Factor XIa inhibitors

Abstract

The present invention provides a compound of Formula (I) ##STR00001##
and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoaguability or fibrotic changes.

Claims

1. A compound of Formula I ##STR00152## or a pharmaceutically acceptable salt thereof, where A is 1) 6-membered monocyclic carbocycle unsubstituted or mono-substituted with R.sup.3 or di-substituted with R.sup.3 and R.sup.4, or 2) 10-membered bicyclic carbocycle unsubstituted or substituted with R.sup.3; R.sup.1 is 1) C.sub.1-6 alkyl, or 2) 6-membered monocyclic carbocycle unsubstituted or substituted with R.sup.7; R.sup.1a is H or CH.sub.3; R.sup.2 is benzimidazole, which is unsubstituted or substituted with R.sup.16, R.sup.17 or R.sup.18; R.sup.3 is tetrazole; R.sup.4 is 1) —C(NH)NH.sub.2, 2) —NH.sub.2, 3) Halogen, 4) —C.sub.1-6 alkyl, unsubstituted or substituted with —OH, F or —NH.sub.2; 5) —C(O)OC.sub.1-6 alkyl, 6) —CF.sub.3, 7) —NO.sub.2, 8) —CN, or 9) —OC.sub.1-6 alkyl; R.sup.7 is halogen, —CF.sub.3 or —OCF.sub.3; R.sup.10 is 4-6-membered carbocycle either unsubstituted or substituted with —NHC(O)OH; R.sup.14 is C.sub.1-6 alkyl unsubstituted or substituted with —OH, —C.sub.6H.sub.5, or —((CH.sub.2).sub.n—O).sub.m—CH.sub.3, where m is 1 or 2 and n is 1 or 2; R.sup.16 is and R.sup.17 are each independently 1) 6-membered carbocycle unsubstituted or substituted with R.sup.20, or 2) 6-membered carbocycle unsubstituted or substituted with R.sup.19; R.sup.18 is 1) —C(O)OC.sub.1-6 alkyl, 2) —C(O)OH, 3) halogen, 4) —P(O)(OC.sub.1-6 alkyl)(OC.sub.1-6 alkyl), 5) —P(O)(OH).sub.2, 6) —SO.sub.2C.sub.1-6 alkyl, 7) —CN, 8) —CF.sub.3, 9) —C(O)NHR.sup.10, 10) —NHC(O)OR.sup.14, 11) —NHC(O)R.sup.10, or 12) —P(O)(NHC.sub.1-6 alkyl)(NH C.sub.1-6 alkyl); R.sup.19 and R.sup.20 are each independently 1) halogen, 2) —SO.sub.2C.sub.1-6 alkyl, 3) —CF.sub.3, 4) —CN, 5) —OC.sub.1-6 alkyl, 6) —OCF.sub.3, 7) —C.sub.1-6 alkyl, 8) —C(O)NHR.sup.10, 9) —NHC(O)R.sup.10, 10) —P(O)(OH).sub.2, 11) —P(O)(OC.sub.1-6 alkyl)(OC.sub.1-6 alkyl), or 12) —P(O)(NHC.sub.1-6 alkyl)(NH C.sub.1-6 alkyl).

2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, where A is 1) 6-membered monocyclic carbocycle unsubstituted or mono-substituted with R.sup.3 or di-substituted with R.sup.3 and R.sup.4, or 2) 10-membered bicyclic carbocycle unsubstituted or substituted with R.sup.3; R.sup.1 is 1) C.sub.1-6 alkyl, or 2) 6-membered monocyclic carbocycle unsubstituted or substituted with R.sup.7; R.sup.1a is H or CH.sub.3; R.sup.2 is benzimidazole, which is unsubstituted or substituted with R.sup.18; R.sup.3 is tetrazole; R.sup.4 is 1) —C(NH)NH.sub.2, 2) —NH.sub.2, 3) Halogen, 4) —C.sub.1-6 alkyl, unsubstituted or substituted with —OH, F or —NH.sub.2, 5) —C(O)OC.sub.1-6 alkyl, 6) —CF.sub.3, 7) —NO.sub.2, 8) —CN, or 9) —OC.sub.1-6 alkyl; R.sup.7 is halogen, —CF.sub.3 or —OCF.sub.3; R.sup.10 is 4-6-membered carbocycle either unsubstituted or substituted with —NHC(O)OH; R.sup.14 is C.sub.1-6 alkyl unsubstituted or substituted with —OH, —C.sub.6H.sub.5, or —((CH.sub.2).sub.n—O).sub.m—CH.sub.3, where m is 1 or 2 and n is 1 or 2; R.sup.18 is 1) —C(O)OC.sub.1-6 alkyl, 2) —C(O)OH, 3) halogen, 4) —P(O)(OC.sub.1-6 alkyl)(OC.sub.1-6 alkyl), 5) —P(O)(OH).sub.2, 6) —SO.sub.2C.sub.1-6 alkyl, 7) —CN, 8) —CF.sub.3, 9) —C(O)NHR.sup.10, 10) —NHC(O)OR.sup.14, 11) —NHC(O)R.sup.10, or 12) —P(O)(NHC.sub.1-6 alkyl)(NH C.sub.1-6 alkyl).

3. A compound of claim 2 of formula Ia ##STR00153## or a pharmaceutically acceptable salt thereof, where A is 1) 6-membered monocyclic carbocycle unsubstituted or mono-substituted with R.sup.3 or di-substituted with R.sup.3 and R.sup.4, or 2) 10-membered bicyclic carbocycle unsubstituted or substituted with R.sup.3; R.sup.1 is 1) C.sub.1-6 alkyl, or 2) 6-membered monocyclic carbocycle unsubstituted or substituted with R.sup.7; R.sup.2 is benzimidazole, which is unsubstituted or substituted with R.sup.18; R.sup.3 is tetrazole; R.sup.4 is —NO.sub.2, C.sub.1-6 alkyl, —CN, —NH.sub.2, or —OC.sub.1-6 alkyl; R.sup.7 is halogen, —CF.sub.3 or —OCF.sub.3; R.sup.10 is 4-6-membered carbocycle either unsubstituted or substituted with —NHC(O)OH; R.sup.14 is C.sub.1-6 alkyl unsubstituted or substituted with —OH, —C.sub.6H.sub.5, or —((CH.sub.2).sub.n—O).sub.m—CH.sub.3, where m is 1 or 2 and n is 1 or 2; R.sup.18 is 1) —C(O)OC.sub.1-6 alkyl, 2) —C(O)OH, 3) halogen, 4) —P(O)(OC.sub.1-6 alkyl)(OC.sub.1-6 alkyl), 5) —P(O)(OH).sub.2, 6) —SO.sub.2C.sub.1-6 alkyl, 7) —CN, 8) —CF.sub.3, 9) —C(O)NHR.sup.10, 10) —NHC(O)OR.sup.14, 11) —NHC(O)R.sup.10, or 12) —P(O)(NHC.sub.1-6 alkyl)(NH C.sub.1-6 alkyl).

4. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein A is ##STR00154## R.sup.1 is ##STR00155## R.sup.2 is ##STR00156## R.sup.3 is ##STR00157## R.sup.4 is —NO.sub.2, —CH.sub.3, —CN, —NH.sub.2, or —OCH.sub.3, or R.sup.7 is —Cl, F, or —OCF.sub.3; R.sup.18 is —C(O)OCH.sub.3, —C(O)OCH.sub.2CH.sub.3, —C(O)OH, —F, —P(O)(OCH.sub.2CH.sub.3).sub.2, —P(O)(OH).sub.2, —C(O)OC(CH.sub.3).sub.3, —CN or —P(O)(NHC.sub.1-6 alkyl)(NHC.sub.1-6 alkyl).

5. A compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein A is ##STR00158## R.sup.1 is ##STR00159## R.sup.2 is ##STR00160##

6. A compound, or a pharmaceutically acceptable salt thereof, which is tert-butyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate, (S)-tert-butyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate, (R)-tert-butyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate, (S)-2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid, methyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate, 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid, 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-fluoro-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one, (S)-methyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate, (S)-ethyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole-5-carboxylate, (S)-2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole-5-carboxylic acid, (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-fluoro-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one, (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one, (R)-methyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate, (R)-2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid, (R)-ethyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole-5-carboxylate, (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-fluoro-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one, (S)-diethyl (2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazol-5-yl)phosphonate, (S)-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazol-5-yl)phosphonic acid.

7. A composition for inhibiting thrombus formation in blood comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

Description

EXAMPLES

Example 1

(1) ##STR00056##

Step A: Preparation of tert-butyl 4-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate (1a)

(2) HATU (1.25 g, 3.29 mmol) was added to a stirred solution of i-2a (1.01 g, 2.53 mmol), tert-butyl 4-aminobenzoate (489 mg, 2.53 mmol) and 4-methylmorpholine (0.56 mL, 5.07 mmol) in DMF (12.5 mL), and the reaction mixture was allowed to stir at rt. After 20 h, the reaction mixture was partitioned between EtOAc and water, and the layers were separated. The organic layer was washed with water and brine, dried (Na.sub.2SO.sub.4), filtered and concentrated. The resulting crude brown solid was dissolved in DCM, and hexanes was added to promote precipitation. The slurry was filtered, and the solid was rinsed with DCM and isolated to afford 1a as an off-white solid. Additional quantities of 1a were isolated from purification of the concentrated filtrate by flash chromatography on silica gel (gradient elution; 0%-50% EtOAc/hexanes as eluent). m/z (ES) 574 (MH).sup.+.

Step B: Preparation of 4-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid (1b)

(3) Trifluoroacetic acid (160 μL) was added to a stirred solution of 1a (18 mg, 0.031 mmol) in DCM (0.48 mL) at rt. After 30 min, the reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by preparative reverse phase HPLC on YMC Pack Pro C18 stationary phase (CH.sub.3CN/H.sub.2O as eluent, 0.05% TFA as modifier), and lyophilization of the purified fractions afforded the title compound 1b. m/z (ES) 518 (MH).sup.+.

(4) ##STR00057##

Step C: Preparation of tert-butyl 4-(2-(4-(2-amino-5-chlorophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate (1c)

(5) Tin chloride dihydrate (5.66 g, 25.1 mmol) was added to a stirred suspension of 1a (4.80 g, 8.36 mmol) in EtOH (40 mL; 95% EtOH and 5% IPA), and the reaction mixture was heated to 35° C. After 16 h, the reaction was cooled to rt partially concentrated in vacuo. The resulting mixture was diluted with EtOAc and quenched via addition of 5N NaOH, which resulted in the formation of a white precipitate. The slurry was filtered through a Celite® column, and the column was rinsed with EtOAc. The organics were washed with water and brine, dried (Na.sub.2SO.sub.4), filtered and concentrated to afford 1c as a yellow solid. m/z (ES) 544 (MH).sup.+.

Step D: Preparation of tert-butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate (1d)

(6) Sodium azide (1.36 g, 21.0 mmol) was added to a stirred solution of 1c (3.80 g, 6.98 mmol) and trimethyl orthoformate (3.86 mL, 34.9 mmol) in AcOH (28 mL), and the resulting mixture was heated to 90° C. After 2.5 h, the reaction was cooled to 0° C., diluted with EtOAc and quenched via addition of satd. aq. NaHCO.sub.3. The layers were separated, and the organics were washed with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated. The resulting crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-100% EtOAc/hexanes as eluent) to afford the title compound 1d as a white solid. m/z (ES) 619 (MNa).sup.+.

Step E: Preparation of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid (1e)

(7) Trifluoroacetic acid (6.3 mL) was added to a stirred solution of 1d (1.70 g, 2.85 mmol) in DCM (12.5 mL) at rt. After 20 min, the reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by preparative reverse phase HPLC on YMC Pack Pro C18 stationary phase (CH.sub.3CN/H.sub.2O as eluent, 0.05% TFA as modifier), and lyophilization of the purified fractions afforded the title compound 1e. m/z (ES) 563 (MNa).sup.+.

(8) ##STR00058## 1f: (R)-tert-butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate 1g: (S)-tert-butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate

Step F: Preparation of 1f and 1g

(9) Enantiomers 1f and 1g were separated using preparative normal phase chiral HPLC. A solution of 1d in methanol was injected onto a ChiralCel® OJ-H (available from Chiral Technologies, Inc., Exton, Pa.) semi-preparative (250×20 mm) HPLC column (eluting with 50% methanol and 0.2% diethylamine/CO.sub.2 with a column temperature of 35° C. at 50 mL/min with UV detection at 220 nm). The enantiomers were separated with the faster eluting enantiomer 1f (α.sub.D +52°, methanol) having a retention time of 2.99 min, and the slower eluting enantiomer 1g (α.sub.D −40°, methanol) having a retention time of 4.85 min.

