Bicyclic compounds as ATX inhibitors

Abstract

The invention provides novel compounds having the general formula (I) ##STR00001##
wherein R.sup.1, R.sup.2, Y, W, A, X, m and n are as defined herein, compositions including the compounds and methods of using the compounds.

Claims

1. A compound of formula (I): ##STR00043## wherein: R.sup.1 is: (i) pyridinyl substituted by R.sup.3, R.sup.4 and R.sup.5, or (ii) pyridinyl-C1-6-alkyl substituted by R.sup.3, R.sup.4 and R.sup.5, Y is i) —OC(O)—, or ii) —C(O)—; W is —C(O)—; R.sup.2 is selected from the ring systems O, AO, AW, and AX: ##STR00044## R.sup.3 is C.sub.1-6-alkylcarbonylamino or heterocycloalkyl-C.sub.1-6-alkoxy; R.sup.4 and R.sup.5 are independently selected from the group consisting of i) H, ii) halogen, iii) halo-C.sub.1-6-alkyl, and iv) C.sub.3-8-cycloalkyl; m is 1 or 2; and n is 1; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R.sup.2 is selected from the ring systems O, AO, and AW: ##STR00045## R.sup.3 is selected from the group consisting of i) C.sub.1-6-alkylcarbonylamino, and ii) tetrahydropyranyl-C.sub.1-6-alkoxy; R.sup.4 is selected from the group consisting of i) C.sub.3-8-cycloalkyl, and ii) halo-C.sub.1-6-alkyl; and R.sup.5 is selected from the group consisting of i) H, and ii) halogen.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is ring system AO: ##STR00046##

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is pyridinyl-C.sub.1-6-alkyl substituted by R.sup.3, R.sup.4, and R.sup.5; and Y is —OC(O)—.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from the ring systems O and AO.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is selected from the group consisting of: i) C.sub.3-8-cycloalkyl, and ii) halo-C.sub.1-6-alkyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is selected from the group consisting of i) H, and ii) halogen.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m and n are both 1.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is pyridinyl substituted by R.sup.3, R.sup.4 and R.sup.5; Y is —C(O)—; R.sup.2 is the ring system O; ##STR00047## R.sup.3 is tetrahydropyranyl-C.sub.1-6-alkoxy; R.sup.4 is C.sub.3-8-cycloalkyl; and R.sup.5 is H.

10. The compound of claim 1, wherein the compound is: [2-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone; [2-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carb onyl]-1,3-dihydroisoindol-5-yl]-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone; [2-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carb onyl]-1,3-dihydroisoindol-5-yl]-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl)methanone; 1-[2-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3-dihydroisoindole-5-carbonyl]piperidine-4-sulfonamide; [2-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3-dihydroisoindo1-5-yl]-(3-hydroxy-6,7-dihydro-4H-[1,2]oxazolo[4,5-c]pyridin-5-yl)methanone; [3-(2,2-dimethylpropanoylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl 5-(4-sulfamoylpiperidine-1-carbonyl)-1,3-dihydroisoindole-2-carboxylate; [3-(2,2-dimethylpropanoylamino)-5-(trifluoromethyl)pyridin-2-yl] methyl 5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-1,3-dihydroisoindole-2-carboxylate; or [3-(2,2-dimethylpropanoylamino)-5-(trifluoromethyl)pyridin-2-yl] methyl 5-(3-hydroxy-6,7-dihydro-4H-[1,2]oxazolo[4,5-c]pyridine-5-carbonyl)-1,3-dihydroisoindole-2-carboxylate; or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition, comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

12. A pharmaceutical composition, comprising a compound of claim 10, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

Description

EXAMPLES

(1) All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.

