Benzimidazole derivatives

Abstract

The invention relates to a compound of formula (I) wherein R.sup.1-R.sup.4 are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament.

##STR00001##

Claims

1. A compound of formula (I) ##STR00041## wherein R.sup.1 is alkyl or halogen; R.sup.2 is alkyl, halogen, haloalkyl, alkoxy or cycloalkyl; R.sup.3 is hydrogen or halogen; and R.sup.4 is hydrogen, (oxo-hexahydropyrrolo[1,2-a]pyrazinyl)alkyl, haloalkylpiperazinylalkyl, cycloalkylpiperazinylalkyl, phenylalkyl(oxopiperazinyl)alkyl, alkyl(oxopiperazinyl)alkyl, hydroxyalkyl, phenylamino, halopiperidinylalkyl, alkylcarbonylpiperazinylalkyl, phenyl(alkylamino)alkyl, phenylalkylpiperazinylalkyl, phenylpiperazinylalkyl, oxopiperazinylalkyl, hydroxypiperidinylalkyl, alkylpiperazinylalkyl, dialkylaminoalkyl, piperidinylalkyl, phenylaminoalkyl, phenylalkyl, halophenylalkyl, morpholinylalkyl, haloalkyl, alkyl or phenylalkylamino; or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1, wherein R.sup.1 is halogen.

3. A compound according to claim 1 or 2, wherein R.sup.1 is chlorine.

4. A compound according to any one of claims 1 to 3, wherein R.sup.2 is alkyl.

5. A compound according to any one of claims 1 to 4, wherein R.sup.2 is methyl.

6. A compound according to any one of claims 1 to 5, wherein R.sup.3 is hydrogen or fluorine.

7. A compound according to any one of claims 1 to 6, wherein R.sup.4 is hydrogen, (oxo-hexahydropyrrolo[1,2-a]pyrazinyl)alkyl, cycloalkylpiperazinylalkyl, hydroxyalkyl, halopiperidinylalkyl, phenylalkylpiperazinylalkyl, oxopiperazinylalkyl, alkylpiperazinylalkyl, piperidinylalkyl, phenylaminoalkyl, phenylalkyl, morpholinylalkyl or phenylalkylamino.

8. A compound according to any one of claims 1 to 7, wherein R.sup.4 is hydrogen, (oxo-hexahydropyrrolo[1,2-a]pyrazinyl)methyl, cyclopropylpiperazinylmethyl, hydroxymethyl, halopiperidinylmethyl, phenylmethylpiperazinylmethyl, oxopiperazinylmethyl, methylpiperazinylmethyl, piperidinylmethyl, phenylaminomethyl, phenylmethyl, morpholinylmethyl or phenylmethylamino.

9. A compound according to any one of claims 1 to 8 selected from 6-(2-chloro-4-cyclopropylphenyl)-1-benzimidazole-4-carboxylic acid; 6-(2-chloro-5-fluoro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 6-(2-chloro-4-ethoxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 6-(2-chloro-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 6-(4-chloro-2-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(4-cyclopropylpiperazin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 2-[(4-benzyl-3-oxopiperazin-1-yl)methyl]-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[[3-(trifluoromethyl)piperazin-1-yl]methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(4-methyl-2-oxopiperazin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-(hydroxymethyl)-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-(phenylamino)-1H-benzo[d]imidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(4,4-difluoropiperidin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 2-[(4-acetylpiperazin-1-yl)methyl]-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(N-methylanilino)methyl]-1H-benzimidazole-4-carboxylic acid; 2-[(4-benzylpiperazin-1-yl)methyl]-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(4-phenylpiperazin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(3-oxopiperazin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(4-hydroxypiperidin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(4-methylpiperazin-1-yl)methyl]-1-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-(diethylaminomethyl)-1-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-(piperidin-1-ylmethyl)-1H-benzimidazole-4-carboxylic acid; 2-(anilinomethyl)-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid; 2-benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(4-chlorophenyl)methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-(morpholin-4-ylmethyl)-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(dimethylamino)methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylic acid; 2-(benzylamino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; and 6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; or a pharmaceutically acceptable salt or ester thereof.

10. A compound according to any one of claims 1 to 9 selected from 6-(2-chloro-5-fluoro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(4-cyclopropylpiperazin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-(hydroxymethyl)-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(4,4-difluoropiperidin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 2-[(4-benzylpiperazin-1-yl)methyl]-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(3-oxopiperazin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-[(4-methylpiperazin-1-yl)methyl]-1-benzimidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-(piperidin-1-ylmethyl)-1H-benzimidazole-4-carboxylic acid; 2-(anilinomethyl)-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid; 2-benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 6-(2-chloro-4-methylphenyl)-2-(morpholin-4-ylmethyl)-1H-benzimidazole-4-carboxylic acid; and 2-(benzylamino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; or a pharmaceutically acceptable salt or ester thereof.

11. A process for the preparation of a compound according to any one of claims 1 to 10, comprising the saponification of compound (A1) ##STR00042## in a suitable solvent in the presence of a base or an acid; wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in any one of claims 1 to 10 and R.sup.5 is alkyl.

12. A compound according to any one of claims 1 to 10, when manufactured according to a process of claim 11.

13. A compound according to any one of claims 1 to 10 for use as therapeutically active sub stance.

14. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 10 and a therapeutically inert carrier.

15. The use of a compound according to any one of claims 1 to 10 for the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS).

16. The use of a compound according to any one of claims 1 to 10 for the preparation of a medicament for the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS).

