WO2017091757A1 - Isotopically enriched betrixaban - Google Patents

Abstract

Described herein are deuterated analogs of betrixaban, pharmaceutical compositions comprising the same, and methods of using the same.

Description

ISOTOPICALLY ENRICHED BETRIXABAN

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application Serial Number 62/259,298 filed November 24, 2015, the content of which is incorporated by reference in its entirety into the present disclosure.

FIELD

[0002] The present disclosure relates generally to isotopically enriched betrixaban, pharmaceutical compositions comprising the same, and methods of using the same.

BACKGROUND

[0003] Betrixaban, also known as [2-({4-

[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2- pyridyl))carboxamide, has the following structure:

[0004] The synthesis of this compound and its various salts and crystalline polymorphs have been reported (as in U.S. Patent Nos. 8,946,269; 8,455,440; 8,394,964; and 8,557,852, all of which are hereby incorporated by reference in their entireties).

[0005] Betrixaban is a small molecule anticoagulant that directly inhibits the activity of Factor Xa, an important validated target in the blood coagulation pathway, and thus can prevent thrombosis. SUMMARY

[0006] The present disclosure provides compounds of formula (I) and its salts thereof. Also described herein are pharmaceutical compositions comprising compounds of formula (I), or a pharmaceutically acceptable salt thereof, and methods of using the compounds and compositions described herein.

[0007] The present disclosure provides, in some embodiments, a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of R^a, R^b, R^c, R^d, R^e, R^f, R^g, R^h, R¹, R^j, R^k, R¹, R^m, Rⁿ, R°, R^p, R^q, R^r, R^s, R^£, R^u, and R^v are independently selected from hydrogen and deuterium, wherein said compound is isotopically enriched.

[0008] The present disclosure provides, in some embodiments, a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein each of R^a, R^b, R^c, R^d, R^e, R^f, R^g, R^h, R\ R^j, R^k, R¹, R^m, Rⁿ, R°, R^p, R^q, R^r, R^s, R^£, R^u, and R^v are independently selected from hydrogen and deuterium, and at least one R variable is deuterium.

[0009] Also provided herein, in some embodiments, are pharmaceutical compositions comprising a compound of formula (I), or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] The compounds or pharmaceutically acceptable salts thereof and compositions of the disclosure are useful for treating diseases that are treated by a compound that inhibits coagulation Factor Xa, such as betrixaban. Some embodiments herein provide for methods comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.

[0011] In some embodiments, a method for treating a condition in a subject characterized by undesired thrombosis comprises administering to said subject a therapeutically effective amount of a compound or a composition disclosed herein. In some embodiments, a method for preventing or treating venous thrombosis in a mammal in need thereof comprises administering to said mammal a therapeutically effective amount of a compound or a composition disclosed herein.

[0012] The compounds and compositions disclosed herein are also used as a reagent in methods for determining the concentration of betrixaban in solution, examining the metabolism of betrixaban and other analytical studies. In some embodiments, the compounds disclosed herein are used as internal standards to accurately determine the concentration of betrixaban in biological matrices (e.g., plasma).

DETAILED DESCRIPTION

Compounds

[0013] Compounds described herein are isotopically enriched, meaning the relative abundance of any one or more less prevalent isotopes of a given element is higher than its other isotopic forms of the element present in the naturally occurring percentages. Hydrogen naturally occurs as a mixture of the following isotopes: 1 H (hydrogen or protium), D ( 2 H or deuterium), and T ( H or tritium). The natural abundance of deuterium is 0.015%. It is well recognized in the art that some variation of natural isotopic abundance can occur in synthesized compounds, which can depend on the origin of the synthetic materials used in the syntheses of the compounds. Further, a skilled artisan recognizes that in all chemical compounds with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D.

[0014] In some embodiments, the compounds disclosed herein are based on increasing the amount of deuterium present in betrixaban above its natural abundance. This increasing is called enrichment or deuterium-enrichment. Thus, it is understood that, when a particular position is designated as having deuterium in a compound of the present disclosure, the abundance of deuterium at that position is greater than the natural abundance of deuterium. Accordingly, the compounds of the present disclosure exhibit a level of deuterium that has been enriched to be greater than its natural abundance of 0.015%.

[0015] Unless otherwise stated, when a position is designated specifically as "H" or

"hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Unless otherwise stated, when a position is designated specifically as "D" or "deuterium," the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium). In other words, the position designated as having deuterium has a minimum isotopic enrichment factor of at least 3340 at each atom designated as deuterium in a compound.

[0016] Any atom not specifically designated as a particular isotope in compounds disclosed herein is meant to represent any stable isotope of that atom.

[0017] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0018] In some embodiments, a compound disclosed herein has an isotopic enrichment factor for each designated deuterium atom of 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), 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 6633.3 (99.5% deuterium incorporation).

[0019] The term "isotopologue" refers to a species that differs from a specific compound of this disclosure only in the isotopic composition thereof.

[0020] The term "compound," when referring to compounds of the disclosure, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.

However, as set forth above the relative amount of such isotopologues will be less than 49.9% of the compound.