Example 1

[2-[2-Cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3,4-dihydro-1H-isoquinolin-6-yl]-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone

(2) ##STR00026##

(3) To a solution of 1,2,3,4-tetrahydroisoquinolin-6-yl(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone;hydrochloride (intermediate 1; 50 mg, 156 μmol) in N,N-dimethylformamide (4 ml) was added 4-methylmorpholine (94.9 mg, 938 μmol), 2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carboxylic acid (CAS-RN 1810776-23-8; 43.4 mg, 156 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (59.5 mg, 156 μmol) at room temperature, then after 16 h the reaction mixture was partitioned between sat. aq. sodium hydrogen carbonate solution and a mixture of ethyl acetate and 2-methyltetrahydrofuran. The organic layer was washed with ammonium chloride solution and brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:2.5) produced the title compound (71 mg, 84%). White foam, MS: 543.4 (M+H).sup.+.

(4) The following examples were prepared according to example 1, replacing 1,2,3,4-tetrahydroisoquinolin-6-yl(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone;hydrochloride by the appropriate amine and 2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carboxylic acid by the appropriate carboxylic acid.

(5) TABLE-US-00002 Ex. Systematic Name Amine/Carboxylic acid MS, m/e 1.01 [2-cyclopropyl-6-(oxan-4- 5,6-dihydro-4H-pyrrolo[3.4- 518.4 ylmethoxy)pyridin-4-yl]-[2-(1,4,6,7- d][1,3]oxazol-2-yl(1,4,6,7- (M − H).sup.− tetrahydrotriazolo[4,5-c]pyridine-5- telrahydrotriazolo[4,5-c]pyridin-5- carbonyl)-4.6-dihydropyrrolo[3,4- yl)methanone; hydrochloride d][1,3]oxazol-5-yl]methanone (intermediate 1.1)/2-cyclopropyl-6- (oxan-4-ylmethoxy)pyridine-4- carboxylic acid (CAS-RN 1810776-23-8) 1.02 [2-[2-cyclopropyl-6-(oxan-4- 2,3-dihydro-1H-isoindol-5- 529.3 ylmethoxy)pyridine-4-carbonyl]-1,3- yl(1,4,6,7-tetrahydrotriazolo]4,5- (M + H).sup.+ dihydroisoindol-5-yl]-(1,4,6,7- c]pyridin-5- tetrahydrotriazolo[4,5-c]pyridin-5- yl)methanone; hydrochloride yl)methanone (intermediate 1.2)/2-cyclopropyl-6- (oxan-4-ylmethoxy)pyridine-4- carboxylic acid (CAS-RN 1810776-23-8) 1.03 [2-cyclopropyl-6-(oxan-4- 4,5,6,7-tetrahydro- 550.3 ylmethoxy)pyridin-4-yl-[2-(1,4,6,7- [1,3]thiazolo[5,4-c]pyndin-2- (M + H).sup.+ tetrahydrotriazolo[4,5-c]pyridine-5- yl(1,4,6,7-tetrahydrotriazolo[4,5- carbonyl)-6,7-dihydro-4H- c]pyridin-5- [1,3]thiazolo[5,4-c]pyridin-5- yl)methanone: hydrochloride yl]methanone (iniermediate 1.3)/2-cyclopropyl- 6-(oxan-4-ylmethoxy)pyridine-4- carboxylic acid (CAS-RN 1810776-23-8)

Example 2

[2-[2-Cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3-dihydroisoindol-5-yl]-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl)methanone

(6) ##STR00030##

(7) To a mixture of 2-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3-dihydroisoindole-5-carboxylic acid (intermediate 2; 60 mg, 142 μmol) in N,N-dimethylformamide (4 ml) was added 4-methylmorpholine (115 mg, 1.14 mmol), 4,5,6,7-tetrahydro-[1,2]oxazolo[5,4-c]pyridin-3-ol;hydrochloride (CAS-RN 64603-91-4; 32.6 mg 184.6 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (75.6 mg, 198.8 μmol) at room temperature, then after 16 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane/methanol 9:1) produced the title compound (46 mg, 61%). Yellow foam, MS: 545.3 (M+H).sup.+.