17. A compound according to any one of claims 1 to 10 for use in the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS).

18. A method for the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS), which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 10 to a patient in need thereof.

19. The invention as hereinbefore described.

Description

EXAMPLES

Abbreviations

[0177] DCM=dichloromethane; DMSO=dimethyl sulfoxide; ESI=electrospray ionization; EtOAc=ethyl acetate; HPLC=high performance liquid chromatography; MeOH=methanol; MS=mass spectrometry; RT=room temperature; TFA=trifluoroacetic acid; THF=tetrahydrofuran.

Example 1

6-(2-Chloro-4-cyclopropylphenyl)-1-benzimidazole-4-carboxylic acid

[0178] ##STR00009##

a) 1-(tert-Butyl) 4-methyl 6-bromo-1H-benzo[d]imidazole-1,4-dicarboxylate

[0179] To a suspension of methyl 6-bromo-1H-benzo[d]imidazole-4-carboxylate (750 mg, 2.94 mmol, Eq: 1) and N-ethyldiisopropylamine (988 mg, 1.31 ml, 7.64 mmol, Eq: 2.6) in dichloromethane (20 ml) were added di-tert-butyl dicarbonate (1.35 g, 6.17 mmol, Eq: 2.1) and DMAP (36.7 mg, 294 μmol, Eq: 0.1). The reaction was stirred at room temperature overnight, then it was poured into 50 ml of water and extracted with EtOAc (2×50 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% EtOAc in heptane) to obtain the title compound 1-(tert-butyl) 4-methyl 6-bromo-1H-benzo[d]imidazole-1,4-dicarboxylate (846.9 mg, 2.38 mmol, 80.8% yield) as white solid, MS (ESI): 355.029 [M+H]+.

b) Methyl 6-(2-chloro-4-cyclopropylphenyl)-1H-benzo[d]imidazole-4-carboxylate

[0180] To a light yellow solution of 1-(tert-butyl) 4-methyl 6-bromo-1H-benzo[d]imidazole-1,4-dicarboxylate (50 mg, 134 μmol, Eq: 1) in 1,4-dioxane (1.2 ml) was added (2-chloro-4-cyclopropylphenyl)boronic acid (39.4 mg, 201 Eq: 1.5). Cesium carbonate (88 mg, 267 μmol, Eq: 2) dissolved in water (0.6 ml) was added. The reaction mixture was degassed with Argon before 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (5.46 mg, 6.69 μmol, Eq: 0.05) was added. The mixture was heated to 90° C. for 1 hour. The reaction mixture was poured into 20 ml of water and extracted with EtOAc (3×20 ml). The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to obtain the title compound methyl 6-(2-chloro-4-cyclopropylphenyl)-1H-benzo[d]imidazole-4-carboxylate (31.6 mg, 95.4 μmol, 71.4% yield) as light brown solid, MS (ESI): 327.13 [M+H]+.

c) 6-(2-Chloro-4-cyclopropylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0181] To a solution of methyl 6-(2-chloro-4-cyclopropylphenyl)-1H-benzo[d]imidazole-4-carboxylate (30 mg, 91.8 μmol, Eq: 1) in tetrahydrofuran (1.2 ml) was added lithium hydroxide monohydrate (7.7 mg, 184 Eq: 2) dissolved in water (0.6 ml). The reaction mixture was warmed to 65° C. and stirred for 3 h. For work-up HCl (2M, 91.8 μl, 184 μmol, Eq: 2) was added, the mixture was concentrated in vacuo. The residue was treated with methyltetrahydrofuran and the crystals were filtered off to obtain the title compound 6-(2-chloro-4-cyclopropylphenyl)-1-benzimidazole-4-carboxylic acid (20.6 mg, 65 μmol, 70.8% yield) as white solid, MS (ESI): 313.074 [M+H]+.

Example 2

6-(2-Chloro-5-fluoro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0182] ##STR00010##

The title compound was obtained in comparable yield analogous to the procedure described for Example 1 using (2-chloro-5-fluoro-4-methylphenyl)boronic acid instead of (2-chloro-4-cyclopropylphenyl)boronic acid in step b), off-white solid, MS (ESI): 305.1 [M+H]+.

Example 3

6-(2-Chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0183] ##STR00011##

The title compound was obtained in comparable yield analogous to the procedure described for Example 1 using (2-chloro-4-methylphenyl)boronic acid instead of (2-chloro-5-fluoro-4-methylphenyl)boronic acid in step b), off-white solid, MS (ESI): 287.1 [M+H]+.

Example 4

6-(2-Chloro-4-ethoxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0184] ##STR00012##

a) Methyl 6-(2-chloro-4-ethoxyphenyl)-1H-benzo[d]imidazole-4-carboxylate

[0185] (2-Chloro-4-ethoxyphenyl)boronic acid (84.6 mg, 401 μmol, Eq: 1.5) and 1-(tert-butyl) 4-methyl 6-bromo-1H-benzo[d]imidazole-1,4-dicarboxylate (100 mg, 267 μmol, Eq: 1) were solved in 1,4-dioxane (6 ml) and water (3 ml). Cesium carbonate (352 mg, 1.07 mmol, Eq: 4) was added and the mixture was degassed by bubbling argon through the mixture (5 min) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10.9 mg, 13.4 μmol, Eq: 0.05) was added. The reaction was stirred in a sealed tube at 90° C. The mixture was taken up in EtOAc and washed with water, saturated NH.sub.4Cl solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtrated and evaporated. The residue was diluted with CH.sub.2Cl.sub.2, evaporated with silica gel to dryness and purified by flash chromatography (silica gel, 40 g, with 0% to 100% EtOAc in heptane) to obtain the title compound methyl 6-(2-chloro-4-ethoxyphenyl)-1H-benzo[d]imidazole-4-carboxylate (58.6 mg, 177 μmol, 44.1% yield) as off-white solid, MS (ESI): 331.2 [M+H]+.

