Patent Publication Number: US-2011071197-A1

Title: Bis-aryl compounds for use as medicaments

Description:
FIELD OF THE INVENTION 
     This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of the production of leukotrienes, such as leukotriene C 4 . The compounds are of potential utility in the treatment of respiratory and/or inflammatory diseases. The invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production. 
     BACKGROUND OF THE INVENTION 
     Arachidonic acid is a fatty acid that is essential in the body and is stored in cell membranes. They may be converted, e.g. in the event of inflammation, into mediators, some of which are known to have beneficial properties and others that are harmful. Such mediators include leukotrienes (formed by the action of 5-lipoxygenase (5-LO), which acts by catalysing the insertion of molecular oxygen into carbon position 5) and prostaglandins (which are formed by the action of cyclooxygenases (COXs)). Huge efforts have been devoted towards the development of drugs that inhibit the action of these metabolites as well as the biological processes that form them. 
     Of the leukotrienes, leukotriene (LT) B 4  is known to be a strong proinflammatory mediator, while the cysteinyl-containing leukotrienes C 4 , D 4  and E 4  (CysLTs) are mainly very potent bronchoconstrictors and have thus been implicated in the pathobiology of asthma. It has also been suggested that the CysLTs play a role in inflammatory mechanisms. The biological activities of the CysLTs are mediated through two receptors designated CysLT 1  and CysLT 2 , but the existence of additional CysLT receptors has also been proposed. Leukotriene receptor antagonists (LTRAs) have been developed for the treatment of asthma, but they are often highly selective for CysLT 1 . It may be hypothesised that better control of asthma, and possibly also COPD, may be attained if the activity of both of the CysLT receptors could be reduced. This may be achieved by developing unselective LTRAs, but also by inhibiting the activity of proteins, e.g. enzymes, involved in the synthesis of the CysLTs; 5-LO, 5-lipoxygenase-activating protein (FLAP), and leukotriene C 4  synthase may be mentioned. However, a 5-LO or a FLAP inhibitor would also decrease the formation of LTB 4 . For a review on leukotrienes in asthma, see H.-E Claesson and S.-E. Dahlén  J. Internal Med.  245, 205 (1999). 
     There are many diseases/disorders that are inflammatory in their nature or have an inflammatory component. One of the major problems associated with existing treatments of inflammatory conditions is a lack of efficacy and/or the prevalence of side effects (real or perceived). 
     Asthma is a chronic inflammatory disease affecting 6% to 8% of the adult population of the industrialized world. In children, the incidence is even higher, being close to 10% in most countries. Asthma is the most common cause of hospitalization for children under the age of fifteen. 
     Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled β-agonists. Patients with more severe asthma are typically treated with anti-inflammatory compounds on a regular basis. 
     There is a considerable under-treatment of asthma, which is due at least in part to perceived risks with existing maintenance therapy (mainly inhaled corticosteroids). These include risks of growth retardation in children and loss of bone mineral density, resulting in unnecessary morbidity and mortality. As an alternative to steroids, LTRAs have been developed. These drugs may be given orally, but are considerably less efficacious than inhaled steroids and usually do not control airway inflammation satisfactorily. 
     This combination of factors has led to at least 50% of all asthma patients being inadequately treated. 
     A similar pattern of under-treatment exists in relation to allergic disorders, where drugs are available to treat a number of common conditions but are underused in view of apparent side effects. Rhinitis, conjunctivitis and dermatitis may have an allergic component, but may also arise in the absence of underlying allergy. Indeed, non-allergic conditions of this class are in many cases more difficult to treat. 
     Chronic obstructive pulmonary disease (COPD) is a common disease affecting 6% to 8% of the world population. The disease is potentially lethal, and the morbidity and mortality from the condition is considerable. At present, there is no known pharmacological treatment capable of changing the course of COPD. 
     Other inflammatory disorders which may be mentioned include:
         (a) pulmonary fibrosis (this is less common than COPD, but is a serious disorder with a very bad prognosis. No curative treatment exists);   (b) inflammatory bowel disease (a group of disorders with a high morbidity rate. Today only symptomatic treatment of such disorders is available); and   (c) rheumatoid arthritis and osteoarthritis (common disabling inflammatory disorders of the joints. There are currently no curative, and only moderately effective symptomatic, treatments available for the management of such conditions).       

     Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several malignancies are known to have inflammatory components adding to the symptomatology of the patients. 
     Thus, new and/or alternative treatments for respiratory and/or inflammatory disorders would be of benefit to all of the above-mentioned patient groups. In particular, there is a real and substantial unmet clinical need for an effective anti-inflammatory drug capable of treating inflammatory disorders, in particular asthma and COPD, with no real or perceived side effects. 
     The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. 
     International patent application WO 2007/113337 discloses a fluorescence based test system, which is employed to measure the formation of the HIV gp41 six-helix bundle. Various biaryl compounds were the subject of such a test. 
     Various compounds have been disclosed in inter alia journal article  Macromolecules  1993, 26, 5143-5148 by D. E. Fjare, in Russian journal article  Vysokomolekulyarnye Soedineniya , Seiya A 1987, 29(11), 2333-9, Russian patents SU759548, SU749859 and SU759548, and Indian journal article  E - journal of Chemistry  2004, 1(5), 243-250. However, there is no disclosure that the compounds disclosed in any of these documents may be useful as medicaments. 
     International patent application WO 2005/075410 discloses various compounds for use as medicaments. However, this document does not disclose biaryl ring systems, in which each aromatic ring is further substituted (directly or via a linker group) with another aromatic group. 
     US patent application US 2005/0014169 and international patent application WO 2004/076640 both disclose various biaryl compounds that may act as nuclease inhibitors, with the latter document further stating that the compounds disclosed therein may be useful in the treatment of cancer. However, there is no mention in either document that the compounds disclosed therein may be useful in the treatment of inflammation. 
     International patent application WO 2006/125593 and European patent application EP 1 113 000 both disclose compounds that may have potential use in the treatment of inflammation. However, the former document predominantly relates to biaryl ring systems that are not further substituted with aromatic groups, and the latter mainly relates to biaryl compounds containing a cycloalkylamido moiety, but not a carboxylic acid group, or isostere thereof. 
     International patent applications WO 2007/113254, WO 2005/053609, WO 01/066098, WO 2006/104957, WO 2006/055625, WO 2005/042520 and WO 01/023347 as well as U.S. Pat. No. 6,251,917, US 2004/0229891, US 2004/0082641, US 2005/0277640 and US 2007/0066660 all disclose various biaryl compounds. However, none of these documents mention that the compounds disclosed therein may be useful as inhibitors of LTC 4  synthase, and therefore of use in the treatment of inflammation. 
     US patent application US 2004/0209882 discloses various methods and compositions of triazine compounds, which may be useful in treating pathophysiological conditions. However, there is no specific disclosure in this document of two aromatic groups linked with an oxygen atom, each of which aromatic groups are further substituted with an aromatic group. 
     Japanese patent application JP 3056431 discloses compounds containing two phenyl groups linked by way of a carbon, oxygen or sulfur atom, which may be useful in treating inflammatory diseases (e.g. arthritis). However, there is no specific disclosure in this document of two aromatic groups linked with an oxygen or sulfur atom, each aromatic group being further substituted with an aromatic group. 
     DISCLOSURE OF THE INVENTION 
     According to the invention, there is provided a compound of formula I, 
     
       
         
         
             
             
         
       
     
     wherein
 
either one of D 2a  and D 2b  represents D 2 , and the other represents —C(-L 2 -Y 2 )═;
 
Y represents —O— or —S(O) m —;
 
each of D 1 , D 2  and D 3  respectively represent —C(R 1a )═, —C(R 1b )═ and —C(R 1c )═, or,
 
each of D 1 , D 2  and D 3  may alternatively and independently represent —N═;
 
ring A represents:
 
     
       
         
         
             
             
         
       
     
     each of E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2c )═, —C(R 2d )═ and —C(H)═, or, each of E a1 , E a2 , E a3 , E a4  and E a5  may alternatively and independently represent —N═;
 
one of R 2b , R 2c  and R 2d  represents the requisite -L 3 -Y 3  group, and the others independently represent hydrogen, -L 1a -Y 1a  or a substituent selected from X 1 ;
 
     
       
         
         
             
             
         
       
     
     E b1  and E b2  respectively represent —C(R 3a )═ and —C(R 3b )═;
 
Y b  represents —C(R 3c )═ or —N═;
 
W b  represents —N(R 3d )—, —O— or —S—;
 
one of R 3a , R 3b  and, if present, R 3c  and R 3d , represents the requisite -L 3 -Y 3  group, and the remaining R 3a , R 3b  and (if present) R 3c  substituents represents hydrogen, -L 1a -Y 1a  or a substituent selected from X 2 , and the remaining R 3d  substituent (if present) represents hydrogen or a substituent selected from R z1 ; or
 
     
       
         
         
             
             
         
       
     
     E c1  and E c2  each respectively represent —C(R 4a )═ and —C(R 4b )═;
 
Y c  represents —C(R 4e )═ or —N═;
 
W c  represents —N(R 4d )—, —O— or —S—;
 
one of R 4a , R 4b  and, if present, R 4c  and R 4d  represents the requisite -L 3 -Y 3  group, and the remaining R 4a , R 4b  and, if present, R 4c  substituents represent hydrogen, -L 1a -Y 1a  or a substituent selected from X 3 , and the remaining R 4d  substituent (if present) represents hydrogen or a substituent selected from R z2 ;
 
R z1  and R z2  independently represent a group selected from Z 1a ;
 
R 1a , R 1b  and R 1c  independently represent hydrogen or a group selected from Z 2a , or, halo, —CN, —N(R 6b )R 7b , —N(R 5d )C(O)R 6c , —N(R 5e )C(O)N(R 6d )R 7d , —N(R 5f )C(O)OR 6e , —N 3 , —NO 2 , —N(R 5g )S(O) 2 N(R 6f )R 7f , —OR 5h , —OC(O)N(R 6g )R 7g , —OS(O) 2 R 5i , —N(R 5k )S(O) 2 R 5m , —OC(O)R 5n , —OC(O)OR 5p  or —OS(O) 2 N(R 6i )R 7i ;
 
X 1 , X 2  and X 3  independently represent a group selected from Z 2a , or, halo, —CN, —N(R 6b )R 7b , —N(R 5d )C(O)R 6c , —N(R 5e )C(O)N(R 6d )R 7d , —N(R 5f )C(O)OR 6e , —N 3 , —NO 2 , —N(R 5g )S(O) 2 N(R 6f )R 7f , —OR 5h , —OC(O)N(R 6g )R 7g , —OS(O) 2 R 5i , —N(R 5k )S(O) 2 R 5m , —OC(O)R 5n , —OC(O)OR 5p  or —OS(O) 2 N(R 6i )R 7i ;
 
Z 1a  and Z 2a  independently represent —R 5a , —C(O)R 5b , —C(O)OR 5c , —C(O)N(R 6a )R 7a , —S(O) m R 5j  or —S(O) 2 N(R 6h )R 7h ;
 
R 5b  to R 5h , R 5j , R 5k , R 5n , R 6a  to R 6i , R 7a , R 7b , R 7d  and R 7f  to R 7i  independently represent, on each occasion when used herein, H or R 5a ; or
 
any of the pairs R 6a  and R 7a , R 6b  and R 7b , R 6d  and R 7d , R 6f  and R 7f , R 6g  and R 7g , R 6h  and R 7h  or R 6i  and R 7i  may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from F, Cl, ═O, —OR 5h  and R 5a ;
 
R 5i , R 5m  and R 5p  independently represent R 5a ;
 
R 5a  represents, on each occasion when used herein, C 1-6  alkyl optionally substituted by one or more substituents selected from halo, —CN, —N 3 , ═O, —OR 8a , —N(R 8b )R 8c , —S(O) n R 8d , —S(O) 2 N(R 8e )R 8f  and/or —OS(O) 2 N(R 8g )R 8h ;
 
n represents 0, 1 or 2;
 
R 8a , R 8b , R 8d , R 8e  and R 8g  independently represent H or C 1-6  alkyl optionally substituted by one or more substituents selected from halo, ═O, —OR 11a , —N(R 12a )R 12b  and/or —S(O) 2 -M 1 ;
 
R 8c , R 8f  and R 8h  independently represent H, —S(O) 2 CH 3 , —S(O) 2 CF 3  or C 1-6  alkyl optionally substituted by one or more substituents selected from F, Cl, ═O, —OR 13a , —N(R 14a )R 14b  and/or —S(O) 2 -M 2 ; or
 
R 8b  and R 8c , R 8e  and R 8f  or R 8g  and R 8h  may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from F, Cl, ═O and/or C 1-3  alkyl optionally substituted by one or more substituents selected from ═O and fluoro;
 
M 1  and M 2  independently represent —CH 3 , —CH 2 CH 3 , —CF 3  or —N(R 15a )R 15b ;
 
R 11a  and R 13a  independently represent H, —CH 3 , —CH 2 CH 3 , —CF 3  or —CHF 2 ;
 
R 12a , R 12b , R 14a , R 14b , R 15a  and R 15b  independently represent H, —CH 3  or —CH 2 CH 3 ,
 
Y 1  and Y 1a  independently represent, on each occasion when used herein, —N(H)SO 2 R 9a , —C(H)(CF 3 )OH, —C(O)CF 3 , —C(OH) 2 CF 3 , —C(O)OR 9b , —S(O) 3 R 9c , —P(O)(OR 9d ) 2 , —P(O)(OR 9e )N(R 10f )R 9f , —P(O)(N(R 10g )R 9g ) 2 , —B(OR 9h ) 2 , —C(CF 3 ) 2 OH, —S(O) 2 N(R 10i )R 9i  or any one of the following groups:
 
     
       
         
         
             
             
         
       
     
     R 9a  represents on each occasion when used herein, C 1-8  alkyl, a heterocycloalkyl group, an aryl group or a heteroaryl group which are optionally substituted by one or more substituents selected from G 1  and/or Z 1 ;
 
R 9b  to R 9z , R 9aa , R 9ab , R 10f , R 10g , R 10i  and R 10j  independently represent, on each occasion when used herein, C 1-8  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 1  and/or Z 1 ; or
 
R 9b  to R 9z , R 9aa , R 9ab , R 10f , R 10g , R 10i  and R 10j  independently represent, on each occasion when used herein, hydrogen; or
 
any pair of R 9f  and R 10f , R 9g  and R 10g , and R 9i  and R 10i , may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen), in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from F, Cl, ═O, —OR 5h  and/or R 5a ;
 
Y 2  and Y 3  independently represent an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A;
 
A represents, on each occasion when used herein:
 
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
 
II) C 1-8  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 1  and/or Z 1 ; or
 
III) a G 1  group;
 
G 1  represents, on each occasion when used herein, halo, cyano, —N 3 , —NO 2 , —ONO 2  or -A 1 -R 16a ;
 
wherein A 1  represents a single bond or a spacer group selected from —C(O)A 2 -, —S—, —S(O) r A 3 -, —N(R 17a )A 4 - or —OA 5 -, in which:
 
A 2  represents a single bond, —O—, —N(R 17b )— or —C(O)—;
 
A 3  represents a single bond, —O— or —N(R 17c )—;
 
A 4  and A 5  independently represent a single bond, —C(O)—, —C(O)N(R 17d )—, —C(O)O—, —S(O) r — or —S(O) r N(R 17e )—;
 
Z 1  represents, on each occasion when used herein, ═O, ═S, ═NOR 16h , ═NS(O) 2 N(R 17f )R 16c , ═NCN or ═C(H)NO 2 ;
 
B represents, on each occasion when used herein:
 
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G 2 ;
 
II) C 1-8  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 2  and/or Z 2 ; or
 
III) a G 2  group;
 
G 2  represents, on each occasion when used herein, halo, cyano, —N 3 , —NO 2 , —ONO 2  or -A 6 -R 18a ;
 
wherein A 6  represents a single bond or a spacer group selected from —C(O)A 7 -, —S—, —S(O) r A 8 -, —N(R 19a )A 9 - or —OA 10 -, in which:
 
A 7  represents a single bond, —O—, —N(R 19b )— or —C(O)—;
 
A 8  represents a single bond, —O— or —N(R 19c )—;
 
A 9  and A 10  independently represent a single bond, —C(O)—, —C(O)N(R 19d )—, —C(O)O—, —S(O) r — or —S(O) r N(R 19e )—;
 
Z 2  represents, on each occasion when used herein, ═O, ═S, ═NOR 18b , ═NS(O) 2 N(R 19f )R 18c , ═NCN or ═C(H)NO 2 ;
 
R 16a , R 16b , R 16c , R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 18a , R 18b , R 18c , R 19a , R 19b , R 19c , R 19d , R 19e  and R 19f  are independently selected from:
 
i) hydrogen;
 
ii) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G 3 ;
 
iii) C 1-8  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 3  and/or Z 3 ; or
 
any pair of R 16a  to R 16c  and R 17a  to R 17f , and/or R 18a  to R 18c  and R 19a  to R 19f , may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G 3  and/or Z 3 ;
 
G 3  represents, on each occasion when used herein, halo, cyano, —N 3 , —NO 2 , —ONO 2  or -A 11 -R 20a ;
 
wherein A 11  represents a single bond or a spacer group selected from —C(O)A 12 -, —S—, —S(O) r A 13 -, —N(R 21a )A 14 - or —OA 15 -, in which:
 
A 12  represents a single bond, —O—, —N(R 21b )— or —C(O)—;
 
A 13  represents a single bond, —O— or —N(R 21c )—;
 
A 14  and A 15  independently represent a single bond, —C(O)—, —C(O)N(R 21d )—, —C(O)O—, —S(O) r — or —S(O) r N(R 21e )—;
 
Z 3  represents, on each occasion when used herein, ═O, ═S, ═NOR 20b , ═NS(O) 2 N(R 21f )R 20c , ═NCN or ═C(H)NO 2 ;
 
each r independently represents, on each occasion when used herein, 1 or 2;
 
R 20a , R 20b , R 20c , R 21a , R 21b , R 21c , R 21d , R 21e  and R 21f  are independently selected from:
 
i) hydrogen;
 
ii) C 1-6  alkyl or a heterocycloalkyl group, both of which groups are optionally substituted by one or more substituents selected from halo, C 1-4  alkyl, —N(R 22a )R 23a , —OR 22b  and ═O; and
 
iii) an aryl or heteroaryl group, both of which are optionally substituted by one or more substituents selected from halo, C 1-4  alkyl (optionally substituted by one or more substituents selected from ═O, fluoro and chloro), —N(R 22c )R 23b  and —OR 22d ; or
 
any pair of R 20a  to R 20c  and R 21a  to R 21f  may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 or 2 double bonds, which ring is optionally substituted by one or more substituents selected from halo, C 1-4  alkyl, —N(R 22e )R 23c , —OR 22f  and ═O;
 
L 1  and L 1a  independently represent a single bond or C 1-6  alkylene in which any one of the carbon atoms may be replaced by Q;
 
Q represents —C(R y1 )(R y2 )—, —C(O)— or —O—;
 
R y1  and R y2  independently represent H, F or X 4 ; or
 
R y1  and R y2  may be linked together to form a 3- to 6-membered ring, which ring optionally contains a heteroatom, and which ring is optionally substituted by one or more substituents selected from F, Cl, ═O and X 5 ;
 
L 2  and L 3  independently represent a single bond or a spacer group selected from —(CH 2 ) p —C(R y3 )(R y4 )—(CH 2 ) q -A 16 -, —(CH 2 ) p —C(O)A 17 -, —(CH 2 ) p —S—, (CH 2 ) p —SC(R y3 )(R y4 )—, —(CH 2 ) p —S(O)A 21 -, —(CH 2 ) p —S(O) 2 A 18 -, —(CH 2 ) p —N(R w )A 19 - or —(CH 2 ) p —OA 20 -, in which:
 
A 16  represents a single bond, —O—, —C(O)—, or —S(O) m —;
 
A 17 , A 18  and A 21  independently represent a single bond, —C(R y3 )(R y4 )—, —O—, —N(R w )— or —N(R w )SO 2 —;
 
A 19  and A 20  independently represent a single bond, —C(R y3 )(R y4 )—, —C(O)—, —C(O)C(R y3 )(R y4 )—, —C(O)N(R w )—, —C(O)O—, —S(O) 2 — or —S(O) 2 N(R w )—;
 
p and q independently represent, on each occasion when used herein, 0, 1 or 2;
 
m represents, on each occasion when used herein, 0, 1 or 2;
 
R y3  and R y4  independently represent, on each occasion when used herein, H, F or X 6 ; or
 
R y3  and R y4  may be linked together to form a 3- to 6-membered ring, which ring optionally contains a heteroatom, and which ring is optionally substituted by one or more substituents selected from F, Cl, ═O and X 7 ;
 
R w  resents, on each occasion when used herein, H or X 8 ;
 
X 4  to X 8  independently represent C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, —CN, —N(R 24a )R 25a , —OR 24b , ═O, aryl and heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from halo, C 1-4  alkyl (optionally substituted by one or more substituents selected from fluoro, chloro and ═O), —N(R 24a )R 25b  and —OR 24d )), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from halo, C 1-4  alkyl (optionally substituted by one or more substituents selected from fluoro, chloro and ═O), —N(R 26a )R 26b , —OR 26c  and —C(O)R 26d );
 
R 22a , R 22b , R 22c , R 22d , R 22e , R 22f , R 23a , R 23b , R 23c , R 24a , R 24b , R 24c , R 24d , R 25a , R 25b , R 26a , R 26b , R 26c  and R 26d  are independently selected from hydrogen and C 1-4  alkyl, which latter group is optionally substituted by one or more substituents selected from fluoro, chloro and/or ═O,
 
or a pharmaceutically-acceptable salt thereof,
 
for use in the treatment of a disease in which inhibition of the synthesis of leukotriene C 4  is desired and/or required,
 
which compounds and salts are referred to hereinafter as “the compounds of the invention”.
 
     Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. 
     Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention. 
     Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. 
     Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention. 
     Unless otherwise specified, C 1-q  alkyl, and C 1-q  alkylene, groups (where q is the upper limit of the range), defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming, in the case of alkyl, a C 3-q  cycloalkyl group or, in the case of alkylene, a C 3-q  cycloalkylene group). Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Further, unless otherwise specified, such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms and unless otherwise specified, be unsaturated (forming, for example, in the case of alkyl, a C 2-q  alkenyl or a C 2-q  alkynyl group or, in the case of alkylene, a C 2-q  alkenylene or a C 2-q  alkynylene group). In the case of alkylene groups, it is preferred that they are acyclic and/or straight-chain, but may be saturated or unsaturated. 
     The term “halo”, when used herein, includes fluoro, chloro, bromo and iodo. 
     Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2-q  heterocycloalkenyl (where q is the upper limit of the range) or a C 7-q  heterocycloalkynyl group. C 2-q  heterocycloalkyl groups that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called “spiro”-compound. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S-oxidised form. 
     For the avoidance of doubt, the term “bicyclic” (e.g. when employed in the context of heterocycloalkyl groups) refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring. The term “bridged” (e.g. when employed in the context of heterocycloalkyl groups) refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate). 
     Aryl groups that may be mentioned include C 6-14  (such as C 6-13  (e.g. C 6-10 )) aryl groups. Such groups may be monocyclic or bicyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. C 6-14  aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are preferably linked to the rest of the molecule via an aromatic ring. 
     Heteroaryl groups that may be mentioned include those which have between 5 and 14 (e.g. 10) members. Such groups may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic and wherein at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom). Heteroaryl groups that may be mentioned include acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazopyridyl (including imidazo[4,5-b]pyridyl, imidazo[5,4-b]pyridyl and imidazo[1,2-a]pyridyl), indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,3,4-thiadiazolyl), thiazolyl, oxazolopyridyl (including oxazolo[4,5-b]pyridyl, oxazolo[5,4-b]pyridyl and, in particular, oxazolo[4,5-c]pyridyl and oxazolo[5,4-c]pyridyl), thiazolopyridyl (including thiazolo[4,5-b]pyridyl, thiazolo[5,4-b]pyridyl and, in particular, thiazolo[4,5-c]pyridyl and thiazolo[5,4-c]pyridyl), thiochromanyl, thienyl, triazolyl (including 1,2,3-triazolyl and 1,2,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. However, when heteroaryl groups are polycyclic, they are preferably linked to the rest of the molecule via an aromatic ring. Heteroaryl groups may also be in the N- or S-oxidised form. 
     Heteroatoms that may be mentioned include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulphur. 
     For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which X 1  and X 2  both represent R 68 , i.e. a C 1-6  alkyl group optionally substituted as hereinbefore defined, the alkyl groups in question may be the same or different. Similarly, when groups are substituted by more than one substituent as defined herein, the identities of those individual substituents are not to be regarded as being interdependent. For example, when there are two X 1  substituents present, which represent —R 3a  and —C(O)R 3b  in which R 3b  represents R 3a , then the identities of the two R 3a  groups are not to be regarded as being interdependent. Likewise, when Y 2  or Y 3  represent e.g. an aryl group substituted by G 1  in addition to, for example, C 1-8  alkyl, which latter group is substituted by G 1 , the identities of the two G 1  groups are not to be regarded as being interdependent. 
     For the avoidance of doubt, when a term such as “R 5a  to R 5h ” is employed herein, this will be understood by the skilled person to mean R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g  and R 4h  inclusively. 
     For the avoidance of doubt, when the term “an R 5  group” is referred to herein, we mean any one of R 5a  to R 5k , R 5m , R 5n  or R 5p . 
     For the avoidance of doubt, where it is stated herein that “any pair of R 16a  to R 16c  and R 17a  to R 17f  . . . may . . . be linked together”, we mean that any one of R 16a , R 16b  or R 16c  may be linked with any one of R 17a , R 17b , R 17c , R 17d , R 17e  or R 17f  to form a ring as hereinbefore defined. For example, R 16a  and R 17b  (i.e. when a G 1  group is present in which G 1  represents -A′-R 16a , A 1  represents —C(O)A 2  and A 2  represents —N(R 17b )—) or R 16b  and R 17f  may be linked together with the nitrogen atom to which they are necessarily attached to form a ring as hereinbefore defined. 
     For the avoidance of doubt, the compounds of the invention relate to either of the following compounds of formula I, 
     
       
         
         
             
             
         
       
     
     The skilled person will appreciate that, given that there is an essential ‘-L 3 -Y 3 ’ group present in the compound of formula I, then when ring A represents ring I), then at least one of —C(R 2b )═, —C(R 2c )═ and —C(R 2d )═ must be present, in which the any one of the relevant R 2b , R 2c  and R 2d  groups represents the essential -L 3 -Y 3  group. 
     When L 1  or L 1a  represents C 1-6  alkylene in which any one of the carbon atoms is replaced with Q, it is preferred that the C 1-6  alkylene group is interrupted by Q. That it, it may e.g. represent —C q1 (alkylene)-Q-C q2 (alkylene), in which the sum of q1 and q2 equals 6, provided that neither q1 nor q2 represents 0. 
     Compounds of the invention that may be mentioned include those in which: 
     each r independently represents, on each occasion when used herein, 2;
 
L 2  and L 3  independently represent a single bond or a spacer group selected from —(CH 2 ) p —C(R y3 )(R y4 )—(CH 2 ) q -A 16 , —(CH 2 ) p —C(O)A 17 -, —(CH 2 ) p —S—, —(CH 2 ) p —SC(R y3 )(R y4 )—, —(CH 2 ) p —S(O) 2 A 18 -, —(CH 2 ) p —N(R w )A 19 - or —(CH 2 ) p —OA 20 -, in which the integers are as defined herein.
 
     Further compounds of the invention that may be mentioned include those in which: 
     when D 2a  represents D 2 ; D 2b  represents —C(-L 2 -Y 2 )═; D 1 , D 2  and D 3  respectively represent —C(R 1a )═, —C(R 1b )═ and —C(R 1b )═; ring A represents ring (I); E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2b )═, —C(R 2d )═ and —C(H)═; R 1a , R 1b , R 1c  and R 2d  all represent hydrogen, R 2c  represents the requisite -L 3 -Y 3  group, L 1  represents a single bond, Y 1  represents —C(O)OR 9b ; R 9b  represents methyl or, preferably, hydrogen; L 2  represents —N(H)-A 19 ; L 3  represents —N(R w )-A 19 -; A 19  represents (in each case) —S(O) 2 —, then Y 2  and Y 3  do not both represent 4-methylphenyl when Y represents —O—, R w  represents H, R 2b  represents X 1  in which X 1  represents —OR 5h , and R 5h  represents n-butyl. 
     Compounds of the invention that may be mentioned include those in which for example when: 
     D 2a  represents D 2 ;
 
D 2b  represents —C(-L 2 -Y 2 )═;
 
D 1 , D 2  and D 3  respectively represent —C(R 1a )═, —C(R 1b )═ and —C(R 1c )═;
 
ring A represents ring (I);
 
E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2d )═, —C(R 2d )═ and —C(H)═;
 
R 1a , R 1b , R 1c  and R 2d  independently represent hydrogen;
 
one of R 2b  and R 2c  represents the requisite -L 3 -Y 3  group;
 
when R 2c  represents the requisite -L 3 -Y 3  group, then R 2b  represents -L 1a -Y 1a , or, preferably hydrogen or a substituent selected from X 1 ;
 
when R 2b  represents the requisite -L 3 -Y 3  group, then R 2b  represents -L 1a -Y 1a ;
 
X 1  represents Z 2a , halo, —CN, —N(R 6b )R 7b , —OR 5h ,
 
Z 2a  represents —R 5a  or —C(O)N(R 6a )R 7a ;
 
R 5a  represents C 1-6  alkyl optionally substituted by one or more substituents selected from halo (e.g. fluoro) or, preferably, —OR 8a ;
 
L 1  and L 1a  independently represent a single bond; and/or
 
Y 1  and Y 1a  independently represent —C(O)OR 9b  (in which R 9b  is preferably hydrogen) or —S(O) 3 R 9c  (in which R 9c  is preferably hydrogen), then preferably:
 
L 2  and L 3  independently represent a single bond or a spacer group selected from —(CH 2 ) p —C(R y3 )(R y4 )—(CH 2 ) q -A 16 -, —(CH 2 ) p —C(O)A 17 -, (CH 2 ) p —S—, —(CH 2 ) p —SC(R y3 )(R y4 )—, —(CH 2 ) p —S(O) 2 A 18 - or —(CH 2 ) p —OA 20 -;
 
A 19  represents (for example when Y represents —S— or, preferably, —O—) a single bond, —C(R y3 )(R y4 )—, —C(O)—, —C(O)C(R y3 )(R y4 )—, —C(O)N(R w )—, —C(O)O— or —S(O) 2 N(R w )—;
 
Y 2  and Y 3  do not independently (e.g. they do not both) represent phenyl substituted at the para-position by e.g. C 1-8  alkyl (e.g. methyl);
 
A represents: I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B; II) a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 1  and/or Z 1 ; or III) a G 1  group;
 
A 1  represents a spacer group selected from —C(O)A 2 -, —S—, —S(O) 2 A 3 -, —N(R 17a )A 4 - or —OA 5 -;
 
R 16a  represents: i) hydrogen; ii) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G 3 ; iii) a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 3  and/or Z 3 ;
 
A 17  represents (for example when p represents 0 and/or when Y represents —O— or —S(O) 2 —), a single bond, —C(R y3 )(R y4 )—, —O— or —N(R w )SO 2 —;
 
Y 2  and Y 3  do not independently (e.g. they do not both) represent phenyl substituted by A;
 
A represents: I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B; or II) C 1-8  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 1  and/or Z 1 ;
 
G 1  represents, on each occasion when used herein, cyano, —N 3  or —ONO 2  (alternatively, and more preferably, G 1  represents, on each occasion when used herein, halo or cyano);
 
A 1  represents a single bond or a spacer group selected from —C(O)A 2 -, —S— or —S(O) 2 A 3 -;
 
A 4  and A 5  independently represent —C(O)—, —C(O)N(R 17d )—, —C(O)O—, —S(O) 2 — or —S(O) 2 N(R 17e )—;
 
Y 2  and Y 3  do not independently (e.g. they do not both) represent phenyl substituted by G 1 , in which G 1  is preferably halo (e.g. bromo), —NO 2  or -A 1 -R 16a , A 1  represents or —N(R 17a )A 4 - or —OA 5 -, in which A 4  and A 5  preferably represent single bonds; R 16a  represents hydrogen or C 1-8  alkyl (e.g. methyl); and/or R 17a  represents hydrogen;
 
A 19  represents (e.g. when p represents 0) a single bond, —C(R y3 )(R y4 )—, —C(O)C(R y3 )(R y4 )—, —C(O)N(R w )—, —C(O)O—, —S(O) 2 — or —S(O) 2 N(R w )—;
 
when A 19  represents —C(O)— (e.g. when p represents 0), the Y 2  and Y 3  do not both represent phenyl substituted e.g. at the para position with A, in which A represents G 1  and G 1  represents —NO 2 ;
 
G 1  represents halo, cyano, —N 3 , —ONO 2  or -A 1 -R 16a ;
 
when R 5a  or R 8a  to R 8h  represents optionally substituted C 1-6  alkyl, then preferably they are not substituted with both ═O and —OR 8a , or ═O and —OR 13a  (as appropriate) at the terminal positions of the alkyl group (so forming, for example a —C(O)OR 8a  or —C(O)OR 13a  group).
 
     Compounds of the invention that may be mentioned include those in which for example when: 
     D 2a  represents D 2 ;
 
D 2b  represents —C(-L 2 -Y 2 )═;
 
D 1 , D 2  and D 3  respectively represent —C(R 1a )═, —C(R 1b )═ and —C(R 1c )═;
 
ring A represents ring (I);
 
E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2c )═, —C(R 2d )═ and —C(H)═;
 
R 1a , R 1b , R 1c  and R 2d  independently represent hydrogen;
 
one of R 2b  and R 2c  (e.g. R 2c ) represents the requisite -L 3 -Y 3  group and the other (e.g. R 2b ) represents -L 1a -Y 1a ;
 
-L 1 -Y 1  and -L 1a -Y 1a  both represent —S(O) 3 H, then preferably:
 
A 19  represents (e.g. when p represents 0) a single bond, —C(R y3 )(R y4 )—, —C(O)—, —C(O)C(R y3 )(R y4 )—, —C(O)N(R w )—, —C(O)O— or —S(O) 2 N(R w )—;
 
Y 2  and Y 3  do not both represent phenyl substituted at the para-position;
 
A represents: I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B; II) C 1-8  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 1  and/or Z 1 ;
 
G 1  represents halo, cyano, —N 3  or —ONO 2  (preferably, halo or cyano);
 
A 1  represents a single bond or a spacer group selected from —C(O)A 2 -, —S—, —S(O) 2 A 3 - or —N(R 17a )A 4 -;
 
A 5  represents a single bond, —C(O)—, —C(O)N(R 17d )—, —C(O)O— or —S(O) 2 N(R 17e )—;
 
R 16a  represents: i) hydrogen; or ii) C 1-8  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 3  and/or Z 3 ;
 
G 3  represents, on each occasion when used herein, halo, cyano, —N 3  or —ONO 2  (preferably, halo or cyano);
 
A 11  represents a single bond or a spacer group selected from —C(O)A 12 -, —S—, —S(O) 2 A 13 - or —OA 15 -;
 
A 14  represents —C(O)—, —C(O)N(R 21d )—, —C(O)O—, —S(O) 2 — or —S(O) 2 N(R 21e )—.
 
     Compounds of the invention that may be mentioned include those in which, for example, when D 1 , D 2  and D 3  respectively represent —C(R 1e )═, —C(R 1b )═ and —C(R 1c )═; ring A represents ring (I) and E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2c )═, —C(R 2d )═ and —C(H)═, then: 
     when Y 2  and Y 3  both represent a heteroaryl (e.g. a 4- to 10-membered heteroaryl) group, then L 1  and, if present, L 1a , independently represent a single bond, C 1-6  alkylene in which any one of the carbon atoms is interrupted by Q, or C 1-6  alkylene in which any one of the carbon atoms is replaced with —C(O)— or —C(R y1 )(R y2 )—;
 
when Y 2  and Y 3  both represent a heteroaryl group, then L 2  and L 3  do not both represent single bonds.
 
     Further compounds of the invention that may be mentioned include those in which in which, for example, when D 1 , D 2  and D 3  respectively represent —C(R 1a )═, —C(R 1b )═ and —C(R 1c )═; ring A represents ring (I) and E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2c )═, —C(R 2d )═ and —C(H)═, then: 
     L 1  represents a single bond, C 1-6 alkylene in which any one of the carbon atoms is interrupted by Q, or C 1-6  alkylene in which any one of the carbon atoms is replaced with —C(O)— or —C(R y1 )(R y2 )—;
 
R 5a  represents, on each occasion when used herein, C 1-6  alkyl optionally substituted by one or more substituents selected from halo, —CN, —N 3 , —OR 8a , —N(R 8b )R 8c , —S(O) n R 8d , —S(O) 2 N(R 8e )R 8f  or —OS(O) 2 N(R 8g )R 8h ;
 
R 5a  represents, on each occasion when used herein, alkyl optionally substituted by one or more substituents selected from halo, —CN, —N 3 , ═O, —N(R 8b )R 8c , —S(O) n R 8d , —S(O) 2 N(R 8e )R 8f  or —OS(O) 2 N(R 8g )R 8h ;
 
(e.g. one of) L 2  and L 3  independently represent(s) a spacer group selected from —(CH 2 ) p —C(R y3 )(R y4 )—(CH 2 ) q -A 16 -, —(CH 2 ) p —C(O)A 17 -, —(CH 2 ) p —S—, —(CH 2 ) p —SC(R y3 )(R y4 )—, —(CH 2 ) p —S(O) 2 A 18 -, —(CH 2 ) p —N(R w )A 19 - or —(CH 2 ) p —OA 20 -;
 
(e.g. one of) Y 2  and Y 3  represent(s) an aryl group optionally substituted as defined herein.
 
     Further compounds of the invention that may be mentioned include those in which, for example, when D 1 , D 2  and D 3  respectively represent —C(R 1a )═, —C(R 1b )═ and —C(R 1c )═; ring A represents ring (I); and E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2c )═, —C(R 2d )═ and —C(H)═, then: 
     when R 1a , R 1b , R 1c  or, if present, X 1  represent —N(R 5d )C(O)R 6c , and R 6c  represents R 5a , then R 5a  represents a linear or branched C 1-6  alkyl group optionally substituted by one or more substituents selected from halo, —CN, —N 3 , ═O, —OR 5a , —N(R 8b )R 8c , —S(O) n R 8d , —S(O) 2 N(R 8e )R 8f  or —OS(O) 2 N(R 8g )R 8h ;
 
R 1a , R 1b , R 1c , X 1 , X 2  and X 3  independently represent a group selected from Z 2a , or, halo, —CN, —N(R 6b )R 7b , —N(R 5e )C(O)N(R 6d )R 7d , —N(R 5f )C(O)OR 6e , —N 3 , —NO 2 , —N(R 5g )S(O) 2 N(R 6f )R 7f , —OR 5h , —OC(O)N(R 6g )R 7g , —OS(O) 2 R 5i , —N(R 5k )S(O) 2 R 5m , —OC(O)R 5n , —OC(O)OR 5p  or —OS(O) 2 N(R 6i )R 7i .
 
     Yet further compounds of the invention that may be mentioned include those in which: 
     when, for example, ring A represents ring (I); L 2  or L 3  represent —N(R w )A 19 -; A 19  represents a single bond; and/or R w  represents H, then:
 
Y 2  or Y 3  (as appropriate) do not represent a benzimidazolyl (such as one attached to the L 2  or L 3  group via the imidazolyl moiety, e.g. benzimidazol-2-yl) group;
 
when Y 2  or Y 3  represents heteroaryl, then it is preferably a monocyclic heteroaryl group or a bicyclic heteroaryl group containing 1 to 4 heteroatoms consisting of 1, 3 or 4 nitrogen heteroatoms, 1 or 2 oxygen heteroatoms and/or 1 sulfur atom, for instance, the bicyclic heteroaryl group may contain 1 nitrogen, oxygen or sulfur heteroatom (all of which are optionally substituted by one or more substituents selected from A);
 
when Y 2  or Y 3  represents a polycyclic (e.g. bicyclic) heteroaryl group, then it is preferably not attached to the L 2  or L 3  group via a ring containing a heteroatom;
 
Y 2  and/or Y 3  (as appropriate) represent(s) aryl or a 5- or 6-membered monocyclic ring (all of which are optionally substituted by one or more substituents selected from A).
 
     Further compounds of the invention that may be mentioned include those in which, for example when Y represents —O—, then ring A and/or the D 1  to D 3 -containing ring does not represent a triazinyl ring. That is ring A does not represent ring (I) in which E al , E a3  and E a5  all represent —N═ and/or D 1 , D 2b  and D 3  do not all represent —N═. 
     Further compounds of the invention that may be mentioned include those in which for example when Y represents —S(O) 2 —, and either L 2  or L 3  represent —C(O)N(H)—, then Y 2  or Y 3  (as appropriate) do not represent a tricyclic heteroaryl group (e.g. dibenzothiophene). 
     Further compounds of the invention that may be mentioned include those in which for example when there is an X′, X 2 , R z1 , X 3  or R z2  substituent present, then: 
     X 1 , X 2 , R z1 , X 3  or R z2  do not represent —C(O)N(R 6a )R 7a , in which R 6a  and R 7a  represent R 5a  and R 5a  represents C 1-6  alkyl (e.g. ethyl) terminally substituted with a ═O group (so forming an aldehyde);
 
for example when R 6a  and/or R 7a  represent R 5a , then R 5a  represents, C 1-6  alkyl optionally substituted by one or more substituents selected from halo, —CN, —N 3 , —OR 8a , —N(R 8b )R 8c , —S(O) n R 8d , —S(O) 2 N(R 8e )R 8f  or —OS(O) 2 N(R 8g )R 8h .
 
     Preferred compounds of the invention include those in which: 
     one (e.g. D 1 , D 2  (e.g. D 2a ) or D 3 ) or none of D 1 , D 2  and D 3  represent —N═;
 
D 1 , D 2  and D 3  respectively represent —C(R 1a )═, —C(R 1b )═ and —C(R 1c )═;
 
R 1a  and R 1c  independently represent hydrogen;
 
R 1b  represents hydrogen or a substituent as defined herein (e.g. halo, such as fluoro);
 
when ring A represents ring (I), then two (e.g. E a1  and E a2 ), preferably, one (e.g.
 