(8) The following examples were prepared according to example 2, replacing 2-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3-dihydroisoindole-5-carboxylic acid by the appropriate caboxylic acid and 4,5,6,7-tetrahydro-[1,2]oxazolo[5,4-c]pyridin-3-ol;hydrochloride by the appropriate amine.

(9) TABLE-US-00003 Ex. Systematic Name Carboxylic acid/Amine MS, m/e 2.01 1-[2-[2-cyclopropyl-6-(oxan-4- 2-[2-cyclopropyl-6-(oxan-4- 569.3 ylmethoxy)pyridine-4-carbonyl]-1,3- ylmethoxy)pyridine-4-carbonyl]-1,3- (M + H).sup.+ dihydroisoindole-5-carbonyl]piperidine- dihydroisoindole-5-carboxylic acid 4-sulfonamide (intermediate 2)/piperidine-4- sulfonamide; hydrochloride 2.02 [2-[2-cyclopropyl-6-(oxan-4- 2-[2-cyclopropyl-6-(oxan-4- 545.2 ylmethoxy)pyridine-4-carbonyl]-1,3- ylmethoxy)pyridine-4-carbonyl]-1,3- (M + H).sup.+ dihydroisoindol-5-yl]-(3-hydroxy-6,7- dihydroisoindole-5-carboxylic acid dihydro-4H-[1,2]oxazolo[4,5-c]pyridin- (intermediate 2)/4,5,6,7-tetrahydro- 5-yl)methanone [1,2]oxazolo[4,5-c]pyridin-3-ol (CAS-RN 53602-00-9) 2.03 [3-(2,2-dimethylpropanoylamino)-5- 2-[[3-(2,2- 612.3 (trifluoromethyl)pyndin-2-yl]methyl dimethylpropanoylamino)-5- (M + H).sup.+ 5-(4-sulfamoylpiperidine-1-carbonyl)- (trifluoromethyl)pyridin-2- 1,3-dihydroisoindole-2-carboxylate yl]methoxycarbonyl]-1,3- dihydroisoindole-5-carboxylic acid (intermediate 3)/piperidine-4- sulfonamide; hydrochloride 2.04 [3-(2,2-dimethylpropanoylamino)-5- 2-[[3-(2,2- 588.2 (trifluoromethyl)pyridin-2-yl]methyl 5- dimethylpropanoylamino)-5- (M + H).sup.+ (3-hydroxy-5,7-dihydro-4H- (trifluoromethyl)pyridin-2- [1,2]oxazolo[5,4-c]pyridine-6- yl]methoxycarbonyl]-1,3- carbonyl)-1,3-dihydroisoindole-2- dihydroisoindole-5-carboxylic acid carboxylate (intermediate 3)/4,5,6,7-tetrahydro- [1,2]oxazolo[5,4-c]pyridin-3- ol; hydrochloride (CAS-RN 64603-91-4) 2.05 [3-(2,2-dimethylpropanoylamino)-5- 2-[[3-(2,2- 588.2 (trifluoromethyl)pyridin-2-yl]methyl 5- dimethylpropanoylamino)-5- (M + H).sup.+ (3-hydroxy-6,7-dihydro-4H- (trifluoromelhyl)pyridin-2- [1,2]oxazolo[5,4-c]pyridine-5- yl]methoxycarbonyl]-1,3- carbonyl)-1,3-dihydroisoindole-2- dihydroisoindole-5-carboxylic acid carboxylate (intermediate 3)/4,5,6,7-tetrahydro- [1,2]oxazolo[4,5-c]pyridin-3-ol (CAS-RN 53602-00-9) 2.06 [3-(2,2-dimethylpropanoylamino)-5- 5-[[3-(2,2- 603.3 (trifluoromethyl)pyridin-2-yl]methyl dimethylpropanoylamino)-5- (M + H).sup.+ 2-(4-sulfamoylpiperidine-1-carbonyl)- (trifluoromethyl)pyridin-2- 4,6-dihydropyrrolo[3,4- yl]methoxycarbonyl]-4,6- d][1,3]oxazole-5-carboxylate dihydropyrrolo[3,4-d][1,3]oxazole- 2-carboxylic acid (intermediate 3.1)/piperidine-4- sulfonamide; hydrochloride

