Therapeutic compounds and compositions

Abstract

To provide therapeutic compounds and compositions.SOLUTION: The present invention provides compounds that inhibit Factor XIa or kallikrein and pharmaceutically acceptable salts thereof and compositions thereof. The present invention also provides methods of making these compounds or pharmaceutically acceptable salts thereof and compositions, and methods of use thereof. The present invention features compounds that inhibit Factor XIa or kallikrein and methods for preventing or treating undesired thrombosis or angioedema (e.g., hereditary angioedema) by administering one or more of these compounds alone or in combination with other molecules to a mammal.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to USSN 62 / 752,503, filed October 30, 2018, which is incorporated by reference in its entirety. [Background technology]

[0002] 2. Background of the Invention Blood clotting is the first line of defense against blood loss after injury. The blood clotting "cascade" requires several circulating serine protease zymogens, regulatory cofactors and inhibitors. Each enzyme, once produced from its zymogen, specifically cleaves the next zymogen in the cascade to produce an active protease. This process is repeated until finally thrombin cleaves fibrinopeptides from fibrinogen to produce fibrin, which polymerizes to form a clot. Although efficient clot formation limits blood loss at the site of trauma, it also poses the risk of systemic coagulation, resulting in large thrombi. Under normal circumstances, hemostasis maintains a balance between clot formation (coagulation) and clot elution (fibrinolysis). However, in certain disease states, such as acute myocardial infarction and unstable angina, rupture of established atherosclerotic plaques leads to abnormal thrombus formation in coronary artery vessels.

[0003] Diseases resulting from blood clotting, such as myocardial infarction, unstable angina, atrial fibrillation, stroke, pulmonary embolism and deep vein thrombosis, are the leading causes of death in developed countries. Current anticoagulant therapies, such as injectable unfractionated and low molecular weight (LMW) heparins, and orally administered warfarin (Coumadin), pose a risk of bleeding episodes and exhibit interpatient variability, necessitating intensive monitoring and titration of therapeutic doses. Thus, there is a great medical need for novel anticoagulants that do not suffer from some or all of the side effects of currently available drugs.

[0004] Factor XIa is an attractive therapeutic target involved in pathways relevant to these diseases. Increased factor XIa levels or factor XIa activity have been shown to be associated with venous thrombosis (Meijers et al., N. Engl. J. Med. 342:696, 2000), acute myocardial infarction (Minnema et al., Arterioscler Thromb Vasc Biol 20:2489, 2000), acute coronary syndromes (Butenas et al., Thromb Haemost 99:142, 2008), coronary artery disease (Butenas et al., Thromb Haemost 99:142, 2008), chronic obstructive pulmonary disease (Jankowski et al., Thromb Res 127:242, 2011), aortic stenosis (Blood Coagul Fibrinolysis, 22:473, 2011), acute cerebrovascular ischemia (Undas et al., Eur J Clin Invest, Factor XIa activity has been observed in several thromboembolic disorders, including systolic heart failure due to ischemic cardiomyopathy (Zabcyk et al., Pol Arch Med Wewn. 120:334, 2010) and pulmonary fibrosis (Pfizer, Inc., 2011). Patients lacking factor XI due to inherited factor XI deficiency exhibit few, if any, ischemic strokes (Salomon et al., Blood, 111:4113, 2008). At the same time, the loss of factor XIa activity leaves one of the pathways that initiates coagulation intact and hemostasis is not disturbed. In humans, factor XI deficiency can result in mild to moderate bleeding disorders, especially in tissues with high levels of local fibrinolytic activity, such as the urinary tract, nose, oral cavity, and tonsils. Moreover, hemostasis is nearly normal in factor XI-deficient mice (Gailani, Blood Coagul Fibrinolysis, 8:134, 1997). Moreover, inhibition of factor XI has been found to attenuate other diseases and dysfunctions, including arterial hypertension and vascular inflammation (Kossmann et al. Sci. Transl. Med. 9, eaah4923 (2017)). Therefore, compounds that inhibit factor XIa have the potential to prevent or treat a wide range of disorders while avoiding the side effects and therapeutic challenges of interfering with drugs that inhibit other components of the coagulation pathway.Furthermore, due to the limited efficacy and adverse side effects of some current therapeutic agents for inhibiting undesired thrombosis (e.g., deep vein thrombosis, hepatic vein thrombosis and stroke), there is a need for improved compounds and methods for preventing or treating undesired thrombosis (e.g., those related to factor XIa). Another therapeutic target is the enzyme kallikrein. Human plasma kallikrein is a serine protease that can be responsible for activating several downstream factors (e.g., bradykinin and plasmin) that are important for coagulation and, for example, blood pressure, inflammation, and pain control. Kallikrein is expressed, for example, in the prostate, epidermis, and central nervous system (CNS), and can be involved, for example, in the liquefaction of semen, the cleavage of cell adhesion proteins, and the regulation of neuroplasticity in the CNS. In addition, kallikrein can be involved in tumorigenesis, as well as the development of cancer and angioedema, for example hereditary angioedema. Hyperactivation of the kallikrein-kinin pathway can result in several disorders, including angioedema, for example hereditary angioedema (Schneider et al., J. Allergy Clin. Immunol. 120:2, 416, 2007). To date, no therapeutic approaches have been developed for HAE. Treatment options are limited (e.g., WO 2003 / 076458), and therefore there is a need for therapeutic agents to prevent or treat these diseases. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2003 / 076458 [Non-patent literature]

[0006] [Non-Patent Document 1] Meijers et al., N. Engl. J. Med. 342:696, 2000 [Non-Patent Document 2] Minnema et al., Arterioscler Thromb Vasc Biol 20:2489, 2000 [Non-Patent Document 3] Butenas et al., Thromb Haemost 99:142, 2008 [Non-Patent Document 4] Jankowski et al., Thromb Res 127:242, 2011 [Non-Patent Document 5] Blood Coagul Fibrinolysis, 22:473, 2011 [Non-Patent Document 6] Undas et al., Eur J Clin Invest, 42:123, 2012 [Non-Patent Document 7] Zabcyk et al., Pol Arch Med Wewn. 120:334, 2010 [Non-Patent Document 8] Salomon et al., Blood, 111:4113, 2008 [Non-Patent Document 9] Gailani, Blood Coagul Fibrinolysis, 8:134, 1997 [Non-Patent Document 10] Kossmann et al. Sci. Transl. Med. 9, eaah4923 (2017) Summary of the Invention [Means for solving the problem]

[0007] Summary of the Invention The present invention features compounds that inhibit factor XIa or kallikrein, and methods for preventing or treating undesired thrombosis or angioedema (e.g., hereditary angioedema) by administering one or more of these compounds, alone or in combination with other molecules, to a mammal. The present invention also provides methods for designing or selecting additional factor XIa or kallikrein inhibitors using these structures. Desirably, these compounds have certain structural, physical, and spatial features that allow them to interact with specific residues in the active site of factor XIa or kallikrein.

[0008] In one aspect, the present invention provides compound 1: [ka] Or a pharmaceutically acceptable salt thereof, for example, the hydrochloride salt of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is crystalline. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof exists as a substantially pure crystalline solid form.

[0009] In one embodiment, a pharma- ceutically acceptable salt of formula (I): [ka] is provided herein.

[0010] The pharma- ceutically acceptable salt of formula (I) is the hydrochloride salt of compound 1, also referred to herein as compound 1·HCl. In some embodiments, compound 1·HCl is crystalline. In some embodiments, compound 1·HCl exists as a substantially pure crystalline solid form. In some embodiments, compound 1·HCl has an XRPD pattern substantially as depicted in FIG. 9.

[0011] In one embodiment, a pharma- ceutically acceptable salt of formula (I): [ka] or a solvate (e.g., hydrate) thereof, comprising the steps of: [ka] or a solvate (e.g., hydrate) thereof in a solvent, thereby preparing a first solution, and adding hydrogen chloride to the first solution, thereby producing a pharma- ceutically acceptable salt of Formula (I).

[0012] In some embodiments, the salt of formula (II) is dissolved in an aprotic solvent. In some embodiments, the solvent comprises (e.g., consists of, or consists essentially of) acetonitrile. In some embodiments, hydrogen chloride is added by bubbling HCl gas through the first solution, or by adding another solution containing HCl (e.g., the salt An ethereal solution of the acid is added to the first solution.

[0013] In some embodiments, the starting amount of the salt of formula (II) or its solvate (e.g., hydrate) is greater than or equal to 500 grams. In some embodiments, the starting amount of the salt of formula (II) or its solvate (e.g., hydrate) is greater than or equal to 1 kilogram. In some embodiments, the method produces greater than 300 grams (e.g., greater than about 350 grams (e.g., about 368 grams)) of a pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate).

[0014] In some embodiments, the method produces a pharma- ceutically acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) in greater than about 50% yield (e.g., about 55% yield). In some embodiments, the method produces a pharma- ceutically acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) in greater than about 75% yield. In some embodiments, the method produces a pharma- ceutically acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) in greater than about 90% yield. In some embodiments, the method produces a pharma- ceutical acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) in greater than about 99% yield. In some embodiments, the purity of the pharma- ceutical acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) is about 80%. In some embodiments, the purity of the pharma- ceutical acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) is about 81%.

[0015] In some embodiments, the method further comprises purifying the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) by dissolving the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) in a solvent (e.g., isopropyl alcohol) and then precipitating the dissolved pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) using another solvent (e.g., methyl tert-butyl ether). In some embodiments, the purity of the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) after precipitation is greater than 98%. In some embodiments, the purity of the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) after precipitation is about 98%.

[0016] In some embodiments, the method further comprises purifying the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) by slurrying the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) in a solvent (e.g., isopropyl alcohol) and then filtering the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) to separate the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) from the solvent. In some embodiments, the purity of the pharma- ceutical acceptable salt of formula (I) or its solvate (e.g., hydrate) after slurrying and isolating is greater than 98%. In some embodiments, the purity of the pharma- ceutical acceptable salt of formula (I) or its solvate (e.g., hydrate) after slurrying and isolating is about 98%.

[0017] In some embodiments, the method comprises reacting a compound of formula (III) [ka] with trifluoroacetic acid to prepare the salt of formula (II).

[0018] In some embodiments, the method further comprises contacting the compound of Formula (III) with a silane (e.g., triethylsilane).

[0019] In some embodiments, the method produces more than 500 grams (eg, more than 1 kg) of a compound of formula (III).

[0020] In some embodiments, the method comprises reacting a compound of formula (IV) [ka] to a compound of formula (V) [ka] The method includes the step of preparing a compound of formula (III) by contacting

[0021] In some embodiments, the method produces more than 1 kilogram (e.g., about 1.3 kg) of a compound of formula (III). In some embodiments, the method is carried out in the presence of a solvent. In some embodiments, the method is carried out in the presence of a base (e.g., 1,8-diazabicyclo(5.4.0)undec-7-ene).

[0022] In some embodiments, the method comprises reacting a compound of formula (VI) [ka] to a compound of formula (VII) [ka] The method includes the step of preparing a compound of formula (IV) by contacting

[0023] In some embodiments, the method produces more than 500 grams (eg, more than 900 grams) of a compound of formula (IV).

[0024] In some embodiments, the compound of formula (III) is purified by a purification method that is not chromatographic. In some embodiments, the purification method includes slurrying the compound of formula (III) in a solvent (e.g., heptane) and then filtering the compound of formula (III) to separate the compound of formula (III) from the solvent. In some embodiments, the purity of the compound of formula (III) is greater than 90%.

[0025] In some embodiments, the compound of formula (I) is purified by a purification method that is not chromatographic.

[0026] In one embodiment, a crystalline pharma- ceutically acceptable salt of formula (I): [ka] is provided herein.

[0027] In one aspect, the present invention is directed to a pharmaceutical composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients. In some embodiments, the composition is provided as a liquid formulation (e.g., a solution). In some embodiments, the composition is provided as a solid formulation (e.g., a capsule, a pill, a tablet, or a powder).

[0028] In some embodiments, each crystalline solid form is characterized and identified by parameters derived from one or more of the above analytical methods: API (free base) percentage and estimated purity of each sample, determined by HPLC analysis. X-ray diffraction patterns are expressed as 2-theta (2θ) degrees as abscissa and peak intensities as ordinate, determined by analysis by XRPD. These patterns are also referred to herein as XRPD patterns.

[0029] In some embodiments, a solid form is determined to be crystalline by the presence of sharp individual peaks in the corresponding XRPD pattern.

[0030] In an embodiment, a method of treating a thromboembolic disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject's blood is contacted with the artificial surface.

[0031] In an embodiment, a method for reducing the risk of a thromboembolic disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject's blood is contacted with the artificial surface.

[0032] In an embodiment, a method for preventing a thromboembolic disorder in a subject in need thereof comprises administering to said subject and administering to said subject an effective amount of a compound represented by the following: [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject's blood is contacted with the artificial surface.

[0033] In some embodiments of the methods provided herein, the artificial surface is in contact with blood in the circulatory system of the subject. In some embodiments, the artificial surface is an implantable prosthesis, a dialysis catheter, a cardiopulmonary bypass circuit, an artificial heart valve, a ventricular assist device, or the like. , a small bore graft, a central venous catheter, or an extracorporeal membrane oxygenation (ECMO) device. In some embodiments, the artificial surface causes or is associated with a thromboembolic disorder. In some embodiments, the thromboembolic disorder is venous thromboembolism, deep vein thrombosis, or pulmonary embolism. In some embodiments, the thromboembolic disorder is a blood clot.

[0034] In some embodiments, the method further comprises conditioning the artificial surface with a separate dose of the compound or a pharma- ceutically acceptable salt thereof before contacting the artificial surface with blood in the subject's circulatory system. In some embodiments, the method further comprises conditioning the artificial surface with a separate dose of the compound or a pharma- ceutically acceptable salt thereof before or during administration of the compound or a pharma- ceutically acceptable salt thereof to the subject. In some embodiments, the method further comprises conditioning the artificial surface with a separate dose of the compound or a pharma- ceutically acceptable salt thereof before and during administration of the compound or a pharma- ceutically acceptable salt thereof to the subject.

[0035] In an embodiment, a method of treating blood in a subject in need thereof comprises administering to the subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof.

[0036] In an embodiment, a compound represented by: [ka] or a pharma- ceutical acceptable salt thereof, comprising the steps of: (i) administering to a subject the compound or a pharma- ceutically acceptable salt thereof prior to or during contacting the artificial surface with the subject's blood; and (ii) exposing the artificial surface to the compound or the blood of the subject prior to or during contacting the artificial surface with the blood of the subject. or a pharma- ceutically acceptable salt thereof. Including, Thereby, provided herein are methods of maintaining plasma levels of the compound, or a pharma- ceutically acceptable salt thereof, in the blood of a subject.

[0037] In some embodiments of the methods described herein, the compound or a pharma- ceutically acceptable salt thereof maintains a constant activated partial thromboplastin time (aPTT) in the subject's blood before and after contact with the artificial surface. In some embodiments, the compound or a pharma-ceutically acceptable salt thereof is administered to the subject before and during contact of the subject's blood with the artificial surface.

[0038] In some embodiments, the artificial surface is conditioned with the compound or a pharma- ceutically acceptable salt thereof before and during contacting the artificial surface with the subject's blood. In some embodiments, the method further prevents or reduces the risk of clot formation in the subject's blood contacting the artificial surface.

[0039] In some embodiments, the artificial surface is a cardiopulmonary bypass circuit. In some embodiments, the artificial surface is an extracorporeal membrane oxygenation (ECMO) device. In some embodiments, the ECMO device is a veno-venous ECMO device or a veno-arterial ECMO device.

[0040] In an aspect, a method of preventing or reducing the risk of a thromboembolic disorder in a subject during or after a medical procedure is provided, comprising:

[0041] (i) administering to a subject prior to, during or after a medical procedure an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof; and (ii) contacting the artificial surface with blood of the subject. thereby preventing or reducing the risk of thromboembolic disorders during or after a medical procedure.

[0042] In some embodiments, the artificial surface is conditioned with the compound, or a pharma- ceutically acceptable salt thereof, prior to administering the compound to a subject before, during, or after a medical procedure.

[0043] In some embodiments, the artificial surface is conditioned with a solution comprising the compound or a pharma- ceutically acceptable salt thereof prior to administering the compound or a pharma- ceutically acceptable salt thereof to a subject prior to, during or after a medical procedure. In some embodiments, the solution is a saline solution, Ringer's solution or blood. In some embodiments, the solution further comprises blood. In some embodiments, the blood is obtained from a subject or a donor.

[0044] In some embodiments, the thromboembolic disorder is a blood clot.

[0045] In some embodiments, the medical procedure is: i) cardiopulmonary bypass; ii) extracorporeal membrane oxygenation; The methods include one or more of: oxygenation and pumping of blood, iii) assisted pumping of blood (intracorporeal or extracorporeal), iv) dialysis of blood, v) extracorporeal filtration of blood, vi) withdrawal of blood from a subject into a storage container for later use in an animal or human subject, vii) use of venous or arterial intraluminal catheters, viii) use of devices for diagnostic or interventional cardiac catheterization, ix) use of intravascular devices, x) use of prosthetic heart valves, and xi) use of prosthetic grafts.

[0046] In some embodiments, the medical procedure includes cardiopulmonary bypass. In some embodiments, the medical procedure includes blood oxygenation and pumping by extracorporeal membrane oxygenation (ECMO). In some embodiments, the ECMO is veno-venous ECMO or veno-arterial ECMO.

[0047] In one aspect, the present invention is directed to a method of reducing the risk of stroke (e.g., ischemia, e.g., transient ischemic event, large vessel acute ischemic stroke) in a subject suffering from an ischemic event (e.g., transient ischemic event), comprising administering to the subject an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, administration reduces the risk of stroke (e.g., large vessel acute ischemic stroke) in the subject compared to a subject not administered the compound. In some embodiments, administration reduces the risk of atrial fibrillation in the subject compared to a subject not administered the compound.