E a1  or E a2 ) or, e.g. more preferably, none of E a1 , E a2 , E a3 , E a4  and E a5  represent a —N═ group;
 
E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2c )═, —C(R 2d )═ and —C(H)═;
 
only one of R 2b , R 2c  and R 2d  (e.g. R 2b ) may represent -L 1a -Y 1a ;
 
when one of R 2b , R 2c  and R 2d  represents -L 1a -Y 1a , then Y 1a  is preferably 5-tetrazolyl or, more preferably, —COOR 9b , in which R 9b  is preferably C 1-4  alkyl or H;
 
R 3c  and R 3d  independently represent F, Cl, —CH 3 , —CF 3  or, more preferably, hydrogen;
 
for example when ring A represents ring (II) then, one of R 3a  and R 3b  represents a substituent X 2  or, more preferably, H or -L 1a -Y 1a , and the other represents the requisite -L 3 -Y 3  group;
 
R 4b  and R 4c  independently represent F, Cl, —CH 3 , —CF 3  or, more preferably, hydrogen;
 
for example when ring A represents ring (III) then, one of R 4a  and, if present, R 4d  represents a substituent X 3  or, more preferably, H or -L 1a -Y 1a , and the other represents the requisite -L 3 -Y 3  group;
 
when any one of R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c  or R 4d  (e.g. R 3a , R 3b , R 4a  or R 4d ) represents -L 1a -Y 1a , then Y 1a  is preferably a 5-tetrazolyl group or —COOR 9b , in which R 9b  is preferably C 1-4  alkyl or H;
 
R 1a , R 1b , R 1c  (when such R 1a , R 1b  and R 1c  groups represent a substituent, i.e. a group other than hydrogen), X 1 , X 2  and X 3  independently represent a group selected from Z 2a , or, halo, —CN, —N(R 6b )R 7b , —N(R 5d )C(O)R 6c , —N 3 , —NO 2 , —OR 5h  or —N(R 5k )S(O) 2 R 5m  (more preferably such R 1a , R 1b  and R 1c  groups independently represent hydrogen, or a substituent selected from Z 2a , or, halo, —CN, —N(R 6b )R 7b , —N(R 5d )C(O)R 6c , —OR 5h  or —N(R 5k )S(O) 2 R 5m , and each X 1 , X 2  and X 3  independently represents a group selected from Z 2a , or, halo, —CN, —N(R 6b )R 7h , —N(R 5d )C(O)R 6h , —OR 5h  or —N(R 5k )S(O) 2 R 5m );
 
Z 1a  and Z 2a  independently represent —C(O)OR 5c , —C(O)N(R 6a )R 7a  or, preferably, —R 5a ;
 
when any of the pairs R 6a  and R 7a , R 6b  and R 7b , R 6d  and R 7d , R 6f  and R 7f , R 6g  and R 7g , R 6h  and R 7h  or R 6i  and R 7i  are linked together, they form a 5- or 6-membered ring optionally substituted by F, —OCH 3  or, preferably, ═O or R 5a , and which ring optionally contains an oxygen or nitrogen heteroatom (which nitrogen heteroatom may be optionally substituted, for example with a methyl group, so forming e.g. —N(H)— or —N(CH 3 )—);
 
R 5c  and R 5j  independently represent R 5a ;
 
when R 5a , R 8a , R 8b , R 8d , R 8e  and R 8g  represent C 1-6  alkyl optionally substituted by one or more halo substituents, then those halo substituents are preferably F or Cl (especially fluoro);
 
R 5a  represents C 1-6  (e.g. C 1-4 ) alkyl optionally substituted by one or more substituents selected from Cl, —N 3 , preferably, ═O, —N(R 8b )R 8c  and, more preferably, F and —OR 8a ;
 
m and n independently represent 2;
 
when any one of R 8a , R 8b , R 8d , R 8e  and R 8g  represents C 1-6  alkyl substituted by halo, then preferred halo groups are fluoro and chloro (especially fluoro);
 
R 8a , R 8b , R 8d , R 8e  and R 8g  independently represent H or C 1-3  alkyl optionally substituted by one or more fluoro atoms;
 
R 8c , R 8f  and R 8h  independently represent H, —S(O) 2 CH 3 , —S(O) 2 CF 3  or C 1-3  alkyl optionally substituted by one or more fluoro atoms, or the relevant pairs (i.e. R 8b  and R 8c , R 8e  and R 8f  or R 8g  and R 8h ) are linked together as defined herein;
 
when R 8b  and R 8c , R 8e  and R 8f  or R 8g  and R 8h  are linked together, they form a 5- or 6-membered ring, optionally substituted by one or more (e.g. one or two) substituents selected from F, ═O or —CH 3 ;
 
M 1  and M 2  independently represent —N(R 15a )R 15b  or, preferably, —CH 3  or —CF 3 ;
 
R 11a , R 12a , R 12b , R 13a , R 14a , R 14b , R 15a  and R 15b  independently represent —CH 2 CH 3 , —CF 3  (in the case of R 11a  and R 13a ) or, preferably, H or —CH 3 ;
 
Y 1  and Y 1a  independently represent —N(H)S(O) 2 R 9a , —C(O)OR 9b , —S(O) 2 N(R 10i )R 9i  or 5-tetrazolyl;
 
when Y 1  and/or Y 1  represents —P(O)(OR 9d ) 2 , then, preferably, one R 9d  group represents hydrogen and the other represents an alkyl group as defined herein (so forming a —P(O)(O-alkyl)(OH) group) or, more preferably, both R 9d  groups represent hydrogen (so forming a —P(O)(OH) 2  group);
 
when any pair of R 9f  and R 10f , R 9g  and R 10g , and R 9i  and R 10i  are linked together to form a 3- to 6-membered ring as hereinbefore defined, that ring is optionally substituted by one or more substituents selected from Cl, and, preferably, F, ═O and/or R 5a ;
 
R 9a  represents C 1-4  (e.g. C 1-3 ) alkyl optionally substituted by one or more halo (e.g. fluoro) atoms or, when D 2a  is D 2  and represents —N═, an aryl group (e.g. phenyl) substituted by one or more halo (e.g. fluoro or chloro) atoms;
 
R 9b  to R 9z , R 9aa , R ab , R 10f , R 10g , R 10i  and R 10j  independently represent hydrogen or C 1-6  (e.g. C 1-4 ) alkyl optionally substituted by one or more halo (e.g. fluoro) atoms;
 
R 9b  represents H;
 
R 10i  represents H;
 
R 9i  represents hydrogen or C 1-3  alkyl (such as methyl, ethyl and isopropyl);
 
A represents: aryl (e.g. phenyl) optionally substituted by B; C 1-8  alkyl optionally substituted by G 1  and/or Z 1 ; or G 1 ;
 
G 1  represents N 3 , —NO 2 , or, preferably, halo, cyano or -A 1 -R 16a ;
 
A 2  represents a single bond or —O—;
 
A 4  represents —C(O)N(R 17d )—, —C(O)O— or, more preferably, a single bond or —C(O)—;
 
A 5  represents —C(O)— or, preferably, a single bond;
 
Z 1  represents ═S, ═NCN, preferably, ═NOR 16b  or, more preferably, ═O;
 
B represents: heteroaryl (e.g. oxazolyl, thiazolyl, thienyl or pyridyl) or, more preferably, aryl (e.g. phenyl) optionally substituted by G 2 ; C 1-6  alkyl optionally substituted by G 2  and/or Z 2 ; or, preferably, B represents G 2 ;
 
G 2  represents cyano, preferably, —NO 2  or, more preferably, halo or -A 6 -R 18a  (alternatively, G 2  represents cyano, or, preferably, halo or -A 6 -R 18a );
 
A 6  represents a single bond, —N(R 19a )A 9 - or —OA 10 -;
 
A 9  represents —C(O)N(R 19d )—, —C(O)O— or, more preferably, a single bond or —C(O)—;
 
A 10  represents a single bond;
 
Z 2  represents ═S, ═NCN, preferably, ═NOR 18b  or, more preferably, ═O;
 
R 16a , R 16b , R 16c , R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 18a , R 18b , R 18c , R 19a , R 19b , R 19c , R 19d , R 19e  and R 19f  are independently selected from hydrogen, aryl (e.g. phenyl) or heteroaryl (which latter two groups are optionally substituted by G 3 ) or C 1-6  (e.g. C 1-6 ) alkyl (optionally substituted by G 3  and/or Z 3 ), or the relevant pairs are linked together as hereinbefore defined;
 
when any pair of R 16a  to R 16c  and R 17a  to R 17f , or R 18a  to R 18c  and R 19a  to R 19f  are linked together, they form a 5- or 6-membered ring, optionally substituted by one or more (e.g. one or two) substituents selected from G 3  and/or Z 3 ;
 
G 3  represents halo or -A 11 -R 20a ;
 
A 11  represents a single bond or —O—;
 
A 12  represents a single bond or, preferably, —N(R 21b )—;
 
A 13  represents a single bond or, preferably, —N(R 21c )—;
 
A 14  and A 15  independently represent a single bond, —C(O)— or —S(O) 2 —;
 
Z 3  represents ═S, ═NOR 20b  or, preferably, ═O;
 
R 20a , R 20b , R 20c , R 21a , R 21b , R 21c , R 21d , R 21e  and R 21f  are independently selected from H, C 1-3  (e.g. C 1-2 ) alkyl (e.g. methyl) optionally substituted by one or more halo (e.g. fluoro) atoms, or optionally substituted aryl (e.g. phenyl), or the relevant pairs are linked together as defined herein;
 
when any pair of R 20a  to R 20c  and R 21a  to R 21f  are linked together, they form a 5- or 6-membered ring, optionally substituted by one or more (e.g. one or two) substituents selected from halo (e.g. fluoro) and C 1-2  alkyl (e.g. methyl);
 
R y1  and R y2  independently represent hydrogen or methyl, or, they are linked together to form a 3-membered cyclopropyl group;
 
Q represents —C(R y1 )(R y2 )— or —C(O)—;
 
L 2  and L 3  independently represent —(CH 2 ) p —C(R y3 )(R y4 )—(CH 2 ) q -A 16 -, —(CH 2 ) p —C(O)A 17 -, —(CH 2 ) p —S—, —SC(R y3 )(R y4 )—, —(CH 2 ) p —S(O) 2 A 18 -, —(CH 2 ) p —N(R w )A 19 - or —(CH 2 ) p —O—;
 
A 16  represents a single bond or, preferably, —C(O)—;
 
A 18  represents —N(R w )— or a single bond;
 
A 19  represents a single bond, —C(R y3 )(R y4 )—, —C(O)—, —C(O)C(R y3 )(R y4 )—, —C(O)O—, —S(O) 2 — or —C(O)N(R w )—;
 
A 20  represents a single bond or —C(R y3 )(R y4 )—;
 
R y3  and R y4  independently represent H or X 6 , or, are linked together to form a 3-membered cyclopropyl group;
 
X 4  to X 8  independently represent C 1-6  (e.g. C 1-4 ) alkyl (optionally substituted by fluoro) or aryl (e.g. phenyl) optionally substituted by one or more substituents selected from halo, C 1-3  alkyl and —C(O)R 26d ;
 
R 22a , R 22b , R 22c , R 22d , R 22e , R 22f , R 23a , R 23b , R 23c , R 24a , R 24b , R 24c , R 24d , R 25a  and R 25b  independently represent hydrogen or C 1-2  alkyl optionally substituted by ═O or, more preferably, one or more fluoro atoms;
 
R 26a , R 26b , R 26c  and R 26d  independently represent hydrogen or C 1-4  alkyl optionally substituted by one or more fluoro atoms.
 
     More preferred compounds of the invention include those in which: 
     when ring A represents ring (I), in which there is one —N═ group present, then E a1 , E a3  or E a5  represents such a group;
 
when ring A represents ring (II), then W b  may represent —N(R 3d )— (so forming a pyrrolyl or imidazolyl ring) or, more preferably, when Y b  represents —C(R 3c )═, then W b  preferably represents —O— or, particularly, —S— (so forming a furanyl or, particularly, a thienyl ring) or when Y b  represents —N═, then W b  preferably represents —O— or —S— (so forming, for example, an oxazolyl or thiazolyl ring);
 
R 3c  and R 3d  independently represent H;
 
when ring A represents ring (III), then W c  preferably represents —N(R 4d )—;
 
R 4d  represents H;
 
X 1 , X 2  and X 3  independently represent halo (e.g. chloro or, especially fluoro), —CN, —NO 2 ,
 
     —OR 5h  or Z 2a ; 
     R 5h  represents R 5a ;
 
Z 2a  represents —R 5a ;
 
R 5a  represents C 1-4  alkyl (such as methyl, ethyl and isopropyl) optionally substituted by one or halo (e.g. fluoro), so forming for example a difluoromethyl or trifluoromethyl group;
 
R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g  and R 8h  independently represent H or C 1-3  alkyl optionally substituted by one or more fluoro atoms.
 
     Preferred rings that ring A may represents include imidazolyl (e.g. 2-imidazolyl), preferably, furanyl (e.g. 2-furanyl), thienyl (e.g. 2-thienyl), oxazolyl (e.g. 2-oxazolyl), thiazolyl (e.g. 2-thiazolyl), pyridyl (e.g. 2- or 4-pyridyl), pyrrolyl (e.g. 3-pyrrolyl), imidazolyl (e.g. 4-imidazolyl) or, more preferably, phenyl. Alternatively, other preferred rings that A may represents include furanyl (e.g. 2-furanyl), thienyl (e.g. 2-thienyl), imidazolyl (e.g. 2-imidazolyl), oxazolyl (e.g. 2-oxazolyl), thiazolyl (e.g. 2-thiazolyl), or preferably pyridyl (e.g. 3-pyridyl) or phenyl. 
     Preferred rings that the D 1  to D 3 -containing ring may represent include 2-, 3- or 4-pyridyl or, preferably, phenyl. 
     Preferred aryl and heteroaryl groups that Y 2  and Y 3  may independently represent include optionally substituted (i.e. by A) phenyl, naphthyl, pyrrolyl, furanyl, thienyl (e.g. 2-thienyl or 3-thienyl), imidazolyl (e.g. 2-imidazolyl or 4-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl), indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinolizinyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, tetrazolyl, benzothiazolyl, and/or benzodioxanyl, group. Preferred values include pyridyl (e.g. 3-pyridyl), benzofuranyl (e.g. 5-benzofuranyl), isoquinolinyl (which may be partially saturated, for example forming 1,2,3,4-tetrahydroisoquinolinyl, e.g. 1,2,3,4-tetrahydroisoquinolin-7-yl) and, more particularly, phenyl. Alternatively, other preferred aryl and heteroaryl groups that Y 2  and Y 3  may independently represent include optionally substituted thienyl (e.g. 2-thienyl), oxazolyl (e.g. 2-oxazolyl), thiazolyl (e.g. 2-thiazolyl), or more preferably, phenyl. 
     Preferred optional substituents on Y 2  and Y 3  groups include: 
     —NO 2 ; or, more preferably,
 
halo (e.g. fluoro, chloro or bromo);
 
cyano;
 
C 1-6  alkyl, which alkyl group may be cyclic, part-cyclic, unsaturated or, preferably, linear or branched (e.g. C 1-4  alkyl (such as propyl (e.g. n-propyl and isopropyl), ethyl or, preferably, butyl (e.g. t-butyl or n-butyl) or methyl), all of which are optionally substituted with one or more halo (e.g. fluoro) groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl);
 
heterocycloalkyl, such as a 5- or 6-membered heterocycloalkyl group, preferably containing a nitrogen atom and, optionally, a further nitrogen or oxygen atom, so forming for example morpholinyl (e.g. 4-morpholinyl), piperazinyl (e.g. 4-piperazinyl) or piperidinyl (e.g. 1-piperidinyl and 4-piperidinyl) or pyrrolidinyl (e.g. 1-pyrrolidinyl), which heterocycloalkyl group is optionally substituted by one or more (e.g. one or two) substituents selected from C 1-3  alkyl (e.g. methyl) and ═O;
 
     —OR 26 ; 
     —SR 26 ; 
     —C(O)R 26 ; 
     —C(O)OR 26 ; 
     —N(R 26 )R 27 ; and 
     —S(O) 2 R 28 ; 
     wherein R 26  and R 27  independently represent, on each occasion when used herein, H, C 1-6  alkyl, such as C 1-5  (e.g. C 1-4 ) alkyl (e.g. ethyl, n-propyl, cyclopentyl, or, preferably, butyl (e.g. t-butyl or, preferably, n-butyl), cyclopropyl, methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a trifluoromethyl group) or aryl (e.g. phenyl) optionally substituted by one or more halo or C 1-3  (e.g. C 1-2 ) alkyl groups (which alkyl group is optionally substituted by one or more halo (e.g. fluoro) atoms); and R 26  preferably represents aryl or, particularly C 1-6  alkyl, for example as defined in respect of R 26  and R 27 . 
     Particularly preferred compounds of the invention include those in which: 
     D 2b  or, preferably, D 2a  represents D 2 , and the other (i.e. preferably D 2b ) represents —C(-L 2 -Y 2 );
 
D 1  and D 3  respectively represent —C(R 1a )═ and —C(R 1c )═;
 
D 2  represents —C(R 1b )═ or —N═;
 
when R 1a , R 1b  or R 1c  represent a substituent other than hydrogen, then that substituent is preferably —OR 5h , —N(R 6h )R 7h , —CN or, more preferably, Z 2a  (e.g. R 5a , such as C 1-3  alkyl optionally substituted by one or more fluoro atoms) or halo (e.g. fluoro);
 
R 1a , R 1b  and R 1c  independently represent hydrogen or a substituent as defined herein (especially halo, e.g. fluoro);
 
any one of R 1a , R 1b  and R 1c  (e.g. R 1c  or, preferably, R 1b ) represents hydrogen or a substituent as defined herein (especially halo, e.g. fluoro), and the others represent hydrogen (most preferably R 1a , R 1b  and R 1c  independently represent hydrogen);
 
ring A represents ring I) as hereinbefore defined;
 
E a1  represents —C(H)═ or —N═;
 
E a2  represents —C(R 2c )═ or —N═;
 
E a3  and E a4  represent —C(R 2b )═, and —C(R 2d )═, respectively;
 
E a5  represents —C(H)═;
 
only one of E a1 , E a2 , E a3 , E a4  and E a5  may represent —N═ (or each of these respectively represent —C(H)═, —C(R 2b )═, —C(R 2c )═, —C(R 2d )═ and —C(H)═);
 
one of R 2b  or R 2c  (preferably R 2c ) represents the requisite -L 3 -Y 3  group and the other represents a substituent selected from X 1  or, preferably, hydrogen or -L 1a -Y 1a ;
 
R 2d  represents hydrogen;
 
X 1 , X 2  and X 3  independently represent —OR 5h , Z 2a , or, most preferably halo (e.g. chloro or, especially, fluoro) (e.g. X 1  represents fluoro);
 
L 1  and L 1a  independently represent a single bond or C 1-4  (e.g. C 1-3 ) alkylene (e.g. methylene or ethylene), which alkylene group is optionally unsaturated (so forming, for example, —CH 2 ═CH 2 —);
 
L 1  represents a single bond or C 1-4  alkylene (e.g. methylene, ethylene or ethenylene), in which any one of the carbon atoms may be replaced by —C(O)—;
 
L 1a  represents a single bond;
 
Y 1  and Y 1a  independently represent 5-tetrazolyl (e.g. unsubstituted 5-tetrazolyl) or, preferably, —C(O)OR 9b  or —N(H)SO 2 R 9a ;
 
R 9a  represents an aryl group optionally substituted by one or more (e.g. two) halo (e.g. fluoro or chloro) atoms;
 
R 9b  represents hydrogen or C 1-6  (e.g. C 1-4 ) alkyl (such as butyl, e.g. t-butyl, or methyl);
 
Y 2  and Y 3  independently represent aryl (e.g. phenyl) or heteroaryl (e.g. a monocyclic 5- or 6-membered or a bicyclic 9- or 10-membered heteroaryl group preferably containing one to three heteroatom(s) selected from sulfur or, particularly, nitrogen or oxygen, so forming for example pyridyl, benzofuranyl or fully or partially aromatic isoquinolinyl), both of which are optionally substituted by one or more (e.g. one to three) substituents selected from A;
 
A represents I) C 1-8  (e.g. C 1-6 ) alkyl (e.g. n-butyl, t-butyl or methyl) optionally substituted by one or more substituents selected from G 1 ; or II) G 1 ;
 
G 1  represents —NO 2 , or, more preferably, halo (e.g. fluoro or chloro), cyano or -A 1 -R 16a ;
 
A 1  represents a single bond, —C(O)A 2 -, —S—, —S(O) 2 A 3 -, —N(R 17a )A 4 - or —OA 5 -;
 
A 2 , A 3 , A 4  and A 5  independently represent a single bond;
 
R 16a  represents hydrogen or C 1-6  alkyl (such as C 1-6  alkyl or C 3-5  cycloalkyl, e.g. cyclopropyl, cyclopentyl, butyl, isopropyl, ethyl or methyl) optionally substituted by one or more groups selected from G 3 ;
 
R 17a  represents hydrogen or, preferably, C 1-6  (e.g. C 1-3 ) alkyl (such as methyl);
 
G 3  represents halo (e.g. fluoro);
 
L 2  and L 3  independently represent a spacer group selected from —(CH 2 ) p —C(O)A 17 -, —(CH 2 ) p —S(O) 2 A 18 -, —(CH 2 ) p —N(R w )A 19 - and —(CH 2 ) p —OA 20  (e.g. —(CH 2 ) p —O—);
 
p represents 0 or 1;
 
when L 2  or L 3  represent —(CH 2 ) p —S(O) 2 A 18 -, —(CH 2 ) p —N(R w )A 19 - or —(CH 2 ) p —O—, then p preferably represents 0;
 
when L 2  or L 3  represent —(CH 2 ) p —C(O)A 17 -, then p may represent 0 or 1;
 
A 17  represents —N(R w )— or, preferably, —N(R w )SO 2 —;
 
A 18  represents —N(R w )—;
 
A 19  represents a single bond, —C(R y3 )(R y4 )—, —C(O)—, —C(O)C(R y3 )(R y4 )—, —S(O) 2 — or —C(O)N(R w )—;
 
A 20  represents a single bond;
 
R w  represents hydrogen or X 8 ;
 
when A 17  represents —N(R w )SO 2 —, then R w  represents hydrogen;
 
when A 19  represents —C(O)N(R w )—, then R w  represents hydrogen;
 
R y3  and R y4  independently represent hydrogen;
 
X 8  represents C 1-4  alkyl (e.g. butyl or methyl) or aryl (e.g. phenyl) optionally substituted by one or more substituents selected from halo (e.g. chloro or, preferably, fluoro) and —C(O)R 26d  (so forming for example a halophenyl or cyclopropylcarbonylphenyl group);
 
R 26d  represents C 1-4  alkyl (e.g. cyclic C 3-4  alkyl such as cyclopropyl).
 
     Preferred Y 2  and Y 3  groups include: when they represent aryl groups, 2,5-dichlorophenyl, 4-chloro-2-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 4-isopropylphenyl, 2-methoxy-4,5-difluorophenyl, 2-methoxy-4,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-fluorophenyl, 3-methoxyphenyl, 2-methoxy-5-chlorophenyl and, more preferably, unsubstituted phenyl, 3,4-difluorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-chlorophenyl, 2-fluoro-5-chlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-2,5-difluorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,6-difluorophenyl, 2-fluoro-3-chlorophenyl, 2-fluoro-4-chlorophenyl, 2,3-difluorophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-n-butoxyphenyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3,5-dimethoxyphenyl, 4-trifluoromethoxyphenyl, 2,3-dimethoxyphenyl, 4-(cyclopentyloxy)phenyl, 4-n-butylphenyl, 4-tert-butylphenyl, 2-chloro-5-nitrophenyl, 2-chloro-5-trifluoromethylphenyl, 4-(cyclopropanecarbonyl)phenyl, 4-(trifluoromethylthio)-phenyl, 2-hydroxy-5-chlorophenyl, 2-fluoro-4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-dimethylaminophenyl, 2-chloro-4-trifluoromethylphenyl, 4-methylphenyl, 4-(methanesulfonyl)phenyl, 2-methyl-3-fluorophenyl, 2-methyl-3-chlorophenyl, 2-hydroxy-3,5-dichlorophenyl, and; when they represent monocyclic heteroaryl groups, 2-chloropyrid-3-yl, 2,5-dichloropyrid-3-yl and, more preferably, 6-trifluoromethylpyrid-3-yl and 2-methyl-6-trifluoromethylpyrid-3-yl; when they represent bicyclic heteroaryl groups, 5-benzofuranyl and tetrahydroisoquinolinyl (e.g. 1,2,3,4-tetrahydroisoquinolin-7-yl). 
     Preferred substituents on Y 2  and Y 3  groups include isopropyl and, preferably, halo (e.g. fluoro or chloro), —NO 2 , cyano, methyl, butyl (e.g. n-butyl or t-butyl), trifluoromethyl (—CF 3 ), hydroxy (—OH), methoxy, ethoxy, isopropoxy, n-butoxy, trifluoromethoxy, cyclopentyloxy, —C(O)-cyclopropyl, trifluoromethylthio (—S—CF 3 ), dimethylamino (—N(CH 3 ) 2 ) and methanesulfonyl (—S(O) 2 CH 3 ). 
     Specific L 2  and L 3  groups that may be mentioned include —N(H)—, —N(CH 3 )—, —N(n-butyl)-, —N(phenyl)- (e.g. —N(4-cyclopropylcarbonylphenyl)-), —N(H)—CH 2 —, —N(H)C(O)—, —N(CH 3 )C(O)—, —N(phenyl)-C(O)— (e.g. —N(4-fluorophenyl)-C(O)—), —N(H)S(O) 2 —, —N(CH 3 )S(O) 2 —, —N(H)C(O)CH 2 —, —N(H)—C(O)—N(H)—, —S(O) 2 —N(H)—, —C(O)N(H)S(O) 2 —, —CH 2 —C(O)N(H)S(O) 2 — and —O—. 
     Particularly preferred compounds of the invention include those of the examples described hereinafter. 
     Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter. 
     According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I which process comprises: 
     (i) for compounds of formula I in which Y represents —S(O)— or —S(O) 2 —, oxidation of a compound of formula II, 
     
       
         
         
             
             
         
       
     
     wherein ring A, D 1 , D 2a , D 2b , D 3 , L 1 , L 3  and Y 3  are as hereinbefore defined, in the presence of a suitable oxidising agent, for example meta chloro per benzoic acid, KMnO 4 , t-butylammoniumperiodate and/or potassium peroxymonosulfate (e.g. Oxone®). In order to provide selective oxidisation to provide either compounds of formula I in which Y represents —S(O)— or —S(O) 2 —, the skilled person will appreciate that the length of time (and the number of equivalents of the oxidising agent) or the use of certain oxidising agents may provide for better selectivity. For example, for the formation of compounds of formula I in which Y represents —S(O)—, the oxidising agent of choice is preferably t-butylammoniumperiodate (and preferably one equivalent, or a slight excess, is employed). Such a reaction may be performed in the presence of a suitable solvent such as dichloromethane, and optionally in the presence of a catalyst such as 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III)chloride, under an inert atmosphere. For the formation of compounds of formula I in which Y represents —S(O) 2 —, the oxidising agent is preferably potassium peroxymonosulfate (e.g. Oxone®), which reaction may be performed in the presence of a suitable solvent such as tetrahydrofuran;
 
(ii) for compounds of formula I in which L 2  and/or L 3  represents —(CH 2 ) p —N(R w )A 19 - in which p represents 0 and R w  represents H, reaction of a compound of formula III,
 
     
       
         
         
             
             
         
       
     
     or a protected derivative thereof (e.g. an amino-protected derivative) wherein one of D 2ax  and D 2bx  represents D 2  and the other represents —C(-L 2a )═ (i.e. the L 2a  substituent is attached to either one of D 2ax  and D 2bx ), L 2a  represents —NH 2  or -L 2 -Y 2 , L 3a  represents —NH 2  or -L 3 -Y 3 , provided that at least one of L 2a  and L 3a  represents —NH 2 , and ring A, Y, D 1 , D 2 , D 3 , L 1  and Y 1  are as hereinbefore defined, with:
 
(A) when A 19  represents —C(O)N(R w )—, in which R w  represents H:
         (a) a compound of formula IV,       

       Y a —N═C═O  IV
             ; or       (b) with CO (or a reagent that is a suitable source of CO (e.g. Mo(CO) 6  or CO 2 (CO) 8 )) or a reagent such as phosgene or triphosgene in the presence of a compound of formula V,       

       Y a —NH 2   V
 
     wherein, in both cases, Y a  represents Y 2  or Y 3  (as appropriate/required) as hereinbefore defined. For example, in the case of (a) above, in the presence of a suitable solvent (e.g. THF, dioxane or diethyl ether) under reaction conditions known to those skilled in the art (e.g. at room temperature). In the case of (b), suitable conditions will be known to the skilled person, for example the reactions may be carried out in the presence of an appropriate catalyst system (e.g. a palladium catalyst), preferably under pressure and/or under microwave irradiation conditions. The skilled person will appreciate that the compound so formed may be isolated by precipitation or crystallisation (from e.g. n-hexane) and purified by recrystallisation techniques (e.g. from a suitable solvent such as THF, hexane (e.g. n-hexane), methanol, dioxane, water, or mixtures thereof). The skilled person will appreciate that for preparation of compounds of formula I in which -L 2 -Y 2  represents —C(O)N(H)—Y 2  and -L 3 -Y 3  represents —C(O)N(H)—Y 3  and Y 2  and Y 3  are different, two different compounds of formula IV or V (as appropriate) will need to be employed in successive reaction steps. For the preparation of such compounds starting from compounds of formula III in which both of L 2a  and L 3a  represent —NH 2 , then mono-protection (at a single amino group) followed by deprotection may be necessary, or the reaction may be performed with less than 2 equivalents of the compound of formula IV or V (as appropriate);
 
(B) when A 19  represents —S(O) 2 N(R w )—, reaction with a compound of formula VA,
 
       Y a —N═S═O  VA
 
     wherein Y a  is as hereinbefore defined, for example under reaction conditions described hereinbefore in respect of process step (ii)(A)(a) above, followed by standard oxidation reaction conditions (for example, reaction in the presence of an oxidising reagent such as meta-chloroperbenzoic acid in the presence of a suitable solvent such as dichloromethane e.g. as described in  Journal of Organic Chemistry , (1988) 53(13), 3012-16, or, KMnO 4 , e.g. as described in  Journal of Organic Chemistry , (1979), 44(13), 2055-61. The skilled person will also appreciate that the compound of formula VA may need to be prepared, for example from a corresponding compound of formula V as defined above, and SO 2  (or a suitable source thereof) or SOCl 2 ;
 
(C) when A 19  represents a single bond, with a compound of formula VI,
 
       Y a -L a   VI
 
     wherein L a  represents a suitable, leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. —OS(O) 2 CF 3 , —OS(O) 2 CH 3 , —OS(O) 2 PhMe or a nonaflate) or —B(OH) 2  (or a protected derivative thereof, e.g. an alkyl protected derivative, so forming, for example a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group) and Y a  is as hereinbefore defined, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc) 2 , CuI (or CuI/diamine complex), copper tris(triphenyl-phosphine)bromide, Pd(OAc) 2 , Pd 2 (dba) 3  or NiCl 2  and an optional additive such as Ph 3 P, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, NaI or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et 3 N, pyridine, N,N′-dimethylethylenediamine, Na 2 CO 3 , K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , t-BuONa or t-BuOK (or a mixture thereof, optionally in the presence of 4 Å molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or a mixture thereof) or in the absence of an additional solvent when the reagent may itself act as a solvent (e.g. when Y a  represents phenyl and L a  represents bromo, i.e. bromobenzene). This reaction may be carried out at room temperature or above (e.g. at a high temperature, such as the reflux temperature of the solvent system that is employed) or using microwave irradiation;
 
(D) when A 19  represents —S(O) 2 —, —C(O)—, —C(R y3 )(R y4 )—, —C(O)—C(R y3 )(R y4 )— or —C(O)O—, with a compound of formula VII,
 
       Y a -A 19a -L a   VII
 
     wherein A 19a  represents —S(O) 2 —, —C(O)—, —C(R y3 )(R y4 )—, —C(O)—C(R y3 )(R y4 )— or —C(O)O—, and Y a  and L a  are as hereinbefore defined, and L a  is preferably, bromo or chloro, under reaction conditions known to those skilled in the art, the reaction may be performed at around room temperature or above (e.g. up to 40-180° C.), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, N-ethyldiisopropylamine, N-(methylpolystyrene)-4-(methylamino)pyridine, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium tert-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine or mixtures thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine);
 
(iii) for compounds of formula I in which one of L 2  and L 3  represents —N(R w )C(O)N(R w )— and the other represents —NH 2  (or a protected derivative thereof) or —N(R w )C(O)N(R w )—, in which R w  represents H (in all cases) reaction of a compound of formula VIII,
 
     
       
         
         
             
             
         
       
     
     wherein one of D 2ay  and D 2by  represents D 2  and the other represents —C(-J 2 )═ (i.e. the J 2  substituent is attached to either one of D 2ax  and D 2bx ), one of J 1  or J 2  represents —N═C═O and the other represents -L 2 -Y 2  or -L 3 -Y 3  (as appropriate), —NH 2  (or a protected derivative thereof) or —N═C═O (as appropriate), and ring A, Y, D 1 , D 2 , D 3 , L 1  and Y 1  are as hereinbefore defined, with a compound of formula V as hereinbefore defined, under reaction conditions known to those skilled in the art, such as those described hereinbefore in respect of process step (ii)(A)(b) above;
 
(iv) reaction of a compound of formula IX,
 
     
       
         
         
             
             
         
       
     
     wherein one of D 2az  and D 2bz  represents D 2  and the other represents —C(—Z y )═ (i.e. the Z y  substituent is attached to either one of D 2az  and D 2bz ), Z X  and Z y  independently represent a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. —OS(O) 2 CF 3 , —OS(O) 2 CH 3 , —OS(O) 2 PhMe or a nonaflate), —B(OH) 2 , —B(OR wx ) 2 , —Sn(R wx ) 3  or diazonium salts, in which each R wx  independently represents a C 1-6  alkyl group, or, in the case of —B(OR wx ) 2 , the respective R wx  groups may be linked together to form a 4- to 6-membered cyclic group (such as a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), and ring A, Y, D 1 , D 2 , D 3 , L 1  and Y 1  are as hereinbefore defined, with a (or two separate) compound(s) (as appropriate/required) of formula X, 
       Y a -L x -H  X
 
     wherein L x  represents L 2  or L 3  (as appropriate/required), and Y a  is as hereinbefore defined, under suitable reaction conditions known to those skilled in the art, for example such as those hereinbefore described in respect of process (ii)(B) or (ii)(C) above or (e.g. when L x  represents —S(O) 2 A 18 -, in which A 18  represents —N(R w )—) under Ullman reaction conditions such as those described in  Tetrahedron Letters , (2006), 47(28), 4973-4978. The skilled person will appreciate that when compounds of formula I in which L 2  and L 3  are different are required, then reaction with different compounds of formula X (for example, first reaction with a compound of formula X in which 12 represents —N(R w )A 19 -, followed by reaction with another, separate, compound of formula X in which L x  represents —OA 20 -) may be required;
 
(v) compounds of formula I in which there is a R w  group present that does not represent hydrogen (or if there is R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25  or R 26  group present, which is attached to a heteroatom such as nitrogen or oxygen, and which does/do not represent hydrogen), may be prepared by reaction of a corresponding compound of formula I in which such a group is present that does represent hydrogen with a compound of formula XI,
 
       R wy -L b   XI
 
     wherein R wy  represents either R w  (as appropriate) as hereinbefore defined provided that it does not represent hydrogen (or R w  represents a R 5  to R 19  group in which those groups do not represent hydrogen), and L b  represents a suitable leaving group such as one hereinbefore defined in respect of L a  or —Sn(alkyl) 3  (e.g. —SnMe 3  or —SnBu 3 ), or a similar group known to the skilled person, under reaction conditions known to those skilled in the art, for example such as those described in respect of process step (ii)(C) above. The skilled person will appreciate that various groups (e.g. primary amino groups) may need to be mono-protected and then subsequently deprotected following reaction with the compound of formula XI;
 
(vi) compounds of formula I in which there is a R w  group present that does not represent hydrogen, an aryl group or a heteroaryl group (or if there is a R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25  or R 26  group present, which is attached to a heteroatom such as nitrogen or oxygen, and which does/do not represent hydrogen, an aryl group or a hetereoaryl group), may be prepared by reaction of a corresponding compound of formula I in which such a group is present that does represent hydrogen with a compound of formula XII,
 
       R wy -L c   XII
 
     wherein R wy  represents either R w  (as appropriate) as hereinbefore defined (e.g. R w  represents C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, —CN, —N(R 24a )R 25a , —OR 24b , ═O)) provided that it does not represent hydrogen, an aryl group or a heteroaryl group (or R w  represents a R 5  to R 19  group in which those groups do not represent hydrogen, an aryl group or a heteroaryl group), and L c  represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. —OS(O) 2 CF 3 , —OS(O) 2 CH 3 , —OS(O) 2 PhMe or a nonaflate), or a similar group known to the skilled person, under reaction conditions known to those skilled in the art. The reaction may be performed at around room temperature or above (e.g. up to 40-180° C.), optionally in the presence of a suitable base (e.g. sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-ethyldiisopropylamine or mixtures thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine);
 
(vii) for compounds of formula I that contain only saturated alkyl groups, reduction of a corresponding compound of formula I that contains an unsaturation, such as a double or triple bond, in the presence of suitable reducing conditions, for example by catalytic (e.g. employing Pd) hydrogenation;
 
(viii) for compounds of formula I in which Y 1  and/or, if present, Y 1a  represents —C(O)OR 9b , —S(O) 3 R 9c , —P(O)(OR 9d ) 2 , or —B(OR 9h ) 2 , in which R 9b , R 9c , R 9d  and R 9h  represent hydrogen (or, e.g. in the case of compounds in which Y 1  and/or Y 1a  represent —C(O)OR 9b , other carboxylic acid or ester protected derivatives (e.g. amide derivatives)), hydrolysis of a corresponding compound of formula I in which R 9b , R 9c , R 9d  or R 9h  (as appropriate) does not represent H, or, for compounds of formula I in which Y represents —P(O)(OR 9d ) 2  or S(O) 3 R 9c , in which R 9c  and R 9d  represent H, a corresponding compound of formula I in which Y represents either —P(O)(OR 9e )N(R 10f )R 9f , —P(O)(N(R 10g )R 9g ) 2  or —S(O) 2 N(R 10i )R 9i  (as appropriate), all under standard conditions, for example in the presence of an aqueous solution of base (e.g. aqueous 2M NaOH) optionally in the presence of an (additional) organic solvent (such as dioxane), which reaction mixture may be stirred at room or, preferably, elevated temperature for a period of time until hydrolysis is complete (e.g. 5 hours);
 
(ix) for compounds of formula I in which Y 1  and/or, if present, Y 1a  represents —C(O)OR 9b , S(O) 3 R 9c , —P(O)(OR 9d ) 2 , —P(O)(OR 9e )N(R 10f )R 9f  or —B(OR 9h ) 2  and R 9b  to R 9e  and R 9h  (i.e. those R 9  groups attached to an oxygen atom) do not represent H:
         (A) esterification (or the like) of a corresponding compound of formula I in which R 9b  to R 9e  and R 9h  represent H; or   (B) trans-esterification (or the like) of a corresponding compound of formula I in which R 9b  to R 9e  and R 9h  do not represent H (and does not represent the same value of the corresponding R 9b  to R 9e  and R 9h  group in the compound of formula I to be prepared),
 
under standard conditions in the presence of the appropriate alcohol of formula XIII,
       

       R 9za OH  XIII
 
     in which R 9za  represents R 9b  to R 9e  or R 9h  (as appropriate) provided that it does not represent H, for example further in the presence of acid (e.g. concentrated H 2 SO 4 ) at elevated temperature, such as at the reflux temperature of the alcohol of formula XIII;
 
(x) for compounds of formula I in which Y 1  and/or, if present, Y 1a  represents —C(O)OR 9b , —S(O) 3 R 9c , —P(O)(OR 9d ) 2 , —P(O)(OR 9e )N(R 10f )R 9f , —P(O)(N(R 10g )R 9g ) 2 , —B(OR 9h ) 2  or —S(O) 2 N(R 10i )R 9i , in which R 9b  to R 9i , R 10f , R 10g  and R 10i  are other than H, and L 1  and/or, if present, L 1a , are as hereinbefore defined, provided that they do not represent C 1-6  alkylene in which the carbon atom that is attached to ring A or the D 1  to D 3 -containing ring is replaced with —O—, reaction of a compound of formula XIV,
 
     
       
         
         
             
             
         
       
     
     wherein at least one of L 5  and L 5a  represents an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a —Mg-halide, a zinc-based group or a suitable leaving group such as halo or —B(OH) 2 , or a protected derivative thereof (e.g. an alkyl protected derivative, so forming for example a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), and the other may represent -L 1 -Y 1  or -L 1a -Y 1a  (as appropriate), and ring A, D 1 , D 2a , D 2b , D 3 , L 3  and Y 3  are as hereinbefore defined (the skilled person will appreciate that the compound of formula XIV in which L 5  and/or L 5a  represents an alkali metal (e.g. lithium), a Mg-halide or a zinc-based group may be prepared from a corresponding compound of formula XIV in which L 5  and/or L 5a  represents halo, for example under conditions such as Grignard reaction conditions, halogen-lithium exchange reaction conditions, which latter two may be followed by transmetallation, all of which reaction conditions are known to those skilled in the art), with a compound of formula XV, 
       L 6 -L xy -Y b   XV
 
     wherein L xy  represents L 1  or L 1a  (as appropriate) and Y b  represents —C(O)OR 9b , —S(O) 3 R 9c , —P(O)(OR 9d ) 2 , —P(O)(OR 9e )N(R 10f )R 9f , —P(O)(N(R 10g )R 9g ) 2 , —B(OR 9h ) 2  or —S(O) 2 N(R 10i )R 9i , in which R 9b  to R 9i , R 10f , R 10g  and R 10i  are other than H, and L 6  represents a suitable leaving group known to those skilled in the art, such as halo (especially chloro or bromo), for example when Y b  represents —C(O)OR 9b  or —S(O) 3 R 9c , or C 1-3  alkoxy, for example when Y b  represents —B(OR 9h ) 2 . For example, for compounds of formula I in which L 1  represents a single bond and Y 1  represents —C(O)OR 9b , the compound of formula XV may be Cl—C(O)OR 9b . The reaction may be performed under standard reaction conditions, for example in the presence of a polar aprotic solvent (e.g. THF or diethyl ether). The skilled person will appreciate that compounds of formula XIV in which L 5  represents —B(OH) 2  are also compounds of formula I;
 
(xi) compounds of formula I in which L 1  and/or, if present, L 1a  represent a single bond, and Y 1  and/or, if present, Y 1a  represent either: B(OR 9h ) 2  in which R 9h  represents H; —S(O) 3 R 9c ; or any one of the following groups:
 
     
       
         
         
             
             
         
       
     
     in which R 9j , R 9k , R 9m , R 9n , R 9p , R 9r , R 9s , R 9t , R 9u , R 9v , R 10j  and R 9x  represent hydrogen, and R 9w  is as hereinbefore defined, may be prepared in accordance with the procedures described in international patent application WO 2006/077366;
 
(xia) for compounds of formula I in which L 1  and/or, if present, L 1a  represent(s) an unsubstituted 5-tetrazolyl group, reaction in accordance with procedures described in international patent application WO 2006/077366, for example, reaction of a compound corresponding to a compound of formula I, but in which the relevant L 1  and/or L 1a  group represents —C≡N, in the presence of an appropriate reagent that effects the conversion, e.g. NaN 3 , or the like, optionally in the presence of a base (such as an amine base, e.g. 1-methylpyrrolidin-2-one or the like) and an additive (such as one described herein, e.g. triethylammonium hydrochloride), for example at elevated temperature, e.g. above 80° C., such as above 100° C., e.g. about 150° C.;
 
(xii) compounds of formula I in which L 1  and/or, if present, L 1a  represent a single bond, and Y 1  and/or, if present, Y 1a  represent any one of the following groups:
 
     
       
         
         
             
             
         
       
     
     in which R 9y , R 9z  and R 9aa  represent H, may be prepared by reaction of a compound corresponding to a compound of formula I, but in which Y 1  and/or, if present, Y 1a  represents —CN, with hydroxylamine (so forming a corresponding hydroxyamidino compound) and then with SOCl 2 , R j —OC(O)Cl (e.g. in the presence of heat; wherein R j  represents a C 1-6  alkyl group) or thiocarbonyl diimidazole (e.g. in the presence of a Lewis Acid such as BF 3* OEt 2 ), respectively, for example under reaction conditions such as those described in Naganawa et al,  Bioorg. Med. Chem.,  (2006), 14, 7121;
 
(xiii) compounds of formula I in which L 1  and/or, if present, L 1a  represent a single bond, and Y 1  and/or, if present, Y 1a  represent any one of the following groups:
 
     
       
         
         
             
             
         
       
     
     in which R 9ab  is as hereinbefore defined, may be prepared by reaction of a compound of formula XIV wherein at least one of L 5  and L 5a  represents an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a —Mg-halide, a zinc-based group or a suitable leaving group such as halo or —B(OH) 2 , or a protected derivative thereof (e.g. an alkyl protected derivative, so forming for example a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), and the other may represent -L 1 -Y 1  or -L 1a -Y 1a  (as appropriate), and ring A, D 1 , D 2a , D 2b , D 3 , L 3  and Y 3  are as hereinbefore defined (the skilled person will appreciate that the compound of formula XIV in which L 5  and/or L 5a  represents an alkali metal (e.g. lithium), a Mg-halide or a zinc-based group may be prepared from a corresponding compound of formula XIV in which L 5  and/or L 5a  represents halo, for example under conditions such as Grignard reaction conditions, halogen-lithium exchange reaction conditions, which latter two may be followed by transmetallation, all of which reaction conditions are known to those skilled in the art), with a compound of formula XVIa or XVIb, 
     