Example 3

[2-Cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]-[2-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-4,6-dihydropyrrolo[3,4-d][1,3]oxazol-5-yl]methanone

(10) ##STR00037##

(11) To a mixture of 5,6-dihydro-4H-pyrrolo[3,4-d][1,3]oxazol-2-yl-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl)methanone;hydrochloride (intermediate 4; 60 mg, 173 μmol) in N,N-dimethylformamide (4 ml) was added 4-methylmorpholine (140 mg, 1.38 mmol), 2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carboxylic acid (CAS-RN 1810776-23-8; 47.9 mg 173 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (65.7 mg, 173 μmol) at room temperature, then after 16 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane/methanol 9:1) produced the title compound (40 mg, 43%). Light yellow foam, MS: 536.3 (M+H).sup.+.

(12) The following examples were prepared according to example 3, replacing 5,6-dihydro-4H-pyrrolo[3,4-d][1,3]oxazol-2-yl-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl)methanone;hydrochloride by the appropriate amine and 2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carboxylic acid by the appropriate carboxylic acid.

(13) TABLE-US-00004 Ex. Systematic Name Amine/Carboxylic acid MS, m/e 3.01 1-[5-[2-cyclopropyl-6-(oxan-4- 1-(5,6-dihydro-4H-pyrrolo[3,4- 576.2 ylmethoxy)pyridine-4-carbonyl]-4,6- d][1,3]thiazole-2- (M + H).sup.+ dihydropyrrolo[3,4-d][1,3]thiazole-2- carbonyl)piperidine-4- carbonyl]piperidine-4-sulfonamide sulfonamide; hydrochloride (intermediate 1.4)/2- cyclopropyl-6-(oxan-4- ylmethoxy)pyridine-4-carboxylic acid (CAS-RN 1810776-23-8) 3.02 1-[5-[2-cyclopropyl-6-(oxan-4- 1-(5,6-dihydro-4H-thieno[2,3- 575.3 ylmethoxy)pyridine-4-carbonyl]-4,6- c]pyrrole-2-carbonyl)piperidine- (M + H).sup.+ dihydrothieno[2,3-c]pyrrole-2- 4-sulfonamide; hydrochloride carbonyl]piperidine-4-sulfonamide (intermediate 1.5)/2- cyclopropyl-6-(oxan-4- ylmethoxy)pyridine-4-carboxylic acid (CAS-RN 1810776-23-8)

Example 4

[3-(2,2-Dimethylpropanoylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,6-dihydropyrrolo[3,4-d][1,3]oxazole-5-carboxylate

(14) ##STR00040##

(15) To a solution of N-[2-(hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl]-2,2-dimethylpropanamide (intermediate 5; 92.2 mg 334 μmol) in acetonitrile (10 mL) was added 1,1′-carbonyldiimidazole (54.1 mg 334 μmol). The reaction mixture was heated to 50° C. for 3 hours. Triethylamine (153 mg 1.52 mmol) and 5,6-dihydro-4H-pyrrolo[3,4-d][1,3]oxazol-2-yl(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone;hydrochloride (intermediate 4.1; 90 mg 334 μmol) were added and the reaction mixture was heated to reflux. Then after 15 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/heptane 7:3) produced the title compound (121 mg, 71%). Light yellow foam, MS: 561.4 (M−H).sup.−.

(16) The following example was prepared according to example 4, replacing N-[2-(hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl]-2,2-dimethylpropanamide (intermediate 5) by the appropriate alcohol and 5,6-dihydro-4H-pyrrolo[3,4-d][1,3]oxazol-2-yl(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone;hydrochloride (intermediate 4.1) by the appropriate amine.