[0021] The term "pharmaceutically acceptable salt" is meant to include salts of the compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the particular compounds described herein. When compounds described herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically- acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, Ν,Ν'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, poly amine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0022] When compounds described herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of

pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,

monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge, S. M., et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66: 1-19). Certain compounds contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0023] Certain salt forms for betrixaban are disclosed in U.S. Patent No. 7,598,276, which is incorporated by reference. In particular, this patent discloses that betrixaban forms a salt with an acid. Similarly, deuterated compounds disclosed herein may form a salt with an acid. The acid may be selected from the group consisting of hydrochloric, lactic, maleic, phenoxy acetic, propionic, succinic, adipic, ascorbic, camphoric, gluconic, phosphic, tartric, citric,

methanesulfonic, fumaric, glycolic, naphthalene- 1,5-disulfonic, gentisic and benzenesulfonic. In some embodiments, the acid is selected from the group consisting of hydrochloric, lactic, maleic, phenoxy acetic, propionic, and succinic. In another embodiment, the acid is maleic acid. When referring to a salt form of betrixaban or deuterated compounds disclosed herein, the ion form of the salt is used. For example, if such a compound forms a salt with maleic acid, the salt is referred to as the maleate salt.

[0024] In some embodiments, the present disclosure provides a compound represented by formula (I):

(I) or a pharmaceutically acceptable salt thereof, wherein each of R^a, R^b, R^c, R^d, R^e, R^f, R^g, R^h, R¹, R^j, R^k, R¹, R^m, Rⁿ, R°, R^p, R^q, R^r, R^s, R^£, R^u, and R^v are independently selected from hydrogen and deuterium, wherein said compound of formula (I) is isotopically enriched.

[0025] In some embodiments is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound has deuterium enrichment of at least about 0.5%, at least about 1%, at least about 2%, at least about 4.5%, at least about 9%, at least about 14%, at least about 18%, at least about 23%, at least about 27 %, at least about 32%, at least about 36%, at least about 41%, at least about 45%, at least about 50%, at least about 55%, at least about 59%, at least about 64%, at least about 68%, at least about 73%, at least about 77%, at least about 82%, at least about 86%, at least about 91%, at least about 95%, or at least 100%. For instance, in one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of about 4.5% where one R variable is deuterium. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment less than about 4.5% but above the natural abundance of deuterium where one R variable is partially deuterated.

[0026] In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 0.5%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 4.5%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 9%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 14%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 18%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 23%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 27 %. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 32%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 36%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 41%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 45%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 50%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 55%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 59%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 64%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 68%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 73%, at least about 77%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 82%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 86%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 91%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least about 95%. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have deuterium enrichment of at least 100%.

[0027] Some embodiments disclosed herein provide for a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one R variables, or each of the R variables have deuterium enrichment.

[0028] In one embodiment, at least one R variable has deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least one R variable has deuterium enrichment of at least 50.1%. In one embodiment, at least one R variable has deuterium enrichment of at least 90%. In one embodiment, at least one R variable has deuterium enrichment of at least 99%. In one embodiment, at least one R variable has deuterium enrichment of at least 99.5%. In one embodiment, at least one R variable has deuterium enrichment of at least 99.9%.

[0029] In one embodiment, at least two R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least two R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least two R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least two R variables

independently have deuterium enrichment of at least 99%. In one embodiment, at least two R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least two R variables independently have deuterium enrichment of at least 99.9%.

[0030] In one embodiment, at least three R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least three R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least three R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least three R variables

independently have deuterium enrichment of at least 99%. In one embodiment, at least three R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least three R variables independently have deuterium enrichment of at least 99.9%.

[0031] In one embodiment, at least four R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least four R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least four R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least four R variables

independently have deuterium enrichment of at least 99%. In one embodiment, at least four R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least four R variables independently have deuterium enrichment of at least 99.9%.

[0032] In one embodiment, at least five R variables independently have deuterium

enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least five R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least five R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least five R variables

independently have deuterium enrichment of at least 99%. In one embodiment, at least five R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least five R variables independently have deuterium enrichment of at least 99.9%.

[0033] In one embodiment, at least six R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least six R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least six R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least six R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least six R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least six R variables independently have deuterium enrichment of at least 99.9%.

[0034] In one embodiment, at least seven R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least seven R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least seven R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least seven R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least seven R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least seven R variables independently have deuterium enrichment of at least 99.9%.

[0035] In one embodiment, at least eight R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least eight R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least eight R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least eight R variables

independently have deuterium enrichment of at least 99%. In one embodiment, at least eight R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least eight R variables independently have deuterium enrichment of at least 99.9%.

[0036] In one embodiment, at least nine R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least nine R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least nine R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least nine R variables

independently have deuterium enrichment of at least 99%. In one embodiment, at least nine R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least nine R variables independently have deuterium enrichment of at least 99.9%. [0037] In one embodiment, at least ten R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. %. In one embodiment, at least ten R variables independently have deuterium

enrichment of at least 50.1%. In one embodiment, at least ten R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least ten R variables

independently have deuterium enrichment of at least 99%. In one embodiment, at least ten R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least ten R variables independently have deuterium enrichment of at least 99.9%.

[0038] In one embodiment, at least eleven R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least eleven R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least eleven R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least eleven R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least eleven R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least eleven R variables independently have deuterium enrichment of at least 99.9%.

[0039] In one embodiment, at least twelve R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least twelve R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least twelve R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least twelve R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least twelve R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least twelve R variables independently have deuterium enrichment of at least 99.9%. [0040] In one embodiment, at least thirteen R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least thirteen R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least thirteen R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least thirteen R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least thirteen R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least thirteen R variables independently have deuterium enrichment of at least 99.9%.

