Substituted piperidines as CCR3 antagonists

3-Bromo-N-methyl-5-nitro-benzamide

To a solution of 3-bromo-5-nitro-benzoic acid (2.1 g) in DCM (50 ml) was added oxalylchloride (1.5 ml). 1 drop of DMF was added and the reaction stirred at room temperature for 2 h. The reaction was concentrated in vacuum. This was dissolved in THF and added dropwise to a pre-cooled 2M solution of methylamine in THF (22 ml) at 0° C. This was allowed to warm to room temperature and further stirred overnight. The reaction mixture was filtered and the filtrate concentrated in vacuum. The residue was dissolved in EtOAc and washed with water. The organic layer was separated, dried and concentrated in vacuum to leave the product (2.1 g). Rt 1.37 min (method D).

5-(3-Bromo-5-nitro-phenyl)-1-methyl-1H-tetrazole

To a solution of 3-bromo-N-methyl-5-nitro-benzamide (0.6 g) in DCM (15 ml) at −15° C. was added triflic anhydride (0.6 ml) and the reaction stirred for 30 min. Sodium azide (226 mg) was added and the reaction allowed to warm to room temperature and stirred further overnight. NaHCO₃(aq) was added to neutralise the reaction and the mixture extracted into EtOAc. The organic layer was separated, dried and concentrated in vacuum and the residue purified by flash chromatography (9:1 to 2:8 cyclohexane:EtOAc) to give the title compound (290 mg). R_f=0.51 (3:2 cyclohexane:EtOAc).

3-Bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine

A solution of 5-(3-Bromo-5-nitro-phenyl)-1-methyl-1H-tetrazole (2.1 g) in EtOAc (100 ml) was hydrogenated on a H-cube® apparatus at 20° C., room pressure with a flow rate of 1 ml/min using a Raney-Ni cartridge. After reaction completion, the mixture was concentrated in vacuum and triturated with MeOH. The solid was filtered and further triturated and air-dried to give the title compound (290 mg). Rt 1.25 min (method D).

Step 4

1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylic acid [3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide

To a solution of 1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylic acid as DIPEA salt (2.6 g) in DMF (100 ml) was added DIPEA (2.1 g), and HATU (4 g). 3-Bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine (1.4 g) was added and the reaction stirred overnight at rt. The reaction mixture was filtered and the filtrate partitioned between water and EtOAc. The organic layer was separated, dried and concentrated in vacuum and the residue purified by flash chromatography (DCM:MeOH 100:0 to 95:5 gradient) to give the title compound (400 mg). R_f=0.19 (95:5 DCM:MeOH).

Step 5

3-({1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carbonyl}-amino)-5-(1-methyl-1H-tetrazol-5-yl)-benzoic acid methyl ester

To a solution of 1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylic acid [3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide (400 mg) in MeOH (20 ml) was added triethylamine (140 μl), DMF (5 ml), and [1,1′-bis(diphenylphosphino)-ferrocen]palladium (II) chloride (50 mg) and the reaction stirred for 2 d at 80° C. under a 3 bar CO atmosphere. The reaction mixture was filtered and the filtrate concentrated in vacuum. The residue was partitioned between water and EtOAc and the organic layer was then separated, dried and concentrated in vacuum. The residue was purified by flash chromatography (DCM: MeOH 100:0 to 95:5 gradient) to give the title compound (400 mg). R_f=0.37 (95:5 DCM:MeOH).

Step 6

3-({1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carbonyl}-amino)-5-(1-methyl-1H-tetrazol-5-yl)-benzoic acid

To a solution of 3-({1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carbonyl}-amino)-5-(1-methyl-1H-tetrazol-5-yl)-benzoic acid methyl ester (270 mg) in MeOH (10 ml) at room temperature was added 4M NaOH (aq) (10 ml) and the reaction stirred overnight. The organic and aqueous layers were separated and the organic layer concentrated in vacuum. The residue was triturated in toluene and diethyl ether successively leaving the title compound (220 mg). R_t=0.96 min (method E).

Synthesis of Building Block B17

##STR00097##

To a stirred solution of 1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylic acid (500 mg) in DMF (5 ml) at room temperature was added DIPEA (1.1 ml) followed by HATU (1.1 g). After 45 min, intermediate I13 (0.34 g) was added and the reaction stirred overnight at rt. Saturated brine solution was added followed by EtOAc. The organic layer was separated, dried and concentrated in vacuum and the residue purified by HPLC to give the product (557 mg). (R_t1 50 min, method D)

Synthesis of I13 for Building Block B17

To a stirred solution of the product of step 1 (557 mg) in dioxane (5 ml) was added lithium hydroxide (195 mg) dissolved in a sufficient amount of water. After overnight stirring, the reaction was acidified with HCl(aq) (4M), then concentrated in vacuum. The residue was purified by HPLC to afford building block B17 (155 mg). (R_t1.34 min, method D).

