WO2025221912A1 - Therapeutic compounds and methods - Google Patents

Abstract

The invention provides a compound of formula (I): (I) or a salt thereof, wherein R¹-R², L¹-L², A. B, C, x, and y have any of the values described in the specification, as well as compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds are useful as thrombin inhibitors.

Description

THERAPEUTIC COMPOUNDS AND METHODS RELATED APPLICATION

This application claims priority to United States Provisional Application Number 63/635,234 that was filed on 17 April 2024. The entire content of the application referenced above is hereby incorporated by reference herein.

BACKGROUND

Regulation of thrombin commands a high interest in the medical community because it is a key enzyme involved in blood coagulation and platelet activation, thus being an important drug target for preventing thrombotic disorders such as heart attacks, deep vein thrombosis, pulmonary embolism, and stroke.

Currently there is a need for thrombin inhibitors. In particular, there is a need for thrombin inhibitors that act through different mechanisms (e.g., allosteric modulators with fractional efficacy of inhibition) and have varied properties (e.g., varied half-lives and varied inactivation parameters).

SUMMARY

Thrombin inhibiting molecules with unique structures and function have been identified, representing an exciting class of compounds that is different from all clinically used anticoagulants. Enzyme kinetic studies show that these molecules are direct allosteric inhibitors of thrombin. Allosteric regulation of thrombin leads to a more controlled inhibition of coagulation that may overcome the bleeding risks associated with current anticoagulant therapies. Moreover, a subset of analogs has been shown to have a short half-life in plasma and represent a first-in-class type of anticoagulant that would meet clinical needs that are currently unmet with current anticoagulants.

In one aspect, a compound of formula (I): or a salt thereof, wherein: ring A is a 1,4-phenyldiyl or a (6-membered heteroaryl)diyl; ring B is a 1,4-phenyldiyl or a (6-membered heteroaryl)diyl; ring C is a 1,4-phenyldiyl or a (6-membered heteroaryl)diyl;

R¹ is -C(=O)R^a, -COOH, -COOR^a, or -C(=O)NR^bR^c;

R² is H, OH, or (Ci-C3)alkoxy;

L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 15 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S-, -S(=O)-, -S(=O)2-, -N(R^Z)-, =N-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3-Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3- Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci- Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, and carboxy; each L² is independently a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 15 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -0-, -S, -S(=0)-, -S(=0)2-, =N-, -N(R^V)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3-Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci- Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^W)2, hydroxy, and carboxy; x is 0 or 1; y is 0, 1, or 2;

R^a is (Ci-Ce)alkyl; each R^b and R^c is independently selected from the group consisting of H, (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, (C3-C6)cycloalkyl(Ci-Ce)alkyl, aryl, heteroaryl, aryl(Ci-Ce) alkyl and heteroaryl(Ci-Ce) alkyl; or R^b andR^c together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino is optionally substitutes with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C3- Ce)cycloalkyl, and (C3-C6)cycloalkyl(Ci-Ce)alkyl; each R^vis independently H or (Ci-Ce)alkyl; each R^wis independently H or (Ci-Ce)alkyl each R^z is independently H or (Ci-Ce)alkyl; and each R^y is independently H or (Ci-Ce)alkyl is provided.

A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is also provided.

A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy is also provided.

A method for reducing coagulation in an animal, comprising administering a compound that allosterically inhibits thrombin to the animal is also provided.

A method for reducing coagulation in an animal, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the animal is also provided.

A method for inhibiting thrombin in an animal (e.g., a mammal such as a human) comprising administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided.

A method for allosterically inhibiting thrombin in an animal (e.g., a mammal such as a human) comprising administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided.

A method for modulating blood coagulation in an animal (e.g., a mammal such as a human) comprising administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided.

A compound of formula (I) or a pharmaceutically acceptable salt thereof for reducing coagulation is also provided.

A compound that allosterically inhibits thrombin for reducing coagulation is also provided. A compound of formula (I) or a pharmaceutically acceptable salt thereof for inhibiting thrombin is also provided.

A compound of formula (I) or a pharmaceutically acceptable salt thereof for allosterically inhibiting thrombin is also provided.

A compound of formula (I) or a pharmaceutically acceptable salt thereof for modulating blood coagulation is also provided.

The use of a compound that allosterically inhibits thrombin to prepare a medicament for reducing coagulation in an animal is also provided.

The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for reducing coagulation in an animal is also provided.

The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for inhibiting thrombin in an animal (e.g., a mammal such as a human) is also provided.

The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for allosterically inhibiting thrombin in an animal (e.g., a mammal such as a human) is also provided.

The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for modulating blood coagulation in an animal (e.g., a mammal such as a human) is also provided.

The invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula (I) or a salt thereof.

Compounds bearing ester functionalities are likely prone to be cleaved by plasma esterases. Although this is a major concern for designing drugs in general, it is a key advantage for designing anticoagulants to be used in acute care settings. Due to their anticipated short halflives, their effects would be rapidly reversed by immediately ceasing their continuous infusion administration. Additionally, risk of bleeding would be minimal and possibly zero due to the uncompetitive mode of inhibition displayed by the compounds. This way, no antidote would be required. Alternatively, compounds lacking ester bonds would evade the action of plasma esterases and display longer half-lives for oral dosing in more traditional therapy settings and in long-term use in outpatient setting. For short acting agents (short half-life) administered by IV drip (role for an anticoagulant which is cleared rapidly upon discontinuation): Emergency room applications or other emergency setting where anticoagulant activity is needed for short time (acute coronary syndrome and/or pulmonary embolism. Heparin is currently used but only clears in 4-6 hours, more predictable and controlled PK over unfractionated heparin could replace unfractionated heparin in some applications because unfractionated heparin is one of the most difficult medicines to use, has much interpatient variability, and many side-effects). Another setting is with pregnancy and labor. Pregnant patients are switched to heparin prior to labor and delivery, but heparin is very unpredictable, and with an agent with short half-life the delivery of drug could be stopped when labor started.

Certain specific compounds also have metabolites, particularly those generated through esterase cleavage, that are already known to be inactive and safe in the human body (Figure 1).

BRIEF DESCRIPTION OF DRAWINGS

Fig 1- Illustrates esterase enhanced cleavage to provide inactive metabolites.

Fig 2. Shows a Lineweaver-Burk plot of data from Example 14.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.

The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., Ci-8 means one to eight carbons). Examples include (Ci-Cs)alkyl, (C2-Cs)alkyl, Ci-Ce)alkyl, (C2-Ce)alkyl and (C3-Ce)alkyl. Examples of alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and higher homologs and isomers.

The term "alkoxy" refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”).

The term “cycloalkyl” refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C3-C8)carbocycle). The term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms, about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. For example, multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane, etc). Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane.

The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

The term “heterocycle” refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are further described below. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from cycloalkyl, aryl, and heterocycle to form the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. In one embodiment the term heterocycle includes a 3-15 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered heterocycle. In one embodiment the term heterocycle includes a 3-8 membered heterocycle. In one embodiment the term heterocycle includes a 3-7 membered heterocycle. In one embodiment the term heterocycle includes a 3-6 membered heterocycle. In one embodiment the term heterocycle includes a 4-6 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered monocyclic or bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle heterocycle comprising 1 to 3 heteroatoms. In one embodiment the term heterocycle includes a 3-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2, 3, 4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-l,l'- isoindolinyl]-3'-one, isoindolinyl-l-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, and 1,4-di oxane. The term “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl.

As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

As used herein, the term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy- protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4^th edition, Wiley-Interscience, New York, 2006.

As used herein a wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.

The terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition. The terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention,

The phrase "therapeutically effective amount" or “effective amount” includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

The term “animal” includes mammals, fish, amphibians, reptiles, birds and invertebrates. The term “mammal” includes humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the animal is a mammal. In one embodiment, the animal is a human. The term “patient” as used herein refers to any animal including mammals. In one embodiment, the patient is a mammalian patient. In one embodiment, the patient is a human patient.

The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.

It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (²H or D). As a non-limiting example, a -CH3 group may be substituted with -CD3.

The pharmaceutical compositions of the invention can comprise one or more excipients. When used in combination with the pharmaceutical compositions of the invention the term “excipients” refers generally to an additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions of the invention the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

When a bond in a compound formula herein is drawn in a non- stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.

Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded. Specifically, (Ci-Ce)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, secbutyl, pentyl, 3-pentyl, or hexyl; (C3-Ce)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (Ci-Ce)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N- oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).

A specific value for L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, =N-, -N(R^Z)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3-Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci- Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, and carboxy.

A specific value for L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, =N-, -N(R^Z)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3-Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci- Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, and carboxy. A specific value for L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), and carboxy.

A specific value for L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

A specific value for L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

A specific value for L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from halo and oxo (=0).

A specific value for L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -0-, -S, -S(=0)-, -S(=0)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), and carboxy. A specific value for L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

A specific value for L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

A specific value for L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from halo and oxo (=0).

A specific value for L¹ is selected from the group consisting of

A specific value for L¹ is -CH2-CH2-C(=O)-O-.

A specific value for L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -0-, -S, -S(=0)-, -S(=0)2-, =N-, -N(R^Z)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3-Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci- Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, and carboxy.

A specific value for L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -0-, -S, -S(=0)-, -S(=0)2-, =N-, -N(R^Z)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3-Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci- Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, and carboxy.

A specific value for L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -0-, -S, -S(=0)-, -S(=0)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), and carboxy.

A specific value for L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -0-, -S, -S(=0)-, -S(=0)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0). A specific value for L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

A specific value for L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from halo and oxo (=0).

A specific value for L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci- Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), and carboxy.

A specific value for L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

A specific value for L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

A specific value for L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from halo and oxo (=0).

A specific value for L² is selected from the group consisting of:

A specific value for L² is -CH2-CH2-C(=O)-O-.

A specific value for x is 0.

A specific value for x is 1.

A specific value for y is 0.

A specific value for y is 1.

A specific value for y is 2.

A specific value for R^a is methyl, ethyl, propyl, or isopropyl.

Specifically, each R^b and R^c is independently selected from the group consisting of H and (Ci-Ce)alkyl.

A specific value for R² is H.

A specific value for R² is OH.

A specific value for R² is (Ci-C3)alkoxy.

A specific value for R² is methoxy.

A specific value for ring A is a 1,4-phenyldiyl.

A specific value for ring A is a (6-membered heteroaryl)diyl.

A specific value for ring A is pyridine-2,5-diyl, pyrimidine-2,5-diyl, or a pyrazin,2,5-diyl.

A specific value for ring B is a 1,4-phenyldiyl.

A specific value for ring B is a (6-membered heteroaryl)diyl.

A specific value for ring B is pyridine-2,5-diyl, pyrimidine-2,5-diyl, or a pyrazin,2,5-diyl.

A specific value for ring C is a 1,4-phenyldiyl. A specific value for ring C is a (6-membered heteroaryl)diyl.

A specific value for ring C is pyridine-2,5-diyl, pyrimidine-2,5-diyl, or a pyrazin,2,5-diyl.

A specific compound or salt is a compound of formula (la): or a salt thereof.

A specific compound or salt is selected from the group consisting of: A specific compound or salt is selected from the group consisting of:: and salts thereof.

A specific compound or salt is selected from the group consisting of:

and salts thereof.

5 A specific compound or salt is selected from the group consisting of

and salts thereof.

A specific compound or salt is not: or a salt thereof.

A specific value for L¹ does not comprise an amide group.

A specific value for L² does not comprise an amide group.

In one specific embodiment, L¹ and L² do not comprise an amide group.

In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula (I) can be useful as an intermediate for isolating or purifying a compound of formula (I). Additionally, administration of a compound of formula (I) as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a- ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

The compounds of formula (I) can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Examples of useful dermatological compositions which can be used to deliver the compounds of formula (I) to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of formula (I) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

Compounds of the invention can also be administered in combination with other therapeutic agents, for example, other antibiotic agents. Accordingly, in one embodiment the invention also provides a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier. The invention also provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of formula (I) or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat a bacterial infection.

The invention will now be illustrated by the following non-limiting Examples.

EXAMPLES

Examples 1-2

Detailed synthesis and characterization are reported below. General methods for preparation of oligomeric derivatives, briefly, consist of dissolving corresponding monomeric analog under alkaline conditions, followed by dropwise addition of a solution containing the corresponding N-hydroxysuccinimide ester. Reaction rates at room temperature were slow, and heat was generally avoided to prevent additional formation of side products. Purification of products was generally accomplished by extraction, purification by column chromatography and preparative HPLC. The purified fractions were concentrated under vacuum and lyophilized to afford products as solids.

Protection of 3-(4-hydroxyphenyl)propionic acid with TBDMS to provide 3-(4-tert- butyldimethylsilyloxyphenyl)propionic acid.

3-(4-hydroxyphenyl)propionic acid (500 mg, 3.01 mmol) and imidazole (512.2 mg, 7.525 mmol) were dissolved in DMF (2 mL). Stirred at room temperature until dissolved. TBDMSC1 (544.2 mg, 3.61 mmol) was added. Stirred at room temperature for 20 hours. Reaction was quenched with cold water (3 mL). The mixture was transferred to a separatory funnel and extracted with a mixture of 1 : 1 hexanes/ethyl acetate (3 x 5 mL). Product was recovered in the organic layer, dried over sodium sulfate, filtered, and rotary evaporated.

Product purification was accomplished using a benchtop Cl 8 column. The mixture was dissolved in water and loaded onto a column packed with C18 silica resin (1 x 5.8 cm, 6.5 mL bed volume). Thoroughly eluted with water (300 mL) under gravity flow. Then, changed eluent system to 5% ACN in H2O (100 mL) and then to 30% ACN in water. Eluent was collected in fractions (1 mL) using an automated collector and 83 analyzed at 210 and 254 nm. After all impurities (210 nm absorbance) had been eluted, eluent system was switched to 80% ACN in water. Eluent was collected in fractions (1 mL) using an automated collector and analyzed at 210 and 254 nm. Fractions containing product were pooled, condensed under vacuum, and lyophilized. Product was a clear oil at room temperature. Yield: 848.0 mg, 99%. Acylation of 3-(4-terCbutyldimethylsilyloxyphenyl)propionic acid with NHS ester

NHS (158.8 mg, 1.38 mmol) and 3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid (322.5 mg, 1.15 mmol) were dissolved in anhydrous THF (1 mL) under argon atmosphere. To the resulting solution was added DCC (284.7 mg, 1.38 mmol) dissolved in THF (2 mL). The reaction mixture was stirred at room temperature for 14 hours, at which time THF was removed under vacuum to give a white solid. Cold dioxane (3 mL) was added to the solid, mixed and filtered to remove the insoluble DCU. The filtrate was dried under vacuum. The resulting solid was treated with cold water (5 mL), and the product was extracted from the resulting suspension with DCM (5 x 5 mL). The organic layer was dried over sodium sulfate, filtered, and condensed under vacuum to afford a white powder. Yield: 427.3 mg, 98%. 1H NMR (300 MHz, CD3CN) 5 7.08 (d, J= 8.4 Hz, 2H), 6.80 - 6.75 (m, 2H), 3.02 - 2.95 (m, 2H), 2.94 - 2.83 (m, 4H), 2.80 (d, J= 7.9 Hz, 4H), 0.98 (s, 9H), 0.20 (d, J= 2.9 Hz, 6H).

Example 1. Synthesis of 3-(4-((3-(4-hydroxyphenyl)propanoyl)oxy)phenyl)propanoic acid

Method 1: (the title compound was isolated as a byproduct): tobramycin sulfate (13.29 mg, 0.028 mmol), was dissolved in NaHCOs(aq) (2 mL). In a separate flask, 3-(4- hydroxyphenyl)propionic acid N-hydroxysuccinimide ester (37.4 mg, 0.142 mmol) was dissolved in DMF (1 mL). The resulting solution was added into the reaction mixture with a syringe at a constant rate of 0.37 mL/h, and stirred at room temperature for 16 hours. The reaction mixture was placed in an ice water bath and quenched with IN HCl(aq), added dropwise until pH 7. The mixture was centrifuged (3500 rpm, 4 °C, 15 min) and the supernatant was removed. Cold water was added to the precipitate and centrifuged once more. The supernatant was removed. This procedure was repeated five times. The supernatants collected after each centrifugation were combined, condensed under vacuum, and freeze-dried. The resulting white solid was dissolved in water and loaded onto a benchtop Cl 8 silica column (1 x 5.8 cm, 6.5 mL bed volume). Eluted with water. Eluent was collected in fractions (1 mL) under gravity flow using an automated collector and analyzed at 210 and 254 nm. Salts were first eluted (210 nm absorbance). Changed eluent system to 7.5% ACN in water. Fractions containing product were pooled, condensed under vacuum, and lyophilized to give a white solid. Yield: 7.6 mg, 34%.

Method 2: 3-(4-hydroxyphenyl)propionic acid (126.2 mg, 0.759 mmol) was dissolved in ACN (3 mL). DIPEA (489.8 mg, 3.79 mmol) was added dropwise. In a separate flask, 3-(4- hydroxyphenyl)propionic acid N-hydroxysuccinimide ester (100 mg, 0.379 mmol) was dissolved in ACN (1.5 mL). The resulting solution was added to the reaction mixture at a constant rate of 0.25 mL/h. The mixture was stirred at room 85 temperature for 48 hours. The organic solvent was removed under vacuum. The resulting solid was treated with water (5 mL), and the resulting suspension was extracted with DCM (3 x 5 mL). The organic layer was concentrated under vacuum and purified by preparative HPLC (column: Luna 10g Cl 8 100A, 250 x 21.20 mm; method: 30-95% ACN over 30 minutes, 216-254 nm, 10 mL/min). The purified fractions containing product were concentrated under vacuum and freeze-dried to obtain a white solid. Yield: 26.8 mg, 23%. 1H NMR (300 MHz, MeOD) 5 7.25 (d, J= 8.6 Hz, 2H), 7.10 (d, J= 8.6 Hz, 2H), 6.93 - 6.89 (m, 2H), 6.76 - 6.71 (m, 2H), 2.92 (t, J= 7.7 Hz, 4H), 2.84 (dd, J= 10.2, 4.2 Hz, 2H), 2.60 (t, J= 7.6 Hz, 2H). Calculated ESLMS [M+Na] m/z = 337.1, found 337.1.

Example 2. Synthesis of 3-(4-((3-(4-((3-(4-hydroxyphenyl)propanoyl)oxy)phenyl)- propanoyl)oxy)phenyl)propanoic acid

Method 1: (the title compound was isolated as a byproduct): neomycin sulfate (120 mg, 0.132 mmol) was dissolved in NaHCOs(aq) (5 mL). In a separate flask, 3-(4-hydroxyphenyl)- propionic acid N-hydroxysuccinimide ester (312.8 mg, 1.188 mmol) was dissolved in DMF (2 mL). The resulting solution was added into the reaction mixture with a syringe at a constant rate of 0.37 mL/h. Stirred at room temperature for 16 hours. The mixture was placed in an ice bath and quenched with IN HCl(aq), added dropwise until pH ~ 7. The mixture was centrifuged (3500 rpm, 4 °C, 15 minutes) and the supernatant was removed. Added cold water to the precipitate and centrifuged once more. The supernatant was removed. This procedure was repeated five times. The precipitate was dissolved in ACN:H20 (9: 1). The resulting solution was loaded into a column of amberlite cation (H+ form) exchange resin (23 mL bed volume). Eluted in ACbTEbO (4: 1) (three column volumes). The fractions collected were analyzed at 210 and 254 nm. Fractions displaying high absorbance at 254 nm were pooled, concentrated under vacuum, and lyophilized. Further purification was accomplished by preparative HPLC (column: Luna 10g C18 100A, 250 x 21.20 mm; method: 30-95% ACN over 30 minutes, 216-254 nm, 10 mL/min). The fractions containing purified product were rotary evaporated to remove organic solvent and the resulting aqueous suspension was lyophilized to give a white solid. Yield: 10.6 mg, 6%.

Method 2: 3-(4-hydroxyphenyl)propionic acid (126.2 mg, 0.759 mmol) was dissolved in ACN (3 mL). DIPEA (489.8 mg, 3.79 mmol) was added dropwise. In a separate flask, 3-(4- hydroxyphenyl)propionic acid N-hydroxysuccinimide ester (100 mg, 0.379 mmol) was dissolved in ACN (1.5 mL). The resulting solution was added to the reaction mixture at a constant rate of 0.25 mL/h. The mixture was stirred at room temperature for 48h. The organic solvent was removed under vacuum. The resulting product was extracted with DCM (3 x 5 mL) and water (5 mL). The organic layer was concentrated under vacuum and purified by preparative HPLC (column: Luna lOp C18 100A, 250 x 21.20 mm; method: 30-95% ACN over 30 minutes, 216-254 nm, 10 mL/min). The purified fractions containing product were concentrated under vacuum and freeze-dried to obtain a white solid. Yield: 2.07 mg, 15%. 1H NMR (300 MHz, MeOD) 5 7.27 (dd, J= 17.6, 8.4 Hz, 4H), 7.11 (d, J= 8.3 Hz, 2H), 6.93 (dd, J= 13.7, 8.4 Hz, 4H), 6.75 (d, J= 8.4 Hz, 2H), 3.08 - 2.80 (m, 11H), 2.60 (t, J= 7.6 Hz, 2H). Calculated ESIMS [M+Na] m/z = 485.2, found 485.2.

Example 3. Synthesis of 3-(4-((3-(4-methoxyphenyl)propanoyl)oxy)phenyl)propanoic acid

3-(4-hydroxyphenyl)propionic acid N-hydroxysuccinimide ester (37.1 mg, 0.134 mmol) and 3-(4-hydroxyphenyl)propionic acid (333.7 mg, 2.0 mmol) were dissolved in pyridine (1 mL). The resulting solution was stirred at room temperature for 48 hours. Pyridine was removed by rotary evaporation. The resulting solid was dissolved in DCM (10 mL); the unreacted starting materials and impurities were extracted away from the solution with water (5 x 10 mL). The organic layer was collected, concentrated under vacuum, and purified by preparative HPLC (column: Luna 10g Cl 8 100A, 250 x 21.20 mm; method: 70-95% ACN over 12-20 minutes, 216-254 nm, 10 mL/min). The purified fractions were condensed under vacuum and lyophilized to afford the expected product as a white solid. Yield: 4.0 mg, 9%. 1H NMR (300 MHz, MeOD) 5 7.25 (d, J= 8.6 Hz, 2H), 7.20 (d, J= 8.7 Hz, 2H), 6.93 - 6.90 (d, , J= 8.6 Hz, 2H), 6.89 - 6.86 (d, , J= 8.7 Hz, 2H), 3.79 (s, 3H), 2.99 - 2.94 (m, 2H), 2.93 - 2.85 (m, 4H), 2.60 (t, J= 7.6 Hz, 2H). Calculated ESLMS [M + Na] m/z = 351.12, found 351.12.

Example 4. Synthesis of 4-(3-oxobutyl)phenyl 3-(4-hydroxyphenyl)propanoate

3-(4-hydroxyphenyl)propionic acid N-hydroxysuccinimide ester (30 mg, 0.114 mmol) and 4-(4-hydroxyphenyl)butan-2-one (93.6 mg, 0.570 mmol) were dissolved in pyridine (2 mL). The resulting solution was stirred at room temperature for 96 hours. Then, the solution was stirred at 45 °C for additional 96 hours. Pyridine was removed by rotary evaporation. The resulting solid was dissolved with DCM (10 mL), and the solution was extracted with water (3 x 10 mL). The organic layer was collected, concentrated under vacuum, and purified by preparative HPLC (column: Luna lOp Cl 8 100A, 250 x 21.20 mm; method: 50-95% ACN over 12-20 min, 216-254 nm, 12 mL/min). The purified fractions were condensed under reduced pressure and lyophilized to afford the product as a white solid. Yield: 2.8 mg, 8%. 1H NMR (300 MHz, eOD) 5 7.22 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.92 - 6.87 (d, J = 8.6 Hz, 2H), 6.76 - 6.71 (d, J = 8.6 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 2.86 - 2.79 (m, 6H), 2.14 - 2.05 (d, 3H). Calculated ESLMS [M + Na] m/z = 335.13, found 335.12.

Example 5. Synthesis of 4-(3-amino-3-oxopropyl)phenyl 3-(4-hydroxyphenyl)propanoate

3-(4-hydroxyphenyl)propanamide (40 mg, 0.242 mmol) was dissolved in acetonitrile (2 mL). DIPEA (156.4 mg, 1.21 mmol) was added to the solution, which was stirred at room temperature for 10 minutes. Then, 3-(4-hydroxyphenyl)propionic acid N-hydroxysuccinimide ester (31.8 mg, 0.121 mmol), dissolved in acetonitrile (2 mL), was added dropwise to the reaction mixture at a constant rate of 0.3 mL/h, using an automated injector. The reaction mixture was stirred at room temperature for 48 hours. After this time, the solvent was removed by rotary evaporation. The resulting white solid was dissolved in a mixture of 1 : 1 ACN/water, and the resulting solution was purified by preparative HPLC (column: Luna lOp Cl 8 100A, 250 x 21.20 mm; method: 40-95% ACN over 22 min, 216-254 nm, 12 mL/min). The purified fractions were condensed under vacuum and lyophilized to afford the product as a white solid. Yield: 8.8 mg, 127 23.2%. 1H NMR (300 MHz, MeOD) 5 7.23 (d, J= 8.6 Hz, 2H), 7.10 (d, J= 8.5 Hz, 2H), 6.91 (d, J= 8.7 Hz 2H), 6.74 (d, J= 8.5 Hz, 2H), 2.95 - 2.89 (m, 4H), 2.86 - 2.82 (m, 2H), 2.50 (t, J= 8.5, 2H). Calculated ESLMS [M + Na] m/z = 336.1, found 336.1; calculated ESLMS [M + H] m/z = 314.1, found 314.1.

Example 6. Synthesis of 4-(3-(4-(3-amino-3-oxopropyl)phenoxy)-3-oxopropyl)phenyl 3- (4-hydroxyphenyl) propanoate

NH₂

3-(4-hydroxyphenyl)propanamide (40 mg, 0.242 mmol) was dissolved in acetonitrile (2 mL). DIPEA (156.4 mg, 1.21 mmol) was added to the resulting solution, which was stirred at room temperature for 10 minutes. Then, 3-(4-hydroxyphenyl)propionic acid N-hydroxysuccinimide ester (31.8 mg, 0.121 mmol), dissolved in acetonitrile (2 mL), was added dropwise to the reaction mixture using an automated injector at a constant rate of 0.3 mL/h. The reaction mixture was stirred at room temperature for 48 hours. After this time, the solvent was rotary evaporated. The resulting white solid was dissolved in a mixture of 1 : 1 ACN/water, and purified by preparative HPLC (column: Luna lOp Cl 8 100A, 250 x 21.20 mm; method: 40-95% ACN over 22 min, 216-254 nm, 12 mL/min). The purified fractions were condensed under vacuum and lyophilized to afford the product as a white solid. Yield: 4.4 mg, 11.6%. 1H NMR (300 MHz, MeOD) 5 7.30 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H), 2.96 - 2.85 (m, 8H), 2.50 (t, J = 7.7 Hz, 2H). Calculated ESLMS [M + Na] m/z = 484.2, found 484.2; calculated ESI-MS [M + H] m/z = 462.2, found 462.2.

Example 7. Synthesis of 3-(4-((3-phenylpropanoyl)oxy)phenyl)propanoic acid

3-(4-hydroxyphenyl)propionic acid (86.36 mg, 0.52 mmol) was dissolved in ACN

(1 mL). DIPEA (137.0 mg, 1.06 mmol) was added dropwise to the resulting solution, which was then stirred at room temperature for 10 minutes. Hydrocinnamic acid N-hydroxysuccinimide ester (25.7 mg, 0.104 mmol) was added to reaction mixture, which was then stirred at room temperature for 96 hours. The mixture was concentrated under vacuum and purified by flash column chromatography on silica gel (7:3 ethyl acetatehexanes). The fractions containing the purified product were concentrated under vacuum and further purified by preparative HPLC (column: Luna 10g C18 100A, 250 x 21.20 mm; method: 40-95% ACN over 12 - 20 min, 216- 254 nm, 12 mL/min). The fractions containing the pure product were concentrated under vacuum and freeze-dried to afford a white solid. Yield: 4.6 mg, 15%. 1H NMR (300 MHz, CDC13) 5 7.36 - 7.30 (m, 2H), 7.27 (d, J= 4.6 Hz, 2H), 7.23 (d, J= 2.8 Hz, 1H), 7.20 (d, J= 8.5 Hz, 2H), 6.96 - 6.91 (m, 2H), 3.07 (t, J= 7.6 Hz, 2H), 2.95 (t, J= 7.7 Hz, 2H), 2.88 (t, J= 7.5 Hz, 2H), 2.67 (t, J= 7.7 Hz, 2H). Calculated ESI-MS: [M+Na] m/z = 321.1, found 321.1.

Exemple 8. Synthesis of 4-(2-(3-(4-hydroxyphenyl)propanamido)ethyl)benzoic acid

4-(2-aminoethyl)benzoic acid (15.99 mg, 0.079 mmol) was dissolved in ACN (1 mL).

DIPEA (20.5 mg, 0.16 mmol) was added dropwise to the resulting solution, which was then stirred at room temperature for 10 minutes. 3-(4-hydroxyphenyl)propionic acid N- hydroxysuccinimide ester (17.4 mg, 0.066 mmol) dissolved in ACN (1 mL) was added dropwise to the reaction mixture, which was stirred at room temperature for additional 48 hours. The solvent was rotary evaporated, and the resulting solid was dissolved in a mixture of 9: 1 (ethyl acetate-hexanes, 5 mL). Impurities and unreacted starting materials were extracted away from the solution with cold water (3 x 5 mL). The organic layer was collected, rotary evaporated, and purified by preparative HPLC (column: Luna lOp C18 122 100A, 250 x 21.20 mm; method: 30- 70% ACN over 15-23 min, 216-254 nm, 10 mL/min). The purified fractions were concentrated under vacuum and freeze-dried to afford the product as a white solid. Yield: 11.28 mg, 55%. 1H NMR (300 MHz, MeOD) 5 7.94 (d, J= 8.5 Hz, 2H), 7.24 (d, J= 8.3 Hz, 2H), 7.02 (d, J= 8.2 Hz, 2H), 6.71 (d, J= 8.3 Hz, 2H), 3.40 (dd, J= 9.4, 4.8 Hz, 2H), 2.79 (t, J= 6.8 Hz, 4H), 2.40 (t, J= 7.5 Hz, 2H). Calculated ESI-MS [M+Na] m/z = 336.1, found 336.1; calculated ESI-MS [M+H] m/z = 314.12, found 314.12.

Example 9. Synthesis of 2-(4-((3-(4-hydroxyphenyl)propanamido)methyl)phenyl)acetic acid

4-Aminomethylphenylacetic acid (60 mg, 0.297 mmol) was dissolved in acetonitrile (1.5 mL). DIPEA (134.3 mg, 1.04 mmol) was added dropwise. Then, a solution of 3-(4- hydroxyphenyl)propionic acid N-hydroxysuccinimide ester (93.99 mg, 0.357 mmol) in ACN (1.5 mL) was added to the reaction mixture at a constant rate of 0.2 mL/h, using an automated injector. The resulting mixture was stirred at room temperature for 24 hours. After this time, the solvent was rotary evaporated. The resulting solid was dissolved in a mixture of 1 : 1 ACN/water, and the solution was purified by preparative HPLC (column: Luna 10g C18 100A, 250 x 21.20 mm; method: 10-95% ACN over 17 min, 216-254 nm, 12 mL/min). The purified fractions were condensed under reduced pressure and lyophilized to afford the desired product as a white solid. Yield: 64.5 mg, 69.3%. 1H NMR (300 MHz, MeOD) 5 7.21 (d, J= 7.9 Hz, 2H), 7.05 (dd, 4H), 6.69 (d, J= 8.4 Hz, 2H), 4.31 (s, 2H), 3.58 (s, 2H), 2.85 (t, J= 13 Hz, 2H), 2.49 (t, J= 7.4 Hz, 2H). Calculated ESI-MS [M + Na] m/z = 336.12, found 336.12; calculated ESI-MS [M + H] m/z = 314.14, found 314.14. Example 10. Additional Compounds

Using procedures similar to those described herein, the following compounds can also be prepared. Example 11. Additional Compounds

Using procedures similar to those described herein, the following compounds can also be prepared. Example 12. Additional Compounds

Using procedures similar to those described herein, the following compounds can also be

Example 13. Thrombin inhibition assay

Inhibition of thrombin was measured using a chromogenic substrate hydrolysis assay, where heparin was used as negative control. TSP buffer was used as the incubation medium in the experiments, consisting of 50 mM Tris HC1 buffer, 150 mM NaCl and 1 mg/mL polyethylene glycol 8000, pH 7.4. To 60 pL of compound solutions at various concentrations ranging from 0.001 to 1 mg/mL was added 10 pL of thrombin solution (31.2 pM) and incubated for 15 min at 37 °C. Following incubation, 90 pL of substrate (1 mM N-p-Tosyl-Gly-Pro-Arg p- nitroanilide in 2: 1 DMSO/TSP buffer solution) was dispensed to each well of a 96-well plate. Release of /?-nitroaniline was monitored by measuring absorbance at 405 nm using a Synergy TM 2 microplate reader equipped with an external dispense module (BioTek Insruments, Inc., Winooski, VT).

Enzyme activity was determined by calculating the initial rate of each progression curve in the linear region and expressed as a percentage of the initial rate of the uninhibited enzyme. Data were analyzed in PrismTM 7 (GraphPad Software, Inc., La Jolla, CA) using nonlinear regression curve fit to determine the ICso values displayed by each compound. Nonparametric data were analyzed by the Mann-Whitney U-test using GraphPad Prism

7 (GraphPad Software, La Jolla). P-values of 0.05 or less were considered significant. Error bars in all figures indicate means ± SE. Data for representative compounds is provided in the following table.

Example 14. Mechanism of Action - Inhibition at a Non-Traditional Site

The mechanism of thrombin inhibition by compound of Example 2 (3-(4-((3-(4-((3-(4- hydroxyphenyl)propanoyl)oxy)phenyl)- propanoyl)oxy)phenyl)propanoic acid) is described herein. Initial velocity studies for enzyme kinetics were performed by maintaining concentrations of the thrombin inhibitor (compound of Example 2) at 0, 0.5[IC₅₀], [IC₅₀], 2[IC₅₀] and 4[ICso] and varying the thrombin-specific substrate concentration (0.155-0.308 mM N- - Tosyl-Gly-Pro-Arg /?-nitroanilide). The inhibitor, at the various concentrations, was incubated with thrombin (1.95 pM) for 15 minutes at 37 °C in TSP buffer. After incubation, substrate was rapidly dispensed to each well. Increase in absorbance was measured at 405 nm every 6 seconds for 1 minute. The mechanism of inhibition was determined by fitting the initial velocity at each thrombin substrate concentration using Michaelis-Menten kinetics in SigmaPlot (Systat Software, San Jose, CA), from which the Lineweaver-Burk plot shown in Figure 2 was obtained.

As the concentrations of compound from Example 2 increased, there was a decrease in both the Km and Vmax values. The Lineweaver-Burk plot yields parallel lines, showing a typical pattern of uncompetitive (allosteric) mode of inhibition. This mode of inhibition is rare in drug discovery and the experiment carried out to determine this mode of inhibition used a synthetic peptide substrate of thrombin. Therefore, additional studies may be granted to confirm this mode of inhibition by compound from Example 2 using a natural substrate of thrombin such as fibrinogen. An uncompetitive inhibitor is known for binding preferentially to the enzymesubstrate complex, but it does not bind to the free enzyme. In this case, initial binding of substrate to the enzyme’s active site induces a conformational change, creating a new binding site for the inhibitor. For this reason, an uncompetitive (allosteric) inhibitor is a regulator of the enzyme’s activity rather than simply an inhibitor. While a competitive inhibitor exhibits the potential to completely knockout the enzyme’s activity if overdosed, an uncompetitive inhibitor would not present this risk. For instance, if the enzyme is in its free state, the uncompetitive inhibitor does not interfere with the enzyme’s catalytic activity for other substrates. If the enzyme is overactive for that specific substrate, then the binding of an uncompetitive inhibitor is favored, increasing the rate of enzymatic inhibition. Therefore, allosteric inhibitors are anticipated to exhibit safer therapeutic profiles than active site inhibitors and thus can have diminished potential for bleeding. Example 15.

Stability of compounds in human plasma (Lithium Heparin, BioreclamationIVT) was determined over time by area under curve analysis from reversed-phase analytical HPLC. Data for representative compounds is provided in the following table.

Example 16. The following illustrate representative pharmaceutical dosage forms, containing a compound of formula (I) ('Compound X'), for therapeutic or prophylactic use in humans.

(i) Tablet 1 mg/tablet

Compound X= 100.0

Lactose 77.5

Povidone 15.0

Croscarmellose sodium 12.0

Microcrystalline cellulose 92.5

Magnesium stearate 3,0

300.0 (ii) Tablet 2 mg/tablet

Compound X= 20.0

Microcrystalline cellulose 410.0

Starch 50.0

Sodium starch glycolate 15.0

Magnesium stearate 5,0

500.0

(iii) Capsule mg/capsule

Compound X= 10.0

Colloidal silicon dioxide 1.5

Lactose 465.5

Pregelatinized starch 120.0

Magnesium stearate 3,0

600.0

(iv) Injection 1 (1 mg/ml) mg/ml

Compound X= (free acid form) 1.0

Dibasic sodium phosphate 12.0

Monobasic sodium phosphate 0.7

Sodium chloride 4.5

1.0 N Sodium hydroxide solution

(pH adjustment to 7.0-7.5) q.s.

Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml

Compound X= (free acid form) 10.0

Monobasic sodium phosphate 0.3

Dibasic sodium phosphate 1.1

Polyethylene glycol 400 200.0

1.0 N Sodium hydroxide solution

(pH adjustment to 7.0-7.5) q.s.

Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can

Compound X= 20.0

Oleic acid 10.0

Trichloromonofluoromethane 5,000.0

Dichlorodifluoromethane 10,000.0

Di chlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

CLAIMS What is claimed is:

1. A compound of formula (I): or a salt thereof, wherein: ring A is a 1,4-phenyldiyl or a (6-membered heteroaryl)diyl; ring B is a 1,4-phenyldiyl or a (6-membered heteroaryl)diyl; ring C is a 1,4-phenyldiyl or a (6-membered heteroaryl)diyl;

R¹ is -C(=O)R^a, -COOH, -COOR^a, or -C(=O)NR^bR^c;

R² is H, OH, or (Ci-C3)alkoxy;

L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 15 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S-, -S(=O)-, -S(=O)2-, -N(R^Z)-, =N-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3-Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3- Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci- Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, and carboxy; each L² is independently a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 15 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -0-, -S, -S(=0)-, -S(=0)2-, =N-, -N(R^V)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3-Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-C6)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci- Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^W)2, hydroxy, and carboxy; x is 0 or 1; y is 0, 1, or 2;

R^a is (Ci-Ce)alkyl; each R^b and R^c is independently selected from the group consisting of H, (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, (C3-C6)cycloalkyl(Ci-Ce)alkyl, aryl, heteroaryl, aryl(Ci-Ce) alkyl and heteroaryl(Ci-Ce) alkyl; or R^b andR^c together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino is optionally substitutes with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C3- Ce)cycloalkyl, and (C3-C6)cycloalkyl(Ci-Ce)alkyl; each R^vis independently H or (Ci-Ce)alkyl; each R^wis independently H or (Ci-Ce)alkyl each R^z is independently H or (Ci-Ce)alkyl; and each R^y is independently H or (Ci-Ce)alkyl.

2. The compound or salt of claim 1, wherein L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, =N-, -N(R^Z)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3-Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci- Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3- Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, and carboxy.

3. The compound or salt of claim 1, wherein L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, =N-, -N(R^Z)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3-Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci- Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3- Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, and carboxy.

4. The compound or salt of claim 2, wherein L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3- Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), and carboxy.

5. The compound or salt of claim 2, wherein L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

6. The compound or salt of claim 2, wherein L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

7. The compound or salt of claim 2, wherein L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from halo and oxo (=0).

8. The compound or salt of claim 3, wherein L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3- Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), and carboxy.

9. The compound or salt of claim 3, wherein L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

10. The compound or salt of claim 3, wherein L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

11. The compound or salt of claim 3, wherein L¹ is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from halo and oxo (=0).

12. The compound or salt of claim 1, wherein L¹ is selected from the group consisting of

13. The compound or salt of claim 1, wherein L¹ is -CH2-CH2-C(=O)-O-.

14. The compound or salt of any one of claims 1-13, wherein L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, =N-, -N(R^Z)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3-Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3- Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci- Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci- Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, and carboxy.

15. The compound or salt of any one of claims 1-13, wherein L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, =N-, -N(R^Z)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or (C3- Ce)carbocycle and wherein each carbon atom, 3-7 membered heterocycle, and (C3- Ce)carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci- Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), =NH, and carboxy; and wherein each 5-6-membered heteroaryl is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci- Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, and carboxy.

16. The compound or salt of claim 14, wherein L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3- Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), and carboxy.

17. The compound or salt of claim 14, wherein L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -S(=O)-, -S(=O)2-, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

18. The compound or salt of claim 14, wherein L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

19. The compound or salt of claim 14, wherein L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from halo and oxo (=0).

20. The compound or salt of claim 15, wherein L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci-Ce)alkoxycarbonyl, cyano, halo, -N(R^y)2, hydroxy, oxo (=0), and carboxy.

21. The compound or salt of claim 15, wherein L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -0-, -S, or -N(R^Z)- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

22. The compound or salt of claim 15, wherein L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, hydroxy, and oxo (=0).

23. The compound of claim 15, wherein L² is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to about 5 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O- and wherein each carbon atom, is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from halo and oxo (=0).

24. The compound or salt of any one of claims 1-13, wherein L² is selected from the group consisting of -

25. The compound or salt of any one of claims 1-13, wherein L² is -CH2-CH2-C(=O)-O-.

26. The compound or salt of any one of claims 1-25, wherein x is 0.

27. The compound or salt of any one of claims 1-25, wherein x is 1.

28. The compound or salt of any one of claims 1-27, wherein y is 0.

29. The compound or salt of any one of claims 1-27, wherein y is 1.

30. The compound or salt of any one of claims 1-27, wherein y is 2.

31. The compound or salt of any one of claims 1-30, wherein R^a is methyl, ethyl, propyl, or isopropyl.

32. The compound or salt of any one of claims 1-31, wherein each R^b and R^c is independently selected from the group consisting of H and (Ci-Ce)alkyl.

33. The compound or salt of any one of claims 1-32, wherein R² is H.

34. The compound or salt of any one of claims 1-32, wherein R² is OH.

35. The compound or salt of any one of claims 1-32, wherein R² is (Ci-C3)alkoxy.

36. The compound or salt of any one of claims 1-32, wherein R² is methoxy.

37. The compound or salt of any one of claims 1-36, wherein ring A is a 1,4-phenyldiyl.

38. The compound or salt of any one of claims 1-36, wherein ring A is a (6-membered heteroaryl)diyl.

39. The compound or salt of any one of claims 1-36, wherein ring A is pyridine-2,5-diyl, pyrimidine-2,5-diyl, or a pyrazin,2,5-diyl.

40. The compound or salt of any one of claims 1-39, wherein ring B is a 1,4-phenyldiyl.

41. The compound or salt of any one of claims 1-39, wherein ring B is a (6-membered heteroaryl)diyl.

42. The compound or salt of any one of claims 1-39, wherein ring B is pyridine-2,5-diyl, pyrimidine-2,5-diyl, or a pyrazin,2,5-diyl.

43. The compound or salt of any one of claims 1-42, wherein ring C is a 1,4-phenyldiyl.

44. The compound or salt of any one of claims 1-42, wherein ring C is a (6-membered heteroaryl)diyl.

45. The compound or salt of any one of claims 1-42, wherein ring C is pyridine-2,5-diyl, pyrimidine-2,5-diyl, or a pyrazin,2,5-diyl.

46. The compound or salt of any one of claims 1-36, which is a compound of formula (la): or a salt thereof.

47. The compound or salt of claim 1 which is selected from the group consisting of:

48. The compound or salt of claim 1 which is selected from the group consisting of: and salts thereof.

49. The compound or salt of claim 1 which is selected from the group consisting of: and salts thereof.

50. The compound or salt of claim 1 which is selected from the group consisting of:

and salts thereof.

51. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

52. The composition of claim 51, which is formulated for intravenous administration.

53. A method for reducing coagulation in an animal, comprising administering a compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof to the animal.

54. The method of claim 53, wherein the compound or the pharmaceutically acceptable salt is administered intraveneously.

55. A method for inhibiting thrombin in an animal comprising administering to the animal a compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof.

56. A method for allosterically inhibiting thrombin in an animal comprising administering to the animal a compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof.

57. A method for modulating blood coagulation in an animal comprising administering to the animal a compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof.

58. A compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof for use in medical therapy.

59. A compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof for reducing coagulation.

60. A compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof for inhibiting thrombin.

61. A compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof for allosterically inhibiting thrombin.

62. A compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof for modulating blood coagulation.

63. The use of a compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof to prepare a medicament for reducing coagulation in an animal.

64. The use of a compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof to prepare a medicament for inhibiting thrombin in an animal.

65. The use of a compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof to prepare a medicament for allosterically inhibiting thrombin in an animal.

66. The use of a compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof to prepare a medicament for reducing coagulation in an animal.

67. The use of a compound of formula (I) as described in any one of claims 1-50 or a pharmaceutically acceptable salt thereof to prepare a medicament for modulating blood coagulation in an animal.