[0048] In one aspect, the invention is directed to a method of reducing non-CNS systemic embolism (e.g., ischemia, e.g., a transient ischemic event) in a subject suffering from an ischemic event (e.g., a transient ischemic event), comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the administration reduces non-CNS systemic embolism in the subject compared to a subject not administered the compound.

[0049] In one aspect, the present invention is directed to a method of treating deep vein thrombosis, the method comprising administering to a subject suffering from an ischemic event (e.g., a transient ischemic event) an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0050] In one aspect, the present invention is directed to a method of preventing deep vein thrombosis, comprising administering to a subject suffering from deep vein thrombosis (e.g., a subject previously treated for deep vein thrombosis) an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In one aspect, the present invention is directed to a method of reducing the risk of deep vein thrombosis recurrence, comprising administering to a subject suffering from deep vein thrombosis (e.g., a subject previously treated for deep vein thrombosis) an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, administration reduces the risk of deep vein thrombosis recurrence in the subject, as compared to a subject not administered the compound.

[0051] In one aspect, the present invention is directed to a method of preventing venous thromboembolism, e.g., deep vein thrombosis or pulmonary embolism, in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In embodiments, the subject is undergoing surgery. In some embodiments, the subject is administered the compound, pharma- ceutically acceptable salts thereof, or compositions thereof before, during, or after surgery. In some embodiments, the subject is undergoing knee or hip replacement surgery. In some embodiments, the subject is undergoing orthopedic surgery. In some embodiments, the subject is undergoing lung surgery. In some embodiments, the subject is undergoing treatment for cancer, for example, by surgery. In some embodiments, the subject suffers from a chronic medical condition. In some embodiments, the venous thromboembolism is associated with cancer. In some embodiments, the compounds, pharma- ceutically acceptable salts thereof, or compositions described herein are primary agents in the prophylaxis of deep vein thrombosis or venous thromboembolism. In some embodiments, the compounds, pharma- ceutically acceptable salts thereof, or compositions described herein are used as long-term treatment. In one aspect, the present invention is directed to a method of reducing the risk of venous thromboembolism, e.g., deep vein thrombosis or pulmonary embolism, in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the subject is undergoing surgery. In some embodiments, the subject is administered the compound, a pharma- ceutically acceptable salt thereof, or a composition thereof after surgery. In some embodiments, the subject is undergoing knee or hip replacement surgery. In some embodiments, the subject is undergoing orthopedic surgery. In some embodiments, the subject is undergoing lung surgery. In some embodiments, the subject is undergoing treatment for cancer, e.g., by surgery. In some embodiments, the subject suffers from a chronic medical condition. In some embodiments, the thromboembolic disorder is associated with cancer. In some embodiments, the compound, a pharma- ceutically acceptable salt thereof, or a composition described herein is a primary agent for reducing the risk of a thromboembolic disorder. In some embodiments, the compounds, pharma- ceutically acceptable salts thereof, or compositions described herein are used as long-term treatments.

[0052] In one aspect, the present invention is directed to a method of reducing the risk of stroke (e.g., large vessel acute ischemic stroke) or systemic embolism in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein, e.g., Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein, e.g., a composition comprising Compound 1. In some embodiments, the subject suffers from atrial fibrillation (e.g., non-valvular atrial fibrillation). In some embodiments, the subject suffers from renal impairment (e.g., end-stage renal disease).

[0053] In one aspect, the present invention is directed to a method of preventing stroke (e.g., large vessel acute ischemic stroke) or systemic embolism in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein, e.g., Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein, e.g., a composition comprising Compound 1. In some embodiments, the subject suffers from atrial fibrillation (e.g., non-valvular atrial fibrillation). In some embodiments, the subject suffers from renal impairment (e.g., end-stage renal disease).

[0054] In one aspect, the invention is directed to a method of reducing the risk of recurrence of pulmonary embolism (e.g., symptomatic pulmonary embolism), comprising administering to a subject suffering from pulmonary embolism (e.g., a subject previously treated for pulmonary embolism) an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, administration reduces the risk of recurrence of pulmonary embolism in the subject, as compared to a subject not administered the compound.

[0055] In one aspect, the present invention provides a method of preventing pulmonary embolism in a subject suffering from pulmonary embolism (e.g., a subject who has previously been treated for pulmonary embolism), comprising administering to the subject an effective amount of Compound 1. or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0056] In one aspect, the invention is directed to a method of reducing the risk of recurrence of pulmonary embolism (e.g., symptomatic pulmonary embolism), comprising administering to a subject suffering from deep vein thrombosis (e.g., a subject who has previously been treated for deep vein thrombosis) an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, administration reduces the risk of recurrence of pulmonary embolism in the subject, as compared to a subject not administered the compound.

[0057] In one aspect, the invention is directed to a method of preventing pulmonary embolism in a subject suffering from deep vein thrombosis (e.g., a subject who has previously been treated for deep vein thrombosis), comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0058] In one aspect, the invention features a method of treating deep vein thrombosis in a subject who has previously been administered an anticoagulant, the method including administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the anticoagulant was administered parenterally for 5 to 10 days.

[0059] In one aspect, the invention features a method of treating pulmonary embolism in a subject who has previously been administered an anticoagulant, the method including administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the anticoagulant was administered parenterally for 5-10 days.

[0060] In one aspect, the present invention is directed to a method of treating a subject having an ischemic event (e.g., transient ischemia), comprising administering to the subject Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the compound is administered to the subject within 24 hours or less, e.g., 12, 10, 9, 8, 7, 6 hours or less, after the onset of the ischemic event in the subject.

[0061] In one aspect, the present invention is directed to a method of treating a subject having an ischemic event (e.g., transient ischemia), comprising administering to the subject Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the compound is administered to the subject within more than 2 to 12 hours, e.g., more than 2 to 10 hours or less, more than 2 to 8 hours or less, after the onset of the ischemic event in the subject.

[0062] In one aspect, the present invention is directed to a method of treating hypertension, e.g., arterial hypertension, in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, hypertension, e.g., arterial hypertension, leads to atherosclerosis. In some embodiments, hypertension is , pulmonary arterial hypertension.

[0063] In one aspect, the present invention is directed to a method of reducing the risk of hypertension, e.g., arterial hypertension, in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, hypertension, e.g., arterial hypertension, leads to atherosclerosis. In some embodiments, the hypertension is pulmonary arterial hypertension.

[0064] In one aspect, the present invention is directed to a method of preventing hypertension, e.g., arterial hypertension, in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, hypertension, e.g., arterial hypertension, leads to atherosclerosis. In some embodiments, the hypertension is pulmonary arterial hypertension.

[0065] In one aspect, the present invention is directed to a method of reducing inflammation in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the inflammation is vascular inflammation. In some embodiments, the vascular inflammation is associated with atherosclerosis. In some embodiments, the vascular inflammation is associated with thromboembolic disease in the subject. In some embodiments, the vascular inflammation is angiotensin II-induced vascular inflammation.

[0066] In one aspect, the present invention is directed to a method of preventing leukocyte infiltration of blood vessels in a subject, the method comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0067] In one aspect, the present invention is directed to a method of preventing angiotensin II-induced endothelial dysfunction in a subject, the method comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0068] In one aspect, the present invention is directed to a method of preventing thrombin proliferation in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, thrombin proliferation occurs on platelets.

[0069] In one aspect, the present invention is directed to a method of treating hypertension-associated renal insufficiency in a subject, the method comprising administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof).

[0070] In one aspect, the present invention is directed to a method of preventing hypertension-associated renal insufficiency in a subject, the method comprising administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof).

[0071] In one aspect, the present invention is directed to a method of reducing the risk of hypertension-associated renal insufficiency in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0072] In one aspect, the present invention is directed to a method of treating renal fibrosis in a subject, the method comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0073] In one aspect, the present invention is directed to a method of preventing renal fibrosis in a subject, the method comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0074] In one aspect, the present invention is directed to a method of reducing the risk of renal fibrosis in a subject, the method comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0075] In one aspect, the present invention is directed to a method of treating kidney damage in a subject, the method comprising administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof).

[0076] In one aspect, the present invention is directed to a method of preventing kidney damage in a subject, the method comprising administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof).

[0077] In one aspect, the present invention is directed to a method of reducing the risk of kidney damage in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In one aspect, the present invention is directed to a method of inhibiting factor XIa in a subject, comprising administering to a subject suffering from ischemia an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the ischemia is coronary ischemia. In some embodiments, the subject is a mammal (e.g., a human). In some embodiments, the subject is undergoing surgery (e.g., knee or hip replacement). In some embodiments, the ischemia is coronary ischemia. In some embodiments, the subject is a subject with non-valvular atrial fibrillation. In some embodiments, the subject has one or more of the following risk factors for stroke: previous stroke (e.g., ischemic, unknown, hemorrhagic), transient ischemic attack, or non-CNS systemic embolism. In some embodiments, the subject has one or more of the following risk factors for stroke: age 75 years or older, hypertension, heart failure or left ventricular ejection fraction (e.g., less than or equal to 35%), or diabetes.

[0078] In some embodiments, the compound is administered orally or parenterally (e.g., intravenously). In some embodiments, the compound is administered orally. In some embodiments, the compound is administered parenterally (e.g., intravenously). In one embodiment, the compounds are administered by subcutaneous administration.

[0079] In some embodiments, the compound is administered prior to an ischemic event (eg, to a subject at risk for an ischemic event).

[0080] In some embodiments, the compound is administered after an ischemic event (e.g., a transient ischemic event). In some embodiments, the compound is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or more after an ischemic event (e.g., a transient ischemic event). In some embodiments, the compound is administered about 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more after an ischemic event (e.g., a transient ischemic event).

[0081] In some embodiments, the compound is administered in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered after administration of the compound. In some embodiments, the additional therapeutic agent is administered orally. In some embodiments, the additional therapeutic agent is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, or 24 hours or more after administration of the compound. In some embodiments, the additional therapeutic agent is administered at least 1, 2, 3, 4, 5, 6, 7, 14, 21, or 28 days or more after administration of the compound. In some embodiments, the additional therapeutic agent is administered about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, or more after administration of the compound.

[0082] In some embodiments, the additional therapeutic agent is administered for an extended period of time (e.g., about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days or longer) after administration of the compound.

[0083] In some embodiments, the additional therapeutic agent is selected from the group consisting of side effects (e.g., active pathological bleeding or severe hypersensitivity reactions (e.g., anaphylactic reactions), spinal and / or epidural hematomas, gastrointestinal disorders (e.g., upper abdominal pain, dyspepsia, toothache), general disorders and administration site conditions (e.g., fatigue), infections and insults (e.g., sinusitis, urinary tract infections), musculoskeletal and connective tissue disorders (e.g., back pain, osteoarthritis), respiratory, thoracic and longitudinal disorders (e.g., oropharyngeal pain), injuries, poisoning and procedural complications (e.g., wound discharge), musculoskeletal and connective tissue disorders (e.g., For example, acromiocytosis, muscle spasms), nervous system disorders (e.g., fainting), skin and subcutaneous tissue disorders (e.g., pruritus, blisters), blood and lymphatic system disorders (e.g., agranulocytosis), gastrointestinal disorders (e.g., retroperitoneal hemorrhage), hepatobiliary disorders (e.g., jaundice, cholestasis, cytolytic hepatitis), immune system disorders (e.g., hypersensitivity, anaphylactic reactions, anaphylactic shock, angioedema), nervous system disorders (e.g., intracerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis), skin and subcutaneous tissue disorders (e.g., Stevens-Johnson syndrome).

[0084] In some embodiments, the additional therapeutic agent is an NSAID (eg, aspirin or naproxen), a platelet aggregation inhibitor (eg, clopidogrel), or an anticoagulant (eg, warfarin or enoxaparin).

[0085] In some embodiments, the additional therapeutic agents provide an additive therapeutic effect. In some embodiments, the additional therapeutic agents provide a synergistic therapeutic effect.

[0086] In another aspect, the invention features a pharmaceutical composition that includes a compound described herein (eg, Compound 1) and a pharma- ceutically acceptable excipient.

[0087] In another aspect, the present invention provides a method for modulating (e.g., inhibiting) factor XIa in a patient. The method includes administering to a patient in need thereof an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof), thereby modulating (e.g., inhibiting) factor XIa.

[0088] In another aspect, the invention features a method of treating a thromboembolic disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). The thromboembolic disorder can be arterial cardiovascular thromboembolic disorder, arterial thrombosis, venous cardiovascular thromboembolic disorder, and thromboembolic disorder in the ventricles; including unstable angina, acute coronary syndromes, first myocardial infarction, recurrent myocardial infarction, ischemia (e.g., coronary ischemia, sudden ischemic death, or transient ischemic attack), stroke (e.g., large vessel acute ischemic stroke), atherosclerosis, peripheral arterial occlusive disease, venous thromboembolism, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis due to (a) artificial valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to artificial surfaces that promote thrombosis.

[0089] In another aspect, the invention features a method for preventing a thromboembolic disorder in a subject, the method including administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof). The thromboembolic disorder can be arterial cardiovascular thromboembolic disorder, arterial thrombosis, venous cardiovascular thromboembolic disorder, and thromboembolic disorder in the ventricles; including unstable angina, acute coronary syndromes, first myocardial infarction, recurrent myocardial infarction, ischemia (e.g., coronary ischemia, sudden ischemic death, or transient ischemic attack), stroke (e.g., large vessel acute ischemic stroke), atherosclerosis, peripheral arterial occlusive disease, venous thromboembolism, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis due to (a) artificial valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to artificial surfaces that promote thrombosis.

[0090] In another aspect, the invention features a method for reducing the risk of a thromboembolic disorder in a subject, the method comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). The thromboembolic disorder can be arterial cardiovascular thromboembolic disorder, arterial thrombosis, venous cardiovascular thromboembolic disorder, and thromboembolic disorder in the ventricles; including unstable angina, acute coronary syndromes, first myocardial infarction, recurrent myocardial infarction, ischemia (e.g., coronary ischemia, sudden ischemic death, or transient ischemic attack), stroke (e.g., large vessel acute ischemic stroke), atherosclerosis, peripheral arterial occlusive disease, venous thromboembolism, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis due to (a) artificial valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to artificial surfaces that promote thrombosis.

[0091] In one aspect, the present invention provides a method of treating end stage renal disease in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a compound as described herein. The present invention relates to methods comprising administering a composition (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0092] In one aspect, the present invention is directed to a method of preventing end stage renal disease in a subject, the method comprising administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof).

[0093] In one aspect, the present invention is directed to a method of reducing the risk of end stage renal disease in a subject, the method comprising administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof).

[0094] In another aspect, the invention features a method of treating a thromboembolic disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof), wherein the subject is exposed to an artificial surface. In some embodiments, the artificial surface contacts the subject's blood. In some embodiments, the artificial surface is an extracorporeal surface. In some embodiments, the artificial surface is a surface of an implantable prosthesis, e.g., a mechanical valve. In some embodiments, the artificial surface is a surface of a dialysis catheter. In some embodiments, the artificial surface is a surface of a cardiopulmonary bypass circuit. In some embodiments, the artificial surface is a surface of an artificial heart valve. In some embodiments, the artificial surface is a surface of a ventricular assist device. In some embodiments, the artificial surface is a surface of a small diameter graft. In some embodiments, the artificial surface is a surface of a central venous catheter. In some embodiments, the artificial surface is a surface of an extracorporeal membrane oxygenation (ECMO) device. In some embodiments, the artificial surface causes or is associated with a thromboembolic disorder. In some embodiments, the thromboembolic disorder is venous thromboembolism. In some embodiments, the thromboembolic disorder is deep vein thrombosis. In some embodiments, the thromboembolic disorder is pulmonary embolism.

[0095] In another aspect, the invention features a method of reducing the risk of a thromboembolic disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof), wherein the subject is exposed to an artificial surface. In some embodiments, the artificial surface contacts the subject's blood. In some embodiments, the artificial surface is an extracorporeal surface. In some embodiments, the artificial surface is a surface of an implantable prosthesis, e.g., a mechanical valve. In some embodiments, the artificial surface is a surface of a dialysis catheter. In some embodiments, the artificial surface is a surface of a cardiopulmonary bypass circuit. In some embodiments, the artificial surface is a surface of an artificial heart valve. In some embodiments, the artificial surface is a surface of a ventricular assist device. In some embodiments, the artificial surface is a surface of a small diameter graft. In some embodiments, the artificial surface is a surface of a central venous catheter. In some embodiments, the artificial surface is a surface of an extracorporeal membrane oxygenation (ECMO) device. In some embodiments, the artificial surface causes or is associated with a thromboembolic disorder. In some embodiments, the thromboembolic disorder is venous thromboembolism. In some embodiments, the thromboembolic disorder is deep vein thrombosis. In some embodiments, the thromboembolic disorder is pulmonary embolism.

[0096] In another aspect, the present invention provides a method for preventing a thromboembolic disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., Compound 2). In some embodiments, the method includes administering to a subject a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof, wherein the subject is exposed to an artificial surface. In some embodiments, the artificial surface contacts the subject's blood. In some embodiments, the artificial surface is an extracorporeal surface. In some embodiments, the artificial surface is a surface of an implantable prosthesis, e.g., a mechanical valve. In some embodiments, the artificial surface is a surface of a dialysis catheter. In some embodiments, the artificial surface is a surface of a cardiopulmonary bypass circuit. In some embodiments, the artificial surface is a surface of an artificial heart valve. In some embodiments, the artificial surface is a surface of a ventricular assist device. In some embodiments, the artificial surface is a surface of a small diameter graft. In some embodiments, the artificial surface is a surface of a central venous catheter. In some embodiments, the artificial surface is a surface of an extracorporeal membrane oxygenation (ECMO) device. In some embodiments, the artificial surface causes or is associated with a thromboembolic disorder. In some embodiments, the thromboembolic disorder is venous thromboembolism. In some embodiments, the thromboembolic disorder is deep vein thrombosis. In some embodiments, the thromboembolic disorder is pulmonary embolism.