##STR00098##

Ethyl 2-bromo-4-methyl-3-oxopentanoate

To a suspension of sodium acetate (1.9 g) in glacial acetic acid (15 ml) was added 4-methyl-3-oxo-pentanoic acid ethyl ester (2 g) and the reaction mixture cooled to 10° C. Bromine (0.7 ml) was then added dropwise. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction was complete (by TLC) and was concentrated in vacuum affording 3.8 g crude ethyl product which was used directly in the next synthetic step.

Ethyl 2-amino-4-isopropylthiazole-5-carboxylate (I13)

A solution of thiourea (1.1 g) in ethanol (10 mL) was brought to reflux. Ethyl 2-bromo-4-methyl-3-oxopentanoate (3.0 g) was then added and the reaction mixture refluxed further for 1 h. The reaction was complete (by TLC) and was concentrated in vacuum. Flash chromatography (100% DCM→90:10 DCM:MeOH) afforded the product (1.1 g).

Synthesis of Building Block B18

##STR00099##

Intermediate I14 was synthesized according to procedure D with subsequent saponification.

Synthesis of Intermediate I16

##STR00100##

2-chloro-6-methylnicotinic acid (9 g), of aq ammonia (44 ml), of Cu(II)SO₄(0.9 g) and of sodium sulphide (0.32 g) were added to an autoclave and heated to 155° C. overnight. The crude product was suspended in water to yield product 115 (3.6 g). The filtrate was concentrated and again suspended in water to yield a further 1.9 g of product 115. HPLC: R_t=0.37 min (method D)

Synthesis of Building Block B20

To 50 ml of MeOH was added dropwise acetylchloride (3 ml) at rt. After 15 min, intermediate I15 (2.3 g) was added and the mixture was stirred overnight at 50° C. After concentrating the solution, the resulting residue was suspended in acetone and then filtered and dried at 50° C. in vacuum, to yield product 116 (4.1 g).

HPLC: R_t=0.91 min (method D)

Synthesis of Building Block B19

##STR00101##

B19 was synthesized in analogy to B17. Synthesis of I13a for building block B19 was analogous to that for I13.

##STR00102##

##STR00103##

B20 was synthesized in analogy to B17. Synthesis of I13b for building block B20 was analogous to that for I13.

##STR00104##

S.2.3. Synthesis of Building Blocks with Formula C

Synthesis of Building Block C1

##STR00105##

Building block A1, as its N,N-diisopropylethylamine salt (500 mg), was suspended in dry DMF (7 ml) under inert atmosphere and TBTU (836 mg) was added, followed by N,N-diisopropylethylamine (0.53 ml). After stirring for 1 h at room temperature, hexamethyldisilazane (0.44 ml) was added and the mixture was stirred for 6 h. Further portions of TBTU (334 mg) and hexamethyldisilazane (0.22 ml) were added and the reaction was stirred for further 18 h. The solvent was evaporated under reduced pressure and residue partitioned between saturated aqueous solution of NaHCO₃and EtOAc. The layers were separated and the aqueous phase extracted with EtOAc. The combined organic extracts were washed with brine, dried under Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (20 g Isolute® silica gel cartridge; eluent: DCM/MeOH/NH₄OH 95/5/0.5) affording the title compound. (295 mg). HPLC (R_t)=1.24 min (method M)

S.2.4. Synthesis of Building Blocks with Formula D

Synthesis of Building Block D1

##STR00106##

Intermediate I17 was prepared starting from (R)-2-amino-3-tert-butoxycarbonylamino-propionic acid methyl ester hydrochloride (10.00 g) and 4-oxo-piperidine-1-carboxylic acid phenyl ester (12.07 g), following the procedures described for the synthesis of I9. Product obtained 19.50 g (content 70%). HPLC (R_t)=3.20 min (method Q)

##STR00107##

Intermediate I18 was prepared starting from I17 (19.5 g, content 70%) and following the procedures described for the synthesis of I10. Product obtained 12.50 g (content 75%).

HPLC (R_t)=1.96 min (method H)

##STR00108##

Intermediate I19 was prepared starting from I18 12.50 g (content 75%) and following the procedures described for the synthesis of I11. Product obtained=2.90 g. HPLC (R_t)=2.79 min (method H)

##STR00109##

Intermediate I20 was prepared starting from I19 (2.70 g) and following the procedures described for the synthesis of I12. Product obtained=2.45 g (content 85%) used in the next step without any further purification. HPLC (Rt)=3.00 min (method H)

##STR00110##

To an ice-chilled solution of intermediate I20 (2.40 g, content 85%) in THF (60 ml) and water (10 ml) was added lithium hydroxide monohydrate (0.68 g, 16.30 mmol). The temperature was allowed to warm to 25° C. and the resulting solution stirred until complete disappearance of the starting material (3 h). The organic solvent was evaporated under reduced pressure, the aqueous residue diluted with water 10 ml), acidified to pH 2.5 with 4N HCl. EtOAc (50 ml) was added, the phases separated, the organic layer washed with brine (20 ml), dried over Na₂SO₄and evaporated to dryness. The residue was triturated with a 1/1 n-hexane/Et₂O mixture, the solid dried at 40° C. under vacuum to afford I21 (1.90 g). HPLC (R_t)=2.65 min (method H)

