 1-methyl-2-pyrrolidone (2.8 ml). The reaction medium is stirred at a temperature of 80° C. overnight.

[0331] The crude product is filtered and then purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylate (223.4 mg; 63%) is obtained in the form of a white solid.

[0332] .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.25 (dt, J=11.1, 5.3 Hz, 4H), 1.33-1.55 (m, 1H), 1.86-2.12 (m, 1H), 2.60 (q, J=7.6 Hz, 2H), 3.18 (td, J=11.1, 3.6 Hz, 2H), 3.35 (s, 2H), 3.79 (dt, J=11.4, 3.3 Hz, 2H), 3.93 (s, 3H), 4.57 (d, J=7.2 Hz, 2H), 6.93-7.06 (m, 2H), 7.12-7.23 (m, 2H), 7.80 (d, J=1.7 Hz, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.48 (s, 1H)

[0333] MS: [M+H]=514

Example 60: Synthesis of 5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylic acid amide

[0334] ##STR00261##

[0335] Aqueous ammonia (1.05 ml) is added to a solution of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylate (210.0 mg; 0.41 mmol) in N,N-dimethylformamide (1.05 ml).

[0336] The reaction medium is stirred for 3 days at room temperature and for 2 days at a temperature of 60° C. The reaction medium is diluted and extracted with dichloromethane. The organic phases are combined, dried (MgSO.sub.4), filtered and concentrated to dryness.

[0337] The crude product is filtered and then purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.2% of ammonium carbonate). The 5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylic amide is obtained in the form of a white solid.

[0338] .sup.1H NMR (Chloroform-d) δ: 0.94 (d, J=6.7 Hz, 6H), 1.25 (t, J=7.6 Hz, 3H), 1.38-1.51 (m, 4H), 1.59-1.69 (m, 1H), 2.08-2.21 (m, 1H), 2.67 (q, J=7.6 Hz, 2H), 3.25-3.39 (m, 4H), 3.90-4.01 (m, 2H), 4.59 (d, J=7.2 Hz, 2H), 5.75 (s, 1H), 6.00 (s, 1H), 6.94-7.00 (m, 2H), 7.11-7.18 (m, 2H), 7.62 (d, J=1.7 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.19 (s, 1H)

[0339] MS: [M+H]=499

Part IV: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 4

[0340] ##STR00262##

Example 61: Synthesis of N-(4-ethylphenyl)-N-isobutyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide

[0341] ##STR00263##

1. Synthesis of Intermediate 60.1

[0342] ##STR00264##

[0343] N-Bromosuccinimide (120 mg; 0.67 mmol) is added to a solution of 1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (200 mg; 0.56 mmol) in dichloromethane (5 ml). The reaction medium is stirred for 16 hours at room temperature, diluted with dichloromethane and extracted.

[0344] The organic phase is washed with saturated NH.sub.4Cl solution, with saturated NaHCO.sub.3 solution and with water, dried (MgSO.sub.4), filtered and concentrated to dryness.

[0345] The 3-bromo-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (260 mg; 100%) is obtained in the form of a pale yellow solid with a compliant .sup.1H NMR.

[0346] MS: [M+H]=436

2. Synthesis of Intermediate 60.2

[0347] ##STR00265##

[0348] A mixture of 3-bromo-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (260 mg; 0.60 mmol), cesium carbonate (388 mg; 1.19 mmol) and 4-(bromomethyl)tetrahydropyran (160 mg; 0.89 mmol) in N-methyl-2-pyrrolidone (3 ml) is stirred for 1 hour at a temperature of 80° C.

[0349] The reaction medium is diluted with ethyl acetate (30 ml). The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated to dryness.

[0350] The 3-bromo-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (350 mg; 100%) is obtained in the form of a clear yellow oil with a compliant .sup.1H NMR.

[0351] MS: [M+H]=534

3. Synthesis of Compound 14 According to the Invention

[0352] ##STR00266##

[0353] 2.5 M n-Butyllithium (900 μl; 2.24 mmol) is added, under argon, to a solution of 3-bromo-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (200 mg; 0.37 mmol) in tetrahydrofuran (3 ml) at a temperature of −78° C. The reaction medium is stirred for 30 minutes, paraformaldehyde (980 mg; 2.24 mmol) is then added, the temperature is allowed to return to room temperature and the medium is then stirred for 3 hours at a temperature of 60° C.