(10) TABLE-US-00005 TABLE 1A R 0 1Aa 1Ba 1Ab 1Bb 1Ac 1Bc 1Ad 1Bd 1Ae 1Be 1Af 1Bf 1Ag 1Bg 1Ah 1Bh 1Ai 1Bi 0 1Aj — 1Ak 1Bk 1Al 1Bl 1Am 1Bm 1An 1Bn 1Ao 1Bo 1Ap 1Bp 1Aq 1Bq 1Ar 1Br 1As 1Bs 0 1At 1Bt 1Au 1Bu 1Av 1Bv 1Aw 1Bw 1Ax 1Bx 1Ay 1By 1Az 1Bz 1Aaa 1Baa 1Aab 1Bab
Table 1A. Parent Ion m/z (MH).sup.+ data for compounds For 1Aa: 2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-(2H)-yl)-N-(1H-indazol-5-yl)-3-phenylpropanamide; m/z (ES) 514 (MH).sup.+. For 1Ab: 2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-phenylpropanamide; m/z (ES) 530 (MH).sup.+. For 1Ac: 2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-(2H)-yl)-3-phenyl-N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propanamide; m/z (ES) 582 (MH).sup.+. For 1Ad: N-(4-(2H-tetrazol-5-yl)phenyl)-2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide; m/z (ES) 542 (MH).sup.+. For 1Ae: 2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-phenylpropanamide; m/z (ES) 531 (MH).sup.+. For 1Af: N-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(4-(5-chloro-2-nitrophenyl-2-oxopyridin-1(2)-yl)-3-phenylpropanamide; m/z (ES) 515 (MH).sup.+. For 1Ag: ethyl (4-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)phenyl)carbamate; m/z (ES) 582 (MNa).sup.+. For 1Ah: N-(1H-benzo[d]imidazol-6-yl)-2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide; m/z (ES) 514 (MH).sup.+. For 1Ai: methyl (3-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-(4-chlorophenyl)propanamido)phenyl)carbamate; m/z (ES) 547 (MH).sup.+. For 1Aj: 4-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 518 (MH).sup.+. For 1Ak: methyl (3-((2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-(2H)-yl)-3-phenylpropanamido)methyl)phenyl)carbamate; m/z (ES) 561 (MH).sup.+. For 1Al: methyl (4-((2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)methyl)phenyl)carbamate; m/z (ES) 561 (MH).sup.+. For 1Am: tert-butyl 2-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate; m/z (ES) 607 (MH).sup.+. For 1An: tert-butyl 2-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanoyl)octahydropyrrolo[3,4-c]azepine-5(1H)-carboxylate; m/z (ES) 621 (MH).sup.+. For 1Ao: benzyl 2-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanoyl)-2,7-diazaspiro[4.5]decane-7-carboxylate; m/z (ES) 655 (MH).sup.+. For 1Ap: tert-butyl 4-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanoyl)-3-(hydroxymethyl)piperazine-1-carboxylate; m/z (ES) 597 (MH).sup.+. For 1Aq: 1-(1-(2-benzyl-4-(2-methoxyphenyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)-4-(5-chloro-2-nitrophenyl)pyridin-2(1H)-one; m/z (ES) 663 (MH).sup.+. For 1Ar: 4-(5-chloro-2-nitrophenyl)-1-(1-oxo-3-phenyl-1-(1-phenyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)propan-2-yl)pyridin-2(1H)-one; m/z (ES) 629 (MH).sup.+. For 1As: 2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-N-(cyclobutylmethyl)-3-phenyl-N-((tetrahydrofuran-2-yl)methyl)propanamide; m/z (ES) 550 (MH).sup.+. For 1 At: 4-(5-chloro-2-nitrophenyl)-1-(1-(3-(2,2-difluoro-1-hydroxyethyl)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)pyridin-2(1H)-one; m/z (ES) 532 (MH).sup.+. For 1Au: 4-(5-chloro-2-nitrophenyl)-1-(1-oxo-3-phenyl-1-(6-(pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)propan-2-yl)pyridin-2(1H)-one; m/z (ES) 556 (MH).sup.+. For 1Av: 1-(1-(4-((1H-benzo[d]imidazol-2-yl)methyl)-1,4-diazepan-1-yl)-1-oxo-3-phenylpropan-2-yl)-4-(5-chloro-2-nitrophenyl)pyridin-2(1H)-one; m/z (ES) 611 (MH).sup.+. For 1Aw: 4-(5-chloro-2-nitrophenyl)-1-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)piperidin-1-yl)-1-oxo-3-phenylpropan-2-yl)pyridin-2(1H)-one; m/z (ES) 551 (MH).sup.+. For 1Ax: 4-(5-chloro-2-nitrophenyl)-1-(1-oxo-3-phenyl-1-(1-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propan-2-yl)pyridin-2(1H)-one; m/z (ES) 601 (MH).sup.+. For 1Ay: 4-(5-chloro-2-nitrophenyl)-1-(1-oxo-3-phenyl-1-(3-(pyridin-3-yl)piperidin-1-yl)propan-2-yl)pyridin-2(1H)-one; m/z (ES) 543 (MH).sup.+. For 1Az: 4-(5-chloro-2-nitrophenyl)-1-(1-(3-isopropyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-1-oxo-3-phenylpropan-2-yl)pyridin-2(1H)-one; m/z (ES) 546 (MH).sup.+. For 1Aaa: N-(2-(1H-indol-3-yl)ethyl)-2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-N-(2-hydroxyethyl)-3-phenylpropanamide; m/z (ES) 585 (MH).sup.+. For 1Aab: 4-(5-chloro-2-nitrophenyl)-1-(1-(3-(4-(dimethylamino)phenyl)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)pyridin-2(1H)-one; m/z (ES) 571 (MH).sup.+. For 1Bb: 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-phenylpropanamide; m/z (ES) 553 (MH).sup.+. For 1Bh: N-(1H-benzo[d]imidazol-6-yl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide; m/z (ES) 537 (MH).sup.+.

