Triazole derivatives

Abstract

The present invention relates to compounds of formula I ##STR00001##
wherein R.sup.1 is CH.sub.3 R.sup.1 is methyl, ethyl, CF.sub.3, CH.sub.2OH, cyclopropyl or cyano, or R.sup.1 and R.sup.1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring; R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol; R.sup.3 is Cl, F, CF.sub.3, cyano, methyl, methoxy, isopropyl, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl;
or to a pharmaceutically acceptable salt or acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. The compounds of formula I may be used in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder.

Claims

1. A compound of formula I: ##STR00111## wherein R.sup.1 is CH.sub.3 R.sup.1 is methyl, ethyl, CF.sub.3, CH.sub.2OH, cyclopropyl or cyano, or R.sup.1 and R.sup.1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring; R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol; R.sup.3 is Cl, F, CF.sub.3, cyano, methyl, methoxy, isopropyl, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

2. A compound of formula IA according to claim 1, ##STR00112## wherein R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol; R.sup.3 is Cl, F, CF.sub.3, cyano, methyl, methoxy, isopropyl, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

3. A compound of formula IA according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: N-tert-Butyl-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide; N-tert-Butyl-3-(4-fluorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide; N-tert-Butyl-3-(4-chlorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide; N-tert-Butyl-3-(3-methyl-1,2,4-triazol-4-yl)-5[4-(trifluoromethyl)-phenyl]-benzamide; N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-fluorophenyl)-benzamide; N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-benzamide; N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5[4-(trifluoromethyl)-phenyl]-benzamide; N-tert-Butyl-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; N-tert-Butyl-3-(4-chlorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; N-tert-Butyl-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5[4-(trifluoromethyl)-phenyl]-benzamide; N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide; N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(2-hydroxypropan-2-yl)-1,2,4-triazol-4-yl]-benzamide; N-tert-Butyl-3-(3,4-difluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; N-tert-Butyl-3-(4-methoxyphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)benzamide; N-tert-Butyl-3-(4-chloro-3-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; N-tert-Butyl-3-(4-fluoro-3-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; N-tert-Butyl-3-(3-fluoro-4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; N-tert-Butyl-3-(4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; N-tert-Butyl-3-(4-cyano-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; and N-tert-Butyl-3-(4-cyclopropyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide.

4. A compound of formula IB according to claim 1 ##STR00113## wherein R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol; R.sup.3 is Cl, F, CF.sub.3, cyano, methyl, methoxy, isopropyl, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

5. A compound of formula IB according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(1,2,4-triazol-4-yl)-benzamide; N-(2-Methylbutan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5[4-(trifluoromethyl)-phenyl]-benzamide; 3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; and 3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide.

6. A compound of formula IC according to claim 1 ##STR00114## wherein R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol; R.sup.3 is Cl, F, CF.sub.3, cyano, methyl, methoxy, isopropyl, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

7. A compound of formula IC according to claim 6, wherein the compound is 3-(4-Fluorophenyl)-5-(1,2,4-triazol-4-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide or a pharmaceutically acceptable salt thereof.

8. A compound of formula ID according to claim 1 ##STR00115## wherein R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol; R.sup.3 is Cl, F, CF.sub.3, cyano, methyl, methoxy, isopropyl, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

9. A compound of formula ID according to claim 8, or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(4-Fluorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; 3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; or N-(1-hydroxy-2-methylpropan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5[4-(trifluoromethyl)-phenyl]-benzamide.

10. A compound of formula IE according to claim 1 ##STR00116## wherein R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol; R.sup.3 is Cl, F, CF.sub.3, cyano, methyl, methoxy, isopropyl, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

11. A compound of formula IE according to claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide; 3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5 [4-(trifluoromethyl)-phenyl]-benzamide; 3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide; 3-(3-tert-Butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide; N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; 3 -(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-(3-propan-2-yl -1,2,4-triazol-4-yl)-benzamide; N-(2-Cyclopropyl-propan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5 -[4-(trifluoromethyl)-phenyl]-benzamide; and 3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide.