[0354] The reaction medium is hydrolyzed with 1M hydrochloric acid solution (5 ml) at room temperature for 10 days, and diluted with ethyl acetate (50 ml).

[0355] The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated to dryness.

[0356] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 3-hydroxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (20 mg; 11%) is obtained in the form of a colorless oil.

[0357] .sup.1H NMR (CD3OD-d4) δ: 0.90 (d, J=6.7 Hz, 7H), 1.22 (t, J=7.6 Hz, 3H), 1.27-1.58 (m, 4H), 1.71 (d, J=12.7 Hz, 2H), 2.16 (s, 1H), 2.64 (q, J=7.7 Hz, 2H), 3.35 (s, 2H), 3.41 (t, J=11.6 Hz, 2H), 3.96 (dd, J=11.9, 4.1 Hz, 2H), 4.66 (s, 2H), 6.92 (d, J=9.0 Hz, 1H), 7.00 (d, J=7.9 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.6 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H)

[0358] MS: [M+H]=486

Part V: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 5

[0359] ##STR00267##

Example 62: Synthesis of 3 amino 1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide

[0360] ##STR00268##

1. Synthesis of Intermediate 61.1

[0361] ##STR00269##

[0362] A solution of (4-ethylphenyl)isobutylamine (0.80 g; 4.51 mmol) and pyridine (0.36 ml; 4.51 mmol) in tetrahydrofuran (8 ml) is added to a solution of 5-chlorosulfonyl-2-fluorobenzoic acid (1.44 g; 5.87 mmol) in tetrahydrofuran (8 ml).

[0363] The reaction medium is stirred for 19 hours at room temperature, hydrolyzed with aqueous 1N HCl solution and diluted with ethyl acetate.

[0364] The organic phase is washed with aqueous 1N HCl solution. The organic phase is dried (Na.sub.2SO.sub.4), filtered and concentrated.

[0365] The crude product is chromatographed on silica gel (eluent: dichloromethane/methanol, from 0 to 10% of methanol) and then by preparative HPLC (C18 column, eluent: from 60% to 70% of acetonitrile in water/0.1% of formic acid). The 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic acid (0.56 g; 33%) is obtained in the form of an off-white solid with a compliant .sup.1H NMR.

[0366] MS: [M−H]=378

2. Synthesis of Intermediate 61.2

[0367] ##STR00270##

[0368] A solution of 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic acid (0.59 g; 1.55 mmol) in thionyl chloride (5.0 ml) is stirred for 3 hours at reflux and then concentrated to dryness. The 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoyl chloride (0.62 g; 100%) is obtained in the form of a brown oil.

[0369] MS: [M−H]=397

3. Synthesis of Intermediate 61.3

[0370] ##STR00271##

[0371] A 0.5M solution of ammonia in dioxane (8.4 ml; 4.2 mmol) is added portionwise over a period of 43 hours to a solution of 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoyl chloride (0.31 g; 0.78 mmol) in tetrahydrofuran (3 ml). The reaction medium is hydrolyzed with aqueous NaHCO.sub.3 solution and extracted with ethyl acetate.

[0372] The extracted organic phase is washed with 1N sodium hydroxide, dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 20 to 50% of ethyl acetate). The 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzamide (0.17 g; 58%) is obtained in the form of a white solid with a compliant .sup.1H NMR.

[0373] MS: [M−H]=379

4. Synthesis of Intermediate 61.4

[0374] ##STR00272##

[0375] Triethylamine (0.19 ml; 1.35 mmol) and then trifluoroacetic anhydride (93 μl; 0.67 mmol) are added to a solution of 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzamide (0.17 g; 0.45 mmol) at 0° C. The reaction medium is stirred for 1 hour, hydrolyzed for 15 minutes and extracted with ethyl acetate. The organic phases are combined, dried (Na.sub.2SO.sub.4), filtered and concentrated.