(11) TABLE-US-00006 TABLE 1B R 0 4-F-phenyl 1Ca 1Da 1Ea 1Fa 3-F-phenyl 1Cb 1Db 1Eb 1Fb 4-Cl-phenyl 1Cc 1Dc 1Ec 1Fc 3-Cl-phenyl 1Cd 1Dd 1Ed 1Fd 4-(CF3O)- 1Ce 1De 1Ee 1Fe phenyl
Table 1B. Parent Ion m/z (MH).sup.+ data for compounds For 1Ca: 4-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)propanamido)benzoic acid; m/z (ES) 536 (MH).sup.+. For 1Cc: 4-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-(4-chlorophenyl)propanamido)benzoic acid; m/z (ES) 552 (MH).sup.+. For 1Cd: 4-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-(3-chlorophenyl)propanamido)benzoic acid; m/z (ES) 552 (MH).sup.+. For 1 Da: 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)propanamido)benzoic acid; m/z (ES) 559 (MH).sup.+. For 1Db: 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-(3-fluorophenyl)propanamido)benzoic acid; m/z (ES) 559 (MH).sup.+. For 1De: 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-(4-(trifluoromethoxy)phenyl)propanamido)benzoic acid; m/z (ES) 625 (MH).sup.+. For 1Ea: (S)-4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)propanamido)benzoic acid; m/z (ES) 559 (MH).sup.+. For 1Eb: (S)-4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-(3-fluorophenyl)propanamido)benzoic acid; m/z (ES) 559 (MH).sup.+. For 1Ef: (S)-4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 541 (MH).sup.+. For 1Fa: (R)-4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)propanamido)benzoic acid; m/z (ES) 559 (MH).sup.+. For 1Fb: (R)-4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-(3-fluorophenyl)propanamido)benzoic acid; m/z (ES) 559 (MH).sup.+. For 1Ff: (R)-4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 541 (MH).sup.+.

(12) TABLE-US-00007 TABLE 1C R 1Ga 1Ha 1Gb 1Hb
Table 1C. Parent Ion m/z (MH).sup.+ data for compounds For 1Ga: (S)-ethyl (4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)propanamido)phenyl)carbamate; m/z (ES) 624 (MNa).sup.+. For 1Gb: (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N,3-bis(4-fluorophenyl)propanamide; m/z (ES) 533 (MH).sup.+. For 1Ha: (R)-ethyl (4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)propanamido)phenyl)carbamate; m/z (ES) 624 (MNa).sup.+. For 1Hb: (R)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N,3-bis(4-fluorophenyl)propanamide; m/z (ES) 533 (MH).sup.+.

Example 2

(13) ##STR00097##

Step A: Preparation of tert-butyl 4-(2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate (2a)

(14) Compound 2a was prepared following procedures similar to those described in Example 1, step A for the preparation of compound 1a, substituting i-1c for i-2a. m/z (ES) 497 (MH).sup.+.

Step B: Preparation of tert-butyl 4-(2-(4-(4-cyanophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate (2b)

(15) Compound 2b was prepared following procedures similar to those described in Intermediate i-2, Step B for the preparation of compound i-2b, substituting 2a and (4-cyanophenyl)boronic acid for i-1b and (5-chloro-2-nitrophenyl)boronic acid. m/z (ES) 520 (MH).sup.+.

Step C: Preparation of tert-butyl 4-(2-(4-(4-carbamimidoylphenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate (2c)

(16) Lithium bis(trimethylsilyl)amide (144 μL of a 1.0 M THF solution, 0.144 mmol) was added to a stirred solution of 2b (15 mg, 0.029 mmol) in THF (0.29 mL), and the resulting mixture was allowed to stir at rt. After 20 min, the reaction was quenched via addition of methanol, and the solvent was removed in vacuo. The resulting crude residue was redissolved in THF, and 4M HCl in dioxane was added. After stirring at rt for 30 min, the mixture was concentrated in vacuo to afford the title compound 2c. m/z (ES) 537 (MH).sup.+.

Step D: Preparation of 4-(2-(4-(4-carbamimidoylphenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid (2d)

(17) Compound 2d was prepared following procedures similar to those described in Example 1, step E for the preparation of compound 1e, substituting 2c for 1d. m/z (ES) 481 (MH).sup.+.

(18) TABLE-US-00008 TABLE 2 R 2Aa 00 2Ab 01 2Ac 02 2Ad 03 2Ae 04 2Af 05 2Ag 06 2Ah 07 2Ai 08 2Aj
Table 2. Parent Ion m/z (MH).sup.+ data for compounds For 2Aa: 4-(2-(4-(2-(1-hydroxyethyl)phenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 483 (MH).sup.+. For 2Ab: 4-(2-(4-(2-methylquinolin-5-yl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 504 (MH).sup.+. For 2Ac: 4-(2-(4-(isoquinolin-4-yl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 490 (MH).sup.+. For 2Ad: 4-(2-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 457 (MH).sup.+. For 2Ae: 4-(2-(4-(2-(ethoxycarbonyl)cyclohex-1-en-1-yl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 515 (MH).sup.+. For 2Af: 4-(2-(4-chloro-2′-oxo-[3,4′-bipyridin]-1′(2′H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 474 (MH).sup.+. For 2Ag: 4-(2-(4-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 533 (MH).sup.+. For 2Ah: 4-(2-(2-oxo-4-(2-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 507 (MH).sup.+. For 2Ai: 4-(2-(4-(2-(2H-tetrazol-5-yl)phenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 507 (MH).sup.+. For 2Aj: 4-(2-(4-(2-chloro-5-cyanophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoic acid; m/z (ES) 498 (MH).sup.+.

Example 3

(19) ##STR00109##

Step A: Preparation of tert-butyl 3-amino-4-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanamido)benzoate (3a)

(20) Compound 3a was prepared following procedures similar to those described in Example 1, step A for the preparation of compound 1a, substituting tert-butyl 3,4-diaminobenzoate for tert-butyl 4-aminobenzoate. m/z (ES) 611 (MNa).sup.+.

Step B: Preparation of tert-butyl 2-(1-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate (3b)

(21) A stirred solution of 3a (1.32 g, 2.24 mmol) in AcOH (30 mL) was heated to 70° C. After 2 h, the reaction mixture was cooled to rt and concentrated in vacuo. The resulting crude residue was partitioned between EtOAc and satd. aq. NaHCO.sub.3. The layers were separated, and the organics were dried (Na.sub.2SO.sub.4), filtered and concentrated to afford 3b as a light brown foam. m/z (ES) 571 (MH).sup.+.

Step C: Preparation of tert-butyl 2-(1-(4-(2-amino-5-chlorophenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate (3c)

(22) Compound 3c was prepared following procedures similar to those described in Example 1, step C for the preparation of compound 1c, substituting compound 3b for compound 1a. m/z (ES) 541 (MH).sup.+.

Step D: tert-butyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate (3d)

(23) Compound 3d was prepared following procedures similar to those described in Example 1, step D for the preparation of compound 1d, substituting compound 3c for compound 1c. m/z (ES) 594 (MH).sup.+.