(17) TABLE-US-00005 Ex. Systematic Name Alcohol/Amine MS, m/e 4.01 [5-chloro-4-cyano-2-(2,2- N-[4-chloro-5-cyano-2- 569.2 dimethylpropanoylamino)phenyl]methyl 2- (hydroxymethyl)phenyl]-2,2- (M + H).sup.+ (3-hydroxy-5,7-dihydro-4H- dimethylpropanamide [1,2]oxazolo[5,4-c]pyridine-6-carbonyl)- (intermediate 6)/5,6-dihydro-4H- 4,6-dihydropyrrolo[3,4-d][1,3]oxazole-5- pyrrolo[3.4-d][1,3]oxazol-2-yl-(3- carboxylate hydroxy-5,7-dihydro-4H- [1,2]oxazolo[5,4-c]pyridin-6- yl)methanone; hydrochloride (intermediate 4)

Example 4.02

[3-(2,2-Dimethylpropanoylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl 2-(4-sulfamoylpiperidine-1-carbonyl)-4,6-dihydrothieno[2,3-c]pyrrole-5-carboxylate and 2,2-dimethyl-N-[2-[[2-(4-sulfamoylpiperidine-1-carbonyl)-4,6-dihydrothieno[2,3-c]pyrrol-5-yl]methyl]-5-(trifluoromethyl)pyridin-3-yl]propanamide

(18) ##STR00042##

(19) To a solution of N-[2-(hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl]-2,2-dimethylpropanamide (intermediate 5; 60.5 mg 219 μmol) in acetonitrile (8 ml) was added 1,1′-carbonyldiimidazole (35.5 mg, 219 μmol). The reaction mixture was heated to 50° C. for 3 hours. Triethylamine (121 mg, 1.19 mmol) and 1-(5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carbonyl)piperidine-4-sulfonamide;hydrochloride (intermediate 1.5; 70 mg 199 μmol) were added and the reaction mixture was heated to reflux. Then after 15 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (Gemini NX 3u 50×4.6 mm) produced the title compound (47 mg, 38%). White foam, MS: 618.3 (M+H).sup.+.

Intermediate 1

1,2,3,4-Tetrahydroisoquinolin-6-yl(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone;hydrochloride

Step 1: tert-Butyl 6-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

(20) To a solution of 2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (CAS-RN 170097-67-3; 300 mg, 1.08 mmol) in N,N-dimethylformamide (5 ml) was added 4-methylmorpholine (547 mg, 5.41 mmol), 4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (CAS-RN 706757-05-3; 141 mg, 1.08 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (411 mg, 1.08 mmol) at room temperature, then after 18 h the reaction mixture was partitioned between sat. aq. sodium hydrogen carbonate solution and a mixture of ethyl acetate and 2-methyltetrahydrofuran. The organic layer was washed with ammonium chloride solution and brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:2.5) produced the title compound (278 mg, 67%). White foam, MS: 384.3 (M+H).sup.+.

Step 2: 1,2,3,4-Tetrahydroisoquinolin-6-yl(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone;hydrochloride

(21) To a solution of tert-butyl 6-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (263 mg, 686 μmol) in 2-propanol (3 ml) was added hydrogen chloride solution (5-6 M in 2-propanol, 3.84 ml). The reaction mixture was stirred at room temperature for 2 h. The solvent was totally evaporated to produce the title compound (219 mg, 100%). White solid, LC/MS: 284.1 (M+H).sup.+.