[0041] In one embodiment, at least fourteen R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least fourteen R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least fourteen R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least fourteen R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least fourteen R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least fourteen R variables independently have deuterium enrichment of at least 99.9%.

[0042] In one embodiment, at least fifteen R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least fifteen R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least fifteen R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least fifteen R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least fifteen R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least fifteen R variables independently have deuterium enrichment of at least 99.9%. [0043] In one embodiment, at least sixteen R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least sixteen R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least sixteen R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least sixteen R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least sixteen R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least sixteen R variables independently have deuterium enrichment of at least 99.9%.

[0044] In one embodiment, at least seventeen R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least seventeen R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least seventeen R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least seventeen R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least seventeen R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least seventeen R variables independently have deuterium enrichment of at least 99.9%.

[0045] In one embodiment, at least eighteen R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least eighteen R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least eighteen R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least eighteen R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least eighteen R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least eighteen R variables independently have deuterium enrichment of at least 99.9%.

[0046] In one embodiment, at least nineteen R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least nineteen R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least nineteen R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least nineteen R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least nineteen R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least nineteen R variables independently have deuterium enrichment of at least 99.9%.

[0047] In one embodiment, at least twenty R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least twenty R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least twenty R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least twenty R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least twenty R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least twenty R variables independently have deuterium enrichment of at least 99.9%.

[0048] In one embodiment, at least twenty-one R variables independently have deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, at least twenty-one R variables independently have deuterium enrichment of at least 50.1%. In one embodiment, at least twenty-one R variables independently have deuterium enrichment of at least 90%. In one embodiment, at least twenty- one R variables independently have deuterium enrichment of at least 99%. In one embodiment, at least twenty-one R variables independently have deuterium enrichment of at least 99.5%. In one embodiment, at least twenty-one R variables independently have deuterium enrichment of at least 99.9%.

[0049] In one embodiment, each of the R variables independently has deuterium enrichment of at least 1%, at least 5%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40 %, at least 50%, at least 50.1%, of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%. In one embodiment, each of the R variables independently has deuterium enrichment of at least 50.1%. In one embodiment, each of the R variables independently has deuterium enrichment of at least 90%. In one embodiment, each of the R variables independently has deuterium enrichment of at least 99%. In one embodiment, each of the R variables

independently has deuterium enrichment of at least 99.5%. In one embodiment, each of the R variables independently has deuterium enrichment of at least 99.9%.

[0050] In some embodiments, the present disclosure provides a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of R^a, R^b, R^c, R^d, R^e, R^f, R^g, R^h, R¹, R^j, R^k, R¹, R^m, Rⁿ, R°, R^p, R^q, R^r, R^s, R^£, R^u, and R^v are independently selected from hydrogen and deuterium, and at least one R variable is deuterium.

[0051] Some embodiments disclosed herein provide for a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, or at least twenty-one R variables are deuterium. For instance, in one embodiment at least one R variable of a compound of formula (I) is deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium, one embodiment at least

deuterium. one embodiment at least

deuterium. In some embodiments, each R variable of a compound of formula (I) is deuterium. Some embodiments disclosed herein provide for a compound of formula (I), or a

pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

[0052] Some embodiments disclosed herein provide for a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R^a, R^b, and R^c are each deuterium and the remaining R variables are independently selected from hydrogen and deuterium. In some embodiments of a compound of formula (I), R^d, R^e, and R^f are each deuterium and the remaining R variables are independently selected from hydrogen and deuterium. In some embodiments of a compound of formula (I), R^£, R^u, and R^v are each deuterium and the remaining R variables are independently selected from hydrogen and deuterium. In some embodiments of a compound of formula (I), R^q, R^r, and R^s are each deuterium and the remaining R variables are independently selected from hydrogen and deuterium. In some embodiments of a compound of formula (I), R^h, R¹, R* and R^k are each deuterium. In some embodiments of a compound of formula (I), R^m, Rⁿ, and R° are each deuterium and the remaining R variables are independently selected from hydrogen and deuterium. In some embodiments of a compound of formula (I), R^g, R¹, and R^p are each deuterium and the remaining R variables are independently selected from hydrogen and deuterium.

[0053] Non-limiting examples of specific compounds of formula (I) are shown in Table 1 below.

Table 1 : Exemplary compounds of formula (I)

J H H H H H H H H H H H H D D D H H H H H H H

K H H H H H H H H H H H H H H H H D D D H H H

L H H H H H H H D D D D H D D D H D D D H H H

M D D D D D D D D D D D D D D D D D D D D D D

N H H H H H H H D D D D H D D D H H H H H H H

O H H H H H H H D D D D H H H H H D D D H H H

P H H H H H H H D D D D H H H H H H H H D D D

Q H H H H H H H D D D D H H H H H D D D D D D

R H H H H H H H H H H H H D D D H H H H D D D

[0054] Compounds A, B, C, D, F, G, H, I, J, L, M, N, O, P, Q, R, and other compounds described herein, including any intermediate compounds, may be synthesized with appropriate deuterated starting materials according any of the synthetic schemes described herein. The syntheses of the compounds disclosed herein can be readily achieved by those of ordinary skill in the art. Relevant procedures and intermediates are described in, e.g., U.S. Patent Nos. 8,455,440; 8,394,964; and 8,557,852, all of which are hereby incorporated by reference in their entireties. Such methods can be carried out utilizing corresponding deuterated starting materials, other isotope-containing reagents, intermediates to synthesize the compounds of formula (I), and/or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure. Certain intermediates can be used with or without purification (including but not limited to filtration, distillation, sublimation, crystallization, trituration, solid phase extraction, chromatography, and others known in the art).