Step E: Preparation of 3e and 3f

(24) Enantiomers 3e and 3f were separated using preparative normal phase chiral HPLC. A solution of 3d in methanol was injected onto a ChiralCel® IC-H (available from Chiral Technologies, Inc., Exton, Pa.) semi-preparative (250×30 mm) HPLC column (eluting with 40% ethanol and 0.2% diethylamine/CO.sub.2 with a column temperature of 35° C. at 70 mL/min with UV detection at 220 nm). The enantiomers were separated with the faster eluting enantiomer 3e (α.sub.D −153°, methanol) having a retention time of 5.44 min, and the slower

(25) ##STR00110##
uting enantiomer 3f (α.sub.D +153°, methanol) having a retention time of 6.28 min. 3e: (S)-tert-butyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate 3f: (R)-tert-butyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate

(26) ##STR00111##

Step F: Preparation of (S)-2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid (3 g)

(27) Trifluoroacetic acid (2.0 mL) was added to a stirred solution of 3e (367 mg, 0.618 mmol) in DCM (5.0 mL) at rt. After 2 h, the reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by preparative reverse phase HPLC on YMC Pack Pro C18 stationary phase (CH.sub.3CN/H.sub.2O as eluent, 0.1% formic acid as modifier), and lyophilization of the purified fractions afforded the title compound 3g. m/z (ES) 538 (MH).sup.+.

(28) TABLE-US-00009 TABLE 3 R R’ H CO2Me 3Aa 3Ba 3Ca H CO2H 3Ab — 3Cb F CO2Et 3Ac 3Bc 3Cc F CO2H 3Ad 3Bd 3Cd F F 3Ae 3Be 3Ce F Br 3Af 3Bf 3Cf
Table 3. Parent Ion m/z (MH).sup.+ data for compounds For 3Aa: methyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate; m/z (ES) 552 (MH).sup.+. For 3Ab: 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid; m/z (ES) 538 (MH).sup.+. For 3Ae: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-fluoro-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 530 (MH).sup.+. For 3Ba: (S)-methyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate; m/z (ES) 552 (MH).sup.+. For 3Bc: (S)-ethyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole-5-carboxylate; m/z (ES) 584 (MH).sup.+. For 3Bd: (S)-2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole-5-carboxylic acid; m/z (ES) 556 (MH).sup.+. For 3Be: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-fluoro-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 530 (MH).sup.+. For 3Bf: 1-(1-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)pyridin-2(1H)-one; m/z (ES) 590 (MH).sup.+. For 3Ca: (R)-methyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate; m/z (ES) 552 (MH).sup.+. For 3Cb: (R)-2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid; m/z (ES) 538 (MH).sup.+. For 3Cc: (R)-ethyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole-5-carboxylate; m/z (ES) 584 (MH).sup.+. For 3Ce: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-fluoro-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 530 (MH).sup.+.

Example 4

(29) ##STR00115##

Step A: Preparation of 2-(4-fluorophenyl)-2-oxoethyl 2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)propanoate (4a)

(30) Cesium carbonate (469 mg, 1.44 mmol) was added to a stirred solution of i-21 (200 mg, 0.480 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (104 mg, 0.480 mmol) in DCE (3.2 mL), and the resulting mixture was heated to 60° C. After 4 h, the reaction was cooled to rt, and partitioned between DCM and water. The layers were separated, and the organics were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to afford the title compound 4a. m/z (ES) 553 (MH).sup.+.

Step B: Preparation of 4-(5-chloro-2-nitrophenyl)-1-(2-(4-fluorophenyl)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one (4b)

(31) Ammonium acetate (98 mg, 1.266 mmol) was added to a solution of 4a (175 mg, 0.317 mmol) in toluene (4.1 mL). The resulting mixture was heated in a microwave reactor at 150° C. for 1 h. After cooling to rt, the reaction was concentrated in vacuo, and the resulting crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-50% EtOAc/hexanes as eluent) to afford the title compound 4b. m/z (ES) 533 (MH).sup.+.

Step C: Preparation of 4-(2-amino-5-chlorophenyl)-1-(2-(4-fluorophenyl)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one (4c)

(32) Compound 4c was prepared following procedures similar to those described in Example 1, step C for the preparation of compound 1c, substituting compound 4b for compound 1a. m/z (ES) 503 (MH).sup.+.

Step D: Preparation of 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one (4d)

(33) Compound 4d was prepared following procedures similar to those described in Example 1, step D for the preparation of compound 1d, substituting compound 4c for compound 1c. m/z (ES) 556 (MH).sup.+.

(34) ##STR00116## 4e: (R)-4-(5-chloro-2-nitrophenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one 4f: (S)-4-(5-chloro-2-nitrophenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one

Step E: Preparation of 4e and 4f

(35) Enantiomers 4e and 4f were separated using preparative normal phase chiral HPLC. A solution of 4b in methanol was injected onto a ChiralCel® IA-H (available from Chiral Technologies, Inc., Exton, Pa.) semi-preparative (250×30 mm) HPLC column (eluting with 75% (2:1) methanol:acetonitrile/CO.sub.2 with a column temperature of 35° C. at 70 mL/min with UV detection at 220 nm). The enantiomers were separated with the faster eluting enantiomer 4e having a retention time of 8.0 min, and the slower eluting enantiomer 4f having a retention time of 17.0 min.

(36) ##STR00117##

Preparation of (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one (4g)

(37) Compound 4g was prepared from compound 4f following procedures similar to those described for the preparation of compound 1c in Example 1, Step C, substituting compound 4f for compound 1a. The product of this reaction was converted to compound 4g by substituting for compound 1c following procedures described in Example 1, Step D for the preparation of compound 1d. m/z (ES) 556 (MNa).sup.+. α.sub.D −490, methanol.