[0097] In another aspect, the invention features a method of treating atrial fibrillation in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the subject also requires dialysis, e.g., kidney dialysis. In some embodiments, the compound described herein is administered to the subject while the subject is undergoing dialysis. In some embodiments, the compound or a pharma- ceutically acceptable salt or composition is administered to the subject before or after undergoing dialysis. In some embodiments, the patient has end stage renal disease. In some embodiments, the subject does not require dialysis, e.g., kidney dialysis. In some embodiments, the patient is at high risk of bleeding. In some embodiments, the atrial fibrillation is associated with another thromboembolic disorder, e.g., blood clots.

[0098] In another aspect, the invention features a method of reducing the risk of atrial fibrillation in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the subject is at high risk of developing atrial fibrillation. In some embodiments, the subject also requires dialysis, e.g., kidney dialysis. In some embodiments, the compound described herein is administered to the subject while the subject is undergoing dialysis. In some embodiments, the compound or a pharma- ceutically acceptable salt or composition is administered to the subject before or after undergoing dialysis. In some embodiments, the patient has end stage renal disease. In some embodiments, the subject does not require dialysis, e.g., kidney dialysis. In some embodiments, the patient is at high risk of bleeding. In some embodiments, the atrial fibrillation is associated with another thromboembolic disorder, e.g., blood clots.

[0099] In another aspect, the invention features a method of preventing atrial fibrillation in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the subject is at high risk of developing atrial fibrillation. In some embodiments, the subject also requires dialysis, e.g., kidney dialysis. In some embodiments, the compound described herein is administered to the subject while the subject is undergoing dialysis. In some embodiments, the compound or a pharma- ceutically acceptable salt or composition is administered to the subject before or after undergoing dialysis. In some embodiments, the patient has end stage renal disease. In some embodiments, the subject does not require dialysis, e.g., kidney dialysis. In some embodiments, the patient is at high risk of bleeding. In some embodiments, atrial fibrillation is caused by another blood Thromboembolic disorders, e.g., associated with blood clots.

[0100] In another aspect, the invention features a method of treating heparin-induced thrombocytopenia in a subject in need thereof, the method including administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof).

[0101] In another aspect, the invention features a method of reducing the risk of heparin-induced thrombocytopenia in a subject in need thereof, the method including administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof).

[0102] In another aspect, the invention features a method of preventing heparin-induced thrombocytopenia in a subject in need thereof, the method including administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof).

[0103] In another aspect, the present invention provides a method of treating heparin-induced thrombocytopenia thrombosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of heparin-induced thrombocytopenia thrombosis .... The method includes administering to a subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof).

[0104] In another aspect, the invention features a method of reducing the risk of heparin-induced thrombocytopenic thrombosis in a subject in need thereof, the method including administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof).

[0105] In another aspect, the invention features a method of preventing heparin-induced thrombocytopenic thrombosis in a subject in need thereof, the method including administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof).

[0106] In another aspect, the invention features a method of preventing a thromboembolic disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof), wherein the subject has cancer or is being treated with a chemotherapy agent. In some embodiments, the subject is concurrently receiving chemotherapy. In some embodiments, the subject has elevated lactase dehydrogenase levels. In some embodiments, the thromboembolic disorder is venous thromboembolism. In some embodiments, the thromboembolic disorder is deep vein thrombosis. In some embodiments, the thromboembolic disorder is pulmonary embolism.

[0107] In another aspect, the present invention provides a method for treating thrombotic microangiopathy in a subject in need thereof. The present invention features a method for treating a thrombotic microangiopathy, the method comprising administering to a subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the thrombotic microangiopathy is hemolytic uremic syndrome (HUS). In some embodiments, the thrombotic microangiopathy is thrombotic thrombocytopenic purpura (TTP).

[0108] In another aspect, the invention features a method of reducing the risk of thrombotic microangiopathy in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the thrombotic microangiopathy is hemolytic uremic syndrome (HUS). In some embodiments, the thrombotic microangiopathy is thrombotic thrombocytopenic purpura (TTP).

[0109] In another aspect, the invention features a method of preventing thrombotic microangiopathy in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the thrombotic microangiopathy is hemolytic uremic syndrome (HUS). In some embodiments, the thrombotic microangiopathy is thrombotic thrombocytopenic purpura (TTP).

[0110] In another aspect, the invention features a method of preventing recurrent ischemia in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof), wherein the subject has an acute coronary syndrome. In some embodiments, the subject has atrial fibrillation. In some embodiments, the subject does not have atrial fibrillation. In another aspect, the invention features a method of treating a subject identified as being at risk, e.g., high risk of stroke (e.g., large vessel acute ischemic stroke) or thrombosis, thereby reducing the likelihood of stroke (e.g., large vessel acute ischemic stroke) or thrombosis in the subject. In some embodiments, the subject is further identified as being at risk of hemorrhage (e.g., hemorrhage) or sepsis. In some embodiments, the treatment is effective without hemorrhage burden. In some embodiments, the treatment is effective to maintain patency of infusion ports and lines. In addition, the compounds described herein (e.g., Compound 1) are useful for treating and preventing other diseases in which thrombin generation is implicated as playing a physiological role. For example, thrombin is involved in contributing to the morbidity and mortality of chronic and degenerative diseases, such as cancer, arthritis, atherosclerosis, vascular dementia, and Alzheimer's disease, by its ability to regulate many different cell types through diverse cellular functions, such as specific cleavage and activation of cell surface thrombin receptors, mitogenic effects, cell proliferation, e.g., restenosis or angiogenesis, abnormal proliferation of vascular cells resulting in release of PDGF, and DNA synthesis. Inhibition of factor XIa effectively blocks thrombin generation, thus neutralizing any physiological effects of thrombin on various cell types. The representative cases discussed above include some, but not all, of the potential clinical situations suitable for treatment with factor XIa inhibitors.

[0111] In another aspect, the invention features a method of treating a subject having edema (e.g., angioedema, e.g., hereditary angioedema), the method including administering to the subject Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof).

[0112] In another aspect, the invention features a method of preventing edema (e.g., angioedema, e.g., hereditary angioedema) in a subject, the method including administering to the subject Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof).

[0113] In another aspect, the invention features a method of reducing the risk of edema (e.g., angioedema, e.g., hereditary angioedema) in a subject, the method including administering to the subject Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof).

[0114] In another aspect, the invention features a method of inhibiting kallikrein in a subject, the method including administering to a subject having edema (e.g., angioedema, e.g., hereditary angioedema) an effective amount of Compound 1, or a pharma- ceutical acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1, or a pharma- ceutical acceptable salt thereof) to the subject.

[0115] In another aspect, the invention features a method of treating a thromboembolic outcome or complication in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the thromboembolic outcome or complication is associated with peripheral vascular intervention (e.g., limb), hemodialysis, catheter ablation, cerebrovascular intervention, organ (e.g., liver) transplantation, surgery (e.g., orthopedic surgery, pulmonary surgery, abdominal surgery, or cardiac surgery (e.g., open heart surgery)), transcatheter aortic valve implantation, large bore interventions used to treat aneurysms, percutaneous coronary intervention, or hemophilia therapy. In some embodiments, the surgery is orthopedic surgery, pulmonary surgery, abdominal surgery, or cardiac surgery. In some embodiments, the cardiac surgery is complex cardiac surgery or lower risk cardiac surgery. In some embodiments, the thromboembolic outcome or complication is associated with percutaneous coronary intervention.

[0116] In another aspect, the invention features a method of preventing thromboembolic consequences or complications in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the thromboembolic consequences or complications are associated with peripheral vascular intervention (e.g., limbs), hemodialysis, catheter ablation, e.g., catheter ablation for atrial fibrillation, cerebrovascular intervention, organ (e.g., liver) transplantation, surgery (e.g., orthopedic surgery, pulmonary surgery, abdominal surgery, or cardiac surgery (e.g., open heart surgery)), transcatheter aortic valve implantation, large bore interventions used to treat aneurysms, percutaneous coronary intervention, or hemophilia therapy. In some embodiments, the surgery is orthopedic surgery, pulmonary surgery, abdominal surgery, or cardiac surgery. In some embodiments, the cardiac surgery is complex cardiac surgery or lower risk cardiac surgery. In some embodiments, the thromboembolic consequences or complications are associated with percutaneous coronary intervention.

[0117] In another aspect, the invention features a method of reducing the risk of thromboembolic outcomes or complications in a subject, the method including administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the thromboembolic outcomes or complications can be peripheral vascular interventions (e.g., limbs), blood The present invention relates to a method for treating hemophilia, comprising administering to a patient a pulmonary or abdominal procedure, such as ...

[0118] In another aspect, the invention features a method of treating restenosis following arterial injury in a subject, the method including administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the arterial injury occurs following cranial artery stent placement.

[0119] In another aspect, the invention features a method of preventing restenosis following arterial injury in a subject, the method including administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the arterial injury occurs following cranial artery stent placement.

[0120] In another aspect, the invention features a method of reducing the risk of restenosis following arterial injury in a subject, the method including administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the arterial injury occurs following cranial artery stent placement.

[0121] In another aspect, the invention features a method of treating hepatic vascular thrombosis in a subject, the method including administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1, or a pharma- ceutically acceptable salt thereof).

[0122] In another aspect, the invention features a method of preventing hepatic vascular thrombosis in a subject, the method including administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1, or a pharma- ceutically acceptable salt thereof).

[0123] In another aspect, the invention features a method of reducing the risk of hepatic vascular thrombosis in a subject, the method including administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1, or a pharma- ceutically acceptable salt thereof).

[0124] In another aspect, the invention features a method of treating non-ST elevation myocardial infarction or ST elevation myocardial infarction, the method including administering to a subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1, or a pharma- ceutically acceptable salt thereof).

[0125] In another aspect, the invention provides a method for preventing non-ST elevation myocardial infarction or ST elevation myocardial infarction in a subject, comprising administering to the subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof). The method includes administering to the subject a composition comprising a compound selected from the group consisting of phenylephrine, ...

[0126] In another aspect, the invention features a method of reducing the risk of non-ST elevation myocardial infarction or ST elevation myocardial infarction in a subject, the method including administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition including Compound 1, or a pharma- ceutically acceptable salt thereof).

[0127] In another aspect, the invention features a method of maintaining vascular patency, comprising administering to a subject an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition described herein (e.g., a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof). In some embodiments, the subject has acute kidney injury. In some embodiments, the subject further undergoes continuous renal replacement therapy.

[0128] In some embodiments of any of the above, the compound or composition described herein is administered orally or parenterally.In certain embodiments, the compound or composition is administered orally.In certain embodiments, the compound or composition is administered after the subject has stopped using a direct oral anticoagulant.In certain embodiments, the subject has used a direct oral anticoagulant for up to about 2.5 years.In certain embodiments, the subject is a mammal, for example, a human.

[0129] In some embodiments of the methods described herein, the pharma- ceutically acceptable salt of the compound is a hydrochloride salt. In some embodiments, the compound is administered to the subject intravenously. In some embodiments, the compound is administered to the subject subcutaneously. In some embodiments, the compound is administered to the subject as a continuous intravenous infusion. In some embodiments, the compound is administered to the subject as a bolus. In some embodiments, the subject is a human. In some embodiments, the subject is at high risk for a thromboembolic disorder. In some embodiments, the thromboembolic disorder is the result of a complication in surgery.

[0130] In some embodiments, the subject is sensitive to or has developed sensitivity to heparin, hi some embodiments, the subject is resistant to or has developed resistance to heparin.

[0131] In some embodiments, the subject is in contact with the artificial surface for at least 1 day (e.g., about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, about 3 months, about 6 months, about 9 months, about 1 year). [Brief description of the drawings]

[0132] [Figure 1] FIG. 1 is an illustrative 1H NMR spectrum of sample number 4 obtained from the procedure in Example 1.

[0133] [Diagram 2] FIG. 2 is an illustrative 1H NMR spectrum of sample number 8 obtained from the procedure in Example 3, step 1.

[0134] [Diagram 3] FIG. 3 is an illustrative 1H NMR spectrum of the crude product obtained from the procedure in Example 3, Step 2.

[0135] [Figure 4] FIG. 4 is an illustrative 1H NMR spectrum of the purified product obtained from the procedure in Example 3, Step 2.

[0136] [Diagram 5] FIG. 5 is an illustrative 1H NMR spectrum of the product obtained from the procedure in Example 3, Step 3.

[0137] [Figure 6] FIG. 6 is an illustrative 1H NMR spectrum of the product obtained from the procedure in Example 3, Step 4.

[0138] [Figure 7] FIG. 7 is an illustrative 13C NMR spectrum of the product obtained from the procedure in Example 3, Step 4.

[0139] [Figure 8] FIG. 8 is an enlarged view of the 13C NMR spectrum in the region of 105 to 180 ppm of FIG.

[0140] [Figure 9] FIG. 9 is an exemplary XRPD pattern of the product obtained from the procedure in Example 3, Step 4.

[0141] [Figure 10] FIG. 10 shows the pressure gradient across a membrane oxygenator for cardiopulmonary bypass experiments performed in a hound dog model.

[0142] [Figure 11] FIG. 11 shows a comparison of the ratio of plasma concentrations to activated partial thromboplastin time (aPTT) measured in a hound dog model.

[0143] [Figure 12] FIG. 12 shows the activated partial thromboplastin time (aPTT) measured in a hound model after administration of Compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0144] Detailed Description definition The term "agitated" as used herein refers to any externally induced movement of a macroscopic constituent of a reaction mixture relative to another macroscopic constituent of the reaction mixture. The term "stirring" as used herein refers to any externally induced movement of a macroscopic constituent of a reaction mixture relative to another macroscopic constituent of the reaction mixture by a stirring device, e.g., induced stirring, and can include conventional internal stirring procedures known to those skilled in the art. As used herein, "XRPD" refers to X-ray powder diffraction.

[0145] As used herein, "slurrying" refers to a method in which a compound described herein is suspended in a solvent (e.g., a polar aprotic solvent or a non-polar solvent) and the suspension is agitated before being collected again (e.g., by filtration).

[0146] As used herein, "crystalline" refers to a solid that has a highly ordered chemical structure: the molecules are arranged in a regular, periodic manner in the three-dimensional space of a lattice.

[0147] The term "substantially crystalline" refers to a form that can be crystalline to at least a certain weight percentage. The certain weight percentage is 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In certain embodiments, the certain weight percentage of crystallinity is at least 90%. In certain other embodiments, the certain weight percentage of crystallinity is at least 95%. In some embodiments, Compound 1 can be a substantially crystalline sample of any of the crystalline solid forms described herein.

[0148] The term "substantially pure" refers to a composition of a specific crystalline solid form of Compound 1, which may be at least a specific weight percentage, free of impurities and / or other solid forms of Compound 1 or a pharma- ceutically acceptable salt thereof. The specific weight percentage is 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, the crystalline solid form of Compound 1 or a pharma- ceutically acceptable salt thereof described herein is substantially pure at a weight percentage between 95% and 100%, for example, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9%.

[0149] As used herein, and unless otherwise specified, the terms "treat", "treating" and "treatment" contemplate actions taken while a subject is afflicted with a specific disease, disorder or condition that reduce the severity of the disease, disorder or condition or arrest or slow the progression of the disease, disorder or condition (also "therapeutic treatment").

[0150] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to achieve a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that achieves a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0151] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound refers to an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that achieves a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0152] Disease, disorder and condition are used interchangeably herein.

[0153] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or geriatric adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. In some embodiments, the pediatric subject is between 0 and 18 years of age. In some embodiments, the adult subject is over 18 years of age.

[0154] As used herein, the term "artificial surface" refers to any non-human or non-animal surface that comes into contact with a subject's blood, for example during a medical procedure. The artificial surface can be a tube for drawing or circulating the subject's blood outside the subject's body. The artificial surface can also be a stent, a valve, an intraluminal catheter, or a system for pumping blood. By way of non-limiting examples, such artificial surfaces can be steel, any type of plastic, glass, silicone, rubber, etc. In some embodiments, the artificial surface is made of at least 50%, 60%, 70%, 80%, 90% or 100% of the subject's blood. 00% exposure.

[0155] As used herein, the term "conditioning" or "conditioned" with respect to an artificial surface refers to priming or flushing an artificial surface (e.g., an extracorporeal surface) with a compound described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, either already present in a priming or flushing solution (e.g., blood, saline solution, Ringer's solution), or as a separate administration to the artificial surface before, during, or after a medical procedure. compound

[0156] Described herein are compounds that inhibit Factor XIa or kallikrein.

[0157] In one aspect, the present invention provides compound 1: [ka] Or a pharmaceutically acceptable salt thereof, for example, the hydrochloride salt of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is crystalline. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof exists as a substantially pure crystalline solid form.

[0158] In one embodiment, a pharma- ceutically acceptable salt of formula (I): [ka] is provided herein.

[0159] The pharma- ceutically acceptable salt of formula (I) is the hydrochloride salt of compound 1, also referred to herein as compound 1·HCl. In some embodiments, compound 1·HCl is crystalline. In some embodiments, compound 1·HCl exists as a substantially pure crystalline solid form. In some embodiments, compound 1·HCl has an XRPD pattern substantially as depicted in FIG. 9.

[0160] In one embodiment, a crystalline pharma- ceutically acceptable salt of formula (I): [ka] is provided herein.

[0161] In some embodiments, salts are formed from the compounds described herein. The compounds described herein may be administered as free acids, zwitterions, or as salts. Salts may also be formed between a cation and a negatively charged substituent on the compounds described herein, such as the deprotonated carboxylic acid moiety of Compound 1. Suitable cationic counterions include sodium, potassium, magnesium, calcium, and ammonium ions (e.g., tetraalkylammonium cations such as tetramethylammonium). In acid addition salts, salts may be formed between anions and a positively charged substituent (e.g., amino group) or basic substituent (e.g., pyridyl) on the compounds described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.