##STR00111##

Intermediate I21 (1.80 g) was dissolved in dry DMF (15 ml), and the resulting solution stirred in a nitrogen atmosphere. HATU (2.46 g) and DIPEA (3.22 ml) were added sequentially and the whole stirred at room temperature for 30 min. 3-cyclopropyl-1-methyl-1H-pyrazole-5-amine (1.02 g) was then added in one portion and the reaction mixture heated at 40° C. overnight. Extra HATU (2.27 g) and 3-cyclopropyl-1-methyl-1H-pyrazole-5-amine (0.68 g) were then added, and the heating maintained for 8 h. The reaction mixture was concentrated under reduced pressure, the resulting residue diluted with water (40 ml) and EtOAc (50 ml). The layers were separated and the organic phase washed with 1M HCl (3×20 ml), 10% aq. Na₂CO₃(2×20 ml), water (1×20 ml) and brine (1×25 ml), dried over Na₂SO₄and evaporated to dryness, affording a solid. The residue was triturated with diisopropyl ether, affording product I22 (1.70 g). HPLC (R_t)=2.85 min (method H)

##STR00112##

A suspension of 10% Pd/C (211 mg) in 80% aq. ethanol (5 ml) was added to a stirred solution of intermediate I22 (1.7 g, content 90%) in EtOH (30 ml). The whole was then stirred under a positive pressure of hydrogen. After 4 h extra catalyst (100 mg) was added and the conditions maintained overnight. The reaction mixture was then filtered over Celite®, the cake carefully washed with EtOH (3×10 ml) and the filtrate evaporated to dryness under reduced pressure. The residue was dissolved in an 8/2 EtOAc/MeOH mixture (30 ml) and treated with HCl (6 ml of a 4N solution in 1,4 dioxane) to form the corresponding hydrochloride salt. The solvent was evaporated to dryness and the residue triturated with MTBE, the solid filtrated and dried at 40° C. under vacuum to afford the building block D1 (1.20 g). HPLC (R_t)=1.60 min (method H)

Synthesis of Building Block D2

##STR00113##

Example 35 (1.0 g) was dissolved in MeOH (20 ml), and Pd/C was added and the mixture was hydrogenated at 50° C. and 50 psi for 12 h. After this period, further Pd/C was added and the mixture was again hydrogenated at 50° C. and 50 psi for 7 h. The solution was then filtered and concentrated in vacuum to give 0.62 g of building block D2 which was used without further purification. HPLC: 0.98 min (method D)

Synthesis of Building Block D3

##STR00114##

Building block D3 was prepared in analogy to building block D2 starting from example 135.

S.2.5 Synthesis of Intermediate I12.2 (Building Block for Procedure E)

see synthesis of building block A6, step 4.

S.2.6. Synthesis of Building Blocks with Formula F

Synthesis of Building Block F1

##STR00115##

2-Chloro-6-methyl-isonicotinamide (1.23 g) and N,N-dimethylformamide dimethyl acetal (1.05 ml) were dissolved in dry DMF (4 ml) under inert atmosphere and the resulting solution was heated to 90° C. and stirred for 1 h. The reaction mixture was cooled to room temperature and a solution of hydrazine acetate (3.32 g) in acetic acid (8 ml) was dropwise added. The mixture was heated to 90° C. and stirred for 1 h. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous solution of NaHCO₃and EtOAc. The organic phase was separated, washed with brine, dried under Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash column chromatography (10 g Isolute® silica gel cartridge; gradient elution: hexane/EtOAc from 1/1 to 3/7) affording 2-Chloro-6-methyl-4-(1H-[1,2,4]triazol-3-yl)-pyridine (0.92 g). GC (R_t)=13.21 min (method=3A)

2-Chloro-6-methyl-4-(1H-[1,2,4]triazol-3-yl)-pyridine (120 mg) and 3,4-dihydro-2H-pyran (84 μL) were suspended in dry DCM (3.5 mL) under inert atmosphere and pyridinium p-toluenesulfonate (15.5 mg) was added. The reaction mixture was stirred at room temperature for 18 h. The solution was diluted with DCM, washed with water and brine, dried under Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash column chromatography (10 g Isolute® silica gel cartridge; eluent: hexane/EtOAc 3/7) affording product (155 mg). HPLC (R_t)=1.51 min (method M)