[0055] It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0056] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, N.Y., and references cited therein.

[0057] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure

stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well- known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0058] A non-limiting example of a general synthetic method for the compounds disclosed herein is shown in Scheme 1.

Scheme 1

Compound of formula (I)

Step 1:

[0059] To a mixture of Compound 1, Compound 2, and acetonitrile (87.5 kg, 3.5 parts), anhydrous pyridine is added. Phosphorous oxychloride (23.3 kg, 1.20 eq.) is added while maintaining a temperature of about 25° C. Reaction completion can be confirmed by HPLC analysis. The resulting solution is cooled to 15° C and water is charged slowly while keeping reaction temperature between 12 and 30° C. The reaction mixture is then adjusted to 22° C and agitated for about 5 hours until exotherm ceased. Formation of a slurry is visually confirmed and then filtered. The resulting solid is dried, yielding Compound 3.

Step 2:

[0060] To a Hastelloy reactor, Compound 3, 5% platinum carbon (sulfided), and

dichloromethane are charged. Agitation is started and reactor contents are adjusted to about 22' C. The reactor is pressurized with about 30 psi hydrogen and the reaction mixture is gently heated to about 28° C. Hydrogenation of the reactor contents is performed under about 30 psi at about 28° C until the reaction is complete by HPLC. The contents of the reactor are circulated through a conditioned celite pad. The reactor and celite bed are rinsed forward with two portions of dichloromethane. The filtrate is transferred to and concentrated in a GLMS reactor under an atmospheric pressure. Ethanol is charged and concentration continued under atmospheric pressure. The reaction mixture is then adjusted to 3° C, agitated for about 1 hr, and the resulting slurry filtered onto a jacketed pressure nutsche fitted with filter cloth. The reactor, pump, and lines are rinsed forward with cold ethanol. The wet filter cake is dried under vacuum at 40-50° C with a maximum temperature of water bath of 50° C to achieve dry Compound 4.

Step 3:

[0061] To a Hastelloy reactor, Compound 5 and THF is charged. Reactor contents are agitated at about 22° C until all of the solids had dissolved. The resulting solution is transferred to a lower receiver and the reactor was rinsed forward with THF. Compound 4, THF, and pyridine are charged to a clean reactor. The pump and lines are rinsed forward with THF. Via a metering pump, the Compound 5/THF solution is charged to the reactor, keeping the temperature at≤ 30° C. and rinsing forward with THF. The resulting slurry is agitated at about 22° C for about 2 hours. The reaction is deemed complete by HPLC. The slurry is filtered onto a pressure nutsche fitted with filter cloth. The reactor, pump, lines, and wet cake re rinsed with three portions of ethanol. The wet filter cake is discharged and transferred back to the reactor for slurry wash in ethanol at about 22° C. for about 1 hour. The slurry is filtered onto the pressure nutsche and the reactor, pump, lines, and wet filter cake are rinsed with two portions of ethanol and two portions of THF. The wet filter cake is dried under vacuum. The dried material is milled to give

Compound 6, which is dried under vacuum.

Step 4:

[0062] A slurry of Compound 6 in THF is prepared and adjusted to < 10° C. Lithium dimethyl amide is prepared as follows: hexyllithium (2.3 N/hexane) is added to dimethylamine solution (2 N/THF) maintaining < 10° C. The lithium dimethyl amide solution is charged into the slurry containing the compound 6 keeping the pot temperature of < 10° C. The reaction is deemed complete by HPLC. A buffer solution of NaHC0₃ and Na₂C0₃ is prepared, and above reaction mixture is transferred to this aqueous solution maintaining < 5° C. The product precipitates out and the resulting slurry is adjusted to 20° C over a period of 12 hours. The solid is filtered, and the resulting wet cake is washed with 3.5 kg of deionized water. The solid is filtered off and rinsed forwarded with cold absolute ethanol. The product, a compound of formula (I), is dried.

Compositions

[0063] Disclosed herein are compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0064] The term "pharmaceutically acceptable carrier" refers to any diluent, excipient, or carrier that may be used in the compositions disclosed herein. Pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, 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, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene -polyoxypropylene-block polymers, polyethylene glycol and wool fat. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. They are preferably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

[0065] In some embodiments, the pharmaceutical composition may further comprise an additional therapeutic agent. In such embodiments, the therapeutic agent may be a therapeutic agent useful in combination with betrixaban, such as those described in U.S. Patent No.

8,455,440. In some embodiments, the therapeutic agent is selected from the group consisting of P2Yi₂ receptor antagonist, an antiplatelet agent, an anticoagulant agent, a thrombin inhibitor, a thrombolytic agent, an anti-arrhythmic agent, a blood pressure lowering agent, a cholesterol or triglyceride lowering agent. [0066] The pharmaceutical compositions disclosed herein can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others. Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. Formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.

[0067] Pharmaceutical compositions may be prepared as liquid suspensions or solutions using a sterile liquid, such as oil, water, alcohol, and combinations thereof. Pharmaceutically suitable surfactants, suspending agents or emulsifying agents, may be added for oral or parenteral administration. Suspensions may include oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as poly(ethyleneglycol), petroleum hydrocarbons, such as mineral oil and petrolatum, and water may also be used in suspension formulations.