[0162] Pharmaceutically acceptable salts of the compounds described herein (e.g., pharma- ceutically acceptable salts of Compound 1) can also include those derived from pharma- ceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, 4-acetamidobenzoate, adipate, alginate, 4-aminosalicylate, aspartate, ascorbate, benzoate, benzenesulfonate, hydrogen sulfate, butyrate, citrate, camphorate, camphorsulfonate, carbonate, cinnamate, cyclamate, decanoate, decanedioate, 2,2-dichloroacetate, digluconate, dodecyl sulfate, ethanesulfonate, ethane-1,2-disulfonate, formate, fumarate, galactarate, glucoheptanoate, gluconate, glucohepton ... Glucoronate, glutamate, glutarate, glycerophosphate, glycosaminoglycan Salts include, for example, phosphate, phosphonate, picrate, pivalate, propionate, pyroglutamate, salicylate, sebacate, succinate, stearate, sulfate, tartrate, thiocyanate, toluenesulfonate, tosylate, and undecanoate salts.

[0163] Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and (alkyl)4N+ salts. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water- or oil-soluble or dispersible products may be obtained by such quaternization.

[0164] As used herein, the compounds of the present invention, including Compound 1, are defined to include pharma- ceutically acceptable derivatives or prodrugs thereof. "Pharmaceutically acceptable derivatives or prodrugs" refers to any pharma- ceutically acceptable salts, esters, salts of esters, or other derivatives of the compounds of the present invention that can provide (directly or indirectly) the compounds of the present invention when administered to a recipient. Particularly advantageous derivatives and prodrugs are those that improve the bioavailability of the compounds of the present invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be readily absorbed by the blood) or enhance the delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) compared to the parent species. Preferred prodrugs include derivatives in which groups that enhance aqueous solubility or active transport through the intestinal membrane are attached to the structures of the formulas described herein.

[0165] Any formula or compound described herein is also intended to represent the unlabeled form and isotopically labeled form of the compound, and the isotopically labeled compound has the structure illustrated by the formula shown herein, except that one or more atoms are replaced by an atom with selected atomic mass or mass number.The examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F, 51P, 32P, 35S, 36Cl, 125I, etc.The present invention includes various isotopically labeled compounds as defined herein, for example, those in which radioactive isotopes such as 3H, 13C and 14C are present. Such isotopically labeled compounds are useful for metabolic studies (using 14C), reaction kinetic studies (e.g., using 'H or 3H), detection or imaging techniques (including drug or substrate tissue distribution assays), such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or radioactive treatment of patients. In particular, 18F or labeled compounds may be particularly desirable for PET or SPECT studies, and the isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparations described below, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0166] Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium in this context is considered a substituent of the compounds of the formulas described herein. The concentration of such heavier isotopes, specifically deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the abundance of an isotope and the natural abundance of a specified isotope. When a substituent in a compound of the invention represents deuterium, for each designated deuterium atom, such compounds have an isotopic enrichment factor that is at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 8633.3 (99.5% deuterium incorporation).

[0167] The isotopically labeled compounds described herein can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents in place of previously used non-labeled reagents. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, for example, DO, D6-acetone, D6-DMSO.

[0168] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention can be present in racemic or enantiomerically enriched, e.g., (R)-(S)- or (RS)-configuration, and in certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms with unsaturated bonds may be present in cis-(Z)- or trans-(E)-forms, where possible. Thus, as used herein, the compounds of the present invention are referred to as compounds of the present invention. The compounds may be present in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof. Any resulting mixture of isomers can be separated on the basis of the physicochemical differences of their constituents, for example, by chromatography or fractional crystallization, into pure or substantially pure geometric or optical isomers, diastereomers, racemates.

[0169] Either the resulting racemic form of the final product or intermediates can be resolved into their optical antipodes by known methods, for example by separating the diastereomeric salts obtained with optically active acids or bases to liberate the optically active acidic or basic compounds. Thus, using acidic moieties, the compounds of the present invention can be resolved into their optical antipodes, for example by fractional crystallization of salts formed with optically active acids, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, (+)-O,O'-di-p-toluoyl-D-tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example high performance liquid chromatography (HPLC) using a chiral adsorbent.

[0170] The compounds described herein (e.g., Compound 1) may also be represented in multiple tautomeric forms. In such instances, the present invention includes all tautomeric forms of the compounds described herein. All crystalline forms of the compounds described herein are expressly included in the present invention.

[0171] A compound described herein (eg, Compound 1) can be evaluated for its ability to modulate (eg, inhibit) Factor XIa or kallikrein. Pharmaceutical manufacturing and quality control standards

[0172] Good manufacturing practice (GMP), as it applies to the manufacture of a supply material, means all applicable practices relevant to the manufacture of drug products, including (i) practices promulgated by any regulatory authority having jurisdiction over the manufacture of the supply material in the form of governing law, including the current U.S. Good Manufacturing Practices regulations promulgated by FDA as set forth in 21 U.S.C. 351, 21 C.FR parts 210 and 211 (as amended), and their successors and ICH Q7 - Good Manufacturing Practices for Active Pharmaceutical Ingredients, (ii) practices in the form of draft or final guidance documents (including advisory opinions, compliance policy guides and guidelines) promulgated by any regulatory authority having jurisdiction over the manufacture of the supply material, and (iii) such other industry standards (as defined and specified in a quality agreement) as may be agreed upon by the parties to the specification. How to synthesize a compound

[0173] The compounds described herein can be synthesized by conventional methods, including but not limited to, using commercially available starting materials and reagents.For example, the compounds can be synthesized by utilizing the methods described in U.S. Patent No. 7,501,404, which is incorporated herein by reference, or by using the methods described in the Examples herein.

[0174] The compounds described herein can be purified using a variety of techniques within the art of organic synthetic chemistry. The compounds described herein, for example, any one of the compounds of formula I, II, III, IV, V, VI, or VII, can be purified using one or more chromatographic methods, for example, column chromatography or HPLC. The compounds described herein, for example, any one of the compounds of formula I, II, III, IV, Compounds of any one of formulas V, V, VI, or VII can be purified by a non-chromatographic purification method, such as recrystallization or slurry formation. In one embodiment, the compounds described herein can be purified using recrystallization. In another embodiment, the compounds described herein can also be purified by slurry formation.

[0175] In some embodiments, the compounds described herein that have been purified by chromatography can also be purified by recrystallization. The compounds described herein can also be purified by slurrying (or reslurrying) the compounds with one or more solvents (e.g., slurries described herein). The compounds described herein can also be purified by powdering with one or more solvents, e.g., powdering as described herein. For example, the compounds described herein that have been purified by chromatography can also be purified by powdering. In a chemical reactor, the powdering process can be performed by suspension or resuspension of the solid product in a solvent or solvent mixture by mechanical agitation. In embodiments, the compounds described herein can also be purified by precipitation from solution using one or more anti-solvents. For example, the compounds described herein that have been purified by chromatography can also be purified by precipitation. In one embodiment, the compounds described herein are purified by simulated moving bed (SMB) chromatography. In one embodiment, the compounds described herein are purified by supercritical fluid chromatography, e.g., supercritical fluid chromatography using liquid carbon dioxide. In one embodiment, the compounds described herein are purified by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.

[0176] In one embodiment, a pharma- ceutically acceptable salt of formula (I): [ka] or a solvate (e.g., hydrate) thereof, comprising the steps of: [ka] or a solvate (e.g., hydrate) thereof in a solvent, thereby preparing a first solution, and adding hydrogen chloride to the first solution, thereby producing a pharma- ceutically acceptable salt of Formula (I).

[0177] In some embodiments, the salt of formula (II) is dissolved in an aprotic solvent. In some embodiments, the solvent comprises acetonitrile (e.g., consists of or consists essentially of acetonitrile). In some embodiments, hydrogen chloride is added to the first solution by bubbling HCl gas through the first solution or by adding another solution that comprises HCl (e.g., an ethereal solution of hydrochloric acid) to the first solution.

[0178] In some embodiments, the starting amount of the salt of formula (II) or its solvate (e.g., hydrate) is greater than or equal to 500 grams. In some embodiments, the starting amount of the salt of formula (II) or its solvate (e.g., hydrate) is greater than or equal to 1 kilogram. In some embodiments, the method produces greater than 300 grams (e.g., greater than about 350 grams (e.g., about 368 grams)) of a pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate).

[0179] In some embodiments, the method produces a pharma- ceutically acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) in greater than about 50% yield (e.g., about 55% yield). In some embodiments, the method produces a pharma- ceutically acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) in greater than about 75% yield. In some embodiments, the method produces a pharma- ceutically acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) in greater than about 90% yield. In some embodiments, the method produces a pharma- ceutical acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) in greater than about 99% yield. In some embodiments, the purity of the pharma- ceutical acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) is about 80%. In some embodiments, the purity of the pharma- ceutical acceptable salt of Formula (I) or a solvate thereof (e.g., a hydrate) is about 81%.

[0180] In some embodiments, the method further comprises purifying the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) by dissolving the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) in a solvent (e.g., isopropyl alcohol) and then precipitating the dissolved pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) using another solvent (e.g., methyl tert-butyl ether). In some embodiments, the purity of the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) after precipitation is greater than 98%. In some embodiments, the purity of the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) after precipitation is about 98%.

[0181] In some embodiments, the method further comprises purifying the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) by slurrying the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) in a solvent (e.g., isopropyl alcohol) and then filtering the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) to separate the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) from the solvent. In some embodiments, the purity of the pharma- ceutical acceptable salt of formula (I) or its solvate (e.g., hydrate) after slurrying and isolating is greater than 98%. In some embodiments, the purity of the pharma- ceutical acceptable salt of formula (I) or its solvate (e.g., hydrate) after slurrying and isolating is about 98%.

[0182] In some embodiments, the method comprises reacting a compound of formula (III) [ka] with trifluoroacetic acid to prepare the salt of formula (II).

[0183] In some embodiments, the method further comprises reacting a compound of formula (III) with a silane (e.g., triethyl The method further comprises contacting a silane.

[0184] In some embodiments, the method produces more than 500 grams (eg, more than 1 kg) of a compound of formula (III).

[0185] In some embodiments, the method comprises reacting a compound of formula (IV) [ka] to a compound of formula (V) [ka] The method includes the step of preparing a compound of formula (III) by contacting

[0186] In some embodiments, the method produces more than 1 kilogram (e.g., about 1.3 kg) of a compound of formula (III). In some embodiments, the method is carried out in the presence of a solvent. In some embodiments, the method is carried out in the presence of a base (e.g., 1,8-diazabicyclo(5.4.0)undec-7-ene).

[0187] In some embodiments, the method comprises reacting a compound of formula (VI) [ka] to a compound of formula (VII) [ka] The method includes the step of preparing a compound of formula (IV) by contacting

[0188] In some embodiments, the method produces more than 500 grams (eg, more than 900 grams) of a compound of formula (IV).

[0189] In some embodiments, the compound of formula (III) is purified by a purification method that is not chromatographic. In some embodiments, the purification method includes slurrying the compound of formula (III) in a solvent (e.g., heptane) and then filtering the compound of formula (III) to separate the compound of formula (III) from the solvent. In some embodiments, the purity of the compound of formula (III) is greater than 90%.

[0190] In some embodiments, the compound of formula (I) is purified by a purification method that is not chromatographic. Methods of treatment, prevention or risk reduction

[0191] The compounds described herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof) can inhibit factor XIa or kallikrein. In some embodiments, the compounds described herein can inhibit both factor XIa and kallikrein. As a result, these compounds can be useful in treating, preventing, or reducing the risk of the disorders described herein.

[0192] Exemplary disorders include coronary and cerebrovascular disease, venous or arterial thrombosis, coagulation syndromes, ischemia (e.g., coronary ischemia) and angina pectoris (stable and unstable), deep vein thrombosis (DVT), hepatic vein thrombosis, disseminated intravascular coagulopathy, Kasabach-Merritt syndrome, pulmonary embolism, myocardial infarction (e.g., ST elevation myocardial infarction or non-ST elevation myocardial infarction (e.g., non-ST elevation myocardial infarction before catheterization), cerebral infarction, cerebral thrombosis, cerebrovascular disease, cerebrovascular accident ... They may also be useful in treating or preventing myocardial infarction, stroke (e.g., large vessel acute ischemic stroke), angina pectoris, and other consequences of atherosclerotic plaque rupture, including thrombotic events associated with acute ischemic attacks, atrial fibrillation (e.g., non-valvular atrial fibrillation), cerebral embolism, thromboembolic complications of surgery (e.g., hip or knee replacement, orthopedic surgery, cardiac surgery, pulmonary surgery, abdominal surgery, or endarterectomy), and peripheral arterial occlusive disease. The compounds of the invention having factor XIa or kallikrein inhibitory activity may also be useful in preventing thromboembolic disorders, such as venous thromboembolism, and in preventing thromboembolic events during or after tissue plasminogen activator-based or mechanical restoration of vascular patency in cancer patients, including those undergoing chemotherapy and / or those with elevated lactase dehydrogenase (LDH) levels. The compounds of the invention having factor XIa or kallikrein inhibitory activity may also be useful as inhibitors of blood coagulation, such as during whole blood preparation, storage and fractionation. Furthermore, the compounds described herein may be used in acute hospital settings where patients are at risk for thromboembolic disorders or complications, or during or before surgery, and in patients with elevated coagulation status, such as cancer patients.

[0193] Factor XIa inhibition, according to the present invention, can be a more effective and safer method of inhibiting thrombosis than inhibition of other coagulation serine proteases such as thrombin or factor Xa. Administration of a small molecule factor XIa inhibitor should have the effect of inhibiting thrombin generation and clot formation with no or substantially no effect on bleeding frequency and little or no impairment of hemostasis. These results are substantially different from those of other "direct acting" coagulation protease inhibitors (e.g., active site inhibitors of thrombin and factor Xa), demonstrating that bleeding times are prolonged and that there is less distinction between antithrombotic efficacy and prolonged bleeding times. A preferred method according to the present invention comprises administering to a mammal a pharmaceutical composition containing at least one compound of the present invention.

[0194] The compounds described herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof) can inhibit kallikrein. As a result, these compounds can be useful for treating, preventing, or reducing the risk of diseases involving inflammation, such as edema (e.g., cerebral edema, macular edema, and angioedema (e.g., hereditary angioedema)). In some embodiments, the compounds of the present invention can be useful for treating or preventing hereditary angioedema. The compounds described herein (e.g., Compound 1), e.g., Compound 1 or a pharma-ceutically acceptable salt thereof, can be useful for treating, preventing, or reducing the risk of, for example, stroke, ischemia (e.g., coronary ischemia), and perioperative blood loss. The methods of the present invention are useful for treating or preventing such conditions, including the action of factor XIa or kallikrein. Thus, the methods of the invention are useful for treating the consequences of atherosclerotic plaque rupture, including cardiovascular diseases associated with activation of the coagulation cascade in thrombotic or thrombogenic conditions.

[0195] More particularly, the methods of the present invention can be used to treat, prevent, or reduce the risk of acute coronary syndromes, such as coronary artery disease, myocardial infarction, unstable angina (including crescendo angina), ischemia (e.g., ischemia due to vascular occlusion), and cerebral infarction. The methods of the invention may further be useful in treating, preventing or reducing the risk of stroke (e.g., large vessel acute ischemic stroke) and related cerebrovascular diseases (including cerebrovascular accidents, vascular dementia and transient ischemic attacks); venous thrombosis and thromboembolism (such as deep vein thrombosis (DVT) and pulmonary embolism); thrombosis associated with atrial fibrillation, ventricular enlargement, dilated cardiomyopathy or heart failure; peripheral arterial disease and intermittent claudication; atherosclerosis due to the formation and implantation of atherosclerotic plaques; restenosis after arterial injury induced either intrinsically (by rupture of atherosclerotic plaques) or extrinsically (by invasive cardiac pathological procedures such as vessel wall injury resulting from angioplasty or cranial artery stenting); disseminated intravascular coagulopathy, Kasabach-Merritt syndrome, cerebral thrombosis and cerebral embolism.

[0196] Additionally, the methods of the invention may be used to treat thromboembolic outcomes or complications associated with cancer, thrombectomy, surgery (e.g., hip replacement, orthopedic surgery), endarterectomy, introduction of prosthetic heart valves, peripheral vascular interventions (e.g., limbs), cerebrovascular interventions, large bore interventions used to treat aneurysms, vascular grafts, artificial organs and implants (e.g., transcatheter aortic valve implantation) or transplantation of organs (e.g., liver transplantation), tissues or cells; percutaneous coronary intervention; catheter ablation; hemophilia therapy; hemodialysis. medications (such as tissue plasminogen activator or similar agents, and surgical restoration of vascular patency) in patients suffering from myocardial infarction, stroke (e.g., large vessel acute ischemic stroke), pulmonary embolism, and similar conditions; medications (such as oral contraceptives, hormone replacement, and heparin, for example, to treat heparin-induced thrombocytopenia); sepsis (such as sepsis associated with disseminated intravascular coagulation); pregnancy or childbirth; and for treating, prophylaxis (e.g., preventing) or reducing the risk of another chronic medical condition. The method of the present invention may be used to treat thrombosis due to restraint (e.g., immobilization, hospitalization, bed rest, or limb immobilization, such as with a rigid cast). In some embodiments, thromboembolic consequences or complications are associated with percutaneous coronary intervention.

[0197] Furthermore, the compounds (e.g., Compound 1) or pharma- ceutically acceptable salts thereof, or compositions thereof described herein can be useful for treating, preventing, and reducing the risk of thromboembolic disorders, such as venous thromboembolism, deep vein thrombosis, or pulmonary embolism, or related complications, in subjects exposed to an artificial surface. The artificial surface can be in contact with the subject's blood, for example, as an extracorporeal surface or as a surface of an implanted prosthesis. Such artificial surfaces include, but are not limited to, the surfaces of dialysis catheters, cardiopulmonary bypass circuits, artificial heart valves, such as mechanical heart valves (MHVs), ventricular assist devices, small-bore grafts, central venous catheters, and extracorporeal membrane oxygenation (ECMO) devices. Furthermore, thromboembolic disorders or related complications can be caused by or associated with artificial surfaces. For example, the foreign surfaces and various components of mechanical heart valves (MHVs) are prothrombotic and promote thrombin generation through the intrinsic pathway of coagulation. Furthermore, thrombin and FXa inhibitors are not effective in blocking the intrinsic pathway at plasma levels that do not cause severe bleeding, making these inhibitors contraindicated with thromboembolic disorders or associated complications caused by artificial surfaces such as MHV. Thus, the compounds of the present invention, which can be used, for example, as factor XIa inhibitors, are contemplated as alternative therapeutic agents for these purposes.