Syntheses of Building Blocks F2 and F3

2-Chloro-6-methyl-4-[1-(tetrahydro-pyran-2-yl)-1H-[1,2,4]triazol-3-yl]-pyridine (33.0 mg, 0.12 mmol) and building block C1 were dissolved in dry dioxane (1.2 mL) under inert atmosphere and palladium(II)acetate (2.12 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10.9 mg) and caesium carbonate (81.0 mg) were added subsequently. The mixture was heated to 100° C. and stirred for 18 h. After cooling to room temperature the reaction mixture was diluted with DCM, washed with water and brine, dried under Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash column chromatography (10 g Isolute® silica gel cartridge; gradient elution: DCM/MeOH from 97/3 to 95/5) affording building block F1 (70 mg). HPLC (R_t)=1.75 min (method M)

Building blocks F2 and F3 were prepared in analogy to building block F1

##STR00116##
The chloropyridines were prepared as follows:

2-Chloro-4-[4-(tetrahydro-pyran-2-yl)-1H-[1,2,4]triazol-3-yl]-pyridine

##STR00117##

2-Chloro-4-[4-(tetrahydro-pyran-2-yl)-1H-[1,2,4]triazol-3-yl]-pyridine was prepared in analogy to 2-Chloro-6-methyl-4-[1-(tetrahydro-pyran-2-yl)-1H-[1,2,4]triazol-3-yl]-pyridine. HPLC (R_t)=1.68 min (method M)

2-Chloro-4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyridine

##STR00118##

4-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazole (0.73 g) and 2-chloropyridine-4-boronic acid (0.20 g) were dissolved in dry DMF (2 mL) under inert atmosphere and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II)(102 mg) was added followed by caesium carbonate (0.84 g). The mixture was heated to 80° C. and stirred for 2 h. After cooling to room temperature the reaction mixture was diluted with DCM and the inorganic salts filtered off. The filtrate was washed with water and brine, dried under Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (20 g Isolute® silica gel cartridge; gradient elution: hexane/EtOAc from 10/0 to 8.5/1.5) affording the title compound (144 mg). HPLC (R_t)=1.39 min (method M)

S.3 Synthesis of Reaction Partners for Procedures A-F

S.3.1. Synthesis of Primary or Secondary Amines for Procedures A and B

Synthesis of (I25) for Example 7

##STR00119##

To a stirred mixture of 5-nitroisophthalic acid (20.0 g) in DCM was added oxalyl chloride (36 ml, 2M in DCM), followed by DMF (0.5 ml). The mixture was stirred for 2 h at room temperature, before volatiles were removed in vacuum. The residue was suspended in dry toluene and concentrated again to yield crude I23 (10 g), which was used without further purification in the next step.

I23 (10 g) was dissolved in THF (20 ml) and added dropwise to a solution of methylamine (40 ml, 2M in THF) in THF (80 ml) under stirring at −20° C. After 20 min, the mixture was filtered, and the filtrate concentrated in vacuum. The residue was triturated with diethylether to form a solid that was filtered off and dried to yield intermediate I24 (3.53 g)

Synthesis of N-(8-amino-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)acetamide for Example 10

A solution of intermediate I24 (0.52 g) in MeOH (30 ml) was treated with hydrogen (50 psi) in the presence of Raney-Nickel (90 mg) at room temperature for 14 h. The mixture was then filtered and concentrated in vacuum to afford I25. The compound was used without further purification in the next step.

HPLC (R_t)=0.33 min (method D)

##STR00120##

This intermediate was synthesized according to WO2006040279.

Synthesis of N-(4-Amino-cyclohexyl)-benzenesulfonamide for Example 29

##STR00121##

This intermediate was synthesized analog to WO2001096295.

Synthesis of 3-(4-Amino-2-methyl-phenyl)-[1,3]oxazinan-2-one for Example 30

##STR00122##

This intermediate was synthesized analog to WO2005111029.

Synthesis of 5-Amino-2,3-dihydro-indole-1-carboxylic acid methylamide for Example 37

##STR00123##

This intermediate was synthesized analog to WO2008113760.

Synthesis of 1-(3-Amino-benzyl)-3-cyclohexyl-urea for Example 39

##STR00124##

Step 1: 1-Cyclohexyl-3-(3-nitro-benzyl)-urea

3-Nitro-benzyl-amine (5 g) was suspended in THF (130 ml) and cyclohexyl isocyanate (7 ml) was added dropwise at 25° C. After stirring for 2 h the resulting precipitate was filtered off, washed with diethyl ether and treated with 5% aqueous NH₄OH. After filtering and drying the title compound was isolated (4.5 g, FP 168-169° C.)

Step 2: 1-(3-Amino-benzyl)-3-cyclohexyl-urea

1-Cyclohexyl-3-(3-nitro-benzyl)-urea (4 g) was suspended in ethanol (70 ml) and Raney nickel (2 g) was added. Under stirring aqueous hydrazine solution (2.5 ml, 80%) was added. DMF was added (50 ml) and the reaction mixture was stirred for additional 2 h and filtered. The solution was evaporated i.v. affording the title compound (3 g, R_f=0.43 DCM/ethanol 19:1).