[0068] The compositions disclosed herein are formulated for pharmaceutical administration to a mammal, preferably a human being. Such pharmaceutical compositions may be

administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra- synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The compositions may be administered orally or intravenously. The formulations of the disclosure may be designed as short-acting, fast-releasing, long-acting, sustained-releasing. Still further, compounds can be administered in a local rather than systemic means, such as administration (e.g., injection) as a sustained release formulation.

[0069] Sterile injectable forms of the compositions disclosed herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may 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 may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. 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 versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. Compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection may be in ampoules or in multi-dose containers.

[0070] The pharmaceutical compositions disclosed herein may be in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0071] Alternatively, the pharmaceutical compositions disclosed herein may be in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. [0072] The pharmaceutical compositions disclosed herein may also be in a topical form, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0073] Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds disclosed herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters, wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0074] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment, such as petrolatum.

[0075] The pharmaceutical compositions disclosed herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.

[0076] The compounds disclosed herein may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines. [0077] The compounds disclosed herein may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the salt molecules are coupled. The compounds disclosed herein may also be coupled with suitable polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidinone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, compounds disclosed herein may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydro gels. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.

[0078] Dosage formulations of the compounds disclosed herein to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in lyophilized form or as an aqueous solution. The pH of the

preparations of this disclosure typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by injection, other methods of administration are also anticipated such as intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations (such as tablets, capsules and lozenges) and topical formulations such as ointments, drops and dermal patches. The sterile of this disclosure are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available.

[0079] Typically, about 0.5 to 500 mg of a compound disclosed herein, or a salt or mixture of salts of compound disclosed herein is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice. The amount of the active ingredient(s) in these compositions is such that a suitable dosage in the range indicated below is obtained.

[0080] In some embodiments, a typical dosage of a compounds disclosed herein may range from about 0.001 mg/kg to about 1000 mg/kg, or from about 0.01 mg/kg to about 2.0 mg/kg. In some embodiments, the unit dosage of a compound disclosed herein may be about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, or about 10 mg.

[0081] The compounds of this disclosure may be administered once or several times daily and other dosage regimens may also be useful. In some embodiments, the compounds of this disclosure may be administered once a day. In some embodiments, the compounds of this disclosure may be administered twice a day.

[0082] Any of the above dosage forms containing effective amounts are within the bounds of routine experimentation and within the scope of the disclosure. A therapeutically effective dose may vary depending upon the route of administration and dosage form. The preferred combination of the disclosure is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD₅₀ and ED₅₀. The LD₅₀ is the dose lethal to 50% of the population and the ED₅₀ is the dose therapeutically effective in 50% of the population. The LD₅₀ and ED₅₀ are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.

[0083] In addition to dosage forms described above, pharmaceutically acceptable excipients and carriers and dosage forms are generally known to those skilled in the art and are included in the disclosure. It should be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed in the combination, the age, body weight, general health, sex and diet, renal and hepatic function of the patient, and the time of administration, rate of excretion, combination with other drugs, judgment of the treating physician or veterinarian and severity of the particular disease being treated. [0084] In some embodiments, diagnostic applications of the compounds disclosed herein may utilize formulations such as solutions or suspensions as described above.

Methods of Treatment

[0085] The term "treatment" or "treating" means any treatment of a disease or disorder in a subject, such as a mammal, including:

preventing or protecting against the disease or disorder, that is, causing the clinical symptoms not to develop;

inhibiting the disease or disorder, that is, arresting or suppressing the development of clinical symptoms; and/or

relieving the disease or disorder that is, causing the regression of clinical symptoms.

[0086] As used herein, the term "preventing" refers to the prophylactic treatment of a patient in need thereof. The prophylactic treatment can be accomplished by providing an appropriate dose of a therapeutic agent to a subject at risk of suffering from an ailment, thereby substantially averting onset of the ailment.

[0087] It will be understood by those skilled in the art that in human medicine, it is not always possible to distinguish between "preventing" and "suppressing" since the ultimate inductive event or events may be unknown, latent, or the patient is not ascertained until well after the occurrence of the event or events. Therefore, as used herein the term "prophylaxis" is intended as an element of "treatment" to encompass both "preventing" and "suppressing" as defined herein. The term "protection," as used herein, is meant to include "prophylaxis."

[0088] The term "therapeutically effective amount" refers to that amount of a compound disclosed herein, typically delivered as a pharmaceutical composition, that is sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art. [0089] As used herein, the term "condition" refers to a disease state for which the compounds, salts, compositions and methods of the present disclosure are being used against.

[0090] Some embodiments disclosed herein provide for methods of treating diseases that are beneficially treated by an inhibitor of coagulation factor Xa (such as betrixaban) in a patient in need thereof comprising administering to a patient in need thereof a therapeutically amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Diseases and conditions susceptible to treatment with a compound that inhibits coagulation factor Xa, such as betrixaban, include but are not limited to pulmonary embolism, stroke, thromboembolism, deep venous thrombosis, thrombosis, acute coronary syndrome, disorders of coagulation, microangiopathy and associate disorders such as thrombocytopenic purpura.