(38) TABLE-US-00010 TABLE 4 R R’ 0 H 4Aa 4Ba 4Ca F 4Ae 4Be 4Ce F 4Af — 4Cf F 4Ag 4Bg 4Cg F 4Ah 4Bh 4Ch F 4Ai 4Bi 4Ci F 4Aj 4Bj 4Cj F 4Ak 4Bk 4Ck F 4Al 4Bl 4Cl F 0 4An 4Bn 4Cn FF   4Ao4An 4Bo4Bn 4Co4Cn FF   4Ap4Ao 4Bp4Bo 4Cp4Co FF   4Aq4Ap 4Bq4Bp 4Cq4Cp FF   4Ar4Aq 4Br4Bq 4Cr4Cq F 4Ar 4Br 4Cr
Table 4. Parent Ion m/z (MH).sup.+ data for compounds For 4Aa: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-phenyl-1-(4-(pyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 539 (MH).sup.+. For 4Ag: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(4-(3-fluorophenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 556 (MH).sup.+. For 4Ah: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-(4-chlorophenyl)-1H-imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 572 (MH).sup.+. For 4Ai: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(methylsulfonyl)phenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 616 (MH).sup.+. For 4Aj: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 606 (MH).sup.+. For 4Ak: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 622 (MH).sup.+. For 4Al: 4-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)benzonitrile; m/z (ES) 563 (MH).sup.+. For 4Ao: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(5-methoxypyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 569 (MH).sup.+. For 4Ar: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 607 (MH).sup.+. For 4Be: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(4-(pyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 539 (MH).sup.+. For 4Bh: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-(4-chlorophenyl)-1H-imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 572 (MH).sup.+. For 4Bi: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(methylsulfonyl)phenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 616 (MH).sup.+. For 4Bj: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 606 (MH).sup.+. For 4Bk: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 622 (MH).sup.+. For 4Bl: (S)-4-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)benzonitrile; m/z (ES) 563 (MH).sup.+. For 4Bn: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-(5-chloropyridin-3-yl)-1H-imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 573 (MH).sup.+. For 4Bo: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(5-methoxypyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 569 (MH).sup.+. For 4Bp: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(5-methylpyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 553 (MH).sup.+. For 4Bq: (S)-5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)nicotinonitrile; m/z (ES) 564 (MH).sup.+. For 4Br: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 607 (MH).sup.+. For 4Ce: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(4-(pyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 539 (MH).sup.+. For 4Cf: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 556 (MH).sup.+. For 4Ch: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-(4-chlorophenyl)-1H-imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 572 (MH).sup.+. For 4Ci: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(methylsulfonyl)phenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 616 (MH).sup.+. For 4Cj: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 606 (MH).sup.+. For 4Cl: (R)-4-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)benzonitrile; m/z (ES) 563 (MH).sup.+. For 4Cn: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-(5-chloropyridin-3-yl)-1H-imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 573 (MH).sup.+. For 4Co: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(5-methoxypyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 569 (MH).sup.+. For 4Cp: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(5-methylpyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 553 (MH).sup.+. For 4Cq: (R)-5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)nicotinonitrile; m/z (ES) 564 (MH).sup.+. For 4Cr: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 607 (MH).sup.+.

Example 5

(39) ##STR00140##

Step A: Preparation of (S)-diethyl (2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazol-5-yl)phosphonate (5a)

(40) A degassed suspension of 3Bf (60 mg, 0.102 mmol), diethylphosphite (26 μL, 0.203 mmol), triethylamine (43 μL, 0.305 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.020 mmol) in dioxane (0.50 mL) was heated in a microwave reactor to 120° C. for 15 min. After cooling to rt, the reaction mixture was diluted with EtOAc and filtered through a column of Celite®, which was rinsed with additional portions of EtOAc. The combined organics were dried (Na.sub.2SO.sub.4), filtered and concentrated, and the resulting crude residue was purified by preparative reverse phase HPLC on YMC Pack Pro C18 stationary phase (CH.sub.3CN/H.sub.2O as eluent, 0.05% TFA as modifier), and lyophilization of the purified fractions afforded the title compound 5a. m/z (ES) 648 (MH).sup.+.

Step B: Preparation of (S)-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazol-5-yl)phosphonic acid (5b)

(41) Bromotrimethylsilane (15 μL, 0.116 mmol) was added to a stirred solution of 5a (15 mg, 0.023 mmol) in DCM (0.23 mL), and the resulting mixture was allowed to stir at rt. After 72 h, the reaction was concentrated in vacuo, and the resulting crude residue was purified by preparative reverse phase HPLC on YMC Pack Pro C18 stationary phase (CH.sub.3CN/H.sub.2O as eluent, 0.05% TFA as modifier), and lyophilization of the purified fractions afforded the title compound 5b. m/z (ES) 592 (MH).sup.+.

Example 6

(42) ##STR00141##

Step A: Preparation of N′-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)propanoyl)-4-fluorobenzohydrazide (6a)

(43) Compound 6a was prepared following procedures similar to those described in Example 1, step A for the preparation of compound 1a, substituting 4-fluorobenzohydrazide for tert-butyl 4-aminobenzoate. m/z (ES) 575 (MNa).sup.+.

Step B: Preparation of 4-(5-chloro-2-nitrophenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)pyridin-2(1H)-one (6b)

(44) Burgess reagent was added to a stirred solution of 6a in THF, and the resulting mixture was heated to 65° C. After 2.5 h, the reaction was cooled to rt, diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated. The resulting crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-100% EtOAc/hexanes as eluent) to afford the title compound 6b as a yellow oil. m/z (ES) 535 (MH).sup.+.

(45) ##STR00142##

Step C: Preparation of 2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanehydrazide (6c)

(46) Hydrazine monohydrate (80 μL, 1.65 mmol) was added to a stirred solution of i-2b (35 mg, 0.085 mmol) in ethanol (2.0 mL), and the resulting mixture was heated to reflux. After 1 h, the reaction was cooled to rt and concentrated in vacuo. The resulting crude residue was partitioned between EtOAc and water, and the layers were separated. The organics were washed w/brine, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford the title compound 6c. m/z (ES) 413 (MH).sup.+.

Step D: methyl 4-(2-(2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-phenylpropanoyl)hydrazinocarbonyl)benzoate (6d)

(47) Compound 6d was prepared following procedures similar to those described in Example 1, step A for the preparation of compound 1a, substituting 4-(methoxycarbonyl)benzoic acid for tert-butyl 4-aminobenzoate. m/z (ES) 575 (MH).sup.+.

Step E: Preparation of methyl 4-(5-(1-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1,3,4-oxadiazol-2-yl)benzoate (6e)

(48) Compound 6e was prepared following procedures similar to those described in Example 6, step B for the preparation of compound 6b, substituting compound 6d for compound 6b. m/z (ES) 557 (MH).sup.+.

(49) ##STR00143##

Preparation of 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)pyridin-2(1-one (6f)

(50) Compound 6f was prepared from compound 6c following procedures similar to those described for the preparation of compound 1 in Example 1, Step C, substituting compound 6c for compound 1a. The product of this reaction was converted to compound 6f by substituting for compound 1c following procedures described in Example 1, Step D for the preparation of compound 1d. m/z (ES) 580 (MNa).sup.+.