b) 6-(2-Chloro-4-ethoxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0186] Methyl 6-(2-chloro-4-ethoxyphenyl)-1H-benzo[d]imidazole-4-carboxylate (56 mg, 169 μmol, Eq: 1) was solved in acetic acid (1.18 g, 1.09 ml, 19.6 mmol, Eq: 116). Hydrobromic acid (816 mg, 544 μl, 4.84 mmol, Eq: 28.6) was added at room temperature. The mixture was stirred at 110° C. for 3 h, then it was concentrated at high vacuum at 50° C. The residue was taken up in 15% Na.sub.2CO.sub.3-solution, the aqueous layer was extracted twice with diethylether, the organic layer was washed with water and the combined aqueous layers were acidified with HCl 37% to pH3 and extracted twice with 2-methyltetrahydrofuran. The combined organic layers were dried over Na.sub.2SO.sub.4, filtrated and evaporated. The crude product was purified by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100×30 mm, eluent acetonitrile/water). The solvent acetonitrile was evaporated and the remaining aqueous layer was extracted with 2-methyltetrahydrofuran, the organic layer was washed with water, then dried over Na.sub.2SO.sub.4, filtrated and evaporated to yield the title compound 6-(2-chloro-4-ethoxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid (16.6 mg, 52.4 μmol, 31.0% yield) as light yellow solid, MS (ESI): 317.1 [M+H]+.

Example 5

6-(2-Chloro-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0187] ##STR00013##

The title compound was obtained in comparable yield analogous to the procedure described for Example 4 using (2-chloro-4-(trifluoromethyl)phenyl)boronic acid instead of (2-chloro-4-ethoxyphenyl)boronic acid in step a), light yellow solid, MS (ESI): 341.1 [M+H]+.

Example 6

6-(4-Chloro-2-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0188] ##STR00014##

The title compound was obtained in comparable yield analogous to the procedure described for Example 4 using (4-chloro-2-methylphenyl)boronic acid instead of (2-chloro-4-ethoxyphenyl)boronic acid in step a), light yellow solid, MS (ESI): 287.1 [M+H]+.

Example 7

6-(2-Chloro-4-methylphenyl)-2-[(6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl)methyl]-1H-benzimidazole-4-carboxylic acid

[0189] ##STR00015##

a) Methyl 6-bromo-2-(chloromethyl)-1H-benzo[d]imidazole-4-carboxylate

[0190] To a light yellow solution of methyl 2,3-diamino-5-bromobenzoate (10 g, 40.8 mmol, Eq: 1) in water (100 ml) and HCl cone (100 ml) was added chloroacetic acid (4.24 g, 44.9 mmol, Eq: 1.1). The mixture was heated to 100° C. overnight. The reaction mixture was poured into 25 ml of water and extracted with EtOAc (3×100 ml). The organic layers were dried over MgSO.sub.4 and concentrated in vacuo to obtain the crude intermediate 6-bromo-2-(chloromethyl)-1H-benzo[d]imidazole-4-carboxylic acid (7.14 g, 24.7 mmol, 60.4% yield) as red solid, which was taken up with methanol (150 ml). Sulfuric acid (16 g, 8.7 ml, 163 mmol, Eq: 4) was added. The mixture was heated to reflux over night. The crude reaction mixture was partly concentrated in vacuo, then it was slowly poured into 150 ml saturated NaHCO.sub.3 solution and extracted with EtOAc (3×150 ml). The organic layers were dried over MgSO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 100% EtOAc in heptane) to afford the title compound methyl 6-bromo-2-(chloromethyl)-1H-benzo[d]imidazole-4-carboxylate (4.72 g, 15.3 mmol, 37.5% yield) as brown semisolid, (ESI): 304.94 [M+H]+.

b) Methyl 6-(2-chloro-4-methylphenyl)-2-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-1H-benzo[d]imidazole-4-carboxylate

[0191] To a light brown solution of methyl 6-bromo-2-(chloromethyl)-1H-benzo[d]imidazole-4-carboxylate (100 mg, 329 μmol, Eq: 1) and triethylamine (133 mg, 184 μl, 1.32 mmol, Eq: 4) in tetrahydrofuran (2 ml) was added hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (55.4 mg, 395 μmol, Eq: 1.2). The reaction mixture was stirred at room temp overnight. The mixture was poured into 10 ml of water and extracted twice with EtOAc (2×10 ml). The organic layers were dried over MgSO.sub.4 and concentrated in vacuo to obtain the intermediate which was taken up in dioxane (1.5 ml). (2-Chloro-4-methylphenyl)boronic acid (56.1 mg, 329 μmol, Eq: 1) was added. Potassium phosphate (210 mg, 81.8 μl, 988 μmol, Eq: 3) dissolved in water (0.375 ml) was added. The mixture was degassed during 2 min before X-phos (7.85 mg, 16.5 μmol, Eq: 0.05) and tris(dibenzylideneacetone)dipalladium chloroform adduct (8.53 mg, 8.24 μmol, Eq: 0.025) were added. The mixture was heated to 100° C. for 1 hours. The reaction mixture was poured into 20 ml of water and extracted with EtOAc (3×20 ml). The organic layers were dried over MgSO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 5% MeOH in DCM) to afford the title compound methyl 6-(2-chloro-4-methylphenyl)-2-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-1H-benzo[d]imidazole-4-carboxylate (22.5 mg, 41.8 μmol, 12.7% yield) as light brown solid, MS (ESI): 453.3 [M+H]+.