[0198] The compounds described herein (e.g., Compound 1) or pharma- ceutically acceptable salts thereof, or compositions thereof, may also be useful for treating, preventing, or reducing the risk of atrial fibrillation in a subject in need thereof. For example, the subject may have a high risk of developing atrial fibrillation. The subject may also require dialysis, such as kidney dialysis. The compounds described herein (e.g., Compound 1) or pharma- ceutically acceptable salts thereof, or compositions thereof, may be administered before, during, or after dialysis. Direct oral anticoagulants (DOACs), such as certain FXa or thrombin inhibitors, currently on the market, are contraindicated for atrial fibrillation under such conditions. Thus, the compounds of the present invention, which can be used, for example, as factor XIa inhibitors, are contemplated as alternative therapeutic agents for these purposes. In addition, the subject may be at high risk of bleeding. In some embodiments, the subject may have end-stage renal disease. In other cases, the subject does not require dialysis, such as kidney dialysis. In addition, atrial fibrillation may be associated with another thromboembolic disorder, such as blood clots.

[0199] Furthermore, the compounds described herein (e.g., Compound 1) or its pharma- ceutically acceptable salt, or compositions thereof, can be used to treat, prevent, or reduce the risk of hypertension, e.g., arterial hypertension, in a subject. In some embodiments, hypertension, e.g., arterial hypertension, can lead to atherosclerosis. In some embodiments, hypertension can be pulmonary arterial hypertension.

[0200] Additionally, the compounds described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or compositions thereof, can be used to treat, prevent, or reduce the risk of disorders such as heparin-induced thrombocytopenia, heparin-induced thrombocytopenic thrombosis, or thrombotic microangiopathy, e.g., hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP).

[0201] In some embodiments, the subject is sensitive to heparin or has developed sensitivity to heparin. Heparin-induced thrombocytopenia (HIT) is the development of a drop in platelet count following administration of various forms of heparin. HIT is caused by the formation of abnormal antibodies that activate platelets. HIT can be confirmed by certain blood tests. In some embodiments, the subject is resistant to heparin or has developed resistance to heparin. For example, an activated clotting time (ACT) test can be performed on the subject to test for sensitivity or resistance to heparin. The ACT test is a measure of the intrinsic pathway of coagulation that detects the presence of fibrin formation. Subjects who are sensitive and / or resistant to standard doses of heparin will not reach the target anticoagulation time. Common correlates of heparin resistance include, but are not limited to, previous heparin and / or nitroglycerin infusions and a drop in antithrombin III levels. In some embodiments, the subject has previously been administered an anticoagulant (e.g., bivalirudin / Angiomax).

[0202] The compounds described herein (e.g., Compound 1) or pharma- ceutically acceptable salts thereof, or compositions thereof, can be used to reduce inflammation in a subject. In some embodiments, the inflammation can be vascular inflammation. In some embodiments, the vascular inflammation can be associated with atherosclerosis. In some embodiments, the vascular inflammation can be associated with thromboembolic disease in a subject. In some embodiments, the vascular inflammation can be angiotensin II-induced vascular inflammation.

[0203] The compounds described herein (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or compositions thereof, can be used to treat, prevent, or reduce the risk of renal damage or dysfunction, including end-stage renal disease, hypertension-related renal dysfunction, renal fibrosis, and renal injury, in a subject.

[0204] The method of the present invention can also be used to maintain vascular patency, for example, in patients undergoing thrombectomy, transluminal coronary angioplasty, or in conjunction with vascular procedures such as bypass grafting, arterial reconstruction, atherectomy, vascular graft, stent patency, and organ, tissue or cell implantation, and transplantation. The method of the present invention can be used to inhibit blood coagulation associated with the preparation, storage, fractionation, or use of whole blood. For example, the method of the present invention can be used to maintain whole blood or fractionated blood in liquid phase, such as for analytical and biological testing, for example, for the examination of ex vivo platelet and other cell functions, biological analytical procedures, and quantification of blood-containing constituents, or as required to maintain an extracorporeal blood circuit, such as renal replacement (e.g., hemodialysis) or surgery (e.g., open heart surgery, e.g., coronary artery bypass surgery). In some embodiments, renal replacement can be used to treat patients with acute kidney injury. In some embodiments, renal replacement can be continuous renal replacement therapy.

[0205] Additionally, the methods of the present invention may be useful in the treatment and prevention of prothrombotic complications of cancer.The methods may be useful in the treatment of tumor growth, to prevent angiogenesis, and as an adjunct to chemotherapy for the treatment of cancer, more particularly lung, prostate, colon, breast, ovarian and bone cancer. Extracorporeal membrane oxygenation (ECMO)

[0206] "Extracorporeal Membrane Oxygenation" (or "ECMO"), as used herein, refers to an extracorporeal life support device with a blood pump, an oxygenator, and a vascular access cannula that allows for the generation of an adapted blood flow rate to provide circulatory support or to assist with blood oxygenation and, if necessary, carbon dioxide removal. In veno-venous ECMO, blood is withdrawn from the venous system and undergoes extracorporeal gas exchange. This blood is then reinfused into the venous system. In veno-arterial ECMO, blood is withdrawn from the venous system and undergoes gas exchange and then directly infused into the arterial system to provide partial or complete circulation or cardiac support. Veno-arterial ECMO allows for varying degrees of respiratory support.

[0207] As used herein, "extracorporeal membrane oxygenation" or "ECMO" refers to an extracorporeal life support device that provides circulatory support or generates a suitable blood flow rate to support blood oxygenation. In some embodiments, ECMO involves the removal of carbon dioxide from the subject's blood. In some embodiments, ECMO is performed using an extracorporeal device selected from the group consisting of a blood pump, an oxygenator, and a vascular access cannula.

[0208] As used herein, "venovenous ECMO" refers to a type of ECMO in which blood is withdrawn from a subject's venous system and placed into an ECMO device, gas exchange is performed (including oxygenation of the blood), and then the withdrawn blood is reinfused into the subject's venous system. As used herein, "venoarterial ECMO" refers to a type of ECMO in which blood is withdrawn from a subject's venous system and placed into an ECMO device, gas exchange is performed (including oxygenation of the blood), and then the withdrawn blood is directly infused into the subject's arterial system. In some embodiments, venoarterial ECMO is performed to provide partial circulatory or cardiac support to a subject in need thereof. In some embodiments, venoarterial ECMO is performed to provide complete circulatory or cardiac support to a subject in need thereof.

[0209] The compounds of the present invention can be used to treat, prevent or reduce the risk of thromboembolic disorders in subjects in need thereof, where the subject is exposed to an artificial surface, such as the artificial surface of an extracorporeal membrane oxygenation (ECMO) device (see above), which can be used as a rescue therapy in response to cardiac or pulmonary failure. The surfaces of the ECMO device that are in direct contact with the subject are prone to venous thrombosis. It can be a prothrombotic surface that can lead to thromboembolic disorders such as embolism, e.g., deep vein thrombosis or pulmonary embolism, complicating the treatment of patients requiring ECMO. Circulating clots are the most common mechanical complication (19%). Primary clots can lead to failure of the oxygenator and pulmonary or systemic embolism.

[0210] ECMO is often performed with continuous infusion of heparin as an anticoagulant to combat clot formation. However, cannulation can cause damage to the internal jugular vein, resulting in massive internal bleeding. Bleeding occurs in 30-40% of patients undergoing ECMO and can be life-threatening. This severe bleeding is due to both the required continuous heparin infusion and platelet dysfunction. Approximately 50% of reported deaths are due to severe bleeding complications. Aubron et al. Critical Care, 2013, 17:R73, states that ECMO is a We focused on factors associated with outcomes due to

[0211] Thus, for example, the compound of the present invention can be used as a factor XIa inhibitor and is intended as an alternative replacement for heparin in ECMO treatment.The compound of the present invention is intended as an effective agent that blocks intrinsic pathways at plasma levels that provide effective anticoagulation / antithrombotic effects without significant hemorrhage burden.In some embodiments, the subject is sensitive to heparin or develops sensitivity to heparin.In some embodiments, the subject is resistant to heparin or develops resistance to heparin. Ischemia

[0212] "Ischemia" or "ischemic event" is a vascular disease that generally involves vascular blockage or restriction of blood supply to a tissue. Ischemia can cause a lack of oxygen and glucose, which are necessary for cellular metabolism. Ischemia is generally caused by problematic blood vessels, which results in tissue damage or dysfunction. Ischemia can also refer to a localized loss of blood or oxygen in a given part of the body due to congestion (e.g., vasoconstriction, thrombosis, or embolism). Causes include embolism, atherosclerotic arterial thrombosis, trauma, venous problems, aneurysms, cardiac conditions (e.g., myocardial infarction, mitral valve disease, chronic atrial fibrillation, cardiomyopathies and prostheses), trauma or traumatic injury (e.g., to the extremity resulting in partial or total vascular occlusion), thoracic outlet syndrome, atherosclerosis, hypoglycemia, tachycardia, hypotension, external compression of a blood vessel (e.g., by a tumor), sickle cell disease, localized extreme cold (e.g., from frostbite), application of a tourniquet, glutamate receptor stimulation, arteriovenous malformations, rupture of a large blood vessel supplying a tissue or organ, and anemia.

[0213] A transient ischemic event generally refers to a transient (e.g., short-lived) episode of neurological dysfunction caused by loss of blood flow (e.g., in a focal brain, spinal cord, or retina) without acute infarction (e.g., tissue death). In some embodiments, the transient ischemic event lasts for less than 72 hours, 48 ​​hours, 24 hours, 12 hours, 10 hours, 8 hours, 4 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute. Angioedema

[0214] Angioedema is the rapid swelling of the dermis, subcutaneous tissue, mucous membranes, and submucosal tissues. Angioedema is usually classified as either hereditary or acquired.

[0215] "Acquired angioedema" can be immunological, non-immunological or idiopathic and is caused, for example, by allergy, as a side effect of medication, for example, ACE inhibitor medication.

[0216] "Heritage angioedema" or "HAE" refers to a condition that causes edema (e.g., swelling) that can occur in almost any part of the body, including the face, extremities, neck, throat, pharynx, extremities, gastrointestinal tract, and genitals. HAE refers to a genetic disorder that results in an acute period. Attacks of HAE are often life-threatening, with severity depending on the affected area, e.g., abdominal attacks can result in intestinal obstruction, while swelling of the pharynx and upper airways can lead to asphyxia. The pathogenesis of hereditary angioedema may be related to unhindered activation of the contact pathway with initial production of kallikrein or clotting factors (e.g., factor XII).

[0217] Signs and symptoms may include, for example, mucous membranes of the face, mouth or throat, and tongue skills. Symptoms of angioedema include swelling of the skin, joints, and joints. Itching, pain, decreased sensation, skin pruritus (i.e., hives), or wheezing of the airways in the affected area can also be signs of angioedema. However, for example, in hereditary angioedema, there may be no associated skin rash or skin pruritus. HAE subjects may experience abdominal pain (e.g., abdominal pain lasting 1-5 days, abdominal cramps that increase the subject's white blood cell count), vomiting, weakness, watery diarrhea, or a rash.

[0218] Bradykinin plays an important role in angioedema, especially hereditary angioedema. Bradykinin is released by various cell types in response to many different stimuli and is a pain mediator. Blocking bradykinin production or degradation can lead to angioedema. In hereditary angioedema, the continuous production of the enzyme kallikrein can promote bradykinin formation. Inhibition of kallikrein can block bradykinin production and treat or prevent angioedema.

[0219] Methods described herein can include those in which the blood of a subject is contacted with an artificial surface. For example, in embodiments, a method of treating a thromboembolic disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject's blood is contacted with the artificial surface.

[0220] In an embodiment, a method for reducing the risk of a thromboembolic disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject's blood is contacted with the artificial surface.

[0221] In an embodiment, a method for preventing a thromboembolic disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof, wherein the subject's blood is contacted with the artificial surface.

[0222] In some embodiments of the method provided herein, the artificial surface is in contact with the blood in the circulatory system of the subject.In some embodiments, the artificial surface is an implantable prosthesis, a dialysis catheter, a cardiopulmonary bypass circuit, an artificial heart valve, a ventricular assist device, a small diameter graft, a central venous catheter or an extracorporeal membrane oxygenation (ECMO) device.In some embodiments, the artificial surface causes or is associated with thromboembolic disorder.In some embodiments, the thromboembolic disorder is venous thromboembolism, deep vein thrombosis or pulmonary embolism.In some embodiments, the thromboembolic disorder is a blood clot.

[0223] In some embodiments, the method further comprises conditioning the artificial surface with a separate dose of the compound or a pharma- ceutically acceptable salt thereof before contacting the artificial surface with blood in the subject's circulatory system. In some embodiments, the method further comprises conditioning the artificial surface with a separate dose of the compound or a pharma- ceutically acceptable salt thereof before or during administration of the compound or a pharma- ceutically acceptable salt thereof to the subject. In some embodiments, the method further comprises conditioning the artificial surface with a separate dose of the compound or a pharma- ceutically acceptable salt thereof before and during administration of the compound or a pharma- ceutically acceptable salt thereof to the subject.

[0224] In an embodiment, a method of treating blood in a subject in need thereof comprises administering to the subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof.

[0225] In an embodiment, a compound represented by: [ka] or a pharma- ceutical acceptable salt thereof, comprising the steps of: (i) administering to a subject the compound or a pharma- ceutically acceptable salt thereof prior to or during contacting the artificial surface with the subject's blood; and (ii) conditioning the artificial surface with the compound or a pharma- ceutically acceptable salt thereof prior to or during contacting the artificial surface with the subject's blood. Including, thereby maintaining plasma levels of the compound or a pharma- ceutically acceptable salt thereof in the subject's blood. Provided herein is a method comprising:

[0226] In some embodiments of the methods described herein, the compound or a pharma- ceutically acceptable salt thereof maintains a constant activated partial thromboplastin time (aPTT) in the subject's blood before and after contact with the artificial surface. In some embodiments, the compound or a pharma-ceutically acceptable salt thereof is administered to the subject before and during contact of the subject's blood with the artificial surface.

[0227] In some embodiments, the artificial surface is conditioned with the compound or a pharma- ceutically acceptable salt thereof before and during contacting the artificial surface with the subject's blood. In some embodiments, the method further prevents or reduces the risk of clot formation in the subject's blood contacting the artificial surface.

[0228] In some embodiments, the artificial surface is a cardiopulmonary bypass circuit. In some embodiments, the artificial surface is an extracorporeal membrane oxygenation (ECMO) device. In some embodiments, the ECMO device is a veno-venous ECMO device or a veno-arterial ECMO device.

[0229] In an aspect, a method of preventing or reducing the risk of a thromboembolic disorder in a subject during or after a medical procedure is provided, comprising: (i) administering to a subject prior to, during or after a medical procedure an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof; and (ii) contacting the artificial surface with blood of the subject. thereby preventing or reducing the risk of thromboembolic disorders during or after a medical procedure.

[0230] In some embodiments, the artificial surface is conditioned with the compound, or a pharma- ceutically acceptable salt thereof, prior to administering the compound to a subject before, during, or after a medical procedure.

[0231] In some embodiments, the artificial surface is conditioned with a solution comprising the compound or a pharma- ceutically acceptable salt thereof prior to administering the compound or a pharma- ceutically acceptable salt thereof to a subject prior to, during or after a medical procedure. In some embodiments, the solution is a saline solution, Ringer's solution or blood. In some embodiments, the solution further comprises blood. In some embodiments, the blood is obtained from a subject or a donor.

[0232] In some embodiments, the thromboembolic disorder is a blood clot.

[0233] In some embodiments, the medical procedure includes one or more of: i) cardiopulmonary bypass, ii) oxygenation and pumping of blood with extracorporeal membrane oxygenation, iii) assisted pumping of blood (intracorporeal or extracorporeal), iv) dialysis of blood, v) extracorporeal filtration of blood, vi) withdrawal of blood from a subject into a storage container for later use in an animal or human subject, vii) use of a venous or arterial intraluminal catheter, viii) use of a device for diagnostic or interventional cardiac catheterization, ix) use of an intravascular device, x) use of an artificial heart valve, and xi) use of an artificial graft.

[0234] In some embodiments, the medical procedure includes cardiopulmonary bypass. In some embodiments, the medical procedure includes blood oxygenation and pumping by extracorporeal membrane oxygenation (ECMO). In some embodiments, the ECMO is veno-venous ECMO or veno-arterial ECMO.

[0235] In some embodiments of the methods described herein, the pharma- ceutically acceptable salt of the compound is hydrochloride.In some embodiments, the subject is a human.In some embodiments, the subject has a high risk of thromboembolic disorder.In some embodiments, the thromboembolic disorder is a result of complications in surgery.

[0236] In some embodiments, the subject is sensitive to or has developed sensitivity to heparin, hi some embodiments, the subject is resistant to or has developed resistance to heparin.

[0237] In some embodiments, the subject is in contact with the artificial surface for at least 1 day (e.g., about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, about 3 months, about 6 months, about 9 months, about 1 year). Pharmaceutical Compositions

[0238] The compositions described herein include a compound described herein (e.g., Compound 1), and, if present, an additional therapeutic agent, in an amount effective to achieve treatment of a disease or disease symptom (e.g., a disease associated with factor XIa or kallikrein, etc.).

[0239] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions provided herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices), serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, potassium sorbate, etc.), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, etc.), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin or other solubilizing derivatives, may also be advantageously used to enhance delivery of the compounds of the formulae described herein.