Synthesis of trans-1-(4-Amino-cyclohexyl)-3-phenyl-urea for Example 44

##STR00125##

This intermediate was synthesized analog to WO2005095339.

Synthesis of 1-Methanesulfonyl-pyrrolidin-3-ylamine for Example 53

##STR00126##

This intermediate was synthesized analog to WO2006118256.

Synthesis of 3-Pyridin-4-ylmethyl-phenylamine for Example 66

##STR00127##

This intermediate was synthesized analog to WO2004009546.

Synthesis of 1-(5-Chloro-1H-benzoimidazol-2-yl)-2-methoxy-ethylamine for Example 67

##STR00128##

This intermediate was synthesized analog to WO2004056784.

Synthesis of C-(6-Chloro-2-methyl-pyridin-3-yl)-methylamine for Example 70

##STR00129##

2-Methyl-6-oxo-1,6-dihydro-pyridine-3-carbonitrile

A solution of (E)-3-amino-but-2-enenitrile (100 g) and propynoic acid methyl ester in DMF (200 ml) was stirred at 25° C. for 2 h and refluxed for additional 1 h. Dowtherm (100 ml) was added and the temperature was rised to 230° C. DMF and MeOH were distilled off. The reaction mixture was cooled down, EtOAc (200 ml) was added and the resulting crystals were filtered off and washed with EtOAc and ether affording the title compound (44.8 g, FP>250° C.).

6-Chloro-2-methyl-nicotinonitrile

A mixture of 2-Methyl-6-oxo-1,6-dihydro-pyridine-3-carbonitrile (44 g) and POCl3 (250 ml) was refluxed for 3 h. The reaction mixture was dried down in vacuum and ice followed by conc. aqueous ammonia (300 ml) was added. The aqueous layer was extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuum affording the title compound (23.5 g, BP (18 mbar) 119-120° C.).

C-(6-Chloro-2-methyl-pyridin-3-yl)-methylamine

To a solution of 6-Chloro-2-methyl-nicotinonitrile (6 g) in THF (120 ml) at 25° C. was added NaBH₄(3 g) followed by the dropwise addition of BF₃etherate (6 ml). The reaction mixture was stirred for 3 h. MeOH (100 ml) and 2N HCl (100 ml) was added and refluxed for 1 h. The organic solvent was removed in vacuum and conc. NaOH (40 ml) was added followed by extraction with diethyl ether. The organic layer was separated, dried and concentrated in vacuum followed by filtration over silica gel (EtOAc/MeOH 80:20). The title compound was crystallized from MeOH/HCl (5.5 g)

Synthesis of N-(3-aminophenyl)-N-(2-(azetidin-1-yl)-2-oxoethyl)methanesulfonamide for Example 75

##STR00130##

This intermediate was synthesized analog according to WO2006114371.

Synthesis of N-(3-aminophenyl)-methylsulfonamido)-N,N-dimethylacetamide for Example 76

##STR00131##

This intermediate was synthesized analog to WO2006114371.

Synthesis of N-(3-aminophenyl)-cyclopropane-sulfonamido)-N,N-dimethylacetamide for Example 78

##STR00132##

This intermediate was synthesized analog according to WO2006114371.

Synthesis of 2-[(3-Amino-phenyl)-ethanesulfonylamino]-N,N-dimethyl-acetamide for Example 79

##STR00133##

This intermediate was synthesized analog to WO2006114371.

Synthesis of ethyl 5-amino-3-methylbenzoate for example 88

##STR00134##

2 g acid was dissolved in 22 mL ethanolic HCl and stirred at 60° C. for 2 days. The mixture was then concentrated and used without further purification.

Synthesis of ethyl 3-methylaminobenzoate for Example 92

##STR00135##

2 g acid was dissolved in 22 mL ethanolic HCl and stirred at 60° C. for 2 days. The mixture was then concentrated and used without further purification.

Synthesis of 4-(3,5-Dimethyl-pyrazol-1-yl)-pyridin-2-ylamine for Example 102

##STR00136##

A 10 ml microwave reaction vessel was charged with 4-Chloro-pyridinamine (0.5 g) and 3,5-dimethylpyrazole (1.12 g); hydrochloric acid (37%, 0.5 ml) and dioxane were then added. The reaction mixture was irradiated in a Microwave oven with the following parameters: potency: 150 W; temperature: 120° C.; time: 180 min.

The reaction mixture was cooled at room temperature and treated with diethyl ether (2 ml) and ethanol (1 ml) and sonicated during 30 min. At end of treatment the mixture was cooled during 14 h at 4° C. A solid was filtered off and washed with diethyl ether and n-hexane to furnish the product as the hydrochloride salt (450 mg).

