LV14476B - Sythesis of biologically active 4-acylamino-4,5,6,7-tetrahydroindazoles - Google Patents

Abstract

The invention provides a novel method of synthesis of 4-acylamino-4,5,6,7-tetrahydroindazoles with general formula (I). The method consists of Ritter reaction between 4-hydroxy-4,5,6,7-tetrahydroindazoles or 6,7-dihydroindazoles and various nitriles in acidic medium which generates the corresponding tetrahydroindazolyl cation. Compounds (I) possess analgesic activity.

Description

Description of the Invention

The invention relates to the field of medical chemistry - 1-aryl-3,6,6-trimethyl-, 1-hetaryl-3,6,6-trimethyl and l-aryl-6,6-dimethyl-4-acylamino-4,5,6 , 7-tetrahydroindazole (2) and their analgesic properties.

Several derivatives of tetrahydroindazoles are pharmacologically useful compounds with anti-inflammatory activity [Bhatia, R. K .; Raju, P. B.; Jain, U.K .; Kumar, P. P.; Satyavathi, K. Res. J. Pharm. Biol. Chem. Sci. 2011, 2, 118-129; Nagakura, M .; Ota, T .; Shimidzu, N .; Kawamura, K .; Eto, Y .; Wada, Y. J. Med. Chem. 1979, 22, 48-52], analgesic [Badawey, E.A.M .; El-Ashmawey, I. M. Eur. J. Med. Chem. 1998, 33, 349-361; El-Hawash, S. Α. M .; Badawey, Ε. Α. M .; El-Ashmawey, I. M. Eur. J. Med. Chem. 2006, 41, 155-165], anti-tumor [Connolly, P.J.; Wetter, S. K.; Beers, Κ. N .; Hamel, S. C .; HaynesJohnson, D.; Kiddoe, M .; Kraft, P .; Tsann Lai, M .; Campen, C .; Palmer, S.; Phillips, A. Bioorg. Med. Chem. Lett. 1997, 7,2551-2556], antibacterial [Lorand, T .; Kochi, B .; Emody, L .; Sohar, P. Eur. J. Med. Chem. 1999, 34, 1009-1018], antiviral and many other properties [Cerecetto, H .; Gerpe, A .; Gonzalez, M .; Aran, V. J.; de Ocariz, C. O. Mini-Rev. Med. Chem. 2005.5, 869-878.].

4-Amino-tetrahydroindazoles have been synthesized with good yields in the 1-pyridyl derivatives series by reduction of the corresponding 4-oximes, but this approach has not been successful for the other derivatives. The resulting compounds are patented for their anti-cancer activity and use in the treatment of Alzheimer's disease [Pevarello, P .; Villa, M .; Varasi, M .; Isacchi, A. US Pat. 6716856 (B1), 06.04.2004]

Ritter's reaction is known [Bishop, R .; In Comp.Org.Synth .; Trost, B.M., Fleming, I.; Eg .; Pergamon Press: New York, 1992; Vol. 6, 261; Krimen, L.I .; Cota, D.I. Org. React., 17, 213 (1969); Jirgensons, A .; Bowl, V.; Kalvinsh, I; Gold, M.R., Synthesis 2000, 1709.] for the synthesis of acylamines from hydroxy compounds or olefins and nitriles in the presence of concentrated sulfuric acid as a catalyst. In the THI series, such a reaction is unknown.

The present invention relates to the development of a new process for the preparation of 1-aryl- and 1-heteryl-4-acylamino-4,5,6,7-tetrahydroindazoles and their conversion to 4-amino-4,5,6,7-tetrahydroindazoles. The object of the invention is achieved by reacting alkyl, aryl and hetaryl nitrile (R ³ CN) with 4-hydroxy-4,5,6,7-THI (lac) in one step in an acidic medium at 60-70 ° C to obtain the target compounds 2. with high yield. The reaction medium used was various acids: glacial acetic acid, trifluoroacetic acid, conc. sulfuric acid, conc. phosphoric acid, polyphosphoric acid, conc. perchloric acid, p-toluenesulfonic acid, camphorsulfonic acid and mixtures thereof.

la, 3a: R ¹ = Ph; R ² = H 1b, 3b: R ¹ = Ph; R ² = Me acid

Alternatively, 4-hydroxy-4,5,6,7-THI (la-c) can be converted into 6,7-dihydroindazole derivatives 3, which are further reacted with nitriles in the acidic medium to give the target amides 2.

The resulting group of substances of general formula 2 was found to be substantially non-toxic (LD50> 2000 mg / kg; oral in mice). Representative acyl derivatives 2a [A- (6,6-dimethyl-1-phenyl-4,5,6,7-tetralidro-1 H -indazol-4-yl) -3-methoxy-benzamide] and 2b [A- (3, 6,6-trimethyl-1-phenyl-4,5,6,7-tetrahydro-177-indazol-4-yl) -acetamide] was determined for their analgesic activity in an acetic acid-induced abdominal muscle spasm model in mice. These compounds reduce stomach cramps by 18% and 13%, respectively.

Example 1.

N - (N, N-dimethyl-1-phenyl, 5,6,7-tetrahydro-1 H -indazol-4-yl) -acetanide 1-Phenyl-4-hydroxy-6,6-dimethyl-4,5 To a solution of 6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (1.1 mL, 20 mmol, 5 equiv) with magnetic stirring, then added dropwise acetonitrile (0.4 mL, 8 mmol, 2 equiv.). Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.10 g (95%).

White solid, Rf = 0.06 (T / E = 1/1)

bp 198 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3265, 3068, 2963, 2905, 1645, 1634, 1601, 1554, 1510, 1455, 1396, 1383, 1371, 1293, 1276, 1178, 1141, 1130, 1066, 966.

1 H-NMR (300 MHz, CDCl 3) δ (ppm): 7.60 (s, 1H, H-C (3)), 7.50-7.44 (m, 4H, Ph-N (1)), 7.39-7.31 (m,

1H, Ph-N (1)), 5.73 (d, 1H, ³ / = 8.3 Hz, HNC (4)), 5.14, (ddd, 1H, ³ J = 9.8 Hz, ³ J = 8.3 Hz, ³ J = 7.2 Hz, HC (4)), 2.60 (d, 1H, ² J = 16.0 Hz, Ha-C (7)), 2.43 (d, 1H, ² J = 16.0 Hz, Hb-C (7)), 2.03 (s, 3H, HC (2 ')), 2.01 (ddd, 1H, ² J = 13.2 Hz, ³ J = 7.2 Hz, V = 1.1 Hz, Hb-C (5)), 1.35 (dd, 1H, ² J = 13.0 Hz, ³ J = 9.8 Hz, Ha-C (5)), 1.10 (s, 3H, H ₃ CC (5)), 0.96 (s, 3H, H ₃ CC (5)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 169.7, 139.5, 139.1, 137.9, 129.1, 127.2, 123.3, 118.1, 43.5, 41.8,

36.9, 32.6, 30.8,25.3,23.5.

Elemental Analysis: Calculated for C 18 H 23 N 3 O (279.18): C 72.06, H 7.47, N 14.83; found C 75.85, H 6.96, N

II. 54.

Example 2.

N- (6,6-Dimethyl-1-phenyl, 5,6,7-tetrahydro-2Z-indazol-4-yl) -benzamide 1-Phenyl-4-hydroxy-6,6-dimethyl-4,5,6 To a solution of 7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added magnetic sulfuric acid (1.1 mL, 20 mmol, 5 equiv) with stirring, then benzonitrile was added ( 1.2 mL, 12 mmol, 3 equiv). Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 2).

Yield: 1.00 g (73%).

White solid, Rf = 0.60 (T / E = 2/1)

bp 160 ° C (EtOH / H ₂ O 1/2)

IS (KBr): 3271, 2955, 1627, 1600, 1578, 1534, 1505, 1490, 1401, 1294, 1182, 1149, 1067, 968.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.81 (dd, 2H, ³ J = 7.7 Hz, ⁴ J = 0.9 Hz, Ph-C (1 ')), 7.66 (s, 1H, HC) (3)), 7.54-7.41 (m, 7H, Ph-N (1), Ph-C (1 ')), 7.40-7.32 (m, 1H, Ph-N (1)), 6.34 (d, 1H , ³ J = 8.5 Hz, H-NC (4)), 5.37 (ddd, 1H, ³ J = 9.4 Hz, ³ J = 8.5 Hz, ³ J = 5.8 Hz, HC (4)), 2.62 (dd, 1H , ² J = 16.2 Hz, ⁴ J = 1.1 Hz, H * -C (7)), 2.48 (d, 1H, ² J = 16.0 Hz, Hb-C (7)), 2.12 (ddd, 1H, ² J) = 12.8 Hz, ³ J = 5.8 Hz, ⁴ J = 1.1 Hz, Ha-C (5)), 1.49 (dd, 1H, ² J = 12.8 Hz, ³ J = 9.4 Hz, H _b -C (5)) , 1.14 (s, 3H, H ₃ CC (5)), 1.02 (s, 3H, H ₃ CC (5)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 167.1, 139.7, 139.2, 138.2, 134.5, 131.6, 129.2, 128.6, 127.2,

126.9, 123.4,118.0,43.6, 42.4, 37.0, 32.8, 30.8, 25.6.