       
         
         
             
             
         
       
     
     wherein R ab  is as hereinbefore defined and L d  represents (as appropriate) an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a —Mg-halide, a zinc-based group or a suitable leaving group such as halo or —B(OH) 2 , or a protected derivative thereof (e.g. an alkyl protected derivative, so forming for example a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), the skilled person will appreciate that the compound of formula XVIa or XVIb in which L d  represents an alkali metal (e.g. lithium), a Mg-halide or a zinc-based group may be prepared from a corresponding compound of formula XVIa or XVIb in which L d  represents halo, for example under conditions such as Grignard reaction conditions, halogen-lithium exchange reaction conditions, which latter two may be followed by transmetallation, all of which reaction conditions are known to those skilled in the art. The reaction may be performed under standard reaction conditions, for example in the presence of a suitable solvent (e.g. THF, diethyl ether, dimethyl formamide) and, if appropriate, in the presence of a suitable catalyst (e.g. Pd(OAc) 2 ) and base (e.g. K 2 CO 3 ). The skilled person will appreciate that compounds of formula XIV in which L 5  represents —B(OH) 2  are also compounds of formula I;
 
(xiv) for compounds of formula I in which L 1  and/or, if present, L 1a  represent a single bond, and Y 1  and/or, if present, Y 1a  represent —C(O)OR 9b  in which R 9b  is H, reaction of a compound of formula XIV as hereinbefore defined but in which L 5  and/or L 5a  (as appropriate) represents either:
         (I) an alkali metal (for example, such as one defined in respect of process step (ix) above); or   (II) —Mg-halide,
 
with carbon dioxide, followed by acidification under standard conditions known to those skilled in the art, for example, in the presence of aqueous hydrochloric acid;
 
(xv) for compounds of formula I in which L 1  and/or, if present, L 1a  represent a single bond, and Y 1  and/or, if present, Y 1a  represent —C(O)OR 9b , reaction of a corresponding compound of formula XIV as hereinbefore defined but in which L 5  and/or L 5a  (as appropriate) is a suitable leaving group known to those skilled in the art (such as a sulfonate group (e.g. a triflate) or, preferably, a halo (e.g. bromo or iodo) group) with CO (or a reagent that is a suitable source of CO (e.g. Mo(CO) 6  or CO 2 (CO) 8 )), in the presence of a compound of formula XVII,
       

       R 9b OH  XVII
 
     wherein R 9b  is as hereinbefore defined, and an appropriate catalyst system (e.g. a palladium catalyst, such as PdCl 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 Cl 2 , Pd(Ph 3 P) 4 , Pd 2 (dba) 3  or the like) under conditions known to those skilled in the art;
 
(xvi) for compounds of formula I in which Y represents —O— or —S—, reaction of either a compound of formula XVIII or XIX,
 
     
       
         
         
             
             
         
       
     
     respectively with a compound of formula XX or XXI, 
     
       
         
         
             
             
         
       
     
     wherein (in all cases) Y z  represents —O— or —S—, Z ab  represents a suitable leaving group such as one hereinbefore defined in respect of Z x  or, more preferably fluoro, and ring A, D 1 , D 2a , D 2b , D 3 , L 1 , Y 1 , L 3  and Y 3  are as hereinbefore defined, under standard nucleophilic aromatic substitution reaction conditions, for example in the presence of a suitable base and solvent (such as those hereinbefore defined in process step (ii)(D) above);
 
(xvii) for compounds of formula I in which L 1  or, if present, L 1a  represents C 1-6  alkylene, and Y 1  and, if present, Y 1a  preferably represent —C(O)OR 9b  in which R 9b  is other than hydrogen, reaction of a compound of formula XXII
 
     
       
         
         
             
             
         
       
     
     wherein ring A, Y, D 1 , D 2a , D 2b , D 3 , L 3  and Y 3  are as hereinbefore defined, with a compound of formula XXIII, 
       Z aa -L aa -Y aa   XXIII
 
     wherein L aa  represents C 1-6  alkylene, Y aa  represents Y 1  (or Y 1a ) as hereinbefore defined, but preferably —C(O)OR 9b  in which R 9b  is other than hydrogen, Z aa  represents a suitable leaving group such as one hereinbefore defined in respect of Z x , and preferably represents bromo, under standard electrophilic aromatic substitution reaction conditions, e.g. in the presence of a suitable base and solvent such as those mentioned hereinbefore in respect of process step (ii)(C), or optionally in the presence of a Lewis acid such as AlCl 3  under Friedel-Crafts conditions;
 
(xviii) for compounds of formula I in which L 1  represents —CH═CH—, reaction of a compound of formula XXIV,
 
     
       
         
         
             
             
         
       
     
     wherein ring A, Y, D 1 , D 2a , D 2b , D 3 , L 3  and Y 3  are as hereinbefore defined, with a compound of formula XXV, 
       (EtO) 2 P(O)CH 2 —Y 1   XXV
 
     or the like, or a compound of formula XXVI, 
       (Ph) 3 P═CH—Y 1   XXVI
 
     wherein (in both cases), Y 1  is as hereinbefore defined (and preferably represents —C(O)OR 9b , in which R 9b  is preferably other than hydrogen), under standard Horner-Wadsworth-Emmons, or Wittig, reaction conditions, as appropriate;
 
(xix) for compounds of formula I in which L 2  and/or L 3  represent —(CH 2 ) p —C(O)A 17 - in which A 17  represents —N(R w )— or —N(R w )SO 2 —, reaction of a corresponding compound of formula XXVII,
 
     
       
         
         
             
             
         
       
     
     or a protected derivative thereof (e.g. an amino-protected derivative) wherein one of D 2aa  and D 2ba  represents D 2  and the other represents —C(-L 2b )= (i.e. the L 2b  substituent is attached to either one of D 2aa  and D 2ba ), L 2b  represents —(CH 2 ) p —C(O)OH or -L 2 -Y 2 , L 3b  represents —(CH 2 ) p —C(O)OH or -L 3 -Y 3 , provided that at least one of L 2b  and L 3b  represents —(CH 2 ) p —C(O)OH, and ring A, Y, D 1 , D 2 , D 3 , L 1  and Y 1  are as hereinbefore defined, with a compound of formula XXVIII, 
       H(R w )N-Q a -Y a   XXVIII
 
     wherein Q a  represents a direct bond or —S(O) 2 —, and R w  and Y a  are as hereinbefore defined, under standard coupling reaction conditions, for example in the presence of a suitable coupling reagent (e.g. 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or hydrochloride thereof), N,N′-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate, benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluoro-phosphate, bromo-tris-pyrrolidinophosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetra-fluorocarbonate, 1-cyclohexyl-carbodiimide-3-propyloxymethyl polystyrene, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and/or O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium tert-butoxide and/or lithium diisopropylamide (or variants thereof), an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine) and a further additive (e.g. 1-hydroxybenzotriazole hydrate). Alternatively, the carboxylic acid group of the compound of formula XXVII may be converted under standard conditions to the corresponding acyl chloride (e.g. in the presence of SOCl 2  or oxalyl chloride), which acyl chloride is then reacted with a compound of formula XXVIII, for example under similar conditions to those mentioned above;
 
(xx) for compounds of formula I in which L 1 -Y 1  represents —C(O)N(H)SO 2 R 9a , reaction of a corresponding compound of formula XXIX,
 
     
       
         
         
             
             
         
       
     
     wherein ring A, Y, D 1 , D 2a , D 2b , D 3 , L 3  and Y 3  are as hereinbefore defined, with a compound of formula XXX, 
       H 2 N—SO 2 R 9a   XXX
 
     wherein R 9a  is as hereinbefore defined, under standard coupling reaction conditions, for example in the presence of a suitable coupling reagent (e.g. 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or hydrochloride thereof), N,N′-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 2-(1H-benzotriazol-1,1,3,3-tetramethyluronium hexa-fluorophosphate, benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluoro-phosphate, bromo-tris-pyrrolidinophosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetra-fluorocarbonate, 1-cyclohexyl-carbodiimide-3-propyloxymethyl polystyrene, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and/or O-benzotriazol-1-yl-N,N′,N′-tetramethyluronium tetrafluoroborate), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium tert-butoxide and/or lithium diisopropylamide (or variants thereof), an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine) and a further additive (e.g. 1-hydroxybenzotriazole hydrate). Alternatively, the carboxylic acid group of the compound of formula XXIX may be converted under standard conditions to the corresponding acyl chloride (e.g. in the presence of SOCl 2  or oxalyl chloride), which acyl chloride is then reacted with a compound of formula XXX, for example under similar conditions to those mentioned above;
 
(xxi) for compounds of formula I in which L 1 -Y 1  represents —C(O)N(H)SO 2 R 9a , reaction of a corresponding compound of formula XXXI,
 
     
       
         
         
             
             
         
       
     
     wherein ring A, Y, D 1 , D 2a , D 2b , D 3 , L 3  and Y 3  are as hereinbefore defined, with a compound of formula XXXII, 
       Cl—SO 2 R 9a   XXXII
 
     wherein R 9a  is as hereinbefore defined, under reaction conditions known to those skilled in the art. This reaction may be performed at around room temperature or above (e.g. up to 40-180° C.), optionally in the presence of a suitable base (e.g. sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-ethyldiisopropylamine or mixtures thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine);
 
(xxii) for compounds of formula I in which L 2  or L 3  represent —N(H)—CH 2 —, reductive amination of a compound of formula III as hereinbefore defined, with a compound of formula XXXIII,
 
       Y a —C(O)H  XXXIII
 
     wherein Y a  is as hereinbefore defined, under standard conditions, for example in the presence of a chemoselective reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, or alternatively, as a two-step process included condensation and then reduction, which reduction step in this instance may be performed in the presence of a stronger reducing agent such as sodium borohydride or LiAlH 4 .
 
Compounds of formulae III, VIII, IX and XIV in which Y represents —S(O)— or —S(O) 2 — may be prepared by oxidation of a corresponding compound of formula III, VIII, IX and XIV, respectively, wherein Y represents —S-(for the preparation of —S(O)— or —S(O) 2 —) or —S(O)— (for the preparation of —S(O) 2 —), for example under conditions hereinbefore described in respect to the preparation of compounds of formula I (process step (i)).
 
     Compounds of formula III in which Y preferably represents —O— or —S— (or protected, e.g. mono-protected derivatives thereof) may be prepared by reduction of a compound of formula XXXIV, 
     
       
         
         
             
             
         
       
     
     or a protected derivative thereof (e.g. an amino-protected derivative) wherein one of D 2ax  and D 2bx  represents D 2  and the other represents —C(—Z z2 )═ (i.e. the Z z2  substituent is attached to either one of D 2ax  and D 2bx ), Z z1  represents —N 3 , —NO 2 , -L 3 -Y 3  or a protected —NH 2  group, Z z2  represents —N 3 , —NO 2 , -L 2 -Y 2  or a protected —NH 2  group, provided that at least one of Z z1  and Z z2  represents —N 3  or —NO 2 , under standard reaction conditions known to those skilled in the art, in the presence of a suitable reducing agent, for example reduction by catalytic hydrogenation (e.g. in the presence of a palladium catalyst in a source of hydrogen) or employing an appropriate reducing agent (such as trialkylsilane, e.g. triethylsilane). 
     Compounds of formula III in which both L 2a  and L 3a  represent —NH 2  (or protected derivatives thereof) may also be prepared by reaction of a compound of formula IX as defined above, with ammonia, or preferably with a protected derivative thereof (e.g. benzylamine or Ph 2 C═NH), under conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process step (iv) above). 
     Compounds of formulae III or IX in which L 1  represents a single bond, and Y 1  represents —C(O)OR 9b , may be prepared by: 
     (I) reaction of a compound of formula XXXV, 
     
       
         
         
             
             
         
       
     
     wherein Z q1  and Z q2  respectively represent Z X  and Z y  (in the case of preparation of compounds of formula IX) or L 3a  and L 3b  (in the case of preparation of compounds of formula III), D 2a1  and D 2b1  respectively represent D 2ax  and D 2bx  (in the case of preparation of compounds of formula III) or D 2az  and D 2bz  (in the case of preparation of compounds of formula IX) and ring A, Y, D 1 , D 2ax , D 2bx , D 2az , D 2bz , D 3 , L 3a , L 3b , Z x  and Z y  are as hereinbefore defined, with a suitable reagent such as phosgene or triphosgene in the presence of a Lewis acid, followed by reaction in the presence of a compound of formula XVII as hereinbefore defined, hence undergoing a hydrolysis or alcoholysis reaction step;
 
(II) for such compounds in which R 9b  represents hydrogen, formylation of a compound of formula XXXV as hereinbefore defined, for example in the presence of suitable reagents such as P(O)Cl 3  and DMF, followed by oxidation under standard conditions;
 
(III) reaction of a compound of formula XXXVI,
 
     
       
         
         
             
             
         
       
     
     wherein W 1  represents a suitable leaving group such as one defined by Z x  and Z y  above, and ring A, Y, D 1 , D 2a1 , D 2b1 , D 3 , Z q1  and Z q2  are as hereinbefore defined, are as hereinbefore defined, with CO (or a reagent that is a suitable source of CO (e.g. Mo(CO) 6  or CO 2 (CO) 8 ) followed by reaction in the presence of a compound of formula XVII as hereinbefore defined, under reaction conditions known to those skilled in the art, for example such as those hereinbefore described in respect of preparation of compounds of formula I (process step (ii)(A)(b) or (ii)(C) above), e.g. the carbonylation step being performed in the presence of an appropriate precious metal (e.g. palladium) catalyst;
 
(IV) reaction of a compound of formula XXXVII,
 
     
       
         
         
             
             
         
       
     
     wherein W 2  represents a suitable group such as an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a —Mg-halide or a zinc-based group, and ring A, Y, D 1 , D 2a1 , D 2b1 , D 3 , Z q1  and Z q2  are as hereinbefore defined, with e.g. CO 2  (in the case where R 9b  in the compounds to be prepared represents hydrogen) or a compound of formula XIV in which L xy  represents a single bond, Y b  represents —C(O)OR 6b , in which R 9b  is other than hydrogen, and L 6  represents a suitable leaving group, such as chloro or bromo or a C 1-14  (such as C 1-6  (e.g. C 1-3 ) alkoxy group), under reaction conditions known to those skilled in the art. The skilled person will appreciate that this reaction step may be performed directly after (i.e. in the same reaction pot) the preparation of compounds of formula XXXVII (which is described hereinafter). 
     Compounds of formula III in which D 2ax  represents D 2a , D 2bx  represents —C(-L 2a )═, L 2a  represents —NH 2 , L 1  represents a single bond and Y 1  represents —C(O)OH, may alternatively be prepared by reaction of a compound of formula XXXVIII, 
     
       
         
         
             
             
         
       
     
     wherein L 3a , D 1 , D 2 , D 3 , Y and ring A are as hereinbefore defined, under oxidation reaction conditions, for example such as those described in Sheibley, F. E. and McNulty, J. S.  J. Org. Chem.,  1956; 21, 171-173, e.g. in the presence of H 2 O 2 , which is preferably in the presence of an alkaline solution. Similarly, compounds of formula III in which L 3  represents —NH 2 , which is α to a -L 1a -Y 1a  group present, which represents —C(O)OH, reaction of a compound of formula XXXIX, 
     
       
         
         
             
             
         
       
     
     wherein ring A, D 1 , D 2ax , D 2bx , D 3 , L 2a , Y, L 1  and Y 1  are as hereinbefore defined. 
     Alternatively still, compounds of formula III in which D 2ax  represents D 2a , D 2bx  represents —C(-L 2a )═, L 2a  represents —NH 2 , L 1  represents a single bond and Y 1  represents —C(O)OR 9b , may be prepared by reaction of a compound of formula XL, 
     
       
         
         
             
             
         
       
     
     wherein X q  represents —OH, —NH 2  or —N 3 , and L 3a , D 1 , D 2 , D 3 , Y and ring A are as hereinbefore defined, under standard reaction conditions, for example:
 
(i) when X q  represents —OH, under Schmidt reaction conditions, or variants thereof, in the presence of HN 3  (which may be formed in by contacting NaN 3  with a strong acid such as H 2 SO 4 ). Variants include reaction with diphenyl phosphoryl azide ((PhO) 2 P(O)N 3 ) in the presence of an alcohol (such as tert-butanol; thereby forming a t-Boc protected derivative of formula XL) which may result in the formation of a carbamate intermediate;
 
(ii) when X q  represents —NH 2 , under Hoffmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br 2 ) which may result in the formation of a carbamate intermediate;
 
(iii) when X q  represents —N 3  (which compound itself may be prepared from the corresponding acyl hydrazide under standard diazotization reaction conditions, e.g. in the presence of NaNO 2  and a strong acid such as H 2 SO 4  or HCl), under Curtius rearrangement reaction conditions, which may result in the formation of an intermediate isocyanate (or a carbamate if treated with an alcohol),
 
all of which may be followed by, if necessary (e.g. if the formation of the free amine is desired), hydrolysis, for example in the presence of water and base (e.g. one hereinbefore described in respect of process step (i) above) when a lower alkyl carbamate (e.g. methyl or ethyl carbamate) is formed as an intermediate or under acidic conditions when e.g. a tert-butyl carbamate is formed as an intermediate, or, when a benzyl carbamate intermediate is formed, under hydrogenation reaction conditions (e.g. catalytic hydrogenation reaction conditions in the presence of a precious metal catalyst such as Pd). Similar reactants and reaction conditions may be employed for the preparation of compounds of formula III in which ring A is substituted with a —C(O)OR 9b  group.
 
     Compounds of formula VIII may be prepared by reaction of a corresponding compound of formula II in which L 2a  or L 3a  (as appropriate) represent —NH 2 , with phosgene or triphosgene, for example in the presence of a suitable base (e.g. one hereinbefore defined in respect of preparation of compounds of formula I (e.g. triethylamine). When the compound of formula VIII is synthesised accordingly, it need not be isolated and/or purified when further employed in the synthesis of a compound of formula I (see process step (ii) above). 
     Compounds of formula IX in which Z x  and Z y  represent a sulfonate group may be prepared from corresponding compounds in which the Z x  and Z y  groups represent a hydroxy group, with an appropriate reagent for the conversion of the hydroxy group to the sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) under conditions known to those skilled in the art, for example in the presence of a suitable base and solvent (such as those described above in respect of process step (i), e.g. an aqueous solution of K 3 PO 4  in toluene) preferably at or below room temperature (e.g. at about 10° C.). 
     Compounds of formula XXXIV in which one of Z z1  and Z z2  represents —NO 2  and the other represents -L 2 -Y 2  or -L 3 -Y 3  (as appropriate) may be prepared by reaction of a compound of formula XVIII or XIX as hereinbefore defined, with a compound of formula XLI or XLII, 
     
       
         
         
             
             
         
       
     
     respectively, wherein one of D 2aq  and D 2bq  (preferably D 2aq ) represents D 2  and the other (preferably D 2bq ) represents —C(—NO 2 )═, and Z ab , D 1 , D 2 , D 3 , D 4 , L 1 , Y 1  and ring A are as hereinbefore defined, under standard aromatic nucleophilic aromatic substitution reaction conditions, such as those hereinbefore described in respect of preparation of compounds of formula I (process step (xiv)). The skilled person will appreciate that the presence of the nitro group, e.g. when in the para position to the Z ab  group will promote this reaction step due to its electron withdrawing capabilities. 
     Compounds of formula XXXVII may be prepared in several ways. For example, compounds of formula XXXVII in which W 2  represents an alkali metal such as lithium, may be prepared from a corresponding compound of formula XXXV (in particular those in which Z q1  and/or Z q2  represents a chloro or sulfonate group or, especially, a protected —NH 2  group, wherein the protecting group is preferably a lithiation-directing group, e.g. an amido group, such as a pivaloylamido group, or a sulfonamido group, such as an arylsulfonamido group, e.g. phenylsulfonamide), by reaction with an organolithium base, such as n-BuLi, s-BuLi, t-BuLi, lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidine (which organolithium base is optionally in the presence of an additive (for example, a lithium co-ordinating agent such as an ether (e.g. dimethoxyethane) or an amine (e.g. tetramethylethylenediamine (TMEDA), (−)sparteine or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and the like)), for example in the presence of a suitable solvent, such as a polar aprotic solvent (e.g. tetrahydrofuran or diethyl ether), at sub-ambient temperatures (e.g. 0° C. to −78° C.) under an inert atmosphere. Alternatively, such compounds of formula XXXVII may be prepared by reaction of a compound of formula XXXVI in which W 1  represents chloro, bromo or iodo by a halogen-lithium reaction in the presence of an organolithium base such as t- or n-butyllithium under reaction conditions such as those described above. Compounds of formula XXXVII in which W 2  represents —Mg-halide may be prepared from a corresponding compound of formula XXXVI in which W 1  represents halo (e.g. bromo), for example optionally in the presence of a catalyst (e.g. FeCl 3 ) under standard Grignard conditions known to those skilled in the art. The skilled person will also appreciate that the magnesium of the Grignard reagent or the lithium of the lithiated species may be exchanged to a different metal (i.e. a transmetallation reaction may be performed), for example to form compounds of formula XXXVII in which W 2  represents a zinc-based group (e.g. using ZnCl 2 ). 
     Compounds of formula XXXVIII and XXXIX may be prepared by reaction of a compound of formula XLIII, 
     
       
         
         
             
             
         
       
     
     wherein L 3a , D 1 , D 2 , D 3 , Y and ring A are as hereinbefore defined, or a compound of formula XLIV 
     
       
         
         
             
             
         
       
     
     respectively, wherein ring A, D 1 , D 2ax , D 2bx , D 3 , L 2a , Y, L 1  and Y 1  are as hereinbefore defined, with chloral hydrate, hydroxylamine hydrochloride, sodium sulfate and hydrochloric acid, followed by reaction in the presence of concentrated sulfuric acid, for example as described in the Sheibley et al journal article referenced herein. 
     Compounds of formula XXIX, or XLI in which -L 1 -Y 1  represents —C(O)OH, and compounds of formula XLIII in which there is a -L 1a -Y 1a  group present that represents —C(O)OH may be prepared by hydrolysis of a compound of formula XLV, XLVI or XLVII 
     
       
         
         
             
             
         
       
     
     respectively, wherein Z ab  is as hereinbefore defined, but preferably represents fluoro or bromo, and ring A, D 1 , D 2a , D 2b , D 2aq , D 2bq  and D 3  are as hereinbefore defined, under standard reaction conditions. 
     Compounds of formula XLV, XLVI and XLVII may be preared by reaction of a corresponding compound of formula XLVIII, XLIX or L, 
     
       
         
         
             
             
         
       
     
     respectively, wherein X z  represents fluoro or bromo and ring A, D 1 , D 2a , D 2b , D 2aq , D 2bq  and D 3  are as hereinbefore defined, under standard conditions, for example when X z  represents fluoro, in the presence of an appropriate source of cyanide ions (e.g. KCN) under standard nucleophilic aromatic substitution reaction conditions or, when X z  represents bromo, under palladium catalysed cyanation reaction conditions. 
     Compounds of formulae II, IV, V, VI, VII, X, XI, XII, XIII, XIV, XV, XVIa, XVIb, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXV, XXXVI, XL, XLII, XLIV, XLVIII, XLIX and L are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia “ Comprehensive Organic Synthesis ” by B. M. Trost and I. Fleming, Pergamon Press, 1991. Further, the compounds described herein may also be prepared in accordance with synthetic routes and techniques described in international patent application WO 2006/077366. 
     The substituents D 1 , D 2a , D 2b , D 3 , L 1 , Y 1 , L 3  and Y 3  (as well as L 2  and Y 2 ) in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. For example, in cases where Y 1  (or, if present, Y 1a ) represents —C(O)OR 9b  in which R 9b  does not initially represent hydrogen (so providing at least one ester functional group), the skilled person will appreciate that at any stage during the synthesis (e.g. the final step), the relevant R 9b -containing group may be hydrolysed to form a carboxylic acid functional group (i.e. a group in which R 9b  represents hydrogen). In this respect, the skilled person may also refer to “ Comprehensive Organic Functional Group Transformations ” by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995. Other specific transformation steps include the reduction of a nitro group to an amino group, the hydrolysis of a nitrile group to a carboxylic acid group, and standard nucleophilic aromatic substitution reactions, for example in which a fluoro- or bromo-phenyl group is converted into a cyanophenyl group by employing a source of cyanide ions (e.g. KCN) as a reagent (alternatively, in this case, palladium catalysed cyanation reaction conditions may also be employed). 
     Further, the skilled person will appreciate that the D 1  to D 3 -containing ring, as well as the A ring may be heterocycles, which moieties may be prepared with reference to a standard heterocyclic chemistry textbook (e.g. “ Heterocyclic Chemistry ” by J. A. Joule, K. Mills and G. F. Smith, 3 rd  edition, published by Chapman &amp; Hall, “ Comprehensive Heterocyclic Chemistry II ” by A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, 1996 or “ Science of Synthesis ”, Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006). Hence, the reactions disclosed herein that relate to compounds containing hetereocycles may also be performed with compounds that are pre-cursors to heterocycles, and which pre-cursors may be converted to those heterocycles at a later stage in the synthesis. 
     Compounds of the invention may be isolated from their reaction mixtures using conventional techniques (e.g. recrystallisations). 
     It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups. 
     The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes. 
     Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. By ‘protecting group’ we also include suitable alternative groups that are precursors to the actual group that it is desired to protect. For example, instead of a ‘standard’ amino protecting group, a nitro or azido group may be employed to effectively serve as an amino protecting group, which groups may be later converted (having served the purpose of acting as a protecting group) to the amino group, for example under standard reduction conditions described herein. Protecting groups that may be mentioned include lactone protecting groups (or derivatives thereof), which may serve to protect both a hydroxy group and an α-carboxy group (i.e. such that the cyclic moiety is formed between the two functional group, for example as described hereinafter in the formation of intermediate (I)). 
     The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. 
     The use of protecting groups is fully described in “ Protective Groups in Organic Synthesis”,  3 rd  edition, T. W. Greene &amp; P. G. M. Wutz, Wiley-Interscience (1999). 
     Medical and Pharmaceutical Uses 
     Compounds of the invention are useful because they possess pharmacological activity. Such compounds are therefore indicated as pharmaceuticals. 
     Certain compounds of the invention have not been disclosed before as pharmaceutical, and certain others are novel per se. 
     Hence, in a further embodiment of the invention, there is provided a compound of the invention as hereinbefore defined, provided that: 
     when D 2a  represents D 2 ; D 2b  represents —C(-L 2 -Y 2 )═; D 1 , D 2  and D 3  respectively represent —C(R 1a )═, —C(R 1b )═ and —C(R 1c )═; ring A represents ring (I); E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2c )═, —C(R 2d )═ and —C(H)═; R 1a , R 1b , R 1c  and R 2d  all represent hydrogen:
 
(I) R 2c  represents the requisite -L 3 -Y 3  group, -L 1 -Y 1  represents —C(O)OR 9b ; L 2  represents —N(H)S(O) 2 —; L 3  represents —(CH 2 ) p N(R w )-A 19 -:
 
(1) A 19  represents —S(O) 2 —, p represents 0, then Y 2  and Y 3  do not both represent 4-methylphenyl when:
         (A) Y represents —O— and R 9b  represents H;   (B) Y represents —O— and R 9b  represents methyl, and (in both cases):
           (i) R w  represents H or n-hexyl, and R 2b  represents H;   (ii) R w  represents H, R 2b  represents X 1  in which X 1  represents —OR 5h , and R 5h  represents n-pentyl, isobutyl, n-propyl, ethyl or methyl;   (iii) R w  represents H, R 2b  represents X 1  in which X 1  represents —N(R 6b )R 7b , one of R 6b  or R 7b  represents H, and the other represents methyl, ethyl, n-propyl and n-butyl;   (iv) R w  represents H, R 2b  represents X 1 , X 1  represents Z 2a , in which Z 2a  represents R 5a , and R 5a  represents methyl, —CF 3 , —CH 2 OH, —CH═CH 2 , ethyl or n-propyl;   (v) R w  represents H, R 2b  represents X 1 , in which X 1  represents fluoro, chloro or cyano;   
           (C) R w  represents H, R 2b  represents -L 1a -Y 1a , -L 1a -Y 1a  represents —C(O)OR 9b , and:
           (i) both R 9b  substituents represent hydrogen;   (ii) both R 9b  substituents represent methyl;   
           (D) Y represents —S— and R 9b , R w  and R 2b  all represent H;   (E) Y represents —S—, R 9b  represents methyl, and R w  and R 2b  represent H;   (F) Y represents —O—, R 9b  represents methyl, R w  represents H, R 2b  represents X 1 , X 1  represents Z 2a  and Z 2a  represents —C(O)NH 2 ;
 
(2) p represents 1, Y represents —O—, R 2b  and R w  both represent H, then Y 2  does not represent 4-methylphenyl when:
   (A) R 9b  represents H; or   (B) R 9b  represents methyl, and (in both cases):
           (i) A 19  represents —S(O) 2 — and Y 3  represents 4-methylphenyl, 4-acetylphenyl (i.e. 4-(C(O)CH 3 )phenyl) or 4-nitrophenyl;   (ii) A 19  represents —C(O)—, and Y 3  represents 4-pyridyl;
 
(II) L 1  represents a single bond, Y 1  represents —C(O)OR 9b , R 9b  represents H:
   
           (A) L 2  and L 3  both represent —C(O)N(H)—, R 2c  represents the requisite -L 3 -Y 3  group, R 2b  represents -L 1 -Y 1a , -L 1a -Y 1a  represents —COOH, then:
           (i) when Y represents —S(O) 2 —, then Y 2  and Y 3  do not both represent 4-methoxyphenyl, 3-nitro-4-aminophenyl or 3-nitro-4-hydroxyphenyl;   (ii) when Y represents —O—, then Y 2  and Y 3  do not both represent 4-methoxyphenyl, 4-bromophenyl, 3-nitro-4-aminophenyl, 3-nitro-4-hydroxyphenyl or 2-carboxyphenyl;   
           (B) L 2  and L 3  both represent —C(O)N(H)—, R 2b  represents the requisite -L 3 -Y 3  group, R 2c  represents -L 1 -Y 1a , -L 1a -Y 1a  represents —COOH, when Y represents —O— or —S(O) 2 , then Y 2  and Y 3  do not both represent 4-methoxyphenyl;   (C) L 2  and L 3  both represent —N(H)C(O)—, R 2c  represents the requisite -L 3 -Y 3  group, R 2b  represents -L 1 -Y 1a , -L 1a -Y 1a  represents —COOH, when Y represents —O—, then Y 2  and Y 3  do not both represent 4-nitrophenyl;
 
(III) R 2c  represents the requisite -L 3 -Y 3  group, R 2b  represents -L 1 -Y 1a , -L 1 -Y 1  and -L 1a -Y 1a  both represent —S(O) 3 H, L 2  and L 3  both represent —OS(O) 2 —, Y represents —S(O) 2 —:
   (A) Y 2  and Y 3  do not both represent phenyl, each of which are substituted at the 4-position with A, in which A represents G 1 , G 1  represents -A 1 -R 16a , A 1  represents —N(H)S(O) 2 —, and R 16a  represents either 3-nitrophenyl or 3-aminophenyl;   (B) Y 2  and Y 3  do not both represent 4-nitrophenyl;
 
(IV) R 2c  represents the requisite -L 3 -Y 3  group, -L 1 -Y 1  represents —C(O)OH, L 2  represents —O—CH 2 —, L 3  represents —(CH 2 ) 2 N(R w )—CH 2 —, R w  represents methyl substituted by ═O and —O-tert-butyl, Y represents —S(O) 2 —, then Y 2  and Y 3  do not both represent unsubstituted phenyl groups;
 
(V) Y represents —O—, R 2b  represents -L 1a -Y 1a , -L 1 -Y 1  and -L 1a -Y 1a  represent —COOH, R 2c  represents the requisite -L 3 -Y 3  group, L 2  and L 3  both represent —N(H)S(O) 2 —, then:
   (i) Y 2  and Y 3  do not both represent 4-nitrophenyl, 4-(methanesulfonyl)phenyl (i.e. 4-(-S(O) 2 CH 3 )phenyl), 4-cyanophenyl, 4-(acetamido)phenyl, 4-acetylphenyl (i.e. 4-C(O)CH 3 )phenyl) or 4-methoxyphenyl;
 
(VI) Y represents —O—, R 2b  represents hydrogen, -L 1 -Y 1  represents —COOH, R 2  represents the requisite -L 3 -Y 3  group, L 2  represents —N(H)S(O) 2 —:
   (i) L 3  represents —CH 2 —N(H)S(O) 2 —, then Y 2  and Y 3  do not both represent 4-nitrophenyl, 4-carboxyphenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-(methanesulfonyl)phenyl, 4-(acetamido)phenyl (i.e. 4-(-N(H)C(O)CH 3 ) or 2,5-dimethoxyphenyl;   (ii) L 3  represents —CH 2 —N(H)S(O) 2 —, then Y 2  does not represent 4-nitrophenyl when Y 3  represents 4-(acetamido)phenyl, 2,5-dimethoxyphenyl, 4-carboxyphenyl, 4-cyanophenyl, 2,4-dinitrophenyl, 2-(ethoxycarbonyl)phenyl (i.e. 2-COOCH 3 )phenyl), 4-methoxyphenyl, bromo-6-chloro-pyrid-3-yl or 4-(methanesulfonyl)phenyl;   (iii) L 3  represents —N(H)S(O) 2 —, then Y 2  and Y 3  do not both represent 4-nitrophenyl;
 
(VII) Y represents —O—, R 2c  represents hydrogen, -L 1 -Y 1  represents —COOH, R 2b  represents the requisite -L 3 -Y 3  group:
   (i) L 2  represents —N(H)S(O) 2 —, Y 2  represents 4-carboxyphenyl:
           (a) then when L 3  represents —CH 2 —N(H)—C(O)—CH 2 —, Y 3  does not represent unsubstituted phenyl;   (b) then when L 3  represents —CH 2 —N(H)—C(O)—, Y 3  does not represent unsubstituted 2-furanyl;   
           (ii) then when L 2  represents —N(H)C(O)CH 2 —, L 3  represents —CH 2 —N(H)—C(O)—CH 2 —, Y 2  and Y 3  do not both represent unsubstituted phenyl.       

     According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined, provided that: 
     when D 2a  represents D 2 ; D 2b  represents —C(-L 2 -Y 2 )═; D 1 , D 2  and D 3  respectively represent —C(R 1a )═, —C(R 1b )═ and —C(R 1c )═; ring A represents ring (I); E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2c )═, —C(R 2d )═ and —C(H)═; R 1a , R 1b , R 1c  and R 2d  all represent hydrogen:
 
(I) R 2c  represents the requisite -L 3 -Y 3  group, -L 1 -Y 1  represents —C(O)OR 9b ; L 2  represents —N(H)S(O) 2 —; L 3  represents —(CH 2 ) p N(R w )-A 19 -:
 
(1) A 19  represents —S(O) 2 —, p represents 0, then Y 2  and Y 3  do not both represent 4-methylphenyl when:
         (A) Y represents —O— and R 9b  represents H:
           (i) R w  represents H or n-hexyl, and R 2b  represents H;   (ii) R w  represents H, R 2b  represents X 1  in which X 1  represents —OR 5h , and R 5h  represents n-pentyl, isobutyl, n-propyl, ethyl or methyl;   (iii) R w  represents H, R 2b  represents X 1  in which X 1  represents —N(R 6b )R 7b , one of R 6b  or R 7b  represents H, and the other represents methyl, ethyl, n-propyl and/or n-butyl;   (iv) R w  represents H, R 2b  represents X 1 , X 1  represents Z 2a , in which Z 2a  represents R 5a , and R 5a  represents methyl, —CF 3 , —CH 2 OH, —CH═CH 2 , ethyl or n-propyl;   (v) Fr represents H, R 2b  represents X 1 , in which X 1  represents fluoro, chloro or cyano;   
           (B) Y represents —O—, R 9b  represents methyl, and R w  and R 2b  represent H;   (C) R w  represents H, R 2b  represents -L 1a -Y 1a , -L 1a -Y 1a  represents —C(O)OR 9b , and both R 9b  substituents represent hydrogen;   (D) Y represents —S— and R 9b , R w  and R 2b  all represent H;
 
(2) p represents 1, Y represents —O—, R 2b  and R w  both represent H, then Y 2  does not represent 4-methylphenyl when:
   (A) R 9b  represents H:
           (i) A 19  represents —S(O) 2 — and Y 3  represents 4-methylphenyl, 4-acetylphenyl (i.e. 4-(C(O)CH 3 )phenyl) or 4-nitrophenyl;   (ii) A 19  represents —C(O)—, and Y 3  represents 4-pyridyl;
 
(V) Y represents —O—, R 2b  represents -L 1a -Y 1a , -L 1 -Y 1  and -L 1a -Y 1a  represent —COOH, R 2c  represents the requisite -L 3 -Y 3  group, L 2  and L 3  both represent —N(H)S(O) 2 —, then:
   
           (i) Y 2  and Y 3  do not both represent 4-nitrophenyl, 4-(methanesulfonyl)phenyl (i.e. 4-(-S(O) 2 CH 3 )phenyl), 4-cyanophenyl, 4-(acetamido)phenyl, 4-acetylphenyl (i.e. 4-C(O)CH 3 )phenyl) or 4-methoxyphenyl;
 
(VI) Y represents —O—, R 2b  represents hydrogen, -L 1 -Y 1  represents —COOH, R 2c  represents the requisite -L 3 -Y 3  group, L 2  represents —N(H)S(O) 2 —:
   (i) L 3  represents —CH 2 —N(H)S(O) 2 —, then Y 2  and Y 3  do not both represent 4-nitrophenyl, 4-carboxyphenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-(methanesulfonyl)phenyl, 4-(acetamido)phenyl (i.e. 4-(-N(H)C(O)CH 3 ) or 2,5-dimethoxyphenyl;   (ii) L 3  represents —CH 2 —N(H)S(O) 2 —, then Y 2  does not represent 4-nitrophenyl when Y 3  represents 4-(acetamido)phenyl, 2,5-dimethoxyphenyl, 4-carboxyphenyl, 4-cyanophenyl, 2,4-dinitrophenyl, 2-(ethoxycarbonyl)phenyl (i.e. 2-COOCH 3 )phenyl), 4-methoxyphenyl, 5-bromo-6-chloro-pyrid-3-yl or 4-(methanesulfonyl)phenyl;   (iii) L 3  represents —N(H)S(O) 2 —, then Y 2  and Y 3  do not both represent 4-nitrophenyl;
 
(VII) Y represents —O—, R 2  represents hydrogen, -L 1 -Y 1  represents —COOH, R 2b  represents the requisite -L 3 -Y 3  group:
   (i) L 2  represents —N(H)S(O) 2 —, Y 2  represents 4-carboxyphenyl:
           (a) then when L 3  represents —CH 2 —N(H)—C(O)—CH 2 —, Y 3  does not represent unsubstituted phenyl;   (b) then when L 3  represents —CH 2 —N(H)—C(O)—, Y 3  does not represent unsubstituted 2-furanyl;   
           (ii) then when L 2  represents —N(H)C(O)CH 2 —, L 3  represents —CH 2 —N(H)—C(O)—CH 2 —, Y 2  and Y 3  do not both represent unsubstituted phenyl,
 
for use as a pharmaceutical.
       

     Although compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. “protected”) derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the “active” compounds to which they are metabolised) may therefore be described as “prodrugs” of compounds of the invention. 
     By “prodrug of a compound of the invention”, we include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of the invention are included within the scope of the invention. 
     Furthermore, certain compounds of the invention (including, but not limited to, compounds of formula I in which Y 1  (or, if present, Y 1a ) represents —C(O)OR 9b  in which R 9b  is/are other than hydrogen, so forming an ester group) may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such (including, but not limited to, corresponding compounds of formula I, in which Y 1  (or, if present, Y 1a ) represents —C(O)OR 9b  in which R 9b  represent hydrogen). Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the “active” compounds of the invention to which they are metabolised), may also be described as “prodrugs”. 
     Thus, the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity. 
     Compounds of the invention may inhibit leukotriene (LT) C 4  synthase, for example as may be shown in the test described below, and may thus be useful in the treatment of those conditions in which it is required that the formation of e.g. LTC 4 , LTD 4  or LTE 4  is inhibited or decreased, or where it is required that the activation of a Cys-LT receptor (e.g. Cys-LT, or Cys-LT 2 ) is inhibited or attenuated. The compounds of the invention may also inhibit microsomal glutathione S-transferases (MGSTs), such as MGST-I, MGST-II and/or MGST-III, thereby inhibiting or decreasing the formation of LTD 4 , LTE 4  or, especially, LTC 4 . 
     Compounds of the invention may also inhibit the activity of 5-lipoxygenase-activating protein (FLAP), for example as may be shown in a test such as that described in  Mol. Pharmacol.,  41, 873-879 (1992). Hence, compounds of the invention may also be useful in inhibiting or decreasing the formation of LTE 4 . 
     Compounds of the invention are thus expected to be useful in the treatment of disorders that may benefit from inhibition of production (i.e. synthesis and/or biosynthesis) of leukotrienes (such as LTC 4 ), for example a respiratory disorder and/or inflammation. 
     The term “inflammation” will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions. 
     The term “inflammation” will thus also be understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever. 
     Where a condition has an inflammatory component associated with it, or a condition characterized by inflammation as a symptom, the skilled person will appreciate that compounds of the invention may be useful in the treatment of the inflammatory symptoms and/or the inflammation associated with the condition. 
     Accordingly, compounds of the invention may be useful in the treatment of allergic disorders, asthma, childhood wheezing, chronic obstructive pulmonary disease, bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease (e.g. sarcoidosis, pulmonary fibrosis, scleroderma lung disease, and usual interstitial in pneumonia), ear nose and throat diseases (e.g. rhinitis, nasal polyposis, and otitis media), eye diseases (e.g. conjunctivitis and giant papillary conjunctivitis), skin diseases (e.g. psoriasis, dermatitis, and eczema), rheumatic diseases (e.g. rheumatoid arthritis, arthrosis, psoriasis arthritis, osteoarthritis, systemic lupus erythematosus, systemic sclerosis), vasculitis (e.g. Henoch-Schonlein purpura, Löffler&#39;s syndrome and Kawasaki disease), cardiovascular diseases (e.g. atherosclerosis), gastrointestinal diseases (e.g. eosinophilic diseases in the gastrointestinal system, inflammatory bowel disease, irritable bowel syndrome, colitis, celiaci and gastric haemorrhagia), urologic diseases (e.g. glomerulonephritis, interstitial cystitis, nephritis, nephropathy, nephrotic syndrome, hepatorenal syndrome, and nephrotoxicity), diseases of the central nervous system (e.g. cerebral ischemia, spinal cord injury, migraine, multiple sclerosis, and sleep-disordered breathing), endocrine diseases (e.g. autoimmune thyreoiditis, diabetes-related inflammation), urticaria, anaphylaxis, angioedema, oedema in Kwashiorkor, dysmenorrhoea, burn-induced oxidative injury, multiple trauma, pain, toxic oil syndrome, endotoxin chock, sepsis, bacterial infections (e.g. from  Helicobacter pylori, Pseudomonas aerugiosa  or  Shigella dysenteriae ), fungal infections (e.g. vulvovaginal candidasis), viral infections (e.g. hepatitis, meningitis, parainfluenza and respiratory syncytial virus), sickle cell anemia, hypereosinofilic syndrome, and malignancies (e.g. Hodgkins lymphoma, leukemia (e.g. eosinophil leukemia and chronic myelogenous leukemia), mastocytos, polycytemi vera, and ovarian carcinoma). In particular, compounds of the invention may be useful in treating allergic disorders, asthma, rhinitis, conjunctivitis, COPD, cystic fibrosis, dermatitis, urticaria, eosinophilic gastrointestinal diseases, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and pain. 
     Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. 
     According to a further aspect of the present invention, there is provided a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, LTC 4  synthase and/or a method of treatment of a disease in which inhibition of the synthesis of LTC 4  is desired and/or required (e.g. respiratory disorders and/or inflammation), which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition. 
     “Patients” include mammalian (including human) patients. 
     The term “effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect). 
     Compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form. 
     Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. 
     Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice. 
     According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, as hereinbefore defined (but with certain provisos), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations (e.g. preferred pharmaceutical formulations) that may be mentioned include those in which the active ingredient is present in at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight. 
     The invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined (but with certain provisos), or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier. 
     Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of a respiratory disorder (e.g. thromboxane receptor (TP) antagonists, leukotriene receptor antagonists (LTRAs), glucocorticoids, antihistamines, beta-adrenergic drugs, anticholinergic drugs and PDE 4  inhibitors and/or other therapeutic agents that are useful in the treatment of a respiratory disorder) and/or other therapeutic agents that are useful in the treatment of inflammation and disorders with an inflammatory component (e.g. NSAIDs, coxibs, corticosteroids, analgesics, inhibitors of 5-lipoxygenase, inhibitors of FLAP (5-lipoxygenase activating protein), immunosuppressants and sulphasalazine and related compounds and/or other therapeutic agents that are useful in the treatment of inflammation). 
     According to a further aspect of the invention, there is provided a combination product comprising:
     (A) a compound of the invention, as hereinbefore defined; and   (B) another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation,
 
wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
   

     Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent). 
     Thus, there is further provided: 
     (1) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
 
(2) a kit of parts comprising components:
     (a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and   (b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,
 
which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
   

     The invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier. 
     By “bringing into association”, we mean that the two components are rendered suitable for administration in conjunction with each other. 
     Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components “into association with” each other, we include that the two components of the kit of parts may be: 
     (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
 
(ii) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy.
 
     Compounds of the invention may be administered at varying doses. Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day. For e.g. oral administration, the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion. Advantageously, compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. 
     In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. 
     Compounds of the invention may have the advantage that they are effective inhibitors of LTC 4  synthase. 
     Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise. 
     Biological Tests 
     In Vitro Assay 
     In the assay, LTC 4  synthase catalyses the reaction where the substrate LTA 4  methyl ester is converted to the corresponding LTC 4  methyl ester. Recombinant human LTC 4  synthase is expressed in  Piccia pastoralis  and the purified enzyme is dissolved in 25 mM Tris-buffer pH 7.8 and stored at −80° C. The assay is performed in phosphate buffered saline (PBS) pH 7.4, supplemented with 5 mM glutathione (GSH). The reaction is terminated by addition of acetonitrile/MeOH/acetic acid (50/50/1). The assay is performed at rt in 96-well plates. Analysis of the formed LTC 4  methyl ester is performed with reversed phase HPLC (Waters 2795 utilizing an Onyx Monolithic C18 column). The mobile phase consists of acetonitrile/MeOH/H 2 O (32.5/30/37.5) with 1% acetic acid pH adjusted with NH 3  to pH 5.6, and absorbance measured at 280 nm with a Waters 2487 UV-detector. 
     The following is added chronologically to each well:
     1. 50 μl assay buffer, PBS with 5 mM GSH.   2. 0.5 μl inhibitor in DMSO (final conc. 1 nM-10 μM).   3. 2 μl LTC 4  synthase in PBS. The total protein concentration in this solution is 0.025 mg/ml. Incubation of the plate at room temperature for 10 minutes.   4. 1-1.5 μl LTA 4  methyl ester (final conc. 10 μM). Incubation of the plate at rt for 1 min.   5. 50 μl stop solution.   

     80 μl of the incubation mixture is analysed with HPLC. 
     Alternatively HTRF detection of LTC 4  can be used: 
     In the assay, LTC 4  synthase catalyses the reaction where the substrate LTA 4  is converted to LTC 4 . Recombinant human LTC 4  synthase is expressed in  Piccia pastoralis  and the purified enzyme is dissolved in 25 mM Tris-buffer pH 7.8 supplemented with 0.1 mM glutathione (GSH) and stored at −80° C. The assay is performed in phosphate buffered saline (PBS) pH 7.4 and 5 mM GSH in 384-well plates. 
     The following is added chronologically to each well:
     1. 48 μl LTC 4  synthase in PBS with 5 mM GSH. The total protein concentration in this solution is 0.5 μg/ml.   2. 1 μl inhibitor in DMSO (final conc. 10 μM).   3. Incubation of the plate at room temperature for 10 minutes.   4. 1 μl LTA 4  (final conc. 2.5 μM).   5. Incubation of the plate at room temperature for 5 minutes.   6. 10 μl of the incubation mixture is analysed using homogeneous time resolved fluorescent (HTRF) detection.   

    
    
     EXAMPLES 
     The invention is illustrated by way of the following examples, in which the following abbreviations may be employed: 
     aq aqueous
 
BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
 
Boc tert-butoxycarbonyl
 
brine saturated aqueous solution of NaCl
 
conc concentrated
 
DCM dichloromethane
 
     DMAP 4-N,N-dimethylaminopyridine 
     DMF N,N-dimethylformamide 
     EDCl (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
 
EtOAc ethyl acetate
 
EtOH ethanol
 
eq equivalents
 
MeOH methanol
 
NMR nuclear magnetic resonance
 
Pd—C palladium on charcoal (10%)
 
Pd 2 dba 3  tris(dibenzylideneacetone)dipalladium(0)
 
rt room temperature
 
rx temperature
 
sat saturated
 
TEA triethylamine
 
TFA trifluoroacetic acid
 
TLC thin layer chromatography
 
xantphos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene
 
     Chemicals specified in the synthesis of the compounds in the examples were commercially available from, e.g. Sigma-Aldrich Fine Chemicals or Acros Int. 
     Compounds I-VII 
     6-Hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (I) 
     Trifluoroacetic acid anhydride (41.6 g, 198 mmol) and acetone (19.2 g, 330 mmol) were added to a stirred mixture of 2,5-dihydroxybenzoic acid (10.17 g, 66 mmol) and trifluoroacetic acid (82 mL) at 0° C. The mixture was allowed to slowly reach rt, and was after 14 h concentrated to ⅓ of the volume. EtOAc (15 mL) and NaHCO 3  (sat, 150 mL) were added and the mixture was stirred for 2 h. The layers were separated and the aq phase extracted with EtOAc. The combined extracts were dried (Na 2 SO 4 ), concentrated and purified by chromatography and crystallization, to give the title compound. Yield: 4.33 g (33%). 
     Methyl 5-fluoro-2-nitrobenzoate (II) 
     A mixture of 5-fluoro-2-nitrobenzoic acid (2.0 g, 10.8 mmol), K 2 CO 3  (2.87 g, 16.21 mmol), (CH 3 ) 2 SO 4  (1.771 g, 14.04 mmol) and acetone (20 mL) was heated at rx for 2 h, and stirred at rt for 2 d. Quenching with NH 4 OH, extractive workup (EtOAc), drying (Na 2 SO 4 ), concentration and purification by chromatography gave the title compound. Yield: 1.06 g (50%). 
     Methyl 5-(2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-6-yloxy)-2-nitrobenzoate (III) 
     A mixture of K 2 CO 3  (1.335 g, 7.53 mmol), I (487 mg, 2.51 mmol), II (500 mg, 2.51 mmol), 18-crown-6 (132.7 mg, 0.502 mmol) and DMF was stirred at rt for 4 h. Concentration of the mixture to ⅓ of the volume, dilution with EtOAc (60 mL) and extractive workup (NaHCO 3  (sat), HCl (0.1 M)), drying (Na 2 SO 4 ), concentration and chromatography gave the title compound III. Yield: 840 mg (90%). 
     Methyl 2-hydroxy-5-(3-(methoxycarbonyl)-4-nitrophenoxy)benzoate (IV) 
     A mixture of III (200 mg, 0.54 mmol), NaOMe (87.5 mg, 1.62 mmol) and MeOH (15 mL) was stirred at rt for 1 h. Extractive workup (water, HCl (1 M), EtOAc), drying (Na 2 SO 4 ) and concentration gave the title compound IV. Yield: 180 mg (96%. 
     Methyl 5-(3-(methoxycarbonyl)-4-(trifluoromethylsulfonyloxy)phenoxy)-2-nitro-benzoate (V) 
     Pyridine (86 μL, 1.06 mmol) was slowly added to a mixture of IV (180 mg, 0.52 mmol), triflic anhydride (179.4 mg, 0.636 mmol) and CH 2 Cl 2 . After cooling to 0° C., water was added dropwise before the mixture was allowed to reach rt under stirring for 20 min. EtOAc (20 mL) was added and the mixture was quenched with HCl (0.1 M). Extractive workup (brine, NaHCO 3  (sat)), drying (Na 2 SO 4 ), concentration and chromatography gave the title compound V. Yield: 226 mg (80%). 
     Methyl 5-(3-(methoxycarbonyl)-4-(arylamino)phenoxy)-2-nitrobenzoate (VI) 
     A mixture of V (192 mg, 0.4 mmol), the appropriate aryl amine (1.2 eq, 0.48 mmol), Cs 2 CO 3 , (183 mg, 0.56 mmol), BINAP (18.7 mg, 0.03 mmol), Pd(OAc) 2  (4.5 mg, 0.02 mmol) and toluene (3 mL) was stirred at 100° C. for 7 h and at rt for 12 h. The mixture was filtered through Celite, concentrated and purified by chromatography to give the title compound VI. 
     Methyl 5-(3-(methoxycarbonyl)-4-(arylamino)phenoxy)-2-aminobenzoate (VII) 
     A mixture of VI (0.32 mmol), Pd—C (20 mg), EtOAc (10 mL) and EtOH (10 mL) was hydrogenated at ambient temperature and pressure for 40 min. The mixture was filtered through Celite and the solids washed with EtOAc. Concentration of the combined filtrates gave the title compound VII in 99% yield. 
     Examples 1:1-1:8 
     Procedure A 
     A mixture of VII (0.32 mmol), the appropriate aryl bromide (0.38 mmol), Cs 2 CO 3 , (146 mg, 0.448 mmol), BINAP (15 mg, 0.024 mmol), Pd(OAc) 2  (3.6 mg, 0.016 mmol) and toluene (3 mL) was stirred at 100° C. for 7 h and at rt for 14 h. The mixture was filtered through Celite and the solids washed with EtOAc. Concentration of the combined filtrates gave ester VIII in yields given in Tabe 1. 
     A mixture of ester VIII (0.18 mmol), NaOH (72 mg, 1.8 mmol) in an appropriate solvent (MeOH, EtOH or dioxane (10 mL)), and water (2.5 mL) was heated at rx for 1.5 h. After cooling and concentration, brine was added. Acidification with 1 M HCl to pH ˜2-5, extraction with EtOAc, drying (Na 2 SO 4 ), concentration and chromatography gave title compounds IXa and IXb in yields given in Table 1. 
     Example 1:9 
     The title compound was prepared from VII (0.21 mmol) and 4-butoxy-benzenesulfonyl chloride in accordance with Procedure Y, followed by hydrolysis as described above, see Table 1. 
     Examples 2:1-2:9 
     Procedure B 
     Step 1: Methyl 2-acetamido-5-hydroxybenzoate 
     A mixture of 2-amino-5-hydroxybenzoic acid (9.5 g, 0.06 mol) and acetic anhydride (57.1 g, 0.56 mol) was stirred at 140° C. for 40 min. The mixture was filtered and concentrated. Sodium methoxide (3.5 g, 0.065 mol) and MeOH (150 mL) were added and the mixture was stirred at rt over night. The mixture was concentrated, water (200 mL) was added and the mixture was stirred for 2 h. The solid was collected to give the sub-title compound. Yield: 7.9 g (69%). 
     Step 2: Methyl 2-acetamido-5-(3-(methoxycarbonyl)-4-nitrophenoxy)-benzoate 
     A mixture of compound II (2.0 g, 10.0 mmol), methyl 2-acetamido-5-hydroxy-benzoate (2.1 g, 10.0 mmol), K 2 CO 3  (5.34 g, 30.12 mmol), 18-crown-6 (0.54 g, 2.01 mmol) and DMF (30 mL) was stirred at rt for 3 h. Concentration, extractive workup (EtOAc, NaHCO 3  (5%), HCl (0.1 M), water, brine) and chromatography gave the sub-title compound. Yield: 2.87 g (73%). 
     Methyl 2-amino-5-(3-(methoxycarbonyl)-4-nitrophenoxy)benzoate 
     A mixture of ethyl 2-acetamido-5-(3-(methoxycarbonyl)-4-nitrophenoxy)benzoate (1.45 g, 3.74 mmol), HCl (6 M, 60 mL) and MeOH (60 mL) was heated at rx for 50 min. Concentration, extractive workup (EtOAc, NaHCO 3  (5%), water, brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compound. Yield: 1.17 g (90%). 
     Step 3: Methyl 2-arylamido-5-(3-(methoxycarbonyl)-4-nitrophenoxy)-benzoate 
     A mixture of methyl 2-amino-5-(3-(methoxycarbonyl)-4-nitrophenoxy)benzoate (1.15 g, 3.33 mmol), the appropriate aroyl chloride (4.99 mmol) and toluene was heated at rx for 1 h. After cooling, MeOH (5 mL) was added and after 5 min the mixture was concentrated and EtOAc added. Extractive workup (NaHCO 3  (5%), water, brine), drying (Na 2 SO 4 ), concentration and recrystallisation from EtOH gave the sub-title compound. 
     Step 4: Methyl 2-amino-5-(4-arylamido-3-(methoxycarbonyl)phenoxy)-benzoate (X) 
     A mixture of methyl 2-arylamido-5-(3-(methoxycarbonyl)-4-nitrophenoxy)benzoate (3.33 mmol), Pd—C, EtOH (20 mL) and EtOAc (20 mL) was hydrogenated at ambient temperature and pressure until full conversion was achieved as judged by TLC. The mixture was filtered through Celite and the solids washed with EtOAc. Concentration of the combined filtrates gave the sub-title compound. 
     Alternatively, Ammonium chloride (40 mL, sat) and iron powder (346 mg) were added to a mixture of methyl 2-arylamido-5-(3-(methoxycarbonyl)-4-nitro-phenoxy)benzoate (0.49 mmol), isopropanol (40 mL) and THF (1 mL). The mixture was heated at rx for 2 h. Extractive workup (water, EtOAc), drying and concentration of the extracts gave compound X. 
     Step 5: Examples 2:1-2:9 
     A mixture of the appropriate acid chloride (0.353 mmol), X (0.320 mmol) and toluene was heated at rx for 0.5 h. After cooling, MeOH (5 mL) was added and the mixture was stirred to decompose excess acid chloride. Concentration and chromatography gave the di-ester XI in yields given in Table 2. A mixture of XI (0.22 mmol), NaOH (40 mg, 1.0 mmol), water (4 mL), EtOH (15 mL) and dioxane (15 mL) was heated at 65° C. for 0.5 h. The title compounds XII were obtained after acidification, concentration and recrystallisation. Yields are given in Table 2. 
     Examples 3:1 and 3:2 
     2-Arylamido-5-(3-carboxy-4-nitrophenoxy)benzoic acid 
     The title compounds were obtained from 5-(4-amino-3-(methoxycarbonyl)-phenoxy)-2-nitrobenzoic acid (see Procedure B, Step 2) and the appropriate acid chloride in accordance with Procedure B, Step 5. Yields are given in Table 3. 
     Procedure C 
     Diethyl 5,5′-oxybis(2-aminobenzoate) (XIII) 
     Step 1: 4-(4-{[(2E)-2-(Hydroxyimino)ethanoyl]oxy}phenoxy)phenyl (2E)-(hydroxyimino)acetate 
     A mixture of 4,4′-oxydianiline (20 g, 0.1 mol), water (120 mL) and HCl (conc, 17 mL) was added to a mixture of chloral hydrate (36 g, 0.22 mol), Na 2 SO 4  (520 g) and water (480 mL). A solution of hydroxylamine hydrochloride (44 g) in water (200 mL) was added. The mixture was heated to rx over ˜1 h and maintained at that temperature for 30 min. The mixture was cooled to 40° C. The solid was collected by filtration, washed with cold water and dried to give the sub-title compound (30 g) which was used without further purification. 
     Step 2: 5-[(2,3-Dioxo-2,3-dihydroindol-5-yl)oxy]indole-2,3-dione 
     4-(4-{[(2E)-2-(Hydroxyimino)ethanoyl]oxy}-phenoxy)phenyl (2E)-(hydroxyimino)-acetate (30 g) was added in portions to cold sulfuric acid (120 mL, 100%) keeping the temperature below 50° C. The temperature was increased to 80° C. and the mixture was kept at that temperature for 30 min. The mixture was cooled and ice was added. The solid was collected, washed with cold water and dried to give the sub-title compound (24 g) which was used without further purification. 
     Step 3: 2-Amino-5-(4-amino-3-carboxyphenoxy)benzoic acid 
     Hydrogen peroxide (6%, 350 mL) was added to a mixture of 5-[(2,3-dioxo-2,3-dihydroindol-5-yl)oxy]indole-2,3-dione (24 g) and NaOH (10%, 500 mL). The mixture was allowed to stand at rt for 30 min with occasional stirring. The pH was adjusted to ˜3 with HCl (conc). The solid was collected, washed with cold water and dried to give the sub-title compound (10 g) which was used without further purification. 
     Step 4: Diethyl 5,5′-oxybis(2-aminobenzoate) (XIII) 
     Sulfuric acid (conc, 6.81 g, 0.069 mol) was added to a solution of 2-amino-5-(4-amino-3-carboxyphenoxy)benzoic acid (8 g, 0.0278 mol) in EtOH (100 mL) and the mixture was heated at 80° C. for 48 h. The mixture was cooled to rt and neutralized with solid NaHCO 3 . The solvent was removed under reduced pressure. Water (250 mL) was added and the pH was adjusted to ˜8. The solid was collected, washed with cold water and dried to give the title compound. Yield: 8 g (84%). 
     Examples 4:1-4:4 
     Step 1: Pyridine (0.46 g, 5.8 mmol) was added to XIII (0.5 g, 1.45 mmol) in THF (10 mL). The mixture was cooled to 0° C. and the appropriate acid chloride (3.625 mmol) was added. The mixture was stirred at rt for 8 h, diluted with EtOAc and washed with HCl (1.5 M), NaHCO 3  (10%), water and brine. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated to give the ester XIV which was used without further purification. Yields are given in Table 4. 
     Step 2: LiOHxH 2 O (104 mg, 2.48 mmol) was added to XIV (0.827 mmol) in H 2 O (10 mL) and THF (10 mL). The mixture was stirred at rt for 24 h, diluted with EtOAc and the aq layer was separated. The aq layer was acidified (pH ˜4) with HCl (1.5 M) and the mixture was extracted with EtOAc. The combined extracts were washed with H 2 O, brine, dried (Na 2 SO 4 ) and concentrated. The title compound XV was obtained after trituration with chloroform and filtration, in yields given in Table 4. 
     Examples 5:1-5:3 
     Procedure D 
     Step 1: 2-Amino-5-(4-benzamido-3-carboxyphenoxy)benzoic acid (XVI) 
     Pyridine (2.29 g, 29 mmol) was added to XIII (5 g, 14.5 mmol) in THF (50 mL). The mixture was cooled to 0° C. and benzoyl chloride (2.23 g, 15.97 mmol) was added. The mixture was stirred at rt for 8 h, diluted with EtOAc and washed with HCl (1.5 M), NaHCO 3  (10%), H 2 O and brine. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. Chloroform (30 mL) was added to the residue and dry HCl (g) was passed through the mixture. The solid was collected, washed with diethyl ether and dried to give the sub-title compound XVI. Yield: 2.2 g. 
     Step 2: Compounds XVIII 
     Pyridine (0.25 g, 3.12 mmol) was added to XVI (0.70 g, 1.56 mmol) in THF (10 mL). The mixture was cooled to 0° C. and the appropriate acid chloride (1.87 mmol) was added. The mixture was stirred at rt for 8 h, diluted with EtOAc and washed with HCl (1.5 M), NaHCO 3  (10%), H 2 O and brine. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated to give ester XVII. Hydrolysis in accordance with Procedure C gave the title compounds XVIII, see table 5. 
     Examples 6:1-6:7 
     Procedure E 
     Step 1: Methyl 2-(5-fluoro-2-nitrophenyl)acetate 
     A mixture of 1-fluoro-4-nitrobenzene (10.0 g, 70 mmol), methyl chloroacetate (6.8 mL, 80 mmol) and DMF (350 mL) was slowly added to potassium t-butoxide (20 g) in DMF (175 mL) at −5° C. After 5 min the temperature was allowed to reach rt and the mixture was acidified (KHSO 4 , 1 M). Extractive workup (EtOAc, toluene, brine), drying and concentration gave a material containing the sub-title compound which was used without further purification. 
     Step 2: Methyl 2-acetamido-5-(4-nitro-3-(2-methoxy-2-oxoethyl)-phenoxy)benzoate 
     A mixture of methyl 2-acetamido-5-hydroxybenzoic acid (0.30 g, 1.41 mmol), K 2 CO 3  (0.58 g, 4.2 mmol), 18-crown-6 (1 mg, 4 μmol) and DMSO (2 mL) was added to ⅓ of the material from Step 1. After 72 h at rt, the mixture was diluted with EtOAc and acidified (KHSO 4 , 1 M). The organic phase was washed with water and brine, dried, concentrated and purified by chromatography to give the sub-title compound. Yield: 0.42 g. 
     Step 3: Methyl 2-amino-5-(3-(2-methoxy-2-oxoethyl)-4-nitrophenoxy)-benzoate 
     A mixture of methyl 2-acetamido-5-(4-amino-3-(2-methoxy-2-oxoethyl)phenoxy)-benzoate (0.41 g), MeOH(12 mL), HCl (1 mL, conc) and water (1 mL) was heated at rx for 2 h. Extractive workup (EtOAc, NaHCO 3  (aq), brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compound. Yield: (0.36 g, 100%). 
     Step 4: Methyl 2-arylamido-5-(3-(2-methoxy-2-oxoethyl)-4-nitrophenoxy)-benzoate 
     A mixture of methyl 2-amino-5-(3-(2-methoxy-2-oxoethyl)-4-nitrophenoxy)-benzoate (0.36 g, 1.0 mmol), the appropriate acid chloride (1.1 mmol), TEA (0.15 mL, 1.1 mmol) and DCM was stirred at rt until full conversion was achieved, as judged by TLC. Concentration, extractive workup (EtOAc, NaOH (2 M), HCl (2 M), NaHCO 3  (sat), brine), drying, concentration and purification by chromatography gave the sub-title compound. 
     Step 5: Methyl 5-(4-amino-3-(2-methoxy-2-oxoethyl)phenoxy)-2-arylamido-benzoate (XIX) 
     A mixture of methyl 2-arylamido-5-(3-(2-methoxy-2-oxoethyl)-4-nitrophenoxy)-benzoate (0.24 g, 0.46 mmol), Pd—C (0.10 g) and EtOAc (5 mL) was hydrogenatet at ambient temperature and pressure for 3.5 h. Na 2 SO 4  was added, and after stirring, the mixture was filtered through Celite. Concentration gave the sub-title compound. 
     Step 6: 2-Arylamido-5-(4-arylamido-3-(2-methoxy-2-oxoethyl)phenoxy)-benzoic acid (XXI) 
     A mixture of the appropriate acid chloride (0.31 mmol), compound XIX (0.14 g, 0.29 mmol), TEA and DCM (4 mL) was stirred at rt overnight. MeOH (0.5 mL) was added. Extractive workup (CH 2 Cl 2 , HCl (conc), H 2 O, brine, NaHCO 3  (sat)), drying (Na 2 SO 4 ) and purification by chromatography gave methyl 2-arylamido-5-(4-arylamido-3-(2-methoxy-2-oxoethyl)-phenoxy)benzoate XX in yield given in Table 6. The title compounds (XXI) were obtained by hydrolysis in accordance with Procedure A, see Table 6. 
     Examples 7:1-7:2 
     Procedure F 
     Step 1: Methyl 2-amino-5-hydroxybenzoate 
     H 2 SO 4  (100 mL, 100%) was added to 2-amino-5-hydroxy benzoic acid (100 g, 0.653 mol) in MeOH (2 L) and the mixture was heated at reflux for 48 h. The mixture was cooled, neutralized with solid NaHCO 3  and concentrated. Water (1.5 L) was added and the pH was adjusted ˜8 with solid NaHCO 3 . The solid was collected, washed with cold water and dried to give the sub-title compound. Yield: 94 g (86%). 
     Step 2: Methyl 5-hydroxy-2-[(phenylsulfonyl)amino]benzoate 
     Benzenesulfonyl chloride (104.3 g, 0.591 mol) was added to methyl 2-amino-5-hydroxybenzoate (94 g, 0.563 mol) in pyridine (400 mL) at 0° C. and the mixture was stirred at rt for 5 h. Water was added to decompose unreacted benzenesulfonyl chloride and the mixture was extracted with EtOAc. The combined extracts were washed with HCl (1.5 M), water and brine. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The residue was crystallized from DCM/hexane to give the sub-title compound. Yield: 136 g (78%). 
     Step 3: 5-{3-(Methoxycarbonyl)-4-[(phenylsulfonyl)amino]phenoxy}-2-nitrobenzoic acid 
     5-Fluoro-2-nitrobenzoic acid (81.9 g, 0.442 mol) and K 2 CO 3  (183.2 g, 1.32 mol) were added to methyl 5-hydroxy-2-[(phenylsulfonyl)amino]benzoate (136 g, 0.442 mol) in DMF (700 mL) and the mixture was heated at 120° C. for 24 h. The mixture was cooled to rt and quenched with water. The pH was adjusted to ˜5 with HCl (1.5 M) and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by chromatography to give the sub-title compound. Yield: 132 g (63%). 
     Step 4: 2-Amino-5-{3-(methoxycarbonyl)-4-[(phenylsulfonyl)amino]-phenoxy}benzoic acid (XXII) 
     A mixture of 5-{3-(methoxycarbonyl)-4-[(phenylsulfonyl)amino]phenoxy}-2-nitro-benzoic acid (122 g, 0.259 mol), 10% Pd—C (12 g) and MeOH was hydrogenated at 3 atm for 16 h. The mixture was filtered through Celite and the solids washed with MeOH. The filtrates were concentrated to give the sub-title compound. Yield: 105 g (92%). 
     Example 7:1 
     2-(4-Butylbenzamido)-5-(3-(methoxycarbonyl)-4-(Phenylsulfonamido)phenoxy)-benzoic acid 
     TEA (2.26 mmol, 314 μL) followed by 4-butylbenzoyl chloride (1.13 mmol, 212 μL) was added to XXII (500 mg, 1.13 mmol) in THF (40 mL). The mixture was stirred at rt overnight and most of the solvent was evaporated. The residue was partitioned between HCl (2 M) and EtOAc. The organic phase was washed with water and brine, dried (Na 2 SO 4 ) and concentrated. The residue was crystallized from EtOAc to give the title compound. Yield: 380 mg (56%). See Table 7. 
     Example 7:2 
     2-(4-Butylbenzamido)-5-(3-carboxy)-4-(phenylsulfonamido)phenoxy)benzoic acid 
     A mixture of 2-(4-butylbenzamido)-5-(3-(methoxycarbonyl)-4-(phenylsulfon-amido)phenoxy)benzoic acid (128 mg, 0.212 mmol) EtOH (15 mL) and NaOH (85 mg, 2.12 mmol, in 6 mL of water) was stirred at 85° C. for 30 min. Most of the EtOH was evaporated and the mixture was acidified to pH ˜3 with HCl (2 M). The solid was collected, washed with water and dried to give the title compound. Yield: 108 mg (86% yield). See Table 7. 
     Examples 8:1, 8:3-8:6, 8:9, 8:13-8:14 
     Procedure G 
     Step 1: Methyl 5-(4-nitrophenoxy)-2-acetamidobenzoate 
     A mixture of methyl 2-acetamido-5-hydroxybenzoate (2.372 g, 11.34 mmol), 1-fluoro-4-nitrobenzene (1.560 g, 11.34 mmol), K 2 CO 3  (4.694 g, 34.01 mmol), 18-crown-6 (599 mg, 2.27 mmol) and DMF (60 mL) was stirred at rt for 3 h. The mixture was concentrated, EtOAc (70 mL) was added and, the mixture was filtered. Extractive workup (NaHCO 3  (sat), HCl (0.1 M), water, brine) drying (Na 2 SO 4 ) and concentration gave the sub-title compound. Yield: 2.68 g (72%). 
     Step 2: Methyl 5-(4-nitrophenoxy)-2-aminobenzoate 
     A mixture of methyl 5-(4-nitrophenoxy)-2-acetamidobenzoate (2.68 g, 8.11 mmol), MeOH (200 mL) and HCl (100 mL, 8 M) was heated at rx for 1 h. The pH was adjusted to ˜6 with NaHCO 3  and the mixture was concentrated. Extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compound. Yield: 2.24 g (96%). 
     Step 3: Methyl 5-(4-nitrophenoxy)-2-(arylamido)benzoate 
     A mixture of methyl 5-(4-nitrophenoxy)-2-aminobenzoate (2.19 g, 7.60 mmol), the appropriate aroyl chloride (8.36 mmol) and toluene (45 mL) was heated at rx for 30 min. MeOH (0.5 mL) was added and after a few minutes the solid was collected. Recrystallization from EtOAc gave the sub-title compound. 
     Step 4: Methyl 5-(4-aminophenoxy)-2-(arylamido)benzoate 
     The sub-title compounds were obtained by hydrogenation of methyl 5-(4-nitro-phenoxy)-2-(arylamido)benzoate in accordance with the preparation of XIX, Step 5). 
     Step 5: Examples 8:1, 8:3-8:6, 8:9, 8:13-8:14 
     The title compounds were prepared from methyl 5-(4-aminophenoxy)-2-(arylamido)benzoate and the appropriate acid chloride in accordance with Step 3 above followed by hydrolysis in accordance with procedure A, see Table 8. 
     Example 8:15 
     The title compound was prepared from methyl 5-(4-aminophenoxy)-2-(arylamido)-benzoate by reductive amination and hydrolysis in accordance with Procedure AE. 
     Examples 8:7-8:8, 8:10-8:12 
     Procedure H 
     Step 1: Methyl 5-(4-aminophenoxy)-2-nitrobenzoate 
     A mixture of II (2.0 g, 10.04 mmol), p-aminophenol sulfate (2.08 g, 10.04 mmol), K 2 CO 3  (6.93 g, 50.20 mmol), 18-crown-6 (0.053 g, 0.20 mmol) and DMF (40 mL) was stirred at 55° C. for 24 h. The mixture was concentrated and EtOAc was added. The mixture was filtered, washed (water, brine), dried (Na 2 SO 4 ) and concentrated. Purification by chromatography gave the sub-title compound. 
     Yield: 3.0 g (99%). 
     Step 2: Methyl 5-(4-arylamidophenoxy)-2-nitrobenzoate 
     A mixture of methyl 5-(4-aminophenoxy)-2-nitrobenzoate (2.00 g, 6.94 mmol), the appropriate acid chloride (7.63 mmol) and toluene (30 mL) was heated at rx for 90 min. MeOH (20 mL) was added and after a few minutes the mixture was concentrated and recrystallized from an appropriate solvent to give the sub-title compounds. 
     Step 3: Methyl 2-amino-5-(4-arylamidophenoxy)benzoate 
     The sub-title compounds were obtained by hydrogenation of methyl 5-(4-aryl-amidophenoxy)-2-nitrobenzoate in accordance with the preparation of XIX, Step 5). 
     Step 4: Examples 8:7-8:8, 8:10-8:12 
     A mixture of methyl 2-amino-5-(4-arylamidophenoxy)benzoate (0.41 mmol), the appropriate acid chloride (0.46 mmol), toluene (3 mL) and CH 3 CN (3 mL) was heated at rx for 90 min. MeOH (20 mL) was added and after a few minutes the mixture was concentrated and the residue crystallized from an appropriate solvent to give methyl 2-arylamido-5-(4-arylmidophenoxy)benzoate. Hydrolysis in accordance with Procedure A gave the title compounds, see Table 8. 
     Examples 9:1-9:5 
     The title compounds were prepared from 4-(methylamino)phenol in accordance with Procedure H, see Table 9. 
     Examples 10:1-10:6 
     Procedure J 
     Step 1: Methyl 5-(3-aminophenoxy)-2-nitro-benzoate 
     A mixture of II (3.14 g, 15.0 mmol), 3-aminophenol (1.54 g, 15.0 mmol), K 2 CO 3  (7.90 g, 45.0 mmol), 18-crown-6 (0.39 g, 1.47 mmol) and DMF (40 mL) was stirred at 55° C. for 2 h. Concentration and extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ) and chromatography gave the sub-title compound. 
     Yield: 3.70 g (80%). 
     Step 2: Methyl 5-[3-(aroylamino)phenoxy]-2-nitrobenzoate 
     A mixture of methyl 5-(3-aminophenoxy)-2-nitrobenzoate (1.0 g, 3.47 mmol), the appropriate acid chloride (4.79 mmol) and toluene (45 mL) was heated at reflux for 30 min. MeOH (0.5 mL) was added and after a few minutes the mixture was concentrated. Purification by chromatography gave the sub-title compounds. 
     Step 3: Methyl 5-[3-(aroylamino)phenoxy]-2-aminobenzoate 
     The sub-title compounds were prepared by hydrogenation in accordance with the preparation of XIX, Step 5. 
     Step 4: 5-[3-(Aroylamino)phenoxy]-2-aroylaminobenzoate 
     A mixture of methyl 5-[3-(aroylamino)phenoxy]-2-aminobenzoate (0.348 mmol), the appropriate acid chloride (0.530 mmol) and toluene (45 mL) was heated at reflux for 1 h. MeOH (0.5 mL) was added and after a few minutes the mixture was concentrated. Purification by chromatography gave methyl 5-[3-(aroylamino)-phenoxy]-2-aroylaminobenzoate. Hydrolysis in accordance with Procedure A gave the title compound, see Table 10. 
     Examples 11:3-11:7, 11:13-11:22 
     Procedure K 
     Step 1: Methyl 5-(4-(methylamino)phenoxy)-2-nitrobenzoate 
     A mixture of II (3.0 g, 15 mmol), 4-(methylamino)phenol (3.32 g, 15 mmol), K 2 CO 3  (10.35 g, 75 mmol), 18-crown-6 (3.96 g, 15 mmol) and DMF (20 mL) was stirred at rt for 2 h. Concentration, extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compound. 
     Yield: 2.5 g (55%. 
     Step 2: Methyl 5-(4-(N-methylarylsulfonamido)phenoxy)-2-nitrobenzoate 
     A mixture of methyl 5-(4-(methylamino)phenoxy)-2-nitrobenzoate (0.35 g, 1.13 mmol), the appropriate sulfonyl chloride (1.27 mmol), DMAP (32 mg, 0.26 mmol), TEA (176 mL, 1.27 mmol) and DCM (5 mL) was stirred at rt for 45 min. EtOH (0.5 mL) was added and after 10 min the mixture was concentrated. Extractive workup (DCM, citric acid (10%), brine), drying (Na 2 SO 4 ), concentration, and chromatography gave the sub-title compounds. 
     Step 3: Methyl 2-amino-5-(4-(N-methylarylsulfonamido)phenoxy)benzoate 
     The sub-title compounds were prepared by hydrogenation in accordance with the preparation of XIX, Step 5. 
     Step 4: Examples 11:3-11:7, 11:13-11:22 
     The title compounds were prepared from methyl 2-amino-5-(4-(N-methylaryl-sulfonamido)phenoxy)benzoate and the appropriate acid chloride in accordance with Procedure H, Step 2, followed by hydrolysis in accordance with Procedure A, see Table 11. 
     Example 11:12 
     2-(2,3-Dichlorobenzylamino)-5-{4-[(4-methoxybenzenesulfonyl)methylamino]-phenoxy}benzoic acid 
     The title compound was prepared from methyl 2-amino-5-(4-(N-methylarylsulfon-amido)phenoxy)benzoate and 2,3-dichlorobenzaldehyde by reductive amination using sodiumcyanoborohydride followed by hydrolysis in accordance with Procedure AE, see Table 11. 
     Examples 11:1-11:2, 11:8 
     Procedure L 
     The title compounds were prepared from methyl 5-(4-aminophenoxy)-2-(arylamido)benzoate (see procedure G, Step 4) and the appropriate sulfonyl chloride in accordance with Procedure K, Step 2 followed by hydrolysis in accordance with Procedure A, see Table 11. 
     Examples 11:9-11:11 
     Procedure M 
     Step 1: Methyl 2-(tert-butoxycarbonylamino)-5-hydroxybenzoate 
     A mixture of methyl 2-amino-5-hydroxybenzoate (6.0 g, 35.9 mmol), Boc anhydride (9.4 g, 43 mmol) and EtOH (300 mL) was stirred at 35° C. for 3 d. Concentration and recrystallization from EtOH gave the sub-title compound. Yield: 4.74 g (49%). 
     Step 2: Methyl 2-(tert-butoxycarbonylamino)-5-(4-nitrophenoxy)benzoate 
     A mixture of methyl 2-(tert-butoxycarbonylamino)-5-hydroxybenzoate (4.30 g, 16 mmol), 1-fluoro-4-nitrobenzene (2.40 g, 17 mmol), K 2 CO 3  (11 g, 80 mmol), 18-crown-6 (300 mg, 1.13 mmol) and DMF (100 mL) was stirred at rt for 20 h. Extractive workup (EtOAc, water), drying (Na 2 SO 4 ), concentration and crystallization from EtOAc gave the sub-title compound. Yield: 4.8 g (78%). 
     Step 3: Methyl 2-(tert-butoxycarbonyl(methyl)amino)-5-(4-nitrophenoxy)-benzoate 
     A mixture of methyl 2-(tert-butoxycarbonylamino)-5-(4-nitrophenoxy)benzoate (3.6 g, 9.3 mmol), NaH (80%) (834 mg, 27.8 mmol), CH 3 I (2.9 mL, 46.3 mmol) and DMF was stirred at rt until full conversion was achieved as judged by TLC. Extractive workup (EtOAc, water, NaHCO 3  (sat), citric acid (10%), brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compound. Yield: 1 g (42%). 
     Step 4: Methyl 5-(4-aminophenoxy)-2-(tert-butoxycarbonyl(methyl)amino)-benzoate 
     The sub-title compound was obtained from methyl 2-(tert-butoxycarbonyl(methyl)-amino)-5-(4-nitrophenoxy)benzoate (660 mg, 1.64 mmol) by hydrogenation in accordance with the preparation of XIX, Step 5). Yield: 420 mg (69%). 
     Step 5: Methyl 2-(tert-butoxycarbonyl(methyl)amino)-5-(4-(arylsulfon-amido)phenoxy)benzoate 
     The sub-title compound was obtained from methyl 5-(4-aminophenoxy)-2-(tert-butoxycarbonyl(methyl)amino)benzoate and the appropriate sulfonyl chloride in accordance with Procedure K, Step 2. 
     Step 6: Methyl 2-(methylamino)-5-(4-(arylsulfonamido)phenoxy)benzoate 
     A mixture of methyl 2-(tert-butoxycarbonyl(methyl)amino)-5-(4-(arylsulfonamido)-phenoxy)benzoate (250 mg, 0.427 mmol), TFA (2 mL) and DCM (4 mL) was stirred at rt for 30 min. Extractive workup (DCM, water, NaHCO 3  (sat)), drying (Na 2 SO 4 ) and concentration gave the sub-title compounds. 
     Step 7: Examples 11:9-11:11 
     The title compounds were prepared from methyl 2-(methylamino)-5-(4-(phenylsulfonamido)phenoxy)benzoate and the appropriate acid chloride in accordance with Procedure H, Step 2, followed by hydrolysis in accordance with Procedure A, see Table 11. 
     Example 12:1 
     Procedure N 
     2-(3,4-Difluorophenylamino)-5-(4-(4-fluorophenylamino)phenoxy)benzoic acid 
     Step 1: 4-(Benzyloxy)-N-(4-fluorophenyl)aniline 
     A mixture of 4-benzyloxyaniline hydrochloride (400 mg, 1.7 mmol), 4-fluoro-bromobenzene (350 mg, 2.0 mmol), Pd(OAc) 2  (7.06 mg, 0.03 mmol), BINAP (42.3 mg, 0.068 mmol), Cs 2 CO 3  (1.66 g, 5.10 mmol) and toluene (10 mL) was stirred at 110° C. for 2 h in a sealed tube. The mixture was diluted (EtOAc), filtered and concentrated. Purification by chromatography gave the sub-title compound. Yield: 400 mg (80%). 
     Step 2: 4-(4-Fluorophenylamino)phenol 
     A mixture of 4-(benzyloxy)-N-(4-fluorophenyl)aniline (400 mg, 1.36 mmol), Pd—C (30 mg), EtOAc (20 mL) and EtOH (20 mL) was hydrogenated at ambiemt temperature and pressure during 1 h. Additional Pd—C (100 mg) was added and hydrogenation was continued for 2 h. The mixture was filtered through Celite. The filtrate was concentrated and purified by chromatography to give the sub-title compound. Yield: 220 mg (80%). 
     Step 3: Methyl 5-(4-(4-fluorophenylamino)phenoxy)-2-nitrobenzoate 
     A mixture of II (186 mg, 0.93 mmol), 4-(4-fluorophenylamino)phenol (191 mg, 0.93 mmol), K 2 CO 3  (385 mg, 2.8 mmol), 18-crown-6 (50 mg, 0.19 mmol) and DMF (10 mL) was stirred at rt for 4 h. Extractive workup (EtOAc, NaHCO 3  (sat), water, HCl (0.1 M), brine) and chromatography gave the sub-title compound. Yield: 334 mg (94%). 
     Step 4: Methyl 2-amino-5-(4-(4-fluorophenylamino)phenoxy)benzoate 
     The sub-title compound was obtained from methyl 5-(4-(4-fluorophenylamino)-phenoxy)-2-nitrobenzoate (300 mg, 0.90 mmol) by hydrogenation in accordance with the preparation of XIX, Step 5). Yield: 260 mg (73%). 
     Step 5: 2-(3,4-Difluorophenylamino)-5-(4-(4-fluorophenylamino)phenoxy)-benzoic acid 
     A mixture of methyl 2-amino-5-(4-(4-fluorophenylamino)phenoxy)benzoate (110 mg, 0.32 mmol), 4-bromo-1,2-difluorobenzene (0.38 mmol), Pd(OAc) 2  (3.6 mg, 0.016 mmol), BINAP (15 mg, 0.024 mmol), Cs 2 CO 3  (145 mg, 0.44 mmol) and toluene (3 mL) was heated at 100° C. for 24 h. Dilution with EtOAc, filtration through Celite, concentration and chromatography gave methyl 2-(arylamino)-5-(4-(4-fluorophenylamino)phenoxy)benzoate which was hydrolyzed in accordance with Procedure A, see Table 12. 
     Examples 12:4-12:5 
     Procedure O 
     Step 1: Methyl 5-(4-aminophenoxy)-2-aminobenzoate 
     The sub-title compound was obtained from methyl 5-(4-aminophenoxy)-2-nitrobenzoate (3.00 g, 10.41 mmol, see Procedure H, Step 1) by hydrogenation in accordance with the preparation of XIX, Step 5. Yield: 2.633 g (98%). 
     Step 2: The title compounds were prepared from methyl 5-(4-amino-phenoxy)-2-aminobenzoate (0.20 g, 0.77 mmol) and the appropriate arylbromide (1.85 mmol) in accordance with Procedure A, followed by hydrolysis in accordance with Procedure A, see Table 12. 
     Examples 12:2-12:3 
     Procedure P 
     A mixture of methyl 5-(4-(4-fluorophenylamino)phenoxy)-2-(4-butylberizamido)-benzoate and methyl 5-(4-((N-4-fluorophenyl)-4-butylbenzamido)phenoxy)-2-(4-butylbenzamido)benzoate was obtained as a mixture from methyl 5-(4-amino-phenoxy)-2-(arylamido)benzoate (see Procedure G, Step 4) and 4-butylbenzoyl chloride in accordance with Procedure H, Step 2. Separation by chromatography followed by hydrolysis in accordance with Procedure A gave the title compounds, see Table 12. 
     Examples 13:1-13:3 
     Procedure Q 
     Step 1: Diethyl 5,5′-thiobis(2-nitrobenzoate) 
     A mixture of ethyl 5-chloro-2-nitrobenzoate (5.75 g, 25 mmol), potassium ethyl-xanthogenate (4.0 g, 25 mmol) and EtOH was heated at rx for 40 h. Concentration, addition of EtOAc, filtration and chromatography gave the sub-title compound. Yield: 2.80 g. 
     Step 2: Diethyl 5,5′-thiobis(2-aminobenzoate) 
     A mixture of diethyl 5,5′-thiobis(2-nitrobenzoate) (1.39 g, 3.30 mmol), EtOH (40 mL), Fe powder (1.84 g, 33 mmol), FeCl 3  (0.535 g, 3.3 mmol) and water (20 mL) was stirred at 105° C. for 4 h. Filtration through Celite, concentration, extractive workup (EtOAc, brine), drying (Na 2 SO 4 ), concentration and crystallization gave the sub-title compound. Yield: 780 mg (66%). 
     Step 3: 5,5′-Thiobis(2-(arylamido))benzoic acid 
     The appropriate acid chloride was added via syringe to diethyl 5,5′-thiobis-(2-aminobenzoate) (780 mg, 2.16 mmol) in toluene (10 mL). The mixture was stirred at rt for 24 h and quenched with NaHCO 3  (10%). Concentration and chromatography gave diethyl 5,5′-thiobis(2-(arylamido))benzoate. Hydrolysis in accordance with Procedure A gave the title compounds, see Table 13. 
     Example 14:1 
     Procedure R 
     2-(4-Chloro-phenylamino)-5-[4-(4-chlorophenylamino)phenylsulfanyl]benzoic acid 
     Step 1: Methyl 5-chloro-2-nitrobenzoate 
     Dimethyl sulfate (15 mL, 150 mmol) was added dropwise to a mixture of 5-chloro-2-nitro benzoic acid (20 g, 100 mmol), Na 2 CO 3  (15.9 g, 150 mmol) in acetone. The mixture was heated at rx for 3 h, cooled, filtered and concentrated. Extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ) gave a solution from which the sub-title compound was obtained as a solid after addition of a small amount of petroleum ether and standing in the cold. Yield: 16.9 g (78%). 
     Step 2: Methyl 2-nitro-5-(4-nitrophenylthio)benzoate 
     A mixture of methyl 5-chloro-2-nitrobenzoate (5.0 g, 23.2 mmol), 4-nitrothiophenol (3.96 g, 25.5 mmol), K 2 CO 3  (9.60 g, 69.6 mmol) 18-crown-6 (55 mg, 0.21 mmol) and DMF (40 mL) was stirred at rt for 24 h. Dilution with water (400 mL) and extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave sub-title compound. Yield: 5.17 g (67%). 
     Step 3: Methyl 2-amino-5-(4-aminophenylthio)benzoate 
     The sub-title compound was prepared from methyl 2-nitro-5-(4-nitrophenyl-thio)benzoate in accordance with Procedure Q, Step 2. Yield: (98%). 
     Step 4: 2-(4-Chloro-phenylamino)-5-[4-(4-chlorophenylamino)phenyl-sulfanyl]benzoic acid 
     A mixture of methyl 2-amino-5-(4-aminophenylthio)benzoate (500 mg, 1.82 mmol), 1-bromo-4-chlorobenzene (4.37 mmol), Pd 2  dba 3  (60 mg, 0.065 mmol), BINAP (61 mg, 0.098 mmol), Cs 2 CO 3  (1.7 g, 5.2 mmol) and toluene was stirred at 110° C. for 24 h. The mixture was cooled, diluted with DCM and filtered through Celite. Filtration, concentration and chromatography gave methyl 2-(4-chloro-phenylamino)-5-[4-(4-chlorophenylamino)phenylsulfanyl]benzoate (see Table 14). Hydrolysis in accordance with Procedure A gave the title compound, see Table 14. 
     Example 14:2 
     Procedure S 
     2-(3,4-Difluorophenylamino)-5-[4-(3,4-difluorophenylamino)phenylsulfanyl]-benzoic acid 
     A mixture of methyl 2-amino-5-(4-aminophenylthio)benzoate (500 mg, 1.82 mmol, see procedure R, Step 3) 3,4-difluorophenylboronic acid (5.46 mmol), Cu(OAc) 2  (670 mg, 3.64 mmol), pyridine (297 μL, 3.64 mmol), TEA (507 μL, 3.64 mmol) and DCM (25 mL) was stirred at rt for 5 d. The mixture was filtered, concentrated and purified by chromatography to give methyl 2-(3,4-difluorophenylamino)-5-[4-(3,4-difluorophenylamino)phenylsulfanyl]benzoate. Hydrolysis in accordance with Procedure A gave the title compound, see Table 14. 
     Examples 14:3-14:4 
     Procedure T 
     A mixture of methyl 2-amino-5-(4-aminophenylthio)benzoate (700 mg, 2.55 mmol, see procedure R, Step 3), the appropriate sulfonyl chloride (7.65 mmol) and toluene (15 mL) was heated at 90° C. for 5 h. The mixture was diluted with MeOH, concentrated and purified by chromatography to give methyl 2-(arylsulfonamido)-5-(4-(4-arylsulfonamido)phenylthio)benzoate. Hydrolysis in accordance with Procedure A gave the title compound, see Table 14. 
     Examples 14:5-14:6 
     Procedure U 
     A mixture of 2-amino-5-(4-aminophenylthio)benzoic (150 mg, 0.57 mmol), prepared from methyl 2-amino-5-(4-aminophenylthio)benzoate (see procedure R, Step 3), the appropriate arylisocyanate (1.27 mmol) and dioxane (10 mL) was stirred at rt for 3 h. Water was added and the solid was collected and purified by chromatography to give the title compounds, see Table 14. 
     Examples 15:1-15:3 
     Procedure V 
     A mixture of diethyl 5,5′-thiobis(2-(arylamido)benzoate) (0.4 mmol, see procedure Q), tert-butylammoniumperiodate (192 mg, 0.44 mmol, 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride (5.6 mg, 8 μmol) and DCM (8 mL) was stirred at 0° C. for 0.5 h and at rt for 6 d. The mixture was concentrated and purified by chromatography to give diethyl 5,5′-sulfinylbis(2-(arylamido)benzoate). Hydrolysis in accordance with Procedure A gave the title compound, see Table 15. 
     Examples 16:1-16:2 
     Procedure W 
     Oxone (820 mg, 1.34 mmol) in water (10 mL) was added to diethyl 5,5′-thiobis(2-(arylamido)benzoate) (0.267 mmol, see procedure Q) in THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 h and at rt for 5 days. Extractive workup (water, DCM, brine), drying (Na 2 SO 4 ), concentration and chromatography gave diethyl 5,5′-sulfonylbis(2-(arylamido)benzoate). Hydrolysis in accordance with Procedure A gave the title compound, see Table 16. 
     Examples 17:1-17:5 
     Procedure X 
     Step 1: Methyl 2-(5-(4-aminophenoxy)-2-nitrophenyl)acetate 
     Methyl 2-(5-fluoro-2-nitrophenyl)acetate (0.5 g, 2.35 mmol, see synthesis of XIX, step 1), p-aminophenol H 2 SO 4  (0.4 g, 2.5 mmol), K 2 CO 3  (1.0 g, 7.2 mmol), 18-crown-6 (1 mg, 4 μmol) and DMF (15 mL) was stirred at rt for 4 h and at 45° C. for 24 h. Extractive workup (CH 2 Cl 2 , water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compound. Yield: 50 mg (22%). 
     Step 2: Methyl 2-(5-(4-arylamidophenoxy)-2-nitrophenyl)acetate 
     The sub-title compound was prepared from methyl 2-(5-(4-aminophenoxy)-2-nitrophenyl)acetate and the appropriate acid chloride in accordance with Procedure E, Step 4. 
     Step 3: Methyl 2-(2-amino-5-(4-arylamidophenoxy)phenyl)acetate 
     The sub-title compound was prepared from methyl 2-(5-(4-arylamidophenoxy)-2-nitrophenyl)acetate in accordance with Procedure Q, Step 2). 
     Step 4 
     The title compounds were prepared from methyl 2-(2-amino-5-(4-arylamido-phenoxy)phenyl)acetate and the appropriate acid chloride, in accordance with Procedure E, Step 4, followed by hydrolysis in accordance with Procedure A, see Table 17. 
     Examples 17:6-17:7 
     Procedure Y 
     A mixture of methyl 2-(2-amino-5-(4-arylamidophenoxy)phenyl)acetate (0.36 mmol, procedure X, step 3), the appropriate sulfonyl chloride (0.40 mmol), DMAP (82 mg, 0.67 mmol) and pyridine (2.5 mL) was stirred at rt for a few days. Concentration, extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ), concentration and chromatography, followed by hydrolysis in accordance with Procedure A, gave the title compounds, see Table 17. 
     Examples 18:1-18:6 
     Procedure Z 
     Step 1: Methyl 3-hydroxy-5-(4-nitrophenoxy)benzoate 
     A mixture of methyl 3,5-dihydroxybenzoate (3.0 g, 17.84 mmol), 1-fluoro-4-nitrobenzene (2.517 g, 17.84 mmol), K 2 CO 3  (2.171 g, 19.62 mmol), 18-crown-6 (94 mg, 0.357 mmol) and 10 mL DMF was stirred at rt overnight. Concentration, extractive workup (EtOAc, NaHCO 3  (sat), HCl (0.1 M), brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compound. 
     Yield: 1.34 g (26%). 
     Step 2: 3-(4-Nitrophenoxy)-5-(trifluoromethylsulfonyloxy)benzoic acid 
     Triflic anhydride (916 μL, 5.52 mmol) was added dropwise to a mixture of methyl 3-hydroxy-5-(4-nitrophenoxy)benzoate (1.33 g, 4.60 mmol), pyridine (749 μL, 9.2 mmol), DCM (50 mL) and dioxane (12 mL) at 0° C. and the mixture was stirred at rt for 45 min. HCl (0.1 M, 150 mL) was added. Extractive workup (NaHCO 3 , brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compound. Yield: 1.51 g (78%). 
     Step 3: Methyl 3-(arylamino)-5-(4-nitrophenoxy)benzoate and methyl 3-((aryl)(methyl)amino)-5-(4-nitrophenoxy)benzoate 
     The sub-title compounds were prepared from 3-(4-nitrophenoxy)-5-(trifluoro-methylsulfonyloxy)benzoic acid and 3,4-difluoroaniline or 3,4-difluoro-N-methyl-aniline, respectively, in accordance with the synthesis of intermediate VI. 
     Step 4: Methyl 3-(4-aminophenoxy)-5-(arylamino)benzoate and methyl 3-(4-aminophenoxy)-5-((aryl)(methyl)amino)benzoate 
     The sub-title compounds were prepared from methyl 3-(arylamino)-5-(4-nitrophenoxy)benzoate and methyl 3-((aryl)(methyl)amino)-5-(4-nitrophenoxy)-benzoate, respectively, in accordance with the synthesis of XIX, Step 5. 
     Step 5 Examples 18:1-18:6 
     The title compounds were prepared from methyl 3-(4-aminophenoxy)-5-(arylamino)benzoate or methyl 3-(4-aminophenoxy)-5-((aryl)(methyl)amino)-benzoate and i) the appropriate sulfonyl chloride in accordance with Procedure Y (Examples 18:1 and 18:4); ii) the appropriate arylbromide in accordance with Procedure A (Examples 18:2 and 18:3); or iii) the appropriate acid chloride in accordance with Procedure B (Examples 18:5 and 18:6), followed by hydrolysis in accordance with Procedure A, see Table 18. 
     Examples 19:1-19:3 
     Procedure AA 
     Step 1: N-(Aryl)-3-methoxybenzenesulfonamide 
     A mixture of 3-methoxybenzenesulfonyl chloride (2.06 g, 10 mmol), the appropriate aniline (10 mmol) and pyridine (20 mL) was stirred at it for 18 h. Water (200 mL) was added. Extractive workup (EtOAc, HCl (0.1 M), water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compounds. 
     Step 2: N-(aryl)-3-hydroxybenzenesulfonamide 
     BBr 3  (1.0 M in DCM, 12.7 mL) was added dropwise to N-(aryl)-3-methoxy-benzenesulfonamide (6.33 mmol) in DCM at 0° C. The mixture was stirred at it for 6 h. Extractive workup (DCM, water, brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compounds. 
     Step 3: Methyl 5-(3-(N-(aryl)sulfamoyl)phenoxy)-2-nitrobenzoate 
     A mixture of II (891 mg, 4.47 mmol), N-(aryl)-3-hydroxybenzenesulfonamide (4.54 mmol), K 2 CO 3  (1.85 g, 13.41 mmol), 18-crown-6 (35 mg, 0.132 mmol) and DMF (20 mL) was stirred at it for 4 h and poured into water. Extractive workup (EtOAc, brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compounds. 
     Step 4: Methyl 2-amino-5-(3-(N-(aryl)sulfamoyl)phenoxy)benzoate 
     The sub-title compounds were obtaine by hydrogenation of methyl 5-(3-(N-(aryl)-sulfamoyl)phenoxy)-2-nitrobenzoate in accordance with the synthesis of X, Step 4). 
     Step 5: Methyl 2-(arylsulfonamido)-5-(3-(N-(aryl)sulfamoyl)phenoxy)-benzoate and methyl 2-(arylamido)-5-(3-(N-(aryl)sulfamoyl)phenoxy)benzoate 
     (i) Methyl 2-(arylsulfonamido)-5-(3-(N-(aryl)sulfamoyl)phenoxy)benzoate was prepared from ethyl 2-amino-5-(3-(N-(aryl)sulfamoyl)phenoxy)benzoate and the appropriate sulfonyl chloride in accordance with Procedure Y.
 
(ii) A mixture of methyl 2-amino-5-(3-(N-(aryl)sulfamoyl)phenoxy)benzoate (1 eq), the appropriate acid chloride chloride (1.8 eq), DMAP (0.2 eq) and pyridine (10 mL) was stirred at rt for 24 h. Extractive workup (EtOAc, HCl (0.1 M, 150 mL), water, brine), drying (Na 2 SO 4 ), concentration and purification by chromatography gave methyl 2-(arylamido)-5-(3-(N-(aryl)sulfamoyl)phenoxy)benzoate.
 
     Step 6: The title compounds were prepared from the esters in Step 5 by hydrolysis in accordance with Procedure A, see Table 19. 
     Examples 20:1-20:9 
     Procedure AB 
     Step 1: tert-Butyl 5-fluoro-2-nitrobenzoate 
     A mixture of 5-fluoro-2-nitrobenzoic acid (10 g, 54 mmol), Boc anhydride (17.6 g, 82 mmol), DMAP (2 g, 16 mmol) and tert-butanol was stirred at 50° C. for 2 d and diluted with EtOAc. Extractive workup (citric acid (10%), NaHCO 3  (2 M)), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compound. Yield: 6.5 g (50%). 
     Step 2: tert-Butyl 5-(3-(methoxycarbonyl)phenoxy)-2-nitrobenzoate 
     A mixture of tert-butyl 5-fluoro-2-nitrobenzoate (5.5 g, 22.8 mmol), methyl 3-hydroxybenzoate (3.65 g, 24 mmol), K 2 CO 3  (15.7 g, 114 mmol), 18-crown-6 (300 mg, 1.14 mmol) and DMF (100 mL) was stirred at rt for 20 h and diluted with EtOAc. Extractive workup (water, NaHCO 3  (sat), brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compound. Yield: 8.5 g (98%). 
     Step 3: tert-Butyl 2-amino-5-(3-(methoxycarbonyl)phenoxy)benzoate 
     The sub-title compound was obtained by hydrogenation of tert-butyl 5-(3-(methoxycarbonyl)phenoxy)-2-nitrobenzoate in accordance with the preparation of VII. Yield: 58%. 
     Step 4 
     (i) tert-Butyl 2-(arylsulfonylamino)-5-(3-methoxycarbonyl-phenoxy)-benzoate was prepared from tert-butyl 2-amino-5-(3-(methoxycarbonyl)phenoxy)benzoate and the appropriate sulfonyl chloride in accordance with Procedure Y. 
     (ii) A mixture of tert-butyl 2-amino-5-(3-(methoxycarbonyl)phenoxy)benzoate (1 g, 2.9 mmol), 1-bromo-4-chlorobenzene (630 mg, 3.3 mmol), Cs 2 CO 3  (1.32 g, 4.1 mmol), Pd 2 dba 3  (53 mg, 0.06 mmol), xantphos (50 mg, 0.087 mmol) and toluene was stirred at 110° C. for 2 d. The mixture was filtered through Celite and concentrated. Purification by chromatography gave t-butyl 2-(arylamino)-5-(3-(methoxycarbonyl)phenoxy)benzoate. 
     Step 5: 3-(3-(tert-Butoxycarbonyl)-4-(arylsulfonamido)phenoxy)benzoic acid and 3-(3-(tert-butoxycarbonyl)-4-(arylamino)phenoxy)benzoic acid 
     The sub-title compounds were prepared by hydrolysis of the ester from Step 4 in accordance with Procedure A. 
     Step 6: tert-Butyl 2-(arylsulfonamido)-5-(3-(arylsulfonylcarbamoyl)-phenoxy)benzoate and tert-butyl 2-(arylamino)-5-(3-(arylsulfonylcarbamoyl)-phenoxy)benzoate 
     A mixture of 3-(3-(tert-butoxycarbonyl)-4-(arylsulfonamido)phenoxy)benzoic acid or 3-(3-(tert-butoxycarbonyl)-4-(arylamino)phenoxy)benzoic acid (1 eq), arylsulfonamide (1.1 eq), EDCI (1.5 eq), DMAP (1.5 eq) and DCM(10 mL) was stirred at rt for 20 h. Extractive workup (citric acid (10%), NaHCO 3  (sat)), drying (Na 2 SO 4 ), concentration, and chromatography gave the sub-title compounds. 
     Step 7: 2-(Arylsulfonamido)-5-(3-(arylsulfonylcarbamoyl)phenoxy)benzoic acid and 2-(arylamino)-5-(3-(arylsulfonylcarbamoyl)phenoxy)benzoic acid 
     A mixture of tert-butyl 2-(arylsulfonamido)-5-(3-(arylsulfonylcarbamoyl)phenoxy)-benzoate or tert-butyl 2-(arylamino)-5-(3-(arylsulfonylcarbamoyl)phenoxy)-benzoate (1 eq), Et 3 SiH (2.5 eq), TFA (2 mL) and DCM (4 mL) was stirred at rt for 20 h. The mixture was concentrated and treated with DCM. The solid was collected to give the title compounds, see table 20. 
     Examples 21:1-21:4 
     Procedure AC 
     Step 1: Methyl 2-(arylsulfonylamino)-5-{4-arylamidophenoxy}benzoate 
     The appropriate sulfonyl chloride (68.7 mg, 0.30 mmol) was added to a mixture of methyl 2-amino-5-(4-arylamidophenoxy)benzoate (0.247 mmol, see Procedure H, step 3), DMAP (10 mg, 0.08 mmol) and pyridine (3 mL) at 0° C. and the mixture was stirred at rt for 2 h. Extractive workup (EtOAc, NaHCO 3  (sat), water, brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compounds. 
     Step 2: 2-(Arylsulfonylamino)-5-{4-arylamidophenoxy}benzoic acid 
     A mixture of 2-(arylsulfonylamino)-5-{4-arylamidophenoxy}benzoic acid methyl ester (0.157 mmol), NaOH (44 mg, 1.1 mmol), EtOH (5 mL) and water (2 mL) was heated at rx for 1 h. After cooling and concentration, brine was added. Acidification with HCl (1 M) to pH ˜2-5, extraction with EtOAc, drying (Na 2 SO 4 ), concentration and recrystallization from EtOH/water gave the title compounds, see Table 21. 
     Examples 22:1-22:4 
     Procedure AD 
     Step 1: (E)-3-(5-Fluoro-2-nitrophenyl)acrylic acid ethyl ester 
     A mixture of 5-fluoro-2-nitrobenzaldehyde (5.00 g, 29.6 mmol), (triphenyl-λ-5-phosphanylidene)acetic acid ethyl ester (22.3 g, 64.9 mmol) and benzene (150 mL) was stirred at rx for 6 h. Concentration and chromatography gave the sub-title compound. Yield: 4.0 g (55%). 
     Step 2: (E)-3-[5-(4-Acetylaminophenoxy)-2-nitrophenyl]acrylic acid ethyl ester 
     A mixture of (E)-3-(5-fluoro-2-nitrophenyl)acrylic acid ethyl ester (2.40 g, 10.0 mmol), N-(4-hydroxyphenyl)acetamide (1.60 g, 11.0 mmol), K 2 CO 3  (1.65 g, 12.0 mmol), 18-crown-6 (78.9 mg, 0.3 mmol) and DMF (60 mL) was stirred at 50° C. for 6 h. Concentration, extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compound. Yield: 2.5 g (66%). 
     Step 3: (E)-3-[5-(4-Aminophenoxy)-2-nitrophenyl]acrylic acid methyl ester hydrochloride 
     A mixture of (E)-3-[5-(4-Acetylaminophenoxy)-2-nitrophenyl]-acrylic acid ethyl ester (2.22 g, 6.0 mmol), MeOH (70 mL), HCl (3 mL, conc) and water (9 mL) was heated at rx for 4 h. After cooling to rt, EtOAc was added. The solid was collected to give the sub-title compound. Yield: 1.5 g (71%). 
     Step 4: (E)-3-[5-(4-Benzoylaminophenoxy)-2-nitrophenyl]acrylic acid methyl ester 
     A mixture of (E)-3-[5-(4-aminophenoxy)-2-nitrophenyl]acrylic acid methyl ester hydrochloride (0.70 g, 2.0 mmol), benzoyl chloride (0.28 g, 2.0 mmol), TEA (0.59 mL, 4.2 mmol) and CH 2 Cl 2  was stirred at rt for 24 h. Concentration, extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compound. Yield: 0.60 g (72%). 
     Step 5: (E)-3-[2-Amino-5-(4-benzoylaminophenoxy)phenyl]acrylic acid methyl ester 
     NH 4 Cl (1 mL, sat) and iron powder (280 mg, 5.0 mmol) were added to (E)-3-[5-(4-benzoylaminophenoxy)-2-nitrophenyl]acrylic acid methyl ester (0.42 g 1.0 mmol), in isopropanol (20 mL) and the mixture was heated at rx for 6 h. Filtration, concentration and chromatography gave the sub-title compound. Yield: 0.26 g (66%). 
     Step 6: Example 22:1 
     (E)-3-[5-(4-Benzoylaminophenoxy)-2-(4-butoxybenzenesulfonylamino)phenyl]-acrylic acid 
     The title compound was prepared from (E)-3-[2-Amino-5-(4-benzoylamino-phenoxy)phenyl]acrylic acid methyl ester and 4-butoxybenzenesulfonyl chloride in accordance with Procedure AC, see Table 22. 
     Example 22:3 
     (E)-3-[5-(4-Benzoylaminophenoxy)-2-(4-isopropoxybenzoylamino)phenyl]acrylic acid 
     The title compound was prepared from (E)-3-[2-Amino-5-(4-benzoylamino-phenoxy)phenyl]acrylic acid methyl ester and 4-isopropoxybenzoyl chloride in accordance with the synthesis of XXI, see Table 22. 
     Example 22:2 
     3-[5-(4-Benzoylaminophenoxy)-2-(4-butoxybenzenesulfonylamino)phenyl]-propionic acid 
     A mixture of (E)-3-[5-(4-benzoylamino-phenoxy)-2-(4-butoxybenzenesulfonyl-amino)phenyl]acrylic acid methyl ester (120 mg 0.2 mmol), Pd—C (50 mg) and EtOAc (20 mL) was hydrogenated at ambient temperature and pressure during 6 h. The mixture was filtered through Celite, concentrated and purified by chromatography to give 3-[5-(4-benzoylaminophenoxy)-2-(4-butoxybenzene-sulfonylamino)phenyl]propionic acid methyl ester. Yield: 100 mg (83%). Hydrolysis in accordance with Procedure AC, Step 2, gave the title compound, see Table 22. 
     Example 22:4 
     5-[4-(4-Butoxybenzenesulfonylamino)-3-((E)-2-carboxyvinyl)phenoxy]-2-(4-isopropoxybenzoylamino)benzoic acid 
     The title compound was prepared in accordance with Example 22:1, using methyl 2-acetamido-5-hydroxybenzoate instead of N-(4-hydroxyphenyl)acetamide in Step 2, and using 4-isopropoxybenzenesulfonyl chloride instead of benzene-sulfonyl chloride in Step 4, see Table 22. 
     Examples 23:1-23:5 
     Procedure AE 
     Step 1: (3-Hydroxyphenyl)carbamic acid tert-butyl ester 
     A mixture of 3-aminophenol (5.02 g, 56 mmol), Boc anhydride (12.0 g, 55 mmol) and EtOH (100 mL) was stirred at rt for 3 d. Concentration, extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ), concentration and crystallisation gave the sub-title compound. Yield: 7.9 g (82%). 
     Step 2: 5-(3-tert-butoxycarbonylaminophenoxy)-2-nitrobenzoic acid methyl ester 
     A mixture of II (1.99 g, 10.0 mol), (3-hydroxyphenyl)carbamic acid tert-butyl ester (2.09 g, 10.0 mmol), K 2 CO 3  (1.70 g, 1.2 mmol), 18-crown-6 (0.53 g, 0.02 mmol) and DMF (70 mL) was stirred at rt for 3 d. Concentration, extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ) concentration and crystallization gave the sub-title compound. Yield: 3.00 g (77%). 
     Step 3: 2-Amino-5-(3-tert-butoxycarbonylaminophenoxy)benzoic acid methyl ester 
     Reduction of 5-(3-tert-butoxycarbonylaminophenoxy)-2-nitrobenzoic acid methyl ester in accordance with Procedure AD, Step 5, gave the sub-title compound. Yield: 93%. 
     Step 4: 2-(4-Butoxybenzenesulfonylamino)-5-(3-tert-butoxycarbonylamino-phenoxy)benzoic acid methyl ester 
     The sub-title compound was prepared from 2-amino-5-(3-tert-butoxycarbonyl-aminophenoxy)benzoic acid methyl ester and 4-butoxybenzenesulfonyl chloride in accordance with Procedure AC, Step 1. Yield: 96%. 
     Step 5: 5-(3-Aminophenoxy)-2-(4-butoxybenzenesulfonylamino)benzoic acid methyl ester 
     A mixture of 2-(4-butoxybenzenesulfonylamino)-5-(3-tert-butoxycarbonylamino-phenoxy)benzoic acid methyl ester (0.80 g, 1.7 mmol), TFA (1.5 mL) and DCM was stirred at rt for 2 h. Extractive workup (DCM, NaHCO 3  (sat), H 2 O, brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compound. Yield: 0.65 g (98%). 
     Step 6: 2-(4-Butoxybenzenesulfonylamino)-5-[3-(arylmethylamino)-phenoxy]benzoic acid methyl (Examples 23:1-23:5) 
     A mixture of 5-(3-amino-phenoxy)-2-(4-butoxybenzenesulfonylamino)benzoic acid methyl ester (150 mg. 0.32 mmol), the appropriate aldehyde (0.62 mmol), sodium triacetoxyborohydride (271 mg, 1.28 mol) and DCM (10 mL) was stirred at rt for 3 d. Extractive workup (DCM, H 2 O, brine), drying (Na 2 SO 4 ) and chromatography gave 2-(4-butoxybenzenesulfonylamino)-5-[3-(arylmethylamino)phenoxy]benzoic acid methyl ester. Hydrolysis in accordance with Procedure AC, Step 2) gave the title compounds, see Table 23. 
     Examples 24:1-24:3 
     Procedure AF 
     Step 1: 4-Benzyloxy-N-(3,4-difluorophenyl)aniline 
     A mixture of 4-benzyloxyaniline hydrochloride (3.40 g, 14.4 mmol), 3,4-difluoro-bromobenzene (1.35 mL, 12.0 mmol), Pd(OAc) 2  (54 mg, 0.24 mmol), BINAP (299 mg, 0.48 mmol), Cs 2 CO 3  (11.7 g, 3.60 mmol) and toluene (50 mL) was stirred at 110° C. for 12 h in a sealed tube. The mixture was diluted (EtOAc), filtered and concentrated. Purification by chromatography gave the sub-title compound. Yield: 2.73 g (73%). 
     Step 2: (4-Benzyloxyphenyl)butyl-(3,4-difluorophenyl)amine 
     4-Benzyloxy-N-(3,4-difluorophenyl)aniline (1.24 g, 3.97 mmol) in DMF (50 mL) was added to a suspension of NaH (166 mg, 4.16 mmol, 60% in mineral oil) in DMF (50 mL). Butyl iodide (4.76 ml, 4.16 mmol) was added and the mixture was stirred at rt for 20 min. Extractive workup (EtOAc, H 2 O, brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compound. Yield: 1.45 g (99%). 
     Step 3: 4-[Butyl(3,4-difluorophenyl)amino]phenol 
     A mixture of (4-benzyloxyphenyl)butyl-(3,4-difluorophenyl)amine (1.45 g 3.95 mmol) Pd—C (600 mg), EtOAc (50 mL) and EtOH (50 mL), was hydrogenated at ambient temperature and pressure for 30 min. Filtration, concentration and chromatography gave the sub-title compound. Yield: 1.03 g (94%). 
     Step 4: 5-{4-[Butyl(3,4-difluorophenyl)amino]phenoxy}-2-nitrobenzoic acid methyl ester 
     The sub-title compound was prepared in quantitative yield from 4-[butyl(3,4-difluorophenyl)amino]phenol and methyl 5-fluoro-2-nitrobenzoate in accordance with Procedure N, Step 3. 
     Step 5: 2-Amino-5-{4-[butyl(3,4-difluorophenyl)amino]phenoxy}benzoic acid methyl ester 
     The sub-title compound was prepared from 5-{4-[butyl(3,4-difluorophenyl)amino]-phenoxy}-2-nitrobenzoic acid methyl ester in accordance with the synthesis of X, Step 4). 
     Step 6: 5-{4-[Butyl-(3,4-difluorophenyl)amino]phenoxy}-2-(arylamino)-benzoic acid (Examples 24:1-24:2) 
     The title compounds were prepared from 2-amino-5-{4-[butyl(3,4-difluorophenyl)-amino]phenoxy}benzoic acid methyl ester and the appropriate arylbromide in accordance with Procedure AF, Step 1, followed by hydrolysis in accordance with Procedure A. 
     Example 24:3 
     2-[Butyl(3,4-difluorophenyl)amino]-5-[3-carboxy-4-(3,4-difluorophenylamino)-phenoxy]benzoic acid 
     Compound VI was N-butylated in accordance with Procedure AF, Step 2 to give methyl 5-(4-nitro-3-(methoxycarbonyl)phenoxy)-2-(N-butyl-N-(3,4-difluorophenyl)-amino)benzoate. Hydrogenation in accordance with Step 5 above followed by arylation in accordance with Procedure AG (Example 25:7), using 4-bromo-1,2-difluorobenzene, followed by hydrolysis in accordance with Procedure A gave the title compound, see Table 24. 
     Examples 25:1-25:7 
     Procedure AG 
     Step 1: N-(Aryl)-4-methoxybenzenesulfonamide 
     A mixture of the appropriate aniline (10.0 mmol), 4-methoxybenzenesulfonyl chloride (2.06 g, 10.0 mmol) and pyridine (10 mL) was stirred at rt for 12 h. Extractive workup (EtOAc, 0.5 M HCl (aq), water, brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compounds. 
     Step 2: N-(aryl)-4-hydroxybenzenesulfonamide 
     BBr 3  in DCM (18.8 mL, 1 M) was slowly added to N-(aryl)-4-methoxybenzene-sulfonamide (9.37 mmol) in DCM (20 mL) at −10° C. The mixture was stirred at rt for 24 h and diluted with DCM. Extractive workup (DCM, NaHCO 3  (10%), water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compounds. 
     Step 3: 5-[4-(Arylsulfamoyl)phenoxy]-2-nitrobenzoic acid methyl ester 
     The sub-title compounds were prepared from N-(aryl)-4-hydroxybenzenesulfon-amide and II in accordance with Procedure G, Step 1. 
     Step 4: 2-Amino-5-[4-(arylsulfamoyl)phenoxy]benzoic acid methyl ester 
     FeCl 3 .6H 2 O (0.82 g, 3.0 mmol) in H 2 O (5 mL) followed by iron powder (1.7 g, 30 mmol) were added to 5-[4-(arylsulfamoyl)phenoxy]-2-nitrobenzoic acid methyl ester (3.0 mmol) in EtOH (50 mL). The mixture was heated at rx for 1.5 h. Filtration, concentration, extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compounds. 
     Step 5: 2-Amino-5-[4-(arylsulfamoyl)phenoxy]benzoic acid 
     The sub-title compounds were prepared by hydrolysis of 2-amino-5-[4-(aryl-sulfamoyl)phenoxy]benzoic acid methyl ester in accordance with Procedure AC, Step 2. 
     Step 6: 5-[4-(4-Chlorophenylsulfamoyl)phenoxy]-2-[3-(4-trifluoromethyl-phenylureido]benzoic acid (Example 25: 1) 
     A mixture of 2-amino-5-(4-(N-(4-chlorophenyl)sulfamoyl)phenoxy)benzoic acid (1.0 mmol), 1-isocyanato-4-trifluoromethylbenzene (0.17 mL, 1.2 mmol) and dioxane (10 mL) was stirred at rt for 18 h. Concentration and recrystallization from acetonitrile gave the title compound, see Table 25. 
     Examples 25:2-25:3 
     The title compounds were prepared from 2-(arylsulfonylamino)-5-[4-(arylsulfamoyl)phenoxy]benzoic acid was prepared from 2-amino-5-[4-(arylsulfamoyl)-phenoxy]-benzoic acid methyl ester and 4-butoxybenzenesulfonyl chloridein accordance with Procedure AC, Step 1, followed by hydrolysis in accordance with Procedure AC, Step 2, see Table 25. 
     Examples 25:4-25:6 
     A mixture of 2-amino-5-[4-(arylsulfamoyl)phenoxy]benzoic acid methyl ester (1.0 mmol), the appropriate acid chloride (1.2 mmol), DMAP (24 mg, 0.2 mmol) and pyridine (5 mL) was stirred at rt for 3 d. Concentration, extractive workup (EtOAc, HCl (0.5 M), water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave 2-(aroylamino)-5-[4-(arylsulfamoyl)-phenoxy]-benzoic acid methyl ester which was hydrolyzed in accordance with Procedure AC, Step 2, to give the title compounds, see Table 25. 
     5-[4-(4-Chlorophenylsulfamoyl)phenoxy]-2-(3,4-difluorophenylamino)benzoic acid (Example 25:7) 
     2-Amino-5-[(4-chlorophenylsulfamoyl)phenoxy]benzoic acid methyl ester (0.56 mmol), 4-bromo-1,2-difluorobenzene (1.1 mmol), Pd 2 (dba) 3  (10 mg, 0.011 mmol), xantphos (10 mg, 0.017 mmol), Cs 2 CO 3  (0.365 g, 1.12 mmol) and toluene (5 mL) was stirred at 110° C. for 26 h in a sealed tube. The mixture was diluted (CH 2 Cl 2 ), filtered and concentrated. Purification by chromatography gave 5-[4-(4-Chlorophenylsulfamoyl)phenoxy]-2-(3,4-difluorophenylamino)benzoic acid methyl ester. Yield: 0.23 g (76%). Hydrolysis in accordance with Procedure AC, Step 2, gave the title compound, see Table 25. 
     Examples 26:1-26:5 
     Procedure AH 
     The title compounds were prepared in accordance with Procedure AB using (3-hydroxyphenyl)acetic acid methyl ester instead of methyl 3-hydroxybenzoate in Step 2. (Example 27: 3 is the tert-butyl ester of Example 27: 4.) See Table 26. 
     Examples 27:1-27:5 
     Procedure AI 
     Examples 27:1-27:2, 27:5 
     The title compounds were prepared in accordance with Procedure AC from 2-amino-5-{4-[butyl(aryl)amino]phenoxy}benzoic acid (see Procedure A, Steps 1-5) and the appropriate sulfonyl chloride. See Table 27. 
     Examples 27:3-27:4 
     The title compounds were prepared from 2-amino-5-[4-(arylamino)phenoxy]-benzoic acid methyl ester (prepared in accordance with Procedure M, Steps 1-4, using the appropriate arylbromide in Step 1) and the appropriate sulfonyl chloride, followed by hydrolysis in accordance with Procedure AC. See Table 27. 
     Examples 28:1-28:5 
     Procedure AJ 
     Examples 28:1, 28:4-28:5 
     Step 1: 5-(3-Hydroxyphenoxy)-2-nitrobenzoic acid tert-butyl ester 
     A mixture of 5-fluoro-2-nitrobenzoic acid tert-butyl ester (3.95 g, 16.1 mmol), resorcinol (8.87 g, 80.5 mmol), K 2 CO 3  (11.1 g, 80.5 mmol) and DMF (200 mL) was stirred at rt for 24 h. Concentration and extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave the sub-title compound. Yield: 4.40 g (82%). 
     Step 2: 5-[3-(3,4-difluorophenoxy)phenoxy]-2-nitrobenzoic acid tert-butyl ester 
     A mixture of 5-(3-hydroxyphenoxy)-2-nitrobenzoic acid tert-butyl ester (1.38 g, 4.17 mmol), 3,4-difluorophenylboronic acid (1.64 g, 10.4 mmol), Cu(OAc) 2  (0.84 g, 4.60 mmol), TEA (2.9 mL, 20.8 mmol), pyridine (1.7 mL, 20.8 mmol), molecular sieves (3 Å, 2 g) in DCM was stirred at rt for 24 h. Filtration, concentration and chromatography gave the sub-title compound. Yield: 1.12 g (61%). 
     Step 3: 2-Amino-5-[3-(3,4-difluorophenoxy)phenoxy]benzoic acid tert-butyl ester 
     Hydrogenation of 5-[3-(3,4-difluorophenoxy)phenoxy]-2-nitrobenzoic acid tert-butyl ester in accordance with Procedure E, Step 5, gave the sub-title compound. Yield: 92%. 
     Step 4: The title compounds were prepared from 2-amino-5-[3-(3,4-difluoro-phenoxy)phenoxy]benzoic acid tert-butyl ester and the appropriate sulfonyl chloride, followed by hydrolysis, in accordance with Procedure AC. See Table 28. 
     Example 28:2 
     2-(4-Cyclopentyloxybenzoylamino)-5-[3-(3,4-difluorophenoxy)phenoxy]benzoic acid 
     Oxalyl chloride (0.30 mL, 3.4 mmol) was added to 4-cyclopentyloxybenzoic acid (1.39 g, 0.67 mmol) in toluene (3 mL). The reaction mixture was stirred at rt for 24 h and concentrated to give 4-cyclopentyloxybenzoyl chloride. 2-Amino-5-[3-(3,4-difluorophenoxy)phenoxy]benzoic acid tert-butyl ester (139 mg, 0.34 mmol) in pyridine (3 mL), followed by DMAP (9 mg, 0.07 mmol), were added and the mixture was stirred at rt for 24 h. Concentration, extractive workup (EtOAc, NaHCO 3  (sat), citric acid (10%), water, brine), drying (Na 2 SO 4 ) and chromatography gave of 2-(4-cyclopentyloxybenzoylamino)-5-[3-(3,4-difluoro-phenoxy)phenoxy]-benzoic acid tert-butyl ester. Yield: 155 mg (77%). Hydrolysis in accordance with Procedure AC gave the title compound. See Table 28. 
     Example 28:3 
     5-[3-(3,4-Difluoro-phenoxy)-phenoxy]-2-(3,4-difluoro-phenylamino)-benzoic acid 
     The title compound was prepared from 2-amino-5-[3-(3,4-difluorophenoxy)-phenoxy]benzoic acid tert-butyl ester and 3,4-difluorophenylbromide in 78% yield in accordance with Procedure AF, Step 1, followed by hydrolysis in accordance with Procedure. See Table 28. 
     Examples 29:1-29:3 
     Procedure AK 
     The title compounds were prepared from 2-(arylsulfonylamino)-5-(3-amino-phenoxy)benzoic acid methyl ester was (See Procedure AE, Steps 1-5) and the appropriate acid chloride in accordance with Procedure E, Step 6. See Table 29. 
     Examples 30:1-30:3 
     Procedure AL 
     Step 1: 5-(4-Aminophenoxy)-2-aminobenzoic acid 
     The sub-title compound was prepared from methyl 5-(4-aminophenoxy)-2-aminobenzoate (See Procedure O, Step 1) in accordance with Procedure A. 
     Examples 30:1-30:2 
     Step 2: The appropriate isocyanate (0.9 mmol) was added dropwise to 5-(4-aminophenoxy)-2-aminobenzoic acid (100 mg, 0.41 mmol) in dioxane. The mixture was stirred until no further conversion was achieved as judged by TLC. Water was added and the mixture was cooled. The solid was collected and recrystallized from an appropriate solvent to give the title compounds. See Table 30. 
     Example 30:3 
     2-(4-Trifluoromethoxybenzenesulfonylamino)-5-[4-(4-trifluoromethoxybenzene-sulfonylamino)phenoxy]benzoic acid) 
     4-Trifluoromethoxybenzenesulfonyl chloride (1.46 mmol) was added in portions to a hot mixture of 5-(4-aminophenoxy)-2-aminobenzoic acid (150 mg, 0.61 mmol), Na 2 CO 3  (194 mg, 1.83 mmol) and water (3 mL). The mixture was stirred at 90° C. for 1.5 h, cooled and acidified with HCl (1 M,) to pH ˜2. Extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ), concentration and chromatography gave the title compound. See Table 30. 
     Examples 31:1-31:2 
     Procedure AM 
     Procedure AM for Production of Inhibitors Presented in Table 31 
     The title compounds were prepared from compound XIII, the appropriate aldehyde (4 eq) and sodium triacetoxyborohydride (8 eq) in accordance with Procedure AE. See table 31. 
     Example 32:3 
     4-Butoxy-N-[4-[4-(3,4-difluorophenyamino)phenoxy]-2-(tetrazol-5-yl)phenyl]-benzenesulfonamide 
     Step 1: tert-Butyl 4-hydroxyphenylcarbamate 
     Boc-anhydride (26.1 g, 0.12 mol) was added to 4-aminophenol (10.9 g, 0.10 mol) in EtOH (300 mL). The mixture was stirred at rt for 2 h and concentrated. The sub-title compound was precipitated by addition of t-BuOMe recrystallized from t-BuOMe/petroleum ether. Yield: 12 g (57%). 
     Step 2: tert-butyl 4-(3-cyano-4-nitrophenoxy)phenylcarbamate 
     A mixture of tert-butyl 4-hydroxyphenylcarbamate (2.36 g, 11.30 mmol), 5-chloro-2-nitrobenzonitrile (2.06 g, 11.30 mmol), K 2 CO 3  (4.68 g, 33.90 mmol), 18-crown-6 (0.06 g, 0.23 mmol) and DMF (40 mL) was stirred at rt for 1 h. Concentration and extractive workup (EtOAc, water, brine), drying (Na 2 SO 4 ) and chromatography gave the sub-title compound. Yield: 3.33 g (83%). 
     Step 3: 5-(4-aminophenoxy)-2-nitrobenzonitrile 
     A mixture of tert-butyl 4-(3-cyano-4-nitrophenoxy)phenylcarbamate (1.659 g, 4.67 mmol) and HCl (1 M in MeOH, 80 mL) was stirred at rt for 1.5 h. Concentration, extractive workup (EtOAc, NaHCO 3  (sat), water, brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compound. Yield: 1.137 g (95%). 
     Step 4: 5-(4-(3,4-Difluorophenylamino)phenoxy)-2-nitrobenzonitrile 
     The sub-title compound was prepared in accordance with procedure A, step 1, from 5-(4-aminophenoxy)-2-nitrobenzonitrile (1.13 g, 4.43 mmol) and 4-bromo-1,2-difluorobenzene (0.60 mL, 5.31 mmol). Yield: 6.84 g (51%). 
     Step 5: 2-Amino-5-(4-(3,4-difluorophenylamino)phenoxy)benzonitrile 
     The sub-title compound was prepared from 5-(4-(3,4-difluorophenylamino)-phenoxy)-2-nitrobenzonitrile (814 mg, 2.22 mmol) by hydrogenation in accordance with the preparation of compound VII and purification by chromatography. Yield: 302 mg (40%). 
     Step 6: 4-Butoxy-N-(2-cyano-4-(4-(3,4-difluorophenylamino)phenoxy)-phenyl)benzenesulfonamide 
     The sub-title compound was prepared in accordance with procedure Y and purification by recrystallization from 2-amino-5-(4-(3,4-difluorophenylamino)-phenoxy)benzonitrile (134 mg, 0.40 mmol) and 4-butoxybenzenesulfonyl chloride (67.84 μL, 0.42 mmol). Yield: 191 mg (87%). 
     Step 7: 4-Butoxy-N-[4-[4-(3,4-difluorophenyamino)phenoxy]-2-(tetrazol-5-yl)phenyl]benzenesulfonamide 
     A mixture of 4-butoxy-N-(2-cyano-4-(4-(3,4-difluorophenylamino)phenoxy)-phenyl)benzenesulfonamide (100 mg, 0.18 mmol), NaN 3  (35.5 mg, 0.55 mmol), triethylammonium hydrochloride (75.71 mg, 0.55 mmol) and 1-methylpyrrolidin-2-one (4 mL) was stirred at 150° C. for 2 h. Cold HCl (0.1 M) was added and the mixture was concentrated. Extractive workup (EtOAc, NaHCO 3  (sat) water, brine), drying (Na 2 SO 4 ) and concentration gave the title compound. See Table 32. 
     Examples 32:1-2 
     Step 1: tert-Butyl 4-(4-amino-3-cyanophenoxy)phenylcarbamate 
     The sub-title compound was prepared from tert-butyl 4-(3-cyano-4-nitrophenoxy)-phenylcarbamate (2.168 g, 6.10 mmol) in accordance with the preparation of Example 32: 3, Step 5. Yield. 1.02 g (51%). 
     Step 2: tert-Butyl 4-(3-cyano-4-(4-isopropylphenylsulfonamido)phenoxy)-phenylcarbamate 
     The sub-title compound was prepared in accordance with procedure Y from tert-butyl 4-(4-amino-3-cyanophenoxy)phenylcarbamate (1.0 g, 3.07 mmol) and 4-iso-propylbenzenesulfonyl chloride (0.74 g, 3.4 mmol). Yield: 1.172 g (78%). 
     Step 3: N-(4-(4-aminophenoxy)-2-cyanophenyl)-4-isopropylbenzene-sulfonamide 
     TFA (5 mL) was added dropwise to tert-butyl 4-(3-cyano-4-(4-isopropylphenyl-sulfonamido)phenoxy)phenylcarbamate (0.99 g, 1.95 mmol) in DCM (5 mL) at 0° C. After 0.5 h the mixture was concentrated. Extractive workup (EtOAc, KHCO 3  (sat), water, brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compound. Yield: 0.814 g (100%). 
     Step 4: The title compounds were prepared in accordance with Procedure E, Step 4, from N-(4-(4-aminophenoxy)-2-cyanophenyl)-4-isopropylbenzene-sulfonamide and the appropriate acid chloride in accordance with Procedure E, Steps 4 and 7, see Table 32. 
     Example 33:1 
     2-(3,4-Difluorophenylamino)-5-[5-(3,4-difluorophenylamino)pyridin-2-yloxy]-benzoic acid 
     Step 1: Methyl 2-amino-5-(5-nitropyridin-2-yloxy)benzoate 
     The sub-title compound was prepared from methyl 2-acetamido-5-hydroxy-benzoate (3.14 g, 15 mmol) and 2-chloro-5-nitropyridine (2.38 g, 15 mmol) in accordance with Procedure G, Step 1, giving methyl 2-acetamido-5-(5-nitropyridin-2-yloxy)benzoate, yield: 4.14 g (88%), followed by Procedure G, Step 2, yield: 46%. 
     Step 2: Methyl 2-(3,4-difluorophenylamino)-5-(5-nitropyridin-2-yloxy)-benzoate 
     A mixture of methyl 2-amino-5-(5-nitropyridin-2-yloxy)benzoate (1.0 g, 3.46 mmol), 4-bromo-1,2-difluorobenzene (469 μL, 4.15 mmol), Pd(OAc) 2  (38 mg, 0.73 mmol), xantphos (150 mg, 0.26 mmol), Cs 2 CO 3  (1.58 g, 4.84 mmol) and toluene (20 mL) was heated at 105° C. for 18 h. The mixture was filtered through Celite and the solids washed with EtOAc. Concentration of the combined filtrates gave the sub-title compound which was used without any further purification. Yield: 1.38 g. 
     Step 3: Methyl 5-(5-aminopyridin-2-yloxy)-2-(3,4-difluorophenylamino)-benzoate 
     The sub-title compound was prepared in accordance with Procedure B, Step 4, from methyl 2-(3,4-difluorophenylamino)-5-(5-nitropyridin-2-yloxy)benzoate. Yield: 98%. 
     Step 4: 2-(3,4-Difluorophenylamino)-5-[5-(3,4-difluorophenylamino)pyridin-2-yloxy]benzoic acid 
     The title compound was prepared in accordance with Procedure A from methyl 5-(5-aminopyridin-2-yloxy)-2-(3,4-difluorophenylamino)benzoate and 4-bromo-1,2-difluorobenzene. See Table 33. 
     Example 33:2 
     Step 1: Methyl 5-(6-aminopyridin-3-yloxy)-2-(3,4-difluorophenylamino)-benzoate 
     The sub-title compound was prepared from 5-chloro-2-nitropyridine in accordance with Example 33:1, Steps 1 to 4 
     Step 2: 5-(6-(3-Chloro-2-methylphenylsulfonamido)pyridin-3-yloxy)-2-(3,4-difluorophenylamino)benzoic acid 
     A mixture of methyl 5-(6-aminopyridin-3-yloxy)-2-(3,4-difluorophenylamino)-benzoate (120 mg, 0.32 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (79 mg, 0.35 mmol) and pyridine (3 mL) was stirred at rt overnight. The mixture was acidified and extracted with EtOAc. Concentration of the extracts and purification by chromatography gave methyl 5-(6-(3-chloro-2-methylphenylsulfonamido)-pyridin-3-yloxy)-2-(3,4-difluorophenylamino)benzoate (137 mg, 76%). Hydrolysis in accordance with Procedure A gave the sub-title compound. 
     Methyl 5-(4-bromo-3-fluorophenoxy)-2-nitrobenzoate 
     A mixture of methyl 5-fluoro-2-nitrobenzoate (11.0 g, 55 mmol), 4-bromo-3-fluoro phenol (9.55 g, 50 mmol), K 2 CO 3  (20.7 g, 150 mmol), 18-crown-6 (300 mg) and DMF (100 mL) was stirred at rt for 20 h. The mixture was diluted with water (1 L) and extracted with EtOAc. The combined extracts was washed with water and brine and concentrated. The residue was treated with water and the solid was collected. Recrystallization from EtOH gave the sub-title compound. Yield: (84%). 
     Examples 34:7-34:10 
     Procedure AN 
     Step 1: Methyl 5-(3-fluoro-4-(arylamino)phenoxy)-2-nitrobenzoate 
     The sub-title compounds were prepared in accordance with Procedure R, for the synthesis of Example 14:1, from methyl 5-(4-bromo-3-fluorophenoxy)-2-nitrobenzoate and the appropriate aryl amine. 
     Step 2: Methyl 5-(3-fluoro-4-((aryl)(methyl)amino)phenoxy)-2-nitro-benzoate 
     The sub-title compound was prepared in accordance with procedure M, Step 3 from methyl 5-(3-fluoro-4-(arylamino)phenoxy)-2-nitrobenzoate. 
     Step 3: Methyl 2-amino-5-(3-fluoro-4-((aryl)(methyl)amino)phenoxy)-benzoate 
     The sub-title compound was prepared in accordance with procedure Q, Step 2 from methyl 5-(3-fluoro-4-((aryl)(methyl)amino)phenoxy)-2-nitrobenzoate. 
     Step 4: Methyl 2-(arylamino)-5-(3-fluoro-4-((aryl)(methyl)amino)phenoxy)-benzoate 
     The sub-title compounds were prepared in accordance with Procedure A (Examples 1:1-1:8) from methyl 2-amino-5-(3-fluoro-4-((aryl)(methyl)amino)-phenoxy)benzoate and the appropriate aryl bromide (see Table 34). 
     Alternatively, the sub-title compounds were prepared in accordance with Procedure B, Step 3, from methyl 2-amino-5-(3-fluoro-4-((aryl)(methyl)amino)-phenoxy)benzoate and the appropriate acid chloride (see Table 34) 
     Step 5: 2-(Arylamino)-5-(3-fluoro-4-((aryl)(methyl)amino)phenoxy)-benzoate 
     The title compounds were prepared by hydrolysis in accordance with Procedure A from methyl 2-(arylamino)-5-(3-fluoro-4-((aryl)(methyl)amino)phenoxy)-benzoate, see Table 34. 
     Examples 34:1-34.6 
     Procedure AO 
     The title compounds were prepared in accordance with Procedure AN, omitting step 2, see Table 34. 
     Example 35:1 
     2-(2,4-Dichlorobenzoylamino)-5-[4-(4-trifluoromethylbenzoylamino)phenyl-sulfanyl]benzoic acid 
     The title compound was prepared in accordance with Procedure H from methyl 5-chloro-2-nitrobenzoate and 4-aminobenzenethiol in Step 1 and 2,4-dichlorobenzoyl chloride in Step 2, followed by hydrolysis in accordance with Procedure A, see Table 35. 
     Example 35:2 
     2-(4-Chloro-2-fluoro-benzenesulfonylamino)-5-[4-(4-trifluoromethylbenzoylamino)-phenylsulfanyl]benzoic acid 
     The title compound was prepared in accordance with Procedure H, Steps 1, 2 and 3 from methyl 5-chloro-2-nitrobenzoate, 4-aminobenzenethiol and 4-trifluoro-methylbenzoyl chloride, followed by the reaction with 4-chloro-2-fluorobenzene-sulfonyl chloride in accordance with Procedure AC, Step 1, purification by recrystallisation from EtOH/EtOAc, and hydrolysis in accordance with Procedure A, see Table 35. 
     Examples 36:1-36:5 
     2-Amino-5-{3-(methoxycarbonyl)-4-[(phenylsulfonyl)amino]phenoxy}benzoic acid (250 mg, 0.565 mmol, see Procedure F, Step 4) was added in portions to Na 2 CO 3  (147 mg, 1.38 mmol) in H 2 O (5 mL) at 50° C. The appropriate sulfonyl chloride (0.68 mmol) was added in portions and the mixture was stirred at 70° C. for 30 min and at 85° C. for 30 min. After cooling to rt the mixture was acidified with HCl. The solid was collected and washed with HCl and water. The obtained esters were hydrolyzed in accordance with Procedure A, see Table 36. 
     Examples 37:1-37:6 
     Step 1: Methyl 5-(4-(tert-butoxycarbonyl(methyl)amino)phenoxy)-2-nitrobenzoate 
     The sub-title compound was prepared from 4-(methylamino)phenol in accordance with Procedure AE, Step 1, and Procedure H, Step 1. 
     Step 2: Methyl 2-amino-5-(4-(tert-butoxycarbonyl(methyl)amino)phenoxy)-benzoate 
     The sub-title compound was prepared in accordance with Procedure B, Step 4, from methyl 5-(4-(tert-butoxycarbonyl(methyl)amino)phenoxy)-2-nitrobenzoate. Yield: ˜100%. 
     Step 3: Methyl 544-(tert-butoxycarbonyl(methyl)amino)phenoxy)-2-(4-chlorophenylamino)benzoate 
     The sub-title compound was prepared in accordance with Procedure A, from methyl 2-amino-5-(4-(tert-butoxycarbonyl(methyl)amino)phenoxy)benzoate and 1-bromo-4-chlorobenzene. Yield: 77%. 
     Step 4: Methyl 2-(4-chlorophenylamino)-5-(4-(methylamino)phenoxy)-benzoate 
     TFA (20 mL) was added droppvise to methyl 5-(4-(tert-butoxycarbonyl(methyl)-amino)phenoxy)-2-(4-chlorophenylamino)benzoate (4.73 g, 9.794 mmol) in DCM at rt. After 40 min the mixture was concentrated. Extractive workup (DCM, NaHCO 3  (sat), water, brine), drying (Na 2 SO 4 ) and concentration gave the sub-title compound which was used without further purification. Yield: 3.49 g (93%) 
     Step 5: The title compounds were prepared in accordance with the preparation of Example 33:2, Step 2, from methyl 2-(4-chlorophenylamino)-5-(4-(methylamino)-phenoxy)benzoate and the appropriate sulfonyl chlorides followed by hydrolysis in accordance with procedure A, see Table 37. 
     
       
         
           
               
               
             
               
                   
                 TABLE 1 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Ester 
                 Acid 
               
               
                 No. 
                 Chemical name 
                 Substrate 
                 VIII 
                 IX 
               
               
                   
               
               
                 1:1 
                 5-(3-carboxy-4-(2-chloro-5- 
                 2-bromo-1-chloro-4- 
                 80 
                 69 
               
               
                   
                 trifluoromethylphenylamino)- 
                 trifluoromethyl-benzene 
               
               
                   
                 phenyloxy)-2-(3,4-difluoro- 
               
               
                   
                 phenylamino)benzoic acid 
               
               
                 1:2 
                 3,3′-oxybis[6-(4-fluorophenyl- 
                 1-bromo-4-fluorobenzene 
                 61 
                 69 
               
               
                   
                 amino)benzoic acid] 
               
               
                 1:3 
                 3,3′-oxybis[6-(3,4-difluorophenyl- 
                 4-bromo-1,2-difluorobenzene 
                 78 
                 89 
               
               
                   
                 amino)benzoic acid] 
               
               
                 1:4 
                 5-[3-carboxy-4-(3,4-difluoro- 
                 5-bromobenzofuran 
                 21 
                 81 
               
               
                   
                 phenylamino)phenyloxy]-2- 
               
               
                   
                 (benzofuran-5-ylamino)benzoic 
               
               
                   
                 acid 
               
               
                 1:5 
                 5-[3-carboxy-4-(3,4-difluoro- 
                 5-bromo-2-trifluoromethylpyridine 
                 90 
                 45 
               
               
                   
                 phenylamino)phenyloxy]-2-(6- 
               
               
                   
                 trifluoromethylpyridin-3-yl-amino)- 
               
               
                   
                 benzoic acid 
               
               
                 1:6 
                 5-[3-carboxy-4-(4-nitrophenyl- 
                 1-bromo-4-nitrobenzene 
                 74 
                 34 
               
               
                   
                 amino)phenyloxy]-2-(4-fluoro- 
               
               
                   
                 phenylamino)benzene-carboxylic 
               
               
                   
                 acid 
               
               
                 1:7 
                 5-[3-carboxy-4-(4-cyclopropane- 
                 (4-bromophenyl)(cyclopropyl)methanone 
                 67 
                 26 
               
               
                   
                 carbonylphenylamino)phenyloxy]- 
               
               
                   
                 2-(4-fluorophenylamino)benzene- 
               
               
                   
                 carboxylic acid 
               
               
                 1:8 
                 5-[3-carboxy-4-(3,4-difluorobenz- 
                 4-bromo-1,2-difluorobenzene 
                 55 
                 75 
               
               
                   
                 amido)phenyloxy]-2-(3,4-dichloro- 
               
               
                   
                 benzamido)benzoic acid 
               
               
                 1:9 
                 2-(4-butoxybenzenesulfonyl- 
                 4-butoxybenzenesulfonyl chloride 
                 80 
                 32 
               
               
                   
                 amino)-5-[4-(2-carboxy)(3,4-di- 
               
               
                   
                 fluorophenylamino)phenoxy]- 
               
               
                   
                 benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 2 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Ester 
                 Acid 
               
               
                 No. 
                 Chemical name 
                 Substrate 
                 XI 
                 XII 
               
               
                   
               
               
                 2:1 
                 5-[3-carboxy-4-(4-(trifluoromethylthio)- 
                 4-(trifluoromethylthio)- 
                 73 
                 82 
               
               
                   
                 benzamido)-phenyloxy]-2-(3-chlorobenz- 
                 benzoyl chloride 
               
               
                   
                 amido)benzoic acid 
               
               
                 2:2 
                 5-[3-carboxy-4-(3-chloro-6-fluorobenz- 
                 5-chloro-2-fluoro- 
                 76 
                 69 
               
               
                   
                 amido)phenyloxy]-2-(3-chlorobenz- 
                 benzoyl chloride 
               
               
                   
                 amido)benzoic acid 
               
               
                 2:3 
                 5-[3-carboxy-4-(4-nitrobenzamido)-phenyloxy]- 
                 4-nitrobenzoyl chloride 
                 92 
                 66 
               
               
                   
                 2-(3-chlorobenzamido)benzoic acid 
               
               
                 2:4 
                 5-[3-carboxy-4-(3-nitro-6-chlorobenz- 
                 2-chloro-5-nitrobenzoyl 
                 90 
                 72 
               
               
                   
                 amido)-phenyloxy]-2-(3-chlorobenz- 
                 chloride 
               
               
                   
                 amido)benzoic acid 
               
               
                 2:5 
                 5-[3-carboxy-4-(4-chloro-6-chloro- 
                 2,4-dichlorobenzoyl 
                 92 
                 51 
               
               
                   
                 benzamido)-phenyloxy]-2-(4-butylbenz- 
                 chloride 
               
               
                   
                 amido)benzoic acid 
               
               
                 2:6 
                 5-[3-carboxy-4-(3-chloro-5-chloro- 
                 3,5-dichlorobenzoyl 
                 71 
                 73 
               
               
                   
                 benzamido)-phenyloxy]-2-(4-butylbenz- 
                 chloride 
               
               
                   
                 amido)benzoic acid 
               
               
                 2:7 
                 5-[3-carboxy-4-(3-chloro-4-fluorobenz- 
                 3-chloro-4-fluoro- 
                 91 
                 72 
               
               
                   
                 amido)-phenyloxy]-2-(4-butylbenz- 
                 benzoyl chloride 
               
               
                   
                 amido)benzoic acid 
               
               
                 2:8 
                 5-[3-carboxy-4-(2-chloro-4-fluorobenz- 
                 2-chloro-4-fluoro- 
                 73 
                 81 
               
               
                   
                 amido)-phenyloxy]-2-(4-butylbenz- 
                 benzoyl chloride 
               
               
                   
                 amido)benzoic acid 
               
               
                 2:9 
                 5-[3-carboxy-4-(4-cyanobenzamido)- 
                 4-cyanobenzoyl 
                 87 
                 33 
               
               
                   
                 phenyloxy]-2-(3-chlorobenzamido)benzoic 
                 chloride 
               
               
                   
                 acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
             
               
                   
                 TABLE 3 
               
             
            
               
                   
                   
               
               
                   
                 Chemical name of 
                 Yield (%) 
               
            
           
           
               
               
               
               
               
               
            
               
                 No. 
                 intermediate 
                 Starting material 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 3:1 
                 2-benzamido-5-(3-carboxy-4- 
                 5-(4-amino-3- 
                 benzoyl 
                 77 
                 62 
               
               
                   
                 nitrophenoxy)benzoic acid 
                 (methoxycarbonyl)phenoxy)- 
                 chloride 
               
               
                   
                   
                 2- 
               
               
                   
                   
                 nitrobenzoic acid 
               
               
                 3:2 
                 2-nitro-5-[4-(4-trifluoromethyl- 
                 5-(4-amino-3- 
                 4-trifluoro- 
                 92 
                 47 
               
               
                   
                 benzoylamino)-3-carboxy- 
                 (methoxycarbonyl)phenoxy)- 
                 methyl- 
               
               
                   
                 phenoxy]benzoic acid 
                 2- 
                 benzoyl 
               
               
                   
                   
                 nitrobenzoic acid 
                 chloride 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 4 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 4:1 
                 5-[3-carboxy-4-(4-butyl- 
                 4-butylbenzoyl 
                 57 
                 58 
               
               
                   
                 benzamido)phenyloxy]-2- 
                 chloride 
               
               
                   
                 (4-butylbenzamido)benzoic acid 
               
               
                 4:2 
                 5-[3-carboxy-4-benzamido- 
                 benzoyl chloride 
                 38 
                 55 
               
               
                   
                 phenyloxy]-2- 
               
               
                   
                 benzamidobenzoic acid 
               
               
                 4:3 
                 5-[3-carboxy-4-(4- 
                 4-nitrobenzoyl 
                 59 
                 62 
               
               
                   
                 nitrobenzamido)phenyloxy]-2- 
                 chloride 
               
               
                   
                 (4-nitrobenzamido)benzoic acid 
               
               
                 4:4 
                 5-[3-carboxy-4-(3- 
                 3-chlorobenzoyl 
                 61 
                 60 
               
               
                   
                 chlorobenzamido)phenyloxy]- 
                 chloride 
               
               
                   
                 2-(3-chlorobenzamido)benzoic 
               
               
                   
                 acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 5 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Ester 
                 Acid 
               
               
                 No. 
                 Chemical name 
                 Substrate 
                 XVII 
                 XVIII 
               
               
                   
               
               
                 5:1 
                 5-[3-carboxy-4-(4- 
                 4-butylbenzoyl 
                 58 
                 58 
               
               
                   
                 butylbenzamido)- 
                 chloride 
               
               
                   
                 phenyloxy]-2-benzamidobenzoic 
               
               
                   
                 acid 
               
               
                 5:2 
                 5-[3-carboxy-4-(4- 
                 4-nitrobenzoyl 
                 54 
                 66 
               
               
                   
                 nitrobenzamido)- 
                 chloride 
               
               
                   
                 phenyloxy]-2-benzamidobenzoic 
               
               
                   
                 acid 
               
               
                 5:3 
                 5-[3-carboxy-4-(3- 
                 3- 
                 55 
                 71 
               
               
                   
                 chlorobenzamido)- 
                 chlorobenzoyl 
               
               
                   
                 phenyloxy]-2-benzamidobenzoic 
                 chloride 
               
               
                   
                 acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 6 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Ester 
                 Acid 
               
               
                 No. 
                 Chemical name 
                 Starting material 
                 Substrate 
                 XX 
                 XXI 
               
               
                   
               
               
                 6:1 
                 2-(4-butyl-benzoyl- 
                 methyl 5-(4-amino- 
                 2,4-dichloro- 
                 53 
                 45 
               
               
                   
                 amino)-5-[3-carboxy- 
                 3-(2-methoxy-2- 
                 benzoyl 
               
               
                   
                 methyl-4-(2,4-dichloro- 
                 oxoethyl)phenoxy)- 
                 chloride 
               
               
                   
                 benzoylamino)phenoxy]- 
                 2-(4-butylbenz- 
               
               
                   
                 benzoic acid 
                 amido)benzoate 
               
               
                 6:2 
                 5-[3-carboxymethyl-4-(5- 
                 methyl 5-(4-amino- 
                 4-chloro-2- 
                 25 
                 33 
               
               
                   
                 chloro-2-hydroxybenzoylamino)- 
                 3-(2-methoxy-2- 
                 (chloro- 
               
               
                   
                 phenoxy]-2-(2- 
                 oxoethyl)phenoxy)- 
                 carbonyl)- 
               
               
                   
                 fluoro-4-trifluoromethyl- 
                 2-(2-fluoro-4-(tri- 
                 phenyl 
               
               
                   
                 benzoylamino)benzoic 
                 fluoromethyl)benz- 
                 acetate 
               
               
                   
                 acid 
                 amido)benzoate 
               
               
                 6:3 
                 5-[3-carboxymethyl-4-(5- 
                 methyl 5-(4-amino- 
                 4-chloro-2- 
                 9 
                 56 
               
               
                   
                 chloro-2-hydroxybenzoylamino)phenoxy]- 
                 3-(2-methoxy-2- 
                 (chloro- 
               
               
                   
                 2-(4- 
                 oxoethyl)phenoxy)- 
                 carbonyl)- 
               
               
                   
                 isopropoxybenzoyl- 
                 2-(4-isopropoxy- 
                 phenyl 
               
               
                   
                 amino)benzoic acid 
                 benzamido)- 
                 acetate 
               
               
                   
                   
                 benzoate 
               
               
                 6:4 
                 5-[3-carboxymethyl-4-(3- 
                 methyl 5-(4-amino- 
                 3-chloro- 
                 70 
                 70 
               
               
                   
                 chloro-benzoylamino)- 
                 3-(2-methoxy-2- 
                 benzoyl 
               
               
                   
                 phenoxy]-2-(2-fluoro-4- 
                 oxoethyl)phenoxy)- 
                 chloride 
               
               
                   
                 trifluoromethylbenzoyl- 
                 2-(2-fluoro-4-tri- 
               
               
                   
                 amino)benzoic acid 
                 fluoromethylbenz- 
               
               
                   
                   
                 amido)benzoate 
               
               
                 6:5 
                 5-[3-carboxy-methyl-4-(4- 
                 methyl 5-(4-amino- 
                 4-chloro-2,5- 
                 54 
                 22 
               
               
                   
                 chloro-2,5-difluoro- 
                 3-(2-methoxy-2- 
                 difluorobenzoyl 
               
               
                   
                 benzoylamino)-phenoxy]- 
                 oxoethyl)phenoxy)- 
                 chloride 
               
               
                   
                 2-(2-fluoro-4-trifluoro- 
                 2-(2-fluoro-4- 
               
               
                   
                 methylbenzoylamino)- 
                 trifluoromethylbenz 
               
               
                   
                 benzoic acid 
                 amido)benzoate 
               
               
                 6:6 
                 5-[3-carboxymethyl-4- 
                 methyl 5-(4-amino- 
                 2,4-dichloro- 
                 66 
                 60 
               
               
                   
                 (2,4-dichloro-benzoyl- 
                 3-(2-methoxy-2- 
                 benzoyl 
               
               
                   
                 amino)phenoxy]-2-(4- 
                 oxoethyl)phenoxy)- 
                 chloride 
               
               
                   
                 isopropoxybenzoyl- 
                 2-(4-isopropoxy- 
               
               
                   
                 amino)benzoic acid 
                 benzamido)- 
               
               
                   
                   
                 benzoate 
               
               
                 6:7 
                 5-[3-carboxymethyl-4-(3- 
                 methyl 5-(4-amino- 
                 3-chloro-2- 
                 61 
                 29 
               
               
                   
                 chloro-2-ethoxy-5-tri- 
                 3-(2-methoxy-2- 
                 fluoro-5-tri- 
               
               
                   
                 fluoromethylbenzoyl- 
                 oxoethyl)phenoxy)- 
                 fluoromethyl- 
               
               
                   
                 amino)phenoxy]-2-(4- 
                 2-(4-isopropoxy- 
                 benzoyl 
               
               
                   
                 isopropoxybenzoyl- 
                 benzamido)- 
                 chloride 
               
               
                   
                 amino)benzoic acid 
                 benzoate 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 7 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Mono- 
                 Di- 
               
               
                 No. 
                 Chemical name 
                 Substrate 
                 acid 
                 acid 
               
               
                   
               
               
                 7:1 
                 2-(4-butylbenzamido)-5- 
                 4-butylbenzoyl 
                 56 
                 — 
               
               
                   
                 (3-(methoxycarbonyl)-4- 
                 chloride 
               
               
                   
                 (phenylsulfonamido)- 
               
               
                   
                 phenoxy)benzoic acid 
               
               
                 7:2 
                 2-(4-butylbenzamido)-5-(3- 
                 2-(4- 
                 — 
                 86 
               
               
                   
                 carboxy)-4-(phenylsulfon- 
                 butylbenzamido)-5- 
               
               
                   
                 amido)phenoxy)benzoic 
                 (3- 
               
               
                   
                 acid 
                 (methoxycarbonyl)- 
               
               
                   
                   
                 4-(phenylsulfon- 
               
               
                   
                   
                 amido)phenoxy)- 
               
               
                   
                   
                 benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 8 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
               
            
               
                 No 
                 Chemical name 
                 Substrate 
                 Method 
                 Ester 
                 Acid 
               
               
                   
               
               
                 8:1 
                 5-(4-(4-tert-butylbenzamido)- 
                 4-tert-butylbenzoyl 
                 G 
                 55 
                 78 
               
               
                   
                 phenoxy)-2-(2,4-dichlorobenz- 
                 chloride 
               
               
                   
                 amido)benzoic acid 
               
               
                 8:2 
                 2-(2,4-dichlorobenzamido)-5-(4- 
                 Mono arylated intermediate 
               
               
                   
                 nitrophenoxy)benzoic acid 
               
               
                 8:3 
                 5-[4-(5-chloro-2-hydroxybenzoylamino)phenoxy]- 
                 4-chloro-2-(chloro- 
                 G 
                 67 
                 74 
               
               
                   
                 2-(4-trifluoro- 
                 carbonyl)phenyl 
               
               
                   
                 methylbenzoylamino)-benzoic 
                 acetate 
               
               
                   
                 acid 
               
               
                 8:4 
                 5-[4-(4-(butyl)benzoylamino)- 
                 4-butylbenzoyl chloride 
                 G 
                 82 
                 34 
               
               
                   
                 phenoxy]-2-(4-trifluoromethyl- 
               
               
                   
                 benzoylamino)benzoic acid 
               
               
                 8:5 
                 5-[4-((2-methyl-6-(trifluoro- 
                 2-methyl-6-(trifluoro- 
                 G 
                 76 
                 58 
               
               
                   
                 methyl)-pyridine-3-carbonyl)- 
                 methyl)nicotinoyl 
               
               
                   
                 amino)-phenoxy]-2-(4-(trifluoro- 
                 chloride 
               
               
                   
                 methyl)-benzoylamino)-benzoic 
               
               
                   
                 acid 
               
               
                 8:6 
                 5-[4-(4-dimethylaminobenzoyl- 
                 4-(dimethylamino)- 
                 G 
                 50 
                 74 
               
               
                   
                 amino)phenoxy]-2-(4-trifluoro- 
                 benzoyl chloride 
               
               
                   
                 methylbenzoylamino)benzoic 
               
               
                   
                 acid hydrochloride 
               
               
                 8:7 
                 5-[(4-(2-(4-chlorophenyl)acetyl- 
                 2-(4-chlorophenyl)- 
                 H 
                 70 
                 91 
               
               
                   
                 amino)phenoxy)]-2-(4-trifluoro- 
                 acetyl chloride 
               
               
                   
                 methylbenzoylamino)benzoic 
               
               
                   
                 acid 
               
               
                 8:8 
                 5-(4-benzoylaminophenoxy)-2- 
                 4-butylbenzoyl chloride 
                 H 
                 70 
                 86 
               
               
                   
                 (4-butylbenzoylamino)benzoic 
               
               
                   
                 acid 
               
               
                 8:9 
                 2-(4-butylbenzoylamino)-5-[4- 
                 4-(3,5-dimethoxy- 
                 G 
                 40 
                 66 
               
               
                   
                 (3,5-dimethoxybenzoylamino)- 
                 benzoyl chloride 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 8:10 
                 5-(4-benzoylaminophenoxy)-2- 
                 4-trifluoromethoxy- 
                 H 
                 79 
                 78 
               
               
                   
                 (4-trifluoromethoxy- 
                 benzoyl chloride 
               
               
                   
                 benzoylamino)benzoic acid 
               
               
                 8:11 
                 5-(4-benzoylaminophenoxy)-2- 
                 4-ethoxybenzoyl 
                 H 
                 89 
                 73 
               
               
                   
                 (4-ethoxybenzoylamino)- 
                 chloride 
               
               
                   
                 benzoic acid 
               
               
                 8:12 
                 2-benzoylamino-5-[4-(4-butyl- 
                 benzoyl chloride 
                 H 
                 74 
                 66 
               
               
                   
                 benzoylamino)phenoxy]- 
               
               
                   
                 benzoic acid 
               
               
                 8:13 
                 2-benzoylamino-5-[4-(4-iso- 
                 benzoyl chloride 
                 G 
                 80 
                 83 
               
               
                   
                 propoxybenzoylamino)- 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 8:14 
                 5-[4-(4-isopropoxybenzoyl- 
                 2-methyl-6-trifluoro- 
                 G 
                 69 
                 89 
               
               
                   
                 amino)phenoxy]-2-[(2-methyl- 
                 methylnicotinoyl 
               
               
                   
                 6-trifluoromethylpyridine-3- 
                 chloride 
               
               
                   
                 carbonyl)amino]benzoic acid 
               
               
                 8:15 
                 5-[4-(4-tert-Butylbenzoyl- 
                 2-chlorobenzoyl 
                 H 
                 74 
                 82 
               
               
                   
                 amino)phenoxy]-2-(2-chloro- 
                 chloride 
               
               
                   
                 benzoylino)benzoic acid 
               
               
                 8:16 
                 5-[4-(4-tert-Butylbenzoyl- 
                 2-chloronicotinoyl 
                 H 
                 40 
                 50 
               
               
                   
                 amino)phenoxy]-2-[(2-chloro- 
                 chloride 
               
               
                   
                 pyridine-3-carbonyl)- 
               
               
                   
                 amino]benzoic acid 
               
               
                 8:17 
                 5-[4-(4-tert-Butylbenzoyl- 
                 2,5-dichloro- 
                 H 
                 74 
                 52 
               
               
                   
                 amino)phenoxy]-2-[(2,5-di- 
                 nicotinoyl chloride 
               
               
                   
                 chloropyridine-3-carbonyl)- 
               
               
                   
                 amino]benzoic acid 
               
               
                 8:18 
                 5-[4-(4-tert-Butylbenzoyl- 
                 picolinoyl chloride 
                 H 
                 95 
                 70 
               
               
                   
                 amino)phenoxy]-2-[(pyridine-2- 
               
               
                   
                 carbonyl)-amino]benzoic acid 
               
               
                 8:19 
                 5-[4-(4-tert-Butylbenzoyl- 
                 4-chloro-2- 
                 H 
                 82 
                 60 
               
               
                   
                 amino)phenoxy]-2-(4-chloro-2- 
                 methoxybenzoyl 
               
               
                   
                 methoxybenzoylamino)- 
                 chloride 
               
               
                   
                 benzoic acid 
               
               
                 8:20 
                 5-[4-(4-tert-Butylbenzoyl- 
                 2,5-dichloro- 
                 H 
                 85 
                 80 
               
               
                   
                 amino)phenoxy]-2-[(2,6-di- 
                 nicotinoyl chloride 
               
               
                   
                 chloropyridine-3-carbonyl)- 
               
               
                   
                 amino]benzoic acid 
               
               
                 8:21 
                 5-[4-(4-tert-Butylbenzoyl- 
                 2-chlorobenzoyl 
                 H 
                 74 
                 82 
               
               
                   
                 amino)phenoxy]-2-(2-chloro- 
                 chloride 
               
               
                   
                 benzoylino)benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 9 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 9:1 
                 5-(4-((N-methyl)-4-butylbenz- 
                 4-butylbenzoyl chloride 
                 93 
                 71 
               
               
                   
                 amido)phenoxy)-2-(4-butylbenz- 
               
               
                   
                 amido)benzoic acid 
               
               
                 9:2 
                 5-(4-((N-methyl)-4-tert-butylbenz- 
                 4-methoxybenzoyl chloride 
                 95 
                 65 
               
               
                   
                 amido)phenoxy)-2-(4-methoxybenz- 
               
               
                   
                 amido)benzoic acid 
               
               
                 9:3 
                 5-(4-((N-methyl)-4-tert-butylbenz- 
                 2,4-dichlorobenzoyl 
                 76 
                 70 
               
               
                   
                 amido)phenoxy)-2-(2,4-dichlorobenz- 
                 chloride 
               
               
                   
                 amido)benzoic acid 
               
               
                 9:4 
                 5-(4-((N-methyl)-4-trifluoromethyl- 
                 4-isopropoxybenzoyl 
                 50 
                 48 
               
               
                   
                 benzamido)phenoxy)-2-(4-isopropoxy- 
                 chloride 
               
               
                   
                 benzamido)benzoic acid 
               
               
                 9:5 
                 5-(4-((N-methyl)-4-trifluoromethyl- 
                 2,4-dichlorobenzoyl 
                 92 
                 31 
               
               
                   
                 benzamido)phenoxy)-2-(2,4-dichloro- 
                 chloride 
               
               
                   
                 benzamido)benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 10 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 10:1 
                 5-[(3-(4-(1-butyl)benzoylamino)- 
                 2,6-difluorobenzoyl 
                 60 
                 63 
               
               
                   
                 phenoxy)]-2-(2,6-difluorobenzoyl- 
                 chloride 
               
               
                   
                 amino)benzoic acid 
               
               
                 10:2 
                 5-[(3-(4(1-butyl)benzoylamino)- 
                 4-trifluoromethoxy- 
                 60 
                 62 
               
               
                   
                 phenoxy)]-2-(4-trifluoromethoxy- 
                 benzoyl chloride 
               
               
                   
                 benzoylamino)benzoic acid 
               
               
                 10:3 
                 5-[(3-(4-(1-butyl)benzoylamino)- 
                 2-methoxybenzoyl 
                 85 
                 53 
               
               
                   
                 phenoxy)]-2-(2-methoxybenzoyl- 
                 chloride 
               
               
                   
                 amino)benzoic acid 
               
               
                 10:4 
                 5-[3-((4-(1-butyl)benzoyl)amino)- 
                 2-fluoro-4-trifluoro- 
                 50 
                 72 
               
               
                   
                 phenoxy]-2-(2-fluoro-4-trifluoro- 
                 methylbenzoyl chloride 
               
               
                   
                 methylbenzoylamino)benzoic acid 
               
               
                 10:5 
                 2-(2-fluoro-4-trifluoromethylbenzoyl- 
                 2-fluoro-4-trifluoro- 
                 69 
                 50 
               
               
                   
                 amino)-5-[3-(3-trifluoro-methylbenzoylamino)phenoxy]benzoic 
                 methylbenzoyl chloride 
               
               
                   
                 acid 
               
               
                 10:6 
                 2-(2-fluoro-4-trifluoromethylbenzoyl- 
                 2-fluoro-4-trifluoro- 
                 79 
                 80 
               
               
                   
                 amino)-5-[3-(4-trifluoromethylbenzoyl- 
                 methylbenzoyl chloride 
               
               
                   
                 amino)phenoxy]benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 11 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
               
            
               
                 No 
                 Chemical name 
                 Method 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 11:1 
                 5-[4-(4-butylbenzene- 
                 L 
                 4-butylbenzene- 
                 30 
                 65 
               
               
                   
                 sulfonylamino)phenoxy]-2-(4- 
                   
                 1-sulfonyl 
               
               
                   
                 trifluoromethylbenzoylamino)- 
                   
                 chloride 
               
               
                   
                 benzoic acid 
               
               
                 11:2 
                 5-[4-(2-chloro-4-trifluoromethyl- 
                 L 
                 2-chloro-4- 
                 24 
                 49 
               
               
                   
                 benzenesulfonylamino)phenoxy]- 
                   
                 trifluoromethyl- 
               
               
                   
                 2-(4-trifluoromethylbenzoyl- 
                   
                 benzene-1- 
               
               
                   
                 amino)benzoic acid 
                   
                 sulfonyl chloride 
               
               
                 11:3 
                 5-{4-[(4-methoxybenzene- 
                 K 
                 4-trifluoromethyl- 
                 83 
                 47 
               
               
                   
                 sulfonyl)methylamino]- 
                   
                 benzoyl chloride 
               
               
                   
                 phenoxy}-2-(4-trifluoromethyl- 
               
               
                   
                 benzoylamino)benzoic acid 
               
               
                 11:4 
                 2-(2,4-dichlorobenzoylamino)-5- 
                 K 
                 2,4- 
                 70 
                 24 
               
               
                   
                 {4-[(4-methoxy-benzenesulfonyl)- 
                   
                 dichlorobenzoyl 
               
               
                   
                 methylamino]phenoxy- 
                   
                 chloride 
               
               
                   
                 benzoic acid 
               
               
                 11:5 
                 5-{4-[(4-butyl-benzenesulfonyl)- 
                 K 
                 4-methylbenzoyl 
                 85 
                 80 
               
               
                   
                 methylamino]phenoxy}-2-(4- 
                   
                 chloride 
               
               
                   
                 methylbenzoylamino)benzoic 
               
               
                   
                 acid 
               
               
                 11:6 
                 5-{4-[(4-butylbenzene-sulfonyl)- 
                 K 
                 4-isopropoxy- 
                 88 
                 64 
               
               
                   
                 methylamino]phenoxy}-2-(4- 
                   
                 benzoyl chloride 
               
               
                   
                 isopropoxybenzoylamino)- 
               
               
                   
                 benzoic acid 
               
               
                 11:7 
                 5-{4-[(4-butylbenzenesulfonyl)- 
                 K 
                 2,4-dichloro- 
                 66 
                 42 
               
               
                   
                 methylamino]phenoxy}-2-(2,4- 
                   
                 benzoyl chloride 
               
               
                   
                 dichlorobenzoylamino)benzoic 
               
               
                   
                 acid 
               
               
                 11:8 
                 2-(4-butylbenzoylamino)-5-[4-(4- 
                 L 
                 4-(methyl- 
                 46 
                 44 
               
               
                   
                 methanesulfonylbenzene- 
                   
                 sulfonyl)benzene- 
               
               
                   
                 sulfonylamino)phenoxy]benzoic 
                   
                 sulfonyl chloride 
               
               
                   
                 acid 
               
               
                 11:9 
                 2-(benzoylmethylamino)-5-[4-(4- 
                 M 
                 benzoyl chloride 
                 82 
                 35 
               
               
                   
                 butoxybenzenesulfonylamino)- 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 11:10 
                 5-[4-(4-butoxybenzenesulfonyl- 
                 M 
                 2,3-dichloro- 
                 91 
                 46 
               
               
                   
                 amino)phenoxy]-2-[(2,3-di- 
                   
                 benzoyl chloride 
               
               
                   
                 chlorobenzoyl)methylamino]- 
               
               
                   
                 benzoic acid 
               
               
                 11:11 
                 5-[4-(3-fluoro-2-methylbenzenesulfonylamino)phenoxy]- 
                 M 
                 3-fluoro-2- 
                 37 bis- 
                 65 
               
               
                   
                 2- 
                   
                 methylbenzene- 
                 sulfonyl 
               
               
                   
                 [(4-isopropoxybenzoyl)methyl- 
                   
                 sulfonyl chloride 
               
               
                   
                 aminobenzoic acid 
               
               
                 11:12 
                 2-(2,3-dichlorobenzylamino)-5- 
                 K 
                 2,3-dichloro- 
                 25 
                 44 
               
               
                   
                 {4-[(4-methoxybenzene- 
                   
                 benzaldehyde 
               
               
                   
                 sulfonyl)methyl-amino]- 
               
               
                   
                 phenoxy}benzoic acid 
               
               
                 11:13 
                 2-(4-chlorobenzoylamino)-5-{4- 
                 K 
                 4-chlorobenzoyl 
                 91 
                 74 
               
               
                   
                 [(4-methoxybenzenesulfonyl)- 
                   
                 chloride 
               
               
                   
                 methylamino]phenoxy}benzoic 
               
               
                   
                 acid 
               
               
                 11:14 
                 2-(3-Chloro-benzoylamino)-5-{4- 
                 K 
                 3-chlorobenzoyl 
                 87 
                 51 
               
               
                   
                 [(4-methoxy-benzenesulfonyl)- 
                   
                 chloride 
               
               
                   
                 methyl-amino]-phenoxy}- 
               
               
                   
                 benzoic acid 
               
               
                 11:15 
                 2-(2,5-Dichloro-benzoylamino)- 
                 K 
                 2,5-dichloro- 
                 86 
                 66 
               
               
                   
                 5-{4-[(4-methoxy- 
                   
                 benzoyl chloride 
               
               
                   
                 benzenesulfonyl)-methyl- 
               
               
                   
                 amino]-phenoxy}-benzoic acid 
               
               
                 11:16 
                 2-(2,6-Difluoro-benzoylamino)- 
                 K 
                 2,6-difluoro- 
                 82 
                 69 
               
               
                   
                 5-{4-[(4-methoxy- 
                   
                 benzoyl chloride 
               
               
                   
                 benzenesulfonyl)-methyl- 
               
               
                   
                 amino]-phenoxy}-benzoic acid 
               
               
                 11:17 
                 2-(4-Chloro-2-methoxy- 
                 K 
                 4-Chloro-2- 
                 94 
                 28 
               
               
                   
                 benzoylamino)-5-{4-[(4- 
                   
                 methoxy-benzoyl 
               
               
                   
                 methoxy-benzenesulfonyl)- 
                   
                 chloride 
               
               
                   
                 methyl-amino]-phenoxy}- 
               
               
                   
                 benzoic acid 
               
               
                 11:18 
                 5-{4-[(4-Methoxy- 
                 K 
                 2-trifluoromethyl- 
                 68 
                 75 
               
               
                   
                 benzenesulfonyl)-methyl- 
                   
                 benzoyl chloride 
               
               
                   
                 amino]-phenoxy}-2-(2- 
               
               
                   
                 trifluoromethyl-benzoylamino)- 
               
               
                   
                 benzoic acid 
               
               
                 11:19 
                 5-{4-[(4-Methoxy- 
                 K 
                 2-trifluoro- 
                 87 
                 96 
               
               
                   
                 benzenesulfonyl)-methyl- 
                   
                 methoxy-benzoyl 
               
               
                   
                 amino]-phenoxy}-2-(2- 
                   
                 chloride 
               
               
                   
                 trifluoromethoxy-benzoylamino)- 
               
               
                   
                 benzoic acid 
               
               
                 11:20 
                 2-[(2-Chloro-pyridine-3- 
                 K 
                 2-chloro- 
                 87 
                 100 
               
               
                   
                 carbonyl)-amino]-5-{4-[(4- 
                   
                 nicotinoyl 
               
               
                   
                 methoxy-benzene- 
                   
                 chloride 
               
               
                   
                 sulfonyl)methylamino]- 
               
               
                   
                 phenoxy}benzoic acid 
               
               
                 11:21 
                 2-[(2,5-Dichloropyridine-3- 
                 K 
                 2,5-dichloro- 
                 62 
                 95 
               
               
                   
                 carbonyl)amino]-5-{4-[(4- 
                   
                 nicotinoyl 
               
               
                   
                 methoxybenzenesulfonyl)- 
                   
                 chloride 
               
               
                   
                 methylamino]phenoxy}benzoic 
               
               
                   
                 acid 
               
               
                 11:22 
                 2-(2-Chloro-benzoylamino)-5-{4- 
                 K 
                 2-chlorobenzoyl 
                 97 
                 59 
               
               
                   
                 [(4-methoxybenzenesulfonyl)- 
                   
                 chloride 
               
               
                   
                 methylamino]phenoxy}benzoic 
               
               
                   
                 acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 12 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Method 
                 Ester 
                 Acid 
               
               
                   
               
               
                 12:1 
                 2-(3,4-difluorophenylamino)- 
                 4-bromo-1,2- 
                 N 
                 45 
                 85 
               
               
                   
                 5-(4-(4-fluorophenylamino)- 
                 difluorobenzene 
               
               
                   
                 phenoxy)benzoic acid 
               
               
                 12:2 
                 5-(4-(4-fluorophenylamino)- 
                 4-butylbenzoyl 
                 P 
                 23 
                 87 
               
               
                   
                 phenoxy)-2-(4-butylbenz- 
                 chloride 
               
               
                   
                 amido)benzoic acid 
               
               
                 12:3 
                 5-(4-((N-4-fluorophenyl)4- 
                 4-butylbenzoyl 
                 P 
                 * 
                 * 
               
               
                   
                 butylbenzamido)phenoxy)-2- 
                 chloride 
               
               
                   
                 (4-butylbenzamido)benzoic 
               
               
                   
                 acid 
               
               
                 12:4 
                 5-{4-[bis-(4-cyclopropane- 
                 (4-bromophenyl)(cyclopropyl)methanone 
                 O 
                 30 
                 79 
               
               
                   
                 carbonyl-phenyl)-amino]- 
               
               
                   
                 phenoxy}-2-(4-cycloprop- 
               
               
                   
                 anecarbonyl-phenylamino)- 
               
               
                   
                 benzoic acid 
               
               
                 12:5 
                 2-(4-chloro-phenylamino)-5- 
                 1-bromo-4- 
                 O 
                 47 
                 67 
               
               
                   
                 [4-(4-chloro-phenylamino)- 
                 chlorobenzene 
               
               
                   
                 phenoxy]-benzoic acid 
               
               
                   
               
               
                 * isolated by-product from the synthesis of 12:2 
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 13 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 13:1 
                 2-(4-butylbenzamido)-5-((4-(4- 
                 4-butylbenzoyl 
                 48 
                 31 
               
               
                   
                 butylbenzamido)-3- 
                 chloride 
               
               
                   
                 carboxyphenyl)- 
               
               
                   
                 sulfanyl)benzoic acid 
               
               
                 13:2 
                 2-(3-chlorobenzamido)-5-((4-(3- 
                 3-chlorobenzoyl 
                 38 
                 80 
               
               
                   
                 chlorobenzamido)-3- 
                 chloride 
               
               
                   
                 carboxyphenyl)sulfanyl)benzoic 
               
               
                   
                 acid 
               
               
                 13:3 
                 2-(4-(trifluoromethyl)- 
                 4-(trifluoro- 
                 60 
                 73 
               
               
                   
                 benzamido)-5-((4-(4- 
                 methyl)-benzoyl 
               
               
                   
                 (trifluoromethyl)benzamido)-3- 
                 chloride 
               
               
                   
                 carboxyphenyl)sulfanyl)benzoic 
               
               
                   
                 acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 14 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate/procedure 
                 Ester 
                 Acid 
               
               
                   
               
               
                 14:1 
                 2-(4-chlorophenylamino)-5- 
                 1-bromo-4-chloro- 
                 46 
                 14 
               
               
                   
                 [4-(4-chlorophenylamino)- 
                 benzene/R 
               
               
                   
                 phenylsulfanyl]benzoic acid 
               
               
                 14:2 
                 2-(3,4-difluorophenylamino)- 
                 3,4-difluorophenylboronic 
                 15 
                 43 
               
               
                   
                 5-[4-(3,4-difluoro- 
                 acid/S 
               
               
                   
                 phenylamino)- 
               
               
                   
                 phenylsulfanyl]-benzoic acid 
               
               
                 14:3 
                 2-(4-butyl-benzenesulfonyl- 
                 4-butylbenzene-1-sulfonyl 
                  3 
                 32 
               
               
                   
                 amino)-5-[4-(4-butyl-benzen- 
                 chloride/T 
               
               
                   
                 sulfonylamino)phenyl- 
               
               
                   
                 sulfanyl]benzoic acid 
               
               
                 14:4 
                 2-(4-chloro-benzenesulfonyl- 
                 4-chlorobenzene-1- 
                 30 
                 57 
               
               
                   
                 amino)-5-[4-(4-chloro- 
                 sulfonyl chloride/T 
               
               
                   
                 benzenesulfonylamino)- 
               
               
                   
                 phenylsulfanyl]-benzoic acid 
               
               
                 14:5 
                 2-[3-(4-chlorophenyl)-ureido]- 
                 1-chloro-4-isocyanato- 
                 — 
                 18 
               
               
                   
                 5-{4-[3-(4-chlorophenyl)- 
                 benzene/U 
               
               
                   
                 ureido]phenylsulfanyl}- 
               
               
                   
                 benzoic acid 
               
               
                 14:6 
                 2-[3-(4-trifluoromethyl- 
                 1-isocyanato-4-trifluoro- 
                 — 
                 39 
               
               
                   
                 phenyl)ureido]-5-{4-[3-(4- 
                 methylbenzene/U 
               
               
                   
                 trifluoromethylphenyl)- 
               
               
                   
                 ureido]phenylsulfanyl}- 
               
               
                   
                 benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 15 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No 
                 Chemical name 
                 Substrate 
                 Ester 
                 acid 
               
               
                   
               
               
                 15:1 
                 5-(4-(4-butylbenzamido)-3- 
                 2-(4-butylbenzamido)-5-((4-(4- 
                 43 
                 50 
               
               
                   
                 carboxyphenylsulfinyl)-2-(4- 
                 butylbenzamido)-3-carboxyphenyl)sulfanyl)benzoate 
               
               
                   
                 butylbenzamido)benzoic acid 
               
               
                 15:2 
                 2-(3-chlorobenzamido)-5-(4- 
                 Ethyl 2-(3-chlorobenzamido)-5- 
                 53 
                 42 
               
               
                   
                 (3-chlorobenzamido)-3- 
                 ((4-(3-chlorobenzamido)-3- 
               
               
                   
                 carboxyphenylsulfinyl)benzoic 
                 carboxyphenyl)sulfanyl)benzoate 
               
               
                   
                 acid 
               
               
                 15:3 
                 2-(4-(trifluoromethyl)benz- 
                 Ethyl 2-(4-(trifluoromethyl)benz)- 
                 67 
                 92 
               
               
                   
                 amido)-5-((4-(4-(trifluoromethyl)benzamido)- 
                 amido-5-((4-(4-(trifluoromethyl)- 
               
               
                   
                 3-carboxy- 
                 benzamido)-3-carboxyphenyl)- 
               
               
                   
                 phenyl)sulfinyl)benzoic acid 
                 sulfanyl)benzoate 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 16 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 acid 
               
               
                   
               
               
                 16:1 
                 2-(3-chlorobenzamido)-5-(4- 
                 Ethyl 2-(3-chlorobenz- 
                 72 
                 73 
               
               
                   
                 (3-chlorobenzamido)-3- 
                 amido)-5-((4-(3-chlorobenz- 
               
               
                   
                 carboxyphenylsulfonyl)- 
                 amido)-3-carboxyphenyl)- 
               
               
                   
                 benzoic acid 
                 sulfanyl)-benzoate 
               
               
                 16:2 
                 2-(4-(trifluoromethyl)benz- 
                 Ethyl 2-(4-(trifluoromethyl)- 
                 47 
                 30 
               
               
                   
                 amido)-5-((4-(4-(trifluoro- 
                 benzamido)-5-((4-(4- 
               
               
                   
                 methyl)benzamido)-3- 
                 (trifluoromethyl)benzamido)- 
               
               
                   
                 carboxyphenyl)sulfonyl)- 
                 3-carboxyphenyl)sulfanyl)- 
               
               
                   
                 benzoic acid 
                 benzoate 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 17 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate/metod 
                 Ester 
                 Acid 
               
               
                   
               
               
                 17:1 
                 {2-(3-chloro-benzoylamino)-5- 
                 3-chlorobenzoyl chloride/X 
                 72 
                 71 
               
               
                   
                 [4-(2-fluoro-4-trifluoromethyl- 
               
               
                   
                 benzoylamino)-phenoxy]- 
               
               
                   
                 phenyl}-acetic acid 
               
               
                 17:2 
                 [5-(4-benzoylamino-phenoxy)- 
                 2,3-dichlorobenzoyl 
                 55 
                 59 
               
               
                   
                 2-(2,3-dichloro-benzoylamino)- 
                 chloride/X 
               
               
                   
                 phenyl]-acetic acid 
               
               
                 17:3 
                 [5-(4-benzoylamino-phenoxy)- 
                 4-isopropoxybenzoyl 
                 70 
                 70 
               
               
                   
                 2-(4-isopropoxy-benzoyl- 
                 chloride/X 
               
               
                   
                 amino)-phenyl]-acetic acid 
               
               
                 17:4 
                 {2-(4-butyl-benzoylamino)-5-[4- 
                 4-butylbenzoyl chloride/X 
                 31 
                 29 
               
               
                   
                 (2-fluoro-4-trifluoromethyl- 
               
               
                   
                 benzoylamino)-phenoxy]- 
               
               
                   
                 phenyl}-acetic acid 
               
               
                 17:5 
                 [5-[4-(4-butyl-benzoylamino)- 
                 2,4-dichlorobenzoyl 
                 58 
                 27 
               
               
                   
                 phenoxy]-2-(2,4-dichloro- 
                 chloride/X 
               
               
                   
                 benzoylamino)-phenyl]-acetic 
               
               
                   
                 acid 
               
               
                 17:6 
                 [5-[4-(4-butyl-benzoylamino)- 
                 2-(2,2,2-trifluoroacetyl)- 
                 58 
                 53 
               
               
                   
                 phenoxy]-2-(1,2,3,4-tetrahydro- 
                 1,2,3,4-tetrahydroiso- 
               
               
                   
                 isoquinoline-7-sulfonylamino)- 
                 quinoline-7-sulfonyl 
               
               
                   
                 phenyl]-acetic acid 
                 chloride/Y 
               
               
                 17:7 
                 [5-(4-benzoylamino-phenoxy)- 
                 4-butoxybenzene-1- 
                 60 
                 10 
               
               
                   
                 2-(4-butoxy-benzenesulfonyl- 
                 sulfonyl chloride/Y 
               
               
                   
                 amino)-phenyl]-acetic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 18 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 18:1 
                 3-[4-(2,3-dichloro-benzenesulfonylamino)- 
                 2,3-dichlorobenzene- 
                 66 
                 69 
               
               
                   
                 phenoxy]-5-[(3,4- 
                 1-sulfonyl 
               
               
                   
                 difluoro-phenyl)-methyl-amino]- 
                 chloride 
               
               
                   
                 benzoic acid 
               
               
                 18:2 
                 3-[4-(4-Chloro-phenylamino)- 
                 1-bromo-4- 
                 43 
                 84 
               
               
                   
                 phenoxy]-5-(3,4-difluoro- 
                 chlorobenzene 
               
               
                   
                 phenylamino)-benzoic acid 
               
               
                 18:3 
                 3-[4-(4-Cyclopropanecarbonyl- 
                 (4-bromophenyl)- 
                 40 
                 56 
               
               
                   
                 phenylamino)-phenoxy]-5-[(3,4- 
                 (cyclopropyl)methanone 
               
               
                   
                 difluoro-phenyl)-methyl-amino]- 
               
               
                   
                 benzoic acid 
               
               
                 18:4 
                 3-[4-(3-Chloro-2-methyl-benzene- 
                 3-chloro-2-methyl- 
                 95 
                 65 
               
               
                   
                 sulfonylamino)-phenoxy]-5-(3,4- 
                 benzene-1-sulfonyl 
               
               
                   
                 difluoro-phenylamino)-benzoic 
                 chloride 
               
               
                   
                 acid 
               
               
                 18:5 
                 3-[4-(3-Chloro-benzoylamino)- 
                 3-chlorobenzoyl 
                 63 
                 49 
               
               
                   
                 phenoxy]-5-(3,4-difluoro- 
                 chloride 
               
               
                   
                 phenylamino)-benzoic acid 
               
               
                 18:6 
                 3-[4-(3-Chloro-benzoylamino)- 
                 3-chlorobenzoyl 
                 76 
                 86 
               
               
                   
                 phenoxy]-5-[(3,4-difluoro-phenyl)- 
                 chloride 
               
               
                   
                 methyl-amino]-benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 19 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 19:1 
                 2-(4-Butoxy- 
                 4-butoxybenzene- 
                 64 
                 33 
               
               
                   
                 benzenesulfonylamino)-5- 
                 1-sulfonyl 
               
               
                   
                 [3-(4-chloro-phenylsufamoyl)- 
                 chloride 
               
               
                   
                 phenoxy]-benzoic acid 
               
               
                 19:2 
                 2-(4-Butoxy- 
                 4-butoxybenzene- 
                 64 
                 89 
               
               
                   
                 benzenesulfonylamino)-5-[3- 
                 1-sulfonyl 
               
               
                   
                 (3,4-difluoro-phenylsufamoyl)- 
                 chloride 
               
               
                   
                 phenoxy]-benzoic acid 
               
               
                 19:3 
                 2-(2,4-Dichloro-benzoylamino)- 
                 2,4-dichloro- 
                 41 
                 80 
               
               
                   
                 5-[3-(3,4-difluoro- 
                 benzoyl 
               
               
                   
                 phenylsufamoyl)-phenoxy]- 
                 chloride 
               
               
                   
                 benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 20 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 20:1 
                 2-(4-Butoxy-benzenesulfonylamino)- 
                 3-chloro-2- 
                 83 
                 65 
               
               
                   
                 5-[3-(3-chloro-2-fluoro-benzene- 
                 fluorobenzene- 
               
               
                   
                 sulfonylaminocarbonyl)-phenoxy]- 
                 sulfonamide 
               
               
                   
                 benzoic acid 
               
               
                 20:2 
                 2-(4-Chloro-phenylamino)-5-[3-(3,4- 
                 3,4-difluoro- 
                 83 
                 91 
               
               
                   
                 difluoro-benzenesulfonylamino- 
                 benzenesulfon- 
               
               
                   
                 carbonyl)-phenoxy]-benzoic acid 
                 amide 
               
               
                 20:3 
                 5-[3-(3-Chloro-2-fluoro-benzene- 
                 3-chloro-2- 
                 76 
                 84 
               
               
                   
                 sulfonylaminocarbonyl)-phenoxy]-2- 
                 fluorobenzene- 
               
               
                   
                 (4-chloro-phenylamino)-benzoic acid 
                 sulfonamide 
               
               
                 20:4 
                 2-(4-Butoxy-benzenesulfonylamino)- 
                 4-fluorobenzenesulfonamide 
                 85 
                 — 
               
               
                   
                 5-[3-(4-fluoro-benzenesulfonylamino- 
               
               
                   
                 carbonyl)-phenoxy]-benzoic acid 
               
               
                   
                 t-butyl ester 
               
               
                 20:5 
                 2-(4-Butoxy-benzenesulfonylamino)- 
                 3,4-difluoro- 
                 96 
                 77 
               
               
                   
                 5-[3-(3,4-difluoro-benzenesulfonyl- 
                 benzenesulfon- 
               
               
                   
                 aminocarbonyl)-phenoxy]-benzoic 
                 amide 
               
               
                   
                 acid 
               
               
                 20:6 
                 2-(4-Chloro-phenylamino)-5-[3-(3,4- 
                 3,4-difluoro- 
                 83 
                 — 
               
               
                   
                 difluoro-benzenesulfonylamino- 
                 benzenesulfon- 
               
               
                   
                 carbonyl)-phenoxy]-benzoic acid 
                 amide 
               
               
                   
                 t-butyl ester 
               
               
                 20:7 
                 2-(4-Butoxy-benzenesulfonylamino)- 
                 4-fluorobenzenesulfonamide 
                 85 
                 67 
               
               
                   
                 5-[3-(4-fluoro-benzenesulfonylamino- 
               
               
                   
                 carbonyl)-phenoxy]-benzoic acid 
               
               
                 20:8 
                 5-[3-(4-Fluorobenzenesulfonyl- 
                 4-fluorobenzenesulfonamide 
                 89 
                 79 
               
               
                   
                 aminocarbonyl)-phenoxy]-2-(4- 
               
               
                   
                 chloro-phenylamino)-benzoic acid 
               
               
                 20:9 
                 5-[3-(4-Butoxy-benzenesulfonyl- 
                 4-butoxybenzenesulfonamide 
                 86 
                 84 
               
               
                   
                 aminocarbonyl)-phenoxy]-2-(4- 
               
               
                   
                 chloro-phenylamino)-benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 21 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 21:1 
                 2-(3-Chloro-4-fluoro-benzenesulfonylamino)- 
                 3-chloro-4- 
                 63 
                 92 
               
               
                   
                 5-{4-[(2-methyl-6-trifluoromethyl- 
                 fluorobenzene- 
               
               
                   
                 pyridine-3-carbonyl)-amino]- 
                 sulfonyl 
               
               
                   
                 phenoxy}-benzoic acid 
                 chloride 
               
               
                 21:2 
                 2-(3,5-Dichloro-2-hydroxy-benzene- 
                 3,5-dichloro-2- 
                 60 
                 90 
               
               
                   
                 sulfonylamino)-5-{4-[(2-methyl-6- 
                 hydroxybenzenesulfonyl 
               
               
                   
                 trifluoromethyl-pyridine-3-carbonyl)- 
                 chloride 
               
               
                   
                 amino]-phenoxy}-benzoic acid 
               
               
                 21:3 
                 5-{4-[(4-t-Butyl-benzoyl)-methyl- 
                 4-methoxybenzenesulfonyl 
                  91* 
                  51* 
               
               
                   
                 amino]-phenoxy}-2-(4-methoxy- 
                 chloride 
               
               
                   
                 benzenesulfonylamino)-benzoic acid 
               
               
                 21:4 
                 5-(4-benzoylamino-phenoxy)-2-(4- 
                 4-butoxybenzenesulfonyl 
                 72 
                 91 
               
               
                   
                 butoxy-benzenesulfonylamino)- 
                 chloride 
               
               
                   
                 benzoic acid 
               
               
                   
               
               
                 *4-(methylamino)phenol was used in step 1. 
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 22 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 22:1 
                 (E)-3-[5-(4-Benzoylaminophenoxy)- 
                 4-butoxybenzenesulfonyl 
                 61 
                 54 
               
               
                   
                 2-(4-butoxybenzenesulfonylamino)- 
                 chloride 
               
               
                   
                 phenyl]acrylic acid 
               
               
                 22:2 
                 3-[5-(4-Benzoylaminophenoxy)-2-(4- 
                 4-butoxybenzenesulfonyl 
                 83 
                 85 
               
               
                   
                 butoxybenzenesulfonylamino)- 
                 chloride 
               
               
                   
                 phenyl]propionic acid 
               
               
                 22:3 
                 (E)-3-[5-(4-Benzoylaminophenoxy)- 
                 4-isopropoxy- 
                 62 
                 84 
               
               
                   
                 2-(4-isopropoxy-benzoylamino)- 
                 benzoyl chloride 
               
               
                   
                 phenyl]acrylic acid 
               
               
                 22:4 
                 5-[4-(4-butoxybenzenesulfonyl- 
                 4-butoxybenzenesulfonyl 
                 62 
                 31 
               
               
                   
                 amino)-3-((E)-2-carboxyvinyl)- 
                 chloride 
               
               
                   
                 phenoxy]-2-(4-isopropoxy- 
               
               
                   
                 benzoylamino)benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 23 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 23:1 
                 2-(4-Butoxybenzenesulfonylamino)- 
                 2,3-difluoro- 
                 71 
                 71 
               
               
                   
                 5-[3-(2,3-difluorobenzylamino)- 
                 benzaldehyde 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 23:2 
                 2-(4-Butoxybenzenesulfonylamino)- 
                 2,3-dimethoxy- 
                 97 
                 36 
               
               
                   
                 5-[3-(2,3-dimethoxybenzylamino)- 
                 benzaldehyde 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 23:3 
                 2-(4-Butoxybenzenesulfonylamino)- 
                 2,3-dichloro- 
                 93 
                 35 
               
               
                   
                 5-[3-(2,3-dichlorobenzylamino)- 
                 benzaldehyde 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 23:4 
                 2-(4-Butoxybenzenesulfonylamino)- 
                 3-chloro-2- 
                 69 
                 86 
               
               
                   
                 5-[3-(3-chloro-2-fluorobenzylamino)- 
                 fluorobenzaldehyde 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 23:5 
                 5-[3-(3-Chloro-2-fluorobenzylamino)- 
                 3-chloro-2- 
                 90 
                 54 
               
               
                   
                 phenoxy]-2-(2,4-dichlorobenzene- 
                 fluorobenzaldehyde 
               
               
                   
                 sulfonylamino)benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 24 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 24:1 
                 5-{4-[n-Butyl-(3,4- 
                 4-bromo-1,2- 
                 74 
                 80 
               
               
                   
                 difluorophenyl)- 
                 difluorobenzene 
               
               
                   
                 amino]phenoxy}-2-(3,4- 
               
               
                   
                 difluoro-phenylamino)benzoic 
               
               
                   
                 acid 
               
               
                 24:2 
                 5-{4-[n-Butyl-(3,4-difluoro- 
                 1-bromo-4- 
                 59 
                 85 
               
               
                   
                 phenyl)-amino]phenoxy}-2-(4- 
                 chlorobenzene 
               
               
                   
                 chloro-phenylamino- 
               
               
                   
                 benzoic acid 
               
               
                 24:3 
                 2-[butyl-(3,4- 
                 4-bromo-1,2- 
                 69 
                 36 
               
               
                   
                 difluorophenyl)amino]-5-[3- 
                 difluorobenzene 
               
               
                   
                 carboxy-4-(3,4-difluorophenyl- 
               
               
                   
                 amino)phenoxy]benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 25 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 25:1 
                 5-[4-(4-Chlorophenylsulfamoyl)- 
                 1-isocyanato-4- 
                 — 
                 44 
               
               
                   
                 phenoxy]-2-[3-(4-trifluoromethyl- 
                 (trifluoromethyl)- 
               
               
                   
                 phenyl)ureido]benzoic acid 
                 benzene 
               
               
                 25:2 
                 2-(4-Butoxy-benzenesulfonyl- 
                 4-butoxybenzenesulfonyl 
                 70 
                 92 
               
               
                   
                 amino)-5-[4-(4-chlorophenylsulfamoyl)phenoxy]benzoic 
                 chloride 
               
               
                   
                 acid 
               
               
                 25:3 
                 2-(4-Butoxybenzenesulfonyl- 
                 4-butoxybenzenesulfonyl 
                 71 
                 88 
               
               
                   
                 amino)-5-[4-(3,4-difluorophenyl- 
                 chloride 
               
               
                   
                 sulfamoyl)phenoxy]benzoic acid 
               
               
                 25:4 
                 2-(2,4-Dichlorobenzoylamino)-5-[4- 
                 2,4-dichloro- 
                 30 
                 92 
               
               
                   
                 (3,4-difluorophenylsulfamoyl)- 
                 benzoyl chloride 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 25:5 
                 2-(2,3-Dichlorobenzoylamino)-5-[4- 
                 2,3-dichloro- 
                 30 
                 90 
               
               
                   
                 (3,4-difluorophenylsulfamoyl)- 
                 benzoyl chloride 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 25:6 
                 5-[4-(3,4-Difluoro-phenylsulfamoyl)- 
                 4-isopropoxy- 
                 43 
                 63 
               
               
                   
                 phenoxy]-2-(4-isopropoxybenzoyl- 
                 benzoyl chloride 
               
               
                   
                 amino)benzoic acid 
               
               
                 25:7 
                 5-[4-(4-Chlorophenylsulfamoyl)- 
                 4-bromo-1,2- 
                 76 
                 53 
               
               
                   
                 phenoxy]-2-(3,4-difluorophenyl- 
                 difluorobenzene 
               
               
                   
                 amino)benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 26 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 26:1 
                 5-{3-[2-(4-Butoxybenzenesulfonyl- 
                 4-butoxy- 
                 41 
                 29 
               
               
                   
                 amino)-2-oxoethyl]phenoxy}- 
                 benzenesulfon- 
               
               
                   
                 2-(4-chlorophenylamino)benzoic acid 
                 amide 
               
               
                 26:2 
                 2-(4-Chlorophenylamino)-5-{3-[2- 
                 3,4-difluoro- 
                 54 
                 59 
               
               
                   
                 (3,4-difluorobenzenesulfonylamino)- 
                 benzene- 
               
               
                   
                 2-oxoethyl]phenoxy}benzoic acid 
                 sulfonamide 
               
               
                 26:3 
                 2-(4-Butoxybenzenesulfonylamino)- 
                 3,4-difluoro- 
                 36 
                 — 
               
               
                   
                 5-{3-[2-(3,4-difluorobenzenesulfonyl- 
                 benzene- 
               
               
                   
                 amino)-2-oxoethyl]phenoxy-benzoic 
                 sulfonamide 
               
               
                   
                 acid tert-butyl ester 
               
               
                 26:4 
                 2-(4-Butoxybenzenesulfonylamino)- 
                 3,4-difluoro- 
                 36 
                 43 
               
               
                   
                 5-{3-[2-(3,4-difluorobenzenesulfonyl- 
                 benzene- 
               
               
                   
                 amino)-2-oxoethyl]phenoxy}benzoic acid 
                 sulfonamide 
               
               
                 26:5 
                 2-(4-Butoxybenzenesulfonylamino)- 
                 3-chloro-2- 
                 98 
                 35 
               
               
                   
                 5-{3-[2-(3-chloro-2-fluorobenzene- 
                 fluorobenzene- 
               
               
                   
                 sulfonylamino)-2-oxoethyl]phenoxy}- 
                 sulfonamide 
               
               
                   
                 benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 27 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 27:1 
                 2-(4-Butoxybenzenesulfonylamino)- 
                 4-butoxybenzene- 
                 90 
                 13 
               
               
                   
                 5-{4-[butyl(3,4-difluorophenyl)- 
                 sulfonyl chloride 
               
               
                   
                 amino]phenoxy}benzoic acid 
               
               
                 27:2 
                 5-{4-[Butyl-(3,4-difluoro-phenyl)- 
                 3,4-dimethoxy- 
                 85 
                 30 
               
               
                   
                 amino]phenoxy}-2-(3,4-dimethoxy- 
                 benzenesulfonyl 
               
               
                   
                 benzenesulfonylamino)benzoic acid 
                 chloride 
               
               
                 27:3 
                 2-(4-Butoxybenzenesulfonylamino)- 
                 4-butoxybenzene- 
                 63 
                 62 
               
               
                   
                 5-[4-(3,4-difluorophenylamino)- 
                 sulfonyl chloride 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 27:4 
                 5-[4-(3,4-Difluoro-phenylamino)- 
                 4-methoxybenzenesulfonyl 
                 60 
                 58 
               
               
                   
                 phenoxy]-2-(4-methoxy-benzene- 
                 chloride 
               
               
                   
                 sulfonylamino)-benzoic acid 
               
               
                 27:5 
                 5-{4-[Butyl(3,4-difluoro-phenyl)- 
                 4-chloro-2-fluoro- 
                 82 
                 87 
               
               
                   
                 amino]phenoxy}-2-(4-chloro-2- 
                 benzenesulfonyl 
               
               
                   
                 fluorobenzenesulfonylamino)- 
                 chloride 
               
               
                   
                 benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 28 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 28:1 
                 2-(4-Butoxybenzenesulfonylamino)- 
                 4-butoxybenzene- 
                 84 
                 47 
               
               
                   
                 5-[3-(3,4-difluorophenoxy)phenoxy]- 
                 sulfonyl chloride 
               
               
                   
                 benzoic acid 
               
               
                 28:2 
                 2-(4-Cyclopentyloxybenzoylamino)- 
                 4-(cyclopentyloxy)benzoyl 
                 77 
                 64 
               
               
                   
                 5-[3-(3,4-difluorophenoxy)phenoxy]- 
                 chloride 
               
               
                   
                 benzoic acid 
               
               
                 28:3 
                 5-[3-(3,4-Difluorophenoxy)- 
                 4-bromo-1,2- 
                 78 
                 66 
               
               
                   
                 phenoxy]-2-(3,4-difluoro- 
                 difluorobenzene 
               
               
                   
                 phenylamino)benzoic acid 
               
               
                 28:4 
                 2-(2,4-Dichlorobenzenesulfonyl- 
                 2,4-dichloro- 
                 55 
                 80 
               
               
                   
                 amino)-5-[3-(3,4-difluorophenoxy)- 
                 benzenesulfonyl 
               
               
                   
                 phenoxy]benzoic acid 
                 chloride 
               
               
                 28:5 
                 5-[3-(3,4-Difluorophenoxy)- 
                 4-methoxybenzenesulfonyl 
                 79 
                 53 
               
               
                   
                 phenoxy]-2-(4-methoxybenzene- 
                 chloride 
               
               
                   
                 sulfonylamino)benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 29 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 29:1 
                 2-(4-tert-Butylbenzenesulfonylamino)- 
                 4-tert- 
                 95 
                 71 
               
               
                   
                 5-[3-(4-tert-butylbenzoylamino)- 
                 butyl- 
               
               
                   
                 phenoxy]benzoic acid 
                 benzoyl 
               
               
                   
                   
                 chloride 
               
               
                 29:2 
                 5-[3-(4-Butoxybenzoylamino)phenoxy]- 
                 4-butoxy- 
                 96 
                 66 
               
               
                   
                 2-(2,4-dichlorobenzenesulfonylamino)- 
                 benzoyl 
               
               
                   
                 benzoic acid 
                 chloride 
               
               
                 29:3 
                 5-[3-(4-tert-Butylbenzoylamino)- 
                 4-tert- 
                 93 
                 61 
               
               
                   
                 phenoxy]-2-(2,4-dichlorobenzene- 
                 butyl- 
               
               
                   
                 sulfonylamino)benzoic acid 
                 benzoyl 
               
               
                   
                   
                 chloride 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 30 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 30:1 
                 2-[3-(3-chlorophenyl)ureido]-5-{4- 
                 1-chloro-3- 
                 — 
                 14 
               
               
                   
                 [3-(3-chlorophenyl)ureido]- 
                 isocyanatobenzene 
               
               
                   
                 phenoxy}benzoic acid 
               
               
                 30:2 
                 2-[3-(4-trifluoromethylphenyl)- 
                 1-trifluoromethyl-4- 
                 — 
                 25 
               
               
                   
                 ureido]-5-{4-[3-(4-trifluoromethyl- 
                 isocyanatobenzene 
               
               
                   
                 phenyl)-ureido]-phenoxy}benzoic acid 
               
               
                 30:3 
                 2-(4-trifluoromethoxybenzene- 
                 4-trifluoromethoxybenzene- 
                 — 
                 18 
               
               
                   
                 sulfonylamino)-5-[4-(4-trifluoro- 
                 sulfonyl chloride 
               
               
                   
                 methoxybenzenesulfonylamino)- 
               
               
                   
                 phenoxy]-benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 31 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 31:1 
                 5-(3-carboxy-4-(3,4-difluoro- 
                 3,4-difluorobenzaldehyde 
                 86 
                 78 
               
               
                   
                 benzylamino)phenoxy)-2-(3,4-difluoro- 
               
               
                   
                 benzylamino)-benzoic acid 
               
               
                 31:2 
                 5-(3-Carboxy-4-(2,3-difluorobenzyl- 
                 2,3-difluorobenzaldehyde 
                 85 
                 60 
               
               
                   
                 amino)phenoxy)-2-(2,3-difluoro- 
               
               
                   
                 benzylamino)benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 32 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Step 
                   
               
               
                 No. 
                 Chemical name 
                 Substrate 
                 4 or 6 
                 Tetrazole 
               
               
                   
               
               
                 32:1 
                 2,4-Dichloro-N-{4-[4-(4-isopropyl- 
                 2,4-dichloro- 
                 52 
                 25 
               
               
                   
                 benzenesulfonylamino)-3- 
                 benzoyl 
               
               
                   
                 tetrazol-5-yl)phenoxy]phenyl}- 
                 chloride (step 4) 
               
               
                   
                 benzamide 
               
               
                 32:2 
                 4-Isopropoxy-N-{4-[4-(4-iso- 
                 4-isopropoxy- 
                 47 
                 60 
               
               
                   
                 propylbenzenesulfonylamino)-3- 
                 benzoyl 
               
               
                   
                 (tetrazol-5-yl)phenoxy]phenyl}- 
                 chloride (step 4) 
               
               
                   
                 benzamide 
               
               
                 32:3 
                 4-Butoxy-N-[4-[4-(3,4-difluoro- 
                 4-butoxybenzenesulfonyl 
                 87 
                 72 
               
               
                   
                 phenyamino)phenoxy]-2-(tetrazol- 
                 chloride (step 6) 
               
               
                   
                 5-yl)phenyl]benzenesulfonamide 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 33 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Hydrolysis 
               
               
                   
               
               
                 33:1 
                 2-(3,4-Difluorophenylamino)-5-[5- 
                 4-bromo-1,2- 
                 51 
                 41 
               
               
                   
                 (3,4-difluorophenylamino)pyridin-2- 
                 difluorobenzene 
               
               
                   
                 yloxy]benzoic acid 
               
               
                 33:2 
                 5[6-(3-Chloro-2-methyl-benzene- 
                 3-chloro-2- 
                 76 
                 65 
               
               
                   
                 sulfonylamino)pyridin-3-yloxy]-2-(3,4- 
                 methylbenzene-sulfonyl 
               
               
                   
                 difluorophenylamino)benzoic acid 
                 chloride 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 34 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
               
            
               
                 No 
                 Chemical name 
                 Method 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 34:1 
                 2-(4-Chlorophenyl- 
                 AO 
                 1-bromo-4- 
                 62 
                 85 
               
               
                   
                 amino)-5-[4-(4-chloro- 
                   
                 chlorobenzene 
               
               
                   
                 phenylamino)-3-fluoro- 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 34:2 
                 5-[4-(4-Chloro-phenyl- 
                 AO 
                 2,6-difluorobenzoyl 
                 75 
                 55 
               
               
                   
                 amino)-3-fluoro- 
                   
                 chloride 
               
               
                   
                 phenoxy]-2-(2,6-di- 
               
               
                   
                 fluorobenzoylamino)- 
               
               
                   
                 benzoic acid 
               
               
                 34:3 
                 5-[4-(4-Chlorophenyl- 
                 AO 
                 1-bromo-4,5-difluoro-2- 
                 75 
                 87 
               
               
                   
                 amino)-3-fluorophenoxy]- 
                   
                 methoxybenzene 
               
               
                   
                 2-(4,5-difluoro-2- 
               
               
                   
                 methoxyphenylamino)- 
               
               
                   
                 benzoic acid 
               
               
                 34:4 
                 2-(4-Chloro-2- 
                 AO 
                 1-bromo-4-chloro-2- 
                 90 
                 42 
               
               
                   
                 methoxyphenylamino)- 
                   
                 methoxybenzene 
               
               
                   
                 5-[4-(4-chlorophenyl- 
               
               
                   
                 amino)-3-fluoro- 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 34:5 
                 5-[4-(4-Chlorophenyl- 
                 AO 
                 1-bromo-2- 
                 80 
                 45 
               
               
                   
                 amino)-3-fluoro- 
                   
                 trifluoromethylbenzene 
               
               
                   
                 phenoxy]-2-(2-trifluoro- 
               
               
                   
                 methylphenylamino)- 
               
               
                   
                 benzoic acid 
               
               
                 34:6 
                 2-(2,6-Difluoro- 
                 AO 
                 2,6-difluorobenzoyl 
                 83 
                 91 
               
               
                   
                 benzoylamino)-5-[3- 
                   
                 chloride 
               
               
                   
                 fluoro-4(2-methoxy- 
               
               
                   
                 phenylamino)- 
               
               
                   
                 phenoxy]benzoic acid 
               
               
                 34:7 
                 2-(4-Chlorophenyl- 
                 AN 
                 1-bromo-4- 
                 51 
                 90 
               
               
                   
                 amino)-5-{3-fluoro-4- 
                   
                 chlorobenzene 
               
               
                   
                 [(2-methoxyphenyl)- 
               
               
                   
                 methylamino]- 
               
               
                   
                 phenoxy}benzoic acid 
               
               
                 34:8 
                 2-(4-Chloro-2-fluoro- 
                 AN 
                 1-bromo-4-chloro-2- 
                 52 
                 68 
               
               
                   
                 phenylamino)-5-{3- 
                   
                 fluorobenzene 
               
               
                   
                 fluoro-4-[(2-methoxy- 
               
               
                   
                 phenyl)methylamino]- 
               
               
                   
                 phenoxy}benzoic acid 
               
               
                 34:9 
                 2-(2-Chloro-phenyl- 
                 AN 
                 1-bromo-2- 
                 74 
                 53 
               
               
                   
                 amino)-5-{3-fluoro-4- 
                   
                 chlorobenzene 
               
               
                   
                 [(2-methoxyphenyl)- 
               
               
                   
                 methylamino]- 
               
               
                   
                 phenoxy}benzoic acid 
               
               
                 34:10 
                 2-(2,4-Dichloro- 
                 AN 
                 2,4-dichlorobenzoyl chloride 
                 88 
                 54 
               
               
                   
                 benzoylamino)-5-{3- 
               
               
                   
                 fluoro-4-[(2-methoxy- 
               
               
                   
                 phenyl)methylamino]- 
               
               
                   
                 phenoxy}benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 35 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Chemical name 
                 Substrate 
                 Ester 
                 Hydrolysis 
               
               
                   
               
               
                 35:1 
                 2-(2,4-Dichlorobenzoylamino)-5-[4- 
                 2,4-dichloro-benzoyl 
                 93 
                 68 
               
               
                   
                 (4-trifluoromethylbenzoylamino)- 
                 chloride 
               
               
                   
                 phenylsulfanyl]benzoic acid 
               
               
                 35:2 
                 2-(4-Chloro-2-fluoro-benzene- 
                 4-chloro-2- 
                 83 
                 56 
               
               
                   
                 sulfonylamino)-5-[4-(4-trifluoro- 
                 fluorobenzene- 
               
               
                   
                 methylbenzoylamino)-phenyl- 
                 sulfonyl chloride 
               
               
                   
                 sulfanyl]benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 36 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 36:1 
                 2-(4-butylphenylsulfonamido)-5-(3- 
                 4-butylbenzene-sulfonyl 
                 86 
                 — 
               
               
                   
                 (methoxycarbonyl)-4-(phenylsulfon- 
                 chloride 
               
               
                   
                 amido)phenoxy)benzoic acid 
               
               
                 36:2 
                 2-(4-butylphenylsulfonamido)-5-(3- 
                 4-butylbenzene- 
                 86 
                 74 
               
               
                   
                 carboxy-4-(phenylsulfonamido)- 
                 sulfonyl chloride 
               
               
                   
                 phenoxy)benzoic acid 
               
               
                 36:3 
                 5-(3-carboxy-4-(4-(trifluoromethoxy)- 
                 4-trifluoro- 
                 53 
                 97 
               
               
                   
                 phenylsulfonamido)phenoxy)-2- 
                 methoxybenzen- 
               
               
                   
                 (phenylsulfonamido)benzoic acid 
                 sulfonyl chloride 
               
               
                 36:4 
                 5-(3-carboxy-4-(4- 
                 4-methoxy- 
                 84 
                 95 
               
               
                   
                 methoxyphenylsulfonamido)phenoxy)- 
                 benzenesulfonyl 
               
               
                   
                 2-(phenylsulfonamido)benzoic acid 
                 chloride 
               
               
                 36:5 
                 2-(4-butoxyphenylsulfonamido)-5-(3- 
                 4-butoxy- 
                 59 
                 96 
               
               
                   
                 (methoxycarbonyl)-4-(phenylsulfon- 
                 benzenesulfonyl 
               
               
                   
                 amido)phenoxy)benzoic acid 
                 chloride 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 37 
               
             
            
               
                   
                   
               
               
                   
                 Yield (%) 
               
            
           
           
               
               
               
               
               
            
               
                 No 
                 Chemical name 
                 Substrate 
                 Ester 
                 Acid 
               
               
                   
               
               
                 37:1 
                 2-(4-Chlorophenylamino)-5-{4-[(4- 
                 4-methoxybenzene-sulfonyl 
                 97 
                 56 
               
               
                   
                 methoxybenzenesulfonyl)methyl- 
                 chloride 
               
               
                   
                 amino]phenoxy}benzoic acid 
               
               
                 37:2 
                 2-(4-Chlorophenylamino)-5-{4-[(2- 
                 2-fluorobenzene- 
                 98 
                 52 
               
               
                   
                 fluorobenzenesulfonyl)methyl- 
                 sulfonyl chloride 
               
               
                   
                 amino]phenoxy}benzoic acid 
               
               
                 37:3 
                 2-(4-Chlorophenylamino)-5-{4-[(2,5- 
                 2,5-dichloro- 
                 97 
                 49 
               
               
                   
                 dichlorobenzenesulfonyl)- 
                 benzenesulfonyl 
               
               
                   
                 methylamino]phenoxy}benzoic acid 
                 chloride 
               
               
                 37:4 
                 2-(4-Chlorophenylamino)-5-{4-[(3- 
                 3-methoxybenzene- 
                 80 
                 45 
               