[0240] The pharmaceutical composition may be reconstituted prior to parenteral administration by adding a compatible reconstitution diluent. The pharmaceutical composition may be in the form of a solid freeze-dried composition that can be prepared or in the form of a frozen composition that is adapted to be thawed and, if desired, diluted with a compatible diluent before parenteral administration. In some embodiments, the pharmaceutical composition comprises a powder (e.g., a freeze-dried composition) dissolved in an aqueous medium, such as saline solution, in a unit dose IV bag or bottle at a concentration suitable for intravenous administration to a subject. In some embodiments, the components of a pharmaceutical composition suitable for intravenous administration are separated from each other in a single container, for example, a powder comprising a compound described herein or a pharma- ceutical acceptable salt thereof is separated from an aqueous medium, such as a saline solution. In the examples that follow, the various components are separated by seals that allow the components to be crushed to contact each other to form a pharmaceutical composition suitable for intravenous administration. Route of administration

[0241] The pharmaceutical compositions provided herein may be administered orally, rectally, or parenterally (e.g., intravenous infusion, intravenous bolus injection, inhalation, implantation). The term parenteral, as used herein, includes subcutaneous, intradermal, intravenous (e.g., intravenous infusion, intravenous bolus injection), intranasal, inhalation, pulmonary, transdermal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection, or other injection techniques. The pharmaceutical compositions provided herein may include any conventional non-toxic pharmacologic acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with a pharmacologic acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form.

[0242] The pharmaceutical composition can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oily solution or suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated form. These oil solutions or suspensions may also contain long chain alcohol diluents, or dispersants, or carboxymethylcellulose, or similar dispersants, commonly used in the formulation of pharma- ceutically acceptable dosage forms such as emulsions and / or suspensions. Other commonly used surfactants, such as Tween, Span, or other similar emulsifiers, or bioavailability enhancers, commonly used in the manufacture of pharma- ceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes. In some embodiments, the intravenous pharmaceutical composition comprises a carrier selected from the group consisting of 5% w / w dextrose in water ("5DW") and saline.

[0243] The pharmaceutical compositions provided herein can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions or emulsions are orally administered, the active ingredient may be suspended or emulsified. The pharmaceutical composition may be dissolved in an oily phase or in combination with a suspending agent. If desired, certain sweetening, flavoring, coloring or taste-masking agents may be added.

[0244] The compounds described herein may be administered, for example, by injection, intravenously (e.g., intravenous infusion, intravenous bolus injection), intraarterially, subdermally, intraperitoneally, intramuscularly or subcutaneously; or orally, bucally, nasally, transmucosally, topically, at dosages ranging from about 0.5 to about 100 mg / kg of body weight, alternatively at dosages of 1 mg to 1000 mg / dose, every 4 to 120 hours, or in accordance with the requirements of the particular drug. The methods herein contemplate administration of an effective amount of the compound or compound composition to achieve a desired or specified effect. Typically, the pharmaceutical compositions provided herein are administered about 1 to about 6 times per day (e.g., by intravenous bolus injection), or alternatively, as a continuous infusion. Such administration may be used as a chronic or short-term therapy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound.

[0245] In some embodiments, the pharmaceutical composition formulated for oral, subcutaneous or intravenous administration is administered to the subject once per day to six times per day (e.g., twice per day or four times per day). In some embodiments, the pharmaceutical composition formulated for oral administration is administered to the subject once per day to six times per day (e.g., twice per day or four times per day) for about three to nine months. In some embodiments, the pharmaceutical composition formulated for oral administration is administered to the subject once per day to six times per day (e.g., twice per day or four times per day) for about one year. In some embodiments, the pharmaceutical composition formulated for oral administration is administered to the subject once per day to six times per day (e.g., twice per day or four times per day) for the remainder of the subject's life.

[0246] In some embodiments, the compound or pharmaceutical composition is administered to the subject intravenously. In some embodiments, the compound or pharmaceutical composition is administered to the subject subcutaneously. In some embodiments, the compound or pharmaceutical composition is administered to the subject as a continuous intravenous infusion. In some embodiments, the compound or pharmaceutical composition is administered to the subject as a bolus. In some embodiments, the compound or pharmaceutical composition is administered to the subject as a bolus and then as a continuous intravenous infusion. Combination

[0247] In practicing the methods of the invention, it may be desirable to administer the compounds of the invention (e.g., factor XIa or kallikrein inhibitors) in combination with each other and with one or more other agents to achieve a therapeutic benefit, such as antithrombotic or anticoagulant agents, antihypertensive agents, antiischemic agents, antiarrhythmic agents, platelet function inhibitors, etc. For example, the methods of the invention may be practiced by administering a small molecule factor XIa or kallikrein inhibitor in combination with a small molecule factor XIa or kallikrein inhibitor. More particularly, the methods of the invention may be practiced by administering a small molecule factor XIa or kallikrein inhibitor in combination with aspirin, clopidogrel, ticlopidine or CS-747, warfarin, low molecular weight heparins (such as LOVENOX), GPIIb / GPIIIa blockers, PAI-1 inhibitors (such as XR-330 and T-686, P2Y1 and P2Y12 receptor antagonists); thromboxane receptor antagonists (such as ifetroban), prostacyclin mimetics, thromboxane receptor antagonists (such as ifetroban), ... thromboxane A synthetase inhibitors (such as picotamide), serotonin-2-receptor antagonists (such as ketanserin); compounds that inhibit other coagulation factors such as FVII, FVIII, FIX, FX, prothrombin, TAFI and fibrinogen, or other compounds that inhibit FXI or kallikrein; fibrinolytics (such as TPA, streptokinase), PAI-1 inhibitors, and inhibitors of α-2-antiplasmin (anti-α-2-antiplasmin antibodies F fibrinogen receptor antagonists, inhibitors of alpha-1-antitrypsin, lipid lowering agents (such as HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, AZ4522, and itavastatin) and microsomal triglyceride transfer protein inhibitors (disclosed in U.S. Pat. Nos. 5,739,135, 5,712,279, and 5,760,246). antihypertensives (such as angiotensin-converting enzyme inhibitors (e.g., captopril, lisinopril, or fosinopril); angiotensin-II receptor antagonists (e.g., irbesartan, losartan, or valsartan); ACE / NEP inhibitors (e.g., omapatrilat and gemopatrilat); or β-blockers (such as propranolol, nadolol, and carvedilol). The method of the present invention can be performed by administering a small molecule factor XIa or kallikrein inhibitor in combination with an antiarrhythmic agent, such as amiodarone or dofetilide, in the case of atrial fibrillation. The method of the present invention can also be performed in combination with continuous renal replacement therapy, for example, to treat acute kidney injury.

[0248] In carrying out the method of the present invention, it may be desirable to administer the compounds of the present invention (factor XIa or kallikrein inhibitors) in combination with agents that increase the levels of cAMP or cGMP in cells for therapeutic benefit. For example, the compounds of the present invention may be administered in combination with phosphodiesterase inhibitors (PDE1 inhibitors (such as those described in Journal of Medicinal Chemistry, Vol. 40, pp. 2196-2210

[1997] ), PDE2 inhibitors, P DE3 inhibitors (such as revidinone, pimobendan or olprinone), PDE4 inhibitors (such as rolipram, cilomilast or piclamilast), PDE7 inhibitors or other PDE inhibitors (such as dipyridamole, cilostazol, sildenafil, denbutyrin, theophylline (1,2-dimethylxanthine), ARIFLOT™ (i.e., cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid), arophylline, roflumilast, C-11294 A, CDC-801, BAY-19-8004, cipamfilline, SCH351591, YM-976, PD-189659, mesiopram, pumafentrine, CDC-998, IC-485, and KW-4490) When used in combination, they can have advantageous effects.

[0249] The methods of the invention may be practiced by administering a compound of the invention in combination with a thrombolytic promoter, such as tissue plasminogen activator (natural or recombinant), streptokinase, reteplase, activase, lanoteplase, urokinase, pro-urokinase, anisolated streptokinase plasminogen activator complex (ASPAC), or animal salivary gland plasminogen activator.

[0250] The methods of the invention include combining a compound of the invention with a beta-adrenergic agonist (such as albuterol, terbutaline, formoterol, salmeterol, bitolterol, pirbuterol or fenoterol); an anticholinergic (such as ipratropium bromide); an anti-inflammatory corticosteroid (such as beclomethasone, triamcinolone, budesonide, flumethasone, ticasone, flunisolide or dexamethasone; and anti-inflammatory drugs (such as cromolyn, nedocromil, theophylline, zileuton, zafirlukast, monteleukast and pranleukast). This can be done.

[0251] Small molecule factor XIa or kallikrein inhibitors can act synergistically with one or more of the above agents, thus allowing the use of lower doses of thrombolytic agents, thus reaping the benefits of administering these compounds while minimizing potential hemorrhagic and other side effects. Treatment progress

[0252] The compositions described herein comprise a combined effective amount of a compound of the invention (e.g., a factor XIa or kallikrein inhibitor) and one or more other agents (e.g., additional therapeutic agents), such as antithrombotic or anticoagulant agents, antihypertensive agents, antiischemic agents, antiarrhythmic agents, platelet function inhibitors, etc., to achieve a therapeutic benefit.

[0253] In some embodiments, the additional therapeutic agent is administered after administration of a compound of the invention (e.g., a factor XIa or kallikrein inhibitor). In some embodiments, the additional therapeutic agent is administered 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 18 hours, 24 hours, 48 ​​hours, 72 hours, or more after administration of a compound of the invention (e.g., a factor XIa or kallikrein inhibitor). In some embodiments, the additional therapeutic agent is administered (e.g., orally) after discharge from a medical facility (e.g., a hospital).

[0254] In some embodiments, a compound of the invention (e.g., a factor XIa or kallikrein inhibitor) and an additional therapeutic agent are co-formulated into a single composition or dosage. In some embodiments, a compound of the invention (e.g., a factor XIa or kallikrein inhibitor) and an additional therapeutic agent are administered separately. In some embodiments, a compound of the invention (e.g., a factor XIa or kallikrein inhibitor) and an additional therapeutic agent are administered sequentially. In some embodiments, a compound of the invention (e.g., a factor XIa or kallikrein inhibitor) and an additional therapeutic agent are administered separately and sequentially. Generally, at least one of the compounds of the invention (e.g., factor XIa or kallikrein inhibitors) and the additional therapeutic agent are administered parenterally (e.g., intranasally, intramuscularly, bucally, by inhalation, implantation, transdermal, intravenous (e.g., intravenous infusion, intravenous bolus injection), subcutaneously, intradermal, intranasal, intrapulmonary, transdermal, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or other infusion techniques); orally; or rectally, e.g., intramuscular injection or intravenously (e.g., intravenous infusion, intravenous bolus injection)). In some embodiments, the compounds of the invention are administered parenterally (e.g., intranasally, bucally, intravenously (e.g., intravenous infusion, intravenous bolus injection) or intramuscularly). In some embodiments, the additional therapeutic agent is administered orally. In some embodiments, a compound of the invention (e.g., a factor XIa or kallikrein inhibitor) is administered parenterally (e.g., intranasally, orally, intravenously (e.g., intravenous infusion, intravenous bolus injection), or intramuscularly) and the additional therapeutic agent is administered orally.

[0255] In some embodiments, the compounds of the invention (e.g., factor XIa or kallikrein inhibitors) may be administered once or multiple times per day. The treatment period may last, for example, once a day for about 1, 2, 3, 4, 5, 6, 7 days or longer. In some embodiments, the treatment is long-term (e.g., lifelong). In some embodiments, either a single dose in the form of an individual dosage unit, or several smaller dosage units, or multiple administrations of divided doses at intervals are administered. For example, dosage units may be administered from about 0 hours to about 1 hour, from about 1 hour to about 24 hours, from about 1 to about 72 hours, from about 1 to about 120 hours, or from about 24 hours to at least about 120 hours after injury. Alternatively, the dosage units may be administered about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 40, 48, 72, 96, 120 hours or longer after injury. Subsequent dosage units may be administered any time after the first dose such that a therapeutic effect is achieved. In some embodiments, the first dose is administered orally. In some embodiments, doses subsequent to the first dose are administered parenterally (e.g., intranasal, intramuscular, buccal, inhalation, implantation, transdermal, intravenous (e.g., intravenous infusion, intravenous bolus injection), subcutaneous, intradermal, intranasal, intrapulmonary, transdermal, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or other infusion techniques); orally; or administered rectally.

[0256] In some embodiments, the compounds of the invention (e.g., factor XIa or kallikrein inhibitors) are orally administered as a liquid or solid dosage form for ingestion, e.g., for about 5 minutes to about 1 week; about 30 minutes to about 24 hours, about 1 hour to about 12 hours, about 2 hours to about 12 hours, about 4 hours to about 12 hours, about 6 hours to about 12 hours, about 6 hours to about 10 hours; about 5 minutes to about 1 hour, about 5 minutes to about 30 minutes; about 12 hours to about 1 week, about 24 hours to about 1 week, about 2 days to about 5 days, or about 3 days to about 5 days. In one embodiment, the compounds of the invention (e.g., factor XIa or kallikrein inhibitors) are orally administered as a liquid dosage form. In another embodiment, the compounds of the invention (e.g., factor XIa or kallikrein inhibitors) are orally administered as a solid dosage form.

[0257] If a subject undergoing treatment exhibits a partial response, or a relapse after completion of an initial cycle of treatment, a subsequent course of treatment may be required to achieve a partial or complete therapeutic response (e.g., long-term treatment, e.g., lifelong).

[0258] In some embodiments, a compound of the invention (e.g., a Factor XIa or kallikrein inhibitor) is administered intravenously, e.g., as an intravenous infusion or intravenous bolus injection, for about 5 minutes to about 1 week; about 30 minutes to about 24 hours, about 1 hour to about 12 hours, about 2 hours to about 12 hours, about 4 hours to about 12 hours, about 6 hours to about 12 hours, about 6 hours to about 10 hours; about 5 minutes to about 1 hour, about 5 minutes to about 30 minutes; about 12 hours to about 1 week, about 24 hours to about 1 week, about 2 days to about 5 days, or about 3 days to about 5 days. In one embodiment, a compound of the invention (e.g., a factor XIa or kallikrein inhibitor) is administered as an intravenous infusion for about 5, 10, 15, 30, 45, or 60 minutes or more; about 1, 2, 4, 6, 8, 10, 12, 16, or 24 hours or more; or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more. Dosage and Administration Regimen

[0259] Effective amounts of small molecule factor XIa or kallikrein inhibitors administered according to the present invention may be determined by one of skill in the art. For any particular subject, the specified dose level and frequency of administration may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and length of action of that compound, the subject's race, age, weight, general health, sex and diet, mode and timing of administration, rate of excretion, drug combination, and the severity of the particular condition.

[0260] Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination provided herein may be administered as needed. Subsequently, once symptoms have been alleviated to a desired level, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, to a level at which the improvement in the condition is maintained.

[0261] Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. EXAMPLES

[0262] The starting materials and various intermediates described in the following examples can be obtained from commercial sources, can be prepared from commercially available organic compounds, or can be prepared using known synthetic methods. The scope of the examples described below is not limited and includes certain methods of preparing the intermediates and final products, including their respective purification methods. General Procedure

[0263] All anhydrous reactions were carried out under an atmosphere of nitrogen to maintain an anhydrous atmosphere and maximize yields. All reactions were stirred using an overhead stirring assembly or magnetically with Teflon-coated stir bars. The term "dehydrate" refers to drying the reaction product solution with the specified desiccant and then filtering the solution through a suitable filter paper or through a sintered glass funnel. The terms "concentrated," "concentrated under reduced pressure," or "evaporated" refer to removing the solvent under reduced pressure using a rotary evaporator. Chromatography or chromatographed refers to the use of flash column chromatography on silica gel unless otherwise specified. Flash chromatography refers to column chromatography under gas pressure (e.g., nitrogen) or mechanical pumps for solvent pressurization, such as using commercially available systems supplied by Biotage or other suppliers. Proton NMR spectra (1H) were measured at 400 MHz in the specified solvents and carbon NMR spectra (13C) were measured at 100 MHz unless otherwise specified.

[0264] Abbreviations used in the examples are listed in the Abbreviations Table below. Table of Abbreviations [Table 1A] [ka] Scheme 1 illustrates a general method for the preparation of compound 1·HCl. Example 1 Preparation of the intermediate (R)-(1-isocyanatoethyl)cyclohexane [ka]

[0265] (R)-1-Cyclohexylethanamine was dissolved in DCM and aqueous NaHCO3 was added. The heterogeneous mixture was cooled to -2°C and treated with triphosgene for approximately 6 hours while maintaining the reaction temperature below 5°C. Water was added to the mixture and the phases were separated. The aqueous phase was back extracted twice with DCM. The combined DCM phases were concentrated to give a residue. The residue was treated with heptane and cooled to 5-10°C to give a precipitate. The precipitate was collected and dried to give the title compound in 74% yield.

[0266] The following is an exemplary procedure for Example 1.