Elemental Analysis: Calculated for C ₂₂ H ₂₃ N ₃ O (345.18): C 76.49, H 6.71, N 12.16; found C 76.36, H 6.81, N 11.93.

Example 3.

N- (6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1 H -indazol-4-yl) -trichloroacetamide 1-Phenyl-4-hydroxy-6,6-dimethyl-4 To a solution of 5,6,7-tetrahydro-indazole (0.96 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (2.2 mL, 40 mmol, 10 equiv) with magnetic stirring. then add trichloroacetonitrile (8.0 mL, 80 mmol, 20 equiv). Continue stirring in a sealed flask at 60 ° C for 20 hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 0.9).

Yield: 0.77 g (50%).

White solid, Rf = 0.69 (T / E = 1/1)

bp 145 ° C (EtOH / H ₂ O 1 / 0.9)

IS (KBr): 3034, 2958, 2934, 1601, 1561, 1507, 1424, 1387, 896.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.64 (s, 1H, HC (3)), 7.51-7.45 (m, 4H, Ph-N (1)), 7.41-7.34 (m, 1H, Ph-N (l)), 6.79 (d, 1H, ΐ = Ί.Ί Hz, HNC (4)), 5.13 (ddd, 1H, ³ J = 9.2 Hz, ³ J = 7.7 Hz, ³ / = 6.1 Hz, HC (4)), 2.62 (d, 1H, ² / = 16.4 Hz, Ha-C (7)), 2.49 (d, 1H, ² J = 16.4 Hz, Hb-C (7)), 2.08 (ddd, 1H, ² J = 13.1 Hz, ³ J = 6.1 Hz, ⁴ ./ = 1.0 Hz, H 1 -C (5)), 1.53 (ddd, 1H, ² J = 13.0 Hz, ³ J = 9.2 Hz, H _b -C (5)), 1.15 (s, 3H, H ₃ CC (6)), 1.02 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 161.6, 139.7, 139.1, 137.5, 129.3, 127.7, 123.6, 116.4, 92.6, 44.2,

42.6, 36.7, 32.6,30.4,25.7.

Elemental Analysis: Calculated for C 17 H 15 Cl ₃ N ₃ O (385.05): C 52.80, H 4.69, N 10.87; Found: C 52.80, H 4.56, N 10.79.

Example 4.

N- (6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl) -4-nitrobenzamide 1-Phenyl-4-hydroxy-6,6-dimethyl To a solution of -4,5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (1.1 mL, 20 mmol, 5 equiv) with magnetic stirrer ), then p-nitrobenzonitrile (0.89 g, 6 mmol, 1.5 eq) was added. Continue stirring in a sealed flask for 9 hours at 60 ° C. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.05 g, (65%).

White solid, Rf = 0.55 (T / E = 1/1)

bp 168 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3392, 2960, 2920, 2864, 1645, 1599, 1527, 1504, 1486, 1476, 1454, 1402, 1349, 1191, 975. 11 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.30 (d, 2H, ³ , δ = 8.7 Hz, p-NOj-C ^-Cil '), 7.98 (d, 2H, ³ J = 8.7 Hz, p-NO2-C6H4-C (1 '), 7.64 (s, 1H, HC (3)), 7.49-7.45 (m, 4H, Ph-N (1)), 7.40-7.34 (m, 1H, Ph-N (l)), 6.50 (d, 1H, V = 8.1 Hz, HNC (4)), 5.36 (ddd, 1H, ³ J = 9.6 Hz, ³ J = 8.1 Hz, ³ J = 5.7 Hz , HC (4)), 2.62 (d, 1H, ² J = 16.4 Hz, Ha-C (7)), 2.49 (d, 1H, ² J = 16.4 Hz, Hb-C (7)), 2.13 (dd) , 1H, ² J = 12.8 Hz, ³ J = 5.7 Hz, Ha-C (5)), 1.47 (dd, 1H, ² J = 13.0 Hz, ³ J = 9.6 Hz, H <r = C (5)) , 1.14 (s, 3H, H ₃ C -C (6)), 1.02 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 165.0, 149.6, 140.0, 139.4, 139.3, 138.0, 129.3, 128.2, 127.4,

123.8,123.2, 117.4,43.3,42.8, 37.0, 32.8, 30.8,25.4.

Elemental Analysis: Calculated for C ₂₃ H ₂₄ N ₄ O ₃ (404.18): C 67.68, H 5.68, N 14.35; Found: C 67.80, H 4.56, N 10.79.

Example 5.

N - (6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1 H -indazol-4-yl) -3-methoxy-benzamide 1-Phenyl-4-hydroxy-6, To a solution of 6-dimethyl-4,5,6,7-tetrabidroindazole (0.96 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (0.9 mL, 16 mmol) with magnetic stirrer. (4 eq.), Then m-methoxybenzonitrile (0.80 g, 6 mmol, 1.5 eq.) Was added dropwise. Continue stirring in a stoppered flask at 60 ° C for 15 hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (3: 1).

Yield: 0.81 g (54%).

White solid, Rf = 0.36 (T / E = 3/1)

bp 140 ° C (EtOH / H ₂ O 3/1)

IS (KBr): 3339, 2960, 1641, 1602, 1581, 1527, 1505, 1485, 1406, 1295, 1236, 1046.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.64 (s, 1H, HC (3)), 7.48-7.45 (m, 4H, Ph-N (1)), 7.44-7.41 (m,

1H, Ar-C (l ')), 7.39-7.30 (m, 3H, Ph-N (l), Ar-C (l')), 7.07-7.00 (m, 1H, Ar-C (l ')) ), 6.44 (d, 1H, ³ J = 8.3 Hz, HNC (4)), 5.34 (ddd, 1H, ³ J = 9.6 Hz, ³ / = 8.3 Hz, ³ J = 6.0 Hz, HC (4)), 3.85 (s, 3H, m-CH 3 -O-ArC (1 ')), 2.60 (d, 1H, ² J = 16.2 Hz, Ha-C (7)), 2.46 (d, 1H, ² J = 16.2 Hz) , Hb-C (7)), 2.09 (dd, 1H, V = 12.9 Hz, ³ J = 6.0 Hz, Ha-C (5)), 1.44 (dd, 1H, ² J = 12.9 Hz, ³ J = 9.6 Hz, Hb-C (5)), 1.12 (s, 3H, H ₃ CC (6)), 1.00 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 166.9, 159.8, 139.5, 139.1, 138.0, 135.9, 129.5, 129.1, 127.2,

123.2, 118.6, 117.9,117.7,112.3,55,4,43.4,42.3, 36.9,32.7, 30.7,25.5.

Elementāranaīīze: calculated C ₂₃ H ₂ 5 N ₃ O ₂ (375.19): C 73.57, H 6.71, N 11.19; found C 73.33, H 6.72, N

II. 07

Example 6.

A ^L (6,6-dimethyl-l-phenyl-4,5,6,7-tetrahydro-l // - indazol-4-yl) -acrylamide l-Phenyl-4-hydroxy-6,6-dimethyl-4 To a solution of 5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (1.1 mL, 20 mmol, 5 equiv) with magnetic stirring. then add acrylonitrile (0.5 mL, 8 mmol, 2 equiv.). Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40-50 ° C and the pH is 10-11. The resin product initially solidifies gradually, recrystallizes from ethanol and water. (1: 1).

Yield: 0.84 g (71%).

White solid, Rf = 0.22 (T / E = 1/1)

bp 190 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3277, 3065, 2962, 2908, 1657, 1623, 1600, 1504, 1453, 1411, 1396, 1383, 1259, 1240, 1067, 990,967,954.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.60 (s, 1H, HC (3)), 7.48-7.44 (m, 4H, Ph-N (1)), 7.39-7.32 (m, 1H, Ph-N (l)), 6:33 (dd, 1 H, ³ 7 = 17.0 Hz, ² J = 1.5 Hz, H-C (3 ')), 6.12 (dd, 1H, ³ J = 17.0 Hz, ³ J = 10.2 Hz, HC (2 ')), 5.84 (d, 1H, ³ J = 7.3 Hz, HNC (4)), 5.67 (dd, 1H, ³ / = 10.2 Hz, ² J = 1.5 Hz, Hb- C (3 '), 5.23 (ddd, 1H, V = 9.8 Hz, ³ J = 7.3 Hz, ³ / = 5.8 Hz, HC (4)), 2.58 (d, 1H, ² J = 16.2 Hz, C (7)), 2.45 (d, 1H, ² J = 16.2 Hz, Hb-C (7)), 2.04 (dd, 1H, ² / = 13.0 Hz, ³ J = 5.8 Hz, Ha-C (5) ), 1.38 (dd, 1H, ² / = 13.0 Hz, ³ J = 9.8 Hz, H _b -C (5)), 1.11 (s, 3H, H ₃ CC (6)), 0.98 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 165.1, 139.6, 139.3, 138.1, 130.9, 129.2, 127.2, 126.7, 123.3, 117.9,43.5,41.9,37.0,32.7,30.8,25.4.

Elementāranalīze: calculated C ₈ H ₂₁ N ₃ O (295.17): C 73.19, H 7.17, N 14:23; found C 72.91, H 7.24, N 14.17.

Example 7.