12. A compound of formula IF according to claim 1 ##STR00117## wherein R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol; R.sup.3 is Cl, F, CF.sub.3, cyano, methyl, methoxy, isopropyl, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

13. A compound of formula IG according to claim 1 ##STR00118## R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol; R.sup.3 is Cl, F, CF.sub.3, cyano, methyl, methoxy, isopropyl, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

14. A compound of formula IG according to claim 13, wherein the compound is (RS)-3-(4-Chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide, or a pharmaceutically acceptable salt thereof.

15. A process for the manufacture of a compound of formula I, or a pharmaceutically acceptable salt, as defined in claim l, which process comprises a) reacting a compound of formula II: ##STR00119## with N,N-dimethylformamide-dimethylacetal: ##STR00120## and a compound of formula ##STR00121## to produce a compound of formula I: ##STR00122## b) reacting a compound of formula V: ##STR00123## with a compound of formula IV: ##STR00124## to produce a compound of formula I: ##STR00125## wherein the substituents are as described above, or if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts, or c) reacting a compound of formula VII: ##STR00126## with a compound of formula VIII: ##STR00127## to produce a compound of formula I: ##STR00128##

16. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 and pharmaceutically acceptable excipients.

17. A method for the treatment of schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder which method comprises administering an effective amount of a compound of formula I of claim 1, or a pharmaceutically acceptable salt thereof, to a human in need.

Description

EXAMPLE 1

3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(1,2,4-triazol-4-yl)-benzamide

(1) ##STR00074##

(2) A stirred mixture of 3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzoic acid (intermediate 1) (70.8 mg, 0.25 mmol) and oxalyl chloride (723 mg, 499 l, 5.7 mmol) was cooled to 0 C., DMF (10 l) was added, the reaction mixture was allowed to stir for 2 h at room temperature, was evaporated to dryness, THF (2 ml), commercially available 2-methylbutan-2-amine (26.2 mg, 300 mol) and N,N-diisopropylethylamine (113 mg, 150 l, 875 mol) were added and the reaction mixture was allowed to stir room temperature for 17 h. The crude mixture was purified by flash chromatography on silica [dichloromethane/dichloromethane: MeOH 9:1 (20-80%)] and a second time [dichloromethane/dichloromethane: MeOH 9:1 (0-50%)] to yield the title compound as a light yellow solid (29 mg, 33%), MS (ISP) m/z=353.2 [(M+H).sup.+], mp 212 C.

EXAMPLE 2

N-tert-Butyl-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide

(3) ##STR00075##

(4) The title compound, light yellow solid (30 mg, 35%), MS (ISP) m/z=339.2 [(M+H).sup.+], mp 204 C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzoic acid (intermediate 1) (70.8 mg, 0.25 mmol) and 2-methylbutan-2-amine (21.9 mg, 0.30 mmol).

EXAMPLE 3

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzamide

(5) ##STR00076##

(6) The title compound, light yellow foam (80 mg, 88%), MS (ISP) m/z=365.2 [(M+H).sup.+], mp 135.5 C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzoic acid (intermediate 1) (70.8 mg, 0.25 mmol) and 2-cyclopropylpropan-2-amine hydrochloride (40.7 mg, 0.30 mmol).

EXAMPLE 4

3-(4-Fluorophenyl)-5-(1,2,4-triazol-4-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide

(7) ##STR00077##

(8) The title compound, white foam (20 mg, 20%), MS (ISP) m/z=393.1 [(M+H).sup.+], mp 147 C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(1,2,4-triazol-4-yl)-benzoic acid (intermediate 1) (70.8 mg, 0.25 mmol) and 1,1,1-trifluoro-2-methylpropan-2-amine (38.1 mg, 0.30 mmol).

EXAMPLE 5

N-tert-Butyl-3-(4-fluorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide

(9) ##STR00078##

(10) A mixture of 3-bromo-N-tert-butyl-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide (intermediate 2) (84.3 mg, 0.25 mmol), commercially available (4-fluorophenyl)boronic acid (45.5 mg, 325 mol), 1,2-dimethoxyethane (1.67 ml) and 2M sodium carbonate solution (416 l, 833 mol) was purged with argon in an ultrasonic bath for 5 min, triphenylphosphine (13.1 mg, 50 mol) and palladium(II)acetate (5.61 mg, 25 mol) were added, the reaction mixture was stirred for 3 h under reflux conditions, and was evaporated. After filtration the crude reaction mixture was purified by flash chromatography on silica gel [dichloromethane/dichloromethane: MeOH 9:1 (20-100%)] to yield the title compound as a light grey solid (80 mg, 91%), MS (ISP) m/z=353.1 [(M+H).sup.+], mp 235.5 C.