c) 6-(2-chloro-4-methylphenyl)-2-[(6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl)methyl]-1H-benzimidazole-4-carboxylic acid

[0192] To a light yellow solution of methyl 6-(2-chloro-4-methylphenyl)-24(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-1H-benzo[d]imidazole-4-carboxylate (20 mg, 44.2 μmol, Eq: 1) in tetrahydrofuran (1.5 ml) was added lithium hydroxide monohydrate (3.71 mg, 88.3 Eq: 2) dissolved in water (375 μl). The reaction mixture was heated to 65° C. and stirred during 4 hours. The mixture was quenched with HCl (2M, 44.2 μl, 88.3 μmol, Eq: 2) and concentrated in vacuo. The crude material was purified by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100×30 mm, eluent acetonitrile/water) to obtain the title compound 6-(2-chloro-4-methylphenyl)-2-[(6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl)methyl]-1H-benzimidazole-4-carboxylic acid (7 mg, 15.2 μmol, 34.4% yield) as white solid, MS (ESI): 439.27 [M+H]+.

Example 8

6-(2-Chloro-4-methylphenyl)-2-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0193] ##STR00016##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using 1-(2,2,2-trifluoroethyl)piperazine hydrochloride instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light yellow solid, (MS (ESI): 467.33 [M+H]+.

Example 9

6-(2-Chloro-4-methylphenyl)-2-[(4-cyclopropylpiperazin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid

[0194] ##STR00017##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using 1-cyclopropylpiperazine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light brown solid, (MS (ESI): 425.31 [M+H]+.

Example 10

2-[(4-Benzyl-3-oxopiperazin-1-yl)methyl]-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid

[0195] ##STR00018##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using 1-benzylpiperazin-2-one instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light yellow solid, (MS (ESI): 489.31 [M+H]+.

Example 11

6-(2-Chloro-4-methylphenyl)-2-[[3-(trifluoromethyl)piperazin-1-yl]methyl]-1H-benzimidazole-4-carboxylic acid

[0196] ##STR00019##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using 2-(trifluoromethyl)piperazine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light yellow solid, MS (ESI): 453.22 [M+H]+.

Example 12

6-(2-Chloro-4-methylphenyl)-2-[(4-methyl-2-oxopiperazin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid

[0197] ##STR00020##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using 4-methylpiperazin-2-one instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light yellow solid, MS (ESI): 413.23 [M+H]+.

Example 13

6-(2-Chloro-4-methylphenyl)-2-(hydroxymethyl)-1H-benzimidazole-4-carboxylic acid

[0198] ##STR00021##

a) Methyl 6-(2-chloro-4-methylphenyl)-2-(hydroxymethyl)-1H-benzimidazole-4-carboxylate

[0199] To a light yellow solution of methyl 6-bromo-2-(chloromethyl)-1H-benzo[d]imidazole-4-carboxylate (see Example 7, 40 mg, 132 μmol, Eq: 1) in dioxane (2 ml) was added (2-chloro-4-methylphenyl)boronic acid (23.6 mg, 138 μmol, Eq: 1.05). Potassium phosphate (tribasic) (55.9 mg, 264 μmol, Eq: 2) solved in water (500 μl) was added. The mixture was degassed during 2 min before X-phos (3.14 mg, 6.59 μmol, Eq: 0.05) and tris(dibenzylideneacetone)dipalladium chloroform adduct (3.41 mg, 3.29 μmol, Eq: 0.025) were added. The mixture was heated to 100° C. for 1 hours. For work-up the reaction mixture was poured into 20 ml of water and extracted with EtOAc (3×20 ml). The organic layers were dried over MgSO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to afford the title compound methyl 6-(2-chloro-4-methylphenyl)-2-(hydroxymethyl)-1H-benzo[d]imidazole-4-carboxylate as light yellow solid, MS (ESI): 331.09 [M+H]+.

b) 6-(2-Chloro-4-methylphenyl)-2-(hydroxymethyl)-1H-benzimidazole-4-carboxylic acid

[0200] To a light yellow solution of methyl 6-(2-chloro-4-methylphenyl)-2-(hydroxymethyl)-1H-benzo[d]imidazole-4-carboxylate (12 mg, 36.3 Eq: 1) in tetrahydrofuran (1 ml) was added lithium hydroxide monohydrate (3.04 mg, 72.6 μmol, Eq: 2) dissolved in water (250 μL). The mixture was heated to 65° C. during 4 h, then quenched with HCl (2M, 36.3 μl, 72.6 μmol, Eq: 2) and concentrated in vacuo. The crude material was triturated with diethyl ether (2×5 ml) to obtain the title compound 6-(2-chloro-4-methylphenyl)-2-(hydroxymethyl)-1H-benzimidazole-4-carboxylic acid (12.1 mg, 33.3 μmol, 91.9% yield) as light yellow solid, MS (ESI): 317.13 [M+H]+.