[0376] The 3-cyano-N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (0.17 g; 89%) is obtained in the form of a white solid (HPLC purity=85%) with a compliant .sup.1H NMR.

[0377] MS: [M−H]=361

5. Synthesis of Compound 34 According to the Invention

[0378] ##STR00273##

[0379] Hydrazine hydrate (1.25 ml; 25.7 mmol) is added to a suspension of 3-cyano-N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (0.19 g; 0.45 mmol) in ethanol (2.5 ml). The reaction medium is stirred for 50 minutes at a temperature of 100° C. in a tube. The reaction medium is concentrated.

[0380] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.2% of ammonium carbonate). The 3-amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (78 mg; 53%) is obtained in the form of a solid.

[0381] .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t, J=7.5 Hz, 3H), 1.34-1.48 (m, 1H), 2.59 (q, J=7.7 Hz, 2H), 3.28-3.32 (m, 2H), 5.73 (s, 2H), 6.96 (d, J=7.8 Hz, 2H), 7.16 (d, J=7.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 8.19 (s, 1H), 11.91 (s, 1H).

[0382] MS: [M−H]=373

Example 63: Synthesis of 3-amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide

[0383] ##STR00274##

[0384] 3-Amino-H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (54 mg; 0.14 mmol) in dimethyl sulfoxide (0.80 ml) is added to potassium hydroxide (29 mg; 0.44 mmol) at 85% in dimethyl sulfoxide (0.20 ml). The reaction medium is stirred for 5 minutes and 4-(bromomethyl)tetrahydropyran (27 mg; 0.15 mmol) in dimethyl sulfoxide (0.50 ml) is then added. Stirring is continued for 3 hours 20 minutes, followed by hydrolysis with a few drops of water and filtration through a filter syringe. The filtrate is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid).

[0385] The 3-amino-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (30 mg; 44%) is obtained in the form of a colorless oil.

[0386] .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.21-1.47 (m, 5H), 2.59 (q, J=7.6 Hz, 2H), 3.23 (td, J=11.5, 2.4 Hz, 2H), 3.77-3.88 (m, 2H), 4.03 (d, J=7.0 Hz, 2H), 6.92-7.01 (m, 2H), 7.16 (d, J=8.3 Hz, 2H), 7.26 (dd, J=8.9, 1.8 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 8.17 (d, J=1.7 Hz, 1H).

[0387] MS: [M−H]=471

Part VI: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 6

[0388] ##STR00275##

Example 64: Synthesis of 3-(tetrahydrofuran-4-ylidinemethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide

[0389] ##STR00276##

1. Synthesis of Intermediate 63.1

[0390] ##STR00277##

[0391] A mixture of 1H-indazole-6-sulfonyl chloride (500 mg; 2.31 mmol), pyridine (3 ml) and (4-ethylphenyl)oxetan-3-ylmethylamine (491 mg; 2.77 mmol) is stirred for 30 minutes at a temperature of 50° C. The reaction medium is diluted with ethyl acetate.

[0392] The organic phase is washed with saturated NH.sub.4Cl solution, with saturated NaHCO.sub.3 solution and with water. It is dried over magnesium sulfate, filtered and concentrated to dryness.

[0393] The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The 1H-Indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (640 mg; 78%) is obtained in the form of a colorless oil and is obtained with a compliant .sup.1H NMR.

[0394] MS: [M+H]=358

2. Synthesis of Intermediate 63.2

[0395] ##STR00278##

[0396] N-Bromosuccinimide (956 mg; 5.37 mmol) is added to a solution of 1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (1.60 g; 4.48 mmol) in dichloromethane (10 ml). The reaction medium is stirred for 16 hours at room temperature and diluted with dichloromethane.

[0397] The organic phase is extracted and washed with saturated ammonium chloride solution, with saturated sodium hydrogen carbonate solution and with water. It is dried (MgSO.sub.4), filtered and concentrated to dryness. The 3-bromo-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (1.9 g; 97%) is obtained in the form of a pale yellow solid with a compliant .sup.1H NMR.