[0091] In some embodiments, a method for inhibiting the activity of coagulation factor Xa in a cell comprises contacting the cell with a compound or composition disclosed herein. In some embodiments, a method for treating a disease that is beneficially treated by an inhibitor of coagulation factor Xa in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. Also disclosed herein are methods of treating a disease that is beneficially treated by betrixaban in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I). Such diseases are well known in the art and are disclosed in, but not limited to the following patents and published applications, each of which is hereby incorporated by reference in its entirety: 7,598,276, 8,455,440, and 8,557,852.

[0092] Some embodiments disclosed herein provide for methods for treating a condition in a subject characterized by undesired thrombosis comprising administering to said subject a therapeutically effective amount of the compound of formula (I) or a composition comprising a compound of formula (I).

[0093] In some embodiments, a method for preventing or treating venous thrombosis in a mammal in need thereof comprises administering to the mammal a therapeutically effective amount of a compound disclosed herein or a composition disclosed herein. [0094] In some embodiments, a method for treating a condition in a mammal characterized by undesired thrombosis comprises administering to said mammal a therapeutically effective amount of a compound disclosed herein or a composition disclosed herein.

[0095] The compounds disclosed herein may also be used in combination with at least one other therapeutic or diagnostic agent. In some embodiments, the compounds disclosed herein may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. In some embodiments, the at least one therapeutic agent may be a therapeutic agent useful in combination with betrixaban, such as those described in U.S. Patent No. 8,455,440. In some embodiments, the at least one therapeutic agent is selected from the group consisting of P2Yi₂ receptor antagonist, an antiplatelet agent, an anticoagulant agent, a thrombin inhibitor, a thrombolytic agent, an anti- arrhythmic agent, a blood pressure lowering agent, a cholesterol or triglyceride lowering agent.

[0096] The compounds disclosed herein may act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion. These compounds may also allow for reduced doses of the thrombolytic agents to be used and therefore minimize potential hemorrhagic side-effects. The compounds disclosed herein can be utilized in vivo, ordinarily in mammals such as primates, humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.

Diagnostic Methods and Kits

[0097] The compounds and compositions disclosed herein are also useful as reagents in methods for determining the concentration of betrixaban in solution or biological sample such as plasma, examining the metabolism of betrixaban and other analytical studies.

[0098] Some embodiments disclosed herein provide for a method of determining the concentration, such as in a solution or a biological sample, of betrixaban, comprising: adding a known concentration of a compound of formula (I) to the solution or biological sample; subjecting the solution or biological sample to a measuring device that distinguishes betrixaban from a compound of formula (I); calibrating the measuring device to correlate the detected quantity of the compound of formula (I) with the known concentration of the compound of formula (I) added to the biological sample or solution; and measuring the quantity of betrixaban in the biological sample with said calibrated measuring device; and determining the

concentration of betrixaban in the solution of sample using the correlation between detected quantity and concentration obtained for a compound of formula (I).

[0099] Measuring devices that can distinguish betrixaban from the corresponding compound of formula (I) include any measuring device that can distinguish between two compounds that differ from one another only in isotopic abundance. Exemplary measuring devices include a mass spectrometer, nuclear magnetic resonance spectrometer, or infrared spectrometer.

[0100] Some embodiments disclosed herein provide for a method of evaluating the metabolic stability of a compound of formula (I) comprising the steps of contacting the compound of formula (I) with a metabolizing enzyme source for a period of time and comparing the amount of the compound of formula (I) with the metabolic products of the compound of formula (I) after the period of time.

[0101] Some embodiments disclosed herein provide for a method of evaluating the metabolic stability of a compound of formula (I) in a patient following administration of the compound of formula (I). This method comprises obtaining a serum, urine or feces sample from the patient at a period of time following the administration of the compound of formula (I) to the subject; and comparing the amount of the compound of formula (I) with the metabolic products of the compound of formula (I) in the serum, urine or feces sample.

[0102] Some embodiments disclosed herein provide for a kit for use to treat pulmonary embolism, stroke, thromboembolism, deep venous thrombosis, thrombosis, myocardial infarction, and acute coronary syndrome. These kits comprise a pharmaceutical composition comprising a compound of formula (I) or a salt thereof, wherein said pharmaceutical

composition is in a container, and instructions describing a method of using the pharmaceutical composition to treat pulmonary embolism, stroke, thromboembolism, deep venous thrombosis, thrombosis, and acute coronary syndrome. [0103] The container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition. Examples include bottles, ampules, divided or multi- chambered holders, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re- sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn contained within a box. In some embodiments, the container is a blister pack.

[0104] The kits disclosed herein may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition. Such device may include an inhaler if said composition is an inhalable composition; a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit. In some

embodiments, the kits disclosed herein may comprise in a separate vessel of container a pharmaceutical composition comprising at least one therapeutic agent, such as any of those listed above for use for co-administration with a compound described herein.

EXAMPLES

[0105] Unless stated otherwise, the abbreviations used throughout the specification have the following meanings.