EXAMPLE 6

N-tert-Butyl-3-(4-chlorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide

(11) ##STR00079##

(12) The title compound, off-white solid (90 mg, 98%), MS (ISP) m/z=369.2 [(M+H).sup.+], mp 241 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide (intermediate 2) (84.3 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 mol).

EXAMPLE 7

N-tert-Butyl-3-(3-methyl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

(13) ##STR00080##

(14) The title compound, off-white solid (90 mg, 90%), MS (ISP) m/z=403.2 [(M+H).sup.+], mp 225.5 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide (intermediate 2) (84.3 mg, 0.25 mmol) and (4-trifluoromethyl-phenyl)boronic acid (61.7 mg, 325 mol).

EXAMPLE 8

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-fluorophenyl)-benzamide

(15) ##STR00081##

(16) The title compound, white solid (98 mg, 99%), MS (ISP) m/z=395.3 [(M+H).sup.+], mp 279 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-tert-butyl-1,2,4-triazol-4-yl)-benzamide (intermediate 3) (94.8 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 mol).

EXAMPLE 9

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-benzamide

(17) ##STR00082##

(18) The title compound, white solid (100 mg, 97%), MS (ISP) m/z=411.2 [(M+H).sup.+], mp 292.5 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-tert-butyl-1,2,4-triazol-4-yl)-benzamide (intermediate 3) (94.8 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 mol).

EXAMPLE 10

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

(19) ##STR00083##

(20) The title compound, white solid (110 mg, 99%), MS (ISP) m/z=445.3 [(M+H).sup.+], mp 280.5 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-tert-butyl-1,2,4-triazol-4-yl)-benzamide (intermediate 3) (94.8 mg, 0.25 mmol) and (4-trifluoromethyl-phenyl)boronic acid (61.7 mg, 325 mol).

EXAMPLE 11

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

(21) ##STR00084##

(22) The title compound, white solid (110 mg, 94%), MS (ISP) m/z=471.3 [(M+H).sup.+], mp 242.5 C., was prepared in accordance with the general method of example 5 from 3-bromo-5-(3-tert-butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 4) (101 mg, 0.25 mmol) and (4-trifluoromethyl-phenyl)boronic acid (61.7 mg, 325 mol).

EXAMPLE 12

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide

(23) ##STR00085##

(24) The title compound, white foam (90 mg, 86%), MS (ISP) m/z=421.3 [(M+H).sup.+], mp 111 C., was prepared in accordance with the general method of example 5 from 3-bromo-5-(3-tert-butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 4) (101 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 mol).

EXAMPLE 13

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide

(25) ##STR00086##

(26) The title compound, white foam (90 mg, 82%), MS (ISP) m/z=437.3 [(M+H).sup.+], mp 136.5 C., was prepared in accordance with the general method of example 5 from 3-bromo-5-(3-tert-butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 4) (101 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 mol).

EXAMPLE 14

N-tert-Butyl-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(27) ##STR00087##

(28) The title compound, white solid (90 mg, 95%), MS (ISP) m/z=381.2 [(M+H).sup.+], mp 240.5 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 mol).

EXAMPLE 15

N-tert-Butyl-3-(4-chlorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(29) ##STR00088##

(30) The title compound, white solid (99 mg, 100%), MS (ISP) m/z=397.2 [(M+H).sup.+], mp 239.5 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 mol).

EXAMPLE 16

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(31) ##STR00089##

(32) The title compound, off-white foam (100 mg, 98%), MS (ISP) m/z=407.3 [(M+H).sup.+], mp 101 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-cyclopropylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 6) (97.8 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 mol).

EXAMPLE 17

3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(33) ##STR00090##

(34) The title compound, white foam (100 mg, 95%), MS (ISP) m/z=423.3 [(M+H).sup.+], mp 105 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-cyclopropylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 6) (97.8 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 mol).

