Biphenyl Derivatives

Abstract

The invention relates to a compound of formula (I) wherein R.sup.1—R.sup.3 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) ##STR00015## wherein R.sup.1 is —NHC(O)—R.sup.3 or —OR.sup.3; R.sup.2 is halogen; and R.sup.3 is triazolylalkyl, alkyl(oxo-dihydropyrimidinyl)alkyl, morpholinylalkyl, imidazolylalkyl, (dioxo-thiazinanyl)alkyl or phenylalkyl; or a pharmaceutically acceptable salt or ester thereof.

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

3. A compound according to claim 1 or 2, wherein R.sup.3 is triazolylalkyl, morpholinylalkyl or imidazolylalkyl.

4. A compound according to any one of claims 1 to 3, wherein R.sup.3 is triazolylmethyl, morpholinylmethyl or imidazolylethyl.

5. A compound according to any one of claims 1 to 4 selected from 4-(2-(1H-1,2,4-triazol-1-yl)acetamido)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylic acid; 2′-chloro-4′-methyl-4-(2-(2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetamido)-[1,1′-biphenyl]-3-carboxylic acid; 2′-chloro-4′-methyl-4-(3-morpholinopropanamido)-[1,1′-biphenyl]-3-carboxylic acid; 5-(2-chloro-4-methylphenyl)-2-[(2-morpholin-4-ylacetyl)amino]benzoic acid; 5-(2-chloro-4-methylphenyl)-2-[(2-phenylacetyl)amino]benzoic acid; 5-(2-chloro-4-methylphenyl)-2-(2-imidazol-1-ylethoxy)benzoic acid; 5-(2-chloro-4-methylphenyl)-2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]benzoic acid; and 5-(2-chloro-4-methylphenyl)-2-phenylmethoxybenzoic acid; or a pharmaceutically acceptable salt or ester thereof.

6. A compound according to any one of claims 1 to 5 selected from 4-(2-(1H-1,2,4-triazol-1-yl)acetamido)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylic acid; 5-(2-chloro-4-methylphenyl)-2-[(2-morpholin-4-ylacetyl)amino]benzoic acid; and 5-(2-chloro-4-methylphenyl)-2-(2-imidazol-1-ylethoxy)benzoic acid; or a pharmaceutically acceptable salt or ester thereof.

7. A process for the preparation of a compound according to any one of claims 1 to 6, comprising the following step: the saponification of a compound of formula (A1) ##STR00016## with a base or an acid in a suitable solvent for 1-18 h at 0°-70° C., wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in any one of claims 1 to 7 and R.sup.4 is alkyl (C1-C8).

8. A compound according to any one of claims 1 to 6, when manufactured according to a process of claim 7.

9. A compound according to any one of claims 1 to 6 for use as therapeutically active substance.

10. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 6 and a therapeutically inert carrier.

11. The use of a compound according to any one of claims 1 to 6 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).

12. The use of a compound according to any one of claims 1 to 6 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).

13. A compound according to any one of claims 1 to 6 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).

14. 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 6 to a patient in need thereof.

15. The invention as hereinbefore described.

Description

EXAMPLES

[0072] Abbreviations

[0073] DCM=dichloromethane; DMF=dimethylformamide; DMSO=dimethyl sulfoxide; ESI=electrospray ionization; EtOAc=ethyl acetate; HPLC=high performance liquid chromatography; MS=mass spectrometry; RT=room temperature.

Synthesis of Intermediate A

Methyl 4-amino-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate

[0074] ##STR00005##

[0075] Methyl 2-amino-5-bromobenzoate (5 g, 21.7 mmol, Eq: 1), (2-chloro-4-methylphenyl) boronic acid (3.7 g, 21.7 mmol, Eq: 1) and potassium phosphate (9.23 g, 43.5 mmol, Eq: 2) were combined with dioxane (80 ml) and water (20 ml). The vial was degassed with argon before X-phos (518 mg, 1.09 mmol, Eq: 0.05) and tris(dibenzylideneacetone)dipalladium-chloroform adduct (562 mg, 543 μmol, Eq: 0.025) were added. The vial was closed and the reaction mixture was heated to 110° C. and stirred for 2 h. The reaction mixture was poured into 50 ml of water and extracted with EtOAc (3×50 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, 120 g, 0% to 40% EtOAc in heptane). The fractions were combined, concentrated and dried in vacuo to afford the title compound methyl 4-amino-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate (5.08 g, 15.7 mmol, 72.3% yield) as brown solid. MS (ESI): 276.17 [M+H]+.