(51) ##STR00144##

Step F: Preparation of 6g and 6h

(52) Enantiomers 6g and 6h were separated using preparative normal phase chiral HPLC. A solution of 6f in methanol was injected onto a ChiralCel® AS-H (available from Chiral Technologies, Inc., Exton, Pa.) semi-preparative (25×2 mm) HPLC column (eluting with 12% methanol/CO.sub.2 with a column temperature of 35° C. at 75 mL/min with UV detection at 220 nm). The enantiomers were separated with the faster eluting enantiomer 6g (α.sub.D +160°, methanol) having a retention time of 10.75 min, and the slower eluting enantiomer 6h (α.sub.D −145°, methanol) having a retention time of 12.09 min.

(53) TABLE-US-00011 TABLE 6 R 3-pyridyl 6Aa 6Ba 6Ca 4-Cl- 6Ab 6Bb 6Cb phenyl 4-CF3- 6Ac 6Bc 6Cc phenyl 4-(OCF3)- 6Ad 6Bd 6Cd phenyl
Table 6. Parent Ion m/z (MH).sup.+ data for compounds For 6Aa: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 541 (MH).sup.+. For 6Ab: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 596 (MNa).sup.+. For 6Ba: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 541 (MH).sup.+. For 6Bb: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 574 (MH).sup.+. For 6Bc: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 608 (MH).sup.+. For 6Bd: (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 624 (MH).sup.+. For 6ca: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 541 (MH).sup.+. For 6Cb: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one; m/z (ES) 574 (MH).sup.+. For 6Cd: (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)ethyl)pyridin-2(1H)-one; m/z (ES) 624 (MH).sup.+.

Example 7

(54) ##STR00148##

Step A: Preparation of 2-(4-(5-chloro-2-nitrophenyl)-2-oxopyridin-1(2H)-yl)-3-(4-fluorophenyl)-N-(2-(4-fluorophenyl)-2-oxoethyl)propanamide (7a)

(55) Compound 7a was prepared following procedures similar to those described in Example 1, step A for the preparation of compound 1a, substituting 2-amino-1-(4-fluorophenyl)ethanone for tert-butyl 4-aminobenzoate. m/z (ES) 574 (MNa).sup.+.

Step B: Preparation of 4-(5-chloro-2-nitrophenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-fluorophenyl)oxazol-2-yl)ethyl)pyridin-2(1H)-one (7b)

(56) Burgess reagent (65 mg, 0.272 mmol) was added to a stirred solution of 7a (75 mg, 0.136 mmol) in THF (0.68 mL), and the resulting mixture was heated to 65° C. After 2 h, the reaction mixture was partitioned between EtOAc and water. The layers were separated, and the organics were washed with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated. The resulting crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-100% EtOAc/hexanes as eluent) to afford the title compound 7b. m/z (ES) 534 (MH).sup.+.

Step C: Preparation of 4-(2-amino-5-chlorophenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-fluorophenyl)oxazol-2-yl)ethyl)pyridin-2(1H)-one (7c)

(57) Compound 7c was prepared following procedures similar to those described in Example 1, step C for the preparation of compound 1c, substituting compound 7b for compound 1a.

Step D: Preparation of 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(2-(4-fluorophenyl)-1-(5-(4-fluorophenyl)oxazol-2-yl)ethyl)pyridin-2(1H)-one (7d)

(58) Compound 7d was prepared following procedures similar to those described in Example 1, step D for the preparation of compound 1d, substituting compound 7c for compound 1c. m/z (ES) 557 (MH).sup.+.

(59) ##STR00149## For 7e: 4-(5-chloro-2-nitrophenyl)-1-(2-phenyl-1-(5-phenyloxazol-2-yl)ethyl)pyridin-2(1H)-one. m/z (ES) 498 (MH).sup.+.

Example 8

(60) ##STR00150##

Step A: Preparation of 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(7-iodo-3,3a,4,9b-tetrahydrochromeno[3,4-d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one (8a)

(61) Compound 8a was prepared following procedures similar to those described in Example 4, steps A and B for the preparation of compound 4b, substituting compound i-2a for compound i-2l, and i-5d for 2-bromo-1-(4-fluorophenyl)ethanone in Example 4, step A. m/z (ES) 674 (MH).sup.+.

Step B: Preparation of 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-3,3a,4,9b-tetrahydrochromeno[3,4-d]imidazole-7-carbonitrile (8b)

(62) Compound i-2a (22 mg, 0.032 mmol), zinc cyanide (3.8 mg, 0.032 mmol), 1,1′-bis(diphenylphosphino)ferrocene (1.8 mg, 3.20 mol) and tris(dibenzylideneacetone)dipalladium(0) (5.8 mg, 6.4 mol) were suspended in DMF:water (0.21 mL of a 99:1 mixture). The reaction mixture was degassed and heated to 120° C. for 35 min. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with brine. The organics were dried (Na.sub.2SO.sub.4), filtered and concentrated, and the resulting crude residue was purified by preparative reverse phase HPLC on YMC Pack Pro C18 stationary phase (CH.sub.3CN/H.sub.2O as eluent, 0.05% TFA as modifier), and lyophilization of the purified fractions afforded the title compound 8b. m/z (ES) 573 (MH).sup.+.

(63) ##STR00151## For 8c: 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-3a,4,5,10b-tetrahydro-3H-benzo[2,3]oxepino[4,5-d]imidazole-8-carbonitrile; m/z (ES) 587 (MH).sup.+.

Factor XIa Assay

(64) The effectiveness of compound of the present invention as inhibitors of Coagulation Factor XIa can be determined using a relevant purified serine protease, and an appropriate synthetic substrate. The rate of hydrolysis of the chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and presence of compounds of the present invention. Assays were conducted at room temperature or at 37° C. Hydrolysis of the substrate resulted in release of amino trifluoromethylcoumarin (AFC), which was monitored spectrofluorometrically by measuring the increase in emission at 510 nm with excitation at 405 nm. A decrease in the rate of fluorescence change in the presence of inhibitor is indicative of enzyme inhibition. Such methods are known to one skilled in the art. The results of this assay are expressed as the inhibitory constant, K.sub.i.

(65) Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4 containing 150 mM NaCl, 5 mM CaCl.sub.2, and 0.1% PEG 8000 (polyethylene glycol; JT Baker or Fisher Scientific). Determinations were made using purified human Factor XIa at a final concentration of 40 pM (Sekisui Diagnostics) and the synthetic substrate, Z-Gly-Pro-Arg-AFC, TFA salt (Sigma #C0980) at a concentration of 100 μM.