N- (6,6-Dimethyl-1-phenyl, 5,6,7-tetrahydro-1 H -indazol-4-yl) -chloroacetamide 1-Phenyl-4-hydroxy-6,6-dimethyl-4,5 To a solution of 6,7-tetrahydro-indazole (0.96 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (2.2 mL, 40 mmol, 10 equiv) with magnetic stirring, then Chloroacetonitrile (1.0 mL, 16 mmol, 4 eq) was added. Continue stirring in a stoppered flask at 60 ° C for 25 hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40-50 ° C and the pH is 10-11. The resin product initially solidifies gradually, recrystallizes from ethyl acetate and hexane. (1: 2). Yield: 0.87 g (69%).

White solid R _f = 0.35 (T / E = 1/1) kp 173 ° C (EtOAc / Hex 1/2)

IS (KBr): 3253, 3076, 2961, 1648, 1562, 1505, 1402, 1249, 1165, 968.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.62 (s, 1H, HC (3)), 7.50-7.45 (m, 4H, Ph-N (1)), 7.40-7.33 (m, 1H, Ph-N (1)), 6.75 (d, 1H, ³ J = 8.1 Hz, HNC (4)), 5.16 (ddd, 1H, V = 9.6 Hz, ³ J = 8.1 Hz, ³ J = 5.8 Hz , HC (4)), 4.14 (d, 1H, ² J = 15.3 Hz, Ha-C (2 ')), 4.08 (d, 1H, ² J = 15.3 Hz, Hb-C (2')), 2.61 (d, 1H, ² J = 16.2 Hz, Ha-C (7)), 2.46 (d, 1H, ² J = 16.2 Hz, Hb-C (7)), 2.02 (dd, 1H, ² J = 13.0 Hz) V = 5.8 Hz, H-C (5)), 1:46 (dd, 1H, ² J = 13.0 Hz, ³ J = 9.6 Hz, H-C (5)), 1.13 (s, 3H, H ₃ CC ( 6)), 0.99 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 165.6, 139.5, 139.3, 137.9, 129.2, 127.4, 123.5, 117.2, 43.3, 42.7, 42.4, 36.9, 32.7, 30.6, 25.6.

Elemental Analysis: Calculated for C 17 H 20 N ₃ OCl (317.13): C 64.25, H 6.34, N 13.22; Found: C, 64.11; H, 6.27; N, 13.00.

Example 8.

N- (6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1 H -indazol-4-yl) -2-fluorobenzamide 1-Phenyl-4-hydroxy-3.6 To a solution of 6-trimethyl-4,5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (1.1 mL, 20 mL) with magnetic stirring. mmol, 5 eq.) then add o-fluorobenzonitrile (0.9 mL, 8 mmol, 2 eq.). Continue stirring in a stoppered flask at 60 ° C for 25 hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.04 g (69%).

White solid, Rf = 0.48 (T / E = 1/1)

b.p. 69 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3388, 3066, 2951, 1648, 1616, 1501, 1396, 1320, 1297, 1258, 1219, 1099, 968, 924.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.15 (dt, 1H, J = 7.9 Hz, / = 1.9 Hz, δFC ₆ H ₄ -C (1 ')), 7.67 (s, 1H, HC) (3)), 7.52-7.43 (m, 5H, oFC ₆ H ₄ -C (l '), Ph-N (l)), 7.39-7.32 (m, 1H, Ph-N (l)), 7.30 (d) , 1H, J = 7.7 Hz, F-C6H4-C (l ')), 7.11 (dd, 1 H, 7 = 12.2 Hz, ³ J = 8.3 Hz, F-C6H4-C (l')), 6.91 (dd , 1H, JN.F = 12.2 Hz, ³ J = 8.9 Hz, HNC (4)), 5.40 (ddd, 1H, V = 9.4 Hz, 7 = 8.5 Hz, ³ J = 5.8 Hz, HC (4)), 2.63 (d, 1H, ² J = 15.8 Hz, Ha-C (7)), 2.49 (d, 1H, 7 = 15.8 Hz, H _b -C (7)), 2.14 (dd, 1H, ² J = 13.0) Hz, ³ J = 5.8 Hz, H-C (5)),

l. 53 (dd, 1H, ² J = 13.0 Hz, ³ J = 9.4 Hz, H _b -C (5)), 1.14 (s, 3H, H ₃ CC (6)), 1.03 (s, 3H, H ₃ CC) (6)).

¹³ C-NMR (75 MHz, CDCl 3) δ (ppm): 163.0 (d, 7 _C -f = 3 Hz), 160.7 (d, J _C -f = 247 Hz), 139.7, 139.2,

138.1, 133.4 (d, 7c-f = 9 Hz), 132.1 (d, J _C f = 2 Hz), 129.2, 127.2, 124.9 (d, J _C f = 3 Hz), 123.4, 121.1 (d, Jc-f = 12 Hz), 117.8, 116.0 (d, J _C -f = 25 Hz), 43.5, 42.4.37.0, 32.7, 30.6.25.8.

Elemental Analysis: Calculated for C23H24N3OF (377.19): C 73.19, H 6.41, N 11.13; Found: C 69.79, H 6.18, N 14.86.

Example 9.

N - (3,6,6-Trimethyl-1-pyrid-2-yl-4,5,6,7-tetrahydro-1 H -indazol-4-yl) -acetamide 1- (Pyrid-2-yl) - To a solution of 4-hydroxy-3,6,6-trimethyl-4,5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv.) In glacial acetic acid (4 mL) was added concentrated sulfuric acid with stirring. (1.1 mL, 20 mmol, 5 equiv), then add acetonitrile (0.4 mL, 8 mmol, 2 equiv). Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.04 g (87%).

White solid, Rf = 0.08 (T / E - 1 / l)

bp 160 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3307, 3279, 2952, 1659, 1639, 1595, 1563, 1557, 1486, 1471, 1445, 1378, 1090, 1042. 1 H-NMR (300 MHz, CDCl 3) δ (ppm): 8.39 ( ddd, 1H, ³ J = 4.9 Hz, ⁴ / = 1.9 Hz, V = 0.9 Hz, Py-N (1)), 7.83 (ddd, 1H, ³ J = 8.5 Hz, ³ J = 7.2 Hz, ⁴ J = 0.9 Hz, Py-N (l)), 7.76 (ddd, 1H, ³ J = 10.2 Hz, ³ J = 7.2 Hz, ⁴ J =

l. 9 Hz, Py-N (l)), 7.12 (ddd, 1H, ³ J = 7.2 Hz, ³ J = 4.9 Hz, ⁴ J = 1.3 Hz, Py-N (l)), 5.64 (d, 1H, ³ J = 9.2 Hz, HNC (4)), 5.16 (ddd, 1H, ³ J = 9.2 Hz, ³ J = 9.0 Hz, ³ J = 6.0 Hz, HC (4)), 2.95 (d, 1H, ² J = 17.7 Hz, HAC (7)), 2.87 (d, 1 H, ² / = 17.7 Hz, H-C (7)), 2.24 (s, 3H, HC (2 ')), 2:03 (s, 3H, H ₃ CC (3)), 1.89 (ddd, 1H, ² J = 13.0 Hz, ³ J = 6.0 Hz, ⁴ J = 0.9 Hz, Ha-C (5)), 1.29 (dd, 1H, ² J = 13.0 Hz, ³ J = 9.0 Hz, H _b -C (5)) 1.09 (s, 3H, H ₃ CC (6)), 0.95 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl 3) δ (ppm): 169.2,153.0, 148.2,147.5,141.8, 138.3, 120.6,116.3,114.8,43.9, 41.3,38.8, 32.2, 30.6, 25.8,23.4,12.6.

Elemental Analysis: Calculated for C 17 H 22 N 4 O (298.13): C 68.43, H 7.43, N 18.78; found C 68.44, H 7.49, N 18.74.

Example 10.

N- (3,6,6-Trimethyl-1-pyrid-2-yl-4,5,6,7-tetrahydro-1H-indazol-4-a) -chloroacetamide 1- (Pyrid-2-yl) -4 To a solution of -hydroxy-3,6,6-trimethyl-4,5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (magnetic stirring). 2.2 mL, 40 mmol, 10 equiv), then add chloroacetonitrile (1.0 mL, 16 mmol, 4 equiv). Continue to stir in the sealed flask for 11 hours at 60 ° C. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40-50 ° C and the pH is 10 11. 1: 2).

Yield: 1.01 g (76%).

White solid, Rf = 0.64 (T / E = 1/3)

p.p. 156 ° C (EtOAc / Hex 1/2)

IS (KBr): 3246, 3073, 2951, 2899, 2870, 1604, 1583, 1564, 1557, 1538, 1482, 1446, 1430, 1382, 1371, 1252.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.39 (ddd, 1H, ³ J = 4.9 Hz, ⁴ J = 1.7 Hz, ⁵ J = 0.8 Hz, Py-N (1)), 7.85 (dt, 1H, ⁴ J = 8.3 Hz, ⁵ J = 0.9 Py-N (1)), 7.77 (ddd, 1H, ³ J = 8.3 Hz, ³ J = 7.2 Hz, ⁴ J = 1.9 Hz, Py- N (l)), 7.13 (ddd, 1H, ³ J = 7.2 Hz, ³ J = 4.9 Hz, ⁴ / = 1.1 Hz, Py-N (l)), 6.63 (d, 1H, ³ J = 8.9 Hz, HNC (4)), 5.19 (ddd, 1H, ³ J = 8.9 Hz, ³ J = 8.7 Hz, ³ J = 6.0 Hz, HC (4)), 4.11 (s, 2H, HC (2 ')), 3.00 (d, 1H, ² J = 17.7 Hz, H, C (7)), 2.93 (d, 1H, ² J = 17.7 Hz, Hb-C (7)), 2.25 (s, 3H, HCC (3)) , 1.97 (ddd, 1H, ² J = 13.0 Hz, ³ J = 6.0 Hz, ⁴ J = 0.8 Hz, Ha-C (5)), 1.47 (dd, 1H, V = 13.2 Hz, ³ J = 8.7 Hz, H _b -C (5)), 1.13 (s, 3H, H ₃ CC (6)), 1.00 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 165.1, 153.1, 148.1, 147.5, 142.0, 138.3, 120.7, 115.5, 114.8,43.5,

42.6, 42.0, 38.8, 32.1, 30.3, 26.2, 12.6.