[0398] MS: [M+H]=436

3. Synthesis of Intermediate 63.3

[0399] ##STR00279##

[0400] A mixture of 3-bromo-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (700 mg; 1.60 mmol), pyridinium p-toluenesulfonate (202 mg; 0.80 mmol) and 3,4-dihydro-2H-pyran (0.58 ml; 6.42 mmol) in tetrahydrofuran (10 ml) is stirred for 16 hours at 80° C. The reaction medium is diluted with ethyl acetate (20 ml) and extracted.

[0401] The organic phase is washed with saturated NH.sub.4Cl solution, with saturated NaHCO.sub.3 solution and with water, dried (MgSO.sub.4), filtered and concentrated to dryness.

[0402] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (500 mg; 57%) is obtained in the form of a white solid.

[0403] .sup.1H NMR (DMSO-d6) δ: 0.86 (dd, J=13.3, 6.7 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.38-1.63 (m, 3H), 1.68-1.81 (m, 1H), 1.98 (d, J=10.7 Hz, 2H), 2.60 (q, J=7.6 Hz, 2H), 3.36-3.41 (m, 2H), 3.67-3.76 (m, 1H), 6.00 (dd, J=9.3, 2.4 Hz, 1H), 6.95-7.02 (m, 2H), 7.16-7.21 (m, 2H), 7.41 (dd, J=8.5, 1.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.99 (s, 1H)

[0404] MS: [M+H]=520

4. Synthesis of Intermediate 63.4

[0405] ##STR00280##

[0406] A mixture of p-toluenesulfonyl hydrazide (286 mg; 1.54 mmol), 4-formyltetrahydropyran (175 mg; 1.54 mmol) and 1,4-dioxane (2 ml) is stirred for 1 hour under argon. Lithium tert-butoxide (125 mg; 1.54 mmol), X-PHOS (18 mg; 0.04 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (40 mg; 0.04 mmol) and 3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (200 mg; 0.38 mmol) are added under argon, and the reaction medium is stirred for 5 hours at 100° C.

[0407] The reaction medium is diluted with 20 ml of ethyl acetate and extracted. The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated.

[0408] The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate).

[0409] The 1-(tetrahydropyran-2-yl)-3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (100 mg; 48%) is obtained in the form of a yellow oil with a compliant .sup.1H NMR.

[0410] MS: [M+H]=538

5. Synthesis of Compound 62 According to the Invention

[0411] ##STR00281##

[0412] A mixture of 1-(tetrahydropyran-2-yl)-3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (100 mg; 0.19 mmol), acetic acid (6 ml) and water (2 ml) is stirred for 5 hours at a temperature of 80° C. The reaction medium is diluted with 20 ml of ethyl acetate and extracted. The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated.

[0413] The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The 3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (80 mg; 93%) is obtained in the form of a white solid.

[0414] .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J=6.7 Hz, 7H), 1.17 (t, J=7.6 Hz, 3H), 1.41 (dt, J=13.6, 6.8 Hz, 1H), 2.60 (q, J=7.3 Hz, 2H), 2.93 (t, J=5.4 Hz, 2H), 3.65 (t, J=5.5 Hz, 2H), 3.73 (t, J=5.4 Hz, 2H), 6.61 (s, 1H), 6.95 (d, J=8.3 Hz, 2H), 7.13-7.21 (m, 2H), 7.22 (dd, J=8.5, 1.5 Hz, 1H), 7.63-7.67 (m, 1H), 7.98 (d, J=8.5 Hz, 1H).

[0415] MS: [M+H]=454

Example 65: Synthesis of 3-(tetrahydropyran-4-ylmethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide

[0416] ##STR00282##

[0417] 3-(Tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (60 mg; 0.13 mmol) in methanol (3 ml) in the presence of palladium (5% Pd on activated charcoal: Degussa type) (14 mg) is placed for 16 hours under hydrogen (1 atm). The reaction medium is filtered through Celite. The filtrate is concentrated to dryness. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The 3-(tetrahydropyran-4-ylmethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (30 mg; 50%) is obtained in the form of a white solid.