Example 14

6-(2-Chloro-4-methylphenyl)-2-(phenylamino)-1H-benzo[d]imidazole-4-carboxylic acid

[0201] ##STR00022##

a) Methyl 4,5-diamino-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate

[0202] To a solution of methyl 2,3-diamino-5-bromobenzoate (2 g, 8.16 mmol, Eq: 1) in dioxane (40 ml) was added (2-chloro-4-methylphenyl)boronic acid (1.39 g, 8.16 mmol, Eq: 1). Potassium phosphate (tribasic) (3.46 g, 16.3 mmol, Eq: 2) dissolved in water (10 ml) was added. The reaction mixture was degassed during 2 min before X-phos (195 mg, 408 μmol, Eq: 0.05) and tris(dibenzylideneacetone)dipalladium chloroform adduct (211 mg, 204 μmol, Eq: 0.025) were added. The mixture was heated to 110° C. for 2 hours, then poured into 100 ml of water and extracted with EtOAc (3×100 ml). The organic layers were dried over MgSO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 70% EtOAc in heptane) to afford the title compound methyl 4,5-diamino-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate (2.06 g, 6.85 mmol, 84% yield) as dark brown gum, 291.11 [M+H]+.

b) Methyl 2-((tert-butoxycarbonyl)amino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate

[0203] A mixture of methyl 4,5-diamino-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate (450 mg, 1.55 mmol, Eq: 1), 1,3-di-boc-2-methylisothiourea (714 mg, 2.38 mmol, Eq: 1.54) and (+)-camphor-10-sulfonic acid monohydrate (27.3 mg, 107 μmol, Eq: 0.069) in ethanol (10.8 ml) was refluxed for 3 h, then the mixture was cooled to room temperature and filtered. The grey filter cake was washed three times with 2 ml of ethanol and dried to afford the title compound methyl 2-((tert-butoxycarbonyl)amino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (582 mg, 1.35 mmol, 87.3% yield) as grey solid, 416.23 [M+H]+.

c) Methyl 2-amino-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate

[0204] In a 25 ml round-bottomed flask, methyl 2-((tert-butoxycarbonyl)amino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (778 mg, 1.87 mmol, Eq: 1) and HCl (1N in dioxane, 11.7 ml, 46.8 mmol, Eq: 25) were combined with dioxane (6.68 ml). The reaction was heated for 5 h at 60° C. For work-up the reaction mixture was diluted with diethyl ether and heptan, the precipitate was filtered off, dried in vacuo to afford the title compound methyl 2-amino-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (546 mg, 1.73 mmol, 92% yield) as an off-white solid, MS (ESI): 316.12 [M+H]+.

d) Methyl 2-bromo-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate

[0205] To a dark green solution of tert.-butyl nitrite (196 mg, 226 μl, 1.9 mmol, Eq: 1.5) and copper (II) bromide (424 mg, 1.9 mmol, Eq: 1.5) in acetonitrile (12 ml) at 60° C. methyl 2-amino-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (400 mg, 1.27 mmol, Eq: 1) was added portionwise. After complete addition the mixture was heated up to 75° C. for 2 hours. The reaction mixture was quenched with 100 ml of 1M HCl and extracted with EtOAc (3×100 ml). The organic layers were dried over MgSO.sub.4 and concentrated in vacuo. Crude material was suspended in MeOH (10 ml). Suspension was stirred for 30 min before solids were filtered off. Solids were washed with MeOH. The crude material (487 mg) was purified by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100×30 mm, eluent acetonitrile/water) to obtain the title compound methyl 2-bromo-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (91.7 mg, 229 μmol, 18.1% yield) as a white solid, MS (ESI): 381.04 [M+H]+.

e) Methyl 6-(2-chloro-4-methylphenyl)-2-(phenylamino)-1H-benzo[d]imidazole-4-carboxylate

[0206] In a 5 ml vial, methyl 2-bromo-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (40 mg, 105 μmol, Eq: 1) and aniline (98.1 mg, 96.2 μl, 1.05 mmol, Eq: 10) were combined with ethanol (0.5 ml). The reaction mixture was heated to 90° C. and stirred overnight. For work-up the reaction mixture was poured into 20 ml of 1M HCl and extracted with EtOAc (3×25 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by chromatography (silica gel, 12 g, 0% to 50% EtOAc in heptane to afford the title compound methyl 6-(2-chloro-4-methylphenyl)-2-(phenylamino)-1H-benzo[d]imidazole-4-carboxylate (36.4 mg, 91.5 μmol, 86.8% yield), off-white solid, MS (ESI): 392.19 [M+H]+.

f) 6-(2-Chloro-4-methylphenyl)-2-(phenylamino)-1H-benzo[d]imidazole-4-carboxylic acid

[0207] To a light yellow solution of methyl 6-(2-chloro-4-methylphenyl)-2-(phenylamino)-1H-benzo[d]imidazole-4-carboxylate (19 mg, 48.5 μmol, Eq: 1) in tetrahydrofuran (500 μl) was added lithium hydroxide (4.07 mg, 97 μmol, Eq: 2) dissolved in water (250 μl). The reaction mixture was heated to 65° C. during 4 hours, then quenched with HCl (48.5 μl, 97 μmol, Eq: 2) and concentrated in vacuo. The crude material was dissolved with a few drops of diethylether and than triturated with Heptan (2×10 ml) to obtain the title compound 6-(2-chloro-4-methylphenyl)-2-(phenylamino)-1H-benzo[d]imidazole-4-carboxylic acid (18 mg, 47.1 μmol, 97.2% yield) as white solid, MS (ESI): 378.13 [M+H]+.