Elemental Analysis: Calculated for CpH11NlOCl (332.14): C, 61.35; H, 6.36; N, 16.83; Found: C 61.39, H 6.33, N 16.83.

Example 11.

N- (3,6,6-Trimethyl-1-pyrid-2-yl-4,5,0,7-tetrahydro-1H-indazol-4-yl) -trichloroacetamide 1- (Pyrid-2- yl) -4-Hydroxy-3,6,6-trimethyl-4,5,6,7-tetrahydro-indazole (0.96 g, 4 mmol, 1 eq) in glacial acetic acid (4 mL) under magnetic stirring, Add concentrated sulfuric acid (1.1 mL, 20 mmol, 5 equiv.) then add trichloroacetonitrile (4.0 mL, 40 mmol, 10 equiv.) Continue stirring in a stoppered flask for 15 hours at 60 ° C. Test the reaction solution on silica gel. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40-50 ° C and the pH is 10 11. The resin product initially solidified gradually, recrystallized from ethanol: water (2: 1) Yield: 0.99 g (62%).

White solid, Rf = 0.41 (T / E = 3/2)

bp 181 ° C (EtOH / H ₂ O 2/1)

IS (KBr): 3302, 2965, 2928, 2356, 2343, 1704, 1681, 1595, 1582, 1520, 1485, 1471, 1445, 1430, 1382, 1371, 1078, 1041.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.40 (d, 1H, ³ J = 4.2 Hz, Py-N (1)), 7.85 (d, 1H, ³ J = 8.2 Hz, PyN ( l)), 7.77 (dd, 1H, ³ J = 8.3 Hz, ³ J = 7.3 Hz, Py-N (l)), 7.15 (dd, 1H, ³ J = 7.2 Hz, ³ J = 4.9 Hz, Py- N (1), 6.74 (d, 1H, ³ J = 8.7 Hz, HNC (4)), 5.13 (ddd, 1H, ³ J = 8.7 Hz, ³ J = 8.3 Hz, ³ J = 6.0 Hz, HC ( 4)), 2.99 (s, 2H, HC (7)), 2.29 (s, 3H, H3 C-C (3)), 2.02 (dd, 1H, ² J = 13.0 Hz, V = 6.0 Hz, Ha-C (5)), (1.53, dd, 1H, ² J = 13.1 Hz, ³ 7 = 8.3 Hz, H _b -C (5)), 1.14 (s, 3H, H ₃ CC (6)), 1:02 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 161.1, 153.1, 148.2, 147.6, 142.2, 138.4, 120.9, 114.9, 114.8, 92.8,

44.1, 42.9, 38.7, 32.1, 30.1, 26.6, 12.7.

Elemental Analysis: Calculated for C17H19N4OCl3 (400.06): C 50.83, H 4.77, N 13.95; Found: C 50.86, H 4.63, N 13.82.

Example 12.

N- (3,6,6-Trimethyl-1-pyrid-2-yl, 5,6,7-tetrahydro-1 H -indazol-4-yl) -benzamide 1- (Pyrid-2-yl) -4 To a solution of -hydroxy-3,6,6-trimethyl-4,5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (magnetic stirring). 1.1 mL, 20 mmol, 5 equiv), then add benzonitrile (0.8 mL, 8 mmol, 2 equiv). Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.22 g (85%).

White solid, Rf = 0.55 (T / E = 1/1)

bp 218 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3291, 3060, 2946, 2927, 2914, 1629, 1582, 1530, 1487, 1470, 1445, 1429, 1382, 1268, 1319, 1301, 1286, 1178, 1148, 1075, 1042.

1 H-NMR (300 MHz, CDCl 3) δ (ppm): 8.41 (d, 1H, ³ , δ = 4.9 Hz, HC (Ar)), 7.85-7.82 (m, 3H, HC (Ar)), 7.75 ( dd, 1H, ³ J = 8.3 Hz, ⁴ J = 1.9 Hz, HC (Ar)), 7.53-7.41 (m, 3H, HC (Ar)), 7.13 (dd, 1H, ³ J = 7.2 Hz, ⁴ J = 4.9 Hz, HC (Ar)), 6.39 (d, 1H, ³ J = 8.9 Hz, HNC (4)), 5.38 (ddd, 1H, V = 9.0 Hz, ³ J = 8.9 Hz, ³ J = 6.0 Hz , HC (4)), 2.96 (s, 2H, HC (7)), 2.24 (s, 3H, H3 C-C (3)), 1.99 (dd, 1H, ² J = 13.0 Hz, ³ J = 6.0 Hz) , HaC (5)), 1.37 (dd, 1H, ² J = 13.0 Hz, ³ J = 9.0 Hz, Hb-C (5)), 1.10 (s, 3H, H3 C-C (6)), 0.99 (s , 3H, H 3 C-C (6)). ¹³ C-NMR (75 MHz, CDCl3) δ (ppm): 166.7, 153.1, 148.3, 147.5, 141.9, 138.3, 134.5, 131.5, 128.6, 126.8, 120.6,116.4,114.8,43.7,41.8,38.8, 32.2, 30.5 , 26.0,12.7.

Elemental Analysis: Calculated for C 22 H 24 N 4 O (360.20): C 73.31, H 6.71, N 15.54; found C 73.37, H 6.73, N 15.59.

Example 13.

N- (3,6,6-Trinyl-1-pyrid-2-yl-4,5,6,7-tetrahydro-1H-indazol-4-yl) -acrylamide 1- (Pyrid-2-yl) - To a solution of 4-hydroxy-3,6,6-trimethyl-4,5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv.) In glacial acetic acid (4 mL) was added concentrated sulfuric acid with stirring. (1.1 mL, 20 mmol, 5 equiv), then add acrylonitrile (0.5 mL, 8 mmol, 2 equiv). Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.00 g (81%).

White solid, Rf = 0.24 (T / E = 1/1)

bp 177 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3237, 3066, 2950, 2932, 1651, 1621, 1593, 1583, 1549, 1486, 1470, 1446, 1427, 1382, 1366, 1320, 1307, 1249, 1147, 1134, 1088, 1069, 1053 , 1042, 988,971.

³ H-NMR (300 MHz, CDCl 3) δ (ppm): 8.39 (d, 1H, ³ J = 4.7 Hz, Py-N (1)), 7.82 (d, 1H, ³ J = 8.3 Hz, PyN (1 )), 7.75 (dd, 1H, ³ J = 7.1 Hz, ⁴ J = 1.9 Hz, Py-N (1)), 7.12 (dd, 1H, ³ J = 7.0 Hz, ³ J = 4.8 Hz, Py-N (l)), 6.33 (dd, 1H, ³ J = 17.0 Hz, ² J = 1.9 Hz, Ha-C (3 ')), 6.19 (dd, 1H, ² J = 17.0 Hz, ³ J = 10.0 Hz, HC (2 '), 6.10 (d, 1H, ³ J = 9.4 Hz, HNC (4)), 5.67 (dd, 1H, ³ J = 10.0 Hz, ² J = 1.9 Hz, Hb-C (3'). ), 5.18 (ddd, 1H, ³ J = 9.4 Hz, ³ J = 9.4 Hz, ³ J = 6.2 Hz, HC (4)), 2.89 (s, 2H, 2H-C (7)), 2.19 (s, 3H, H3 C-C (3)), 1.83 (dd, 1H, ² J = 13.0 Hz, ³ J = 6.2 Hz, Ha-C (5)), 1.11 (dd, 1H, ² J = 13.0 Hz), ³ J = 9.4 Hz, H _b -C (5)), 1.03 (s, 3H, H ₃ CC (6)), 0.91 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl 3) δ (ppm): 164.9, 153.0, 148.5, 147.6, 142.0, 138.4, 130.9, 126.6, 120.7,

116.2, 114.7,43.5,41.2, 38.8, 32.3, 30.6,25.7,12.7.

Elemental Analysis: Calculated for C 18 H ₂₂ N ₄ O (310.18): C 69.65, H 7.14, N 18.05; found C 69.77, H 7.15, N 18.15.

Example 14.

N- (3,6,6-Trimethyl-1-pyrid-2-yl-4,5,6,7-tetrahydro-1H-indazol-4-yl) -2-fluorobenzamide 1- (Pyrid-2- yl) -4-Hydroxy-3,6,6-trimethyl-4,5,6,7-tetrahydro-indazole (0.96 g, 4 mmol, 1 eq) in glacial acetic acid (4 mL) under magnetic stirring, Add concentrated sulfuric acid (1.1 mL, 20 mmol, 5 equiv) then add o-fluorobenzonitrile (0.9 mL, 8 mmol, 2 equiv). Continue stirring in a sealed flask for 8 hours at 60 ° C. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40-50 ° C and the pH is 1011. 1: 1).