EXAMPLE 18

N-tert-Butyl-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

(35) ##STR00091##

(36) The title compound, white foam (70 mg, 99%), MS (ISP) m/z=431.3 [(M+H).sup.+], mp 126 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (60.0 mg, 164 mol) and (4-trifluoromethyl-phenyl)boronic acid (40.6 mg, 214 mol).

EXAMPLE 19

N-(2-Cyclopropyl-propan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

(37) ##STR00092##

(38) The title compound, white foam (50 mg, 86%), MS (ISP) m/z=457.3 [(M+H).sup.+], mp 100 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-cyclopropylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 6) (50.0 mg, 128 mol) and (4-trifluoromethyl-phenyl)boronic acid (31.5 mg, 166 mol).

EXAMPLE 20

3-(4-Fluorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(39) ##STR00093##

(40) The title compound, white foam (90 mg, 91%), MS (ISP) m/z=397.3 [(M+H).sup.+], mp 171.5 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 7) (95.3 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 mol).

EXAMPLE 21

3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(41) ##STR00094##

(42) The title compound, off-white foam (80 mg, 78%), MS (ISP) m/z=413.3 [(M+H).sup.+], mp 180 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 7) (95.3 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 mol).

EXAMPLE 22

N-(1-hydroxy-2-methylpropan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

(43) ##STR00095##

(44) The title compound, light yellow foam (100 mg, 90%), MS (ISP) m/z=447.4 [(M+H).sup.+], mp 214 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 7) (95.3 mg, 0.25 mmol) and (4-trifluoromethyl-phenyl)boronic acid (61.7 mg, 325 mol).

EXAMPLE 23

N-(2-Methylbutan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

(45) ##STR00096##

(46) The title compound, light yellow foam (110 mg, 99%), MS (ISP) m/z=445.4 [(M+H).sup.+], mp 104 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 8) (94.8 mg, 0.25 mmol) and (4-trifluoromethyl-phenyl)boronic acid (61.7 mg, 325 mol).

EXAMPLE 24

3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(47) ##STR00097##

(48) The title compound, off-white foam (98 mg, 99%), MS (ISP) m/z=395.3 [(M+H).sup.+], mp 95 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 8) (94.8 mg, 0.25 mmol) and (4-fluorophenyl)boronic acid (45.5 mg, 325 mol).

EXAMPLE 25

3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(49) ##STR00098##

(50) The title compound, light yellow foam (100 mg, 97%), MS (ISP) m/z=411.3 [(M+H).sup.+], mp 103 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 8) (94.8 mg, 0.25 mmol) and (4-chlorophenyl)boronic acid (50.8 mg, 325 mol).

EXAMPLE 26

N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide

(51) ##STR00099##

(52) The title compound, white solid (60 mg, 43%), MS (ISP) m/z=385.3 [(M+H).sup.+], mp 210 C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoic acid (intermediate 9) (120 mg, 0.36 mmol) and 2-methylbutan-2-amine (32.2 mg, 0.44 mmol).

EXAMPLE 27

N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(2-hydroxypropan-2-yl)-1,2,4-triazol-4-yl]-benzamide

(53) ##STR00100##
Step A

(54) A mixture of 3-amino-N-tert-butyl-5-(4-chlorophenyl)-benzamide (intermediate 10) (0.32 g, 1.06 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (714 mg, 799 l, 5.99 mmol) and toluene (3.5 ml) was allowed to stir for 2 h under reflux conditions, evaporated and purified by flash chromatography on silica gel [dichloromethane/dichloromethane:methanol 9:1 (0-50%)] to yield N-tert-butyl-3-(4-chlorophenyl)-5-[(E)-dimethylaminomethylideneamino]-benzamide (0.31 g, 82%) as an off-white foam, MS (ISP) m/z=358.3 [(M+H).sup.+], mp 79.5 C.