[0267] To a solution of (R)-1-cyclohexylethanamine (0.50 kg, 3.93 mol) in DCM (10.0 L) was added 9% aqueous NaHCO3 (10.0 L) and the mixture was cooled to 0 °C. Triphosgene (0.38 kg, 1.30 mol) was added to the mixture while maintaining the reaction temperature and stirred at 0 °C for 1 h. The reaction was monitored by TLC (100% EA eluent). Water (10 L) was added to the mixture and the phases were separated. The aqueous layer was extracted with DCM (2 x 5.0 L). The organic phase was concentrated to dryness without exceeding 45 °C. Heptane (2 x 1 L) was added to the residue and the mixture was concentrated to give a solid. The solid was dissolved in heptane (6.0 L), dried over MgSO4, rinsed with heptane (0.5 L), and concentrated to give (R)-(1-isocyanatoethyl)cyclohexane. Exemplary yields are shown in Table 1. The NMR spectrum of sample #4 dissolved in CDCl3 is depicted in Figure 1. [Table 1B] Example 2 Preparation of 4-(bromomethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine [ka] Step 1: Preparation of 2-[bis-(4-methoxy-benzyl)-amino]-isonicotinic acid methyl ester [ka]

[0268] A mixture of 2-aminopyridine-4-carboxylic acid methyl ester (5.5 kg) and 4-methoxybenzyl chloride (14.64 kg) in 33 L of acetonitrile was heated to reflux for 3 hours, then 7.3 kg of Et3N was added slowly to the refluxing mixture. The reaction was then cooled to room temperature and continued to stir overnight. The acetonitrile and Et3N were removed. Afterwards, a large amount of water was added to the mixture, thus precipitating the solid. The reaction gave 2-[bis-(4-methoxy-benzyl)-amino]-isonicotinic acid methyl ester (3 kg, 21%) as a white solid after centrifugation and recrystallization of the solid in 5-10 L of isopropanol. Step 2: Preparation of {2-[bis-(4-methoxy-benzyl)-amino]-pyridin-4-yl}-methanol [ka]

[0269] In a 50 L reaction kettle, 16 L of dry THF (0° C.) was added with LiAlH4 (388 g) in portions. Then, 4 kg of 2-[bis-(4-methoxy-benzyl)-amino]-isonicotinic acid methyl ester in THF (16 L) was added dropwise to the mixture while maintaining the reaction temperature at −5° C. Ethyl acetate (900 g), water (388 g) and 15% aqueous NaOH (388 g) were added slowly to the reaction mixture in sequence. After stirring for 10 min, anhydrous Na2SO4 (1.3 kg) was added to the mixture, and the corresponding mixture was stirred for 30 min. The mixture was filtered under vacuum, and the filter cake was washed with THF (12 L) and then filtered. The combined filtrate was concentrated. The resulting solution containing {2-[bis-(4-methoxy-benzyl)-amino]-pyridin-4-yl}-methanol was used directly in the next step without purification. Step 3: Preparation of 4-(bromomethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine [ka]

[0270] {2-[bis-(4-methoxy-benzyl)-amino]-pyridin-4-yl}-methanol (5 kg) and CBr4 (5 kg) were added to 25 L of DCM and the reaction solution was maintained at 0-10°C. A solution of PPh3 (4.32 kg) in 10 L of DCM was then added dropwise to the reaction solution. The reaction was followed by TLC and if {2-[bis-(4-methoxy-benzyl)-amino]-pyridin-4-yl}-methanol was not completely consumed, PPh3 was added to the reaction mixture until {2-[bis-(4-methoxy-benzyl)-amino]-pyridin-4-yl}-methanol was completely consumed. After removal of DCM, the reaction gave an oily product. The oil was stirred in 50% aqueous EtOH (16 L) at room temperature for 1 hour. The mixture was then filtered and the filter cake was washed with a small amount of 50% aqueous EtOH. The remaining filter cake was then dissolved in 50% EtOH (8 L) ) at room temperature for an additional hour, filtered and dried to give a crystalline solid product (5.2 kg). 1 H NMR (CDCl3) δ 3.78 (s, 6H), 4.22 (s, 2H), 4.69 (s, 4H), 6.45 (s, 1H), 5.58 (s, 1H), 6.82 (d, 4H), 7.13 (d, 4H), 8.15 (d. 1H). Example 3 Preparation of (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylate hydrochloride (Compound 1·HCl) [ka] Step 1: Preparation of (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-4-oxoazetidine-2-carboxylic acid [ka]

[0271] (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid was dissolved in THF and cooled to -20°C. The lactam was deprotonated with LDA in THF at about -10 to -20°C and treated with 4-(bromomethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine, keeping the reaction temperature below -10°C. The reaction was stirred at -15°C for several hours, then warmed to room temperature and stirred several hours longer. The mixture was quenched with water and then refluxed for 3 hours. The reaction was cooled to room temperature and treated with 5% aqueous potassium phosphate tripotassium. The phases were separated and the aqueous layer was extracted with EA to remove impurities. The aqueous phase was acidified to pH 3.1 with 6N HCl and extracted with EA. The organic phase was dried and concentrated. Residual EA was driven off with heptane to produce a slurry which was cooled and filtered. The filter cake was dissolved in 40 volumes of IPA and refluxed for approximately 1 hour. The mixture was cooled to room temperature and undissolved solid impurities were removed by filtration. The IPA filtrate was solvent exchanged with heptane to precipitate the product. The slurry was cooled to 5-10°C and filtered. The filter cake was dried to give the title compound in 59% yield.

[0272] Below is an exemplary procedure for Example 3, Step 1.

[0273] To a solution of (4S)-N-(tert-butyldimethylsilyl))-4-oxoazetidine-2-carboxylic acid (1.30 kg, 5.67 mol) in anhydrous THF (20.8 L) was added LDA (2M in THF, 6.06 L, 12.13 mol) at -20°C, followed by a solution of 4-(bromomethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (2765.9 g, 6.47 mol) in THF (10.4 L). The resulting mixture was stirred at -20°C for 5 h and then allowed to warm slowly to room temperature over 16 h. The reaction was monitored by HPLC. Water (2.6 L) was added and the mixture was heated to 60°C and stirred for 3 h. HPLC analysis showed that the starting material was consumed. The mixture was cooled to room temperature and treated with 5% aqueous potassium phosphate tribasic (38.0 L). The phases were separated and the aqueous layer was extracted with EA (3×19.5 L). The aqueous layer was acidified to pH 3.1 with 6N HCl (50 mL) and extracted with EA (2×39.0 L). The organic phase was dried over MgSO4 and concentrated. Residual EA was chased with heptane (2×2.6 L) to produce a slurry, which was filtered, rinsed with heptane (2.6 L) and concentrated. IPA (39.0 L) was added to the solid and the mixture was refluxed for 1 h. The mixture was cooled to room temperature, filtered, rinsed with IPA (2.6 L) and the filtrate was concentrated. Heptane (18.2 L) was added to the concentrated solution, which caused the product to precipitate out of solution. The solid precipitate was filtered, rinsed with heptane (3.9 L) and dried to give (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-4-oxoazetidine-2-carboxylic acid. Exemplary yields and purities are shown in Table 2. The NMR spectrum of sample #8 dissolved in CDCl3 is shown in Figure 2. [Table 2] Step 2: Preparation of (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid [ka]

[0274] (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-4-oxoazetidine-2-carboxylic acid was dissolved in DCM and treated with DBU followed by (R)-(1-isocyanatoethyl)cyclohexane (prepared in Example 1) at ambient temperature. After stirring the reaction mixture for several hours, additional (R)-(1-isocyanatoethyl)cyclohexane was added and stirred several hours longer. The precipitate that formed was filtered. The filter cake was rinsed with several portions of 10% aqueous citric acid until DBU was no longer detectable in the DCM phase as determined by HPLC. The DCM phase was dried and concentrated to give the title compound in 100% yield.

[0275] Below is an exemplary procedure for Example 3, Step 2.

[0276] A solution of (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-4-oxoazetidine-2-carboxylic acid (1868.0 g, 4.55 mol) in DCM (9.34 L) was cooled to 10° C. and, while maintaining the reaction temperature, DBU (2156.7 g, 15.93 mol) was added followed by (R)-(1-isocyanatoethyl) Cyclohexane (1240.3 g, 8.09 mol). The reaction mixture was allowed to warm to room temperature and stirred for 22 h. The reaction was monitored by HPLC. Additional (R)-(1-isocyanatoethyl)cyclohexane (620.2 g, 4.04 g) was added and the mixture was stirred at room temperature. After 4 h, HPLC analysis indicated that the starting material had been consumed. The precipitate that formed was filtered and washed with DCM (1.9 L). The filtrate was extracted with 10% aqueous citric acid (3×9.34 L). The organic layer was dried over Na2SO4, rinsed with DCM (0.5 L) and concentrated to give the crude product. The crude product was chromatographed to give (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid. Exemplary yields and purities are shown in Table 3. NMR spectra of the crude and purified products dissolved in CDCl3 are shown in Figures 3 and 4, respectively. [Table 3] Step 3: Preparation of (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid trifluoroacetate [ka]

[0277] (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid was dissolved in TFA and treated with triethylsilane at room temperature. After stirring for several hours, the reaction was concentrated to give a residue. The residue was dissolved in ACN and extracted with hexanes. The mixture was concentrated again to give a residue. The residue was dissolved in DCM and extracted twice with brine. The organic phase was concentrated to give the title compound in 100% yield.

[0278] Below is an exemplary procedure for Example 3, Step 3.

[0279] (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid (1.3 kg, 4.55 mol) was added to TFA (13.0 L) at 0° C. Triethylsilane (0.74 kg, 6.36 mol) was added to the solution while maintaining the reaction temperature. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction was monitored by HPLC. Additional triethylsilane (0.25 kg, 2.15 mol) was added and the reaction mixture was stirred. After 4 hours, HPLC analysis showed no change in the chromatographic resolution. The result indicated that the starting material had been consumed. The mixture was concentrated to give a residue. The residue was dissolved in ACN (13.0 L) and extracted with hexanes (4×13.0 L). The ACN layer was concentrated to give a residue. The residue was dissolved in DCM (13.0 L) and extracted with 13% NaCl solution (2×13.0 L). The organic layer was dried over Na2SO4 and concentrated to give (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid trifluoroacetate. Exemplary yields and purities are shown in Table 4. The NMR spectrum of the product dissolved in CDCl3 is shown in FIG. 5. [Table 4] Step 4: Preparation of (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid hydrochloride (Compound 1·HCl) [ka]

[0280] Below is an exemplary procedure for Example 3, step 4.

[0281] (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid trifluoroacetate was dissolved in ACN at room temperature and treated with 1M ethereal HCl. After stirring for several hours, seed crystals of the product were added and the mixture was cooled to 0° C. The crystalline product was collected by filtration and dried to give the title compound as a white solid in 55% yield.

[0282] Below is an exemplary procedure for Example 3, step 4.

[0283] (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid trifluoroacetate (1.03 kg, 3.28 mol) dissolved in ACN (4.84 L) was filtered through a Celite® pad, treated with HCl solution (1 M in diethyl ether, 8.43 L, 13.10 mol) and stirred at room temperature for 42 h. The precipitate formed was filtered and washed with diethyl ether (3×0.26 L). The solid was collected and dried in an oven. Exemplary yields and purities are shown in Table 5. [Table 5] Step 5: Purification of (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylate hydrochloride (compound 1·HCl)

[0284] Below is an exemplary procedure for Example 3, step 5.

[0285] Crude compound 1·HCl was stirred in IPA (6.3 L) at room temperature until dissolved. MTBE (6.3 L) was added to the solution and the mixture was stirred for 10 h. The precipitate that formed was filtered and rinsed with MTBE (2.89 L, 2×1.26 L). The solid was redissolved in IPA (4.8 L) and MTBE (2.4 L) was added dropwise to the solution and stirred for 131 h. The precipitate that formed was filtered and rinsed with MTBE (0.96 L, 2×0.64 L) and dried to constant weight. Exemplary yields and purities are shown in Table 6. The solid was further triturated with MTBE (1.47 L), filtered, rinsed with MTBE (3×0.74 L), and dried to constant weight in an oven to give compound 1·HCl. Exemplary yields and purities are shown in Table 7. The H NMR spectrum of the title compound dissolved in CD3OD is shown in FIG. 6, and the C NMR spectrum of the title compound dissolved in CD3OD is shown in FIG. 7 (a zoomed view of the C NMR spectrum in the 105-180 ppm region is shown in FIG. 8). [Table 6] [Table 7A]

[0286] The purified sample was further analyzed by X-ray powder diffraction (XRPD) and the diffractogram is shown in Figure 9. The XRPD patterns were obtained using a PANalytical X'Pe The data were collected using a rt PRO MPD diffractometer. An elliptical graduated multilayer mirror was used to focus the Cu Kα X-rays through the specimen and onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to confirm that the observed position of the Si 111 peak was consistent with the certified position by NIST. The sample specimen was sandwiched between three run-thick films and analyzed in transmission geometry. A beam stop, short anti-scatter element, and a 100-mm thick film were used. An antiscatter extension and an antiscatter knife edge were used to minimize background caused by air. Soller slits on the incident and diffracted beams were used to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) located 240 mm from the specimen and data collection software v.2.2b. Data acquisition parameters for the patterns are displayed above the images in the data section of this report, including the divergence slit (DS) in front of the mirror. [ka] Scheme 2 illustrates an alternative method for the preparation of compound 1·HCl. Example 4 Synthesis of (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid hydrochloride

[0287] This example, in addition to the above examples, describes the synthesis of (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid hydrochloride. Step 1: (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-4-oxoazetidine-2-carboxylic acid [ka]

[0288] Commercially available (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2 The -carboxylic acid (56.5 g, 0.246 mol) was dissolved in THF (850 mL) and cooled to -40 °C. The lactam was deprotonated with lithium diisopropylamide (252.5 mL, 0.505 mol, 2M in THF) at approximately -40 to -20 °C. The resulting mixture was stirred at -40 ± 5 °C for 1 h, cooled to -60 ± 5 °C, and then treated with a pre-cooled solution of 4-(bromomethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (100 g, 0.234 mol) in THF (450 mL) while maintaining the temperature below -40 °C. The reaction was stirred at -40 ± 5 °C for several hours, warmed to room temperature, and stirred overnight. The mixture was then quenched with water (565 mL) and heated to 60 ± 5 °C for 1 h. The reaction mixture was cooled to room temperature and THF was removed under reduced pressure. The aqueous phase was extracted with EA (565 mL x 3) to remove impurities. The aqueous phase was acidified to pH 3.1-3.3 with 6N HCl aqueous solution and extracted with EA (850 mL, then 565 mL). The combined organic phase was dried and concentrated to give (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-4-oxoazetidine-2-carboxylic acid (84.1 g) with a purity of >95% in 74% yield (LC Method 1). Step 2: (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid [ka]

[0289] (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-4-oxoazetidine-2-carboxylic acid (84 g, 0.182 mol) was dissolved in DCM (210 mL) and treated with DBU (97 g, 0.637 mol) at room temperature followed by (R)-(1-isocyanatoethyl)cyclohexane (55.8 g, 0.364 mol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with heptane (2500 mL) and stirred at room temperature for at least 30 minutes, then filtered and dried under vacuum. The crude material was reslurried in heptane (1000 mL) at room temperature for at least 4 hours. The solid was filtered and dried to give the crude product. The crude product was dissolved in DCM (2250 mL) and washed with 10% aqueous citric acid (1000 mL×3). The DCM phase was dried and concentrated to dryness to give (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid (106 g) in 94.7% yield and greater than 95% purity (LC Method 1). Step 3: (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid-trifluoroacetate [ka]

[0290] (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid (100 g, 0.163 mol) was dissolved in trifluoroacetic acid (500 mL) and treated with triethylsilane (75.7 g, 0.65 mol) at room temperature. After stirring overnight at room temperature, the reaction mixture was concentrated to give a residue. The residue was dissolved in ACN and extracted with hexane (3×500 mL). This mixture (ACN layer) was concentrated to dryness again (dried under high vacuum for at least 4 h) to give (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid as its trifluoroacetate salt in 100% yield. Step 4 (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylate hydrochloride [ka]

[0291] (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid trifluoroacetate was dissolved in ACN (350 mL) at room temperature. The cloudy solution was filtered and the insoluble material was rinsed with ACN (50 mL). The filtrate was cooled to 5±5° C. and treated with hydrochloric acid (488 mL, 1N in ether). The mixture was stirred at room temperature overnight. The crystalline product was collected by filtration and dried. The crude product was slurried in isopropyl alcohol (100 mL) at room temperature overnight, filtered, and the solid was rinsed with MTBE (2×50 mL) to give (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid hydrochloride as a white solid (34.8 g) in 71% yield and 98.1% purity (LC Method 2). Example 5 HPLC procedure for analysis of purity (area %) LC method 1

[0292] Summary: Samples are diluted in an appropriate diluent. The resulting solution is analyzed using reverse phase HPLC with UV detection at 215 nm.

[0293] Equipment and materials: Agilent 1100 / 1200 HPLC system or equivalent Column: Agilent Eclipse Plus C18, 4.6 x 100 mm, 3.5 μm Trifluoroacetic acid (TFA), EMD or equivalent HPLC grade acetonitrile (ACN), Fisher or equivalent HPLC grade water (H2O), Fisher or equivalent 0.45μm PTFE Syringe Filter

[0294] Solution preparation: Mobile phase A: 0.1% TFA in HO Add 1.0 mL TFA to 1.0 L H2O. Mix thoroughly. Scale as needed. Mobile phase B: 0.1% TFA in ACN Add 1.0 mL TFA to 1.0 L ACN. Mix thoroughly. Scale as needed. Diluent A: 1:1 ACN / H2O Combine equal volumes of CAN and water. Mix thoroughly. Scale as needed. Diluent B: ACN [Table 7B] [Table 8] LC method 2

[0295] Summary: Samples are diluted 1:1 in acetonitrile:water. The resulting solution is analyzed using reverse phase HPLC with UV detection performed at 215 nm.