Yield: 1.13 g (75%).

White solid, Rf = 0.52 (T / E = 1/1)

bp 174 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3238, 2949, 1638, 1616, 1583, 1552, 1536, 1484, 1448, 1382, 1322, 1225.

¹ H-NMR (300 MHz, CDCl 3) δ (ppm): 8.41 (pis, 1H, Py-N (1)), 8.14 (td, 1H, J = 7.9 Hz, J = 1.9 Hz, ArC (1 ') ), 7.89 (d, 1H, J = Ί.Ί Hz, Py-N (l)), 7.78 (t, 1H, J = 8.0 Hz, Py-N (l)), 7.48 (m, 1H, Ar- C (l ')), 7.30 (d, 1H, J = 7.9 Hz, Ar-C (l')), 7.15 (pls, 1H, Py-N (l)), 7.11 (dd, 1H, J = 12.2 Hz, 7 = 8.3 Hz, Ar-C (1 ')), 6.78 (dd, 1H, JN.F = 12.2 Hz, ³ J = 9.0 Hz, HNC (4)), 5.45 (ddd, 1H, ³ J = 9.0 Hz, 7 = 8.7 Hz, ³ J = 6.0 Hz, HC (4), 2.99 (s, 2H, HC (7)), 2.29 (s, 3H, H3 C-C (3)), 2.09 (dd, 1H, ³ J = 13.2 Hz, 7 = 6.0 Hz, Η * <(5)),

l. 57 (dd, 1H, ³ J = 13.2 Hz, 7 = 8.7 Hz, Hb-C (5)), 1.15 (s, 3H, H3C-C (6)), 1.05 (s, 3H, H3C-C (6) )). ¹³ C-NMR (75 MHz, CDCl 3) δ (ppm): 162.6 (d, J _C -f = 3 Hz), 160.5 (d, 7 _C -f = 247 Hz), 153.1, 148.2, 147.5, 141.9, 138.1, 133.3 (d, _C 7 f = 9 Hz), 132.1 (d, _C f 7 = 2 Hz), 126.8, 124.9 (d, 7 _{C. F} = 3 Hz), 121.0 (d, 7 = _C f 11 Hz), 120.6.116.0 (d, 7 _C -f = 25 Hz), 114.9,43.5,41.7, 38.6,32.0, 30.1, 26.2,12.3.

Elemental Analysis: Calculated for C ₂₂ H ₂₃ N ₄ OF (378.19): C 69.82, H 6.13, N 14.80; Found: C 69.79, H 6.18, N 14.86.

Example 15.

N- (3,6,6-Triinethyl-1-pyrid-2-yl-4,5,6,7-tetrahydro-1 H -indazol-4-yl) -butyrainide 1- (Pyrid-2-yl) ) To a solution of A-hydroxy-3,6,6-trimethyl-4,5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv.) In glacial acetic acid (4 mL) was added concentrated magnetic stirring. sulfuric acid (2.2 mL, 40 mmol, 10 equiv), then dropwise tert-butyl nitrile (1.7 mL, 20 mmol, 5 equiv). Continue stirring in a sealed flask for 8 hours at 60 ° C. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 0.99 g (76%).

White solid, Rf = 0.18 (T / E = 1/1)

bp 165 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3232, 3063, 2957, 2927, 2871, 1639, 1584, 1557, 1486, 1470, 1443, 1382, 1366, 1216, 1058, 1040.

³ H-NMR (300 MHz, CDCl 3) δ (ppm): 8.39 (d, 1H, ³ J = 5.7 Hz, Py-N (1)), 7.84 (d, 1H, ³ J = 8.7 Hz, PyN (1 )), 7.76 (t, 1H, δ = 7.2 Hz, Py-N (l)), 7.13 (ddd, 1H, ³ J = 7.2 Hz, 7 = 4.9 Hz, 7 = 1.1 Hz, Py-N (l) ), 5.67 (d, 1H, J = 9.0 Hz, HNC (4)), 5.17 (ddd, 1H, J = 9.0 Hz, 7 = 9.0 Hz, 7 = 6.0 Hz, HC (4)), 2.90 (s, 2H, HC (7)), 2.25 (s, 3H, H ₃ CC (3)), 2.21 (dd, 2H, 7 = 14.5 Hz, 7 = 8.1 Hz, HC (2 ')), 1.90 (dd, 1H , 7 = 13.0 Hz, 7 = 6.0 Hz, H _b -C (5)), 1.70 (hex, 2H, 7 = 7.5 Hz, HC (3 ')), 1.29 (dd, 1H, 7 = 13.0 Hz, 7 = 9.0 Hz, H _b -C (5)), 1.08 (s, 3H, H ₃ CC (6)), 0.97 (t, 3H, 7 = 7.3 Hz, HC (4 ')), 0.95 (s, 3H) , H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl 3) δ (ppm): 172.2,152.9, 148.2, 147.5,141.9, 138.3, 120.7, 116.4, 114.9, 43.9,

41.1,38.8,38.7,32.2,30.5,25.9,19.2,13.8,12.6.

Elemental Analysis: Calculated for C 19 H 26 N 4 O (326.45): C 69.90, H 8.03, N 17.16; found C 69.89, H 8.08, N 17.24.

Example 16.

N- (3,6,6-Trimethyl-1-pyrid-2-yl-4,5,6,7-tetralidro-1 H -indazol-4-yl) -4-nitrobenzamide 1- (Pyrid-2) -yl) -4-hydroxy-3,6,6-trimethyl-4,5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv) in a solution of glacial acetic acid (4 mL) with magnetic stirrer , add concentrated sulfuric acid (1.1 mL, 20 mmol, 5 equiv), then add p-nitrobenzoyl tril (1.18 g, 8 mmol, 2 equiv). The closed flask is maintained at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40-50 ° C and the pH is 1011. 1: 1). Yield: 1.20 g (74%).

White solid Rf = 0.68 (Ί7Ε = 1/1) kp 196 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3216, 2956, 2926, 1633, 1598, 1583, 1529, 1484, 1447, 1390, 1382, 1368, 1346, 1321, 1047. 1 H-NMR (300 MHz, CDCl 3) δ (ppm): 8.42 (d, 1H, ³ J = 4.7 Hz, Py-N (1)), 8.29 (d, 2H, ³ J = 8.7 Hz, pO2N -C 6 H 4 -C (1 ')), 8.04 (d, 2H, ³ J = 4.7 Hz, p-O 2 N-C ₆ H 4 -C (1')), 7.78 (d, 111.7- 8.1 Hz, Py- N (l)), 7.76 (dd, 1H, ³ J = 8.5 Hz, V = 1.7 Hz, Py-N (l)), 7.15 (dd, 1H, 7 = 6.6 Hz, ³ J = 4.9 Hz, Py- N (I), 6.68 (d, 1H, ³ J = 9.0 Hz, HN (4)), 5.34 (ddd, 1H, ³ J = 9.4 Hz, ³ J = 9.0 Hz, 7 = 6.2 Hz, HC (4 ), 2.94 (s, 2H, HC (7)), 2.19 (s, 3H, H3 C-C (3)), 1.95 (dd, 1H, ² J = 13.0 Hz, ³ J = 6.2 Hz, Ha-C (5)), 1.26 (dd, 1H, ² J = 13.1 Hz, ³ J = 9.4 Hz, H _b -C (5)), 1.09 (s, 3H, H ₃ CC (6)), 0.96 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 164.6, 152.9, 149.6, 148.2, 147.7, 142.2, 140.0, 138.5, 128.2,

123.9, 120.9, 115.8, 114.8,43.5, 42.3, 38.7, 32.3, 30.6,25.8, 12.8.

Elemental Analysis: Calculated for C ₂₂ H ₂₃ N ₅ O ₃ (405.18): C 65.17, H 5.72, N 17.27; found C 65.10, H 5.68, N 17.23.

Example 17.

N - (3,6,6-Trinyl-1-pyrid-2-yl-4,5,6,7-tetrahydro-11 H -indazol-4-yl) -3-methoxy-benzanide 1- (Pyrid-2) -yl) -4-hydroxy-3,6,6-trimethyl-4,5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv) in a solution of glacial acetic acid (4 mL) with magnetic stirrer , add concentrated sulfuric acid (1.1 mL, 20 mmol, 5 equiv), then add τη-methoxybenzonitrile (0.80 g, 6 mmol, 1.5 equiv). Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40-50 ° C and the pH is 1011. 1: 1). Yield: 1.22 g (78%).

White solid, Rf = 0.59 (T / E = 1/1)

b.p. 149 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3278, 2959, 2929, 2869, 2835, 1637, 1609, 1583, 1550, 1487, 1445, 1390, 1381, 1369, 1323, 1301, 1243, 1142, 1133, 1088, 1059, 1039, 989 .