[0418] .sup.1H NMR (DMSO-d6) δ: 0.85 (d, J=6.4 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.23-1.48 (m, 3H), 1.56 (d, J=13.4 Hz, 2H), 1.97 (d, J=11.7 Hz, 1H), 2.56-2.65 (m, 2H), 2.90 (d, J=7.0 Hz, 2H), 3.26 (t, J=11.3 Hz, 2H), 3.82 (dd, J=11.6, 3.8 Hz, 2H), 6.97 (d, J=8.1 Hz, 2H), 7.19 (dd, J=14.2, 8.2 Hz, 3H), 7.62 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 13.15 (s, 1H).

[0419] MS: [M+H]=456

Part VII: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 7

[0420] ##STR00283##

Example 65: Synthesis of 3-morpholin-4-ylmethyl-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide

[0421] ##STR00284##

1. Synthesis of Intermediate 65.1

[0422] ##STR00285##

[0423] Bis(tri-t-butylphosphine)palladium(0) (49 mg; 0.10 mmol) is added to a mixture, degassed under argon, of 3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (500 mg; 0.96 mmol), cesium carbonate (940 mg; 2.88 mmol) and vinylboronic anhydride-pyridine complex (462 mg; 1.92 mmol) in 1,4-dioxane (3 ml) and water (1 ml).

[0424] The reaction medium is stirred for 3 hours at a temperature of 90° C. and filtered through Celite. The filtrate is diluted with ethyl acetate and extracted.

[0425] The organic phase is washed with 20 ml of saturated sodium hydrogen carbonate solution and with 20 ml of water. The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated.

[0426] The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The 1-(tetrahydropyran-2-yl)-3-vinyl-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (400 mg; 89%) is obtained in the form of a beige-colored solid with a compliant .sup.1H NMR.

[0427] MS: [M+H]=468

2. Synthesis of Intermediate 65.2

[0428] ##STR00286##

[0429] 1-(Tetrahydropyran-2-yl)-3-vinyl-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (400 mg; 0.86 mmol) is added to a mixture of (DHQ).sub.2PHAL (1.20 g; 1.46 mmol), tert-butyl alcohol (10 ml) and water (10 ml) cooled to a temperature of 0° C. The reaction medium is stirred for 16 hours at a temperature of 40° C. Sodium sulfite (5 g) is added.

[0430] The reaction medium is stirred for 45 minutes, diluted with ethyl acetate (30 ml) and extracted. The organic phases are combined, washed with saturated Na.sub.2SO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate).

[0431] The 3-(1,2-dihydroxyethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (380 mg; 89%) is obtained in the form of a clear oil with a compliant .sup.1H NMR.

[0432] MS: [M+H]=502

3. Synthesis of Intermediate 65.3

[0433] ##STR00287##

[0434] Sodium metaperiodate (1.62 g; 7.58 mmol) is added to a mixture of 3-(1,2-dihydroxyethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (380 mg; 0.76 mmol), acetone (2 ml), tetrahydrofuran (2 ml) and water (2 ml).

[0435] The reaction medium is stirred for 2 hours 30 minutes at a temperature of 35° C., diluted with ethyl acetate (30 ml) and water (20 ml) and extracted.

[0436] The organic phases are combined, washed with saturated Na.sub.2SO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated. The 3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (120 mg; 34%) is obtained in the form of a white solid with a compliant .sup.1H NMR.

[0437] MS: [M+H]=470

4. Synthesis of Intermediate 65.4

[0438] ##STR00288##

[0439] Morpholine (45 μl; 0.51 mmol) and sodium triacetoxyborohydride (119 mg; 0.56 mmol) are added to a solution of 3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (120 mg; 0.26 mmol) in tetrahydrofuran (3 ml). The reaction medium is stirred for 2 hours at room temperature. The reaction medium is diluted with ethyl acetate (20 ml) and water (10 ml) and extracted.

[0440] The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4) and concentrated.

[0441] The 3-morpholin-4-ylmethyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (130 mg; 94%) is obtained in the form of an oil with a compliant .sup.1H NMR.

[0442] MS: [M+H]=541

5. Synthesis of Compound 64 According to the Invention

[0443] ##STR00289##

[0444] A mixture of 3-morpholin-4-ylmethyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (130 mg; 0.24 mmol), acetic acid (30 ml) and water (10 ml) and a few drops of trifluoroacetic acid is stirred for 4 days at a temperature of 80° C. The reaction medium is diluted with 50 ml of ethyl acetate and extracted.