• Ac = acetate

• Aq. = aqueous

• C = Celsius • Cat. = catalytic

• DCM = dichloromethane

• DMA = dimethylacetamide

• DMF = dimethylformamide

• EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide

• eq. = equivalent

• Et = ethyl

• EtOH = ethanol

• h or hr = hour(s)

• HexLi = hexyl lithium

• HO Ac = acetic acid

• HPLC = high performance liquid chromatography

• Me = methyl

• MeCN = acetonitrile

• MeOH = methanol

• psi = pound per square inch

• Pyr = pyridine

• rt = room temperature

• TEA = triethylamine

• THF = tetrahydrofuran

Example 1: Synthesis of Compound E

Compound E

[0106] To a mixture of compound 2-1 (1.4 g, 3.44 mmol) in pyridine (25 mL) and TEA (2.5 mL) was bubbled through ¾S gas at room temperature until the solution was saturated. The reaction mixture was continuously stirred at room temperature until the reaction went to completion. Concentration under the reduced pressure gave a residue as compound 2-2, which was dissolved in acetone (30 mL), followed by addition of iodomethane (3.0 mL, 48.1 mmol). The resulting mixture was heated to reflux for 3 hours. The yellow precipitate formed was filtered and air dried to give compound 2-3 (1.85 g, 93% yield) as a hydroiodide salt.

[0107] To a solution of dimethyl-d6-amine, HC1 (1.05 g, 12.0 mmol) in methanol (15 mL) was added aqueous NaOH solution (NaOH (0.597 g, 14.9 mmol) in water (2 mL)), followed by addition of HO Ac (1.2 mL, 21.0 mmol). The resulting mixture was added to compound 2-3 (1.85 g, 3.17 mmol). The suspension was heated to reflux until the reaction was completed, and then concentrated under the reduced pressure. The residue was dissolved in acetonitrile and water (1: 1), and filtered to remove the insoluble material. The filtrate was purified on preparative HPLC to give compound E (800 mg, 41% yield) as a trifluoroacetate salt. Example 2: Synthesis of Compound K

-4

Compound K pound 3-3 is synthesized using commercially available compound 3-2 according e in Example 3 in U.S. Patent 8,394,964. Compound 3-4 is synthesized according e in Example 4 in U.S. Patent 8,394,964. Compound K is synthesized according e in Example 6 in U.S. Patent 8,394,964.

Example 3: Synthesis of Compound B

Compound B

[0109] Compound 4-2 is synthesized according to the procedure in Example 1 in U.S. Patent No. 8,575,221, which is hereby incorporated by reference in its entirety. Compound 4-3 is synthesized according to the procedure in Example 427 in U.S. Patent 6,376,515, which is hereby incorporated by reference in its entirety. Compound 4-5 is synthesized according to the procedure in Example 3 in U.S. Patent 8,394,964. Compound 4-6 is synthesized according to the procedure in Example 4 in U.S. Patent 8,394,964. Compound B is synthesized according to the procedure in Example 6 in U.S. Patent 8,394,964. Example 4: Synthesis of Compound J

5.5 5.7 Compound J

[0110] Compound 5-2 is synthesized according to the method described on page 5783 of Srinivasan et al., Angewandte Chemie, 47(31), 5675-5859, 2008, which is hereby incorporated by reference in its entirety. Compound 5-3 is synthesized according to method 1 described in Science of Synthesis, 20a, 137, 2006, which is hereby incorporated by reference in its entirety, or method 2 in Chinese Patent 102372531, which is hereby incorporated by reference in its entirety. Compound 5-4 is synthesized according to the method as described on page 3830 of Okazaki et al., J. Org. Chem., 72(10), 3830-3839, 2007, which is hereby incorporated by reference in its entirety. Compound 5-5 is synthesized according to the method described in WO 2003/097641, which is hereby incorporated by reference in its entirety. Compound 5-6 is synthesized according to the procedure in Example 3 in U.S. Patent 8,394,964. Compound 5-7 is synthesized according to the procedure in Example 4 in U.S. Patent 8,394,964. Compound J is synthesized according to the procedure in Example 6 in U.S. Patent 8,394,964. Example 5: Synthesis of Compound I

Compound I

[0111] Compound 6-3 is synthesized using the starting material 6-1 according to the method described by W.J.S. Lockley, J. Labelled Compounds and Radiopharmaceuticals, 21(1), 45-57, 1984, which is hereby incorporated by reference in its entirety, or is synthesized using the commercially available starting material 6-2 from BOC Sciences Product List according to the method described by S.C. Schou, J. Labelled Compounds and Radiopharmaceuticals, 52(5), 173- 176, 2009, which is hereby incorporated by reference in its entirety. Compound 6-4 is synthesized according to the procedure of steps 1 and 2 in Example 3 in U.S. Patent No. 8,524,907, which is hereby incorporated by reference in its entirety. Compound 6-5 is synthesized according the procedure of step 3 in Example 3 in U.S. Patent No. 8,524,907.

Compound I is synthesized according to the procedure in Example 2 in U.S. Patent No.

8,524,907.

Example 6: Alternative Synthesis of Compound I

6-4

[0112] Compound 7-2 is synthesized using the starting material 7-1 from BOC Sciences Product List as described by R. Zhang et al., Bioorganic & Medicinal Chemistry Letters, 17(9), 2430-2433, 2007, which is hereby incorporated by reference in its entirety, or is synthesized using the starting material 6-3 as described in Example 5 in U.S. Patent 8,394,964, which is hereby incorporated by reference in its entirety. Compound 7-3 is synthesized as described in process A of Example 5 in U.S. Patent 8,394,964, or is synthesized using the starting material 6- 3 through compound 7-4 as described in Example 5 of process B in U.S. Patent 8,394,964. Compound I is synthesized as described in Example 6 in U.S. Patent 8,394,964. Example 7: Synthesis of Compound N

[0113] Compound N is synthesized from compounds 7-5 and 4-8 according to the procedure in Example 6 in U.S. Patent 8,394,964.