¹ H-NMR (300 MHz, CDCl 3) δ (ppm): 8.39 (d, 1H, ³ J = 4.9 Hz, Py-N (1)), 7.81 (d, 1H, ³ J = 8.1 Hz, HC) (Ar)), 7.72 (dd, 1H, ³ J = 7.2 Hz, 7 = 1.9 Hz, HC (Ar)), 7.46 (d, 1H, ³ J = 2.3 Hz, ³ J = 1.5 Hz, HC (Ar)) ), 7.39 (dt, 1H, ³ J = 7.7 Hz, ³ J = 1.1 Hz, HC (Ar)), 7.31 (t, 1H, ³ J = 7.9 Hz, HC (Ar)), 7.11 (ddd, 1H, ³ J = 7.0 Hz, ³ J = 4.9 Hz, ⁴ J = 0.9 Hz, HC (Ar)), 7.03 (ddd, 1H, ³ J = 7.9 Hz, ^A J = 2.5 Hz, 7 = 0.9 Hz, HC (Ar) )), 6.55 (d, 1H, ³ J = 9.0 Hz, HNC (4)), 5.33 (ddd, 1H, ³ J = 9.2 Hz, ³ J = 9.0 Hz, ³ J = 6.0 Hz, HC (4)) , 3.84 (s, 3H, m-CH 3 -OC ₆ H 4 -C (1 ')), 2.93 (s, 2H, HC (7)), 2.21 (s, 3H, H ₃ CC (3)), 1.92 ( dd, 1H, ² J = 13.0 Hz, ³ J = 6.0 Hz, Ha-C (5)), 1.23 (dd, 1H, 7 = 13.0 Hz, ³ J = 9.2 Hz, Hb-C (5)), 1.06 (s, 3H, H ₃ CC (6)), 0.95 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 166.5, 159.9, 153.1, 148.5, 147.6, 142.0, 138.4, 136.0, 129.6, 120.6, 118.7, 117.7, 116.4, 114.7, 112.4, 55.53.53, 41.8, 38.8, 32.3,30.6,25.9, 12.8.

Elemental Analysis: Calculated for C ₂₃ H ₂₆ N ₄ O ₃ (390.21): C 70.75, H 6.71, N 14.35; found C 70.46, H 6.67, N 14.29.

Example 18.

N - (3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1 H -indazol-4-yl) -acetanide 1-Phenyl-4-hydroxy-3,6, To a solution of 6-trimethyl-4,5,6,7-tetrahydroindazole (1.02 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (1.1 mL, 20 mmol) with magnetic stirrer. , eq.), then acetonitrile (0.6 mL, 12 mmol, 3 eq.) was added. Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 0.85 g (76%).

White crystalline substance Rf = 0.12 (T / E 1/2) bp 196 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3248, 3058, 2948, 2369, 1636, 1560, 1507, 1381, 1292, 1109, 1039, 1014.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.45-7.39 (m, 4H, Ph-N (1)), 7.33-7.27 (m, 1H, Ph-N (1)), 5.76 ( d, 1H, ³ J = 8.9 Hz, HNC (4)), 5.16 (dt, 1H, ³ J = 8.9 Hz, ³ J = 6.2 Hz, HC (4)), 2.54 (d, 1H, ² J = 16.2 Hz, HaC (7)), 2.37 (d, 1H, ² J = 16.2 Hz, Hb-C (7)), 2.23 (s, 3H, H3C-C (3)), 1.99 (s, 3H, HC ( 2 ')), 1.95 (dd, 1H, ² J = 13.2 Hz, ³ J = 6.2 Hz, Ha-C (5)), 1.37 (dd, 1H, ² J = 13.2 Hz, ³ J = 8.9 Hz, Hb -C (5)), 1.06 (s, 3H, H ₃ CC (6)), 0.92 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 169.3, 147.1, 140.0, 139.4, 129.2, 126.9, 123.1, 115.0, 44.0, 41.5,

37.2, 32.7, 30.4,25.8, 23.4,12.4.

Elemental Analysis: Calculated for C ₂₃ H ₂₃ N ₃ O (297.18): C 72.70, H 7.80, N 14.13; found C 72.76, H 7.86, N 14.17.

Example 19.

N- (3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1 H -indazol-4-yl) -acrylamide 1-Phenyl-4-hydroxy-3,6,6 Concentrated sulfuric acid (1.1 mL, 20 mmol) was added to a solution of -trimethyl-4,5,6,7-tetrahydroindazole (1.02 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) with magnetic stirring. 5 eq.), Then acrylonitrile (0.5 mL, 8 mmol, 2 eq.) Was added. Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 0.89 g (66%).

Light yellow solid, Rf = 0.16 (T / E = 2/1)

bp 150 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3434, 3050, 2956, 2370, 2345, 1656, 1558, 1251.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.47-7.41 (m, 4H, Ph-N (1)), 7.34-7.28 (m, 1H, Ph-N (1)), 6.32 ( d, 1H, ³ J = 16.8 Hz, Ha-C (3 ')), 6.11 (dd, 1H, ³ J = 16.9 Hz, ³ J = 10.2 Hz, HC (2')), 5.74 (d, 1H, ³ J = 8.9 Hz, HNC (4)), 5.67 (d, 1H, ³ J = 10.2 Hz, Hb-C (3 ')), 5.28 (ddd, 1H, ³ J = 8.9 Hz, ³ J = 8.7 Hz) , ³ J = 6.2 Hz, HC (4)), 2.58 (d, 1H, ² J = 16.2 Hz, Ha-C (7)), 2.40 (d, 1H, ² J = 16.2 Hz, Hb-C (7 )) 2.23 (s, 3H, H ₃ CC (3)), 2:02 (dd, 1H, ² J = 13.3 Hz, ³ J = 6.2 Hz, H-C (5)), 1:45 (dd, 1H, = 13.2 Hz, ³ J = 8.7 Hz, H-C (5)), 1:08 (s, 3H, H ₃ CC (6)), 0.96 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 164.9, 147.3, 140.1, 139.4, 130.8, 129.2, 126.9, 126.7, 123.2,

114.8,43.9,41.6, 37.2, 32.7, 30.3, 25.9, 12.4.

Elemental Analysis: Calculated for C ₁₉ H ₂₃ N ₃ O 1.5 H ₂ O (336.18): C 67.83, H 7.79, N 12.49; found C 67.58, H 7.71, N 12.59.

Example 20.

N- (3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl) -propionamide 1-Phenyl-4-hydroxy-3,6,6-trimethyl To a solution of -4,5,6,7-tetrahydroindazole (1.02 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (1.1 mL, 20 mmol, equiv.) With magnetic stirring. ), then add ethyl nitrile (1.4 mL, 20 mmol, 5 equiv.). Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.05 g (79%).

Light yellow solid, Rf = 0.08 (T / E = 2/1)

bp 147 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3463, 3219, 3066, 2955, 2931, 1656, 1648, 1559, 1507, 1389, 1267, 1110, 1052.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.45-7.40 (m, 4H, Ph-N (1)), 7.34-7.27 (m, 1H, Ph-N (1)), 5.64 ( d, 1H, ³ J = 8.9 Hz, HNC (4)), 5.20 (dt, 1H, ³ J = 8.9 Hz, ³ J = 6.0 Hz, HC (4)), 2.55 (d, 1H, ² J = 16.2 Hz, HAC (7)), 2:39 (d, 1H, ² J = 16.2 Hz, H-C (7)), 2.24 (s, 3H, H ₃ CC (3)), 2.23 (sq, 2H, ³ J = 7.5 Hz, HC (2 ')),

l. 97 (dd, 1H, ² J = 13.2 Hz, ³ J = 6.0 Hz, Ha-C (5)), 1.40 (dd, 1H, ² J = 13.2 Hz, ³ J = 8.9 Hz, Hb-C (5) ), 1.18 (t, 3H, ³ J = 7.5 Hz, HC (3 ')), 1.07 (s, 3H, H ₃ C -C (6)), 0.94 (s, 3H, H ₃ CC (6)).

ⁿ C-NMR (75 MHz, CDC1 ₃₎ δ (ppm): 173.1, 147.1, 140.1, 139.4, 129.2, 126.9, 123.2, 115.1, 44.1, 41.3,

37.2, 32.7, 30.4, 29.9,25.8,12.4,10.0.

Elementāranalīze: calculated Ci9H _{2 3} O0.2 5N H ₂ O (333.70): C 68.34, H 8.30, N 12:58; found C 68.56, H 8.13, N 12.59.

Example 21.

N- (3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl) -butyramide 1-Phenyl-4-hydroxy-3,6,6- To a solution of trimethyl-4,5,6,7-tetrahydroindazole (1.02 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (1.1 mL, 20 mmol, 5 mL) with magnetic stirring. eq.) then add n-butyl nitrile (1.0 mL, 12 mmol, 3 eq.). Continue stirring in a sealed flask for 5 hours at 60 ° C. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.09 g (83%).

White solid, Rf = 0.12 (T / E = 2/1)

bp 196 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3305, 2959, 2370, 1638, 1530, 1507, 1383, 1047.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.47-7.42 (m, 4H, Ph-N (1)), 7.35-7.29 (m, 1H, Ph-N (1)), 5.49 ( d, 1H, ³ J = 9.2 Hz, HNC (4)), 5.22 (ddd, 1H, ³ J = 9.2 Hz, ³ J = 8.7 Hz, ³ J = 6.0 Hz, HC (4)), 2.57 (d, 1H, ² J = 16.0 Hz, Ha-C (7)), 2.41 (d, 1H, ² J = 16.0 Hz, Hb-C (7)), 2.27 (s, 3H, H3 C-C (3)), 2.19 (t, 2H, ³ J = 7.9 Hz HC (2 ')), 2.01 (dd, 1H, ² J = 13.1 Hz, ³ J = 6.0 Hz, Ha-C (5)), 1.72 (hex, 2H, ³ J = 7.5 Hz, HC (3 ')), 1.23 (dd, 1H, ³ J = 13.2 Hz, ³ J = 8.7 Hz, Hb-C (5)), 1.09 (s, 3H, H3 C-C (6 ), 0.98 (t, 3H, ³ J = 7.3 Hz, HC (4 ')), 0.96 (s, 3H, H3 C-C (6)).