Example 15

6-(2-Chloro-4-methylphenyl)-2-[(4,4-difluoropiperidin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid

[0208] ##STR00023##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using 4,4-difluoropiperidine hydrochloride instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light red solid, MS (ESI): 420.21 [M+H]+.

Example 16

2-[(4-Acetylpiperazin-1-yl)methyl]-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid

[0209] ##STR00024##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using 1-acetylpiperazine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), white solid, MS (ESI): 427.26 [M+H]+.

Example 17

6-(2-Chloro-4-methylphenyl)-2-[(N-methylanilino)methyl]-1H-benzimidazole-4-carboxylic acid

[0210] ##STR00025##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using N-methylaniline instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light yellow solid, MS (ESI): 406.18 [M+H]+.

Example 18

2-[(4-Benzylpiperazin-1-yl)methyl]-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid

[0211] ##STR00026##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using 1-benzyl-piperazine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light brown solid, MS (ESI): 475.28 [M+H]+.

Example 19

6-(2-Chloro-4-methylphenyl)-2-[(4-phenylpiperazin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid

[0212] ##STR00027##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using 1-phenyl-piperazine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light brown solid, MS (ESI): 461.29 [M+H]+.

Example 20

6-(2-Chloro-4-methylphenyl)-2-[(3-oxopiperazin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid

[0213] ##STR00028##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using piperazin-2-one instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), off-white solid, MS (ESI): 399.17 [M+H]+.

Example 21

6-(2-Chloro-4-methylphenyl)-2-[(4-hydroxypiperidin-1-yl)methyl]-1H-benzimidazole-4-carboxylic acid

[0214] ##STR00029##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using piperidin-4-ol instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), white solid, MS (ESI): 400.18 [M+H]+.

Example 22

6-(2-Chloro-4-methylphenyl)-2-[(4-methylpiperazin-1-yl)methyl]-1-benzimidazole-4-carboxylic acid

[0215] ##STR00030##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using 1-methyl-piperazine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), white solid, MS (ESI): 399.158 [M+H]+.

Example 23

6-(2-Chloro-4-methylphenyl)-2-(diethylaminomethyl)-1-benzimidazole-4-carboxylic acid

[0216] ##STR00031##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using diethylamine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light brown solid, MS (ESI): 372.147 [M+H]+.

Example 24

6-(2-Chloro-4-methylphenyl)-2-(piperidin-1-ylmethyl)-1H-benzimidazole-4-carboxylic acid

[0217] ##STR00032##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using piperidine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light brown solid, MS (ESI): 384.20 [M+H]+.

Example 25

2-(Anilinomethyl)-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid

[0218] ##STR00033##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using analine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), white solid, MS (ESI): 392.19 [M+H]+.

Example 26

2-Benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0219] ##STR00034##

a) Methyl 2-benzyl-6-bromo-1H-benzimidazole-4-carboxylate

[0220] To a mix of methyl 2,3-diamino-5-bromobenzoate (100 mg, 408 μmol, Eq: 1) and 2-phenylacetic acid (55.6 mg, 408 μmol, Eq: 1) under argon was added phosphorus oxychloride (1 ml). Vial was closed and RM was heated to 110° C. for 2 hours. The reaction mixture was quenched by adding it slowly on 25 ml of saturated NaHCO.sub.3 solution. The aqueous phase was extracted with EtOAc (3×25 ml). The organic layers were dried over MgSO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 70% EtOAc in heptane) to afford the title compound methyl 2-benzyl-6-bromo-1H-benzo[d]imidazole-4-carboxylate (113 mg, 315 μmol, 77.3% yield) as off-white solid, MS (ESI): 347.07 [M+H]+.

b) Methyl 2-benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate

[0221] Methyl 2-benzyl-6-bromo-1H-benzo[d]imidazole-4-carboxylate (107 mg, 310 μmol, Eq: 1), (2-chloro-4-methylphenyl)boronic acid (52.8 mg, 310 μmol, Eq: 1) and potassium carbonate (tribasic) (132 mg, 620 μmol, Eq: 2) were combined with dioxane (1.71 ml) and water (428 μl). The vial was degassed with argon before X-phos (7.39 mg, 15.5 μmol, Eq: 0.05) and tris(dibenzylideneacetone)dipalladium chloroform adduct (8.02 mg, 7.75 μmol, Eq: 0.025) were added. The vial was closed and the reaction mixture was heated to 110° C. and stirred for 1.5 h. For work-up the reaction mixture was poured into 20 ml of water and extracted with EtOAc (3×20 ml). The organic layers were combined, dried over Na.sub.2SO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 60% EtOAc in heptane) to afford the title compound methyl 2-benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (68.2 mg, 167 μmol, 53.9% yield) as brown oil, MS (ESI): 391.121 [M+H]+.

c) 2-Benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0222] To a colorless solution of methyl 2-benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (63.2 mg, 162 μmol, Eq: 1) in tetrahydrofuran (2.34 ml) was added lithium hydroxide monohydrate (13.6 mg, 323 μmol, Eq: 2) dissolved in water (1.17 ml). The mixture was warmed to 65° C. and stirred for 3 h. For work-up HCl (2M, 162 μl, 323 μmol, Eq: 2) was added and concentrated in vacuo. The crude material was purified by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100×30 mm, eluent acetonitrile/water) to obtain the title compound 2-benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid (3.9 mg, 9.94 μmol, 6.14% yield) as white solid, MS (ESI): 377.105 [M+H]+.