Synthesis of Intermediate B

Methyl 2′-chloro-4-hydroxy-4′-methyl-[1,1′-biphenyl]-3-carboxylate

[0076] ##STR00006##

[0077] To a light yellow solution of methyl 5-bromo-2-hydroxybenzoate (2 g, 8.66 mmol, Eq: 1) in dioxane (40 ml) was added (2-chloro-4-methylphenyl)boronic acid (1.48 g, 8.66 mmol, Eq: 1). Potassium phosphate (3.67 g, 17.3 mmol, Eq: 2) solved in water (10 ml) was added. The reaction mixture was degassed during 2 min before X-phos (206 mg, 433 μmol, Eq: 0.05) and tris(dibenzylideneacetone)dipalladium-chloroform adduct (224 mg, 216 μmol, Eq: 0.025) were added. The mixture was heated to 100° C. for 1 hour. The reaction mixture was 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, 40 g, 0% to 20% EtOAc in heptane) to afford the title compound methyl 2′-chloro-4-hydroxy-4′-methyl-[1,1′-biphenyl]-3-carboxylate (1.9 g, 6.39 mmol, 73.8% yield) as light yellow solid, MS (ESI): 277.22 [M+H]+.

Example 1

4-(2-(1H-1,2,4-Triazol-1-yl)acetamido)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylic Acid

[0078] ##STR00007##

[0079] a) Methyl 4-(2-(1H-1,2,4-triazol-1-yl)acetamido)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate

[0080] In a 5 ml vial, methyl 4-amino-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate, Intermediate A (80 mg, 290 μmol, Eq: 1) and 2-(1H-1,2,4-triazol-1-yl)acetic acid (36.9 mg, 290 μmol, Eq: 1) were combined with pyridine (1.25 ml). At −15° C. phosphorus oxychloride (55.2 mg, 33.5 μl, 360 μmol, Eq: 1.24) was added and the reaction mixture was stirred for 1 h. The crude reaction mixture was quenched with water, basified with 10 ml sat NaHCO.sub.3 and extracted with EtOAc (4×50 ml). The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to afford the title compound methyl 4-(2-(1H-1,2,4-triazol-1-yl)acetamido)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate (76.8 mg, 197 μmol, 68% yield) as white solid, MS (ESI): 385.14 [M+H]+.

[0081] b) 4-(2-(1H-1,2,4-Triazol-1-yl)acetamido)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylic acid

[0082] To a light yellow solution (under argon in a 10 ml flask) of methyl 4-(2-(1H-1,2,4-triazol-1-yl) acetamido)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate (40 mg, 104 μmol, Eq: 1) in tetrahydrofuran (1.2 ml) was added lithium hydroxide monohydrate (8.72 mg, 208 μmol, Eq: 2) solved in water (300 μl). The reaction mixture was heated to 65° C. and stirred during 4 hours. The mixture was quenched with HCl 2M (104 μl, 208 μmol, Eq: 2) and concentrated in vacuo. The crude material was triturated with diethyl ether (2×5 ml) and purified by preparative HPLC to obtain the title compound 4-(2-(1H-1,2,4-triazol-1-yl) acetamido)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylic acid (14.6 mg, 39.3 μmol, 37.8% yield) as white solid, MS (ESI): 371.21 [M+H]+.

Example 2

2′-Chloro-4′-methyl-4-(2-(2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetamido)-[1,1′-biphenyl]-3-carboxylic Acid

[0083] ##STR00008##

[0084] The title compound was obtained in comparable yield analogous to the procedure described for Example 1 using 2-(2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetic acid hydrochloride instead of 2-(1H-1,2,4-triazol-1-yl)acetic acid in step a), white solid, (MS (ESI): 412.22 [M+H]+.

Example 3

2′-Chloro-4′-methyl-4-(3-morpholinopropanamido)-[1,1′-biphenyl]-3-carboxylic Acid

[0085] ##STR00009##

[0086] The title compound was obtained in comparable yield analogous to the procedure described for Example 1 using 3-morpholinopropanoic acid hydrochloride instead of 2-(1H-1,2,4-triazol-1-yl)acetic acid in step a), white solid, (MS (ESI): 403.26 [M+H]+.

Example 4

5-(2-Chloro-4-methylphenyl)-2-[(2-morpholin-4-ylacetyl)amino]benzoic Acid

[0087] ##STR00010##

[0088] The title compound was obtained in comparable yield analogous to the procedure described for Example 1 using 2-morpholinoacetic acid instead of 2-(1H-1,2,4-triazol-1-yl) acetic acid in step a), off-white solid, MS (ESI): 389.23 [M+H]+.

Example 5

5-(2-Chloro-4-methylphenyl)-2-[(2-phenylacetyl)amino]benzoic Acid

[0089] ##STR00011##

[0090] a) Methyl 2′-chloro-4′-methyl-4-(2-phenylacetamido)-[1,1′-biphenyl]-3-carboxylate

[0091] To a light yellow solution of methyl 4-amino-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate, Intermediate A (75 mg, 272 μmol, Eq: 1) and triethylamine (55 mg, 75.8 μl, 544 μmol, Eq: 2) in dichloromethane (2 ml) was added 2-phenylacetyl chloride (92.5 mg, 79 μl, 598 μmol, Eq: 2.2). The reaction mixture was stirred at room temp during 4 hours. The reaction mixture was poured into 25 ml saturated NaHCO.sub.3 solution and extracted with dichloromethane (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 30% EtOAc in heptane) to afford the title compound methyl 2′-chloro-4′-methyl-4-(2-phenylacetamido)-[1,1′-biphenyl]-3-carboxylate (67.3 mg, 123 μmol, 45.1% yield) as colorless oil. MS (ESI): 394.11 [M+H]+.