¹³ C-NMR (75 MHz, CDC1 ₃₎ δ (ppm): 172.1, 147.1, 140.2, 139.5, 129.1, 126.8, 123.3, 115.0, 44.1, 41.3,

38.9, 37.2, 32.6, 30.3,25.9, 19.2,13.8, 12.4.

Elementāranalīze: calculated C ₂ oH _{2 3} 7N 0 «0.2 H ₂ O (328.82): C 73.00, H 8.39 N 12.77; found C 73.22, H 8.53, N 12.99.

Example 22.

N- (3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl) -2-fluoro-benzamide 1-Phenyl-4-hydroxy-3 To a solution of 6,6-trimethyl-4,5,6,7-tetrahydroindazole (1.02 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (1.1 mL) with magnetic stirrer. , 20 mmol, 5 equiv), then add o-fluorobenzonitrile (0.9 mL, 8 mmol, 2 equiv). Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: L09 g, (71%).

White solid, Rf = 0.44 (T / E = 2/1) bp 159 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3247, 2957, 2930, 2368, 1648, 1508, 1220, 1103, 1069.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.16 (dd, 1H, ³ J = Ί.Ί Hz, ⁴ J = 1.7 Hz, HC (Ar)), 7.51-7.43 (m, 5H, HC (Ar)), 7.36-7.29 (m, 2H, HC (Ar)), 7.12 (dd, 1H, ³ J = 12.2 Hz, ³ J = 8.3 Hz, HC (Ar)), 6.81 (d, 1H, ³ J = 9.0 Hz, HNC (4)), 5.45 (ddd, 1H, ³ J = 9.2 Hz, ³ J = 8.3 Hz, ³ J = 6.0 Hz, HC (4)), 2.62 (d, 1H, ³ J) = 16.3 Hz, Ha-C (7)), 2.45 (d, 1H, ² J = 16.3 Hz, Hb-C (7)), 2.29 (s, 3H, H3 C-C (3)), 2.14 (dd, 1H, ² J = 13.2 Hz, ³ J = 6.0 Hz, Ha-C (5)), 1.59 (dd, 1H, ³ J = 13.2 Hz, ³ J = 8.3 Hz, Hb-C (5)), 1.12 ( s, 3H, H ₃ CC (6)), 1.02 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 162.6 (d, J _c , _f = 3 Hz), 160.5 (d, J _c , _f = 247 Hz), 147.3, 140.1,

139.6, 133.3 (d, 7 _C -f = 9 Hz), 132.1 (d, J _C -t = 2 Hz), 129.1, 126.8, 124.9 (d, J _{c- r} = 3 Hz), 123.2, 121.0 (d , J _c -f = 12 Hz), 116.0 (d, J _C -f = 25 Hz), 114.6,43.9,42.2,37.3,32.6, 30.1, 26.2,12.5.

Elementāranalīze: calculated C23H24FN3 0 * 1/3 H ₂ O (383.13): C 72.04, H 6.48 and N 10.96; Found: C 72.26, H 6.49, N 10.85.

Example 23.

N- (3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1 H -indazol-4-yl) -benzamide 1-Phenyl-4-hydroxy-3,6,6 Concentrated sulfuric acid (1.1 mL, 20 mmol) was added to a solution of -trimethyl-4,5,6,7-tetrahydroindazole (1.02 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) with magnetic stirring. 5 equiv.), Then add benzonitrile (1.2 mL, 12 mmol, 3 equiv.). Continue stirring in the stoppered flask at 60 ° C for four hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.17 g (80%).

White solid, Rf = 0.26 (T / E = 2/1)

bp 244 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3299, 3057, 2949, 2926, 1630, 1531, 1507, 1375, 1291, 1177, 1024, 1045, 920.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.79 (d, ³ J = 7.3 Hz, Ph-C (1 ')), 7.54-7.44 (m, 7H, Ph-N (1.1) '), 7.38-7.32 (m, 1H, Ph-N (1)), 6.24 (d, 1H, ³ J = 8.7 Hz, HNC (4)), 5.43 (dt, 1H, ³ J = 6.2 Hz, ³ J = 8.7 Hz, HC (4)), 2.62 (d, 1H, ² J = 15.8 Hz, Ha-C (7)), 2.45 (d, 1H, ² J = 15.8 Hz, H 1 -C (7 ), 2.29 (s, 3H, H3 C-C (3)), 2.11 (dd, 1H, ² J = 13.1 Hz, ³ J = 6.2 Hz, Ha-C (5)), 1.56 (dd, 1H, ² J = 13.1 Hz, ³ J = 8.7 Hz, H-C (5)), 1.12 (s, 3H, H ₃ CC (6)), 1:01 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 166.7, 147.2, 140.2, 139.4, 134.5, 131.5, 129.1, 128.7, 126.9,

126.8,123.2, 114.9, 44.0,42.0, 37.2, 32.7, 30.3,26.0,12.5

Elementāranalīze: calculated C ₂₃ H 5 N ₃ O ₂ * l / 3 H ₂ O (365.14): C 75.59, H 7.08 and N 11:50; found C 75.85, H 6.96, N 11.54.

Example 24.

N- (3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl) -trichloroacetamide 1-Phenyl-4-hydroxy-3,6,6-trimethyl To a solution of -4,5,6,7-tetrahydroindazole (1.02 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) was added concentrated sulfuric acid (2.2 mL, 40 mmol, 10 equiv) with a magnetic stirrer. ), then trichloroacetonitrile (8.0 mL, 80 mmol, 20 equiv) was added. Continue stirring in a closed flask at 60 ° C for 12 hours. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.15 g (72%).

White solid, R _f = 0.26 (T / E = 2/1) bp. 146 ° C (EtOH / H 2 O 1/1)

IS (KBr): 3267, 2952, 1696, 1507, 1078.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.48-7.42 (m, 4H, Ph-N (1)), 7.37-7.30 (m, 1H, Ph-N (1, 6.74) , 1H, ³ J = 8.5 Hz, HNC (4)), 5.15 (ddd, 1H, ³ J = 5.8 Hz, ³ ./- 8.1 Hz, ³ J = 8.5 Hz, HC (4)), 2.61 (d, 1 H, ² J = 16.2 Hz, Ha-C (7)), 2.45 (d, 1H, 16.2 Hz, H _b -C (7)), 2.29 (s, 3H, H ₃ CC (3)), 2.07 ( dd, 1H, ² ./- 13.2

Hz, ³ J = 5.8 Hz, H-C (5)), 1:56 (dd, 1H, V- 13.1 Hz, ³ J = 8.1 Hz, H-C (5)), 1.11 (s, 3H, H ₃ CC (6)), 1.00 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CE> Cl ₃ ) δ (ppm): 161.0, 147.1, 140.4, 139.2, 129.2, 127.1, 123.3, 113.3, 92.7, 44.1,

42.9, 37.0, 32.5, 29.8, 26.3, 12.4.

Elemental Analysis: Calculated for C 18 H ₂₀ OCl ₃ N ₃ O (399.07): C 53.95, H 5.03, N 10.49; found C 53.93, H 4.93, N 10.45.

Example 25.

N- (3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1 H -indazol-4-yl) -chloroacetamide 1-Phenyl-4-hydroxy-3,6,6 Concentrated sulfuric acid (1.7 mL, 32 mmol) was added to a solution of -trimethyl-4,5,6,7-tetrahydroindazole (1.02 g, 4 mmol, 1 equiv) in glacial acetic acid (4 mL) with magnetic stirring. 8 eq.), Then chloroacetonitrile (1.0 mL, 16 mmol, 4 eq.) Was added. Continue stirring in a sealed flask for 8 hours at 60 ° C. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (55 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.06 g (80%).

White solid, Rf = 0.60 (T / E = 2/1)

bp 164 ° C (EtOH / H ₂ O 1/1)

IS (KBr): 3221, 3066, 2954, 1648, 1560, 1507, 1383, 1253, 1152, 1040.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.46-7.40 (m, 4H, Ph-N (1)), 7.34-7.27 (m, 1H, Ph-N (1)), 6.67 ( d, 1H, ³ J = 8.7 Hz, HNC (4)), 5.19 (dt, 1H, ³ J = 6.0 Hz, ³ J = 8.7 Hz, HC (4)), 4.09 (s, 2H, HC (2 ') ), 2.58 (d, 1H, ² J = 16.2 Hz, Ha-C (7)), 2.41 (d, 1H, ² J = 16.2 Hz, Hb-C (7)), 2.24 (s, 3H, H ₃ CC (3)), 2.00 (dd, 1H, ² J = 13.0 Hz, ³ J = 6.0 Hz, Ha-C (5)), 1.48 (dd, 1H, ² J = 13.1 Hz, ³ J = 8.7 Hz, H _b -C (5)), 1.11 (s, 3H, H ₃ CC (6)),

l. 00 (s, 3H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl 3) δ (ppm): 165.1, 147.0, 140.1, 139.4, 129.0, 126.8, 123.1, 113.9, 43.5, 42.5, 42.1.37.0, 32.5,30.1,25.9, 12.4.