(55) Step B

(56) A mixture of N-tert-butyl-3-(4-chlorophenyl)-5-[(E)-dimethylaminomethylideneamino]-benzamide (0.31 g, 866 mol), commercially available 2-hydroxy-2-methylpropanehydrazide (162 mg, 1.3 mmol, Eq: 1.5) and acetic acid (434 l) was irradiated in a microwave oven at 140 C. for 15 min in a sealed tube. The mixture was poured into water (10 ml) and extracted with ethyl acetate (310 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO.sub.4) and evaporated. The crude product (0.4 g) was purified by flash chromatography on silica gel [dichloromethane/dichloromethane:methanol 9:1 (0-50%)] to yield the title compound (50 mg, 14%) as white foam, MS (ISP) m/z=413.3 [(M+H).sup.+], mp 163 C.

EXAMPLE 28

N-tert-Butyl-3-(3,4-difluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(57) ##STR00101##
The title compound, off-white foam (70 mg, 70%), MS (ISP) m/z=399.3 [(M+H).sup.+], mp 115 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 mol) and commercially available (3,4-difluoro-phenyl)boronic acid (51.3 mg, 325 mol).

EXAMPLE 29

N-tert-Butyl-3-(4-methoxyphenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(58) ##STR00102##

(59) The title compound, off-white foam (80 mg, 82%), MS (ISP) m/z=393.3 [(M+H).sup.+], mp 107 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 mol) and commercially available (4-methoxy-phenyl)boronic acid (49.4 mg, 325 mol).

EXAMPLE 30

N-tert-Butyl-3-(4-chloro-3-fluorophenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(60) ##STR00103##

(61) The title compound, white foam (70 mg, 68%), MS (ISP) m/z=415.2 [(M+H).sup.+], mp 135 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 mol) and commercially available (4-chloro-3-fluoro-phenyl)boronic acid (56.7 mg, 325 mol).

EXAMPLE 31

N-tert-Butyl-3-(4-fluoro-3-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(62) ##STR00104##

(63) The title compound, white foam (60 mg, 61%), MS (ISP) m/z=395.3 [(M+H).sup.+], mp 106 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 mol) and commercially available (4-fluoro-3-methyl-phenyl)boronic acid (50.0 mg, 325 mol).

EXAMPLE 32

N-tert-Butyl-3-(3-fluoro-4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(64) ##STR00105##

(65) The title compound, white foam (60 mg, 61%), MS (ISP) m/z=395.4 [(M+H).sup.], mp 109 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 mol) and commercially available (3-fluoro-4-methyl-phenyl)boronic acid (50.0 mg, 325 mol).

EXAMPLE 33

N-tert-Butyl-3-(4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(66) ##STR00106##

(67) The title compound, off-white foam (60 mg, 64%), MS (ISP) m/z=377.4 [(M+H).sup.+], mp 100 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 mol) and commercially available (4-methyl-phenyl)boronic acid (44.2 mg, 325 mol).

EXAMPLE 34

N-tert-Butyl-3-(4-cyano-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(68) ##STR00107##

(69) The title compound, off-white solid (50 mg, 52%), MS (ISP) m/z=388.3 [(M+H).sup.+], mp 290 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 mol) and commercially available (4-cyano-phenyl)boronic acid (47.8 mg, 325 mol).

EXAMPLE 35

N-tert-Butyl-3-(4-cyclopropyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide

(70) ##STR00108##

(71) The title compound, off-white foam (40 mg, 40%), MS (ISP) m/z=403.4 [(M+H).sup.+], mp 120 C., was prepared in accordance with the general method of example 5 from 3-bromo-N-tert-butyl-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide (intermediate 5) (91.3 mg, 250 mol) and commercially available (4-cyclopropyl-phenyl)boronic acid (52.6 mg, 325 mop.

EXAMPLE 36

(RS)-3-(4-Chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide

(72) ##STR00109##

(73) The title compound, white solid (50 mg, 43%), MS (ISP) m/z=461.2 [(M+H).sup.+], mp 161.5 C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoic acid (intermediate 9) (82.4 mg, 0.25 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (55.7 mg, 0.30 mmol).

EXAMPLE 37

3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide

(74) ##STR00110##

(75) The title compound, white foam (70 mg, 56%), MS (ISP) m/z=411.3 [(M+H).sup.+], mp 120 C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzoic acid (intermediate 9) (100 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (49.4 mg, 0.36 mmol).