[0445] The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated.

[0446] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 3-morpholin-4-ylmethyl-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (70 mg; 64%) is obtained in the form of a white solid after recrystallization from an acetone/water mixture.

[0447] 1H NMR (DMSO-d6) δ: 0.85 (d, J=6.7 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 2.44 (t, J=4.5 Hz, 4H), 2.61 (t, J=7.6 Hz, 2H), 3.33-3.37 (m, 2H), 3.87 (s, 2H), 6.95-7.00 (m, 2H), 7.15-7.21 (m, 2H), 7.25 (dd, J=8.5, 1.5 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 13.27 (s, 1H).

[0448] MS: [M+H]=457

Example 66: Synthesis of 3-((cis)-2,6-dimethylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide

[0449] ##STR00290##

1. Synthesis of Intermediate 66.1

[0450] ##STR00291##

[0451] cis-2,6-Dimethylmorpholine (50 μl; 0.38 mmol) and sodium triacetoxyborohydride (122 mg; 0.57 mmol) are added to a solution of 3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 0.19 mmol) in tetrahydrofuran (2 ml).

[0452] The reaction medium is stirred for 16 hours at room temperature. The reaction medium is diluted with ethyl acetate (20 ml) and water (10 ml) and extracted. The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4) and concentrated. The 3-((2S,6R)-2,6-dimethylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 83%) is obtained in the form of an oil with a compliant .sup.1H NMR.

[0453] MS: [M+H]=570

2. Synthesis of Compound 65 According to the Invention

[0454] ##STR00292##

[0455] A mixture of 3-((2S,6R)-2,6-dimethylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 0.16 mmol), acetic acid (10 ml) and water (10 ml) and one drop of trifluoroacetic acid is stirred for 16 hours at a temperature of 80° C. The reaction medium is diluted with 50 ml of ethyl acetate and extracted.

[0456] The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated.

[0457] The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 3-((cis)-2,6-dimethylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (52 mg; 67%) is obtained in the form of a colorless oil.

[0458] 1H NMR (DMSO-d6) δ: 0.85 (d, J=6.5 Hz, 6H), 1.02 (d, J=6.1 Hz, 6H), 1.18 (t, J=7.5 Hz, 3H), 1.42 (dt, J=13.3, 7.1 Hz, 1H), 1.74 (t, J=10.7 Hz, 2H), 2.55-2.65 (m, 2H), 2.70-2.80 (m, 2H), 3.33-3.44 (m, 2H), 3.55 (t, J=7.8 Hz, 2H), 3.85 (s, 2H), 6.98 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.6 Hz, 1H), 7.66 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.20 (s, 1H), 13.25 (s, 1H).

[0459] MS: [M+H]=485

Example 67: Synthesis of 3-((S)-3-methylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide

[0460] ##STR00293##

1. Synthesis of Intermediate 67.1

[0461] ##STR00294##

[0462] With a procedure similar to that described for intermediate 67.1, 3-((S)-3-methylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 85%) is obtained in the form of an oil with a compliant .sup.1H NMR.

[0463] MS: [M+H]=555

2. Synthesis of Compound 66 According to the Invention

[0464] With a procedure similar to that described for example 66, 3-((S)-3-methylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (42 mg; 54%) is obtained in the form of a colorless oil.

[0465] 1H NMR (DMSO-d6) δ: 0.86 (d, J=6.8 Hz, 6H), 1.09-1.22 (m, 7H), 1.42 (dt, J=13.9, 6.9 Hz, 1H), 2.16-2.27 (m, 1H), 2.61 (t, J=7.6 Hz, 2H), 3.38 (d, J=19.0 Hz, 5H), 3.58-3.72 (m, 3H), 6.98 (d, J=7.9 Hz, 2H), 7.18 (d, J=7.9 Hz, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 8.04 (d, J=8.6 Hz, 1H), 8.24 (s, 1H), 13.24 (s, 1H).

[0466] MS: [M+H]=471