Example 27

6-(2-Chloro-4-methylphenyl)-2-[(4-chlorophenyl)methyl]-1H-benzimidazole-4-carboxylic acid

[0223] ##STR00035##

The title compound was obtained in comparable yield analogous to the procedure described for Example 26 using 2-(4-chlorophenyl)acetic acid instead of 2-phenylacetic acid in step a), white solid, MS (ESI): 411.13 [M+H]+.

Example 28

6-(2-Chloro-4-methylphenyl)-2-(morpholin-4-ylmethyl)-1H-benzimidazole-4-carboxylic acid

[0224] ##STR00036##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using morpholine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), light brown solid, MS (ESI): 386.19 [M+H]+.

Example 29

6-(2-Chloro-4-methylphenyl)-2-[(dimethylamino)methyl]-1H-benzimidazole-4-carboxylic acid

[0225] ##STR00037##

The title compound was obtained in comparable yield analogous to the procedure described for Example 7 using dimethyl amine instead of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one in step b), white solid, MS (ESI): 344.14 [M+H]+.

Example 30

6-(2-Chloro-4-methylphenyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylic acid

[0226] ##STR00038##

a) Methyl 6-bromo-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate

[0227] Methyl 2,3-diamino-5-bromobenzoate (100 mg, 408 Eq: 1) was combined with TFA (1.5 ml) to give a light yellow solution. Vial was closed under Argon and heated to 70° C. over night. LC-MS showed the reaction was complete. The reaction mixture was quenched with 25 ml sat NaHCO.sub.3 and extracted with DCM (3×25 ml). The organic layers were dried over MgSO.sub.4 and concentrated in vacuo to obtain the crude title compound methyl 6-bromo-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-carboxylate (124 mg, 376 μmol, 92.3% yield) as light brown solid, MS (ESI): 323.00 [M+H]+.

b) 6-(2-Chloro-4-methylphenyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylic acid

[0228] The title compound was obtained in comparable yield analogous to the procedure described for Example 26 using methyl 6-bromo-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate instead of methyl 2-benzyl-6-bromo-1H-benzo[d]imidazole-4-carboxylate in step b), white solid, MS (ESI): 355.09 [M+H]+.

Example 31

2-(Benzylamino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0229] ##STR00039##

a) Methyl 6-bromo-2-((tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-4-carboxylate

[0230] A mixture of methyl 2,3-diamino-5-bromobenzoate (200 mg, 816 μmol, Eq: 1), 1,3-di-boc-2-methylisothiourea (376 mg, 1.26 mmol, Eq: 1.54) and (+)-camphor-10-sulfonic acid monohydrate (14.4 mg, 56.3 μmol, Eq: 0.069) in ethanol (6 ml) was refluxed for 3 h. For work-up the reaction mixture was cooled to room temperature and filtered. The grey filter cake was washed three times with EtOH and dried. It was used without purification in the next step, (281.5 mg, 760 μmol, 93.1% yield) as grey solid, MS (ESI): 370.0372 [M+H]+.

b) Methyl 2-(benzyl(tert-butoxycarbonyl)amino)-6-bromo-1H-benzo[d]imidazole-4-carboxylate

[0231] In a three-necked flask, methyl 6-bromo-2-((tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-4-carboxylate (150 mg, 405 μmol, Eq: 1) and cesium carbonate (158 mg, 486 μmol, Eq: 1.2) were combined with dimethylformamide (12 ml) to give a grey suspension. Then benzylbromide (84.9 mg, 59 μl, 486 μmol, Eq: 1.2) was added at room temperature. The reaction mixture was stirred at room temperature overnight. For work-up the mixture was concentrated in vacuo, the residue was diluted with dichloromethane and evaporated with silica gel to dryness and separated from regioisomers by flash chromatography (silica gel, 80 g, 0% to 40% EtOAc in heptane) to afford the title compound methyl 2-(benzyl(tert-butoxycarbonyl)amino)-6-bromo-1H-benzo[d]imidazole-4-carboxylate (108 mg, 235 μmol, 58.0% yield) as white foam, MS (ESI): 458.1, 460.1 [M−H]−.

c) Methyl 2-(benzyl(tert-butoxycarbonyl)amino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate

[0232] Methyl 2-(benzyl(tert-butoxycarbonyl)amino)-6-bromo-1H-benzo[d]imidazole-4-carboxylate (50 mg, 109 Eq: 1) and (2-chloro-4-methylphenyl)boronic acid (27.8 mg, 163 μmol, Eq: 1.5) were solved in 1,4-dioxane (3 ml) and water (1.5 ml). Cesium carbonate (143 mg, 434 μmol, Eq: 4) was added and the mixture was degassed by bubbling argon through the mixture (5 min), then 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (4.44 mg, 5.43 μmol, Eq: 0.05) was added. The reaction was stirred in a sealed tube at 90° C. for 15 min. For work-up the mixture was taken up in EtOAc and washed with saturated NH.sub.4Cl solution and brine, the organic layer was dried over Na.sub.2SO.sub.4, filtrated and evaporated. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc in heptane) to afford the title compound methyl 2-(benzylamino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (51.5 mg, 102 μmol, 93.5% yield) as white foam, MS (ESI): 506.2 [M+H]+.