[0296] Equipment and materials: Agilent 1100 / 1200 HPLC system or equivalent Column: Agilent Eclipse Plus C18, 4.6 x 100 mm, 3.5 μm Phosphoric Acid, 85% (H3PO4), Macron or equivalent HPLC grade acetonitrile (CAN), Fisher or equivalent HPLC grade water (H2O), Fisher or equivalent

[0297] Solution preparation: Mobile phase A: 0.1% H3PO4 in H2O Add 1.0 mL H3PO4 to 1.0 L H2O. Mix thoroughly. Rescale if necessary. Mobile phase B: 0.1% H3PO4 in ACN Add 1.0 mL H3PO4 to 1.0 L ACN. Mix thoroughly. Rescale if necessary. Diluent: 1:1 ACN / H2O Combine equal volumes of ACN and water. Mix thoroughly. Scale as needed. [Table 9] [Table 10] Example 6 Efficacy study of compound 1 in a cardiopulmonary bypass model in hound dogs

[0298] The objective of this study was to demonstrate the efficacy of Compound 1 compared to standard of care (SOC), heparin, in preventing activation of blood coagulation components during use of a cardiopulmonary bypass (CPB) circuit during extended operation on day 1 in a mongrel hound model. The study design is shown in Table 11. [Table 11]

[0299] The following parameters and endpoints were evaluated in this study: mortality, body weight, physical parameters, clinical pathology parameters (hematology and coagulation), 1212 clotting times, and biological analytical parameters. Experimental design Administration

[0300] Vehicle and test articles were administered by intravenous (IV) infusion once over 135 minutes on Day 1, beginning 30 minutes prior to initiation of cardiopulmonary bypass (CPB) and continuing for 105 minutes of CPB. Group 2 animals received an IV bolus dose of 0.6 μg / mL or 3.0 mg / mL immediately prior to initiating the IV infusion. Groups 3, 4, and 5 animals received an IV bolus dose of 10 mg / kg prior to initiating the IV infusion. The CPB equipment was primed with 10 μg / mL of test article. Surgical procedure

[0301] Group 1 had an infusion pump system with an open system / reservoir. Compound 1 infusion was started 30 minutes before placing the animals on the CPB pump. The CPB pump was primed with 0.9% saline.

[0302] Groups 2, 3, and 4 had an infusion pump device with an open system / reservoir. The venous and arterial sheaths were flushed with Compound 1 at a concentration of 10 μg / mL. An IV bolus dose of the test article was administered immediately prior to the start of the infusion. Compound 1 infusion was started 30 minutes before placing the animals on the CPB pump. CPB patients were primed with Compound 1 at 10 μg / mL prior to starting the CPB pump.

[0303] Group 5 had an infusion pump device with a closed system / "bag". The venous and arterial sheaths were then flushed with 10 μg / mL of Compound 1. An IV bolus dose of Compound 1 was administered immediately prior to initiating the infusion. Compound 1 infusion was started 30 minutes before placing the animals on the CPB pump. result

[0304] Figure 10 shows the pressure gradient evaluated across the membrane oxygenator. Previous studies without anticoagulants have shown that the pressure across the membrane oxygenator is established within 15 minutes of starting the pump and increases exponentially over the next 30 minutes, until the oxygenator becomes occluded and circulation stops. In contrast, with multiple doses of Compound 1, the pressure gradient across the membrane oxygenator remained constant throughout the run, indicating that the test article successfully maintained anticoagulation and allowed the pump to continue running for the entire protocol.

[0305] Figure 11 shows the correlation between plasma concentrations of Compound 1 and aPTT. All animals survived until the end of the study. Overall, Compound 1, at the dose levels used in this study, was not associated with any increased morbidity or mortality during the cardiopulmonary bypass / ECMO protocol.

[0306] During the infusion of Compound 1 and before CPB, the aPTT was moderately to significantly prolonged in all animals (Figure 12). The prolongation of the aPTT persisted throughout the infusion of Compound 1 and CPB. In the groups that received a loading dose of Compound 1 (Groups 2-5), the prolongation of the aPTT was most pronounced before CPB (Groups 3-5) or during the first 30 minutes (Group 2), but then improved slightly before reaching a steady state. Animals in Group 1 did not receive a loading dose of Compound 1, and the prolongation of the aPTT remained relatively constant in this group at all measured time points during the infusion of Compound 1. In all groups, the aPTT trended toward baseline values ​​after the infusion of Compound 1 and the cessation of CPB, but remained moderately prolonged at the conclusion of the study. conclusion

[0307] Administration of Compound 1 in this model successfully prevented activation of blood clotting in the cardiopulmonary bypass components. The anticoagulant effect of Compound 1 was selective for inhibition of activated partial thromboplastin time (aPTT). Furthermore, these data demonstrated that the addition of a bolus dose immediately prior to the start of the infusion allowed the attainment of target plasma levels of Compound 1 to occur rapidly, simultaneously with the desired steady-state levels, and was sufficient to achieve successful operation of 105 minutes of CPB and prevent clotting in the majority of circuit components.

[0308] Overall, these data indicate that Compound 1 may be an acceptable alternative to heparin in preventing blood clotting in a component of cardiopulmonary bypass. Equivalent

[0309] While specific embodiments of the present disclosure have been discussed, the above specification is illustrative and not limiting. Numerous variations of the present disclosure will become apparent to those skilled in the art in light of this specification. The full scope of the present disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0310] Unless otherwise indicated, all numerical values ​​expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless specifically indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. In one embodiment, for example, the following items are provided: (Item 1) Pharmaceutically acceptable salts of formula (I): [ka] or a solvate (e.g., hydrate) thereof, comprising the steps of: A salt of formula (II) in a solvent [ka] or a solvate thereof (e.g., a hydrate) thereof, thereby preparing a first solution; and adding hydrogen chloride to the first solution; This produces a pharma- ceutically acceptable salt of formula (I). (Item 2) 2. The method according to item 1, wherein the salt of formula (II) is dissolved in an aprotic solvent. (Item 3) 3. The method of claim 1 or 2, wherein the solvent comprises (e.g. consists of or consists essentially of) acetonitrile. (Item 4) 4. The method of any one of items 1 to 3, wherein the hydrogen chloride is added to the first solution by bubbling HCl gas through the first solution or by adding a second solution containing HCl (e.g., an ethereal solution of hydrochloric acid) to the first solution. (Item 5) 5. The process according to any one of items 1 to 4, wherein the starting amount of the salt of formula (II) or a solvate (e.g., hydrate) thereof is greater than or equal to 500 grams. (Item 6) The starting amount of the salt of formula (II) or a solvate (e.g., hydrate) thereof is 1 kilogram 6. The method according to any one of items 1 to 5, wherein the amount of the compound is greater than or equal to 1 kilogram. (Item 7) 7. The method of any one of items 1 to 6, wherein the method produces more than 300 grams (e.g., more than about 350 grams (e.g., about 368 grams)) of a pharma- ceutically acceptable salt of formula (I) or a solvate (e.g., a hydrate) thereof. (Item 8) 8. The method according to any one of items 1 to 7, wherein the method produces the pharma- ceutically acceptable salt of formula (I) or a solvate (e.g., a hydrate) thereof in greater than about 50% yield (e.g., about 55% yield). (Item 9) 9. The method according to any one of items 1 to 8, wherein the method produces the pharma- ceutically acceptable salt of formula (I) or a solvate (e.g., a hydrate) thereof in a yield of greater than about 75%. (Item 10) 10. The method according to any one of items 1 to 9, wherein the method produces the pharma- ceutically acceptable salt of formula (I) or a solvate (e.g., a hydrate) thereof in a yield of greater than about 90%. (Item 11) 11. The method according to any one of items 1 to 10, wherein the method produces the pharma- ceutically acceptable salt of formula (I) or a solvate (e.g., a hydrate) thereof in a yield of greater than about 99%. (Item 12) 12. The method according to any one of items 1 to 11, wherein the purity of the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) is about 80%. (Item 13) 13. The method according to any one of items 1 to 12, wherein the purity of the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) is about 81%. (Item 14) 14. The method of any one of items 1 to 13, further comprising purifying the pharma- ceutically acceptable salt of formula (I) or a solvate (e.g., hydrate) thereof by dissolving the pharma- ceutically acceptable salt of formula (I) or a solvate (e.g., hydrate) thereof in a solvent (e.g., isopropyl alcohol) and then precipitating the dissolved pharma- ceutically acceptable salt of formula (I) or a solvate (e.g., hydrate) thereof using another solvent (e.g., methyl tert-butyl ether). (Item 15) 15. The method according to item 14, wherein the purity of the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) after precipitation is greater than 98%. (Item 16) 16. The method according to item 14 or 15, wherein the purity of the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) after precipitation is about 98%. (Item 17) 14. The method of any one of items 1 to 13, further comprising purifying the pharma- ceutically acceptable salt of formula (I) or solvate (e.g., hydrate) thereof by slurrying the pharma- ceutically acceptable salt of formula (I) or solvate (e.g., hydrate) thereof in a solvent (e.g., isopropyl alcohol) and then filtering the pharma- ceutically acceptable salt of formula (I) or solvate (e.g., hydrate) thereof to separate the pharma- ceutically acceptable salt of formula (I) or solvate (e.g., hydrate) thereof from the solvent. (Item 18) 18. The method according to item 17, wherein the purity of the pharma- ceutically acceptable salt of formula (I) or its solvate (e.g., hydrate) after slurrying and isolating is greater than 98%. (Item 19) The pharmacytically acceptable salt of formula (I) or a solvate thereof after slurrying and isolating. 19. The method of claim 17 or 18, wherein the purity of the product (e.g., hydrate) is about 98%. (Item 20) Compound of formula (III) [ka] 20. The method according to any one of items 1 to 19, comprising the step of preparing the salt of formula (II) by contacting with trifluoroacetic acid. (Item 21) 21. The method of any one of the preceding claims, further comprising contacting the compound of formula (III) with a silane (e.g., triethylsilane). (Item 22) 22. The method according to any one of items 1 to 21, wherein the method produces more than 500 grams (e.g., more than 1 kg) of the compound of formula (III). (Item 23) Compound of formula (IV) [ka] to a compound of formula (V) [ka] 23. The method according to any one of items 1 to 22, comprising preparing the compound of formula (III) by contacting (Item 24) 24. The method according to any one of items 1 to 23, wherein the method produces more than 1 kilogram (e.g., about 1.3 kg) of the compound of formula (III). (Item 25) 25. The process according to any one of the preceding items, wherein the process is carried out in the presence of a solvent. (Item 26) 26. The process according to any one of items 1 to 25, wherein the process is carried out in the presence of a base (e.g. 1,8-diazabicyclo(5.4.0)undec-7-ene). (Item 27) Compound of formula (VI) [ka] to a compound of formula (VII) [ka] 27. The method according to any one of items 1 to 26, comprising preparing the compound of formula (IV) by contacting (Item 28) 28. The method according to any one of the preceding claims, wherein the method produces more than 500 grams (e.g., more than 900 grams) of the compound of formula (IV). (Item 29) 29. The method according to any one of items 1 to 28, wherein the compound of formula (III) is purified by a purification method that is not chromatographic. (Item 30) 30. The method of claim 29, wherein the purification method comprises the steps of slurrying the compound of formula (III) in a solvent (e.g., heptane) and then filtering the compound of formula (III) to separate the compound of formula (III) from the solvent. (Item 31) 31. The method according to any one of items 1 to 30, wherein the purity of the compound of formula (III) is greater than 90%. (Item 32) 32. The method according to any one of items 1 to 31, wherein the compound of formula (I) is purified by a purification method that is not chromatographic. (Item 33) Pharmaceutically acceptable crystalline salts of formula (I): [ka] . (Item 34) 1. A method of treating a thromboembolic disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof, wherein blood of the subject is contacted with the artificial surface. (Item 35) 16. A method for reducing the risk of a thromboembolic disorder in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof, wherein blood of the subject is contacted with the artificial surface. (Item 36) A method for preventing a thromboembolic disorder in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof, wherein blood of the subject is contacted with the artificial surface. (Item 37) 37. The method of any one of items 33 to 36, wherein the artificial surface is in contact with blood in the subject's circulatory system. (Item 38) 38. The method of any one of items 33 to 37, wherein the artificial surface is an implantable prosthesis, a dialysis catheter, a cardiopulmonary bypass circuit, an artificial heart valve, a ventricular assist device, a small bore graft, a central venous catheter or an extracorporeal membrane oxygenation (ECMO) device. (Item 39) 39. The method according to any one of items 33 to 38, wherein the artificial surface causes or is associated with the thromboembolic disorder. (Item 40) 40. The method of any one of items 33 to 39, wherein the thromboembolic disorder is venous thromboembolism, deep vein thrombosis or pulmonary embolism. (Item 41) 40. The method of any one of items 33 to 39, wherein the thromboembolic disorder is a blood clot. (Item 42) 42. The method according to any one of items 33 to 41, further comprising conditioning the artificial surface with a separate dose of the compound or a pharma- ceutically acceptable salt thereof before contacting the artificial surface with blood in the subject's circulatory system. (Item 43) 43. The method according to any one of items 33 to 42, further comprising conditioning the artificial surface with a separate dose of the compound or a pharma- ceutically acceptable salt thereof prior to or during administration of the compound or a pharma- ceutically acceptable salt thereof to the subject. (Item 44) 44. The method according to any one of items 33 to 43, further comprising conditioning the artificial surface with a separate dose of the compound or a pharma- ceutically acceptable salt thereof prior to and during administration of the compound or a pharma- ceutically acceptable salt thereof to the subject. (Item 45) 1. A method of treating blood in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof. (Item 46) In the blood of a subject in contact with an artificial surface, a compound represented by [ka] or a pharma- ceutically acceptable salt thereof, said method comprising: (i) administering to the subject the compound or a pharma- ceutically acceptable salt thereof prior to or during contacting the artificial surface with the subject's blood; and (ii) conditioning the artificial surface with the compound or a pharma- ceutically acceptable salt thereof prior to or during contacting the artificial surface with the subject's blood. Including, thereby maintaining plasma levels of the compound, or a pharma- ceutically acceptable salt thereof, in the blood of the subject. (Item 47) 47. The method of claim 46, wherein the compound or a pharma- ceutically acceptable salt thereof maintains a constant activated partial thromboplastin time (aPTT) in the blood of the subject before and after contact with the artificial surface. (Item 48) 48. The method of claim 46 or 47, wherein the compound or a pharma- ceutically acceptable salt thereof is administered to the subject prior to and during contacting the artificial surface with the subject's blood. (Item 49) Prior to and during contacting the artificial surface with the subject's blood, the artificial surface is 49. The method according to any one of items 46 to 48, wherein the conditioning is performed with a compound or a pharma- ceutically acceptable salt thereof. (Item 50) 50. The method of any one of items 46 to 49, wherein the method further prevents or reduces the risk of clot formation in the blood of the subject in contact with the artificial surface. (Item 51) 51. The method of any one of items 48 to 50, wherein the artificial surface is a cardiopulmonary bypass circuit. (Item 52) 51. The method of any one of items 48 to 50, wherein the artificial surface is an extracorporeal membrane oxygenation (ECMO) device. (Item 53) 53. The method of item 52, wherein the ECMO device is a veno-venous ECMO device or a veno-arterial ECMO device. (Item 54) 1. A method of preventing or reducing the risk of a thromboembolic disorder in a subject during or after a medical procedure, comprising: (i) administering to said subject prior to, during or after said medical procedure an effective amount of a compound represented by: [ka] or a pharma- ceutically acceptable salt thereof; and (ii) contacting an artificial surface with blood of the subject. Including, Thereby preventing or reducing the risk of said thromboembolic disorders during or after said medical procedure. (Item 55) 55. The method of claim 54, wherein the artificial surface is conditioned with the compound or a pharma- ceutically acceptable salt thereof prior to, during or after the medical procedure and prior to administering the compound to the subject. (Item 56) 56. The method according to item 54 or 55, wherein the artificial surface is conditioned with a solution containing the compound or a pharma- ceutically acceptable salt thereof prior to, during or after the medical procedure and prior to administering the compound or a pharma- ceutically acceptable salt thereof to the subject. (Item 57) 57. The method of claim 56, wherein the solution is a saline solution, Ringer's solution or blood. (Item 58) 58. The method of any one of items 54 to 57, wherein the thromboembolic disorder is a blood clot. (Item 59) The medical procedure may be i) cardiopulmonary bypass, ii) oxygenation and pumping of blood by extracorporeal membrane oxygenation, iii) assisted pumping of blood (intracorporeal or extracorporeal), iv) dialysis of blood, v) extracorporeal filtration of blood, vi) withdrawal of blood from an animal or human subject into a storage container for later use in the subject, vii) use of a venous or arterial intraluminal catheter, vii 59. The method of any one of items 54 to 58, comprising one or more of: i) use of a device for diagnostic or interventional cardiac catheterization, ix) use of an intravascular device, x) use of an artificial heart valve, and xi) use of an artificial graft. (Item 60) 60. The method of any one of items 54 to 59, wherein the medical procedure comprises cardiopulmonary bypass. (Item 61) 60. The method according to any one of items 54 to 59, wherein the medical procedure comprises blood oxygenation and pumping by extracorporeal membrane oxygenation (ECMO). (Item 62) Item 62. The method of item 61, wherein the ECMO is veno-venous ECMO or veno-arterial ECMO. (Item 63) 63. The method according to any one of items 34 to 62, wherein the pharma- ceutically acceptable salt of the compound is a hydrochloride salt. (Item 64) 64. The method of any one of items 34 to 63, wherein the compound is administered intravenously to the subject. (Item 65) 64. The method of any one of items 34 to 63, wherein the compound is administered to the subject intracutaneously. (Item 66) 64. The method of any one of items 34 to 63, wherein the compound is administered to the subject as a continuous intravenous infusion. (Item 67) 64. The method of any one of items 34 to 63, wherein the compound is administered to the subject as a bolus. (Item 68) 68. The method of any one of items 34 to 67, wherein the subject is a human. (Item 69) 69. The method of any one of items 34 to 68, wherein the subject has an elevated risk of a thromboembolic disorder. (Item 70) 70. The method of claim 69, wherein the thromboembolic disorder is the result of a complication during surgery. (Item 71) 71. The method of any one of items 34 to 70, wherein the subject is heparin sensitive or has developed sensitivity to heparin. (Item 72) 72. The method of any one of items 34 to 71, wherein the subject is resistant to heparin or has developed resistance to heparin. (Item 73) 73. The method of any one of items 34 to 72, wherein the subject has been in contact with the artificial surface for at least one day (e.g., about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, about 3 months, about 6 months, about 9 months, about 1 year). (Item 74) 73. The method of any one of items 34 to 72, wherein the subject is a pediatric subject. (Item 75) 73. The method of any one of items 34 to 72, wherein the subject is an adult.

Claims

[Claim 1] The invention described in the specification.

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