Substituted tetrahydroisoquinoline compounds as factor xia inhibitors

Abstract

The present invention provides compounds of Formula (I): or stereoisomers, pharmaceutically acceptable salts thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of factor XIa and/or plasma kallikrein which may be used as medicaments.

What is claimed is: 
     
         1 . Form HCl:SA-1 of crystalline (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid, which is characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in  FIG. 1 . 
     
     
         2 . Form HCl:SA-1 according to  claim 1  having a powder X-ray diffraction pattern comprising four or more 2θ values (CuKα λ=1.5418 Å): 6.0, 8.3, 8.7, 12.3, 16.2, 16.7, 17.5, 19.9, and 20.4. 
     
     
         3 . Form HCl:SA-1 of crystalline (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid according to  claim 1 , which is characterized by unit cell parameters substantially equal to the following:
 Cell dimensions:
 a=8.3746(2) Å 
 b=20.2236(5) Å 
 c=21.3099(6) Å 
 α=90° 
 β=90° 
 γ=90° 
   Space group: P2(1)2(1)2(1)   Molecules/asymmetric unit: 1   
       wherein measurement of the crystalline form is at a temperature of about 23° C. 
     
     
         4 . Form HCl:SA-1 according to  claim 3 , which is characterized by fractional atomic coordinates substantially as listed in Table 2. 
     
     
         5 . Form HCl:SA-1 of crystalline (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid, to  claim 3  which is characterized by unit cell parameters substantially as listed in Table 4. 
     
     
         6 . Form H.5-1 of crystalline (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid, which is characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in  FIG. 2 . 
     
     
         7 . Form H.5-1 according to  claim 6  having a powder X-ray diffraction pattern comprising four or more 2θ values (CuKα λ=1.5418 Å): 5.9, 7.2, 12.0, 15.7, 17.2, 18.9, 20.3, 24.2, and 26.1. 
     
     
         8 . Form H.5-1 of crystalline (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid according to  claim 6 , which is characterized by unit cell parameters substantially equal to the following:
 Cell dimensions:
 a=13.6547(3) Å 
 b=18.7590(3) Å 
 c=24.7370(5) Å 
 α=90° 
 β=90° 
 γ=90° 
   Space group: 12(1)2(1)2(1)   Molecules/asymmetric unit: 1   Density (calculated): 1.401 Mg/m 3      
       wherein measurement of the crystalline form is at a temperature of about 23° C. 
     
     
         9 . Form H.5-1 according to  claim 8 , which is characterized by fractional atomic coordinates substantially as listed in Table 1. 
     
     
         10 . Form P13 of crystalline (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid, which is characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in  FIG. 3 . 
     
     
         11 . Form P13 according to  claim 10  having a powder X-ray diffraction pattern comprising four or more 2θ values (CuKα λ=1.5418 Å): 8.4, 8.9, 12.7, and 17.9. 
     
     
         12 . The Form according to  claim 1  in substantially pure form. 
     
     
         13 . The Form according to  claim 12 , wherein substantially pure is greater than 90 percent pure. 
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of crystalline Form H.5-1 of (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid of  claim 6  and a pharmaceutically acceptable carrier. 
     
     
         15 . A pharmaceutical composition comprising a therapeutically effective amount of crystalline Form P13 of (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid of  claim 10  and a pharmaceutically acceptable carrier. 
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of crystalline Form HCl:SA-1 of (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of crystalline Form according to  claim 16 . 
     
     
         18 . A method according to  claim 17 , wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart. 
     
     
         19 . A method according to  claim 17 , wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. 
     
     
         20 . A process for preparing crystalline forms of Compound (I) according to  claim 1 , comprising a step of slurrying Compound (I) in a solvent selected from: acetone, methanol, ethanol, CH 2 Cl 2 , DMF, NMP, MEK, 2-BuOH, IPA, IpOAc, MTBE, EtOAc, and BuOAc. 
     
     
         21 . A pharmaceutical composition comprising a therapeutically effective amount of amorphous form of (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid and a pharmaceutically acceptable carrier.