Example 8: Synthesis of Compound O

3-4 Compound O

[0114] Compound O is synthesized from compounds 7-5 and 3-4 according to the procedure in Example 6 in U.S. Patent 8,394,964.

[0115] Compound P is synthesized from compounds 7-5 and 4-6 according to the procedure in Example 6 in U.S. Patent 8,394,964.

Example 10: Synthesis of Compound Q

[0116] Compound 11-1 is synthesized from compound 4-3 and commercially available compound 3-2 according to the procedure described in Example 3 in U.S. Patent 8,394,964. Compound 11-2 is synthesized according to the procedure described in Example 4 in U.S. Patent 8,394,964. Compound Q is synthesized according to the procedure described in Example 6 in U.S. Patent 8,394,964.

Example 11: Synthesis of Compound R

Compound R

[0117] Compound 12-1 is synthesized according to the method described in WO

2003/097641, which is hereby incorporated by reference in its entirety. Compound 12-2 is synthesized according to the procedure in Example 3 in U.S. Patent 8,394,964. Compound 12-3 is synthesized according to the procedure in Example 4 in U.S. Patent 8,394,964. Compound R is synthesized according to the procedure in Example 6 in U.S. Patent 8,394,964.

Example 12: Alternative Synthesis of Compound J

Compound J

[0118] Compound 12-2 is synthesized using commercially available starting material 12- 1. Compounds 12-3 and 5-5 are synthesized according to the methods described in WO

2003/09764. Compound 5-6 is synthesized according to the procedure in Example 3 in U.S. Patent 8,394,964. Compound 5-7 is synthesized according to the procedure in Example 4 in U.S. Patent 8,394,964. Compound J is synthesized according to the procedure in Example 6 in U.S. Patent 8,394,964.

Example 13: Purity of an Internal Standard of Compound I

[0119] In some embodiments, an analytical technique such as liquid chromatography-tandem mass spectrometry (LC/MS/MS) may be used to determine the concentration of betrixaban using an internal standard of Compound I. The purity of an internal standard of Compound I (e.g. , with respect to the presence of any betrixaban therein) may be analyzed via LC/MS/MS by evaluating the peak area ratio of betrixaban to Compound I.

[0120] In one embodiment, the purity of an internal standard of Compound I was determined by preparing a solution of Compound I (50 μg/mL) in 50% acetonitrile, injecting the solution six times, and analyzing the solution at two different channels (452/324 and 458/330) by

LC/MS/MS.

[0121] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

WE CLAIM:

1. A compound of formula

or a pharmaceutically acceptable salt thereof, wherein each of R^A, R^B, R^C, R^D, R^E, R^F, R^G, R^H, R¹, R^J, R^K, R¹, R^M, R^N, R°, R^P, R^Q, R^R, R^S, R^£, R^u, and R^V are independently selected from hydrogen and deuterium, wherein the compound is isotopically enriched.

2. The compound of claim 1, wherein at least one R variable has deuterium enrichment of at least 50.1%.

3. The compound of claim 1, wherein at least one R variable has deuterium enrichment of at least 90%.

4. The compound of claim 1, wherein at least two R variables independently have deuterium enrichment of at least 50.1%.

5. The compound of claim 1, wherein at least two R variables independently have deuterium enrichment of at least 90%.

6. The compound of claim 1, wherein at least three R variables have deuterium enrichment of at least 50.1%.

7. The compound of claim 1, wherein at least three R variables independently have deuterium enrichment of at least 90%.

8. The compound of claim 1, wherein at least four R variables have deuterium enrichment of at least 50.1%.

9. The compound of claim 1, wherein at least four R variables independently have deuterium enrichment of at least 90%.

10. The compound of claim 1, wherein at least six R variables have deuterium enrichment of at least 50.1%.

11. The compound of claim 1, wherein at least six R variables independently have deuterium enrichment of at least 90%.

12. The compound of claim 1, wherein at least nine R variables have deuterium enrichment of at least 50.1%.

13. The compound of claim 1, wherein at least nine R variables independently have deuterium enrichment of at least 90%.

14. The compound of claim 1, wherein at least ten R variables have deuterium enrichment of at least 50.1%.

15. The compound of claim 1, wherein at least ten R variables independently have deuterium enrichment of at least 90%.

16. The compound of claim 1, wherein each R variable independently has deuterium enrichment of at least 50.1%.

17. The compound of claim 1, wherein each R variable independently has deuterium enrichment of at least 90%.

18. The compound of any of the preceding claims, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

19. A pharmaceutical composition comprising a compound of any of the preceding claims and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 8, further comprising at least one therapeutic agent.

21. The pharmaceutical composition of claim 20, wherein the at least one therapeutic agent is selected from the group consisting of a P2Yi₂ receptor antagonist, an antiplatelet agent, an anticoagulant agent, a thrombin inhibitor, a thrombolytic agent, an anti-arrhythmic agent, a blood pressure lowering agent, a cholesterol and a triglyceride lowering agent.

22. A method for treating a condition in a subject characterized by undesired thrombosis comprising administering to said subject a therapeutically effective amount of a compound of any one of claims 1-18 or a composition of any one of claims 19-21.

23. A method for preventing or treating venous thrombosis in a mammal in need thereof comprises administering to said mammal a therapeutically effective amount of a compound of any one of claims 1-18 or a composition of any one of claims 19-21.