Synthesis of 5-amino-tetramethylisophthalamide (I29) for Example 105

##STR00137##

To a stirred solution of mono methyl 5-nitroisophthalate (1.0 g) and DIPEA (1.43 ml) in DCM (30 ml) and DMF (3 ml) was added HATU (1.69 g) at rt. After 10 min, dimethylamine (4.4 ml, 2M solution in THF) was added and stirring was continued for 12 h. Water and sodium bicarbonate were added to the reaction mixture and extracted with DCM. The organic layer was separated and concentrated in vacuum. The reside was further purified by normal phase MPLC (cyclohexane: EtOAc=80:20 to 30:70) to afford intermediate I26 (0.91 g)

HPLC (R_t)=1.29 min (method D)

A mixture of I26(2.5 g), MeOH (20 ml) and LiOH(aq) (8 wt. %, 5.9 ml) was stirred at 50° C. for 1 h. Volatiles were then removed in vacuum and the residue was acidified by treatment with 2 M HCl (aq). The mixture was lyophilized, the remaining solid suspended in water and warmed to 50° C. The resulting suspension was filtered, the solid was washed with water and petrolether and dried in vacuum at 50° C. to yield 127 (1.56 g) that was used without further purification.

HPLC (R_t)=0.27 min (method E)

Synthesis of methyl 3-amino-5-(dimethylcarbamoyl)benzoate for Example 108

HATU (707 mg) was added in two portions to a mixture of 127 (400 mg), DCM (5 ml), DMF (2 ml), diisopropylamine (0.68 ml), and HOBt (227 mg) under stirring at rt. Dimethylamine (2.1 ml, 2M in THF) was added and stirring continued for 48 h. Water and sodium bicarbonate were then added and the resulting mixture was extracted with DCM. The organic layer was separated, dried (Na₂SO₄) and concentrated in vacuum. The residue was further purified by reversed phase HPLC the product containing fractions were combined volatiles removed in vacuum and the remaining aqueous mixture extracted with DCM. The organic layer was concentrated to afford I28 (71 mg).

Step 4

A solution of intermediate I28 (71 mg) in MeOH (10 ml) was treated with hydrogen in the presence of Raney-Nickel (10 mg) at rt. The mixture was then filtered and concentrated in vacuum to afford the title compound I29 (40 mg). The compound was used without further purification in the next step.

HPLC (R_t)=0.70 min (method D)

The reaction partners for example 107 and 106 were synthesized analogously as for example 105.


Intermediate for
the synthesis of		HPLC
example	Structure	method	R_t[min]

107	##STR00138##	D	1.26

106	##STR00139##	D	1.26

A solution of intermediate I26 (0.91 g) in MeOH (40 ml) was treated with hydrogen in the presence of Raney-Nickel (90 mg) at rt. The mixture was then filtered and concentrated in vacuum to afford the title compound (810 mg). The compound was used without further purification in the next step.

HPLC (R_t)=0.98 min (method D)

Synthesis of methyl 3-amino-5-methoxy benzoate for the Synthesis of Example 111

##STR00140##

To a stirred suspension of 3-amino-5-methoxy benzoic acid (500 mg) in a mixture of DCM (4.0 ml) and MeOH (2.0 ml) at 0° C. was added a solution of trimethylsilyldiazomethan in hexane (3.39 ml, 2M) dropwise. After 15 min, the reaction was concentrated in vacuum. The remaining crude product was purified by reversed phase HPLC to yield the trifluoroacetate salt of title compound (280 mg).

HPLC (R_t)=1.02 min (method D)

Synthesis of ethyl 3-amino-5-chloro benzoate for the Synthesis of Example 112

##STR00141##

5-tert-butylisophthalic acid (1.3 g) was dissolved in MeOH (20 ml). The resulting solution was cooled to 0° C. and thionlychloride (0.45 ml) was added dropwise under stirring. After complete addition, the mixture was allowed to warm to room temperature and was stirred for additional 7 h. The mixture was then poured on an ice cold sodium bicarbonate solution and extracted repeatedly with EtOAc. The aqueous phase was acidified with HCl and again extracted with EtOAc. The combined organic layers were washed with brine and concentrated in vacuum. The residue was worked up by flash column chromatography on silica gel (DCM:MeOH=20:1) to yield methyl 5-tert-butylisophthalate (1.3 g).

Under an atmosphere of argon, 5-tert-butylisophthalate (0.5 g) was dissolved in tert.-butanol (20 ml). To the resulting solution, triethylamine (0.35 ml) and diphenyl phosphoreazidate (0.56 ml) were added subsequently. The mixture was then heated to reflux for 12 h, cooled to room temperature and concentrated in vacuum. The residue was taken up in EtOAc, and subsequently washed with dilute aqueous citric acid, saturated sodium bicarbonate solution and brine. The organic layer was concentrated in vacuum and the residue was worked up by flash chromatography (petrol ether:EtOAc=3:1) to yield methyl 3-(tert.-butoxycarbonylamino)-5-tert-butylbenzoate (0.61 g).