(22) The following intermediates were prepared according to intermediate 1, replacing 2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1H-isoquinoline-6-carboxylic acid by the appropriate carboxylic acid and 4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine by the appropriate amine

(23) TABLE-US-00006 No. Systematic Name Carboxylic acid/Amine MS, m/e 1.1 5,6-dihydro-4H- 5-[(2-methylpropan-2- 261.1 pyrrolo[3,4-d][1,3]oxazol- yl)oxycarbonyl]-4,6- (M + H).sup.+ 2-yl(1,4,6,7- dihydropyrrolo[3,4- tetrahydrotriazolo[4,5- d][1,3]oxazole-2-carboxylic c]pyridin-5-yl)methanone; acid (CAS-RN 1211529-82- hydrochloride 6)/4,5,6,7-tetrahydro-1H- [1,2,3]triazolo[4,5-c]pyridine (CAS-RN 706757-05-3) 1.2 2,3-dihydro-1H-isoindol-5- 2-[(2-methylpropan-2- 270.2 yl(1,4,6,7- yl)oxycarbonyl]-1,3- (M + H).sup.+ tetrahydrotriazolo[4,5- dihydroisoindole-5-carboxylic c]pyridin-5-yl)methanone; acid (CAS-RN 149353-71- hydrochloride 9)/4,5,6,7-tetrahydro-1H- [1,2,3]triazolo[4,5-c]pyridine (CAS-RN 706757-05-3) 1.3 4,5,6,7-tetrahydro- 5-[(2-methylpropan-2- 291.1 [1,3]thiazolo[5,4-c]pyridin- yl)oxycarbonyl]-6,7-dihydro- (M + H).sup.+ 2-yl(1,4,6,7- 4H-[1,3]thiazolo[5,4- tetrahydrotriazolo[4,5- c]pyridine-2-carboxylic acid c]pyridin-5-yl)methanone; (CAS-RN 165948-21- hydrochloride 0)/4,5,6,7-tetrahydro-1H- [1,2,3]triazolo[4,5-c]pyridine (CAS-RN 706757-05-3) 1.4 1-(5,6-dihydro-4H- 5-[(2-methylpropan-2- 317.1 pyrrolo[3,4-d][1,3]thiazole- yl)oxycarbonyl]-4,6- (M + H).sup.+ 2-carbonyl)piperidine-4- dihydropyrrolo[3,4- sulfonamide; hydrochloride d][1,3]thiazole-2-carboxylic acid (CAS-RN 774533-81- 2)/piperidine-4-sulfonamide hydrochloride 1.5 1-(5,6-dihydro-4H- 5-[(2-methylpropan-2- 316.1 thieno[2,3-c]pyrrole-2- yl)oxycarbonyl]-4,6- (M + H).sup.+ carbonyl)piperidine-4- dihydrothieno[2,3-c]pyrrole-2- sulfonamide; hydrochloride carboxylic acid (CAS-RN 1369351-45-0)/piperidine-4- sulfonamide hydrochloride

Intermediate 2

2-[2-Cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3-dihydroisoindole-5-carboxylic acid

Step 1: Methyl 2-[2-cycloproyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3-dihydroisoindole-5-carboxylate

(24) To a solution of methyl 2,3-dihydro-H-isoindole-5-carboxylate;hydrochloride (CAS-RN 127168-93-8; 400 mg, 1.78 mmol) in N,N-dimethylformamide (6 ml) was added 4-methylmorpholine (1.08 g, 10.7 mmol), 2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carboxylic acid (CAS-RN 1810776-23-8; 493 mg, 1.78 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (676 mg, 1.78 mmol) at room temperature, then after 18 h the reaction mixture was partitioned between sat. aq. sodium hydrogen carbonate solution and a mixture of ethyl acetate and 2-methyltetrahydrofuran. The organic layer was washed with ammonium chloride solution and brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:2.5) produced the title compound (770 mg, 89%). Yellow oil, MS: 437.2 (M+H).sup.+.

Step 2: 2-[2-Cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3-dihydroisoindole-5-carboxylic acid

(25) To a solution of methyl 2-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3-dihydroisoindole-5-carboxylate (742 mg, 1.7 mmol) in tetrahydrofuran and methanol was added Lithium hydroxide solution (2 M in water, 5.1 ml, 10.2 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between water and diethyl ether. The aqueous layer was acidified with hydrogen chloride solution (1 M in water) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to produce the title compound (663 mg, 92%). Off white foam, MS: 423.2 (M+H).sup.+.