d) Methyl 2-(benzylamino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate

[0233] Methyl 2-(benzyl(tert-butoxycarbonyl)amino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (94 mg, 182 μmol, Eq: 1) was solved in 1,4-dioxane (1 ml). At room temperature 4M HCl in dioxane (1.39 ml, 5.56 mmol, Eq: 30.5) was added. The reaction mixture was stirred overnight at room temperature for 2 days. For work-up the mixture was taken up in EtOAc and washed with saturated NaHCO.sub.3 solution. The organic layer was dried over Na.sub.2SO.sub.4, filtrated and evaporated. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 65% EtOAc in heptane) to afford the title compound methyl 2-(benzylamino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (51.3 mg, 126 μmol, 69.2% yield) as white foam, MS (ESI): 406.2 [M+H]+.

e) 2-(Benzylamino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0234] Methyl 2-(benzylamino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (49.5 mg, 120 μmol, Eq: 1) was solved in THF (1 ml). At room temperature aqueous lithium hydroxide solution (1M, 301 μl, 301 μmol, Eq: 2.5) was added and the mixture was stirred at 65° C. overnight. For work-up the mixture was diluted with water, HCl (2M, 150 μl, 301 μmol, Eq: 2.5) was added and the pH was adjusted to 3. The mixture was extracted three times with 2-methyltetrahydrofuran, the combined organic layers were dried over Na.sub.2SO.sub.4, filtrated and evaporated to afford the title compound 2-(benzylamino)-6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid (44 mg, 112 μmol, 93.3% yield) as white solid, MS (ESI): 392.3 [M+H]+.

Example 32

6-(2-Chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylic acid

[0235] ##STR00040##

The title compound was obtained in comparable yield analogous to the procedure described for Example 26 using methyl 6-bromo-2-methyl-1H-benzimidazole-4-carboxylate instead of methyl 2-benzyl-6-bromo-1H-benzo[d]imidazole-4-carboxylate in step b), white solid, MS (ESI): 301.1 [M+H]+.

Example 33

[0236] Malachite Green Assay to Measure cGAS Activity
Compounds were tested for cGAS inhibition in a coupled enzymatic assay based on Phosphate detection by Malachite Green. Final assay conditions were 20 mM TRIS pH 7.5 (Applichem), 5 mM MgCl.sub.2 (Sigma) and 0.01% BSA (Sigma) supplemented with 80 ATP (Sigma), 80 μM GTP (Sigma) and 100 nM Interferon Stimulating DNA (ISD) (Microsynth). Recombinantly expressed purified human cGAS (residues 161-522) was used at 25 nM.
All compounds were prepared as 10 mM stock solutions in DMSO and a 16 pt dilution series in DMSO with a dilution factor of 2.5 was prepared. 1 μL of DMSO dilution series was transferred to 32.3 μL reaction buffer, mixed by pipetting up/down, spun for 1 minute at 3000 rpm and was visually inspected for precipitation. 5 μL of 3-fold enzyme stock solution were transferred to an empty 384-well Black/Clear Flat Bottom Polystyrene NBS (Corning) rows 3-24. Rows 1-2 were filled with assay buffer. Plates were spun 10 seconds at 1000 rpm (164×g). 5 μL of compound intermediate dilution was added and mixed by pipetting up/down to rows 3-24. Rows 1-2 were filled with 3.1% DMSO assay buffer. Plates were spun 10 seconds at 1000 rpm (164×g). 5 μL 3-fold Nucleotide/DNA mix was added to all wells to start the reaction. Plates were spun 10 seconds at 1000 rpm (164×g) and incubated for 4 hour at room temperature (RT) in the dark. 5 μL 4 U/mL PPase (Sigma) were added to all wells. Plates spun 10 seconds at 1000 rpm (164×g). 10 μL BioMol green Solution (Enzo Life Sciences) was added to all wells. Plates spun 10 seconds at 1000 rpm (164×g) and incubated 30 minutes at RT in the dark. Absorbance data was collected 620 nm on an EnVision Multilable Reader (Perkin Elmer) and the following measurement settings were used: excitation filter photometric was 620 nm; excitation from the top; measurement height was 1 mm; number of flashes was 30; number of flashes integrated was 1.
All plates are checked for abnormalities and outliers in the Blank Control (no protein, row 1) and the Neutral Control (no compound, row 2) are excluded using the 3*SD rule. Data was normalized to 0 and 100% by Blank and Neutral Control and each curve was fitted and judged using the 4 parameter logistic equation to determine the IC50 for cGAS inhibition.
The results of this assay are provided in Table 1. Table 1 provides IC50 values (μM) for cGAS inhibition obtained for particular examples of the present invention as measured by the above-described assay.

TABLE-US-00001 Example IC50 cGAS (μM) 1 4.68 2 0.54 3 0.55 4 4.37 5 3.26 6 2.08 7 0.26 8 0.59 9 0.38 10 0.51 11 0.60 12 1.14 13 0.55 14 1.16 15 0.26 16 1.51 17 1.23 18 0.14 19 1.25 20 0.59 21 0.41 22 0.13 23 0.48 24 0.36 25 0.69 26 1.02 27 1.48 28 0.35 29 0.59 30 3.02 31 0.84 32 2.41

Example A

[0237] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

TABLE-US-00002 Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg
The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution/suspension of the above mentioned film coat.

Example B

[0238] Capsules containing the following ingredients can be manufactured in a conventional manner:

TABLE-US-00003 Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg
The components are sieved and mixed and filled into capsules of size 2.

Example C

[0239] Injection solutions can have the following composition:

TABLE-US-00004 Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml
The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.