[0092] b) 5-(2-Chloro-4-methylphenyl)-2-[(2-phenylacetyl)amino]benzoic acid

[0093] The title compound was obtained in comparable yield analogous to the procedure described for Example 1 using methyl 2′-chloro-4′-methyl-4-(2-phenylacetamido)-[1,1′-biphenyl]-3-carboxylate in step b), light brown solid, MS (ESI): 380.19 [M+H]+.

Example 6

5-(2-Chloro-4-methylphenyl)-2-(2-imidazol-1-ylethoxy)benzoic Acid

[0094] ##STR00012##

[0095] a) Methyl 4-(2-(1H-imidazol-1-yl)ethoxy)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate

[0096] To a light yellow solution of methyl 2′-chloro-4-hydroxy-4′-methyl-[1,1′-biphenyl]-3-carboxylate, Intermediate B (100 mg, 361 μmol, Eq: 1), 2-(1H-imidazol-1-yl)ethan-1-ol (44.6 mg, 398 μmol, Eq: 1.1) and triphenylphosphine (114 mg, 434 μmol, Eq: 1.2) in tetrahydrofuran (2 ml) was added di-tert-butyl azodicarboxylate (108 mg, 470 μmol, Eq: 1.3). The reaction mixture was stirred at room temp over night. 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 4-(2-(1H-imidazol-1-yl)ethoxy)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate (83.8 mg, 204 μmol, 56.5% yield) as colorless viscous oil. MS (ESI): 371.16 [M+H]+.

[0097] b) 5-(2-Chloro-4-methylphenyl)-2-(2-imidazol-1-ylethoxy)benzoic acid

[0098] The title compound was obtained in comparable yield analogous to the procedure described for Example 1 using methyl 4-(2-(1H-imidazol-1-yl)ethoxy)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate in step b), white solid, MS (ESI): 357.19 [M+H]+.

Example 7

5-(2-Chloro-4-methylphenyl)-2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]benzoic Acid

[0099] ##STR00013##

[0100] The title compound was obtained in comparable yield analogous to the procedure described for Example 6 using 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide instead of 2-(1H-imidazol-1-yl)ethan-1-ol in step a), light brown solid, MS (ESI): 424.26 [M+H]+.

Example 8

5-(2-Chloro-4-methylphenyl)-2-phenylmethoxybenzoic Acid

[0101] ##STR00014##

[0102] a) Methyl 4-(benzyloxy)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate

[0103] Methyl 2-(benzyloxy)-5-bromobenzoate (150 mg, 467 μmol, Eq: 1), (2-chloro-4-methylphenyl) boronic acid (79.6 mg, 467 μmol, Eq: 1) and potassium phosphate (tribasic) (198 mg, 934 μmol, Eq: 2) were combined with dioxane (2.5 ml) and water (625 μl). The vial was degassed with argon before X-phos (11.1 mg, 23.4 μmol, Eq: 0.05) and tris(dibenzylideneacetone)dipalladium-chloroform adduct (12.1 mg, 11.7 μmol, Eq: 0.025) were added. The vial was closed and the reaction mixture was heated to 110° C. and stirred for 2 h. The reaction mixture was poured into 40 ml of water and extracted with EtOAc (3×40 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 flash chromatography (silica gel, 40 g, 0% to 40% EtOAc in heptane). The fractions were combined, concentrated and dried in vacuo. The compound was purified by preparative HPLC to afford the title compound methyl 4-(benzyloxy)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate (46.4 mg, 126 μmol, 27.1% yield) as off-white solid, MS (ESI): 367.110 [M+H]+.

[0104] b) 5-(2-Chloro-4-methylphenyl)-2-phenylmethoxybenzoic acid

[0105] The title compound was obtained in comparable yield analogous to the procedure described for Example 1 using methyl 4-(benzyloxy)-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate in step b), off-white solid, MS (ESI): 353.14 [M+H]+.

Example 9

Malachite Green Assay to Measure cGAS Activity

[0106] 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 μM 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.

[0107] 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.

[0108] 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.

[0109] 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 1.83 2 2.09 3 4.82 4 0.32 5 3.07 6 2.8 7 2.67 8 4.21

Example A

[0110] 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

[0111] 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

[0112] 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

[0113] The components are sieved and mixed and filled into capsules of size 2.

Example C

[0114] 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

[0115] 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.