Intermediate 3

2-[[3-(2,2-Dimethylpropanoylamino)-5-(trifluoromethyl)pyridin-2-yl]methoxycarbonyl]-1,3-dihydroisoindole-5-carboxylic acid

Step 1: 2-O-[[3-(2,2-Dimethylpropanoylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl] 5-O-methyl 1,3-dihydroisoindole-2,5-dicarboxylate

(26) To a solution of methyl 2,3-dihydro-1H-isoindole-5-carboxylate;hydrochloride (CAS-RN 127168-93-8; 200 mg, 889 μmol) and triethylamine (180 mg, 1.78 mmol) in dichloromethane (4 ml) was added 1,1′-carbonyldiimidazole. After 1 h at room temperature the reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with citric acid solution (0.25 M in water), water and brine, dried over magnesium sulfate, filtered and evaporated. The solid was suspended in tetrahydrofuran (4 ml) and a solution of N-[2-(hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl]-2,2-dimethylpropanamide (intermediate 5, 246 mg, 889 μmol) in tetrahydrofuran (4 ml) and potassium tert-butoxide solution (2 M in 2-methyltetrahydrofuran; 889 μmol) were added. Then after 30 min. the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:2.5) produced the title compound (364 mg, 85%). Light yellow foam, MS: 480.2 (M+H).sup.+.

Step 2: 2-[[3-(2,2-Dimethylpropanoylamino)-5-(trifluoromethyl)pyridin-2-yl]methoxycarbonyl]-1,3-dihydroisoindole-5-carboxylic acid

(27) The title compound was produced in analogy to intermediate 2, step 2, replacing 2-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3-dihydroisoindole-5-carboxylate by 2-O-[[3-(2,2-dimethylpropanoylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl] 5-O-methyl 1,3-dihydroisoindole-2,5-dicarboxylate. Light yellow foam, MS: 464.3 (M+H).sup.+.

Intermediate 3.1

5-[[3-(2,2-Dimethylpropanoylamino)-5-(trifluoromethyl)pyridin-2-yl]methoxycarbonyl]-4,6-dihydropyrrolo[3,4-d][1,3]oxazole-2-carboxylic acid

(28) The title compound was produced in analogy to intermediate 3, replacing 2,3-dihydro-1H-isoindole-5-carboxylate;hydrochloride by ethyl 5,6-dihydro-4H-pyrrolo[3,4-d][1,3]oxazole-2-carboxylate;hydrochloride. Light yellow foam. MS: 457.1 (M+H).sup.+.

Intermediate 4

5,6-Dihydro-4H-pyrrolo[3,4-d][1,3]oxazol-2-yl-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl)methanone;hydrochloride

Step 1: tert-Butyl 2-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-4,6-dihydropyrrolo[3,4-d][1,3]oxazole-5-carboxylate

(29) To a suspension of 5-[(2-methylpropan-2-yl)oxycarbonyl]-4,6-dihydropyrrolo[3,4-d][1,3]oxazole-2-carboxylic acid (CAS-RN 1211529-86-6; 308 mg, 1.21 mmol) in dichloromethane (5 ml) was added oxalyl chloride (235 mg, 1.82 mmol) and a catalytic amount of N,N-dimethylformamide at 0° C. After 1h at room temperature the mixture was diluted with dichloromethane (5 ml) and added to a mixture of 4,5,6,7-tetrahydro-[1,2]oxazolo[5,4-c]pyridin-3-ol;hydrochloride (CAS-RN 64603-91-4; 214 mg, 1.21 mmol) and N,N-diisopropylethylamine (1.57 g, 12.1 mmol) in N,N-dimethylformamide at 0° C. Then after 15 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane/methanol 9:1) produced the title compound (239 mg, 52%). Light yellow foam, MS: 377.1 (M+H).sup.+.