Elemental Analysis: Calculated for C ₁₈ H ₂₂ ClN ₃ O * 0.5 H ₂ O (331.15): C 63.43, H 6.80, N 12.33; Found: C 63.66, H 6.50, N 12.34.

Example 26.

6,6-Dimethyl-1-phenyl-6,7-dihydro-1H-indazole 1-Phenyl-4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-1 H -indazole (0 , 48 g, 2 mmol) in acetyl chloride (2 mL) is boiled for 1.5 h and then poured into water. The crystallized product is filtered and recrystallized from ethanol / water mixture. Yield: 0.35 g (79%).

bp 80-81 ° C (EtOH / H ₂ O 1/3) 1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.52 (s, 1H, HC (3)), 7.49-7.45 (m, 4H, HC (Ph)), 7.40-7.32 (m, 1H, HC (Ph)), 6.32, 5.44 (2d, 2H, V = 9.6 Hz, HC (4.5)), 2.79 (s, 2H, HC) (7)), 1.09 (s, 6H, H ₃ CC (6)).

Elemental Analysis: Calculated for C15H16N2 (224.30): C 80.32, H 7.19, N 12.49; found C 80.11, H 7.32, N

12.54.

Example 27.

3.6.6- Trimethyl-1-phenyl-6,7-dihydro-1 H -indazole 1-Phenyl-4-hydroxy-3,6,6-trimethyl-4,5,6,7-tetrahydro-1 H A solution of -indazole (0.50 g, 2 mmol) in acetyl chloride (2 mL) is boiled for 1.5 h and then poured into water. The crystallized product is filtered and recrystallized from ethanol / water. Yield: 0.42 g (87%).

mp 57-59 ° C (EtOH / H ₂ O 1/3) 1 H-NMR (300 MHz, CDCl 3) δ (ppm): 7.48-7.41 (m, 4H, HC (Ph)), 7.35-7.28 (m , 1H, HC (Ph)), 6.28 and 5:42 (2d, 2H, ³ 7 = 9.6 Hz, HC (4,5)), 2.75 (s, 2H, HC (7)), 2.31 (s, 3H, H ₃ CC (3)), 1.09 (s, 6H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl 3) δ (ppm): 144.9, 139.5, 138.0, 133.2, 129.1, 126.7, 123.1, 116.9, 115.9, 36.2,

34.4.28.5.11.6.

Elemental Analysis: Calculated for C ₁₆ H ₈ N ₂ (238.33): C 80.63, H 7.61, N 11.75; Found: C 80.30, H 7.66, N 11.64.

Example 28.

3.6.6- Trimethyl-1-pyridin-2-yl-6,7-dihydro-Lif-indazole

A solution of 4-hydroxy-3,6,6-trimethyl-1- (pyridin-2-yl) -4,5,6,7-tetrahydro-1H-indazole (1.6 g, 6 mmol) in acetyl chloride (6 mL) is boiled 2 h and then pour into water. The crystallized product is filtered and recrystallized from ethanol / water. Yield: 1.1 g (74%).

p.p. 73-74 ° C (EtOH) 1 H-NMR (300 MHz, CDCl 3) δ (ppm): 8.40 (ddd, 1H, J = 4.9, 1.9, 0.8 Hz, HC (Py)), 7.87 (dt, 1H, J =

8.3, 0.8 Hz, HC (Py)), 7.75 (ddd, 1H, 7 = 8.3, 7.3, 1.9 Hz, HC (Py)), 7.10 (ddd, 1H, 7 = 7.3,4.9, 1.1, Hz, HC ( py)), 6.22 and 5:44 (2d, 2H, ³ 7 = 9.6 Hz, HC (4,5)), 3.26 (s, 2H, HC (7)), 2.30 (s, 3H, H ₃ CC (3) ), 1.17 (s, 6H, H ₃ CC (6)).

¹³ C-NMR (75 MHz, CDCl 3) δ (ppm): 153.2, 147.6, 145.9, 139.6, 138.1, 134.1, 120.4, 117.1, 116.1,

114.6, 37.6, 33.9, 28.8,11.7.

Elemental Analysis: Calculated for C 15 H 17 N 5 (239.32): C 75.28, H 7.16, N 17.56; Found: C 75.30, H 7.22, N

5:54 p.m.

Example 29.

Synthesis of A- (3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-17H-indazol-4-yl) -acetamide from 3,6,6-trimethyl-1-phenyl-6,7 -dihydro-1 H -indazole

To a solution of 3,6,6-trimethyl-1-phenyl-6,7-dihydro-1H-indazole (1.19 g, 5 mmol, 1 equiv.) In glacial acetic acid (5 mL) was added concentrated sulfuric acid (magnetic stirring). 1.4 mL, 25 mmol, 5 equiv), then add acetonitrile (1.25 mL, 25 mmol, 5 equiv). The flask is kept stirring for three hours at 60 ° C. Check the reaction solution on a silica gel thin-layer chromatography plate. The product is isolated by gradually pouring the reaction solution into 10% aqueous sodium hydroxide solution (70 mL) under cooling and stirring so that the temperature does not exceed 40 - 50 ° C and the pH is 10 - 11. (1: 1).

Yield: 1.16 g (78%)

White crystalline substance Rf = 0.12 (T / E 1/2)

bp 196 ° C (EtOH / H ₂ O 1/1)

Example 30.

Synthesis of N - (6, (- dimethyl-1-phenyl-4,5,6,7-tetrahydro-1 H -indazol-4-yl) -acetamide in trifluoroacetic acid solution 1-Phenyl-4-hydroxy-6,6 To a solution of -dimethyl-4,5,6,7-tetrahydroindazole (0.96 g, 4 mmol, 1 equiv) in trifluoroacetic acid (5 mL) was added acetonitrile (0.4 mL, 8 mmol, 2 equiv). Stirring is continued for 60 hours at 60 [deg.] C. The reaction solution is tested on a silica gel thin-layer chromatography plate. 10 - 11. Initially, the precipitated gum gradually solidified, recrystallized from ethanol and water (1: 1).

Yield: 1.0 g (86%).

White solid, Rf = 0.06 (T / E = 1/1)

bp 198 ° C (EtOH / H ₂ O 1/1)

Example 31.

Synthesis of 6,6-Dimethyl-1-phenyl-6,7-dihydro-LH-indazole in Liquid Sulfur Dioxide 1-Phenyl-4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (0.48 g, 2 mmol) was added cooled sulfur dioxide (20 mL) to the pressure reactor. The reactor is closed and the reaction mixture is kept at + 90 ° C for 8 h. The sulfur dioxide is evaporated at 0 ° C. The residue is crystallized from ethanol / water. Yield: 0.25 g (56%).

Claims (5)

Claims Compounds of general formula I wherein X, R ¹ and R ² are present in all possible combinations and X is N or CH; R ¹ include, but are not limited to: H, alkyl substituents of C to C & R include, but are not limited to: H, alkyl substituents of C to C &, alkenilaizvietotāju from Cj to Ck, CH _n Cl _m, wherein n = 0- 2 and m = 1-3, -CgH5, substituted phenyl ring containing one of the following functional groups at any position: -NO2, -F, -OCH3. 2. A process for the synthesis of compounds I from the corresponding alkyl, haloalkyl, alkenyl nitriles or substituted and unsubstituted aryl nitriles, or HCN or TMSCN and 4-hydroxy-4,5,6,7-tetrahydroindazoles Π, wherein X is N or CH; R ¹ includes, but is not limited to: H and an alkyl substituent from C ¹ to C 6 in an acidic medium consisting of, but not limited to: glacial acetic acid, trifluoroacetic acid, conc. sulfuric acid, conc. phosphoric acid, polyphosphoric acid, conc. perchloric acid, p-toluenesulfoscabic, camphorsulfonic acid and their mixtures, in various combinations with or without the addition of halogen-containing organic solvents, including but not limited to: dichloromethane, chloroform, 1,2-dichloroethane. A process for the synthesis of compounds I from the corresponding alkyl, haloalkyl, alkenyl nitriles or substituted and unsubstituted aryl nitriles, or HCN or TMSCN and 6,7-dihydroindazoles III, wherein X is N yai CH; R ¹ includes, but is not limited to: H and an alkyl substituent from Q to C &lt; 1 > in an acidic medium formed but not limited to: glacial acetic acid, trifluoroacetic acid, conc. sulfuric acid, conc. phosphoric acid, polyphosphoric acid, conc. perchloric acid, -> - toluenesulphonic acid, camphorsulphonic acid and their mixtures, in various combinations with or without halogenated organic solvent additives, including but not limited to: dichloromethane, chloroform, 1,2-dichloroethane. 4. Method for the synthesis of compounds HI from compounds Π in an acidic medium which is formed but limited to: acetyl chloride, glacial acetic acid, trifluoroacetic acid, conc. sulfuric acid, conc. phosphoric acid, polyphosphoric acid, conc. perchloric acid, conc. hydrochloric acid, p-toluenesulfonic acid, camphorsulfonic acid, liquid sulfur dioxide and mixtures thereof in various combinations. 5. The use of compounds I as such or in admixture with other biologically active substances or excipients as analgesics.