Synthesis of methyl 3-amino-5-chloro benzoate for the Synthesis of Example 113

Methyl 3-(tert.-butoxycarbonylamino)-5-tert-butylbenzoate (0.42 g) was dissolved in DCM (5 ml). To the resulting solution, TFA (1 ml) was added, the mixture was stirred for 30 min at room temperature and then concentrated in vacuum. The residue was dissolved in DCM and extracted with aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulphate and concentrated in vacuum to yield ethyl 3-amino-5-tert-butylbenzoate (0.28 g), which was used for the synthesis of example 112 without further purification.

##STR00142##

A solution of methyl 3-chloro-5-nitrobenzoate (300 mg) in THF (50 ml) was treated with hydrogen (3 bar) in the presence of Raney-Nickel (10 mg) at rt. The mixture was then filtered and concentrated in vacuum to afford the title compound (204 mg). The compound was used without further purification in the next step.

HPLC (R_t)=1.36 min (method D)

Synthesis of 3-Methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine for Example 114

##STR00143##

3-Chlorocarbonyl-5-nitro-benzoic acid ethyl ester

To a solution of 5-nitroisophtalic acid monoethyl ester (80 g) in DCM (700 ml) at 25° C. was added 2M oxalyl chloride solution in DCM (63 ml), and DMF (5 ml). The reaction was stirred for 2 h and then concentrated in vacuum. The residue was triturated with toluene and again concentrated in vacuum leaving the title compound (60 g). R_t=1.40 min for derivatised methylester (method D).

N-Methyl-5-nitro-isophthalamic acid ethyl ester

To a 2M solution of methylamine in THF (256 ml) at −20° C. was added a pre-cooled solution of 3-chlorocarbonyl-5-nitro-benzoic acid ethyl ester (60 g) in THF (500 ml) dropwise. This was stirred for 20 min and then filtered. The filtrate was concentrated in vacuum and the solid recrystallised from diethyl ether to give the title compound (22.5 g) as a solid. An oxalyl chloride solution in DCM (63 ml, 2M), was added with DMF (5 ml). The reaction was stirred for 2 h and then concentrated in vacuum. The residue was triturated with toluene and again concentrated in vacuum leaving the title compound (60 g). R_t=1.53 min (method D).

3-(1-Methyl-1H-tetrazol-5-yl)-5-nitro-benzoic acid ethyl ester

To a 2M solution of N-methyl-5-nitro-isophthalamic acid ethyl ester (10 g) in dichloroethane (200 ml) at −20° C. was added pre-cooled triflic anhydride (10 ml) dropwise. This was stirred for 30 min and then sodium azide (4.6 g) was added. This was allowed to warm to room temperature and stirred overnight. The reaction was neutralised with 5% NaHCO₃(aq) solution and the organic and aqueous layers were separated and the organic layer dried and concentrated in vacuum. Flash chromatography (100:0 to 50:50 gradient cyclohexane:EtOAc) afforded the title compound (6.5 g). R_t=1.52 min (method D).

Step 4

3-Amino-5-(1-methyl-1H-tetrazol-5-yl)-benzoic acid ethyl ester

A solution of 3-(1-Methyl-1H-tetrazol-5-yl)-5-nitro-benzoic acid ethyl ester (6.5 g) in EtOAc:ethanol (1:1, 320 ml) was hydrogenated at 20° C. and 50 psi with 10% Pd/C (750 mg). After reaction completion, the mixture was filtered and the filtrate concentrated in vacuum to give the title compound (4.2 g). R_t=1.21 min (method D).

Step 5

[3-Amino-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-methanol

To a solution of 3-Amino-5-(1-methyl-1H-tetrazol-5-yl)-benzoic acid ethyl ester (250 mg) in THF (5 ml) at 0° C. was added pre-cooled 1M LiAlH₄solution in THF (2 ml) dropwise. This was stirred for 3 h. The reaction mixture was poured onto ice-water and extracted into EtOAc. The organic layer was separated, dried and concentrated in vacuum. Flash chromatography (100:0 to 95:5 gradient DCM:MeOH) afforded the title compound (70 mg).

R_f=0.19 (DCM:MeOH 95:5).

Step 6

3-Methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine

A solution of [3-Amino-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-methanol (450 mg) in MeOH (20 ml) with a few drops of conc. HCl (aq) was hydrogenated on a H-cube apparatus at 30° C., and 10 bar with a flow rate of 1 mL/min using a Pd/C cartridge. After reaction completion, the mixture was concentrated in vacuum and the residue basified with a dilute K₂CO₃(aq). This was extracted with EtOAc and the organic layer was separated, dried and concentrated in vacuum. The residue was purified by flash chromatography (98:2 DCM:MeOH) to give the title compound (320 mg).