Step 2: 5,6-Dihydro-4H-pyrrolo[3,4-d][1,3]oxazol-2-yl-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl)methanone;hydrochloride

(30) The title compound was produced in analogy to intermediate 1, step 2, replacing tert-butyl 6-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate by tert-butyl 2-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-4,6-dihydropyrrolo[3,4-d][1,3]oxazole-5-carboxylate. Light brown foam, MS: 277.1 (M+H).sup.+.

Intermediate 4.1

5,6-Dihydro-4H-pyrrolo[3,4-d][1,3]oxazol-2-yl(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone;hydrochloride

(31) The title compound was produced in analogy to intermediate 4, replacing 4,5,6,7-tetrahydro-[1,2]oxazolo[5,4-c]pyridin-3-ol;hydrochloride (CAS-RN 64603-91-4) by 4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine. Light yellow foam, MS: 361.2.

Intermediate 5

N-[2-(Hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl]-2,2-dimethylpropanamide

Step 1: Methyl 3-pivalamide-5-(trifluoromethyl)picolinate

(32) To a brown solution of methyl 3-amino-5-(trifluoromethyl)picolinate (CAS-RN 866775-17-9; 2.00 g, 8.63 mmol) in pyridine (25 mL) was added pivaloyl chloride (2.08 g, 17.3 mmol) at 0° C. After 20 min the ice-bath was removed, then after 5 h the reaction mixture was partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; heptante-ethyl acetate gradient) afforded the title compound (2.46 g, 92%). Light yellow solid, MS: 305.1 (M+H).sup.+.

Step 2: N-(2-(Hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl)pivalamide

(33) To a clear light yellow solution of methyl 3-pivalamido-5-(trifluoromethyl)picolinate (2.45 g, 8.05 mmol) in tetrahydrofuran (60 mL) was added a solution of calcium chloride (1.79 g, 16.1 mmol) in ethanol (60 mL), then sodium borohydride (914 mg, 24.2 mmol) was added in 3 portions over a period of 30 min. The white suspension was stirred for 90 min at room temperature, then partitioned between water and sat. aq. ammonium chloride solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane-ethyl acetate gradient) afforded the title compound (1.97 g; 89%). Light yellow viscous oil, MS: 277.1 (M+H).sup.+.

Intermediate 6

N-[4-Chloro-5-cyano-2-(hydroxymethyl)phenyl]-2,2-dimethylpropanamide

Step 1: Methyl 4-bromo-5-chloro-2-pivalamidobenzoate

(34) The title compound was produced in analogy to intermediate 5, step 1 from methyl 2-amino-4-bromo-5-chlorobenzoate (CAS-RN 1445322-56-4). White solid. MS: 350.0 (M+H).sup.+.

Step 2: Methyl 5-chloro-4-cyano-2-pivalamidobenzoate

(35) A mixture of methyl 4-bromo-5-chloro-2-pivalamidobenzoate (3.14 g, 9.01 mmol), tris(dibenzylideneacetone)dipalladium(0) (82.5 mg, 90.1 μmol), 1,1′-bis(diphenylphosphino)ferrocene (150 mg, 270 μmol), and zinc cyanide (582 mg, 4.95 mmol), zinc powder (23.6 mg, 360 μmol) and zinc acetate (66.1 mg, 360 μmol) in N,N-dimethylformamide (48 mL) and water (1.5 mL) was heated for 20 min at 130° C. under microwave irradiation. After removal of insoluble material under vacuum and concentration of the filtrate, the residue was partitioned between 50% aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed water and brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; heptane-dichloromethane gradient) produced the title compound (2.00 g, 75%). Light yellow solid. MS: 295.1 (M+H).sup.+.

Step 3: N-(4-Chloro-5-cyano-2-(hydroxymethyl)phenyl)pivalamide

(36) The title compound was produced in analogy to intermediate 5, step 2 from methyl 5-chloro-4-cyano-2-pivalamidobenzoate. Light yellow solid. MS: 267.1 (M+H).sup.+.

Example A

(37) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

(38) TABLE-US-00007 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

(39) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

(40) TABLE-US-00008 Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg