Patent Publication Number: US-2009221564-A1

Title: Heterocyclic Compounds and Their Use in the Treatment of Cardiovascular Disease

Description:
FIELD OF THE INVENTION 
     The present invention relates to heterocyclic compounds, their use, their formulation, their preparation, their synthetic intermediates and to other subject matter. The compounds may be useful in the treatment of cardiovascular diseases and conditions, in particular thrombosis. 
     BACKGROUND TO THE INVENTION 
     Proteases are enzymes that catalyse the hydrolysis of covalent peptidic bonds. As examples of serine proteases may be mentioned thrombin (also called Factor IIa), Factor VIIa, Factor Xa, Factor IXa, Factor XIIa, plasmin, tissue kallikrein, pancreatic elastase, pancreatic elastase II, tissue plasminogen activator (also called tPA), Protein C (activated), and urokinase-type plasminogen activator (also called uPA or urokinase). 
     Control of coagulation serine protease activity is a major target in the development of pharmacological agents. Coagulation is a dynamic and complex process in which proteolytic enzymes such as thrombin play a key role. The blood coagulation cascade involves the conversion of zymogens into active enzymes which ultimately convert the soluble plasma protein fibrinogen into an insoluble matrix of highly cross-linked fibrin. Blood clots are composed of activated platelets and fibrin. Examples of such zymogens include Factor XII, Factor XI, Factor IX, Factor X, Factor VII, and prothrombin. These zymogens are activated to form the proteases Factor XIIa, Factor XIa, Factor IXa, Factor Xa, Factor VIIa, and thrombin. 
     There exists a need for effective therapeutic agents for the inhibition of serine proteases, for example in the regulation of hemostasis, and for the prevention and treatment of thrombus formation and other pathological processes in the vasculature induced by thrombin such as, for example, restenosis and inflammation. In particular, there exists a need for effective inhibitors of Factor IXa. There further exists a need for additional anti-tumour agents, including anti-tumour agents having anti-thrombotic activity. 
     Benzothiophene has the structure: 
     
       
         
         
             
             
         
       
     
     SUMMARY OF THE INVENTION 
     The present invention provides compounds and compositions which may be useful in vitro or in vivo for inhibiting one or more serine proteases and/or for the prevention or therapy of conditions in mammals characterized by undesired serine protease activity, or by thrombosis. Also disclosed are compounds and compositions useful for inhibiting serine proteases, in particular Factor IXa. 
     In one aspect, the present invention relates to the use of compounds of Formula (I), including prodrugs, salts, isomers, hydrates and solvates thereof, for the inhibition of serine proteases, particularly in the therapy of diseases or conditions susceptible to treatment by inhibition of a serine protease, for example in the therapy of thrombosis and/or other cardiovascular diseases: 
     
       
         
         
             
             
         
       
     
     wherein
 
ring A is a 5-, 6- or 7-membered ring which is fused with ring B;
 
ring B is a 5-, 6- or 7-membered ring having at least one in-ring atom which is —O— or —S—;
 
each Y is independently a bond or a linker having 1 to 20 (e.g. 1 to 10) in-chain atoms (e.g. selected from C, N, O and S) and comprising, for example, one or more linkages selected from —O—, —N(R 5 )—, —C(O)—, —C(S)—, —S(O) l —, —(CH 2 ) k —, —C(R 6 )(R 7 )—, —C(R 5 )═C(R 5 )—, —C≡C—, carbocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 , and heterocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11  (in some embodiments said linkages may additionally be selected from —N(R 6 )—);
 
R 1  is hydrogen R 11 , or a basic group;
 
R 2  and R 3  are each independently an organic or inorganic substituent, for example and without limitation selected from R 11 ;
 
each R 4  is independently hydrogen, except when Y is a bond; or is hydrocarbyl or heterocyclyl, either of which is optionally substituted, for example with 1, 2, 3, 4 or 5 R 11  (but the invention is not limited to substitution with 1, 2, 3, 4 or 5 R 11 );
 
each R 5  is independently selected from hydrogen, R 11 , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and —(CH 2 ) j -heterocyclyl, the heterocyclyl part of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 ;
 
R 6  and R 7  are each independently selected from R 8 , —OR 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —N(R 9 )R 10 , —C(O)N(R 9 )R 10 , —S(O) l R 8  and —C(R 8 ) 3 , with the proviso that R 7  is not hydrogen;
 
R 8 , R 9  and R 10  are each independently selected from hydrogen, R 11 , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and —(CH 2 ) j -heterocyclyl, the heterocyclyl part of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 ;
 
each R 11  is independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR 12 , —OR 12 , —SR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —OC(O)N(R 12 )R 13 , —S(O) l R 12 , —S(O) l NR 12 R 13 , —S(O) l NR 13 C(O)R 12 , —S(O) l NR 13 C(O)OR 12 , —NR 13 C(O)R 12 , —NR 13 C(O)OR 12 , —NR 13 S(O) l R 12 , —NR 13 C(O)NR 12 R 13 , —C(R 12 ) 3  and R 14  (of these R 11  moieties, one embodiment comprises halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR 12 , —OR 12 , —C(O)R 12 —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 );
 
R 12  and R 13  are the same or different and are each hydrogen or are selected from C 1-6  acyclic aliphatic groups and particularly C 1-6  alkyl, carbocyclyl optionally substituted by a C 1-6  acyclic aliphatic group and bonded to the remainder of the molecule either directly or through a C 1-6  acyclic aliphatic group (particularly —(CH 2 ) j -carbocyclyl or —(CH 2 ) j -carbocyclyl(C 1 -C 6 )alkyl), and heterocyclyl optionally substituted by a C 1-6  acyclic aliphatic group and bonded to the remainder of the molecule either directly or through a C 1-6  acyclic aliphatic group (particularly —(CH 2 ) j -heterocyclyl or —(CH 2 ) j -heterocyclyl(C 1 -C 6 )alkyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR u , —OR v , —SR v , —C(O)R v , —C(O)OR v , —OC(O)R v , —N(R u )R v , —C(O)N(R u )R v , —OC(O)N(R u )R v , —S(O) l NR v , —S(O) l NR u R v , —S(O) l NR u C(O)R v , —S(O) l NR u C(O)OR v , —NR u C(O)R v , NR u C(O)OR v , —NR u S(O) 1 R v , —NR u C(O)NR v R u , —C(R v ) 3 , and C 1-6  alkyl optionally substituted by 1, 2, 3, 4 or 5 halogens, where R u  is H, OH or C 1-6  alkyl optionally substituted by up to 5 halogens and R v  is H or C 1-6  alkyl optionally substituted by up to 5 halogens, e.g. R 12  and R 13  are the same or different and are each hydrogen or are selected from C 1-6  alkyl, —(CH 2 ) j -carbocyclyl and —(CH 2 ) j -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy and C 1-6  alkyl;
 
R 13  additionally may be hydroxy or C 1-6  alkoxy;
 
R 14  is selected from C 1-6  acyclic aliphatic groups and particularly C 1-6  alkyl, C 1-6  acyclic aliphatic-oxy and particularly C 1-6  alkoxy, —(CH 2 ) i —O—(CH 2 ) j -carbocyclyl, —(CH 2 ) i —O—(CH 2 ) j -heterocyclyl, —(CH 2 ) i —O—(CH 2 ) j -carbocyclyl(C 1 -C 6 )alkyl and —(CH 2 ) i —O—(CH 2 ) j -heterocyclyl(C 1 -C 6 )alkyl any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR 12 , —OR 2 , —SR 2 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —OC(O)N(R 12 )R 13 —S(O) l R 12 , —S(O) l NR 12 R 13 , —S(O) l NR 13 C(O)R 12 , —S(O) l NR 13 C(O)OR 12 , —NR 13 C(O)R 12 , —NR 13 C(O)OR 12 , —NR 13 S(O) l R 12 , —NR 13 C(O)NR 12 R 13 , and —C(R 12 ) 3  (of these R 14  moieties, one embodiment comprises C 1-6  alkyl, C 1-6  alkoxy, —(CH 2 ) j -carbocyclyl and —(CH 2 ) j -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy, C 1-6  alkyl and C 1-6  alkoxy);
 
i is 0, 1, 2, 3, 4, 5 or 6
 
j is 0, 1, 2, 3, 4, 5 or 6;
 
k is 1, 2, 3, 4, 5 or 6;
 
l is 0, 1 or 2;
 
m is 0, 1, 2, 3 or 4;
 
n is 0, 1 or 2;
 
p is 0 or 1; and
 
q is 0, 1, 2, 3 or 4;
 
or a pharmaceutically acceptable salt or prodrug thereof.
 
     The compounds of Formula (I) and the embodiments thereof described later in this specification themselves constitute an aspect of the invention. 
     In another aspect, the invention provides novel fused ring heterocyclic compounds including their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrugs. More particularly, the disclosure provides compounds of Formula (II): 
     
       
         
         
             
             
         
       
     
     wherein
 
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7  and A 8  may be the same or different and are each independently selected from —N═, —NH—, —O—, —S—, —CH═ and —CH 2 —, wherein at least one of A 5 , A 6 , A 7  and A 8  is —O— or —S—;
 
A 9  and A 10  are each independently C, CH or N; and
 
other symbols are as defined in relation to Formula (I);
 
or a pharmaceutically acceptable salt or prodrug thereof.
 
     In a further aspect the invention provides a benzothiophene compound, e.g. an amidinobenzothiophene compound, in particular a 2-amidinobenzothiophene compound, the compound being characterised in that it comprises a substituent at one or both of the 4- and 6-positions which substituent comprises a fragment independently selected from any of Formulae (i) to (vi): 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             R is a moiety comprising an optionally substituted carbocyclic or heterocyclic group; 
             X and Y are each independently O or N; 
             p is 0 or 1; and 
             the oxygen atom on the right hand side of the fragment as drawn is bound directly to the 4- or 6-carbon atom of the benzothiophene ring;
 
i.e. said substituent comprises a fragment independently selected from any of Formulae (i) to (vi):
 
           
         
       
    
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof. 
     In a further aspect the invention provides isosteres of the present compounds. 
     The invention includes also pharmaceutical formulations adapted to be administered to a patient and deliver a compound of the invention to the plasma of the patient. 
     The invention also provides formulations, pharmaceutical or otherwise, containing such compounds and includes compositions comprising excipients and diluents, as required. In particular, the disclosure also relates to pharmaceutically acceptable formulations of the compounds described herein, which may be useful as inhibitors of at least Factor IXa. 
     Where the context permits, substituents mentioned herein may be selected from (i) halogen; (ii) moieties having from 1 to 30 plural valent atoms (e.g. 1 to 20, for example 1 to 10, in particular 1, 2, 3 or 4, plural valent atoms), selected from C, N, O and S as well as monovalent atoms selected from hydrogen and halogen, e.g. selected from hydrogen, F, Cl and Br, for example hydrogen, F and Cl. 
     The invention includes in one embodiment compounds and groups in which any one or more hydrogen atoms bonded to a carbon are replaced by a halogen, e.g. F or Cl. Thus, reference to alkyl in this embodiment includes reference to such an alkyl group substituted by one or more halogens. 
     The compounds of the invention may be useful in the therapy (including treatment, prevention and the delay of progression) of cardiovascular diseases or conditions, in particular thrombosis. 
     The extent of protection includes counterfeit or fraudulent products which contain or purport to contain a compound of the invention irrespective of whether they do in fact contain such a compound and irrespective of whether any such compound is contained in a therapeutically effective amount. 
     Included in the scope of protection are packages which include a description or instructions which indicate that the package contains a species or pharmaceutical formulation of the invention and a product which is or comprises, or purports to be or comprise, such a formulation or species. Such packages may be, but are not necessarily, counterfeit or fraudulent. 
     Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. 
     Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. 
    
    
     DESCRIPTION OF VARIOUS EMBODIMENTS 
     Definitions 
     Hydrocarbyl 
     The term “hydrocarbyl” as used herein includes reference to a moiety consisting exclusively of hydrogen and carbon atoms; such a moiety may comprise an aliphatic and/or an aromatic moiety. It may additionally or alternatively comprise an alicyclic moiety. The hydrocarbyl moiety may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, e.g. from 1 to 10 or from 1 to 6 carbon atoms. Examples of hydrocarbyl groups include C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); C 1-6  alkyl substituted by aryl (e.g. benzyl) or by cycloalkyl (e.g cyclopropylmethyl); cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); aryl (e.g. phenyl, naphthyl or fluorenyl) and the like. 
     Aliphatic 
     The term “aliphatic” as used herein includes reference to acyclic or cyclic, saturated or unsaturated carbon moieties, excluding aromatic compounds. (Source: IUPAC Compendium of Chemical Terminology; http://goldbook.iupac.org/index.html). Aliphatic moieties are in particular acyclic hydrocarbyl moieties having, for example, 1, 2, 3, 4, 5 or 6 carbon atoms. 
     Alkyl 
     The terms “alkyl” and “C 1-6  alkyl” as used herein include reference to a straight or branched chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms. This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl and the like. In particular, alkyl may have 1, 2, 3 or 4 carbon atoms. The term “lower alkyl” includes reference to alkyl groups having 1, 2, 3 or 4 carbon atoms. 
     Alkenyl 
     The terms “alkenyl” and “C 2-6  alkenyl” as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one double bond, of either E or Z stereochemistry where applicable. This term includes reference to groups such as ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl and the like. The term “lower alkenyl” includes reference to alkenyl groups having 1, 2, 3 or 4 carbon atoms. 
     Alkynyl 
     The terms “alkynyl” and “C 2-6  alkynyl” as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one triple bond. This term includes reference to groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl and 3-hexynyl and the like. The term “lower alkynyl” includes reference to alkynyl groups having 1, 2, 3 or 4 carbon atoms. 
     Alkoxy 
     The terms “alkoxy” and “C 1-6  alkoxy” as used herein include reference to —O-alkyl, wherein alkyl is straight or branched chain and comprises 1, 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, alkoxy has 1, 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like. The term “lower alkoxyl” includes reference to alkoxyl groups having 1, 2, 3 or 4 carbon atoms. 
     Cycloalkyl 
     The term “cycloalkyl” as used herein includes reference to an alicyclic moiety having 3, 4, 5, 6, 7 or 8 carbon atoms. The group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl and the like. 
     Aryl 
     The term “aryl” as used herein includes reference to an aromatic ring system comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms. Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like. 
     Carbocyclyl 
     The term “carbocyclyl” as used herein includes reference to a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon ring atoms. In particular, carbocyclyl includes a 3- to 10-membered non-aromatic ring or ring system and, in particular, a 5- or 6-membered non-aromatic ring, which may be fully or partially saturated. A carbocyclic moiety is, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like. 
     Heterocyclyl 
     The term “heterocyclyl” as used herein includes reference to a saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulphur. In particular, heterocyclyl includes a 3- to 10-membered non-aromatic ring or ring system and more particularly a 5- or 6-membered ring, which may be fully or partially saturated. 
     A heterocyclic moiety is, for example, selected from oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, especially thiomorpholino, indolizinyl, isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl and the like. 
     Heterocycloalkyl 
     The term “heterocycloalkyl” as used herein includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1, 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur. The group may be a polycyclic ring system but more often is monocyclic. This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolizidinyl and the like. 
     Heteroaryl 
     The term “heteroaryl” as used herein includes reference to an aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur. The group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic, but is more often monocyclic. This term includes reference to groups such as pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like. 
     Halogen 
     The term “halogen” as used herein includes reference to F, Cl, Br or I. In a particular class of embodiments, halogen is F or Cl, of which F is more common. 
     Basic moieties 
     The term “basic moiety” or “basic group” as used herein includes reference to a moiety having an available pair of electrons capable of forming a covalent bond with a proton (i.e. a Brønsted base) or with the vacant orbital of another species (i.e. a Lewis base). A basic moiety is, for example, a moiety containing a basic nitrogen atom, such as an amino acid residue. 
     Amidino 
     The term “amidino” as used herein includes reference to moieties of the general structure —C(NH)NH 2  and derivatives thereof, in particular, those in which a hydrogen is replaced by alkyl, (e.g. methyl or ethyl) or hydroxy. In embodiments, “amidino” means a group of the structure —C(NH)NH 2 . Amidino may be in the form of a pharmaceutically acceptable salt or prodrug thereof. 
     Substituted 
     The term “substituted” as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents. 
     It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds. Additionally, it will of course be understood that the substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled man. 
     Where steric issues determine placement of substituents on a group, the isomer having the lowest conformational energy may be preferred. 
     Optionally 
     Where a compound, moiety, process or product is described as “optionally” having a feature, the disclosure includes such a compound, moiety, process or product having that feature and also such a compound, moiety, process or product not having that feature. Thus, when a moiety is described as “optionally substituted”, the disclosure comprises the unsubstituted moiety and the substituted moiety. 
     Independently 
     Where two or more moieties are described as being “each independently” selected from a list of atoms or groups, this means that the moieties may be the same or different. The identity of each moiety is therefore independent of the identities of the one or more other moieties. 
     Pharmaceutically Acceptable 
     The term “pharmaceutically acceptable” as used herein includes reference to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. This term includes acceptability for both human and veterinary purposes. 
     Prevention 
     The term “prevention” and cognate terms as applied to a disease, disorder or occurrence (by way of non-limiting example, thrombosis or thrombotic diseases or disorders) and the like refers to the primary and secondary prophylaxis thereof, unless the context requires otherwise. When a compound or composition is administered to prevent a disease, disorder or occurrence, it does not mean that the prevention will be completely successful in every patient for an indefinite period, since both curative and prophylactic (preventative) treatments may fail. Preventative or prophylactic treatment therefore includes reference to treatment which, within the scope of sound medical judgment, is appropriate to prevent the disease, disorder or occurrence in question, irrespective of the outcome of the treatment. The invention includes successful and unsuccessful methods of prevention. 
     Thrombosis 
     The term “thrombosis” as used herein refers inter alia to atrophic thrombosis, arterial thrombosis, cardiac thrombosis, coronary thrombosis, creeping thrombosis, infective thrombosis, mesenteric thrombosis, placental thrombosis, propagating thrombosis, traumatic thrombosis and venous thrombosis. 
     Thrombin Inhibitor 
     The term “thrombin inhibitor” as used herein includes reference to a compound or product which, within the scope of sound pharmacological judgement, is potentially or actually pharmaceutically useful as an inhibitor of thrombin, and includes reference to any substance which comprises a pharmaceutically active species and is described, promoted or authorised as a thrombin inhibitor. Such thrombin inhibitors may be selective, that is they are regarded, within the scope of sound pharmacological judgement, as selective towards thrombin in contrast to other proteases; the term “selective thrombin inhibitor” includes reference to substance which comprises a pharmaceutically active species and is described, promoted or authorised as a selective thrombin inhibitor. 
     Factor IXa Inhibitor 
     The terms “Factor IXa” or “FIXa” as used herein include reference to a compound or product which, within the scope of sound pharmacological judgement, is potentially or actually pharmaceutically useful as an inhibitor of Factor IXa, and includes reference to any substance which comprises a pharmaceutically active species and is described, promoted or authorised as a Factor IXa inhibitor. Such Factor IXa inhibitors may be selective, that is they are regarded, within the scope of sound pharmacological judgement, as selective towards thrombin in contrast to other proteases; the term “selective Factor IXa inhibitor” includes reference to any substance which comprises a pharmaceutically active species and is described, promoted or authorised as a selective Factor IXa inhibitor. 
     Product 
     The term “product” or “product of the invention” as used herein includes reference to any product containing a compound of the present invention. In particular the term product relates to compositions containing a compound of the present invention, such as a pharmaceutical composition, for example. 
     Therapeutically Effective Amount 
     The term “therapeutically effective amount” as used herein refers to an amount of a drug, or pharmaceutical agent that, within the scope of sound pharmacological judgement, is calculated to (or will) provide a desired therapeutic response in a mammal (animal or human). The therapeutic response may for example serve to cure, delay the progression of or prevent a disease, disorder or condition. 
     Isosteres 
     The term “isostere” as used herein includes reference to compounds, atoms or groups that have different molecular formulae but exhibit the same or similar properties. Examples of isosteric groups are given below. 
     (a) In-chain isosteres
         (i) —CH 3 , —NH 2 , —OH, —F, Cl   (ii) —Cl, —SH, —PH 2      (iii) —Br, -iso-propyl   (iv) —CH 2 , —NH—, —O—, —S—   (v) —C(O)CH 2 —, —C(O)NH—, —C(O)O—, —C(O)S—   (vi) —HC═, —N═
 
(b) In-ring isosteres
   (i) —CH═CH—, —S—   (ii) —O—, —S—, —CH 2 —, —NH—   (iii) —CH═, —N—       

     Other isosteres exist to mimic functional, or other, groups, for example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. 
     Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isosteres contemplated by the disclosure include: 
     —COOH, —SO 3 H, —SO 2 HNR′, —PO 2 (R′) 2 , —CN, —PO 3 (R′) 2 , —OR′, —SR′, —NHCOR′, —N(R′) 2 , —CON(R′) 2 , —CONH(O)R′, —CONHNHSO 2 R′, —COHNSO 2 R′, and —CONR′CN
 
where R′ is any atom or group which does not impair the carboxylic acid isosteric properties of the moiety or compound.
 
     In addition, carboxylic acid isosteres can include 5- to 7-membered carbocycles or heterocycles containing any combination of CH 2 , O, S, or N in any chemically stable oxidation state, where any of the atoms or groups of said ring structure are unsubstituted or substituted in one or more positions. Isosteres of the are often preferably bio-isosteres. 
     Preferably, any addition of chemical substituents to an isostere, such as a carboxylic acid isostere, retains the properties of the isostere. 
     The following are non-limiting examples of isosteres of the present invention: 
     Mono-valent Moieties: 
     
         
         (i) CH 3 , NH 2 , OH, F, Cl 
         (ii) Cl, PH 2 , SH 
         (iii) Br, i-Pr 
         (iv) I, t-Bu 
       
    
     Bi-valent Moieties: 
     
         
         (i) —CH 2 —, —NH—, —O—, —S—, —Se— 
         (ii) —COCH 2 R—, —CONHR—, —CO 2 R—, —COSR, —NRSO 2 — 
       
    
     Tri-valent Moieties: 
     
         
         (i) —CH═, —N═ 
         (ii) —P═, —As═ 
       
    
     Tetra-valent Moieties: 
     
         
         (i) C, Si 
         (ii) ═C═, ═N + ═, ═P + ═ 
       
    
     Halogen Moieties: 
     
         
         F, Cl, Br, I, CF 3 , CN, N(CN) 2 , C(CN) 3    
       
    
     Thioether Moieties: 
     
         
         —S—, —O—, —C(CN) 2 — and —N(CN)— 
       
    
     Thiourea Moieties: 
     
         
         —NHC(S)NH 2 , —NHC(═NCN)NH 2 , —NHC(═NNO 2 )NH 2 , —C(═NS(O) 2 NH 2 )NH 2    
       
    
     In-ring Moieties: 
     
         
         (i) —CH═CH—, —S— (e.g. in benzene and thiophene) 
         (ii) —CH═, —N═ (e.g. in benzene, pyridine) 
         (iii) —O—, —S—, —CH 2 —, —NH— (e.g. in tetrahydrofuran, tetrahydrothiophene, cyclopentane and pyrrolidine) 
       
    
     Spacers: 
     
         
         —(CH 2 ) 3 — and phenylene 
       
    
     Azomethine: 
     
         
         —N═, —C(CN)═ 
       
    
     Hydrogen: 
     
         
         H, F 
       
    
     Halogen Moieties: 
     
         
         F, Cl, Br, I, CF 3 , CN, N(CN) 2 , C(CN) 3    
       
    
     Carbonyl Moieties: 
     
         
         —C(O)—, —C(S)—, —S(O)—, —C(═NOH)—, —C(═N—)-, 
         —C(O)N(−)-, —CH(CN)—, —C(═C(CN) 2 ))-, —S(O) 2 N(−)-, —S(O) 2 — 
       
    
     Carboxylic Acid Moieties: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Amide Moieties: 
     
         
         C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —C(O)CH 2 CH 3 , —C(O)O—, —NHC(O)—, —NHC(O)O—, —NHS(O)O— 
       
    
     
       
         
         
             
             
         
       
     
     Ester Moieties: 
     
       
         
         
             
             
         
       
     
     Hydroxy Moieties: 
     
         
         —OH, —NHC(O)—, —NHS(O) 2 —, —CH 2 OH, —NH(CN)—, —CH(CN) 2 , —NHC(O)NH 2    
       
    
     Catechol Moieties: 
     
       
         
         
             
             
         
       
     
     Pyridine Moieties: 
     
       
         
         
             
             
         
       
     
     Benzene Moieties: 
     
       
         
         
             
             
         
       
     
     Ring Equivalents: 
     
       
         
         
             
             
         
       
     
     Compounds 
     In one aspect, the present invention provides compounds of Formula (I) as previously defined. In embodiments, one or more of R 11 , R 12 , R 13  and R 14 , e.g. one or both of R 11  and R 14 , are as described in the following paragraph. 
     One class of compounds (and the invention is not limited to this class of compounds) is of the following formula: 
     
       
         
         
             
             
         
       
     
     wherein
 
ring A is a 5-, 6- or 7-membered ring which is fused with ring B;
 
ring B is a 5-, 6- or 7-membered ring having at least one in-ring atom which is —O— or —S—;
 
each Y is independently a bond or a linker having 1 to 20 (e.g. 1 to 10) in-chain atoms (e.g. selected from C, N, O and S) and comprising, for example, one or more linkages selected from —O—, —N(R 5 )—, —C(O)—, —C(S)—, —S(O) l —, —(CH 2 ) k —, —C(R 6 )(R 7 )—, —C(R 5 )═C(R 5 )—, —C≡C—, carbocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 , and heterocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 ;
 
R 1  is hydrogen or R 11 , or a basic group;
 
R 2  and R 3  are each independently selected from R 11 ;
 
each R 4  is independently hydrogen, except when Y is a bond; or is hydrocarbyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 ;
 
each R 5  is independently selected from hydrogen, R 11 , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and —(CH 2 ) j -heterocyclyl, the heterocyclyl part of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 ;
 
R 6  and R 7  are each independently selected from R 8 , —OR 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —N(R 9 )R 10 , —C(O)N(R 9 )R 10 , —S(O) l R 8  and —C(R 8 ) 3 , with the proviso that R 7  is not hydrogen;
 
R 8 , R 9  and R 10  are each independently selected from hydrogen, R 11 , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and —(CH 2 ) j -heterocyclyl, the heterocyclyl part of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 ;
 
each R 11  is independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR 12 , —OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 ;
 
R 12  and R 13  are each independently hydrogen or are selected from C 1-6  alkyl, —(CH 2 ) j -carbocyclyl and —(CH 2 ) j -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy and C 1-6  alkyl;
 
R 14  is selected from C 1-6  alkyl, C 1-6  alkoxy, —(CH 2 ) j -carbocyclyl and —(CH 2 ) j -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy, C 1-6  alkyl and C 1-6  alkoxy;
 
j is 0, 1, 2, 3, 4, 5 or 6;
 
k is 1, 2, 3, 4, 5 or 6;
 
l is 0, 1 or 2;
 
m is 0, 1, 2, 3 or 4;
 
n is 0, 1 or 2;
 
p is 0 or 1; and
 
q is 0, 1, 2, 3 or 4;
 
or a pharmaceutically acceptable salt or prodrug thereof.
 
     A further class of compounds are of Formula (II): 
     
       
         
         
             
             
         
       
     
     wherein
 
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7  and A 8  may be the same or different and are each independently selected from —N═, —NH—, —O—, —S—, —CH═ and —CH 2 —, wherein at least one of A 5 , A 6 , A 7  and A 8  is —O— or —S—;
 
A 9  and A 10  are each independently C, CH or N;
 
and other symbols are as defined previously in this specification, for example:
 
each Y is independently a bond or a linker having 1 to 20 (e.g. 1 to 10) in-chain atoms (e.g. selected from C, N, O and S) and comprising, for example, one or more linkages selected from —O—, —N(R 5 )—, —C(O)—, —C(S)—, —S(O) l —, —(CH 2 ) k —, —C(R 6 )(R 7 )—, —C(R 5 )═C(R 5 )—, —C≡C—, carbocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 , and heterocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 ;
 
R 1  is hydrogen or R 11 , for example a basic moiety;
 
R 2  and R 3  are each independently selected from R 11 ;
 
each R 4  is independently hydrogen, except when Y is a bond; or is hydrocarbyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 ;
 
each R 5  is independently selected from hydrogen, R 11 , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and —(CH 2 ) j -heterocyclyl, the heterocyclyl part of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 ;
 
R 6  and R 7  are each independently selected from R 8 , —OR 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —N(R 9 )R 10 , —C(O)N(R 9 )R 10 , —S(O) l R 8  and —C(R 8 ) 3 , with the proviso that R 7  is not hydrogen;
 
R 8 , R 9  and R 10  are each independently selected from hydrogen, R 11 , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and —(CH 2 ) j -heterocyclyl, the heterocyclyl part of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 ;
 
each R 11  is independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR 12 , —OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 ;
 
R 12  and R 13  are each independently hydrogen or are selected from C 1-6  alkyl, —(CH 2 ) j -carbocyclyl and —(CH 2 ) j -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy and C 1-6  alkyl;
 
R 14  is selected from C 1-6  alkyl, C 1-6  alkoxy, —(CH 2 ) j -carbocyclyl and —(CH 2 ) j -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy, C 1-6  alkyl and C 1-6  alkoxy;
 
j is 0, 1, 2, 3, 4, 5 or 6;
 
k is 1, 2, 3, 4, 5 or 6;
 
l is 0, 1 or 2;
 
m is 0, 1, 2, 3 or 4;
 
n is 0, 1 or 2;
 
p is 0 or 1; and
 
q is 0, 1, 2, 3 or 4;
 
or a pharmaceutically acceptable salt or prodrug thereof.
 
     Embodiments of the invention are described below. It will be appreciated that the features specified in each embodiment may be combined with other specified features, to provide further embodiments. 
     Fused Ring AB 
     In Formula (I), ring A is a 5-, 6- or 7-membered ring which is fused with ring B. Ring B is a 5-, 6- or 7-membered ring having at least one in-ring heteroatom which is —O— or —S—. 
     In one embodiment, ring A is a 5- or 6-membered ring, in particular a 6-membered ring. 
     In a further embodiment, ring A is unsaturated. 
     In a further embodiment, ring A is aromatic. 
     In a further embodiment, ring A is heterocyclic. 
     In a further embodiment, ring A is aromatic and heterocyclic. 
     In a further embodiment, ring A is carbocyclic. 
     In a further embodiment, ring A is aromatic and carbocyclic. 
     In a further embodiment, ring B is a 5- or 6-membered ring, particularly a 5-membered ring. 
     In a further embodiment, ring B is unsaturated. 
     In a further embodiment, ring B contains a single in-ring heteroatom which is —O— or —S—. 
     In a further embodiment, ring B is contains a single in-ring heteroatom and is a 5-membered ring. 
     In a further embodiment, ring B contains two in-ring heteroatoms. 
     In a further embodiment, ring B contains three in-ring heteroatoms. 
     Typically, when two or more heteroatoms are present in ring B, they are separated by at least one in-ring carbon atom. 
     In a further embodiment, ring A is a 5 or 6-membered ring, and ring B is a 5 or 6-membered ring. 
     In a further embodiment, ring A is a 6-membered ring and ring B is a 5- or 6-membered ring. 
     In a further embodiment, ring A is a 6-membered ring and ring B is a 5-membered ring. 
     In a further embodiment, fused ring AB is as defined in Formula (II) below: 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7  and A 8  are each independently selected from —N═, —NH—, —O—, —S—, —CH═ and —CH 2 —, wherein at least one of A 5 , A 6 , A 7  and A 8  is —O— or —S—; 
             A 9  and A 10  are each independently C, CH or N; and 
             the remaining terms are as defined in relation to Formula (I). 
           
         
       
    
     With regard to formula (II) and related formulae, it will be appreciated that the solid lines forming rings A and B may represent single or double bonds depending on the identities of A 1  to A 10 . Thus, each bond within a ring is a double bond or a single bond as required to satisfy valency requirements. As indicated, this applies not only to formula (II) but also, for example, formula (III) and the left hand ring of formula (IV) below, and the subsequently-described sub-classes of these embodiments. 
     In a further embodiment, A 1 , A 2 , A 3 , A 4 , A 9  and A 10  taken together form an aromatic ring. Thus, for example, A 1 , A 2 , A 3 , A 4 , A 9  and A 10  taken together may form a benzene ring. 
     In a further embodiment, at least two of A 1 , A 2 , A 3 , A 4 , A 9  and A 10  are each independently —CH═ and —CH 2 —, and the one or more others are each —N═, —NH—. 
     In a further embodiment, A 1 , A 2 , A 3  and A 4  are each —CH═ (i.e. each comprise an sp 2  carbon atom). 
     In a further embodiment, A 1 , A 2 , A 3 , A 4 , A 9  and A 10  are each ═CH— or —CH 2 — (i.e. each comprise and sp 2  or an sp 3  carbon atom). 
     In a further embodiment, at least one, e.g. exactly one, of A 5 , A 6 , A 7  and A 8  (if present) is S. 
     In a further embodiment, only A 7  is a heteroatom, in particular —S— or —O—. 
     In a further embodiment, p is 0, i.e. the compound is of the Formula (III): 
     
       
         
         
             
             
         
       
     
     Particular embodiments of compounds of the invention include those of Formulae (IV) to (VII) below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In another class of compounds, fused ring AB is one of the following ring systems: 
     
       
         
         
             
             
         
       
     
     Alternatively, fused ring AB may form, by virtue of, for example, cyclisation of one or more substituents, a tricyclic ring system. This may arise because of intramolecular bonding, in particular hydrogen bonding. 
     The bicyclic system AB may of course be substituted by one or more substituents selected from R 2 , R 3  and —Y—R 4 , within the limitation that m is 0 to 4, and n is 0, 1 or 2. Thus, for example, when the options —CH═, —CH 2 — and —NH— are mentioned in the context A 1  to A 10 , the or each hydrogen atom attached to the carbon or nitrogen atoms may be substituted by any one of these substituents. 
     R 1    
     R 1  is attached to ring B and is hydrogen or R 11  or a basic moiety. 
     Included, accordingly, are compounds in which R 1  is an R 11 , e.g. halo. 
     In certain compounds, R 1  is a basic moiety, whether a basic moiety included in the options for R 11  or another one. 
     In one embodiment, R 1  comprises an amino group. Thus, R 1  may be an amino group, for example a substituted or unsubstituted amino group. Examples of substituted amino groups include N-alkylamino (e.g. N-methylamino), N,N-di-alkylamino, hydroxyalkylamino (e.g. 2-hydroxyethylamino or 2-hydroxypropylamino), alkoxyalkylamino (e.g. methoxyethylamino), phenylalkylamino, (e.g. benzylamino), N,N-di-alkylamino, N-phenylalkyl-N-alkylamino, N,N-dialkylphenylamino, alkanoylamino (e.g. acetylamino), benzoylamino, phenylalkoxycarbonylamino, carbamoylamino, aminocarbonylamino, aminoalkyloxyphenylamino, sulfamoylphenylamino and [N-(hydroxyalkyl)-carbamoyl]-phenylamino. 
     In a particular embodiment, R 1  is selected from: 
     (i) -G-NR c R d , especially —C(O)NR c R d  or —C(O)NHR a ; 
     (ii) -G-NR a OH; 
     (iii) -G-NR a C(NR a )H, especially -G-NHC(NH)H;
 
(iv) -G-NR a C(NR a )NR a OH, especially -G-NHC(NH)NHOH;
 
(v) -G-NR a C(NR a )NR a CN, especially -G-NHC(NH)NHCN;
 
(vi) -G-NR a C(NR a )NR a C(O)R a , especially -G-NHC(NH)NHC(O)R a ;
 
(vii) -G-NR a C(NR a )NR a R b , especially -G-NHC(NH)NHR a ;
 
(viii) -G-C(NR a )NR a R b , especially -G-C(NH)NHR a ;
 
(ix) -G-C(NR a )NR a NR a COR a , especially -G-C(NH)NHNHC(O)R a ;
 
(x) -G-C(NR a )NR a C(NR a )NR a R b , especially -G-C(NH)NHC(NH)NH 2 ;
 
(xi) -G-C(NR a )NR a COR a , especially -G-C(NH)NHC(O)R a ;
 
(xii) -G-NR a C(O)R a , especially -G-NHC(O)R a  (e.g. —C(O)NHC(O)R a );
 
(xiii) —OC(O)NR a R b , especially —OC(O)NHR a ;
 
(xiv) —OC(O)NR a C(O)R a , especially —OC(O)NHC(O)R E ;
 
     (xv) —C(O)ONR c R d ; 
     (xvi) -G-N(R 1 )C(O)OR a , especially —CON(R a )C(O)OR a ; 
     (xvii) -G-N(C(O)OR a )C(NH 2 )═NC(O)OR a , especially —N(C(O)OR a )C(NH 2 )═NC(O)OR a ; and 
     (xviii) -G-SC(═NH)NHR a ;
         wherein   G is a bond, —S(O) i , —C(O)— or —C(O)—(CH 2 ) p —C(O)—, wherein p is 1, 2, 3 or 4;   R a  and R b  are each independently an inert organic moiety, typically containing no more than 20 atoms which are not hydrogen or halogen; and   R c  and R d  are each independently hydrogen or a moiety in which the atoms other than hydrogen and halogen are selected from the group consisting of C, N, O and S and number from 1 to 20 (especially 1, 2, 3, 4, 5, 6 or 7) and which contains at least one hydrocarbyl group which is unsubstituted or substituted by halogen and may be aliphatic or carbocyclic, and is for example selected from aryl, alkyl, alkylene, cycloalkyl, cycloalkylene, alkenyl, alkenylene, cycloalkenyl, cycloalkenylene, alkynyl and alkynylene (which may be substituted by halogen and of which alkyl, alkylene, cycloalkyl and aryl form a preferred class), and optionally 1, 2 or 3 heteroatoms selected from O, N and S;   or R c  and R d  together with the attached nitrogen atom form optionally substituted heterocyclyl, for example imidazolyl, oxazolyl, thiazolyl, benzoxazolinyl or thiazolinyl.       

     In one embodiment, R a  and R b  are each independently hydrogen or a moiety in which the non-hydrogen atoms are selected from the group consisting of C, N, O and S and number from 1 to 20 (especially 1, 2, 3, 4, 5, 6 or 7, for example methyl, ethyl, butyl, propyl) and which contains at least one hydrocarbyl group which may be aliphatic or carbocyclic. Thus, for example, R a  and R b  may each be independently selected from aryl, alkyl, alkylene, cycloalkyl, cycloalkylene, alkenyl, alkenylene, cycloalkenyl, cycloalkenylene, alkynyl and alkynylene, and optionally 1, 2 or 3 heteroatoms selected from O, N and S. 
     In a further embodiment, R a  and R b  are each independently hydrogen or C 1-6  alkyl (especially C 1 , C 2 , C 3  or C 4  alkyl), carbocyclyl, —C 1-6  alkyl-carbocyclyl, -carbocyclyl-C 1-6  alkyl, or carbocyclyl (e.g. phenyl or cyclohexyl) optionally substituted by up to three moieties selected from C 1-6  alkyl, C 1-6  alkoxy and halogen. Those R a  and R b  groups which contain one or more alkylic carbon atoms may be interrupted at an alkylic carbon by an —O— linkage. 
     In a further embodiment, R a  and R b  are each independently selected from hydrogen, C 1-6  alkyl (e.g. methyl or ethyl), phenyl and cyclohexyl. Usually, at least one or both of R a  and R b  is hydrogen in groups containing —NR a R b . 
     In a further embodiment, R c  and R d  are each independently selected from hydrogen; C 1-6  alkyl optionally substituted with one or more substituents selected from hydrogen, halogen, carboxyl, C 1-6  alkoxy C 1-6  alkoxycarbonyl; carbocyclyl (especially phenyl or cyclohexyl) optionally substituted with one or more substituents selected from C 1 , C 2 , C 3  or C 4  alkyl; C 1 , C 2 , C 3  or C 4  alkoxy; and halogen; and -alkyl-carbocyclyl, wherein the carbocyclyl part is, for example, phenyl or cyclohexyl, and is optionally substituted with one or more substituents selected from C 1 , C 2 , C 3  or C 4  alkyl; C 1 , C 2 , C 3  or C 4  alkoxy; and halogen. 
     In a further embodiment, R c  and R d  are taken together with the attached nitrogen atom form optionally substituted heterocyclyl, for example imidazolyl, oxazolyl, thiazolyl, benzoxazolinyl or thiazolinyl, and of which is optionally substituted. 
     In a particular embodiment, R 1  is a group of Formula (i): 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             X is a bond, —NR 30 — or —C(O)—; 
             R 14 , R 15  and R 30  are each independently selected from R 18 , —OR 18 , —C(O)R 18 , —C(O)OR 18 , —OC(O)R 18 , —N(R 18 )R 19 , —C(O)N(R 19 )R 20 , —S(O) l R 18  and —C(R 18 ) 3 , e.g. are hydrogen, hydroxy or C 1-6  alkyl; 
             or R 14  and R 15  taken together form ═NR 20 , ═O or ═S; 
             R 16  and R 17  are each independently selected from hydrogen, C 1-6  alkyl, —OR 21  and —NR 18 R 19 ; 
             R 18  and R 19  are each independently selected from hydrogen, R 11 , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; 
             R 20  hydrogen, hydroxy, C 1-6  alkoxy or C 1-6  alkyl, e.g. is hydrogen or C 1-6  alkyl; and 
             R 21  is hydrogen or R 7 . 
           
         
       
    
     In one embodiment of Formula (i), X is a bond or —N(R 30 )—. 
     In another embodiment, X is a bond. 
     In one class of compounds, R 14  and R 15  together form NR 20  and R 16 , R 17  and R 20  are each the same or different and selected from hydrogen, alkyl and hydroxy; for example they may be selected from hydrogen and hydroxy or from hydrogen and alkyl. Alkyl may have 1, 2, 3, 4, 5 or 6 carbon atoms. 
     In a further embodiment, R 14  and R 15  taken together form ═NR 20 , wherein R 20  is usually hydrogen, alkyl or hydroxy, e.g. hydrogen or hydroxy. Accordingly, the invention includes compounds in which R 1  is: 
     
       
         
         
             
             
         
       
     
     Included in the invention are compounds in which R 16  and R 17  are each independently selected from hydrogen, C 1-6  alkyl, C 1-6  alkoxy or hydroxy, e.g. hydrogen or C 1-6  alkyl. 
     In embodiments, R 16  and/or R 17  and/or R 20  are hydrogen. 
     In a particular embodiment, R 1  is a group of Formula (ii): 
     
       
         
         
             
             
         
       
     
     In a further embodiment, R 1  is —C(═NH)NH 2  or —C(═NOH)NH 2 , particularly —C(═NH)NH 2  (amidino). 
     The invention includes a class of compounds in which R 1  is of formula (i) or (ii) above or is halogen, particularly F or Cl. 
     Particularly where R 1  is a basic group, for example of formula (i) or (ii) above, it may be in the form of a pharmaceutically acceptable salt of prodrug thereof, as in the case of other functional groups capable of being converted to a salt or prodrug form. 
     R 2    
     R 2  is an optional substitutent of ring B and is present when q is 1, 2, 3 or 4. R 2  is an organic or inorganic substituent and is often an R 11  atom or group. Typically, each R 2  is independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 2 , —C(O)R 2 , —C(O)OR 2 , —OC(O)R 2 , —N(R 2 )R 3 , —C(O)N(R 2 )R 3 , —S(O) l R 12 , —C(R 2 ) 3  and R 4 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     In one embodiment, q is 0, 1 or 2. 
     In another embodiment, q is 0 or 1. 
     In a further embodiment, q is 0. 
     For the avoidance of doubt, where ring B is substituted with more than one R 2 , each R 2  is independently selected from the range of substituents specified. 
     R 3    
     R 3  is an optional substitutent of ring A and is present when m is 1, 2, 3 or 4. R 3  is an organic or inorganic substituent and is often an R 11  atom or group. Typically, each R 3  is independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 12 , —C(O)R 12 , —C(O)OR 2 , —OC(O)R 2 , —N(R 2 )R 13 —C(O)N(R 2 )R 3 , —S(O) l R 12 , —C(R 2 ) 3  and R 4 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). However, please see under the heading “Summary of the Invention” for a more complete listing of R 11 , R 12 , R 13  and R 14  atoms or groups. 
     For the avoidance of doubt, where ring A is substituted with more than one R 3 , each R 3  is independently selected from the range of substituents specified. 
     R 11    
     R11 is as described under the heading “Summary of the Invention”, namely each R 11  is independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR 12 , —OR 2 , —SR 2 , —C(O)R 2 , —C(O)OR 12 , —OC(O)R 12 —N(R 2 )R 13 —C(O)N(R 2 )R 13 , —OC(O)N(R 12 )R 13 , —S(O) l R 12 , —S(O) l NR 12 R 13 , —S(O) l NR 13 C(O)R 12 , —S(O) l NR 13 C(O)OR 12 , —NR 13 C(O)R 12 , —NR 13 C(O)OR 12 , —NR 13 S(O) l R 12 , —NR 13 C(O)NR 12 R 13 , —C(R 12 ) 3  and R 14 . 
     In one class of compounds, each R 11  is independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, —B(OH) 2 , ═NR 2 , —OR 2 , —C(O)R 2 , —C(O)OR 2 , —OC(O)R 12 , —N(R 2 )R 3 , —C(O)N(R 2 )R 3 , —S(O) l R 2 , —C(R 12 ) 3  and R 4 . In another class of compounds, R 11  is as described in this paragraph except that R 11  as a substituent of R 4  is as described in the previous paragraph. 
     Typically, each R 11  is independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 2 , —C(O)R 2 , —C(O)OR 2 , —OC(O)R 12 , —N(R 2 )R 3 , —C(O)N(R 2 )R 3 , —S(O) l R 2 , —C(R 2 ) 3  and R 4 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     For the avoidance of doubt, where a group is substituted with more than one R 11 , each R 11  is independently selected from the range of substituents specified. The same applies to compounds of the invention comprising more than one R 11  substituent; each R 11  is selected independently of any other R 11  substituent present in the compound. 
     m &amp; n 
     The index m defines the number of R 3  substituents present, and is 0, 1, 2, 3 or 4. 
     The index n defines the number of —Y—R 4  substituents present, and is 0, 1 or 2. 
     In a particular embodiment, the sum of m and n is 1, i.e. either m is 0 and n is 1, or m is 1 and n is 0. 
     In another embodiment, the sum of m and n is 2, i.e. m is 0 and n is 2; m is 1 and n is 1; or m is 2 and n is 0. 
     Included also are compounds in which n is 2 and m is 1. 
     Y 
     Y is present when n is 1 or 2, and is a bond or a linker having 1 to 20 (e.g. 1 to 10) in-chain atoms (e.g. selected from C, N, O and S) and comprising, for example, one or more linkages selected from —O—, —N(R 5 )—, —C(O)—, —C(S)—, —S(O) l —, —(CH 2 ) k —, —C(R 6 )(R 7 )—, —C(R 5 )═C(R 5 )—, —C≡C—, carbocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 , and heterocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 . In embodiments, the one or more linkages may additionally be selected from —N(R 6 )—. 
     In one embodiment, n is 1 and Y is selected from:
         a bond   -Y 1 -;   -Y 1 -Y 2 -Y 3 -;   -Y 1 -Y 2 -Y 3 -Y 4 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -Y 9 -; and   Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -Y 9 -Y 10 -;
 
wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9  and Y 10  are each independently selected from —O—, —N(R 5 )—, —C(O)—, —C(S)—, —S(O) l —, —(CH 2 ) k —, —C(R 6 )(R 7 )—, —C(R 5 )═C(R 5 )—, —C═C—, carbocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 1 , and heterocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 . In some compounds, Y 1 -Y 10  may additionally be selected from —N(R 6 )—.
       

     In another embodiment, n is 2 and each Y is independently selected from:
         a bond   -Y 1 -Y 2 -;   -Y 1 -Y 2 -Y 3 -;   -Y 1 -Y 2 -Y 3 -Y 4 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -Y 9 -; and   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -Y 9 -Y 10 -;
 
wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 1 , Y 6 , Y 7 , Y 8 , Y 9  and Y 10  are each independently selected from —O—, —N(R 5 )—, —C(O)—, —C(S)—, —S(O) l —, —(CH 2 ) k —, —C(R 6 )(R 7 )—, —C(R 5 )═C(R 5 )—, —C≡C— carbocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 , and heterocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 . In embodiments, Y 1 -Y 10  may additionally be selected from —N(R 6 )—.
       

     Y 1  designates a moiety attached to ring AB, i.e. a linker comprising the structure -Y 1 -Y 2 - is directly covalently bonded to ring AB through Y 1 . 
     Of particular mention are compounds in which the or each Y is a linker and is attached to ring AB via a terminal —O— atom of Y. Thus, in the linkers specified above, Y 1  is especially —O—. 
     Of particular mention are compounds comprising at least one —Y—R 4  substituent which is other than alkoxy (in particular methoxy). 
     Also of particular mention are compounds having Y groups which comprise a -Y 1 -Y 2 - moiety other than —O—C(O)— or —S—C(O)—. Thus, certain compounds may comprise at least one —Y—R 4  substituent other than —O—C(O)—R 4  or —S—C(O)—R 4 . In certain compounds, a substituent of the formula —O—C(O)—R 4  or —S—C(O)—R 4  is absent. 
     Also of particular mention are compounds in which the or each Y is a linker and is attached to ring AB via carbocyclylene (e.g phenylene), more particularly —O-carbocyclylene, which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . Thus, in the linkers specified above, Y 1  and Y 2  are especially carbocyclylene (e.g. arylene) optionally substituted with 1, 2, 3, 4 or 5 R 11 , and —O— respectively. 
     Examples of the linker Y 1  are described in Table 2: 
     
       
         
           
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 No. 
                 Y 1   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 —O— 
               
               
                 2 
                 —N(R 5 )— 
               
               
                 3 
                 —C(O)— 
               
               
                 4 
                 —C(S)— 
               
               
                 5 
                 —S(O) l — 
               
               
                 6 
                 —(CH 2 ) k — 
               
               
                 7 
                 —C(R 6 )(R 7 )— 
               
               
                 8 
                 —C(R 5 )═C(R 5 )— 
               
               
                 9 
                 —C≡C— 
               
               
                 10 
                 carbocyclylene 
               
               
                 11 
                 heterocyclylene 
               
               
                   
               
            
           
         
       
     
     Further examples of Y 1  are described in Table 2: 
     
       
         
           
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 No. 
                 Y 1   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 —O— 
               
               
                 2 
                 —NH— 
               
               
                 3 
                 —N(-alkyl)- 
               
               
                 4 
                 —N[—(CH 2 ) k -aryl]- 
               
               
                 5 
                 —C(O)— 
               
               
                 6 
                 —C(S)— 
               
               
                 7 
                 —S— 
               
               
                 8 
                 —S(O)— 
               
               
                 9 
                 —S(O) 2 — 
               
               
                 10 
                 —CH 2 — 
               
               
                 11 
                 —(CH 2 ) 2 — 
               
               
                 12 
                 —(CH 2 ) 3 — 
               
               
                 13 
                 —CH(alkyl)- 
               
               
                 14 
                 —CH[—(CH 2 ) k -aryl]- 
               
               
                 15 
                 —C(alkyl) 2 - 
               
               
                 16 
                 —CH═CH— 
               
               
                 17 
                 —CH═C(alkyl)- 
               
               
                 18 
                 —C(alkyl)═CH— 
               
               
                 19 
                 —C≡C— 
               
               
                 20 
                 cycloalkylene 
               
               
                 21 
                 arylene 
               
               
                 22 
                 heterocycloalkylene 
               
               
                 23 
                 heteroarylene 
               
               
                   
               
            
           
         
       
     
     Further examples of Y 1  are described in Table 4: 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 4 
               
               
                   
                   
               
               
                   
                 No. 
                 Y 1   
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 1 
                 —O— 
               
               
                   
                 2 
                 —NH— 
               
               
                   
                 3 
                 —N(CH 3 )— 
               
               
                   
                 4 
                 —C(O)— 
               
               
                   
                 5 
                 —C(S)— 
               
               
                   
                 6 
                 —CH 2 — 
               
               
                   
                 7 
                 —(CH 2 ) 2 — 
               
               
                   
                 8 
                 —(CH 2 ) 3 — 
               
               
                   
                 9 
                 —CH═CH— 
               
               
                   
                 10 
                 —C≡C— 
               
               
                   
                 11 
                 phenylene 
               
               
                   
                   
               
               
                   
                 12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
            
           
         
       
     
     Examples of the linker -Y 1 -Y 2 - are given in Table 5: 
     
       
         
           
               
               
               
             
               
                 TABLE 5 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 —N(R 5 )— 
                 —O— 
               
               
                 2 
                 —C(O)— 
                 —O— 
               
               
                 5 
                 —(CH 2 ) k — 
                 —O— 
               
               
                 6 
                 —C(R 6 )(R 7 )— 
                 —O— 
               
               
                 7 
                 carbocyclylene 
                 —O— 
               
               
                 8 
                 heterocyclylene 
                 —O— 
               
               
                 9 
                 —O— 
                 —N(R 5 )— 
               
               
                 10 
                 —N(R 5 )— 
                 —N(R 5 )— 
               
               
                 11 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 13 
                 —S(O) l — 
                 —N(R 5 )— 
               
               
                 14 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 15 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 16 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 17 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 18 
                 —O— 
                 —C(O)— 
               
               
                 19 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 21 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 22 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 23 
                 carbocyclylene 
                 —C(O)— 
               
               
                 24 
                 heterocyclylene 
                 —C(O)— 
               
               
                 27 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 28 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 29 
                 carbocyclylene 
                 —C(S)— 
               
               
                 30 
                 heterocyclylene 
                 —C(S)— 
               
               
                 32 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 33 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 34 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 35 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 36 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 37 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 38 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 39 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 40 
                 —C(S)— 
                 —(CH 2 ) k — 
               
               
                 41 
                 —S(O) l — 
                 —(CH 2 ) k — 
               
               
                 43 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 44 
                 —C(R 5 )═C(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 45 
                 —C≡C— 
                 —(CH 2 ) k — 
               
               
                 46 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 47 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 48 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                 49 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 50 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 51 
                 —C(S)— 
                 —C(R 6 )(R 7 )— 
               
               
                 52 
                 —S(O) l — 
                 —C(R 6 )(R 7 )— 
               
               
                 53 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 54 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 55 
                 —C(R 5 )═C(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 56 
                 —C≡C— 
                 —C(R 6 )(R 7 )— 
               
               
                 57 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 58 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 64 
                 —(CH 2 ) k — 
                 —C(R 5 )═C(R 5 )— 
               
               
                 65 
                 —C(R 6 )(R 7 )— 
                 —C(R 5 )═C(R 5 )— 
               
               
                 66 
                 carbocyclylene 
                 —C(R 5 )═C(R 5 )— 
               
               
                 67 
                 heterocyclylene 
                 —C(R 5 )═C(R 5 )— 
               
               
                 68 
                 —(CH 2 ) k — 
                 —C≡C— 
               
               
                 69 
                 —C(R 6 )(R 7 )— 
                 —C≡C— 
               
               
                 70 
                 carbocyclylene 
                 —C≡C— 
               
               
                 71 
                 heterocyclylene 
                 —C≡C— 
               
               
                 72 
                 —O— 
                 carbocyclylene 
               
               
                 73 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 74 
                 —C(O)— 
                 carbocyclylene 
               
               
                 75 
                 —C(S)— 
                 carbocyclylene 
               
               
                 76 
                 —S(O) l — 
                 carbocyclylene 
               
               
                 77 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 78 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 79 
                 carbocyclylene 
                 carbocyclylene 
               
               
                 80 
                 heterocyclylene 
                 carbocyclylene 
               
               
                 81 
                 —O— 
                 heterocyclylene 
               
               
                 82 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 83 
                 —C(O)— 
                 heterocyclylene 
               
               
                 84 
                 —C(S)— 
                 heterocyclylene 
               
               
                 85 
                 —S(O) l — 
                 heterocyclylene 
               
               
                 86 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 87 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 88 
                 carbocyclylene 
                 heterocyclylene 
               
               
                 89 
                 heterocyclylene 
                 heterocyclylene 
               
               
                   
               
            
           
         
       
     
     Particular examples of -Y 1 -Y 2 - are given in Table 6: 
     
       
         
           
               
               
               
             
               
                 TABLE 6 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
               
               
                   
               
             
            
               
                 1 
                 —O— 
                 —N(R 5 )— 
               
               
                 2 
                 —O— 
                 —C(O)— 
               
               
                 3 
                 —O— 
                 —(CH 2   )   k — 
               
               
                 4 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                   
               
            
           
         
       
     
     Further particular examples of -Y 1 -Y 2 - are given in Table 7: 
     
       
         
           
               
               
               
             
               
                 TABLE 7 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
               
               
                   
               
             
            
               
                 1 
                 —O— 
                 —NH— 
               
               
                 2 
                 —O— 
                 —N(-alkyl)— 
               
               
                 3 
                 —O— 
                 —C(O)— 
               
               
                 4 
                 —O— 
                 —CH 2 — 
               
               
                 5 
                 —O— 
                 —(CH 2 ) 2 — 
               
               
                 6 
                 —O— 
                 —CH(phenyl)— 
               
               
                 7 
                 —O— 
                 —CH(benzyl)— 
               
               
                   
               
            
           
         
       
     
     Examples of the linker -Y 1 -Y 2 -Y 3 - are given in Table 8: 
     
       
         
           
               
               
               
               
             
               
                 TABLE 8 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 —C(O)— 
                 —O— 
                 —N(R 5 )— 
               
               
                 2 
                 carbocyclylene 
                 —O— 
                 —N(R 5 )— 
               
               
                 3 
                 heterocyclylene 
                 —O— 
                 —N(R 5 )— 
               
               
                 4 
                 —C(O)— 
                 —N(R 5 )— 
                 —N(R 5 )— 
               
               
                 5 
                 carbocyclylene 
                 —N(R 5 )— 
                 —N(R 5 )— 
               
               
                 6 
                 heterocyclylene 
                 —N(R 5 )— 
                 —N(R 5 )— 
               
               
                 7 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 8 
                 —N(R 5 )— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 9 
                 carbocyclylene 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 10 
                 heterocyclylene 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 11 
                 —N(R 5 )— 
                 —S(O) l — 
                 —N(R 5 )— 
               
               
                 12 
                 carbocyclylene 
                 —S(O) l — 
                 —N(R 5 )— 
               
               
                 13 
                 heterocyclylene 
                 —S(O) l — 
                 —N(R 5 )— 
               
               
                 14 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 15 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 16 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 17 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 18 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 19 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 20 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 21 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 22 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 23 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 24 
                 —O— 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 25 
                 —N(R 5 )— 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 26 
                 —C(O)— 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 27 
                 carbocyclylene 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 28 
                 heterocyclylene 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 29 
                 —O— 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 30 
                 —N(R 5 )— 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 31 
                 —C(O)— 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 32 
                 carbocyclylene 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 33 
                 heterocyclylene 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 34 
                 —N(R 5 )— 
                 —O— 
                 —C(O)— 
               
               
                 35 
                 —C(O)— 
                 —O— 
                 —C(O)— 
               
               
                 36 
                 carbocyclylene 
                 —O— 
                 —C(O)— 
               
               
                 37 
                 heterocyclylene 
                 —O— 
                 —C(O)— 
               
               
                 38 
                 —O— 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 39 
                 —N(R 5 )— 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 40 
                 —C(O)— 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 41 
                 carbocyclylene 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 42 
                 heterocyclylene 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 43 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 44 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 45 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 46 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 47 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 48 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 49 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 50 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 51 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 52 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 53 
                 —O— 
                 carbocyclylene 
                 —C(O)— 
               
               
                 54 
                 —N(R 5 )— 
                 carbocyclylene 
                 —C(O)— 
               
               
                 55 
                 —C(O)— 
                 carbocyclylene 
                 —C(O)— 
               
               
                 56 
                 carbocyclylene 
                 carbocyclylene 
                 —C(O)— 
               
               
                 57 
                 heterocyclylene 
                 carbocyclylene 
                 —C(O)— 
               
               
                 58 
                 —O— 
                 heterocyclylene 
                 —C(O)— 
               
               
                 59 
                 —N(R 5 )— 
                 heterocyclylene 
                 —C(O)— 
               
               
                 60 
                 —C(O)— 
                 heterocyclylene 
                 —C(O)— 
               
               
                 61 
                 carbocyclylene 
                 heterocyclylene 
                 —C(O)— 
               
               
                 62 
                 heterocyclylene 
                 heterocyclylene 
                 —C(O)— 
               
               
                 63 
                 —O— 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 64 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 65 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 66 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 67 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 68 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 69 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 70 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 71 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 72 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 73 
                 —O— 
                 carbocyclylene 
                 —C(S)— 
               
               
                 74 
                 —N(R 5 )— 
                 carbocyclylene 
                 —C(S)— 
               
               
                 75 
                 —C(O)— 
                 carbocyclylene 
                 —C(S)— 
               
               
                 76 
                 carbocyclylene 
                 carbocyclylene 
                 —C(S)— 
               
               
                 77 
                 heterocyclylene 
                 carbocyclylene 
                 —C(S)— 
               
               
                 78 
                 —O— 
                 heterocyclylene 
                 —C(S)— 
               
               
                 79 
                 —N(R 5 )— 
                 heterocyclylene 
                 —C(S)— 
               
               
                 80 
                 —C(O)— 
                 heterocyclylene 
                 —C(S)— 
               
               
                 81 
                 carbocyclylene 
                 heterocyclylene 
                 —C(S)— 
               
               
                 82 
                 heterocyclylene 
                 heterocyclylene 
                 —C(S)— 
               
               
                 83 
                 —O— 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 84 
                 —N(R 5 )— 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 85 
                 —C(O)— 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 86 
                 carbocyclylene 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 87 
                 heterocyclylene 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 88 
                 —O— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 89 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 90 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 91 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 92 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 93 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 94 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 95 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 96 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 97 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 98 
                 —O— 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 99 
                 —N(R 5 )— 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 100 
                 —C(O)— 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 101 
                 carbocyclylene 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 102 
                 heterocyclylene 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 103 
                 —O— 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 104 
                 —N(R 5 )— 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 105 
                 —C(O)— 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 106 
                 carbocyclylene 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 107 
                 heterocyclylene 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 108 
                 —N(R 5 )— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 109 
                 —C(O)— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 110 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 111 
                 heterocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 112 
                 —O— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 113 
                 —N(R 5 )— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 114 
                 —C(O)— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 115 
                 carbocyclylene 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 116 
                 heterocyclylene 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 117 
                 —O— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 118 
                 —N(R 5 )— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 119 
                 carbocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 120 
                 heterocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 121 
                 carbocyclylene 
                 —C(S)— 
                 —(CH 2 ) k — 
               
               
                 122 
                 heterocyclylene 
                 —C(S)— 
                 —(CH 2 ) k — 
               
               
                 123 
                 —N(R 5 )— 
                 —S(O) l — 
                 —(CH 2 ) k — 
               
               
                 124 
                 carbocyclylene 
                 —S(O) l — 
                 —(CH 2 ) k — 
               
               
                 125 
                 heterocyclylene 
                 —S(O) l — 
                 —(CH 2 ) k — 
               
               
                 126 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 127 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 128 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 129 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 130 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 131 
                 carbocyclylene 
                 —C(R 5 )═C(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 132 
                 heterocyclylene 
                 —C(R 5 )═C(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 133 
                 —O— 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 134 
                 —N(R 5 )— 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 135 
                 —C(O)— 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 136 
                 carbocyclylene 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 137 
                 heterocyclylene 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 138 
                 —O— 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 139 
                 —N(R 5 )— 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 140 
                 —C(O)— 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 141 
                 carbocyclylene 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 142 
                 heterocyclylene 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 143 
                 —N(R 5 )— 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                 144 
                 —C(O)— 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                 145 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                 146 
                 heterocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                 147 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 148 
                 —N(R 5 )— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 149 
                 —C(O)— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 150 
                 carbocyclylene 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 151 
                 heterocyclylene 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 152 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 153 
                 —N(R 5 )— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 154 
                 carbocyclylene 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 155 
                 heterocyclylene 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 156 
                 carbocyclylene 
                 —C(S)— 
                 —C(R 6 )(R 7 )— 
               
               
                 157 
                 heterocyclylene 
                 —C(S)— 
                 —C(R 6 )(R 7 )— 
               
               
                 158 
                 —N(R 5 )— 
                 —S(O) l — 
                 —C(R 6 )(R 7 )— 
               
               
                 159 
                 carbocyclylene 
                 —S(O) l — 
                 —C(R 6 )(R 7 )— 
               
               
                 160 
                 heterocyclylene 
                 —S(O) l — 
                 —C(R 6 )(R 7 )— 
               
               
                 161 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 162 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 163 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 164 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 165 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 166 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 167 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 168 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 169 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 170 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 171 
                 carbocyclylene 
                 —C(R 5 )═C(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 172 
                 heterocyclylene 
                 —C(R 5 )═C(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 173 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 174 
                 —N(R 5 )— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 175 
                 —C(O)— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 176 
                 carbocyclylene 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 177 
                 heterocyclylene 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 178 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 179 
                 —N(R 5 )— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 180 
                 —C(O)— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 181 
                 carbocyclylene 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 182 
                 heterocyclylene 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 183 
                 —N(R 5 )— 
                 —O— 
                 carbocyclylene 
               
               
                 184 
                 —C(O)— 
                 —O— 
                 carbocyclylene 
               
               
                 185 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
               
               
                 186 
                 heterocyclylene 
                 —O— 
                 carbocyclylene 
               
               
                 187 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 188 
                 —N(R 5 )— 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 189 
                 —C(O)— 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 190 
                 carbocyclylene 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 191 
                 heterocyclylene 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 192 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
               
               
                 193 
                 —N(R 5 )— 
                 —C(O)— 
                 carbocyclylene 
               
               
                 194 
                 carbocyclylene 
                 —C(O)— 
                 carbocyclylene 
               
               
                 195 
                 heterocyclylene 
                 —C(O)— 
                 carbocyclylene 
               
               
                 196 
                 carbocyclylene 
                 —C(S)— 
                 carbocyclylene 
               
               
                 197 
                 heterocyclylene 
                 —C(S)— 
                 carbocyclylene 
               
               
                 198 
                 —N(R 5 )— 
                 —S(O) l — 
                 carbocyclylene 
               
               
                 199 
                 carbocyclylene 
                 —S(O) l — 
                 carbocyclylene 
               
               
                 200 
                 heterocyclylene 
                 —S(O) l — 
                 carbocyclylene 
               
               
                 201 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 202 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 203 
                 —C(O)— 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 204 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 205 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 206 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 207 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 208 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 209 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 210 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 211 
                 carbocyclylene 
                 —C(R 5 )═C(R 5 )— 
                 carbocyclylene 
               
               
                 212 
                 heterocyclylene 
                 —C(R 5 )═C(R 5 )— 
                 carbocyclylene 
               
               
                 213 
                 —O— 
                 carbocyclylene 
                 carbocyclylene 
               
               
                 214 
                 —N(R 5 )— 
                 carbocyclylene 
                 carbocyclylene 
               
               
                 215 
                 —C(O)— 
                 carbocyclylene 
                 carbocyclylene 
               
               
                 216 
                 —O— 
                 heterocyclylene 
                 carbocyclylene 
               
               
                 217 
                 —N(R 5 )— 
                 heterocyclylene 
                 carbocyclylene 
               
               
                 218 
                 —C(O)— 
                 heterocyclylene 
                 carbocyclylene 
               
               
                 219 
                 —N(R 5 )— 
                 —O— 
                 heterocyclylene 
               
               
                 220 
                 —C(O)— 
                 —O— 
                 heterocyclylene 
               
               
                 221 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
               
               
                 222 
                 heterocyclylene 
                 —O— 
                 heterocyclylene 
               
               
                 223 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 224 
                 —N(R 5 )— 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 225 
                 —C(O)— 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 226 
                 carbocyclylene 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 227 
                 heterocyclylene 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 228 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
               
               
                 229 
                 —N(R 5 )— 
                 —C(O)— 
                 heterocyclylene 
               
               
                 230 
                 carbocyclylene 
                 —C(O)— 
                 heterocyclylene 
               
               
                 231 
                 heterocyclylene 
                 —C(O)— 
                 heterocyclylene 
               
               
                 232 
                 carbocyclylene 
                 —C(S)— 
                 heterocyclylene 
               
               
                 233 
                 heterocyclylene 
                 —C(S)— 
                 heterocyclylene 
               
               
                 234 
                 —N(R 5 )— 
                 —S(O) l — 
                 heterocyclylene 
               
               
                 235 
                 carbocyclylene 
                 —S(O) l — 
                 heterocyclylene 
               
               
                 236 
                 heterocyclylene 
                 —S(O) l — 
                 heterocyclylene 
               
               
                 237 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 238 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 239 
                 —C(O)— 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 240 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 241 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 242 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 243 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 244 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 245 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 246 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 247 
                 carbocyclylene 
                 —C(R 5 )═C(R 5 )— 
                 heterocyclylene 
               
               
                 248 
                 heterocyclylene 
                 —C(R 5 )═C(R 5 )— 
                 heterocyclylene 
               
               
                 249 
                 —O— 
                 carbocyclylene 
                 heterocyclylene 
               
               
                 250 
                 —N(R 5 )— 
                 carbocyclylene 
                 heterocyclylene 
               
               
                 251 
                 —C(O)— 
                 carbocyclylene 
                 heterocyclylene 
               
               
                 252 
                 —O— 
                 heterocyclylene 
                 heterocyclylene 
               
               
                 253 
                 —N(R 5 )— 
                 heterocyclylene 
                 heterocyclylene 
               
               
                 254 
                 —C(O)— 
                 heterocyclylene 
                 heterocyclylene 
               
               
                   
               
            
           
         
       
     
     Particular examples of -Y 1 -Y 2 -Y 3 - are given in Table 9: 
     
       
         
           
               
               
               
               
             
               
                 TABLE 9 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 2 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 3 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 4 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 5 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 6 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 7 
                 —N(R 5 )— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 8 
                 —C(O)— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 9 
                 —C(O)— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 10 
                 —C(O)— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 11 
                 —C(O)— 
                 —N(R 5 )— 
                 —O— 
               
               
                 12 
                 carbocyclylene 
                 —O— 
                 —N(R 5 )— 
               
               
                 13 
                 carbocyclylene 
                 —O— 
                 —C(O)— 
               
               
                 14 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 15 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                 16 
                 carbocyclylene 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 17 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —C(O)— 
               
               
                   
               
            
           
         
       
     
     Further particular examples of -Y 1 -Y 2 -Y 3 - are given in Table 10: 
     
       
         
           
               
               
               
               
             
               
                 TABLE 10 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 2 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 phenylene 
               
               
                 3 
                 phenylene 
                 —O— 
                 —N(R 5 )— 
               
               
                 4 
                 phenylene 
                 —O— 
                 —C(O)— 
               
               
                 5 
                 phenylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 6 
                 phenylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                   
               
            
           
         
       
     
     Further particular examples of -Y 1 -Y 2 -Y 3 - are given in Table 11: 
     
       
         
           
               
               
               
               
             
               
                 TABLE 11 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 —O— 
                 —CH 2 — 
                 phenylene 
               
               
                 2 
                 —O— 
                 —CH 2 — 
                 heterocyclylene 
               
               
                 3 
                 —O— 
                 —(CH 2 ) 2 — 
                 NH 
               
               
                 4 
                 —O— 
                 —(CH 2 ) 2 — 
                 —N(alkyl)- 
               
               
                 5 
                 —O— 
                 —CH(phenyl)- 
                 —CH 2 — 
               
               
                 6 
                 —O— 
                 —CH(phenyl)- 
                 phenylene 
               
               
                 7 
                 —O— 
                 —CH(phenyl)- 
                 heterocyclylene 
               
               
                 8 
                 —NH— 
                 —C(O)— 
                 —CH 2 — 
               
               
                 9 
                 —N(alkyl)- 
                 —C(O)— 
                 —CH 2 — 
               
               
                 10 
                 —C(O)— 
                 —O— 
                 —CH 2 — 
               
               
                 11 
                 —C(O)— 
                 —NH— 
                 —CH 2 — 
               
               
                 12 
                 —C(O)— 
                 —NH— 
                 —O— 
               
               
                 13 
                 —C(O)— 
                 —N(alkyl)- 
                 —O— 
               
               
                 14 
                 phenylene 
                 —O— 
                 —NH— 
               
               
                 15 
                 phenylene 
                 —O— 
                 —N(alkyl)- 
               
               
                 16 
                 phenylene 
                 —O— 
                 —C(O)— 
               
               
                 17 
                 phenylene 
                 —O— 
                 —CH 2 — 
               
               
                 18 
                 phenylene 
                 —O— 
                 —(CH 2 ) 2 — 
               
               
                 19 
                 phenylene 
                 —O— 
                 —CH(phenyl)- 
               
               
                 20 
                 phenylene 
                 —O— 
                 —CH(benzyl)- 
               
               
                 21 
                 phenylene 
                 —C(O)— 
                 —NH— 
               
               
                 22 
                 —CH(phenyl)- 
                 —O— 
                 —C(O)— 
               
               
                   
               
            
           
         
       
     
     Examples of the linker -Y 1 -Y 2 -Y 3 -Y 4 - are given in Table 12: 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 12 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
                 Y 4   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
                 —O— 
               
               
                 2 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
                 —O— 
               
               
                 3 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 —O— 
               
               
                 4 
                 —O— 
                 carbocyclylene 
                 —N(R 5 )— 
                 —O— 
               
               
                 5 
                 —O— 
                 heterocyclylene 
                 —N(R 5 )— 
                 —O— 
               
               
                 6 
                 —O— 
                 —N(R 5 )— 
                 —C(O)— 
                 —O— 
               
               
                 7 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —O— 
               
               
                 8 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —O— 
               
               
                 9 
                 —O— 
                 carbocyclylene 
                 —C(O)— 
                 —O— 
               
               
                 10 
                 —O— 
                 heterocyclylene 
                 —C(O)— 
                 —O— 
               
               
                 11 
                 —O— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —O— 
               
               
                 12 
                 —O— 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —O— 
               
               
                 13 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —O— 
               
               
                 14 
                 —O— 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —O— 
               
               
                 15 
                 —O— 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —O— 
               
               
                 16 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —O— 
               
               
                 17 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —O— 
               
               
                 18 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —O— 
               
               
                 19 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —O— 
               
               
                 20 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —O— 
               
               
                 21 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —O— 
               
               
                 22 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
                 —O— 
               
               
                 23 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
                 —O— 
               
               
                 24 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —O— 
               
               
                 25 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —O— 
               
               
                 26 
                 —O— 
                 carbocyclylene 
                 carbocyclylene 
                 —O— 
               
               
                 27 
                 —O— 
                 heterocyclylene 
                 carbocyclylene 
                 —O— 
               
               
                 28 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
                 —O— 
               
               
                 29 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
                 —O— 
               
               
                 30 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —O— 
               
               
                 31 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —O— 
               
               
                 32 
                 —O— 
                 carbocyclylene 
                 heterocyclylene 
                 —O— 
               
               
                 33 
                 —O— 
                 heterocyclylene 
                 heterocyclylene 
                 —O— 
               
               
                 34 
                 —O— 
                 —(CH 2 ) k — 
                 —O— 
                 —N(R 5 )— 
               
               
                 35 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —N(R 5 )— 
               
               
                 36 
                 —O— 
                 carbocyclylene 
                 —O— 
                 —N(R 5 )— 
               
               
                 37 
                 —O— 
                 heterocyclylene 
                 —O— 
                 —N(R 5 )— 
               
               
                 38 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
                 —N(R 5 )— 
               
               
                 39 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
                 —N(R 5 )— 
               
               
                 40 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 —N(R 5 )— 
               
               
                 41 
                 —O— 
                 carbocyclylene 
                 —N(R 5 )— 
                 —N(R 5 )— 
               
               
                 42 
                 —O— 
                 heterocyclylene 
                 —N(R 5 )— 
                 —N(R 5 )— 
               
               
                 43 
                 —O— 
                 —N(R 5 )— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 44 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 45 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 46 
                 —O— 
                 carbocyclylene 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 47 
                 —O— 
                 heterocyclylene 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 48 
                 —O— 
                 —N(R 5 )— 
                 —S(O) l — 
                 —N(R 5 )— 
               
               
                 49 
                 —O— 
                 —(CH 2 ) k — 
                 —S(O) l — 
                 —N(R 5 )— 
               
               
                 50 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
                 —N(R 5 )— 
               
               
                 51 
                 —O— 
                 carbocyclylene 
                 —S(O) l — 
                 —N(R 5 )— 
               
               
                 52 
                 —O— 
                 heterocyclylene 
                 —S(O) l — 
                 —N(R 5 )— 
               
               
                 53 
                 —O— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 54 
                 —O— 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 55 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 56 
                 —O— 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 57 
                 —O— 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 58 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 59 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 60 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 61 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 62 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 63 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 64 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 65 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 66 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 67 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 68 
                 —O— 
                 carbocyclylene 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 69 
                 —O— 
                 heterocyclylene 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 70 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 71 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 72 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 73 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 74 
                 —O— 
                 carbocyclylene 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 75 
                 —O— 
                 heterocyclylene 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 76 
                 —O— 
                 —(CH 2 ) k — 
                 —O— 
                 —C(O)— 
               
               
                 77 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —C(O)— 
               
               
                 78 
                 —O— 
                 carbocyclylene 
                 —O— 
                 —C(O)— 
               
               
                 79 
                 —O— 
                 heterocyclylene 
                 —O— 
                 —C(O)— 
               
               
                 80 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 81 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 82 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 83 
                 —O— 
                 carbocyclylene 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 84 
                 —O— 
                 heterocyclylene 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 85 
                 —O— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 86 
                 —O— 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 87 
                 —O— 
                 —(CH 2 ) k — 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 88 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 89 
                 —O— 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 90 
                 —O— 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 91 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 92 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 93 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 94 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 95 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 96 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 97 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
                 —C(O)— 
               
               
                 98 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
                 —C(O)— 
               
               
                 99 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —C(O)— 
               
               
                 100 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —C(O)— 
               
               
                 101 
                 —O— 
                 carbocyclylene 
                 carbocyclylene 
                 —C(O)— 
               
               
                 102 
                 —O— 
                 heterocyclylene 
                 carbocyclylene 
                 —C(O)— 
               
               
                 103 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
                 —C(O)— 
               
               
                 104 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
                 —C(O)— 
               
               
                 105 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —C(O)— 
               
               
                 106 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —C(O)— 
               
               
                 107 
                 —O— 
                 carbocyclylene 
                 heterocyclylene 
                 —C(O)— 
               
               
                 108 
                 —O— 
                 heterocyclylene 
                 heterocyclylene 
                 —C(O)— 
               
               
                 109 
                 —O— 
                 —(CH 2 ) k — 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 110 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 111 
                 —O— 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 112 
                 —O— 
                 heterocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 113 
                 —O— 
                 —N(R 5 )— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 114 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 115 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 116 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 117 
                 —O— 
                 carbocyclylene 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 118 
                 —O— 
                 heterocyclylene 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 119 
                 —O— 
                 —N(R 5 )— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 120 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 121 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 122 
                 —O— 
                 carbocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 123 
                 —O— 
                 heterocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 124 
                 —O— 
                 —(CH 2 ) k — 
                 —C(S)— 
                 —(CH 2 ) k — 
               
               
                 125 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
                 —(CH 2 ) k — 
               
               
                 126 
                 —O— 
                 carbocyclylene 
                 —C(S)— 
                 —(CH 2 ) k — 
               
               
                 127 
                 —O— 
                 heterocyclylene 
                 —C(S)— 
                 —(CH 2 ) k — 
               
               
                 128 
                 —O— 
                 —N(R 5 )— 
                 —S(O) l — 
                 —(CH 2 ) k — 
               
               
                 129 
                 —O— 
                 —(CH 2 ) k — 
                 —S(O) l — 
                 —(CH 2 ) k — 
               
               
                 130 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
                 —(CH 2 ) k — 
               
               
                 131 
                 —O— 
                 carbocyclylene 
                 —S(O) l — 
                 —(CH 2 ) k — 
               
               
                 132 
                 —O— 
                 heterocyclylene 
                 —S(O) l — 
                 —(CH 2 ) k — 
               
               
                 133 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 134 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 135 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 136 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 137 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 138 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 139 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 140 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 141 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 142 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 143 
                 —O— 
                 carbocyclylene 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 144 
                 —O— 
                 heterocyclylene 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 145 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 146 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 147 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 148 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 149 
                 —O— 
                 carbocyclylene 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 150 
                 —O— 
                 heterocyclylene 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 151 
                 —O— 
                 —(CH 2 ) k — 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                 152 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                 153 
                 —O— 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                 154 
                 —O— 
                 heterocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
               
               
                 155 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 156 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 157 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 158 
                 —O— 
                 carbocyclylene 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 159 
                 —O— 
                 heterocyclylene 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 160 
                 —O— 
                 —N(R 5 )— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 161 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 162 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 163 
                 —O— 
                 carbocyclylene 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 164 
                 —O— 
                 heterocyclylene 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 165 
                 —O— 
                 —(CH 2 ) k — 
                 —C(S)— 
                 —C(R 6 )(R 7 )— 
               
               
                 166 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
                 —C(R 6 )(R 7 )— 
               
               
                 167 
                 —O— 
                 carbocyclylene 
                 —C(S)— 
                 —C(R 6 )(R 7 )— 
               
               
                 168 
                 —O— 
                 heterocyclylene 
                 —C(S)— 
                 —C(R 6 )(R 7 )— 
               
               
                 169 
                 —O— 
                 —N(R 5 )— 
                 —S(O) l — 
                 —C(R 6 )(R 7 )— 
               
               
                 170 
                 —O— 
                 —(CH 2 ) k — 
                 —S(O) l — 
                 —C(R 6 )(R 7 )— 
               
               
                 171 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
                 —C(R 6 )(R 7 )— 
               
               
                 172 
                 —O— 
                 carbocyclylene 
                 —S(O) l — 
                 —C(R 6 )(R 7 )— 
               
               
                 173 
                 —O— 
                 heterocyclylene 
                 —S(O) l — 
                 —C(R 6 )(R 7 )— 
               
               
                 174 
                 —O— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 175 
                 —O— 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 176 
                 —O— 
                 —(CH 2 ) k — 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 177 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 178 
                 —O— 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 179 
                 —O— 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 180 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 181 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 182 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 183 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 184 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 185 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 186 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 187 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 188 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 189 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 190 
                 —O— 
                 carbocyclylene 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 191 
                 —O— 
                 heterocyclylene 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 192 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 193 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 194 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 195 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 196 
                 —O— 
                 carbocyclylene 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 197 
                 —O— 
                 heterocyclylene 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 198 
                 —O— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 199 
                 —O— 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 200 
                 —O— 
                 —(CH 2 ) k — 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 201 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 202 
                 —O— 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 203 
                 —O— 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 204 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 205 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 206 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 207 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 208 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 209 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 210 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
                 —C(S)— 
               
               
                 211 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
                 —C(S)— 
               
               
                 212 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —C(S)— 
               
               
                 213 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —C(S)— 
               
               
                 214 
                 —O— 
                 carbocyclylene 
                 carbocyclylene 
                 —C(S)— 
               
               
                 215 
                 —O— 
                 heterocyclylene 
                 carbocyclylene 
                 —C(S)— 
               
               
                 216 
                 —O— 
                 —O— 
                 heterocyclylene 
                 —C(S)— 
               
               
                 217 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
                 —C(S)— 
               
               
                 218 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
                 —C(S)— 
               
               
                 219 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —C(S)— 
               
               
                 220 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —C(S)— 
               
               
                 221 
                 —O— 
                 carbocyclylene 
                 heterocyclylene 
                 —C(S)— 
               
               
                 222 
                 —O— 
                 heterocyclylene 
                 heterocyclylene 
                 —C(S)— 
               
               
                 223 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 224 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 225 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 226 
                 —O— 
                 carbocyclylene 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 227 
                 —O— 
                 heterocyclylene 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 228 
                 —O— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 229 
                 —O— 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 230 
                 —O— 
                 —(CH 2 ) k — 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 231 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 232 
                 —O— 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 233 
                 —O— 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 234 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 235 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 236 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 237 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 238 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 239 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 240 
                 —O— 
                 —O— 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 241 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 242 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 243 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 244 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 245 
                 —O— 
                 carbocyclylene 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 246 
                 —O— 
                 heterocyclylene 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 247 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 248 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 249 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 250 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 251 
                 —O— 
                 carbocyclylene 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 252 
                 —O— 
                 heterocyclylene 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 253 
                 —O— 
                 —(CH 2 ) k — 
                 —O— 
                 carbocyclylene 
               
               
                 254 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 carbocyclylene 
               
               
                 255 
                 —O— 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
               
               
                 256 
                 —O— 
                 heterocyclylene 
                 —O— 
                 carbocyclylene 
               
               
                 257 
                 —O— 
                 —N(R 5 )— 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 258 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 259 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 260 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 261 
                 —O— 
                 carbocyclylene 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 262 
                 —O— 
                 heterocyclylene 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 263 
                 —O— 
                 —N(R 5 )— 
                 —C(O)— 
                 carbocyclylene 
               
               
                 264 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 carbocyclylene 
               
               
                 265 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 carbocyclylene 
               
               
                 266 
                 —O— 
                 carbocyclylene 
                 —C(O)— 
                 carbocyclylene 
               
               
                 267 
                 —O— 
                 heterocyclylene 
                 —C(O)— 
                 carbocyclylene 
               
               
                 268 
                 —O— 
                 —(CH 2 ) k — 
                 —C(S)— 
                 carbocyclylene 
               
               
                 269 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
                 carbocyclylene 
               
               
                 270 
                 —O— 
                 carbocyclylene 
                 —C(S)— 
                 carbocyclylene 
               
               
                 271 
                 —O— 
                 heterocyclylene 
                 —C(S)— 
                 carbocyclylene 
               
               
                 272 
                 —O— 
                 —N(R 5 )— 
                 —S(O) l — 
                 carbocyclylene 
               
               
                 273 
                 —O— 
                 —(CH 2 ) k — 
                 —S(O) l — 
                 carbocyclylene 
               
               
                 274 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
                 carbocyclylene 
               
               
                 275 
                 —O— 
                 carbocyclylene 
                 —S(O) l — 
                 carbocyclylene 
               
               
                 276 
                 —O— 
                 heterocyclylene 
                 —S(O) l — 
                 carbocyclylene 
               
               
                 277 
                 —O— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 278 
                 —O— 
                 —C(O)— 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 279 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 280 
                 —O— 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 281 
                 —O— 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 282 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 283 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 284 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 285 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 286 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 287 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 288 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
                 carbocyclylene 
               
               
                 289 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
                 carbocyclylene 
               
               
                 290 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 carbocyclylene 
               
               
                 291 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 carbocyclylene 
               
               
                 292 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
                 carbocyclylene 
               
               
                 293 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
                 carbocyclylene 
               
               
                 294 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 carbocyclylene 
               
               
                 295 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 carbocyclylene 
               
               
                 296 
                 —O— 
                 —(CH 2 ) k — 
                 —O— 
                 heterocyclylene 
               
               
                 297 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 heterocyclylene 
               
               
                 298 
                 —O— 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
               
               
                 299 
                 —O— 
                 heterocyclylene 
                 —O— 
                 heterocyclylene 
               
               
                 300 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 301 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 302 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 303 
                 —O— 
                 carbocyclylene 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 304 
                 —O— 
                 heterocyclylene 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 305 
                 —O— 
                 —N(R 5 )— 
                 —C(O)— 
                 heterocyclylene 
               
               
                 306 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 heterocyclylene 
               
               
                 307 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 heterocyclylene 
               
               
                 308 
                 —O— 
                 carbocyclylene 
                 —C(O)— 
                 heterocyclylene 
               
               
                 309 
                 —O— 
                 heterocyclylene 
                 —C(O)— 
                 heterocyclylene 
               
               
                 310 
                 —O— 
                 —(CH 2 ) k — 
                 —C(S)— 
                 heterocyclylene 
               
               
                 311 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
                 heterocyclylene 
               
               
                 312 
                 —O— 
                 carbocyclylene 
                 —C(S)— 
                 heterocyclylene 
               
               
                 313 
                 —O— 
                 heterocyclylene 
                 —C(S)— 
                 heterocyclylene 
               
               
                 314 
                 —O— 
                 —N(R 5 )— 
                 —S(O) l — 
                 heterocyclylene 
               
               
                 315 
                 —O— 
                 —C(O)— 
                 —S(O) l — 
                 heterocyclylene 
               
               
                 316 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
                 heterocyclylene 
               
               
                 317 
                 —O— 
                 carbocyclylene 
                 —S(O) l — 
                 heterocyclylene 
               
               
                 318 
                 —O— 
                 heterocyclylene 
                 —S(O) l — 
                 heterocyclylene 
               
               
                 319 
                 —O— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 320 
                 —O— 
                 —C(O)— 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 321 
                 —O— 
                 —(CH 2 ) k — 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 322 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 323 
                 —O— 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 324 
                 —O— 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 325 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 326 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 327 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 328 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 329 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 330 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 331 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
                 heterocyclylene 
               
               
                 332 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
                 heterocyclylene 
               
               
                 333 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 heterocyclylene 
               
               
                 334 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 heterocyclylene 
               
               
                 335 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
                 heterocyclylene 
               
               
                 336 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
                 heterocyclylene 
               
               
                 337 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 heterocyclylene 
               
               
                 338 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 heterocyclylene 
               
               
                 339 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
                 —O— 
               
               
                 340 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —O— 
               
               
                 341 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
                 —O— 
               
               
                 342 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
                 —O— 
               
               
                 343 
                 carbocyclylene 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 344 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 345 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
               
               
                 346 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
                 —N(R 5 )— 
               
               
                 347 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
                 —N(R 5 )— 
               
               
                 348 
                 carbocyclylene 
                 —O— 
                 —N(R 5 )— 
                 —C(O)— 
               
               
                 349 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
               
               
                 350 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 351 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
                 —C(O)— 
               
               
                 352 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
                 —C(O)— 
               
               
                 353 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
                 —C(S)— 
               
               
                 354 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(S)— 
               
               
                 355 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
                 —C(S)— 
               
               
                 356 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
                 —C(S)— 
               
               
                 357 
                 carbocyclylene 
                 —O— 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 358 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 359 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —S(O) l — 
               
               
                 360 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
                 —S(O) l — 
               
               
                 361 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
                 —S(O) l — 
               
               
                 362 
                 carbocyclylene 
                 —O— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 363 
                 carbocyclylene 
                 —O— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 364 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
               
               
                 365 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
                 —(CH 2 ) k — 
               
               
                 366 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 367 
                 carbocyclylene 
                 —O— 
                 —N(R 5 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 368 
                 carbocyclylene 
                 —O— 
                 —C(O)— 
                 —C(R 6 )(R 7 )— 
               
               
                 369 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
               
               
                 370 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
               
               
                 371 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 372 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
                 —C(R 6 )(R 7 )— 
               
               
                 373 
                 carbocyclylene 
                 —O— 
                 —N(R 5 )— 
                 carbocyclylene 
               
               
                 374 
                 carbocyclylene 
                 —O— 
                 —C(O)— 
                 carbocyclylene 
               
               
                 375 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 376 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                 377 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
                 carbocyclylene 
               
               
                 378 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
                 carbocyclylene 
               
               
                 379 
                 carbocyclylene 
                 —O— 
                 —N(R 5 )— 
                 heterocyclylene 
               
               
                 380 
                 carbocyclylene 
                 —O— 
                 —C(O)— 
                 heterocyclylene 
               
               
                 381 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
               
               
                 382 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
               
               
                 383 
                 carbocyclylene 
                 —O— 
                 carbocyclylene 
                 heterocyclylene 
               
               
                 384 
                 carbocyclylene 
                 —O— 
                 heterocyclylene 
                 heterocyclylene 
               
               
                   
               
            
           
         
       
     
     Particular examples of -Y 1 -Y 2 -Y 3 -Y 4 - are given in Table 13: 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 13 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
                 Y 4   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —O— 
               
               
                 2 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —O— 
               
               
                 3 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 4 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 5 
                 —O— 
                 —C(H 2 ) k — 
                 —O— 
                 —C(O)— 
               
               
                 6 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —C(O)— 
               
               
                 7 
                 carbocyclylene 
                 —O— 
                 —C(H 2 ) k — 
                 —C(O)— 
               
               
                 8 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 9 
                 carbocyclylene 
                 —O— 
                 —C(H 2 ) k — 
                 carbocyclylene 
               
               
                 10 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
               
               
                   
               
            
           
         
       
     
     Further particular examples of -Y 1 -Y 2 -Y 3 -Y 4 - are given in Table 14: 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 14 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
                 Y 4   
               
               
                   
               
             
            
               
                 1 
                 —O— 
                 —CH 2 — 
                 —C(O)— 
                 —O— 
               
               
                 2 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —O— 
               
               
                 3 
                 —O— 
                 —CH 2 — 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 4 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 5 
                 —O— 
                 —C(H 2 ) 2 — 
                 —O— 
                 —C(O)— 
               
               
                 6 
                 phenylene 
                 —O— 
                 —C(H 2 ) k — 
                 —C(O)— 
               
               
                 7 
                 phenylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
               
               
                 8 
                 phenylene 
                 —O— 
                 —C(H 2 ) k — 
                 phenylene 
               
               
                 9 
                 phenylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 phenylene 
               
               
                   
               
            
           
         
       
     
     Examples of the linker -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 - are given in Table 15: 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 15 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
                 Y 4   
                 Y 5   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 2 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 3 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 4 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 5 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 6 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 7 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 8 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 9 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 10 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 11 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 12 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 13 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 14 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 15 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 16 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 17 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 18 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 19 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 20 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 21 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 22 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 23 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 24 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 25 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 26 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 27 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 28 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 29 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 30 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 31 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 32 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 33 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 34 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 35 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 36 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 37 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 38 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 39 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 40 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 41 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 42 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 43 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 44 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 45 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —N(R 5 )— 
                 —S(O) l — 
               
               
                 46 
                 —O— 
                 —(CH 2 )k 
                 —O— 
                 —C(O)— 
                 —O— 
               
               
                 47 
                 —O— 
                 —(CH 2 )k 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 48 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 49 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 50 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 51 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 52 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 53 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 54 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 55 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
               
               
                 56 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 57 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 58 
                 —O— 
                 —(CH 2 ) k — 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 59 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 60 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 61 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 62 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 63 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 carbocyclylene 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 64 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 heterocyclylene 
                 —(CH 2 ) k — 
                 —S(O) l — 
               
               
                 65 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —O— 
               
               
                 66 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                   
               
            
           
         
       
     
     Particular examples of -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 - are given in Table 16: 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 16 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
                 Y 4   
                 Y 5   
               
               
                   
               
             
            
               
                 1 
                 —O— 
                 —(CH 2 ) 2 — 
                 —O— 
                 —C(O)— 
                 —O— 
               
               
                 2 
                 —O— 
                 —(CH 2 ) 2 — 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 3 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —CH 2 — 
                 —O— 
                 —C(O)— 
               
               
                 4 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —CH 2 — 
                 —O— 
                 —C(O)— 
               
               
                 5 
                 phenylene 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —O— 
               
               
                 6 
                 phenylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                   
               
            
           
         
       
     
     Examples of -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6  are given in Table 17: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 17 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
                 Y 4   
                 Y 5   
                 Y 6   
               
               
                   
               
             
            
               
                 1 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —O— 
                 —C(O)— 
                 —O— 
               
               
                 2 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                 3 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —N(R 5 )— 
                 heterocyclylene 
                 —(CH 2 ) k — 
               
               
                 4 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
                 —N(R 5 )— 
               
               
                 5 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —C(O)— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 6 
                 —O— 
                 —(CH 2 ) k — 
                 heterocyclylene 
                 —C(O)— 
                 —(CH 2 ) k — 
                 carbocyclylene 
               
               
                 7 
                 carbocyclylene 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 8 
                 carbocyclylene 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —C(O)— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                   
               
            
           
         
       
     
     Particular examples of -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 - are given in Table 18: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 18 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
                 Y 4   
                 Y 5   
                 Y 6   
               
               
                   
               
             
            
               
                 1 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —CH 2 — 
                 —O— 
                 —C(O)— 
                 —O— 
               
               
                 2 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —CH 2 — 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
               
               
                   
               
            
           
         
       
     
     Further particular examples of -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 - are given in Table 19: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 19 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
                 Y 4   
                 Y 5   
                 Y 6   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 —O— 
                 —CH(phenyl)- 
                 —CH 2 — 
                 —O— 
                 —C(O)— 
                 —O— 
               
               
                 2 
                 —O— 
                 —CH(phenyl)- 
                 —CH 2 — 
                 —O— 
                 —C(O)— 
                 —NH— 
               
               
                   
               
            
           
         
       
     
     Examples of -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 - are given in Table 20: 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 20 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
                 Y 4   
                 Y 5   
                 Y 6   
                 Y 7   
               
               
                   
               
             
            
               
                 1 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —O— 
                 —C(O)— 
                 —O— 
                 —(CH 2 ) k — 
               
               
                 2 
                 —O— 
                 —C(R 6 )(R 7 )— 
                 —(CH 2 ) k — 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                 3 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —(CH 2 ) k — 
                 —C(O)— 
                 —O— 
               
               
                 4 
                 —O— 
                 —(CH 2 ) k — 
                 —C(R 6 )(R 7 )— 
                 —O— 
                 —C(O)— 
                 —N(R 5 )— 
                 —(CH 2 ) k — 
               
               
                   
               
            
           
         
       
     
     Particular examples of -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 - are given in Table 21: 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 21 
               
               
                   
               
               
                 No. 
                 Y 1   
                 Y 2   
                 Y 3   
                 Y 4   
                 Y 5   
                 Y 6   
                 Y 7   
               
               
                   
               
             
            
               
                 1 
                 —O— 
                 —CH(R 7 )— 
                 —CH 2 — 
                 —O— 
                 —C(O)— 
                 —O— 
                 —CH 2 — 
               
               
                 2 
                 —O— 
                 —CH(R 7 )— 
                 —CH 2 — 
                 —O— 
                 —C(O)— 
                 —NH— 
                 —CH 2 — 
               
               
                 3 
                 —O— 
                 —CH(phenyl)- 
                 —CH 2 — 
                 —O— 
                 —C(O)— 
                 —O— 
                 —CH 2 — 
               
               
                 4 
                 —O— 
                 —CH(phenyl)- 
                 —CH 2 — 
                 —O— 
                 —C(O)— 
                 —NH— 
                 —CH 2 — 
               
               
                   
               
            
           
         
       
     
     With regard to Tables 2 to 21, where —(CH 2 ) k — is mentioned it is often —CH 2 — or —(CH 2 ) 2 —. 
     Where —N(R 5 )— is mentioned, it is often —NH—, —N(CH 3 )— or —N(benzyl)-. 
     Where —S(O) l — is mentioned, it may be —S—, —S(O)— or —S(O) 2 —. 
     Where —C(R 6 )(R 7 )— is mentioned, R 6  is usually selected from hydrogen, C 1-6  alkyl or —C(O)O—C 1-6  alkyl; and R 7  is usually C 1-6  alkyl, —(CH 2 ) j -carbocyclyl or —(CH 2 ) j -heterocyclyl. In particular, R 6  may be hydrogen or C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and R 7  may be C 1-6  alkyl, —(CH 2 ) k -cycloalkyl, —(CH 2 ) j -aryl or —(CH 2 ) j -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . Index j is often 0 or 1, e.g. 0. Thus, in particular in the relevant examples given in Tables 2 to 21, —C(R 6 )(R 7 )— may be —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH(phenyl)- or —C(CH 3 )(phenyl)-, wherein the methyl or phenyl parts are optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Where carbocyclylene is mentioned, it may be substituted with 1, 2, 3, 4 or 5 R 11 . Carbocyclylene is usually cycloalkylene (e.g. cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene) or arylene (e.g. phenylene or naphthylene), either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Where heterocyclylene is mentioned, it may be substituted with 1, 2, 3, 4 or 5 R 11 . Heterocyclylene may be selected from oxiranylene, azirinylene, 1,2-oxathiolanylene, imidazolylene, thienylene, furylene, tetrahydrofurylene, pyranylene, thiopyranylene, thianthrenylene, isobenzofuranylene, benzofuranylene, chromenylene, 2H-pyrrolylene, pyrrolylene, pyrrolinylene, pyrrolidinylene, imidazolylene, imidazolidinylene, benzimidazolylene, pyrazolylene, pyrazinylene, pyrazolidinylene, pyranyol, thiazolylene, isothiazolylene, dithiazolylene, oxazolylene, isoxazolylene, pyridylene, pyrazinylene, pyrimidinylene, piperidylene, especially piperidin-1-ylene, piperazinylene, especially piperazin-1-ylene, pyridazinylene, morpholinylene, especially morpholino, thiomorpholinylene, especially thiomorpholino, indolizinylene, isoindolylene, 3H-indolylene, indolylene, benzimidazolylene, cumarylene, indazolylene, triazolylene, tetrazolylene, purinylene, 4H-quinolizinylene, isoquinolylene, quinolylene, tetrahydroquinolylene, tetrahydroisoquinolylene, decahydroquinolylene, octahydroisoquinolylene, benzofuranylene, dibenzofuranylene, benzothiophenylene, dibenzothiophenylene, phthalazinylene, naphthyridinylene, quinoxalylene, quinazolinylene, quinazolinylene, cinnolinylene, pteridinylene, carbazolylene, β-carbolinylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene, furazanylene, phenazinylene, phenothiazinylene, phenoxazinylene, chromenylene, isochromanylene and chromanylene, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Where alkyl, phenyl, benzyl and phenylene are mentioned, they may be substituted with 1, 2, 3, 4 or 5 R 11 . 
     Included in the invention are linkers which comprise the structure: 
     
       
         
         
             
             
         
       
     
     linked to ring AB through the terminal oxygen. R 7  is as previously described, e.g. C 1-6  alkyl, —(CH 2 ) k -cycloalkyl, —(CH 2 ) k -cycloalkenyl, —(CH 2 ) j -aryl or —(CH 2 ) j -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 , e.g. halo. In particular embodiments, R 7  is a 5- or 6-membered ring, particularly carbocyclic ring, or such a ring substituted by 1, 2, 3, 4 or 5 R 11 , e.g. halo; in either case, the carbocyclic ring may be phenyl but in other embodiments is a wholly or partially saturated analogue thereof. The invention includes compounds which have a linker of said structure and in which n is 1. The invention further includes compounds which have exactly one linker of said structure. 
     Particular linkers comprise or consist of, e.g. consist of, the structure: 
     
       
         
         
             
             
         
       
     
     linked to ring AB through the terminal oxygen. J is O, S, CH 2  or NR 40 , where R 40  is selected from H, hydroxy, C 18  aliphatic (e.g. alkyl having 1, 2, 3 or 4 carbon atoms) optionally substituted by halogen (e.g. methyl or halomethyl, as an example of the latter of which trifluoromethyl may be mentioned). In embodiments, R 40  is H. J is in particular O and in many compounds J is O and R 40  is H. R 7  is as described in the preceding paragraph. The invention includes compounds which have a linker of said structure and in which n is 1. The invention further includes compounds which have exactly one linker of said structure. 
     R 4    
     R 4  is present when n is 1 or 2 and is hydrogen, except when Y is a bond; or is hydrocarbyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . Where n is 2, the R 4  moieties may be the same or different. 
     In one embodiment, the or each R 4  is independently selected from hydrogen (except when Y is a bond); C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; carbocyclyl (e.g. cycloalkyl or aryl) optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and heterocyclyl (e.g. heterocycloalkyl or heteroaryl) optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazole, quinolyl, isoquinolyl, benzoxazole, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with at least one organic or inorganic substituent, e.g. 1, 2, 3, 4 or 5 R 11 . 
     Exemplary carbocycles include those shown in Table 22 below, any of which may be substituted. In embodiments and without limitation, the carbocycles are substituted with 1, 2, 3, 4 or 5 R 11 . 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 22 
               
               
                   
                   
               
               
                   
                 No 
                 R 4   
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
            
           
         
       
     
     Also to be mentioned are wholly or partially saturated analogues of the unsaturated carbocycles in Table 22. Structures 1-4 and 6-9 of Table 22 form one embodiment of the invention. 
     Exemplary heterocycles include those shown in Table 23 below, any of which may be substituted. In embodiments and without limitation, the carbocycles are substituted with 1, 2, 3, 4 or 5 R 11 . 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 23 
               
               
                   
                   
               
               
                   
                 No 
                 R 4   
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 49 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 50 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 53 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 54 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 55 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 56 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 60 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 62 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 63 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 64 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 65 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 66 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 67 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 68 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 69 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
            
           
         
       
     
     When R 4  is carbocyclyl or heterocyclyl, it may in principle be bound to Y (or, when Y is a bond, Ring A) at any available position on the ring. Thus, for example, when R 4  is thiophenyl it may be attached to Y or Ring A at any of the 2-, 3-, 4- or 5-positions. 
     In some compounds, when R 4  is substituted by 1, 2, 3, 4 or 5 R 11 , the or each R 11  is independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 2 , —C(O)R 2 , —C(O)OR 2 , —OC(O)R 2 , —N(R 2 )R 13 , —C(O)N(R 2 )R 3 , —S(O) l R 2 , —S(O) l N(R 2 )R 3 , —C(R 2 ) 3  and R 4 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl), —(CH 2 ) j -heterocyclyl where heterocyclyl is a saturated or unsaturated heterocyclic ring (for example heteroaryl, e.g. pyridinyl or thiophenyl, or heterocycloalkyl, e.g. piperazinyl, piperadinyl, pyrrolidinyl or morpholinyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy, C 1-6  alkoxy, amino, mono- or di-alkylamino, C 1-6  haloalkyl (e.g. trifluoromethyl) or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), and of these substituents may particularly be mentioned halogen (e.g. fluorine or chlorine), hydroxy, or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is in some compounds selected from C 1 -C 6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) i —O—(CH 2 ) j -heteroalkyl, —(CH 2 ) i —O—(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) i —O—(CH 2 ) j -heterocyclyl (e.g. piperazinyl, pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). In particular, R 14  is often selected from C 1 -C 6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. piperazinyl, pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     In a class of compounds comprising individual exemplary compounds presented later in this specification, R 11  as a substituent of R 4 , especially when R 4  is carbocyclyl or heterocyclyl, is C 1 -C 6  alkyl (e.g. methyl); F; Cl; trifluoromethyl; cyano; nitro; hydroxy; hydroxy(C 1 -C 6 )alkyl; —(CH 2 ) j —NR y R z  where R y  and R z  are independently selected from H, C 1 -C 6  alkyl and, less frequently, —OH (e.g. both are H or both are methyl); C 1 -C 6  alkoxy (e.g. methoxy); C 1 -C 6  alkylthio; alkoxyalkyl having from 2 to 8 carbon atoms (e.g. methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl); alkylcarbonyl of which the alkyl part (i) is unsubstituted or is substituted by 1, 2, 3, 4 or 5 halogens or by hydroxy and (ii) has from 1 to 6 carbon atoms (e.g. acetyl); —(CH 2 ) j —N(R w )C(O)alkyl where R w  is H or C 1 -C 6  alkyl; —(O) u —(CH 2 ) j -heterocyclyl where u is 0 or 1 and heterocyclyl is a 5- or 6-membered saturated or unsaturated heterocycle, e.g. piperazinyl, piperidinyl, morpholinyl, pyridinyl; —(O) u —(CH 2 ) j -carbocyclyl where u is 0 or 1 and carbocyclyl is a 5- or 6-membered saturated or unsaturated carbocycle, e.g. phenyl or cyclohexyl; —C(O)—(CH 2 ) j -carbocyclyl or —C(O)—(CH 2 ) j -heterocyclyl where and heterocyclyl are as earlier described in this paragraph; —(CH 2 ) j —S(O) 2 NH-carbocyclyl or —(CH 2 ) j —S(O) 2 NH-heterocyclyl where g, carbocyclyl and heterocyclyl are as earlier described in this paragraph; —(CH 2 ) j —S(O) 2 NR y R z ; —(CH 2 ) j —S(O) 2 NHCOOH; —S(O) 2 NHCOOalkyl where alkyl has from 1 to 6 carbon atoms (e.g. methyl); —(CH 2 ) j —S(O) 2 -alkyl where alkyl has from 1 to 6 carbon atoms (e.g. methyl); —(CH 2 ) j —NR y S(O) 2 -alkyl where alkyl has from 1 to 6 carbon atoms (e.g. methyl); —NR y C(O)-alkyl where alkyl has from 1 to 6 carbon atoms (e.g. methyl); —(CH 2 ) j —OC(O)NR y R z ; —(CH 2 ) j —NR w C(O)NR y R z ; and —(CH 2 ) j —C(O)NR y R z . The value of j in the groups mentioned in this paragraph is 0, 1, 2, 3, 4, 5 or 6 and is 0 in some embodiments; in other embodiments it is 1 or 2, e.g. 1. The carbocyclyl and heterocyclyl groups mentioned in this paragraph as comprised within an R 11  group may be unsubstituted or substituted by 1, 2, 3, 4 or 5 cycle-free R 11  moieties, e.g. by one or two such moieties; often no more than one such substituent contains more than four multivalent atoms. 
     Typically, when R 4  is carbocyclyl or heterocyclyl, it has 0, 1, 2, 3 or 4 substituents; often no more than one such substituent contains more than four multivalent atoms. Thus in one embodiment, all substituent(s) (if there are any) have 0, 1, 2, 3 or 4 multivalent atoms (e.g. 0-3). In another embodiment, there is a single substituent which has more than 4 multivalent atoms whilst any other substituents have 0, 1, 2, 3 or 4 multivalent atoms; in a sub-class there is a single substituent which has more than 3 multivalent atoms whilst any other substituents have 0, 1, 2 or 3. 
     Compounds in which n is 0 
     In one class of compounds, n is 0. 
     Embodiments of Formulae (I) to (VII) in which n is 0 include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In the above embodiments, R 3  is usually 1 or 2, and R 3  is typically selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 —C(O)N(R 12 )R 13 , —S(O)R 12 , —C(R 12 ) 3  and R 14 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     Compounds in which n is 1 
     In another class of compounds, n is 1. 
     Embodiments of Formulae (I) to (VII) in which n is 1 include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (V, 1) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VI, 1) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VII, 1) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In the above embodiments, R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazole, quinolyl, isoquinolyl, benzoxazole, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Also, m is usually 0 or 1, and R 3  is typically selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 2 , —C(O)R 2 , —C(O)OR 12 , —OC(O)R 2 , —N(R 2 )R 3 , —C(O)N(R 2 )R 3 , —S(O) l R 2 , —C(R 2 ) 3  and R 4 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     Compounds in which n is 1 and Y is a bond 
     In one embodiment, n is 1 and Y is a bond. 
     Embodiments of Formulae (I) to (VII) in which n is 1 and Y is a bond include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (V, 1, 0) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VI, 1, 0) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VII, 1, 0) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In the above embodiments, R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     A particular embodiment of Formula (VII, 1, 0) is a compound of Formula (VIII): 
     
       
         
         
             
             
         
       
         
         
           
             wherein t is 0, 1, 2, 3, 4 or 5; 
             or a pharmaceutically acceptable salt of prodrug thereof. 
           
         
       
    
     Particular embodiments of Formula (VIII) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     With regard to Formula (VIII), t is usually 0, 1 or 2, and R 11  is typically independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —R 12 , —C(O)R 12 , —C(O)R 12 , —OC(O)R 12 , N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     With regard to the various embodiments described in this section, m is usually 0 or 1, and R 3  is typically selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     Compounds in which n is 1 and Y is Y 1    
     In another embodiment, n is 1 and Y is Y 1 . 
     Embodiments of Formulae (I) to (VII) in which n is 1 and Y is Y 1  include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (V, 1, 1) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VI, 1, 1) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VII, 1, 1) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Y 1  may be as defined in any of Tables 2, 3 and 4, and is, in particular, —O— or —C≡C—. 
     A particular embodiment of Formula (VII, 1, 1) is a compound of Formula (IX): 
     
       
         
         
             
             
         
       
         
         
           
             or a pharmaceutically acceptable salt of prodrug thereof. 
           
         
       
    
     Embodiments of Formula (IX) include those shown below, and pharmaceutically acceptable salts and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Another particular embodiment of Formula (VII, 1, 1) is a compound of Formula (X): 
     
       
         
         
             
             
         
       
         
         
           
             or a pharmaceutically acceptable salt of prodrug thereof. 
           
         
       
    
     Embodiments of Formula (X) include those shown below, and pharmaceutically acceptable salts and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In one embodiment of Formula (X), R 4  is other than methyl. 
     With regard to the various embodiments described in this section, R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Also, m is usually 0 or 1, and R 3  is typically independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     Compounds in which n is 1 and Y is -Y 1 -Y 2 -. 
     In another embodiment, n is 1 and Y is -Y 1 -Y 2 . 
     Embodiments of Formulae (I) to (VII) in which n is 1 and Y is -Y 1 -Y 2  include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (V, 1, 2) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VI, 1, 2) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VII, 1, 2) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In the above embodiments, -Y 1 -Y 2 - may be as defined in any of Tables 5, 6 and 7, and is in particular —O—CH 2 — or —O—CH(R 7 )—. In a particular class of compounds, -Y 1 -Y 2 - is other than —O—C(O)— or —S—C(O)—. 
     A particular embodiment of Formula (VII, 1, 2) is a compound of Formula (XI): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 21  is hydrogen or R 7 ; 
             or a pharmaceutically acceptable salt of prodrug thereof. 
           
         
       
    
     Embodiments of Formula (XI) include those shown below, and pharmaceutically acceptable salts and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     With regard to Formula (XI), R 21  is typically hydrogen or is selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . More usually, R 21  is hydrogen, or is C 1-6  alkyl (e.g. methyl or ethyl) or phenyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     With regard to the various embodiments described in this section, R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Also, m is usually 0 or 1, and R 3  is typically independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     Compounds in which n is 1 and y is -Y 1 -Y 2 -Y 3 -. 
     In another embodiment, n is 1 and Y is -Y 1 -Y 2 -Y 3 -. 
     Embodiments of Formulae (I) to (VII) in which n is 1 and Y is -Y 1 -Y 2 -Y 3 - include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (V, 1, 3) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VI, 1, 3) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VII, 1, 3) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In the above embodiments, -Y 1 -Y 2 -Y 3 - may be as defined in any of Tables 8, 9, 10 and 11. 
     A particular embodiment of Formula (VII, 1, 3) is a compound of Formula (XII): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 21  is hydrogen or R 7 ; 
             or a pharmaceutically acceptable salt or prodrug thereof. 
           
         
       
    
     Embodiments of Formula (XII) include the following, and pharmaceutically acceptable salts and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     With regard to Formula (XII), R 6  is usually hydrogen and R 21  is typically hydrogen or is selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . More usually, R 6  is hydrogen and R 21  is hydrogen, or is C 1-6  alkyl (e.g. methyl or ethyl) or phenyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     With regard to the various embodiments described in this section, R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Also, m is usually 0 or 1, and R 3  is typically independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     Compounds in which n is 1 and Y is -Y 1 -Y 2 -Y 3 -Y 4 - 
     In another embodiment, n is 1 and Y is -Y 1 -Y 2 -Y 3 -Y 4 -. 
     Embodiments of Formulae (I) to (VII) in which n is 1 and Y is -Y 1 -Y 2 -Y 3 -Y 4 - include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (V, 1, 4) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VI, 1, 4) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VII, 1, 4) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In the above embodiments, -Y 1 -Y 2 -Y 3 -Y 4 - may be as defined in any of Tables 12, 13 and 14. 
     A particular embodiment of Formula (VII, 1, 4) is a compound of Formula (XIII): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 21  is hydrogen or R 7 ; 
             or a pharmaceutically acceptable salt or prodrug thereof. 
           
         
       
    
     Embodiments of Formula (XIII) include the following, and pharmaceutically acceptable salts and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     With regard to Formula (XIII), Y 4  is often —O—, —N(R 5 )— (e.g. —NH—) or —CH 2 —. R 6  is usually hydrogen and R 21  is typically hydrogen or is selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . More usually, R 6  is hydrogen and R 21  is hydrogen, or is C 1-6  alkyl (e.g. methyl or ethyl) or phenyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     With regard to the various embodiments described in this section, R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Also, m is usually 0 or 1, and R 3  is typically independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     Compounds in which n is 1 and Y is -Y 1 -Y 1 -Y 3 -Y 4 -Y 5 - 
     In another embodiment, n is 1 and Y is -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -. 
     Embodiments of Formulae (I) to (VII) in which n is 1 and Y is -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 - include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (V, 1, 5) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VI, 1, 5) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VII, 1, 5) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In the above embodiments, -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 - may be as defined in Table 15 or Table 16. 
     A particular embodiment of Formula (VII, 1, 5) is a compound of Formula (XIV): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 21  is hydrogen or R 7 ; 
             or a pharmaceutically acceptable salt or prodrug thereof. 
           
         
       
    
     Embodiments of Formula (XIV) include the following, and pharmaceutically acceptable salts and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In compounds of Formula (XIV), Y 4  is often —O—, —N(R 5 )— (e.g. —NH—) or —CH 2 —; and Y 5  is typically —CH 2 —, carbocyclylene or heterocyclylene, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     A further embodiment of Formula (VII, 1, 5) is a compound of Formula (XV): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 21  is hydrogen or R 7 ; 
             or a pharmaceutically acceptable salt or prodrug thereof. 
           
         
       
    
     Embodiments of Formula (XV) include the following, and pharmaceutically acceptable salts and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     With regard to Formulae (XIV) and (XV), R 6  is usually hydrogen and R 21  is typically hydrogen or is selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . More usually, R 6  is hydrogen and R 21  is hydrogen, or is C 1-6  alkyl (e.g. methyl or ethyl) or phenyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     With regard to the various embodiments described in this section, R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Also, m is usually 0 or 1, and R 3  is typically independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     Compounds in which n is 1 and Y is -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 - 
     In another embodiment, n is 1 and Y is -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 . 
     Embodiments of Formulae (I) to (VII) in which n is 1 and Y is -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 - include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (V, 1, 6) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VI, 1, 6) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VII, 1, 6) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     In the above embodiments, -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 - may be as defined in any of Tables 17, 18 and 19. 
     A particular embodiment of Formula (VII, 1, 6) is a compound of Formula (XVI): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 21  is hydrogen or R 7 ; 
             or a pharmaceutically acceptable salt or prodrug thereof. 
           
         
       
    
     Embodiments of Formula (XVII) include the following, and pharmaceutically acceptable salts and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     With regard to Formula (XVI), Y 4  and Y 6  are typically each independently —O— or —N(R 5 )— (e.g. —NH)—. R 6  is usually hydrogen and R 21  is typically hydrogen or is selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . More usually, R 6  is hydrogen and R 21  is hydrogen, or is C 1-6  alkyl (e.g. methyl or ethyl) or phenyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     With regard to the various embodiments described in this section, R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Also, m is usually 0 or 1, and R 3  is typically independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —N(R 12 )R 13 , —C(O)N(R 12 )R 13 , —S(O) l R 12 , —C(R 12 ) 3  and R 14 . In this case, R 12  and R 13  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R 14  is often selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) j -aryl (e.g. phenyl or benzyl) and —(CH 2 ) j -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     Compounds in which n is 2 
     In another class of compounds, n is 2. 
     Embodiments of Formulae (I) to (VII) in which n is 2 include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     [The labels “a” and “b” are used to distinguish between each Y] 
     Particular embodiments of Formula (V, 2) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VI, 2) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Particular embodiments of Formula (VII, 1) include those shown below, and pharmaceutically acceptable salts or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     Of particular mention are compounds of Formulae (V, 2.5), (VI, 2.5) and (VII, 2.5), in which —Y, —R 4  and -Y b -R 4  may be the same or different. 
     In the above embodiments, Y a  and Y b  may each be independently a bond or a linker, in particular a linker selected from:
         -Y 1 -;   -Y 1 -Y 2 -;   -Y 1 -Y 2 -Y 3 -;   -Y 1 -Y 2 -Y 3 -Y 4 ;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -;   -Y 1 -Y 2 -Y 3 -Y 4 - Y 5 -Y 6 -;   -Y 1 -Y 2 -Y 3 -Y 4 - Y 5 -Y 6 -Y 7 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -;   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -Y 9 -; and   -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -Y 9 -Y 10 -,       

     In particular, Y a  and Y b  may each be independently selected from any of the options defined in Tables 2 to 21. 
     With regard to the various embodiments described in this section, R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Compounds in which n is 1 and Y is —O—C(R 22 )(R 23 )—Y′- 
     Also of mention are compounds of the following formula: 
     
       
         
         
             
             
         
       
     
     wherein
         Y′ is a bond or a linker having 1 to 18 (e.g. 1 to 10) in-chain atoms (e.g. selected from C, N, O and S) and comprising, for example, one or more linkages selected from —O—, —N(R 5 )—, —C(O)—, —C(S)—, —S(O) l —, —(CH 2 ) k —, —C(R 6 )(R 7 )—, —C(R 5 )═C(R 5 )—, —C≡C—, carbocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 , and heterocyclylene optionally substituted with 1, 2, 3, 4 or 5 R 11 ;   R 22  is carbocyclyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and   R 23  is independently selected from R 8 , —OR 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —N(R 9 )R 10 , —C(O)N(R 9 )R 10 , —S(O) l R 8  and —C(R 8 ) 3 ;
 
or a pharmaceutically acceptable salt or prodrug thereof.
       

     The invention therefore includes compounds of the following formulae: 
     
       
         
         
             
             
         
       
     
     or, in each case, a pharmaceutically acceptable salt or prodrug thereof. 
     In particular, the invention includes compounds of the following formulae: 
     
       
         
         
             
             
         
       
     
     or, in each case, a pharmaceutically acceptable salt or prodrug thereof. 
     Of particular mention is a compound of the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof. 
     With regard to said compounds, R 22  is carbocyclyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . In certain compounds, R 22  is carbocyclyl, for example, selected from cycloalkyl (e.g. cyclopropyl or cyclohexyl) and aryl (e.g. phenyl or naphthyl), either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . In other compounds, R 22  is heterocyclyl, for example, selected from morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . Often, R 22  is monocyclic carbocyclyl or monocyclic heterocyclyl, e.g. containing 3, 4, 5, 6 or 7 ring atoms. In particular compounds, R 22  is selected from phenyl, cyclopropyl or pyridinyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . Of particular mention are compounds in which R 22  is unsubstituted phenyl or phenyl optionally substituted with 1, 2 or 3 substituents independently selected from hydroxy, C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl) and C 1-6  alkoxy (e.g. C 1 , C 2 , C 3  or C 4  alkoxy) and up to 5 halogens (e.g. fluorine or chlorine), wherein alkyl and the alkyl part of alkoxy are unsubstituted or are substituted by halogen, e.g. F or Cl, for example by 1, 2, 3, 4 or 5 halogens. 
     In certain compounds, R 23  is hydrogen or C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl) optionally substituted with 1, 2, 3, 4 or 5 R 11 . R 23  is often hydrogen. 
     Of mention are compounds in which R 22  is selected from phenyl, cyclopropyl and pyridinyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and R 23  is hydrogen or C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl) optionally substituted with 1, 2, 3, 4 or 5 R 11 . Of particular mention are compounds in which R 22  is phenyl optionally substituted with 1, 2, 3, 4 or 5 R 11 , and R 23  is hydrogen. 
     In a further embodiment, the invention provides a compound of the following formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein t is 0, 1, 2, 3, 4 or 5;
 
or a pharmaceutically acceptable salt or prodrug thereof. In a class of compounds, R 11  is halogen, e.g. F or Cl; in some compounds, R 11  is additionally selected from C 1-4  alkyl or C 1-4  alkoxy, optionally substituted in each case by up to 5 halogens.
 
           
         
       
    
     Thus, the invention includes compounds of the following formulae: 
     
       
         
         
             
             
         
       
     
     or, in each case, a pharmaceutically acceptable salt or prodrug thereof. 
     In particular, the invention includes compounds of the following formulae: 
     
       
         
         
             
             
         
       
     
     or, in each case, a pharmaceutically acceptable salt or prodrug thereof. 
     Of particular mention is a compound of the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof. 
     With regard to the above compounds, Y′ may, for example, contain at least one linkage selected from —O—, —N(R 5 )—, —C(O)—, —S(O) l —, —(CH 2 ) k — and —C(R 6 )(R 7 )—. In embodiments, Y contains at least two or said linkages, for example two, three or four of said linkages. Of mention are compounds in which Y′ comprises at least one —C(O)— linkage. Also of mention are compounds in which Y′ comprises at least one heterocyclylene linkage. Of further mention are compounds in which Y′ comprises two, three, four or five in-chain atoms. 
     In certain compounds, -Y′-R 4  is a group of the following formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             V and W are each independently selected from —O—, —N(R 5 )—, —(CH 2 ) k — and —C(R 6 )(R 7 )—; and 
             d is 1, 2 or 3. 
           
         
       
    
     Exemplary -Y′-R 4  groups include the following: 
     
       
         
         
             
             
         
       
     
     In certain compounds, d is 1 or 2. Of mention are compounds in which d is 1. 
     With regard to the various formulae described in this section, R 4  may, in particular, be selected from C 1-6  alkyl (e.g. C 1 , C 2 , C 3  or C 4  alkyl), cycloalkyl (e.g. cyclopropyl or cyclohexyl), aryl (e.g. phenyl or naphthyl) and heterocyclyl (e.g. morpholinyl, pyridinyl, piperazinyl, benzothiophenyl, thiophenyl, pyrimidinyl, isoxazolyl, furazanyl, furanyl, benzothiazolyl, thiazolyl, pyrrolyl, triazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzofurazanyl, piperidinyl, pyrrolidinyl or 1,4-benzodioxanyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Of mention are compounds in which R 4  is carbocyclyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     Also of mention are compounds in which R 4  comprises a basic moiety, for example a basic nitrogen atom. Said basic moiety may be present in, for example, a carbocyclyl or heterocyclyl group, or in an R 11  substituent. In certain compounds, R 4  is carbocyclyl or heterocyclyl, either of which is substituted with 1, 2, 3, 4 or 5 R 11 , wherein at least one R 11  comprises a basic moiety. Said R 11  may, for example, comprise a basic nitrogen atom. In other compounds, R 4  is heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 11 , wherein said heterocyclyl group comprises at least one basic nitrogen atom. 
     In certain compounds, R 4  is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazole and pyridinyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R 11 . 
     With regard to compounds of said formulae, m is usually 0 or 1. Of mention are compounds in which m is 0. Also of mention are compounds in which m is 1 and R 3  is selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano and nitro. Particular compounds include those in which m is 0 and those in which m is 1 and R 3  is fluorine. 
     Particular Benzothiophene Compounds 
     The symbols used in this section of the specification are as defined in the section. 
     In another aspect, the present invention provides benzothiophene, e.g. amidinobenzothiophene, Factor IXa inhibitors which comprise a substituent at one or both of the 4- and 6-positions, wherein the or each substituent comprises a fragment independently selected from any of Formulae (i) to (vi): 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             R is a moiety comprising an optionally substituted carbocyclic or heterocyclic group; and 
             the oxygen atom on the right hand side of the fragment as drawn is bound directly to the 4- or 6-carbon atom of the benzothiophene ring;
 
or a pharmaceutically acceptable salt or prodrug thereof.
 
           
         
       
    
     In a particular embodiment, the compounds are 2-amidinobenzothiophene compounds. 
     Benzothiophene Ring 
     The 2-, 4- and 6-positions of benzothiophene are indicated below: 
     
       
         
         
             
             
         
       
     
     The benzothiophene ring may comprise one or more other substituents in addition to those mentioned above. The identity and number of any other substituents is not critical to this aspect of the invention. What is critical to this aspect is that the compound, a Factor IXa inhibitor, has the described substituent at one or both of the 4- and 6-positions. In embodiments, the thiophene part of benzothiophene is unsubstituted except for a 2-substituent selected from halo and Formula (A): 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             X is a bond, —NR 30 — or —C(O)—; 
             R 14 , R 15  and R 30  are each independently selected from R 18 , —OR 18 , —C(O)R 18 , —C(O)OR 18 , —OC(O)R 18 , —N(R 18 )R 19 , —C(O)N(R 19 )R 20 —S(O) l R 18  and —C(R 18 ) 3 , e.g. are hydrogen, hydroxy or C 1-6  alkyl; 
             or R 14  and R 15  taken together form ═NR 20 , ═O or ═S; 
             R 16  and R 17  are each independently selected from hydrogen, C 1-6  alkyl, —OR 21  and —NR 18 R 19 ; 
             R 18  and R 19  are each independently selected from hydrogen, R 11 , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; and heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 11 ; 
             R 20  hydrogen, hydroxy, C 1-6  alkoxy or C 1-6  alkyl, e.g. is hydrogen or C 1-6  alkyl; and 
             R 21  is hydrogen or R 7 . 
           
         
       
    
     In one embodiment of Formula (A), X is a bond or —N(R 30 )—. 
     In another embodiment, X is a bond. 
     In one class of compounds, R 14  and R 15  together form NR 20  and R 16 , R 17  and R 20  are each the same or different and selected from hydrogen, alkyl and hydroxy; for example they may be selected from hydrogen and hydroxy or from hydrogen and alkyl. Alkyl may have 1, 2, 3, 4, 5 or 6 carbon atoms. 
     In a further embodiment, R 14  and R 15  taken together form ═NR 20 , wherein R 20  is usually hydrogen, alkyl or hydroxy, e.g. hydrogen or hydroxy. Accordingly, the invention includes compounds in which R 1  is of Formula (B): 
     
       
         
         
             
             
         
       
     
     Included in the invention are compounds in which R 16  and R 17  are each independently selected from hydrogen, C 1-6  alkyl, C 1-6  alkoxy or hydroxy, e.g. hydrogen or C 1-6  alkyl. 
     In embodiments, R 16  and/or R 17  and/or R 20  are hydrogen. 
     In a particular embodiment, the 2-substituent is a group of Formula (C): 
     
       
         
         
             
             
         
       
     
     In a further embodiment, R 1  is —C(═NH)NH 2  or —C(═NOH)NH 2 , particularly —C(═NH)NH 2  (amidino). 
     The 2-substituent is in particular amidino. Where the thiophene part is additionally substituted, it may be substituted with halogen or moieties having 1 or 2 plural valent atoms, for example, F, Cl, methyl, methoxy, ethyl and trifluoroethyl. 
     The benzene part of the benzothiophene ring may be substituted with 1, 2 or 3 substituents selected from (i) halogen; (ii) moieties having from 1 to 30 plural valent atoms (e.g. 1 to 20, for example 1 to 10, exemplary moieties having 1, 2, 3 or 4 plural valent atoms), typically selected from C, N, O and S as well as monovalent atoms selected from H and halogen, e.g. selected from hydrogen, F, Cl and Br, for example hydrogen, F and Cl. 
     In particular the benzene part may be substituted with from 1 to 5, e.g. 1, 2 or 3, R a , wherein: 
     each R a  is independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR b , OR b , —SR b , —C(O)R b , —C(O)OR b , —OC(O)R b , N(R b )R c , —C(O)N(R b )R c , OC(O)N(R b )R c , —S(O) l R b , —S(O) l NR b R c , —S(O) l NR b C(O)R c , —S(O) l NR c C(O)OR b , —NR c C(O)R b , NR c C(O)OR b , —NR c S(O) l R b , —NR c C(O)NR b R c , —C(R b ) 3  and R d ;
 
R b  and R c  are the same or different and are each hydrogen or are selected from C 1-6  acyclic aliphatic groups and particularly C 1-6  alkyl, carbocyclyl optionally substituted by a C 1-6  acyclic aliphatic group and bonded to the remainder of the molecule either directly or through a C 1-6  acyclic aliphatic group (particularly —(CH 2 ) j -carbocyclyl or —(CH 2 ) j -carbocyclyl(C 1 -C 6 )alkyl), and heterocyclyl optionally substituted by a C 1-6  acyclic aliphatic group and bonded to the remainder of the molecule either directly or through a C 1-6  acyclic aliphatic group (particularly —(CH 2 ) j -heterocyclyl or —(CH 2 ) j -heterocyclyl(C 1 -C 6 )alkyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR u , —OR v , —SR v , —C(O)R v , —C(O)OR v , —OC(O)R v , —N(R u )R v , C(O)N(R u )R v , —OC(O)N(R u )R v , —S(O) l R v , —S(O) l NR u R v , —S(O) l NR u C(O)R v , —S(O) l NR u C(O)OR v , —NR u C(O)R v , —NR u C(O)OR v , —NR u S(O) l R v , —NR u C(O)NR v R u , —C(R v ) 3 , and C 1-6  alkyl optionally substituted by 1, 2, 3, 4 or 5 halogens, where R u  is H, OH or C 1-6  alkyl optionally substituted by up to 5 halogens and R v  is H or C 1-6  alkyl optionally substituted by up to 5 halogens, e.g. R b  and R c  are the same or different and are each hydrogen or are selected from C 1-6  alkyl, —(CH 2 ) j -carbocyclyl and —(CH 2 ) j -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy and C 1-6  alkyl;
 
R c  additionally may be hydroxy or C 1-6  alkoxy;
 
R d  is selected from C 1-6  acyclic aliphatic groups and particularly C 1-6  alkyl, C 1-6  acyclic aliphatic-oxy and particularly C 1-6  alkoxy, —(CH 2 ) i —O—(CH 2 ) j -carbocyclyl, —(CH 2 ) i —O—(CH 2 ) j -heterocyclyl, —(CH 2 ) i —O—(CH 2 ) j -carbocyclyl(C 1 -C 6 )alkyl and —(CH 2 ) i —O—(CH 2 ) j -heterocyclyl(C 1 -C 6 )alkyl any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR b , —OR b , —SR b , —C(O)R b , —C(O)OR b , —OC(O)R b , —N(R b )R c , —C(O)N(R b )R c , —OC(O)N(R b )R c , —S(O) l R b , —S(O) l NR b R c , —S(O) l NR b C(O)R c , —S(O) l NR c C(O)OR b , —NR c C(O)R b , —NR c C(O)OR b , —NR c S(O) l R b , —NR c C(O)NR b R c , and C(R b ) 3 ;
         wherein:   i and j are the same or different and are 0, 1, 2, 3, 4, 5 or 6.       

     In an embodiment:
         each R 1  is independently selected from each halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR b , OR b , —C(O)R b , —C(O)OR b , —OC(O)R b , —N(R b )R c , —C(O)N(R b )R c , —S(O) l R b , —C(R b ) 3  and R d ;   R b  and R c  are each independently hydrogen or selected from C 1-6  alkyl, —(CH 2 ) k -carbocyclyl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy and C 1-6  alkyl;   R d  is selected from C 1-6  alkyl, C 1-6  alkoxy, —(CH 2 ) k -carbocyclyl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy, C 1-6  alkyl and C 1-6  alkoxy;   k is 0, 1, 2, 3, 4, 5 or 6; and   l is 0, 1 or 2.       

     Usually, the or each R a  is halogen (e.g. fluorine or chlorine) or is an inert organic group, for example C 1-6  alkyl (e.g. methyl or ethyl) or C 1-6  alkoxy (e.g. methoxy or ethoxy), either of which is optionally substituted by halogen (e.g. fluorine or chlorine, as in the case of trifluoromethyl). As mentioned above, where an alkyl or alkyl-substituted group is mentioned, alkyl typically has 1, 2, 3 or 4 carbon atoms. 
     In some compounds of the invention, the benzene part is substituted once or twice, having a first substituent which comprises a fragment as defined herein; and an optional second substituent which is R a  (which in turn is usually halogen, e.g. fluorine or chlorine). 
     In other compounds, the benzothiophene ring is substituted at both of the 4- and 6-positions by fragments, which may be the same of different, of any of Formulae (i) to (vi). In one class of compounds, the 4-fragment is of the same formula as the 6-fragment. Thus, for example, the 4- and 6-substituents may be identical, or may be different but share a common formula. In another class, the 4-fragment is of a different formula to the 6-fragment. 
     Included are compounds substituted at the 4-position by a fragment of Formula (ii), (iii), (iv), (v) or (vi); at the 6-position by a fragment of Formula (i); or at the 4-position by a fragment of Formula (ii), (iii), (iv), (v) or (vi) and at the 6-position by a fragment of Formula (i). Of particular mention are compounds substituted at the 4-position by a fragment of Formula (ii); at the 6-position by a fragment of Formula (i); or at the 4-position by a fragment of Formula (ii) and at the 6-position by a fragment of Formula (i). 
     Fragment (i) 
     A compound of the invention may comprise, at the 4- and/or 6-position, a substituent comprising a fragment of the Formula (i): 
     
       
         
         
             
             
         
       
     
     wherein R is as previously defined. 
     As previously stated, and as applies to each of fragments (i) to (vi), the oxygen atom on the right hand side of the fragment as drawn is bound directly to the 4- or 6-carbon atom of the benzothiophene ring. 
     In one class of compounds, a substituent comprising a fragment of Formula (i) is bound at the 4-position of the benzothiophene ring. 
     In another class of compounds, a substituent comprising a fragment of Formula (i) is bound at the 6-position of the benzothiophene ring. 
     The fragment of Formula (i) may be selected from one of the following fragments, particularly when the substituent is present at the 6-position: 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             R 1  is hydrogen or is selected from C 1-6  alkyl, —(CH 2 ) k -carbocyclyl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
             R 2  is selected from hydrogen and C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and 
             k is 0, 1, 2, 3, 4, 5 or 6. 
           
         
       
    
     Thus, a substituent comprising fragment (i) may be of the following Formula: 
     
       
         
         
             
             
         
       
     
     In one class of compounds, R 1  is hydrogen, or C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 1  may be hydrogen, methyl or ethyl. 
     In another class of compounds, R 2  is hydrogen or C 1 , C 2 , C 3  or C 4  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 2  may be hydrogen or methyl. 
     In a further class of compounds, R comprises (e.g. is) aryl or heteroaryl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R a . Aryl and heteroaryl are often monocyclic, e.g. having 5 or 6 ring members, being, for example, phenyl or thiophenyl. Sometimes, aryl and heteroaryl are polycyclic, e.g. bicyclic, having, for example, 8, 9 or 10 ring members. In particular, R may be phenyl or thiophenyl (also called thienyl), either of which is optionally substituted with 1, 2, 3, 4 or 5 R a . Where R is thiophenyl, it may be thiophen-2-yl. 
     Of particular mention are fragments of the following Formulae: 
     
       
         
         
             
             
         
       
         
         
           
             wherein n is 0, 1, 2, 3, 4 or 5. 
           
         
       
    
     Also of particular mention are substituents of the following Formulae: 
     
       
         
         
             
             
         
       
     
     In Formulae (i.4), (i.5), (i.6) and (i.7), n may, in particular, be 0, 1, or 2. Where present, the or each R a  may be, for example, independently selected from halogen (e.g. fluorine or chlorine), C 1-6  alkoxy (e.g. methoxy or ethoxy) and alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl). More usually, n is 0. 
     In Formulae (i.6) and (i.7), R 1  is typically hydrogen or C 1 , C 2 , C 3  or C 4  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 1  may be hydrogen, methyl or ethyl. 
     In a particular class of compounds, a fragment or substituent of any of Formulae (i.1) to (i.7) is present at the 6-position of the benzothiophene ring. 
     Fragment (ii) 
     A compound of the invention may comprise, at the 4- and/or 6-position, a substituent comprising a fragment of the Formula (ii): 
     
       
         
         
             
             
         
       
     
     R is as previously defined. 
     In one class of compounds, a substituent comprising a fragment of Formula (ii) is bound at the 4-position of the benzothiophene ring. 
     In another class of compounds, a substituent comprising a fragment of Formula (ii) is bound at the 6-position of the benzothiophene ring. 
     The fragment of Formula (ii) may be selected from one of the following fragments, particularly when the substituent is present at the 4-position: 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             R 3  and R 4  are each independently hydrogen or selected from C 1-6  alkyl, —(CH 2 ) k -carbocyclyl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
             or R 3  and R 4  together with the nitrogen atom to which they are attached form heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ; 
             R 5  is selected from hydrogen and C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and 
             k is 0, 1, 2, 3, 4, 5 or 6. 
           
         
       
    
     Thus, a substituent comprising fragment (ii) may be of the following Formula: 
     
       
         
         
             
             
         
       
     
     In one class compounds, R 3  is hydrogen or is selected from C 1-6  alkyl, —(CH 2 ) k -aryl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 3  may be selected from cycloalkyl (e.g. cyclohexyl), aryl (e.g phenyl), —CH 2 -aryl (e.g. benzyl), —CH 2 CH 2 -aryl, heterocyclyl, —CH 2 -heterocyclyl and —CH 2 CH 2 -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . 
     In a further class of compounds, R 4  is hydrogen, or C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 4  may hydrogen, methyl or ethyl. 
     In a further class of compounds, R 3  and R 4  taken together with the nitrogen atom to which they are attached form heterocycloalkyl (e.g. pyrrolidinyl or piperidinyl) optionally substituted with 1, 2, 3, 4 or 5 R a . 
     In a further class of compounds, R 5  is hydrogen or C 1 , C 2 , C 3  or C 4  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 5  may be hydrogen or methyl. 
     In a further class of compounds, R comprises (e.g. is) aryl or heteroaryl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R a . Aryl and heteroaryl are often monocyclic, e.g. having 5 or 6 ring members, being, for example, phenyl or thiophenyl. Sometimes, aryl and heteroaryl are polycyclic, e.g. bicyclic, having, for example, 8, 9 or 10 ring members. In particular, R may be phenyl optionally substituted with 1, 2, 3, 4 or 5 R a . 
     Of particular mention are fragments of the following Formula: 
     
       
         
         
             
             
         
       
     
     Of particular mention are substituents of the following Formula: 
     
       
         
         
             
             
         
       
     
     In Formulae (ii.6) and (ii.7), R 4  is usually hydrogen or C 1-6  alkyl (e.g. methyl) and n may, in particular, be 0, 1, or 2. Where present, the or each R a  may be, for example, independently selected from halogen (e.g. fluorine or chlorine), C 1-6  alkoxy (e.g. methoxy or ethoxy) and C 1-6  alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl). More usually, n is 0. 
     In Formula (ii.7), R 3  is typically —(CH 2 ) k -carbocyclyl or —(CH 2 ) k -heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 3  may be selected from cycloalkyl (e.g. cyclohexyl), aryl (e.g phenyl), —CH 2 -aryl (e.g. benzyl), —CH 2 CH 2 -aryl, heterocyclyl, —CH 2 -heterocyclyl and —CH 2 CH 2 -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . 
     In a particular class of compounds, a fragment or substituent of any of Formulae (ii.1) to (ii.7) is present at the 4-position of the benzothiophene ring. 
     Fragment (iii) 
     A compound of the invention may comprise, at the 4- and/or 6-position, a substituent comprising a fragment of the Formula (iii): 
     
       
         
         
             
             
         
       
     
     wherein R is as previously defined. 
     In one class of compounds, a substituent comprising a fragment of Formula (iii) is bound at the 4-position of the benzothiophene ring. 
     In another class of compounds, a substituent comprising a fragment of Formula (iii) is bound at the 6-position of the benzothiophene ring. 
     The fragment of Formula (iii) may be selected from one of the following fragments, particularly when the substituent is present at the 4-position: 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             R 6  is hydrogen or is selected from C 1-6  alkyl, —(CH 2 ) k -carbocyclyl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
             R 7 , R 8  and R 9  are each independently selected from hydrogen and C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and 
             k is 0, 1, 2, 3, 4, 5 or 6. 
           
         
       
    
     Thus, a substituent comprising fragment (iii) may be of the following Formula: 
     
       
         
         
             
             
         
       
     
     In one class of compounds, R 6  is hydrogen, or C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 6  may be hydrogen, methyl or ethyl. 
     In another class of compounds, R 7 , R 8  and R 9  are each independently hydrogen or C 1 , C 2 , C 3  or C 4  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 7 , R 8  and R 9  may be each independently hydrogen or methyl. 
     In a further class of compounds, R comprises (e.g. is) aryl or heteroaryl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R a . Aryl and heteroaryl are often monocyclic, e.g. having 5 or 6 ring members, being, for example, phenyl or thiophenyl. Sometimes, aryl and heteroaryl are polycyclic, e.g. bicyclic, having, for example, 8, 9 or 10 ring members. In particular, R may be phenyl optionally substituted with 1, 2, 3, 4 or 5 R a . 
     Of particular mention are fragments of the following Formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein n is 0, 1, 2, 3, 4 or 5. 
           
         
       
    
     Also of particular mention are substituents of the following Formula: 
     
       
         
         
             
             
         
       
     
     In Formulae (iii.12) and (iii.13), n may, in particular, be 0, 1, or 2. Where present, the or each R a  may be, for example, independently selected from halogen (e.g. fluorine or chlorine), C 1-6  alkoxy (e.g. methoxy or ethoxy) and alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl). More usually, n is 0. 
     In Formula (iii.13), R 6  is typically hydrogen or C 1 , C 2 , C 3  or C 4  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 1  may hydrogen, methyl or ethyl. 
     In a particular class of compounds, a fragment or substituent of any of Formulae (iii.1) to (iii.13) is present at the 4-position of the benzothiophene ring. 
     Fragment (iv) 
     A compound of the invention may comprise, at the 4- and/or 6-position, a substituent comprising a fragment of the Formula (iv): 
     
       
         
         
             
             
         
       
     
     wherein R is as previously defined. 
     In one class of compounds, a substituent comprising a fragment of Formula (iv) is bound at the 4-position of the benzothiophene ring. 
     In another class of compounds, a substituent comprising a fragment of Formula (iv) is bound at the 6-position of the benzothiophene ring. 
     The fragment of Formula (iv) may be selected from one of the following fragments, particularly when the substituent is present at the 4-position: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             wherein 
             R 10  and R 11  are each independently hydrogen or selected from C 1-6  alkyl, —(CH 2 ) k -carbocyclyl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
             or R 10  and R 11  together with the nitrogen atom to which they are attached form heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ; 
             R 12 , R 13  and R 14  are each independently selected from hydrogen and C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and 
             k is 0, 1, 2, 3, 4, 5 or 6. 
           
         
       
    
     Thus, a substituent comprising fragment (iv) may be of the following Formula: 
     
       
         
         
             
             
         
       
     
     In one class compounds, R 10  is hydrogen or is selected from C 1-6  alkyl, —(CH 2 ) k -aryl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 10  may be selected from cycloalkyl (e.g. cyclohexyl), aryl (e.g phenyl), —CH 2 -aryl (e.g. benzyl), —CH 2 CH 2 -aryl, heterocyclyl, —CH 2 -heterocyclyl and —CH 2 CH 2 -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . 
     In a further class of compounds, R 11  is hydrogen or C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 11  may hydrogen, methyl or ethyl. 
     In a further class of compounds, R 10  and R 11  taken together with the nitrogen atom to which they are attached form heterocycloalkyl (e.g. pyrrolidinyl or piperidinyl) optionally substituted with 1, 2, 3, 4 or 5 R a . 
     In another class of compounds, R 12 , R 13  and R 14  are each independently hydrogen or C 1 , C 2 , C 3  or C 4  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 12 , R 13  and R 14  may each be hydrogen or methyl. 
     In a further class of compounds, R comprises (e.g. is) aryl or heteroaryl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R a . Aryl and heteroaryl are often monocyclic, e.g. having 5 or 6 ring members, being, for example, phenyl or thiophenyl. Sometimes, aryl and heteroaryl are polycyclic, e.g. bicyclic, having, for example, 8, 9 or 10 ring members. In particular, R may be phenyl optionally substituted with 1, 2, 3, 4 or 5 R a . 
     Of particular mention are fragments of the following formula: 
     
       
         
         
             
             
         
       
     
     Also of particular mention are substituents of the Formula (iv.13): 
     
       
         
         
             
             
         
       
     
     In Formulae (iv.6) and (iv.17), R 11  is usually hydrogen or C 1-6  alkyl (e.g. methyl) and n may, in particular, be 0, 1, or 2. Where present, the or each R a  may be, for example, independently selected from halogen (e.g. fluorine or chlorine), C 1-6  alkoxy (e.g. methoxy or ethoxy) and alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl). More usually, n is 0. 
     In Formula (iv.17), R 3  is typically —(CH 2 ) k -carbocyclyl or —(CH 2 ) k -heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 RF. In particular, R 3  may be selected from aryl (e.g phenyl), —CH 2 -aryl (e.g. benzyl), —CH 2 CH 2 -aryl, heterocyclyl, —CH 2 -heterocyclyl and —CH 2 CH 2 -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . 
     In a particular class of compounds, a fragment or substituent of any of Formulae (iv.1) to (iv.17) is present at the 4-position of the benzothiophene ring. 
     Fragment (v) 
     A compound of the invention may comprise, at the 4- and/or 6-position, a substituent comprising a fragment of the Formula (v): 
     
       
         
         
             
             
         
       
     
     R is as previously defined. 
     In one class of compounds, a substituent comprising a fragment of Formula (v) is bound at the 4-position of the benzothiophene ring. 
     In another class of compounds, a substituent comprising a fragment of Formula (v) is bound at the 6-position of the benzothiophene ring. 
     The fragment of Formula (v) may be selected from one of the following fragments, particularly when the substituent is present at the 4-position: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             wherein 
             R 15  is hydrogen or is selected from C 1-6  alkyl, —(CH 2 ) k -carbocyclyl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
             R 16 , R 17 , R 18  and R 19  are each independently selected from hydrogen and C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and 
             k is 0, 1, 2, 3, 4, 5 or 6. 
           
         
       
    
     Thus, the substituent comprising fragment (v) may be of the following Formula: 
     
       
         
         
             
             
         
       
     
     In one class of compounds, R 15  is hydrogen, or C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 15  may be hydrogen, methyl or ethyl. 
     In another class of compounds, R 16 , R 17 , R 18  and R 19  are each independently hydrogen or C 1 , C 2 , C 3  or C 4  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 16 , R 17 , R 18  and R 19  may each be hydrogen or methyl. 
     In a further class of compounds, R comprises (e.g. is) aryl or heteroaryl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R a . Aryl and heteroaryl are often monocyclic, e.g. having 5 or 6 ring members, being, for example, phenyl or thiophenyl. Sometimes, aryl and heteroaryl are polycyclic, e.g. bicyclic, having, for example, 8, 9 or 10 ring members. In particular, R may be phenyl optionally substituted with 1, 2, 3, 4 or 5 R a . 
     Of particular mention are fragments of the following Formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein n is 0, 1, 2, 3, 4 or 5. 
           
         
       
    
     Also of particular mention are substituents of the following Formula: 
     
       
         
         
             
             
         
       
     
     In Formulae (v.24) and (v.25), R 16  is usually hydrogen or C 1-6  alkyl (e.g. methyl) and n may, in particular, be 0, 1, or 2. Where present, the or each R a  may be, for example, independently selected from halogen (e.g. fluorine or chlorine), C 1-6  alkoxy (e.g. methoxy or ethoxy) and alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl). More usually, n is 0. 
     In Formula (v.25), R 15  is typically hydrogen or C 1 , C 2 , C 3  or C 4  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 15  may be hydrogen, methyl or ethyl. 
     In a particular class of compounds, a fragment or substituent of any of Formulae (v.1) to (v.25) is present at the 4-position of the benzothiophene ring. 
     Fragment (vi) 
     A compound of the invention may comprise, at the 4- and/or 6-position, a substituent comprising a fragment of the Formula (vi): 
     
       
         
         
             
             
         
       
     
     wherein R is as previously defined. 
     In one class of compounds, a substituent comprising a fragment of Formula (vi) is bound at the 4-position of the benzothiophene ring. 
     In another class of compounds, a substituent comprising a fragment of Formula (vi) is bound at the 6-position of the benzothiophene ring. 
     The fragment of Formula (vi) may be selected from one of the following fragments, particularly when the substituent is present at the 4-position: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             wherein 
             R 20  and R 21  are each independently hydrogen or selected from C 1-6  alkyl, —(CH 2 ) k -carbocyclyl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a ; 
             or R 20  and R 21  together with the nitrogen atom to which they are attached form heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ; 
             R 22 , R 23 , R 24  and R 25  are each independently selected from hydrogen and C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and 
             k is 0, 1, 2, 3, 4, 5 or 6. 
           
         
       
    
     Thus, a substituent comprising fragment (vi) may be of the following Formula: 
     
       
         
         
             
             
         
       
     
     In one class compounds, R 20  is hydrogen or is selected from C 1-6  alkyl, —(CH 2 ) k -aryl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 20  may be selected from cycloalkyl (e.g. cyclohexyl), aryl (e.g phenyl), —CH 2 -aryl (e.g. benzyl), —CH 2 CH 2 -aryl, heterocyclyl, —CH 2 -heterocyclyl and —CH 2 CH 2 -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . 
     In a further class of compounds, R 21  is hydrogen, or C 1-6  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 11  may hydrogen, methyl or ethyl. 
     In a further class of compounds, R 20  and R 21  taken together with the nitrogen atom to which they are attached form heterocycloalkyl (e.g. pyrrolidinyl or piperidinyl) optionally substituted with 1, 2, 3, 4 or 5 R a . 
     In another class of compounds, R 22 , R 23 , R 24  and R 25  are each independently hydrogen or C 1 , C 2 , C 3  or C 4  alkyl optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 22 , R 23 , R 24  and R 25  may be each independently hydrogen or methyl. 
     In a further class of compounds, R comprises (e.g. is) aryl or heteroaryl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R a . Aryl and heteroaryl are often monocyclic, e.g. having 5 or 6 ring members, being, for example, phenyl or thiophenyl. Sometimes, aryl and heteroaryl are polycyclic, e.g. bicyclic, having, for example, 8, 9 or 10 ring members. In particular, R may be phenyl optionally substituted with 1, 2, 3, 4 or 5 R a . 
     Of particular mention are fragments of the Formula (vi.36): 
     
       
         
         
             
             
         
       
     
     Also of particular mention are substituents of the Formula (vi.37): 
     
       
         
         
             
             
         
       
     
     In Formulae (vi.36) and (vi.37), R 20  and R 21  may be each independently hydrogen or C 1-6  alkyl (e.g. methyl), and n may, in particular, be 0, 1, or 2. Where present, the or each R a  may be, for example, independently selected from halogen (e.g. fluorine or chlorine), C 1-6  alkoxy (e.g. methoxy or ethoxy) and alkoxycarbonyl (e.g methoxycarbonyl or ethoxycarbonyl). More usually, n is 0. 
     In Formula (vi.37), R 19  is typically —(CH 2 ) k -carbocyclyl or —(CH 2 ) k -heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R a . In particular, R 19  may be selected from aryl (e.g phenyl), —CH 2 -aryl (e.g. benzyl), —CH 2 CH 2 -aryl, heterocyclyl, —CH 2 -heterocyclyl and —CH 2 CH 2 -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . 
     In a particular class of compounds, a fragment or substituent of any of Formulae (vi.1) to (vi.37) is present at the 4-position of the benzothiophene ring. 
     R 
     R comprises (e.g. is) a carbocyclic or heterocyclic group, either of which is optionally substituted. 
     In one class of compounds, R is a moiety comprising an optionally substituted carbocyclic or heterocyclic group linked to the remainder of the fragment via a linker, L, having 1, 2, 3, 4 or 5 in-chain atoms, e.g. 1 or 2 atoms. Exemplary linkers include alkylene and alkylene substituted by 1, 2, 3, 4 or 5 R a , wherein each R a  is typically hydroxy or halogen (e.g. fluorine or chlorine). Particular linkers are methylene and ethylene. 
     In another class of compounds, R is an optionally substituted carbocyclic or heterocyclic group. The group may be unsubstituted, or substituted with 1, 2, 3, 4 or 5 R a . 
     When R comprises (in particular, is) an optionally substituted carbocyclic group, the carbocycle may be a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon ring atoms. In particular, R may comprise a 3- to 10-membered non-aromatic ring or ring system and, in particular, a 5- or 6-membered non-aromatic ring, which may be fully or partially saturated. Exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . In a particular embodiment, R is phenyl optionally substituted with 1, 2, 3, 4 or 5 R a . In a particular class of compounds, R is unsubstituted, an exemplary group being phenyl. 
     When R comprises (in particular, is) an optionally substituted heterocyclic group, the heterocycle may be a saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulphur. In particular, R may comprise a 3- to 10-membered non-aromatic ring or ring system and more particularly a 5- or 6-membered ring, which may be fully or partially saturated. Exemplary heterocyclyl groups include oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, especially thiomorpholino, indolizinyl, isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl and the like, any of which is optionally substituted with 1, 2, 3, 4 or 5 R a . In a particular embodiment, R is thiophenyl (e.g. thiophen-2-yl or thiophen-3-yl) optionally substituted with 1, 2, 3, 4 or 5 R a . In another particular embodiment, R is thiophenyl. 
     R a    
     R a  may be as previously described. In embodiments, each R a  is independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, —B(OH) 2 , ═NR b , —OR b , —C(O)R b , C(O)OR b , OC(O)R b , —N(R b )R c , —C(O)N(R b )R c , —S(O) l R b , —C(R b ) 3  and R d ; wherein R b  and R c  are each independently hydrogen or selected from C 1-6  alkyl, —(CH 2 ) k -carbocyclyl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy and C 1-6  alkyl; R d  is selected from C 1-6  alkyl, C 1-6  alkoxy, —(CH 2 ) k -carbocyclyl and —(CH 2 ) k -heterocyclyl, any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, hydroxy, C 1-6  alkyl and C 1-6  alkoxy; k is 0, 1, 2, 3, 4, 5 or 6; and l is 0, 1 or 2. 
     For example, the or each R a  may be halogen (e.g. fluorine or chlorine) or an inert organic group, for example C 1-6  alkyl (e.g. methyl or ethyl), C 1-6  alkoxy (e.g. methoxy or ethoxy), either of which is optionally substituted by halogen (e.g. fluorine or chlorine). As mentioned above, where an alkyl or alkyl-substituted group is mentioned, alkyl typically has 1, 2, 3 or 4 carbon atoms. 
     R a  may be selected from (i) halogen; (ii) moieties having from 1 to 30 plural valent atoms (e.g. 1 to 20, for example 1 to 10, in particular 1, 2, 3 or 4, plural valent atoms), selected from C, N, O and S as well as monovalent atoms selected from hydrogen and halogen, e.g. selected from hydrogen, F, Cl and Br, for example hydrogen, F and Cl. 
     R a  may be a hydrogen bond acceptor, examples of such groups include halogen (e.g. fluorine), hydroxy, tertiary amino groups and carbonyl groups. Alternatively, R a  may be a hydrogen bond donor, examples of such groups including hydroxy and primary and secondary amine groups. 
     In certain compounds, each R a  is independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, trifluoromethyl, cyano, nitro, oxo, —OR b , —C(O)R b , —C(O)OR b , —OC(O)R b , —N(R b )R c , —C(O)N(R b )R c , —S(O) l R b , —C(R b ) 3  and R d . In this case, R b  and R c  are usually each independently hydrogen or selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) k -aryl (e.g. phenyl or benzyl) and —(CH 2 ) k -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). R d  is usually selected from C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl), —(CH 2 ) k -aryl (e.g. phenyl or benzyl) and —(CH 2 ) k -heteroaryl (e.g. pyridinyl or thiophenyl), any of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen (e.g. fluorine or chlorine), hydroxy or C 1-6  alkyl (e.g. methyl, ethyl, propyl or butyl). 
     For the avoidance of doubt, where a group is substituted with more than one R a , each R 1  is independently selected from the range of substituents specified. The same applies to compounds of the invention comprising more than one R a  substituent; each R a  is selected independently of any other R a  substituent present in the compound. 
     This is the end of the section “Particular Benzothiophene Compounds”. 
     Exemplary Compounds 
     Examples of compounds of the invention include those shown below. It will of course be appreciated that where a salt is shown, this is merely an illustrative example and non-limiting and other salts are contemplated, as are the free acids and bases of the salts. Each compound may, therefore, be in the form of the free compound, a salt, or a prodrug. Where a nitrogen atom forming only two bonds is shown, this represents NH. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     As further compounds may be mentioned: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Form of Compounds 
     Where applicable, compounds of the invention may exist in open ring or closed ring form, depending on conditions and environment. In particular, where substituents are such that a further ring may form on the benzothiophene ring by intermolecular reaction of substituents, the compound may exist in equilibrium between open and closed ring states. This is particularly the case for closed ring prodrugs and isosteres, such as cyclic esters, for example. 
     Furthermore, the interactions between substituents such as those described above may be intermolecular electrostatic interactions, such as hydrogen bonding, as well as, or instead of, covalent bonds. 
     Any asymmetric carbon atoms may be present in (R)-, (S)- or (R,S)-configuration, for example in (R)- or (S)-configuration. Radicals having any unsaturation are present in cis-, trans- or (cis,trans) form. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers. 
     The compounds of the inventions can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the disclosure includes all variant forms of the compounds. 
     Stereoisomeric mixtures, e.g. mixtures of diastereomers, can be separated into their corresponding isomers in a manner known per se by means of suitable separation methods. Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of a starting compound or in a compound of the invention. Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands. 
     The compounds may be in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington&#39;s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US, 1985, p. 1418, the disclosure of which is hereby incorporated by reference; see also Stahl et al, Eds, “Handbook of Pharmaceutical Salts Properties Selection and Use”, Verlag Helvetica Chimica Acta and Wiley-VCH, 2002. 
     The invention therefore also includes pharmaceutically-acceptable salts of the disclosed compounds, such as those in which the parent compound is modified by making acid or base salts thereof. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. 
     Salts are especially the pharmaceutically acceptable acid addition salts of compounds of the invention. Such salts are formed, for example, by compounds of the invention having a basic nitrogen atom as acid addition salts, preferably with organic or inorganic acids, especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, hydrohalic acids, such as hydrochloric acid; sulfuric acid; or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucosemonocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids, such as glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine, N-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, benzoic acid, salicylic acid, 1- or 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, glucuronic acid, galacturonic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid. 
     In the presence of negatively charged radicals, such as carboxy or sulfo, salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines. 
     In the presence of a basic group and an acid group in the same molecule, a compound of the disclosure (or an N-oxide thereof) may also form internal salts. 
     For isolation or purification it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. Only the pharmaceutically acceptable salts or the free compounds (optionally in the form of pharmaceutical compositions) are used therapeutically, and those are therefore preferred. Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I (or an N-oxide thereof) with a basic nitrogen atom, especially the pharmaceutically acceptable salts. 
     The invention includes prodrugs of the aforementioned compounds, which can be metabolically converted to the subject compounds by the recipient host. As used herein, a prodrug is a compound that exhibits pharmacological activity after undergoing a chemical transformation in the body. An example of such a prodrug is a pharmaceutically acceptable ester of a carboxylic acid. 
     The invention therefore includes prodrugs for the active pharmaceutical species of the invention, for example in which one or more functional groups are protected or derivatised but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group. The term “prodrug,” as used herein, represents compounds which are transformed in vivo to the parent compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; H Bundgaard, ed, Design of Prodrugs, Elsevier, 1985; and Judkins, et al. Synthetic Communications, 26(23), 4351-4367 (1996); and The organic chemistry of drug design and drug action by Richard B Silverman in particular pages 497 to 546; each of which is incorporated herein by reference. 
     Prodrugs therefore include drugs having a functional group which has been transformed into a reversible derivative thereof. Typically, such prodrugs are transformed to the active drug by hydrolysis. As examples may be mentioned the following: 
     
       
         
           
               
               
             
               
                   
               
               
                 Functional Group 
                 Reversible derivative 
               
               
                   
               
             
            
               
                 Carboxylic acid 
                 Esters, including e.g. acyloxyalkyl esters, amides 
               
               
                 Alcohol 
                 Esters, including e.g. sulfates and phosphates as 
               
               
                   
                 well as carboxylic acid esters 
               
               
                 Amidino 
                 Amidoximes, carbamateamidino 
               
               
                 Amine 
                 Amides, carbamates, imines, enamines, 
               
               
                 Boronic acid 
                 Diol ester 
               
               
                 Carbonyl (aldehyde, 
                 Imines, oximes, acetals/ketals, enol esters, 
               
               
                 ketone) 
                 oxazolidines and thiazoxolidines 
               
               
                   
               
            
           
         
       
     
     Prodrugs also include compounds convertible to the active drug by an oxidative or reductive reaction. As examples may be mentioned:
         Oxidative activation
           N- and O-dealkylation   Oxidative deamination   N-oxidation   Epoxidation   
           Reductive activation
           Azo reduction   Sulfoxide reduction   Disulfide reduction   Bioreductive alkylation   Nitro reduction.   
               

     Also to be mentioned as metabolic activations of prodrugs are nucleotide activation, phosphorylation activation and decarboxylation activation. 
     Of particular mention are compounds in which R 1  is an amidino group in prodrug form. Examples of compounds which may be useful as amidino prodrugs include those described by Su et al. (J. Med. Chem., 1997, 40, 4308-4318), who describe the use of N-benzyloxycarbonyl- and N-(acyloxy)methoxycarbonyl amidine derivatives; by Boykin et al. (Bioorg. Med. Chem. Lett., 1996, 6, 3017-3020), who describe the use of amidoximes and O-alkylamidoximes; and by Weller et al. (J. Med. Chem., 1996, 39, 3139-3147) who describe the use of N-alkoxycarbonylamidines as amidine prodrugs. 
     Alkoxycarbonyl (carbamoyl) and acyloxymethyl carbamate groups may provide a bioconvertable prodrug of amine and amidine nitrogens (see, for example, Saulnier, et al. (1994) Bioorg. Med. Chem. Letts. 4(16):1985 1990). Lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl, optionally substituted phenoxycarbonyl groups, groups such as benzyloxycarbonyl and p-methoxybenzyloxycarbonyl and amide oximes are known as prodrug moieties for these functional groups (see, for example, EP-A-0743320). 
     In exemplary compounds, R 1  is amidoxime or carbamateamidino. 
     The prodrugs may be used, for example, to increase solubility, stability, permeability, or to control efflux. 
     Other prodrugs may be carrier-linked or modified to enhance usability of active transport mechanisms. In particular, the prodrugs are pharmaceutically acceptable salts, esters or solvates. 
     Use 
     Compounds of the invention may be useful as Factor IXa inhibitors. The compounds may be useful as an antagonist or a partial antagonist of Factor IXa. Compounds of the invention have been tested for their Factor IXa inhibitory activity. Included in the tested compounds are those shown to have IC 50  values for Factor IXa of less than 50 μm. Some compounds have been found to have an IC 50  of less than 10 μm. Particular compounds have been demonstrated to have an IC 50  for Factor IXa of less than 1 μm. Suitable methods for determining IC 50  values will be apparent to those skilled in the art, and are exemplified herein. 
     The compounds may show selectivity for Factor IX versus other proteases of the coagulation (e.g. thrombin, FVIIa, FXa) or the fibrinolytic cascades (e.g. plasminogen activators, plasmin) or other trypsin-like enzymes such as trypsin, enterokinase, thrombin, kallikrein, plasmin, urokinase, plasminogen activators and the like. The compounds may also be useful in the inhibition of one or more of Factor XII, Factor XI, Factor X, Factor VII and prothrombin. The compounds may be dual urokinase and Factor IX inhibitors. In particular, compounds of the invention may show selectivity for Factor IXa over uPA. For example, compounds may have IC 50  values for Factor IXa which are at least 10 times greater than for uPA. 
     Compounds of the present invention may be useful in the therapy (i.e. the treatment, prevention or delay of progression of) a cardiovascular disease or condition, for example thrombosis (including arterial, venous, cerebrovascular, coronary or deep vein thrombosis, or thrombosis associated with surgical procedures), stroke, long periods of confinement or other associated states such as pro-coagulant states, for example, which may include anti-phospholipid antibody syndrome, protein C deficiency and protein S deficiency, and inflammation, for example systemic lupus erythmatosis (SLE), diseases associated with the treatment of the kidney by haemodialysis and/or venous haemofiltration, cardiovascular disease, such as, myocardial infarction, arrhythmia, or annurism, for example. In particular, the compounds may be used to treat thrombosis, and to prevent the occurrence or re-occurrence of thrombosis and secondary thrombotic events. 
     Moreover, products of the disclosure may have utility in prophylaxis of re-occlusion (i.e. thrombosis) after thrombolysis, percutaneous trans-luminal angioplasty (PTA) and coronary bypass operations; the prevention of re-thrombosis after microsurgery and vascular surgery in general. Further indications include the therapeutic and/or prophylactic treatment of disseminated intravascular coagulation caused by bacteria, multiple trauma, intoxication or any other mechanism; anticoagulant treatment when blood is in contact with foreign surfaces in the body such as vascular grafts, vascular stents, vascular catheters, mechanical and biological prosthetic valves or any other medical device; and anticoagulant treatment when blood is in contact with medical devices outside the body such as during cardiovascular surgery using a heart-lung machine or in haemodialysis. 
     The compounds may be useful in the therapy of an arterial disease selected from acute coronary syndromes, cerebrovascular thrombosis, peripheral arterial occlusion and arterial thrombosis resulting from atrial fibrillation, valvular heart disease, arterio-venous shunts, indwelling catheters or coronary stents. According to the invention, such conditions include, for example, any thrombotically mediated acute coronary or cerebrovascular syndrome, any thrombotic syndrome occurring in the venous system, any coagulopathy, and any thrombotic complications associated with extracorporeal circulation or instrumentation. The invention still further provides a method for inhibiting the coagulation of biological samples (e.g. stored blood products and samples). 
     Examples of conditions involving arterial thrombosis include unstable angina (severe constrictive pain in chest of coronary origin), myocardial infarction (heart muscle cell death resulting from insufficient blood supply), ischemic heart disease (local ischemia due to obstruction, such as by arterial narrowing, of blood supply), reocclusion during or after percutaneous transluminal coronary angioplasty, restenosis after percutaneous transluminal coronary angioplasty, occlusion of coronary artery bypass grafts, and occlusive cerebrovascular disease. Also with regard to arterio-venous (mixed) thrombosis, anti-thrombotic compounds of the invention may be useful for maintaining patency in arteriovenous shunts. Indications involving arterial thrombosis include acute coronary syndromes (especially myocardial infarction and unstable angina), cerebrovascular thrombosis and peripheral arterial occlusion and arterial thrombosis occurring as a result of atrial fibrillation, valvular heart disease, arterio-venous shunts, indwelling catheters or coronary stents. Accordingly, in another aspect there is provided a method of treating a disease or condition selected from this group of indications, comprising administering to a mammal, especially a human patient, a product of the disclosure. The disclosure includes products for use in an arterial environment, e.g. a coronary stent or other arterial implant, having a coating which comprises a product according to the disclosure. The products of the disclosure may be used prophylactically to treat an individual at risk of suffering from arterial thrombosis or a condition or disease involving arterial thrombosis or therapeutically (including to prevent re-occurrence of thrombosis or secondary thrombotic events). 
     The compounds may be useful for the prevention of thrombosis in procedures involving an extracorporeal blood circuit, for example a surgical procedure such as coronary artery bypass graft (CABG) surgery. The compounds of this disclosure may be incorporated into a cardiopulmonary bypass machine or may be administered externally to the extracorporeal blood circuit. More usually, they may be administered intravenously to the patient by infusion. In one method, the disclosed products may be used to prevent thrombosis in surgery. In particular, the products of the present invention may be used to prevent thrombosis during CABG surgery. Thus the disclosure contemplates medicaments to prevent thrombosis in the extracorporeal circuit during CABG surgery. 
     It is known that hypercoagulability may lead to thromboembolic diseases. Examples of venous thromboembolism which may be treated or prevented with compounds of the disclosure include obstruction of a vein, obstruction of a lung artery (pulmonary embolism), deep vein thrombosis, thrombosis associated with cancer and cancer chemotherapy, thrombosis inherited with thrombophilic diseases such as Protein C deficiency, Protein S deficiency, antithrombin III deficiency, and Factor V Leiden, and thrombosis resulting from acquired thrombophilic disorders such as systemic lupus erythematosus (inflammatory connective tissue disease). Also with regard to venous thromboembolism, compounds of the disclosure are useful for maintaining patency of indwelling catheters. 
     Examples of cardiogenic thromboembolism which may be treated or prevented with compounds of the disclosure include thromboembolic stroke (detached thrombus causing neurological affliction related to impaired cerebral blood supply), cardiogenic thromboembolism associated with atrial fibrillation (rapid, irregular twitching of upper heart chamber muscular fibrils), cardiogenic thromboembolism associated with prosthetic heart valves such as mechanical heart valves, and cardiogenic thromboembolism associated with heart disease. 
     The compounds may be used as modulators of the intrinsic and/or extrinsic clotting pathway by inhibiting the biological activities of one or more enzymes associated therewith. As such, the compounds of the invention may be useful in application such as management, treatment, or control of diseases in humans associated with one or both of the intrinsic or extrinsic clotting pathway, for example, diseases that are contemplated may be any disease, or disease state, associated with one or more of the intrinsic or extrinsic clotting pathway and may be, for example, stroke, myocardial infarction, deep vein thrombosis, inflammation (acute and chronic) and clotting associated with surgery and haemodialysis. 
     Other conditions associated with hypercoagulability and thromboembolic diseases which may be mentioned inherited or acquired deficiencies in heparin cofactor II, circulating antiphospholipid antibodies (Lupus anticoagulant), homocysteinemia, heparin induced thrombocytopenia and defects in fibrinolysis. 
     The present compounds may be useful in controlling hemostasis and especially for inhibiting coagulation, for example in the treatment or prevention of secondary events after myocardial infarction. 
     The compounds may also be used in the treatment of patients by haemodialysis, by providing the product in a dialysis solution. The invention therefore includes dialysing solutions and dialysing concentrates which comprise a product of the disclosure, as well as the use of the compounds in dialysis therapy. 
     The compounds may be useful in the treatment or prevention of undesirable cell proliferation. The undesirable cell proliferation is typically undesirable hyperplastic cell proliferation, for example proliferation of smooth muscle cells, especially vascular smooth muscle cells. The compounds may particularly find application in the treatment of intimal hyperplasia, one component of which is proliferation of smooth muscle cells. Restenosis can be considered to be due to neointimal hyperplasia; accordingly intimal hyperplasia in the context of the disclosure includes restenosis. 
     Compounds of the invention may be useful in the treatment of ischemic disorders. More particularly, they may be used in the treatment (whether therapeutic or prophylactic) of an ischemic disorder in a patient having, or at risk of, non-valvular atrial fibrillation (NVAF). Ischemic disorders are conditions whose results include a restriction in blood flow to a part of the body. The term will be understood to include thrombosis and hypercoagulability in blood, tissues and/or organs. Particular uses that may be mentioned include the prevention and/or treatment of ischemic heart disease, myocardial infarction, systemic embolic events in e.g. the kidneys or spleen, and more particularly of cerebral ischemia, including cerebral thrombosis, cerebral embolism and/or cerebral ischemia associated with non-cerebral thrombosis or embolism (in other words the treatment (whether therapeutic or prophylactic) of thrombotic or ischemic stroke and of transient ischemic attack), particularly in patients with, or at risk of, NVAF. 
     Compounds of the invention may be combined and/or co-administered with another cardiovascular treatment agent. There are large numbers of cardiovascular treatment agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be selected for use with a product of the disclosure for the prevention of cardiovascular disorders by combination drug therapy. Such an agent can be one or more agents selected from, but not limited to several major categories, namely, a lipid-lowering drug, including an IBAT (ileal Na + /bile acid cotransporter) inhibitor, a fibrate, niacin, a statin, a CETP (cholesteryl ester transfer protein) inhibitor, and a bile acid sequestrant, an anti-oxidant, including vitamin E and probucol, a IIb/IIIa antagonist (e.g. abciximab, eptifibatide, tirofiban), an aldosterone inhibitor (e.g. spirolactone and epoxymexrenone), an adenosine A2 receptor antagonist (e.g. losartan), an adenosine A3 receptor agonist, a beta-blocker, acetylsalicylic acid, a loop diuretic and an ACE (angiotensin converting enzyme) inhibitor. 
     Compounds of the invention may further be combined and/or co-administered with thrombolytics such as tissue plasminogen activator (natural, recombinant or modified), streptokinase, urokinase, prourokinase, anisoylated plasminogen-streptokinase activator complex (APSAC), animal salivary gland plasminogen activators, and the like, in the treatment of thrombotic diseases, in particular myocardial infarction. The compounds of the disclosure may be combined and/or co-administered with any antithrombotic agent with a different mechanism of action, such as the antiplatelet agents acetylsalicylic acid, ticlopidine, clopidogrel, thromboxane receptor and/or synthetase inhibitors, prostacyclin mimetics and phosphodiesterase inhibitors and ADP-receptor (P 2  T) antagonists. 
     In particular, compounds of the invention may be combined and/or co-administered with a cardioprotectant, for example an adenosine A1 or A3 receptor agonist. In particular, the compounds may be used in combination or co-administration with a lipid-lowering drug, a fibrate, niacin, a statin, a CETP inhibitor, a bile acid sequestrant, an anti-oxidant, a IIb/IIIa antagonist, an aldosterone inhibitor, an A2 antagonist, an A3 agonist, a beta-blocker, acetylsalicylic acid, a loop diuretic, an ace inhibitor, an antithrombotic agent with a different mechanism of action, an antiplatelet agent, a thromboxane receptor and/or synthetase inhibitor, a fibrinogen receptor antagonist, a prostacyclin mimetic, a phosphodiesterase inhibitor, an ADP-receptor (P 2  T) antagonist, a thrombolytic, a cardioprotectant or a COX-2 inhibitor. More particularly, a compound or product of the invention may be used in conjunction with a non-steroidal anti-inflammatory drug (NSAID), e.g. a COX-2 inhibitor, and used to treat or prevent an inflammatory disease or condition, for example nephritis, systemic lupus, erythematosus, rheumatoid arthritis, glomerulonephritis, vasculitis and sarcoidosis. Accordingly, the compounds of the disclosure may be combined and/or co-administered with an NSAID. 
     Formulations &amp; Administration 
     Compounds of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, as an oral or nasal spray or via inhalation, The compounds may be administered in the form of pharmaceutical preparations comprising prodrug or active compound either as a free compound or, for example, a pharmaceutically acceptable non-toxic organic or inorganic acid or base addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses. 
     Typically, therefore, the pharmaceutical compounds of the invention may be administered orally or parenterally (“parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.) to a host to obtain an protease-inhibitory effect. In the case of larger animals, such as humans, the compounds may be administered alone or as compositions in combination with pharmaceutically acceptable diluents, excipients or carriers. 
     Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. 
     In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require inhibition of Factor IXa activity, an appropriate dosage level may generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, e.g. once or twice per day. The dosage regimen may be adjusted to provide the optimal therapeutic response. 
     According to a further aspect of the invention there is thus provided a pharmaceutical composition including a compound of the invention, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     Pharmaceutical compositions of this invention for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. 
     These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol or phenol sorbic acid. It may also be desirable to include isotonic agents such as sugars or sodium chloride, for example. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents (for example aluminum monostearate and gelatin) which delay absorption. 
     In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. 
     Injectable depot forms may be made by forming microencapsule matrices of the drug in biodegradable polymers, for example polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. 
     Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or one or more: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol, for example. 
     Oral formulations may contain a dissolution aid. Examples of dissolution aids include nonionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g. sorbitan trioleate), polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g. chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acid and salts thereof, and glycine or taurine conjugate thereof); ionic surface active agents, such as sodium laurylsulfate, fatty acid soaps, alkylsulfonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts. 
     The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion. Examples of embedding compositions include polymeric substances and waxes. 
     The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. 
     The active compounds may be in finely divided form, for example it may be micronised. 
     Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof. 
     Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. 
     Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p 33 et seq. 
     Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. 
     In a specific aspect, the present invention provides products, particularly kits, for producing a single-dose administration unit. The products (kits) may each contain both a first container having the active compound (optionally combined with additives, for example anti-oxidant, preservative and, in some instances, tonicity agent) and a second container having the carrier/diluent (for example water, optionally containing one or more additives, for example tonicity agent). As examples of such products may be mentioned single and multi-chambered (e.g. dual-chamber) pre-filled syringes; exemplary pre-filled syringes are available from Vetter GmbH, Ravensburg, Germany. Such dual chamber syringes or binary syringes will have in one chamber a dry preparation including or consisting of the active compound and in another chamber a suitable carrier or diluent such as described herein. The two chambers are joined in such a way that the solid and the liquid mix to form the final solution. 
     The following Examples illustrate the invention. 
     EXAMPLES 
     General procedures for obtaining compounds of the invention are described below, together with specific Examples of the synthesis and inhibitory activities of particular compounds of the invention. It will be appreciated that these processes are provided solely for the purpose of illustrating the invention and should not be construed as limiting. A process utilising similar or analogous reagents and/or conditions known to one skilled in the art may also be used to obtain a compound of the invention. 
     Scheme 1: General Procedure for the Synthesis of 6-Substituted Benzothiophene Analogues 
     A general methodology for synthesising compounds of the invention is shown in Scheme 1 below: 
     
       
         
         
             
             
         
       
     
     Step (i) 
     In step (i) of Scheme 1, intermediate 1 is either coupled with a benzene or thiophene alcohol by Misunobu reaction, or alkylated with a benzene or thiophene halide in the presence of a base. 
     Intermediate 1 may be synthesised by the route shown in Scheme 2. 
     Many benzylic halides or alcohols are commercially available. Where they are not commercially available, they may be prepared either by bromination from corresponding phenyl acetic acid (Scheme 3) or from corresponding aldehyde by a cyanohydrin reaction (Scheme 4). Thiophene alcohols can be synthesised by reduction from corresponding aldehydes or ketones (Scheme 5). 
     In step (ii), the Boc protecting group is then removed with an acid (such as TFA, HCl or formic acid) or by magnesium perchlorate when the products are acid sensitive, such as most thiophene analogues. 
     By way of example, intermediate 7 was synthesised according to step (i) of Scheme 1. 
     
       
         
         
             
             
         
       
     
     1 (150 mg, 0.51 mmol) was stirred with 4-chloromandelate (155 mg, 0.77 mmol) in dry THF at room temperature under argon followed by triphenylphosphine (202.1 mg, 0.77 mmol). A solution (1 ml) of DEAD in dry THF was then added dropwise over a period of 15 minutes. The reaction mixture was stirred for 15 hours and purified through a column (silica gel, 2:8 ethyl acetate:hexane) to furnish 198 mg of the title compound 7 (81%).  1 H NMR (DMSO-d6): δ 3.73 (s, 3H, CH 3 ), 6.31 (s, 1H, alpha H), 7.43 (d, 1H, ArH), 7.58 (m, 2H, m-Cl—ArH), 7.65 (m, 2H, o-Cl—ArH), 7.84 (s, 1H, ArH), 8.04 (d, 1H, ArH), 8.33 (s, 1H, ArH), 9.4 (NH, bs). MS: ES+ 476 (M+H). 
     Step (ii) 
     In step (ii) of Scheme 1, the Boc protecting group is then removed with an acid (such as TFA, HCl or formic acid) or by magnesium perchlorate when the products are acid sensitive, such as most thiophene analogues. 
     Scheme 2: Synthesis of Intermediate 1 
     Intermediate 1 of Scheme 1 may be obtained according to the procedure of Scheme 2: 
     
       
         
         
             
             
         
       
     
     a. Synthesis of Thioacetonitrile 2 
     
       
         
         
             
             
         
       
     
     Acetylthioacetonitrile (23.00 g, 0.198 mol) was added to a solution of dry methanol (150 ml) containing amberlyst-15 (5 g) and the reaction mixture was refluxed at 85° C. under argon overnight. The reaction mixture was then allowed to cool to room temperature, and then filtered into a vessel containing dry amberlyst-15 (5 g). Solvent removal under vacuum gave a brown oil (12.13 g, 84%).  1 H NMR (DMSO-d6): δ 3.49 (s, 2H), 3.98 (s, 1H). 
     b. Synthesis of 2-cyano-6-methoxybenzothiophene 3 
     
       
         
         
             
             
         
       
     
     Thioacetonitrile 1 was added dropwise to a solution of 2-fluoro-4-methoxybenzaldehyde and DBU in anhydrous DMF under argon at room temperature. The reaction mixture was stirred for 20 minutes prior to heating to 60° C. and stirring at 60° C. overnight. Solvent was removed under vacuum, and the residue was dissolved in DCM, and then washed with 1M HCl, water. The aqueous layer was extracted with DCM. Combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure. Part of the pure product was obtained by recrystallising the crude residue from EtOAc/hexane (11.40 g), and more product was obtained by flash column chromatography of the concentrated mother liquors (silica gel, 2:8 EtOAc/hexane) to yield a yellow solid (9.23 g), yield: 68.1%.  1 H NMR (DMSO-d6): δ 3.76 (s, 3H), 7.07 (d, 1H), 7.65 (s, 1H), 7.81 (d, 1H), 8.18 (s, 1H). MS: ES+ 189.8 (M+H). 
     c. Synthesis of 2-cyano-6-hydroxybenzothiophene 4 
     
       
         
         
             
             
         
       
     
     1.0 M Boron tribromide solution in DCM (328 ml, 0.328 mol) was added dropwise to a cooled solution of 2-cyano-6-methoxybenzothiophene (20.6 g, 0.109 mol) in DCM (350 ml) at −78° C. under argon. The reaction mixture was stirred at −78° C. for 1 hour, then allowed to warm to room temperature and stirring at room temperature overnight. The excess reagent was quenched by ice and saturated NaHCO 3  solution. The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic layers were dried over magnesium sulphate, and concentrated to afford a tan coloured solid (12.90 g, 67%).  1 H NMR (DMSO-d6): δ 7.09 (d, 1H), 7.49 (s, 1H), 7.90 (d, 1H), 8.29 (s, 1H), 10.40 (s, 1H, D 2 O labile). MS: ES+ 175.81 (M+H). 
     d. Synthesis of 6-allyloxy-2-cyanobenzothiophene 5 
     
       
         
         
             
             
         
       
     
     Sodium hydride (60% in mineral oil) (3.25 g, 0.081 mol) was added in several portions to a stirred cold solution of 2-cyano-6-hydroxybenzothiophene (12.86 g, 0.0735 mol) in DMSO at 5° C. under argon, and the reaction mixture was stirred for 20 minutes. Allyl bromide (6.96 ml, 0.081 mol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. Reaction mixture was poured onto iced water (250 ml) and extracted with EtOAc. The combined organic extracts were washed with 1M NaOH solution, dried over magnesium sulphate and concentrated under reduced pressure to afford a light brown solid (15.81 g, 100%).  1 H NMR (DMSO-d6): δ 4.46 (d, 2H), 5.31 (d, 1H), 5.41 (d, 1H), 6.04 (m, 1H), 7.15 (d, 1H), 7.71 (s, 1H), 7.89 (d, 1H), 8.26 (s, 1H). MS: ES+ 215.89 (M+H). 
     e. Synthesis of 6-allyloxy-2-amidinebenzothiophene 6a 
     
       
         
         
             
             
         
       
     
     1M Lithiumtrimethylsilylamide solution in THF (95.60 ml, 0.0956 mol) was added to a stirred cooled solution of 6-allyloxy-2-cyanobenzothiophene (15.81 g, 0.0735 mol) in THF (200 ml) at −78° C. under argon. The reaction mixture was stirred for 10 minutes at −78° C. then allowing the temperature to rise to room temperature and stirred for 1.5 hours at room temperature. 4M HCl solution in dioxane (20 ml, 0.08 mol) was added and stirred at room temperature for 16 hours. Solvent removal under vacuum yielded a brown semi-solid (40.485 g), no further purification was undertaken.  1 H NMR (DMSO-d6): δ 4.69 (s, 2H), 5.30 (d, 1H), 5.45 (d, 1H), 6.05-6.12 (m, 1H), 7.16 (d, 1H), 7.77 (s, 1H), 7.94 (d, 1H), 8.34 (s, 1H), 9.30 (b, 3H). MS: ES+ 232.91 (M+H). 
     f. Synthesis of 6-allyloxy-2-(t-butyloxycarbonyl)amidinebenzothiophene 6b 
     
       
         
         
             
             
         
       
     
     To a stirred solution of crude 6-allyloxy-2-amidinebenzothiophene (40.495 g) and diisopropylethylamine (38.33 ml, 0.22 mol) in dioxane and water (1:1, 40 ml) at room temperature, di-tert-butyl-dicarbonate (19.23 g, 0.088 mol) was added and stirred for 2 hours. Reaction mixture was diluted with EtOAc, then the organic layer was separated, and aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and concentrated. The crude residue was purified by crystallisation from ether to yield a light brown solid (15.98 g). More product was obtained from the purification of concentrated mother liquid by flash chromatography (silica gel, 8:2 EtOAc/hexane) (2.316 g). Yield: 74.5%.  1 H NMR (DMSO-d6): δ 1.44 (s, 9H), 4.64 (d, 2H), 5.25 (d, 1H), 5.45 (d, 1H), 6.20 (m, 1H), 7.03 (d, 1H), 7.54 (s, 1H), 7.77 (d, 1H), 8.22 (s, 1H), 9.07 (s, 2H). MS: ES+ 333 (M+H). 
     g. Synthesis of 2-(N-t-butyloxycarbonyl)amidine-6-hydroxybenzothiophene 1 
     
       
         
         
             
             
         
       
     
     To a stirred cooled solution of tetrakis(triphenylphosphine)palladium(0) (1.27 g, 0.11% mol) and 6-allyloxy-2-(t-butyl)amidinebenzothiophene (18.296 g, 0.055 mol) in DCM (250 ml) at 0° C. under argon, phenylsilane (7.45 ml, 0.0605 mol) was added dropwise and the reaction mixture was stirred at room temperature for one hour. Dropwise addition of water was undertaken until H 2  (g) evolution ceased and stirred for 30 minutes. The organic layer was separated; aqueous layer was extracted with DCM. The combined organic layers were dried over magnesium sulphate and concentrated. Bi-phase recrystallisation using DCM and hexane was conducted on the crude residue to afford a yellow solid (4.494 g), and flash chromatography on concentrated mother liquors gave more product as a yellow solid (silica: 20% EtOAc/hexane) (3.692 g). Yield: 58%.  1 H NMR (DMSO-d6): δ 1.67 (s, 9H), 7.12 (d, 1H), 7.46 (s, 1H), 7.92 (d, 1H), 8.40 (s, 1H), 9.27 (s, 2H), 10.19 (s, 1H). MS: ES+ 292.94 (M+H). 
     Scheme 3: Synthesis of Benzyl Halides 
     Benzyl halides (for use in step (i) of Scheme 1) may be synthesised according to Scheme 3: 
     
       
         
         
             
             
         
       
     
     By way of example, methyl α-bromo-3,4-difluorophenylacetate 8 was synthesised according to Scheme 3. 
     
       
         
         
             
             
         
       
     
     3,4-Difluoroacetic acid (500 mg, 2.90 mmol) and thionyl chloride (848 μl, 11.62 mmol) were stirred at 65° C. for 30 minutes. (N.B. NMR showed a slight shift downfield of the a protons from 3.53 to 3.63 ppm). To this solution, NBS (1.185 g, 6.66 mmol) and 7 drops of HBr/HOAc were added with more CCl 4  and heated at 70° C. for 10 minutes and then 85° C. for 2.5 hrs. The succinimide precipitate was filtered and the reaction mixture concentrated. The latter was heated with methanol with a few drops of HCl (4M in 1,4-dioxane) at 65° C. for 30 minutes. The product was purified through a column (silica gel, 1:9 MeOH:DCM) to provide the desired compound.  1 H NMR (DMSO-d6): δ 3.74 (s, CO 2 Me, 3H), 5.99 (s, α-H, 1H), 7.11 (d, o-H, 1H), 7.34-7.31 (m, o- &amp; p-Hs, 2H). MS: ES+ 266.95 (M+H). 
     Scheme 4: Synthesis of Benzyl Alcohols 
     Benzyl alcohols (for use in step (i) of Scheme 1) may be synthesised according to Scheme 4: 
     
       
         
         
             
             
         
       
     
     By way of example, methyl 3-methoxycarbonylmandelate 9 was synthesised according to Scheme 4. 
     
       
         
         
             
             
         
       
     
     A mixture of methyl 3-formylbenzoate (1 g, 6 mmol), acetone cyanohydrin (0.7 mL, 9 mmol), sodium cyanide (7.1 mg, 0.145 mmol) and tetrabutylammonium chloride (11 mg, 0.04 mmol) in DCM (5 mL) and water (2.5 mL) was stirred at room temperature for 18 hours. The organic layer was separated, and aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried over magnesium sulfate. Solvent removal gave a yellow oil. Concentrated hydrochloric acid (5 mL) was added to this oil, and the mixture is stirred at 100° C. for 2 hours. After cooling, the reaction mixture was extracted with EtOAc, and organic layer was washed with water, then dried over magnesium sulphate, and concentrated to give an off-white solid (1.08 g). Methanol (30 mL) and 0.5 mL 4M HCl solution in dioxane were added to this solid, and the reaction solution was stirred at refux temperature for one hour. Solvent was removed, and the residue was purified by column chromatography (silica gel, 1:1 hexane:EtOAc) to afford 9 as a white solid (0.69 g, 51.3% over the three steps).  1 H NMR (CD 3 OD): δ 3.59 (s, 3H, ArCOOCH 3 ), 3.80 (s, 3H, COOCH 3 ), 5.17 (s, 1H, CH), 7.38 (t, 1H, ArH), 7.58 (d, 1H, ArH), 7.86 (d, 1H, ArH), 8.00 (s, 1H, ArH). MS: ES+ 225 (M+H). 
     Schemes 5 and 6: Synthesis of Substituted Thiophene Alcohols 
     Thiophene alcohols (for use in step (i) of Scheme 1) may be synthesised according to Scheme 5 or Scheme 6: 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     By way of example, 5-chloro-2-thienylmethanol 10 was synthesised according to Scheme 5. 
     
       
         
         
             
             
         
       
     
     Sodium borohydride (0.19 g, 5 mmol) was added slowly to the solution of 5-chloro-2-thiophenecarboxaldehyde (0.53 mL, 5 mmol) in methanol (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then diluted into ethyl acetate, and washed 0.5M HCl. The organic layer was dried and concentrated to give a yellow liquid as desired product (W=0.68 g, 92%).  1 H NMR (CDCl 3 ): δ 4.73 (s, 2H), 6.78-6.80 (m, 2H). 
     As another example, ethyl 2-hydroxy, 2-thienylacetate 11 was synthesised according to Scheme 6. 
     
       
         
         
             
             
         
       
     
     Sodium cyanoborohydride (0.63 g, 10 mmol) was added slowly to a solution of ethyl thiophene-2-glyoxylate (1.84 g, 10 mmol) in ethanol, water and acetic acid (8:3:1, total 70 mL). The reaction mixture was stirred at room temperature for 8 hours, then acidified with 1M HCl to a pH of 1, and extracted with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate, water, then dried over magnesium sulphate, and concentrated to afford 11 as a pale yellow oil (W=1.94 g, 100%).  1 H NMR (CDCl 3 ): δ 1.29 (t, 3H, CH 3 ), 3.59 (b, 1H, OH), 4.28-4.34 (m, 2H, COOCH2), 5.42 (d, 1H, CH), 6.99-7.02 (m, 1H), 7.12 (d, 1H), 7.29 (dd, J=2 Hz, 1H). 
     Example 1 
     Compound 219 
     
       
         
         
             
             
         
       
     
     Compound 219 was obtained according to the procedure recited in steps (i) and (ii) of Scheme 1. 
     Step (i) 
     
       
         
         
             
             
         
       
     
     2-(N-tert-butoxycarbonyl) amidino-6-(2-thienyl-2-ethoxycarbonyl)methyl benzothiophene ether 13 was obtained from intermediate 1 according to the procedure given in step (i) of Scheme 1. 
     Step (ii) 
     Magnesium perchlorate (0.03 g, 0.13 mmol) was added to a solution of 13 (56 mg, 0.119 mmol) in acetonitrile (2 mL), and the reaction solution was stirred at 80° C. for 3 hours, then concentrated. The crude product was purified by column (silica gel, 9:1 DCM: MeOH) to give compound 219 as an off-white solid (18 mg, 47%).  1 H NMR (DMSO-d6): δ 1.14 (t, 3H, CH 3 , J=7.8 Hz), 4.10-4.18 (m, 2H, COOCH 2 ), 6.21 (s, 1H, CHCOO), 6.94 (2d, J=5 Hz, 1H, ArH), 7.14 (dd, J1=2.3 Hz, J2=8.9 Hz, 1H, ArH), 7.20 (d, J=3.3 Hz, 1H, ArH), 7.38 (dd, J1=1 Hz, J2=5.1 Hz, 1H, ArH), 7.49 (d, J=2.3 Hz, 1H, ArH), 7.82 (d, J=9 Hz, 1H, ArH), 8.06 (s, 1H, ArH). MS: ES+361 (M+H). 
     Example 2 
     Compound 244 
     
       
         
         
             
             
         
       
     
     Compound 244 was obtained by Boc deprotection of Intermediate 1 using TFA. Intermediate 1 (100 mg, 0.34 mmol) was heated at 65° C. with DL-ethyl-2-bromovalerate (64.55111, 0.37 mmol) and K 2 CO 3  (52 mg, 0.37 mmol) in acetonitrile for 10 hours. This was subsequently purified through a small flash chromatography (SiO 2 , 20:80 ethyl acetate:hexane) to furnish 131 mg of the title compound 244 as a yellow solid (yield: 90%).  1 H NMR (DMSO-d6): δ 9.5 (bs, NH, 3H), 8.28 (s, ArH, 1H), 7.97 (dd, ArH, 1H), 7.68 (bs, ArH, 1H), 7.16 (d, ArH, 1H), 5.03 (t, α-H, 1H), 4.15 (q, ester CH 2 , 2H), 1.90 (q, α-CH 2 , 2H), 1.5 (dq, β-CH 2 , 2H), 1.16 (t, ester CH 3 , 3H) and 0.94 (t, χ-CH 3 , 3H). MS: ES+ 321 (M+H). 
     Example 3 
     Compound 444 
     Compound 444 was obtained according to the procedure described in Scheme 6 below: 
     
       
         
         
             
             
         
       
     
     Example 4 
     Compound 446 
     Compound 446 was obtained according to the procedure described in Scheme 7 below: 
     
       
         
         
             
             
         
       
     
     Example 5 
     Activity Assay 
     Various compounds of the disclosure were tested for their activity against Factor IXa, Factor Xa, uPA, plasmin, and thrombin. Examples of the testing procedures are described below: 
     Method A 
     100 μl Factor IXa (5 μg/ml in assay buffer) and 20 μl vehicle or compound solution were added to 60 μl assay buffer (50 mM Tris, 100 mM NaCl, 5 mM CaCl 2 , 0.5% PEG 6000, pH 7.4) and incubated for 5 minutes at 37° C. After the incubation period, 20 μl of factor IXa substrate (S2366, 5 mM in assay buffer) was added and changes in Vmax monitored on a plate reader for 10 minutes using a wavelength of 405 nm at 37° C. 
     Method B 
     50 μl Factor Xa (40 ng/ml in assay buffer) and 20 μl vehicle or compound solution were added to 110 μl assay buffer (100 mM Na orthophosphate (80% Na 2 HPO 4  and 20% NaH 2 PO 4 ), 200 mM NaCl, 0.5% PEG 6000, 0.02% Na azide, pH 7.5) and incubated for 5 minutes at 37° C. After the incubation period, 20 μl of factor Xa substrate (50 μM, S2765) was added and changes in Vmax monitored on a plate reader for 10 minutes using a wavelength of 405 nm at 37° C. 
     Method C 
     50 μl Plasmin (75 ng/ml in assay buffer) and 20 μl vehicle or compound solution were added to 110 μl assay buffer (100 mM Na orthophosphate (80% Na 2 HPO 4  and 20% NaH 2 PO 4 ), 200 mM NaCl, 0.5% PEG 6000, 0.02% Na azide, pH 7.5) and incubated for 5 minutes at 37° C. After the incubation period, 20 μl of plasmin substrate (7 mM, S2366) was added and changes in Vmax monitored on a plate reader for 10 minutes using a wavelength of 405 nm at 37° C. 
     Method D 
     50 μl Urokinase (33.3 ng/ml in assay buffer) and 20 μl vehicle or compound solution were added to 110 μl assay buffer (100 mM Na orthophosphate (80% Na 2 HPO 4  and 20% NaH 2 PO 4 ), 200 mM NaCl, 0.5% PEG 6000, 0.02% Na azide, 0.01% BSA, pH 7.5) and incubated for 5 minutes at 37° C. After the incubation period, 20 μl of urokinase substrate (1.6 mM, S2444) was added and changes in Vmax monitored on a plate reader for 10 minutes using a wavelength of 405 nm at 37° C. 
     The results of the tests showed that the listed compounds include those which have an IC 50  for Factor IXa of 50 μm or less.