R_f=0.46 (95:5 DCM:MeOH)

S3.2 Synthesis of aromatic-chlorides or -bromides for Procedure C

Synthesis of 2-Chloro-4-(3,5-dimethyl-isoxazol-4-yl)-pyridine for Example 187

##STR00144##

The title compound was prepared from 4-bromo-3,5-dimethylisoxazole generally according to the synthetic procedure described for 2-Chloro-4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyridine. HPLC (R_t)=0.81 min (method N)

Synthesis of 2-Chloro-6-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridine for Example 188

##STR00145##

To a suspension of 2-chloro-6-methyl-isonicotinamide (0.50 g, 2.93 mmol) in dry DCM (10 ml), dry pyridine (0.26 ml) was added and the mixture was cooled to 0° C. under inert atmosphere. Trifluoroacetic anhydride (0.45 ml) was added dropwise under stirring, the cooling bath was removed and the reaction mixture was stirred for 4 h. After this period other portions of pyridine (0.074 ml) and trifluoroacetic anhydride (0.12 ml) were added and the mixture stirred at room temperature for further 3 h.

The reaction was quenched with aqueous solution of NaHCO₃, the phases were separated and the aqueous layer extracted with DCM. The combined organic extracts were washed with brine, dried under Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The crude product was obtained (0.378 g) and used in next step without further purification. HPLC (R_t)=1.65 min (method M)

2-Chloro-6-methyl-isonicotinonitrile (378 mg) was dissolved in ethanol (4 ml) and hydroxylamine hydrochloride (379 mg) was added followed by a solution of sodium carbonate (577 mg) in water (8 ml). The reaction mixture is heated to 75° C. and stirred for 18 h. Ethanol was evaporated under reduced pressure and the aqueous residue extracted with EtOAc. The combined extracts were washed with water and brine, dried under Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The crude product was obtained (401 mg) and used in next step without further purification. HPLC (R_t)=0.67 min (method M)

2-Chloro-N-hydroxy-6-methyl-isonicotinamidine (120 mg) was suspended in trimethylorthoacetate (3 ml) under inert atmosphere and acetic acid (0.3 ml) was added. The mixture was heated to 100° C. and stirred for 2 h. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue partitioned between EtOAc and aqueous solution of NaHCO₃. The organic layer was separated, washed with water and brine, dried under Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash column chromatography (10 g Isolute® silica gel cartridge; gradient elution: hexane/EtOAc from 10/0 to 9/1) affording the title compound (107 mg).

HPLC (R_t)=3.17 min (method L).

Synthesis of methyl 2,6 dibromo-isonicotinate for the Synthesis of Example 194

##STR00146##

In a three necked round bottom flask equipped with a mechanic stirrer and gas outlet solid cirtrazinic acid (15 g) and phosphorous oxybromide (45 g) were thoroughly mixed and heated to 140° C. for 12 to 14 h. The resulting mixture was cooled to 0° C. before MeOH (100 ml) was added carefully under vigorous stirring. The resulting mixture was then poured into a cooled (0° C.) aqueous sodium carbonate solution (1M, 500 ml), before Chloroform (500 ml) was added. The biphasic mixture was filtered through a paper filter, before the organic layer was separated. After filtering through charcoal, the solution was concentrated in vacuum. The residue was purified by MPLC (DCM:MeOH=100:3 to 100:6) to yield methyl 2,6 dibromo-isonicotinate (13.7 g).

HPLC (R_t)=1.62 (method D)

Synthesis of methyl 2-bromo-6-methoxyisonicotinate for Example 195

##STR00147##

A solution of sodium methoxide (375 mg) and methyl 2,6 dibromo-isonicotinate (1.0 g) in MeOH (20 ml) was heated in a microwave oven at 130° C. for 30 min. Then additional sodium methoxide (281 mg) was added and heating continued for additional 15 min at 130° C. Concentrated sulfuric acid (1.86 ml) was then added to the reaction mixture and the resulting suspension was heated for 4 h at 80-85° C.

After cooling to room temperature, the mixture was poured in an ice cold aqueous sodium carbonate solution (100 mL) and extracted with DCM (100 ml). The organic layer was separated, dried over Na₂SO₄and concentrated in vacuum. The residue was purified by MPLC (DCM:MeOH=100:3 to 100:5) to yield 710 mg of a 70:30 mixture of desired product (497 mg) and the corresponding trimethyl cirtrazinic acid (213 mg). The mixture was used for subsequent transformations without further purification.

HPLC (R_t)=1.66 min (method D)

Synthesis of 2-Chloro-6-methyl-4-(1-methyl-1H-tetrazol-5-yl)-pyridine for Example 191

##STR00148##

2-Chloro-6,N,N-trimethyl-isonicotinamide

To a solution of 2-Chloro-6-methyl-isonicotinic acid (1 g) in DMF (200 ml) at 25° C. was added DIPEA (2.9 mL) and TBTU (1.8 ml). After 5 min, dimethylamine (0.75 g) was added dropwise. This was stirred overnight. The reaction was added to water and extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuum. Flash:chromatography (9:1 to 2:8 gradient cyclohexane:EtOAc) afforded the title compound (320 mg). R_f=0.56 (1:1 cyclohexane:EtOAc)