(66) Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ≦0.1 K.sub.m into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. Initial velocities of product formation in the absence (V.sub.o) or presence of inhibitor (V.sub.i) were measured. Assuming competitive inhibition, and that unity is negligible compared K.sub.m/[S], [I]/e, and [I]/e (where [S], [I], and e respectively represent the total concentrations, of substrate, inhibitor and enzyme), the equilibrium constant (K.sub.i) for dissociation of the inhibitor from the enzyme can be obtained from the dependence of V.sub.o/V.sub.i on [I] shown in the following equation.
V.sub.o/V.sub.i=1+[I]/K.sub.i

(67) The activities shown by this assay indicate that the compounds of the invention may be therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.

Factor XIa Inhibition

(68) TABLE-US-00012 Example hFXIa Ki (nM) 1Ag 400 1Al 340 1Aw >10000 1Bc <5 1Ea 6 1Ef <5 1Ff 6 2d 370 2Af 7750 3g <5 3Bc 320 3Bd <5 3Ca 825 3Ce 417 4Aa <5 4Af 154 4Ar 275 4Bi 39 4Bn 18 4Bp 54 4Cl <5 4Co 1035 5b <5 6h 240 6Aa 280

(69) The present invention is not limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the relevant art and are intended to fall within the scope of the appended claim.

(70) Compounds of the Formula (I) can be administered both as a monotherapy and in combination with other therapeutic agents, including antithrombotics (anticoagulants and platelet aggregation inhibitors), thrombolytics (plasminogen activators), other profibrinolytically active substances, hypotensives, blood sugar regulators, lipid-lowering agents and antiarrhythmics.

(71) The Factor XIa inhibitors can also be co-administered with suitable anticoagulants, including, but not limited to, other Factor XIa inhibitors, thrombin inhibitors, thrombin receptor antagonists, factor VIIa inhibitors, factor Xa inhibitors, factor IXa inhibitors, factor XIIa inhibitors, adenosine diphosphate antiplatelet agents (e.g., P2Y12 antagonists), fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), other anticoagulants such as aspirin, and thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies. Such anticoagulants include, for example, apixaban, dabigatran, cangrelor, ticagrelor, vorapaxar, clopidogrel, edoxaban, mipomersen, prasugrel, rivaroxaban, and semuloparin. For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and thrombin inhibitors. Factor XIa inhibitors may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter.

(72) Alternatively or additionally, one or more additional pharmacologically active agents may be administered in combination with a compound of the invention. The additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which is different from the compound of the invention, and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents when such forms are sold commercially or are otherwise chemically possible. Generally, any suitable additional active agent or agents, including but not limited to anti-hypertensive agents, additional diuretics, anti-atherosclerotic agents such as a lipid modifying compound, anti-diabetic agents and/or anti-obesity agents may be used in any combination with the compound of the invention in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents). Examples of additional active agents which may be employed include but are not limited to angiotensin converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril); angiotensin II receptor antagonists also known as angiotensin receptor blockers or ARBs, which may be in free-base, free-acid, salt or pro-drug form, such as azilsartan, e.g., azilsartan medoxomil potassium (EDARBI®), candesartan, e.g., candesartan cilexetil (ATACAND®), eprosartan, e.g., eprosartan mesylate (TEVETAN®), irbesartan (AVAPRO®), losartan, e.g., losartan potassium (COZAAR®), olmesartan, e.g., olmesartan medoximil (BENICAR®), telmisartan (MICARDIS®), valsartan (DIOVAN®), and any of these drugs used in combination with a thiazide-like diuretic such as hydrochlorothiazide (e.g., HYZAAR®, DIOVAN HCT®, ATACAND HCT®), etc.); potassium sparing diuretics such as amiloride HCl, spironolactone, epleranone, triamterene, each with or without HCTZ; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors; enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; aliskiren (2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamid hemifumarate) SPP600, SPP630 and SPP635); endothelin receptor antagonists; vasodilators (e.g. nitroprusside); calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine, nicardipine); potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam); sympatholitics; beta-adrenergic blocking drugs (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartate, nadolol, propranolol, sotalol, timolol); alpha adrenergic blocking drugs (e.g., doxazocin, prazocin or alpha methyldopa); central alpha adrenergic agonists; peripheral vasodilators (e.g. hydralazine); lipid lowering agents, e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such as atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®), and fluvastatin (particularly the sodium salt sold in LESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®), and ezetimibe in combination with any other lipid lowering agents such as the HMG-CoA reductase inhibitors noted above and particularly with simvastatin (VYTORIN®) or with atorvastatin calcium; niacin in immediate-release or controlled release forms, and particularly niacin in combination with a DP antagonist such as laropiprant (TREDAPTIVE®) and/or with an HMG-CoA reductase inhibitor; niacin in immediate-release or controlled release forms, and particularly niacin in combination with a DP antagonist and/or with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists; metabolic altering agents including insulin sensitizing agents and related compounds for the treatment of diabetes such as biguanides (e.g., metformin), meglitinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones also referred to as glitazones (e.g., pioglitazone, rosiglitazone), alpha glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors, (e.g., sitagliptin (JANUVIA®), alogliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids (e.g., bromocriptine), combination medications such as JANUMET® (sitagliptin with metformin), and injectable diabetes medications such as exenatide and pramlintide acetate; or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases including but not limited to diazoxide; and including the free-acid, free-base, and pharmaceutically acceptable salt forms, pro-drug forms, e.g., esters, and salts of pro-drugs of the above medicinal agents, where chemically possible. Trademark names of pharmaceutical drugs noted above are provided for exemplification of the marketed form of the active agent(s); such pharmaceutical drugs could be used in a separate dosage form for concurrent or sequential administration with a compound of the invention, or the active agent(s) therein could be used in a fixed dose drug combination including a compound of the invention.

(73) Typical doses of Factor XIa inhibitors of the invention in combination with other suitable anti-platelet agents, anticoagulation agents, or thrombolytic agents may be the same as those doses of Factor XIa inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, or may be substantially less that those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient's therapeutic needs.

(74) The compounds are administered to a mammal in a therapeutically effective amount. By “therapeutically effective amount” it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat (i.e. prevent, inhibit or ameliorate) the thromboembolic and/or inflammatory disease condition or treat the progression of the disease in a host.

(75) The compounds of the invention are preferably administered alone to a mammal in a therapeutically effective amount. However, the compounds of the invention can also be administered in combination with an additional therapeutic agent, as defined below, to a mammal in a therapeutically effective amount. When administered in a combination, the combination of compounds in preferably, but not necessarily, a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55, occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared with the individual components.

(76) By “administered in combination” or “combination therapy” it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.