               
                   
                 methoxybenzenesulfonyl)methyl- 
                 sulfonyl chloride 
               
               
                   
                 amino]phenoxy}benzoic acid 
               
               
                 37:5 
                 2-(4-Chlorophenylamino)-5-{4- 
                 4-trifluoromethoxy- 
                 96 
                 34 
               
               
                   
                 [methyl(4-trifluoromethoxy- 
                 benzenesulfonyl chloride 
               
               
                   
                 benzenesulfonyl)amino]phenoxy}- 
                   
               
               
                   
                 benzoic acid 
               
               
                 37:6 
                 5-{4-[(5-Chloro-2-methoxy- 
                 5-Chloro-2-methoxy- 
                 95 
                 29 
               
               
                   
                 benzenesulfonyl)methylamino]- 
                 benzenesulfonyl 
               
               
                   
                 phenoxy}-2-(4-chloro- 
                 chloride 
               
               
                   
                 phenylamino)benzoic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 38 
               
             
            
               
                   
               
               
                 Spectroscopic data 
               
            
           
           
               
               
            
               
                 Ex. 
                   1 H NMR (DMSO-d 6 , 200 or 400 MHz), δ: 
               
               
                   
               
               
                  1:1 
                 13.6-12.8 (2H, br s) 9.68 (1H, s) 9.3 (1H, br s) 7.73 (1H, d, J = 8.3 Hz) 
               
               
                   
                 7.67 (1H, s) 7.50-7.48 (2H, m) 7.38-7.17 (7H, m) 7.06-7.02 (1H, m) 
               
               
                  1:2 
                 9.4-9.2 (2H, br s) 7.47-7.39 (2H, m) 7.32-7.08 (12H, m) 
               
               
                  1:3 
                 9.4-9.2 (2H, br s) 7.49-7.43 (2H, m) 7.41-7.24 (6H, m) 7.19 (2H, dd, 
               
               
                   
                 J = 9.2 and 2.6 Hz) 7.11-6.98 (2H, m) 
               
               
                  1:4 
                 9.5-9.2 (2H, br s) 7.98 (1H, d, J = 1.8 Hz) 7.57 (1H, d, J = 8.8 Hz) 7.52 (1H, 
               
               
                   
                 d, J = 1.8 Hz) 7.48-7.39 (2H, m) 7.37-7.08 (7H, m) 7.06-6.95 (1H, m) 
               
               
                   
                 6.90 (1H, d, J = 1.8 Hz) 
               
               
                  1:5 
                 8.47-8.37 (1H, m) 7.71-7.47 (4H, m) 7.39 (1H, d, J = 8.8 Hz) 
               
               
                   
                 7.33-7.08 (5H, m) 6.97-6.85 (1H, m) 
               
               
                  1:6 
                 9.6-9.5 (1H, br s) 9.5-9.4 (1H, br s) 8.23-8.09 (2H, m) 7.65-7.46 (3H, m) 
               
               
                   
                 7.42-7.12 (9H, m) 
               
               
                  1:7 
                 9.79-9.12 (2H, br s) 8.01-7.90 (2H, m) 7.53-7.41 (3H, m) 7.31-7.06 (9H, 
               
               
                   
                 m) 2.87-2.71 (1H, m) 1.03-0.89 (4H, m) 
               
               
                  1:8 
                 13.5-13.2 (2H, br s) 9.4-9.3 (1H, br s) 9.3-9.2 (1H, br s) 7.51-7.40 (4H, 
               
               
                   
                 m) 7.39-7.35 (1H, m) 7.34-7.25 (2H, m) 7.2-7.12 (4H, m) 7.09-6.98 (1H, 
               
               
                   
                 m) 
               
               
                  1:9 
                 9.4-9.2 (1H, br s) 7.72-7.58 (2H, m) 7.54-7.94 (11H, m) 4.00 (2H, t, J = 6.5 Hz) 
               
               
                   
                 1.75-1.57 (2H, m) 1.47-1.32 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                  2:1 
                 14.5-13.2 (2H, br s) 11.96 (1H, s) 11.92 (1H, s) 8.64-8.57 (2H, m) 
               
               
                   
                 8.06-8.02 (2H, m) 7.93-7.86 (4H, m) 7.72-7.57 (4H, m) 7.45-7.39 (2H, m) 
               
               
                  2:2 
                 14.4-13.4 (2H, br s) 11.93 (1H, s) 11.75 (1H, d, J = 5.4 Hz) 8.62-8.57 (2H, 
               
               
                   
                 m) 7.94-7.87 (3H, m) 7.75-7.40 (8H, m) 
               
               
                  2:3 
                 14.4-13.5 (2H, br s) 12.08 (1H, s) 11.96 (1H, s) 8.62-8.56 (2H, m) 
               
               
                   
                 8.44-8.39 (2H, m) 8.18-8.14 (2H, m) 7.94-7.87 (2H, m) 7.73-7.57 (4H, m) 
               
               
                   
                 7.46-7.40 (2H, m) 
               
               
                  2:4 
                 14.2-13.4 (2H, br s) 11.95 (1H, s) 11.39 (1H, s) 8.62-8.54 (2H, m) 
               
               
                   
                 8.38-8.31 (2 H, m) 7.95-7.87 (3H, m) 7.74-7.54 (4H, m) 7.48-7.39 (2H, m) 
               
               
                  2:5 
                 14.50-12.99 (2H, br s) 11.94 (1H, s) 11.39 (1H, s) 8.71 (1H, d, J = 9.6 Hz) 
               
               
                   
                 8.48 (1H, d, J = 9.6 Hz) 7.90-7.69 (4H, m) 7.63-7.53 (3H, m) 
               
               
                   
                 7.47-7.34 (4H, m) 2.66 (2H, t, J = 8.0 Hz) 1.67-1.48 (2H, m) 1.41-1.19 (2H, m) 
               
               
                   
                 0.89 (3H, t, J = 7.4 Hz) 
               
               
                  2:6 
                 14.53-13.19 (2H, br s) 11.94 (1H, s) 11.84 (1H, s) 8.72 (1H, d, J = 9.3 Hz) 
               
               
                   
                 8.47 (1H, d, J = 9.3 Hz) 7.96-7.80 (5H, m) 7.63-7.54 (2H, m) 
               
               
                   
                 7.48-7.33 (4H, m) 2.65 (2H, t, J = 7.4 Hz) 1.67-1.47 (2H, m) 1.40-1.19 (2H, m) 
               
               
                   
                 0.88 (3H, t, J = 7.4 Hz) 
               
               
                  2:7 
                 14.73-13.01 (2H, br s) 11.94 (1H, s) 11.84 (1H, s) 8.71 (1H, d, J = 9.3 Hz) 
               
               
                   
                 8.53 (1H, d, J = 9.3 Hz) 8.10 (1H, dd, J = 7.3 and 2.0 Hz) 7.99-7.89 (1H, m) 
               
               
                   
                 7.88-7.81 (2H, m) 7.71-7.54 (3H, m) 7.47-7.33 (4H, m) 2.65 (2H, t, J = 7.3 Hz) 
               
               
                   
                 1.66-1.48 (2H, m) 1.40-1.19 (2H, m) 0.88 (3H, t, J = 7.3 Hz) 
               
               
                  2:8 
                 14.41-13.11 (2H, br s) 11.94 (1H, s) 11.39 (1H, s) 8.71 (1H, d, J = 9.3 Hz) 
               
               
                   
                 8.51 (1H, d, J = 9.3 Hz) 7.90-7.73 (3H, m) 7.67-7.52 (3H, m) 
               
               
                   
                 7.47-7.32 (5H, m) 2.65 (2H, t, J = 7.7 Hz) 1.66-1.48 (2H, m) 1.40-1.20 (2H, m) 
               
               
                   
                 0.89 (3H, t, J = 7.1 Hz) 
               
               
                  2:9 
                 11.99 (1H, s) 11.93 (1H, s) 8.61-8.56 (2H, m) 8.09-8.06 (4H, m) 
               
               
                   
                 7.94-7.86 (2H, m) 7.70-7.57 (4H, m) 7.46-7.40 (2H, m) 
               
               
                  3:1 
                 14.2-13.7 (1H, br s) 12.23 (1H, s) 8.80 (1H, d, J = 9.1 Hz) 8.09 (1H, J = 8.8 Hz) 
               
               
                   
                 7.98 (2H, d, J = 7.2 Hz) 7.80-7.77 (1H, m) 7.67-7.55 (4H, m) 
               
               
                   
                 7.30-7.23 (2H, m) 
               
               
                  3:2 
                 14.79-13.02 (2H, br s) 12.34 (1H, s) 8.73 (1H, d, J = 8.9 Hz) 
               
               
                   
                 8.22-7.93 (5H, m) 7.79 (1H, d, J = 2.9 Hz) 7.58 (1H, dd, J = 8.9 and 2.9 Hz) 
               
               
                   
                 7.31-7.20 (2H, m) 
               
               
                  4:1 
                 12.1 (2H, s) 8.73 (2H, d, J = 9.1 Hz) 7.87 (4H, d, J = 8.2 Hz) 7.62 (2H, d, 
               
               
                   
                 J = 3.0 Hz) 7.45-7.38 (6H, m) 2.67 (4H, t, J = 7.6 Hz) 1.64-1.54 (4H, m) 
               
               
                   
                 1.37-1.28 (4H, m) 0.91 (6H, t, J = 7.3 Hz) 
               
               
                  4:2 
                 12.2 (2H, s) 8.72 (2H, d, J = 9.1 Hz) 7.97 (4H, d, J = 7.1 Hz) 7.67-7.56 (8H, 
               
               
                   
                 m) 7.45-7.37 (2H, m) 
               
               
                  4:3 
                 12.1 (2H, s) 8.61 (2H, d, J = 9.1 Hz) 8.43 (4H, d, J = 8.8 Hz) 8.18 (4H, d, 
               
               
                   
                 J = 8.8 Hz) 7.63 (2H, d, J = 3.0 Hz) 7.45 (2H dd, J = 9.1 and 3.0 Hz) 
               
               
                  4:4 
                 12.0 (2H, s) 8.68 (2H, d, J = 9.1 Hz) 8.01-8.05 (2H, m) 7.97 (2H, d, J = 7.8 Hz) 
               
               
                   
                 7.81-7.78 (2H, m) 7.73-7.65 (4H, m) 7.51 (2H, dd, J = 9.11 and 3.0 Hz) 
               
               
                  5:1 
                 12.6-12.4 (2H, m) 8.73 (2H, dd, J = 3.2 and 9.0 Hz) 7.98 (2H, d, J = 7.1 Hz) 
               
               
                   
                 7.88 (2H, d, J = 8.0 Hz) 7.65-7.54 (5H, m) 7.43-7.35 (4H, m) 2.67 (2H, t, 
               
               
                   
                 J = 7.5 Hz) 1.63-1.55 (2H, m) 1.37-1.28 (2H, m) 0.91 (3H, t, J = 7.3 Hz) 
               
               
                  5:2 
                 12.9 (1H, br s) 12.4 (1H, br s) 8.72 (1H, d, J = 9.1 Hz) 8.62 (1H, d, J = 9.1 Hz) 
               
               
                   
                 8.42 (2H, d, J = 8.7 Hz) 8.20 (2H, d, J = 8.9 Hz) 8.00-7.95 (2H, m) 
               
               
                   
                 7.67-7.55 (5H, m) 7.44-7.35 (2H, m) 
               
               
                  5:3 
                 14.0 (1H, br s) 12.02-11.95 (2H, m) 8.72 (1H, d, J = 9.1 Hz) 8.61 (1H, d, 
               
               
                   
                 J = 9.1 Hz) 7.99-7.89 (4H, m) 7.75-7.71 (1H, m) 7.68-7.57 (6H, m), 
               
               
                   
                 7.48-7.41 (2H, m) 
               
               
                  6:1 
                 12.6-12.2 (2H, br s) 11.99 (1H, s) 10.09 (1H, s) 8.73 (1H, d, J = 9.2 Hz) 
               
               
                   
                 7.93-7.82 (2H, m) 7.79-7.74 (1H, m) 7.65-7.57 (3H, m) 7.50-7.37 (4H, m) 
               
               
                   
                 7.07-6.96 (2H, m) 3.69 (2H, s) 2.68 (2H, t, J = 7.5 Hz) 1.69-1.52 (2H, m) 
               
               
                   
                 1.43-1.23 (2H, m) 0.91 (3H, d, J = 7.3 Hz) 
               
               
                  6:2 
                 12.6-12.3 (2H, br s) 12.1-12.0 (1H, br s) 11.8-12.0 (1H, br s) 
               
               
                   
                 10.4-10.2 (1H, br s) 8.64 (1H, d, J = 9.1 Hz) 8.17-8.06 (1H, m) 8.02-7.91 (2H, m) 
               
               
                   
                 7.85-7.76 (1H, m) 7.67 (1H, d, J = 8.5 Hz) 7.60 (1H, d, J = 2.9 Hz) 
               
               
                   
                 7.52-7.39 (2H, m) 7.13-6.98 (3H, m) 3.66 (2H, s) 
               
               
                  6:3 
                 12.7-12.2 (2H, br s) 12.2-11.8 (2H, br s) 10.3-10.2 (1H, br s) 8.72 (1H, d, 
               
               
                   
                 J = 9.1 Hz) 7.98 (1H, d, J = 2.6 Hz) 7.94-7.85 (2H, m) 7.67 (1H, d, J = 8.7 Hz) 
               
               
                   
                 7.61 (1H, d, J = 2.9 Hz) 7.48 (1H, dd, J = 8.7 and 2.6 Hz) 7.41 (1H, dd, 
               
               
                   
                 J = 9.1, 2.9 Hz) 7.14-6.97 (5H, m) 4.75 (1H, septet, J = 6.0 Hz) 3.66 (2H, s) 
               
               
                   
                 1.31 (6H, d, J = 6.0 Hz) 
               
               
                  6:4 
                 11.90 (1H, d, J = 2.9 Hz) 10.08 (1H, s) 8.67 (1H, d, J = 8.3 Hz) 8.10 (1H, 
               
               
                   
                 m) 7.99-7.74 (4H, m) 7.69-7.49 (3H, m) 7.46-7.36 (2H, m) 7.08-6.95 (2H, 
               
               
                   
                 m) 3.63 (2H, s) 
               
               
                  6:5 
                 11.90 (1H, d, J = 3.6 Hz) 10.03 (1H, s) 8.64 (1H, d, J = 8.3 Hz) 
               
               
                   
                 8.18-8.07 (1H, m) 8.02-7.69 (4H, m) 7.64-7.57 (1H, m) 7.54-7.38 (2H, m) 
               
               
                   
                 7.11-6.96 (2H, m) 3.66 (2H, s) 
               
               
                  6:6 
                 11.98 (1H, s) 10.09 (1H, s) 8.73 (1H, d, J = 8.3 Hz) 7.95-7.85 (2H, m) 
               
               
                   
                 7.76 (1H, d, J = 1.5 Hz) 7.66-7.55 (3H, m) 7.46-7.35 (2H, m) 7.17-6.93 (4H, m) 
               
               
                   
                 4.75 (1H, septet, J = 5.9 Hz) 3.67 (2H, s) 1.30 (6H, d, J = 5.9 Hz) 
               
               
                  6:7 
                 12.1-11.9 (1H, br s) 10.10 (1H, s) 8.73 (1H, d, J = 9.1 Hz) 8.10 (1H, d, 
               
               
                   
                 J = 2.0 Hz) 7.94-7.84 (3H, m) 7.63 (1H, d, J = 2.9 Hz) 7.49 (1H, d, J = 8.4 Hz) 
               
               
                   
                 7.42 (1H, dd, J = 9.1 and 2.9 Hz) 7.15-6.97 (4H, m) 4.75 (1H, septet, 
               
               
                   
                 J = 6.0 Hz) 4.19 (2H, q, 7.0 Hz) 3.68 (2H, s) 1.35 (3H, t, 7.0 Hz) 1.31 (6H, 
               
               
                   
                 d, J = 6.0 Hz) 
               
               
                  7:1 
                 13.97 (br s, 1H) 11.94 (s, 1H) 10.06 (s, 1H) 8.70 (d, J = 9.1 Hz, 1H), 
               
               
                   
                 7.90-7.83 (m, 2H) 7.75-7.63 (m, 3H) 7.60-7.51 (3H, m) 7.49-7.28 (m, 6H) 
               
               
                   
                 3.71 (s, 3H) 2.71-2.61 (m, 2H) 1.65-1.52 (m, 2H) 1.40-1.25 (m, 2H) 0.91 (t, 
               
               
                   
                 J = 7.3 Hz, 3H) 
               
               
                  7:2 
                 11.91 (1H, s), 8.69 (1H, d, J = 9.1 Hz), 7.89-7.83 (2H, m), 7.78-7.73 (2H, 
               
               
                   
                 m), 7.68-7.61 (1H, m), 7.59-7.50 (4H, m), 7.43-7.32 (4H, m), 
               
               
                   
                 7.30-7.24 (1H, m), 2.71-2.63 (2H, m), 1.65-1.52 (2H, m), 1.39-1.25 (2H, m), 
               
               
                   
                 0.91 (3H, t, J = 7.3 Hz) 
               
               
                  8:1 
                 14.22-13.94 (1H, br s) 10.18 (1H, s) 8.57 (1H, d, J = 9.0 Hz) 
               
               
                   
                 7.93-7.46 (11H, m) 7.13 (1H, dd, J = 9.0 and 2.9 Hz) 6.99 (2H, m) 1.30 (9H, s) 
               
               
                  8:2 
                 11.87 (1H, s) 8.90 (1H, d, J = 8.9 Hz) 8.63-8.54 (2H, m) 8.16-8.00 (3H, m) 
               
               
                   
                 7.98-7.82 (2H, m) 7.56-7.45 (2H, m) 
               
               
                  8:3 
                 14.60-12.96 (1H, br s) 12.01 (1H, s) 11.87 (1H, s) 10.46 (1H, s) 
               
               
                   
                 8.62 (1H, d, J = 9.0 Hz) 8.20-7.93 (5H, m) 7.80-7.69 (2H, m) 7.57 (1H, d, J = 3.3 Hz) 
               
               
                   
                 7.52-7.37 (2H, m) 7.17-6.70 (3H, m) 
               
               
                  8:4 
                 14.60-13.00 (1H, br s) 12.01 (1H, s) 10.23 (1H, s) 8.61 (1H, d, J = 9.0 Hz) 
               
               
                   
                 8.19-8.10 (2H, m) 8.03-7.77 (6H, m) 7.55 (1H, d, J = 3.0 Hz) 
               
               
                   
                 7.44-7.31 (3H, m) 7.14-7.04 (2H, m) 2.66 (2H, t, J = 7.5 Hz) 1.67-1.49 (2H, m) 
               
               
                   
                 1.41-1.19 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                  8:5 
                 12.01 (1H, s) 10.67 (1H, s) 8.61 (1H, d, J = 9.0 Hz) 8.23-8.10 (3H, m) 
               
               
                   
                 8.03-7.94 (2H, m) 7.89 (1H, d, J = 7.9 Hz) 7.82-7.73 (2H, m) 7.56 (1H, d, 
               
               
                   
                 J = 2.9 Hz) 7.41 (1H, dd, J = 9.0 and 2.9 Hz) 7.17-7.08 (2H, m) 2.65 (3H, s) 
               
               
                  8:6 
                 16.0-15.9 (1H, br s) 9.90 (1H, s) 8.68 (1H, d, J = 8.8 Hz) 8.28-8.11 (2H, 
               
               
                   
                 m) 8.04-7.69 (6H, m) 7.66-7.55 (1H, m) 7.15-6.90 (3H, m) 6.85-6.69 (2H, 
               
               
                   
                 m) 3.00 (6H, s) 
               
               
                  8:7 
                 14.3-13.4 (1H, br s) 11.95 (1H, s) 10.22 (1H, s) 8.56 (1H, d, J = 8.8 Hz) 
               
               
                   
                 8.13-8.09 (2H, m) 7.97-7.93 (2H, m) 7.63-7.58 (2H, m) 7.50-7.49 (1H, m) 
               
               
                   
                 7.39-7.31 (5H, m) 7.03-6.99 (2H, m) 3.62 (2H, s) 
               
               
                  8:8 
                 14.1-13.6 (1H, br s) 11.93 (1H, s) 10.28 (1H, s) 8.68 (1H, d, J = 9.2 Hz) 
               
               
                   
                 8.00-7.74 (6H, m) 7.64-7.46 (4H, m) 7.45-7.31 (3H, m) 7.13-7.00 (2H, m) 
               
               
                   
                 2.65 (2H, t, J = 7.6 Hz) 1.67-1.48 (2H, m) 1.40-1.19 (2H, m) 0.89 (3H, t, 
               
               
                   
                 J = 7.2 Hz) 
               
               
                  8:9 
                 14.0-13.6 (1H, br s) 11.97 (1H, s) 10.23 (1H, s) 8.71 (1H, d, J = 9.2 Hz) 
               
               
                   
                 7.92-7.74 (4H, m) 7.56 (1H, d, J = 3.0 Hz) 7.47-7.35 (3H, m) 
               
               
                   
                 7.13-7.05 (2H, m) 7.11 (2H, d, J = 2.2 Hz) 6.72 (1H, t, J = 2.2 Hz) 3.83 (6H, s) 
               
               
                   
                 2.68 (2H, t, J = 7.5 Hz) 1.69-1.50 (2H, m) 1.42-1.21 (2H, m) 0.91 (3H, t, J = 7.2 Hz) 
               
               
                  8:10 
                 12.00 (1H, s) 10.31 (1H, s) 8.61 (1H, d, J = 9.1 Hz) 8.14-8.02 (2H, m) 
               
               
                   
                 8.01-7.91 (2H, m) 7.88-7.77 (2H, m) 7.67-7.47 (6H, m) 7.39 (1H, dd, 
               
               
                   
                 J = 9.1 and 3.0 Hz) 7.17-7.03 (2H, m) 
               
               
                  8:11 
                 11.88 (1H, s) 10.28 (1H, s) 8.08 (1H, d, J = 9.1 Hz) 8.00-7.73 (6H, m) 
               
               
                   
                 7.62-7.44 (4H, m) 7.36 (1H, dd, J = 9.1 and 2.5 Hz) 7.16-6.98 (4H, m) 
               
               
                   
                 4.11 (2H, q, J = 6.8 Hz), 1.35 (3H, t, J = 6.9 Hz) 
               
               
                  8:12 
                 14.2-13.5 (1H, br s) 11.95 (1H, s) 10.20 (1H, s) 8.67 (1H, d, J = 9.2 Hz) 
               
               
                   
                 8.00-7.73 (6H, m) 7.69-7.49 (4H, m) 7.42-7.28 (3H, m) 7.12-6.99 (2H, m) 
               
               
                   
                 2.71-2.57 (2H, m) 1.67-1.47 (2H, m) 1.40-1.18 (2H, m) 0.88 (3H, t, J = 7.3 Hz) 
               
               
                  8:13 
                 11.94 (1H, s) 10.11 (1H, s) 8.67 (1H, d, J = 9.3 Hz) 7.96-7.89 (4H, m) 
               
               
                   
                 7.81-7.76 (2H, m) 7.64-7.53 (4H, m) 7.37 (1H, dd, J = 9.3 and 2.9 Hz) 
               
               
                   
                 7.07-6.99 (4H, m) 4.72 (1H, septet, J = 5.9 Hz) 1.28 (6H, d, J = 5.9 Hz) 
               
               
                  8:14 
                 (DMSO-d 6  + CF 3 COOH) 11.26 (1H, s) 11.12 (1H, s) 8.30 (1H, d, J = 8.8 Hz) 
               
               
                   
                 8.23 (1H, d, J = 7.8 Hz) 7.96-7.86 (3H, m) 7.84-7.74 (2H, m) 7.46 (1H, 
               
               
                   
                 d, J = 2.9 Hz) 7.35 (1H, dd, J = 8.8 Hz, J = 2.9 Hz) 7.11-6.97 (4H, m) 
               
               
                   
                 4.72 (1H, septet, J = 5.9 Hz) 2.68 (3H, s) 1.28 (6H, d, J = 5.9 Hz) 
               
               
                  8:15 
                 12.10-11.85 (1H, br s) 8.52-8.48 (1H, m) 8.14-8.09 (2H, m) 
               
               
                   
                 7.98-7.93 (2H, m) 7.53 (1H, dd, J = 7.8 and 1.7 Hz) 7.41 (1H, d, J = 2.9 Hz) 
               
               
                   
                 7.40-7.31 (2H, m) 7.24 (1H, dd, J = 8.9 and 2.9 Hz) 6.88-6.83 (2H, m) 
               
               
                   
                 6.60-6.55 (2H, m) 6.43-6.28 (1H, br s) 4.35 (2H, s) 
               
               
                  9:1 
                 14.1-13.8 (1H, br s) 11.97 (1H, s) 8.69 (1H, d, J = 9.2 Hz) 7.91-7.81 (2H, 
               
               
                   
                 m) 7.52 (1H, d, J = 2.9 Hz) 7.46-7.36 (2H, m) 7.32 (1H, dd, J = 8.9 and 3.1 Hz) 
               
               
                   
                 7.24-7.12 (4H, m) 7.10-7.01 (2H, m) 6.99-6.88 (2H, m) 3.36 (3H, s) 
               
               
                   
                 2.67 (2H, t, J = 7.4 Hz) 2.59-2.50 (2H, m) 1.68-1.11 (8H, m) 0.91 (3H, t, 
               
               
                   
                 J = 7.4 Hz) 0.84 (3H, t, J = 7.1 Hz) 
               
               
                  9:2 
                 14.2-13.8 (1H, br s) 11.93 (1H, s) 8.68 (1H, d, J = 9.1 Hz) 7.98-7.86 (2H, 
               
               
                   
                 m) 7.55 (1H, d, J = 2.9 Hz) 7.34-7.04 (9H, m) 7.00-6.89 (2H, m) 3.85 (3H, 
               
               
                   
                 s) 3.36 (3H, s) 1.22 (9H, s) 
               
               
                  9:3 
                 11.46 (1H, s) 8.45 (1H, d, J = 8.9 Hz) 7.81 (1H, d, J = 1.9 Hz) 7.73 (1H, d, 
               
               
                   
                 J = 8.4 Hz) 7.60 (1H, dd, J = 8.4 and 1.9 Hz) 7.51 (1H, d, J = 3.1 Hz) 
               
               
                   
                 7.33-7.16 (7H, m) 7.00-6.92 (2H, m) 3.36 (3H, s) 1.22 (9H, s) 
               
               
                  9:4 
                 14.2-13.8 (1H, br s) 11.99 (1H, s) 8.68 (1H, d, J = 9.1 Hz) 7.94-7.84 (2H, 
               
               
                   
                 m) 7.73-7.59 (2H, m) 7.58-7.43 (3H, m) 7.36-7.19 (3H, m) 7.15-7.04 (2H, 
               
               
                   
                 m) 7.00-6.88 (2H, m) 4.75 (1H, septet, J = 6.1 Hz) 3.39 (3H, s) 1.30 (6H, 
               
               
                   
                 d, J = 6.1 Hz) 
               
               
                  9:5 
                 14.2-13.7 (1H, br s) 12.7-12.1 (1H, br s) 8.49 (1H, d, J = 9.1 Hz) 7.79 (1H, 
               
               
                   
                 d, J = 2.0 Hz) 7.74-7.43 (7H, m) 7.29-7.18 (3H, m) 6.93 (2H, d, J = 8.8 Hz) 
               
               
                   
                 3.39 (3H, s) 
               
               
                 10:1 
                 11.54 (1H, s) 10.22 (1H, s) 8.49 (1H, d, J = 8.8 Hz) 7.85-7.80 (2H, m) 
               
               
                   
                 7.70-7.50 (4H, m) 7.45-7.23 (6H, m) 6.79 (1H, dd, J = 7.8 and 2.0 Hz) 
               
               
                   
                 2.63 (2H, t, J = 7.5 Hz) 1.63-1.48 (2H, m) 1.34-1.23 (2H, m) 0.88 (3H, t, 
               
               
                   
                 J = 7.3 Hz) 
               
               
                 10:2 
                 11.95 (1H, s) 10.21 (1H, s) 8.62 (1H, d, J = 8.8 Hz) 8.08-8.04 (2H, m) 
               
               
                   
                 7.84-7.80 (2H, m) 7.60-7.53 (5H, m) 7.45-7.28 (4H, m) 6.78 (1H, dd, 
               
               
                   
                 J = 7.8 and 2.0 Hz) 2.62 (2H, t, J = 7.8 Hz) 1.59-1.52 (2H, m) 
               
               
                   
                 1.33-1.22 (2H, m) 0.87 (3H, t, J = 7.3 Hz) 
               
               
                 10:3 
                 13.8-13.6 (1H, br s) 12.16 (1H, s) 10.22 (1H, s) 8.84 (1H, d, J = 8.8 Hz) 
               
               
                   
                 7.99 (1H, dd, J = 7.8 and 2.0 Hz) 7.84-7.80 (2H, m) 7.61-7.50 (4H, m) 
               
               
                   
                 7.42-7.29 (4H, m) 7.24-7.20 (1H, m) 7.14-7.06 (1H, m) 6.78 (1H, dd, 
               
               
                   
                 J = 7.8 and 2.0 Hz) 3.99 (3H, s) 2.62 (2H, t, J = 7.8 Hz) 1.62-1.48 (2H, m) 
               
               
                   
                 1.33-1.19 (2H, m) 0.87 (3H, t, J = 7.3 Hz) 
               
               
                 10:4 
                 12.2-11.9 (1H, br s) 10.24 (1H, s) 8.64 (1H, d, J = 8.9 Hz) 8.18-8.05 (1H, 
               
               
                   
                 m) 8.00-7.75 (4H, m) 7.66-7.52 (3H, m) 7.48-7.28 (4H, m) 6.80 (1H, dd, 
               
               
                   
                 J = 8.1 and 2.1 Hz) 2.65 (2H, t, J = 7.6 Hz) 1.66-1.49 (2H, m) 
               
               
                   
                 1.40-1.20 (2H, m) 0.89 (3H, t, J = 7.1 Hz) 
               
               
                 10:5 
                 12.1-11.9 (1H, br s) 10.55 (1H, s) 8.65 (1H, d, J = 9.1 Hz) 8.30-8.20 (2H, 
               
               
                   
                 m) 8.17-8.06 (1H, m) 8.03-7.90 (2H, m) 7.85-7.72 (2H, m) 7.69-7.36 (5H, 
               
               
                   
                 m) 6.86 (1H, dd, J = 8.0 and 2.2 Hz) 
               
               
                 10:6 
                 14.2-13.7 (1H, br s) 12.2-11.9 (1H, br s) 10.54 (1H, s) 8.64 (1H, d, J = 9.1 Hz) 
               
               
                   
                 8.17-8.05 (3H, m) 8.00-7.75 (4H, m) 7.66-7.58 (2H, m) 
               
               
                   
                 7.56-7.50 (1H, m) 7.48-7.35 (2H, m) 6.89-6.81 (1H, m) 
               
               
                 11:1 
                 12.04 (1H, s) 10.14 (1H, s) 8.57 (1H, d, J = 9.2 Hz) 8.18-8.09 (2H, m) 
               
               
                   
                 8.02-7.93 (2H, m) 7.66-7.57 (2H, m) 7.47 (1H, d, J = 2.8 Hz) 
               
               
                   
                 7.40-7.27 (3H, m) 7.13-7.04 (2H, m) 6.99-6.90 (2H, m) 2.61 (2H, t, J = 7.5 Hz) 
               
               
                   
                 1.62-1.44 (2H, m) 1.35-1.16 (2H, m) 0.86 (3H, t, J = 7.2 Hz) 
               
               
                 11:2 
                 10.71 (1H, s) 8.62 (1H, d, J = 9.0 Hz) 8.19-8.10 (4H, m) 7.93-7.87 (3H, m) 
               
               
                   
                 7.54 (1H, d, J = 3.0 Hz) 7.11-7.06 (2H, m) 7.03 (1H, dd, J = 9.0 and 3.0 Hz) 
               
               
                   
                 6.91-6.86 (2H, m) 
               
               
                 11:3 
                 12.1-12.0 (1H, br s) 8.63 (1H, d, J = 9.2 Hz) 8.20-8.11 (2H, m) 
               
               
                   
                 8.03-7.95 (2H, m) 7.57 (1H, d, J = 3.0 Hz) 7.48-7.39 (3H, m) 7.16-6.97 (6H, m) 
               
               
                   
                 3.84 (3H, s) 3.09 (3H, s) 
               
               
                 11:4 
                 14.1-13.6 (1H, br s) 11.45-11.35 (1H, br s) 8.50 (1H, d, J = 9.2 Hz) 
               
               
                   
                 7.82 (1H, d, J = 1.8 Hz) 7.74 (1H, d, J = 8.2 Hz) 7.61 (1H, dd, J = 8.2 and 1.8 Hz) 
               
               
                   
                 7.52 (1H, d, J = 3.0 Hz) 7.48-7.38 (3H, m) 7.16-6.96 (6H, m) 3.84 (3H, s) 
               
               
                   
                 3.09 (3H, s) 
               
               
                 11:5 
                 8.73 (1H, d, J = 9.1 Hz) 7.92-7.81 (2H, m) 7.58 (1H, d, J = 2.9 Hz) 
               
               
                   
                 7.52-7.29 (7H, m) 7.15-6.91 (4H, m) 3.10 (3H, s) 2.74-2.60 (2H, m) 2.40 (3H, 
               
               
                   
                 s) 1.64-1.47 (2H, m) 1.37-1.21 (2H, m) 0.87 (3H, t, J = 7.2 Hz) 
               
               
                 11:6 
                 14.4-13.7 (1H, br s) 12.0-11.9 (1H, br s) 8.73 (1H, d, J = 9.2 Hz) 
               
               
                   
                 7.97-7.83 (2H, m) 7.58 (1H, d, J = 2.9 Hz) 7.50-7.34 (5H, m) 7.19-6.93 (6H, m) 
               
               
                   
                 4.75 (1H, septet, J = 6.1 Hz) 3.10 (3H, s) 2.66 (2H, t, J = 7.2 Hz) 1.67-1.47 (2H, 
               
               
                   
                 m) 1.36-1.20 (2H, m) 1.31 (6H, d, J = 6.1 Hz) 0.88 (3H, t, J = 7.1 Hz) 
               
               
                 11:7 
                 11.5-11.4 (1H, br s) 8.50 (1H, d, J = 9.2 Hz) 7.82 (1H, d, J = 1.8 Hz) 
               
               
                   
                 7.74 (1H, d, J = 8.1 Hz) 7.61 (1H, dd, J = 8.1 and 1.8 Hz) 7.53 (1H, d, J = 2.9 Hz) 
               
               
                   
                 7.48-7.35 (5H, m) 7.16-6.94 (4H, m) 3.10 (3H, s) 2.72-2.61 (2H, m) 
               
               
                   
                 1.64-1.47 (2H, m) 1.38-1.20 (2H, m) 0.82 (3H, t, J = 7.3 Hz) 
               
               
                 11:8 
                 12.05 (1H, s) 10.48 (1H, s) 8.68 (1H, d, J = 9.2 Hz) 8.20-8.06 (2H, m) 
               
               
                   
                 8.04-7.92 (2H, m) 7.92-7.80 (2H, m) 7.52 (1H, d, J = 3.0 Hz) 
               
               
                   
                 7.46-7.35 (2H, m) 7.33 (1H, dd, J = 9.3 and 3.0 Hz) 7.18-7.04 (2H, m) 
               
               
                   
                 7.03-6.93 (2H, m) 3.29 (3H, s) 2.67 (2H, t, J = 7.6 Hz) 1.68-1.50 (2H, m) 
               
               
                   
                 1.42-1.21 (2H, m) 0.90 (3H, t, J = 7.2 Hz) 
               
               
                 11:9 
                 10.2-9.9 (1H, br s) 7.71-7.55 (2H, m) 7.54-6.97 (12H, m) 6.95-6.81 (2H, 
               
               
                   
                 m) 4.00 (2H, t, J = 6.5 Hz) 3.25; 3.15 (3H, s) 1.75-1.60 (2H, m) 
               
               
                   
                 1.50-1.32 (2H, m) 0.98-0.84 (3H, m) 
               
               
                  11:10 
                 10.2-10.0 (1H, br s) 7.80-7.27 (5H, m) 7.26-6.80 (9H, m) 4.00 (2H, t, 
               
               
                   
                 J = 6.5 Hz) 3.26; 3.04 (3H, s) 1.78-1.59 (2H, m) 1.51-1.31 (2H, m) 
               
               
                   
                 0.99-0.84 (3H, m) 
               
               
                  11:11 
                 10.7-10.4 (1H, br s) 7.66 (1H, d, J = 7.2 Hz) 7.51-7.32 (2H, m) 
               
               
                   
                 7.29-6.96 (7H, m) 6.94-6.81 (2H, m) 6.77-6.59 (2H, m) 4.55 (1H, septet, J = 6.1 Hz) 
               
               
                   
                 3.22 (3H, s) 2.44 (3H, d, J = 2.4 Hz) 1.19 (6H, d, J = 6.1 Hz) 
               
               
                  11:12 
                 13.1-12.9 (1H, br s) 8.5-8.1 (1H, br s) 7.62-7.52 (1H, m) 7.49-7.28 (5H, 
               
               
                   
                 m) 7.20-6.96 (5H, m) 6.89-6.77 (2H, m) 6.61 (1H, d, J = 9.2 Hz) 4.60 (2H, 
               
               
                   
                 s) 3.83 (3H, s) 3.05 (3H, s) 
               
               
                 12:1 
                 9.4-9.1 (1H, br s) 8.03 (1H, s) 7.43 (1H, d, J = 2.8 Hz) 7.40-7.22 (3H, m) 
               
               
                   
                 7.19 (1H, dd, J = 9.0 and 2.8 Hz) 7.11-6.98 (7H, m) 6.96-6.88 (2H, m) 
               
               
                 12:2 
                 12.8-12.5 (1H, br s) 8.87 (1H, d, J = 9.1 Hz) 8.08 (1H, s) 7.91-7.84 (2H, 
               
               
                   
                 m) 7.54 (1H, d, J = 2.8 Hz) 7.43-7.33 (2H, m) 7.27 (1H, dd, J = 9.1 and 2.8 Hz) 
               
               
                   
                 7.14-6.91 (8H, m) 2.66 (2H, t, J = 7.7 Hz) 1.67-1.48 (2H, m) 
               
               
                   
                 1.41-1.25 (2H, m) 0.90 (3H, t, J = 7.2 Hz) 
               
               
                 12:3 
                 14.2-14.0 (1H, br s) 8.74 (1H, d, J = 9.1 Hz) 7.97-7.86 (2H, m) 
               
               
                   
                 7.71-7.64 (1H, m) 7.41-7.05 (13H, m) 6.99-6.86 (2H, m) 2.64 (2H, t, J = 7.7 Hz) 
               
               
                   
                 2.52 (2H, t, overlapped with DMSO) 1.99-1.38 (4H, m) 1.38-1.11 (4H, m) 
               
               
                   
                 0.88 (3H, t, J = 7.4 Hz) 0.85 (3H, t, J = 7.5 Hz) 
               
               
                 12:4 
                 10.95-9.83 (1H, br s) 8.03-7.91 (6H, m) 7.63 (1H, d, J = 3.0 Hz) 7.51 (1H, 
               
               
                   
                 d, J = 9.0 Hz) 7.28-6.98 (11H, m) 2.89-2.70 (3H, m) 1.03-0.88 (12H, m) 
               
               
                 12:5 
                 9.50-9.20 (1H, br s) 8.19 (1H, s) 7.43 (1H, d, J = 3.0 Hz) 7.35-7.31 (2H, 
               
               
                   
                 m) 7.27 (1H, d, J = 9.3 Hz) 7.22-7.18 (4H, m) 7.15 (1H, dd, J = 9.3 and 3.0 Hz) 
               
               
                   
                 7.09-7.05 (2H, m) 6.99-6.90 (4H, m) 
               
               
                 13:1 
                 12.5-12.3 (2H, br s) 8.71 (2H, d, J = 8.8 Hz) 7.97 (2H, d, J = 2.4 Hz) 
               
               
                   
                 7.89-7.81 (4H, m) 7.62 (2H, dd, J = 8.8 and 2.4 Hz) 7.43-7.34 (4H, m) 
               
               
                   
                 2.65 (4H, t, J = 7.7 Hz) 1.65-1.48 (4H, m) 1.39-1.19 (4H, m) 0.88 (6H, t, J = 7.3 Hz) 
               
               
                 13:2 
                 12.2-12.1 (2H, br s) 8.64 (2H, d J = 8.5 Hz) 8.02-7.85 (6H, m) 
               
               
                   
                 7.78-7.57 (6H, m) 
               
               
                 13:3 
                 12.22 (2H, s) 8.67 (2H, d, J = 8.8 Hz) 8.19-8.10 (4H, m) 8.03-7.94 (6H, 
               
               
                   
                 m) 7.70 (2H dd J = 8.8 and 2.3 Hz) 
               
               
                 14:1 
                 13.7-12.9 (1H, br s) 9.67-9 57 (1H, br s) 8.46 (1H, s) 7.84 (1H, d, J = 2.3 Hz) 
               
               
                   
                 7.42-7.32 (3H, m) 7.29-7.15 (7H, m) 7.09-6.98 (4H, m) 
               
               
                 14:2 
                 13.6-12.9 (1H, br s) 9.65-9.54 (1H, br s) 8.48 (1H, s) 7.86 (1H, d, J = 2.3 Hz) 
               
               
                   
                 7.45-7.29 (3H, m) 7.28-7.14 (4H, m) 7.13-6.96 (4H, m) 
               
               
                   
                 6.89-6.79 (1H, m) 
               
               
                 14:3 
                 10.31 (1H, s) 7.75 (1H, d, J = 2.3 Hz) 7.70-7.59 (4H, m) 7.40-7.26 (5H, m) 
               
               
                   
                 7.21 (1H, dd, J = 8.6 2.3 Hz) 7.10-6.96 (4H, m) 2.65-2.53 (4H, overlap 
               
               
                   
                 with DMSO) 1.60-1.42 (4H, m) 1.35-1.15 (4H, m) 0.86 (6H, t, J = 7.2 Hz) 
               
               
                 14:4 
                 10.41 (1H, s) 7.80-7.7 (5H, m) 7.67-7.50 (4H, m) 7.30 (1H, d, J = 8.4 Hz) 
               
               
                   
                 7.22 (1H, dd, J = 8.4 2.2 Hz) 7.12-6.96 (4H, m) 
               
               
                 14:5 
                 12.1-11.5 (1H, br s) 9.78 (1H, s) 9.27 (1H, s) 9.25 (1H, s) 8.25 (1H, d, 
               
               
                   
                 J = 8.8 Hz) 7.92 (1H, d, J = 2.4 Hz) 7.56-7.42 (6H, m) 7.39-7.20 (7H, m) 
               
               
                 14:6 
                 12.1-11.8 (1H br s) 10.08 (1H, s) 9.70 (1H, s) 9.56 (1H, s) 8.25 (1H, d, 
               
               
                   
                 J = 8.6 Hz) 7.96 (1H, d, J = 2.4 Hz) 7.79-7.46 (10H, m) 7.37 (1H, dd, J = 8.7 
               
               
                   
                 2.3 Hz) 7.32-7.22 (2H, m) 
               
               
                 15:1 
                 12.4-12.2 (2H, br s) 8.81 (2H, d, J = 8.8 Hz) 8.32 (2H, d, J = 2.2 Hz) 
               
               
                   
                 7.93 (2H, dd, J = 8.8 and 2.2 Hz) 7.84-7.81 (4H, m) 7.39-7.34 (4H, m) 
               
               
                   
                 2.63 (4H, t, J = 7.7 Hz) 1.58-1.52 (4H, m) 1.31-1.24 (4H, m) 0.87 (6H, t, J = 7.3 Hz) 
               
               
                 15:2 
                 12.36 (2H, s) 8.76 (2H, d, J = 8.8 Hz) 8.35 (2H, d, J = 2.3 Hz) 
               
               
                   
                 8.04-7.86 (6H, m) 7.76-7.55 (4H, m) 
               
               
                 15:3 
                 12.35 (2H, s) 8.79 (2H, d, J = 8.8 Hz) 8.37 (2H, d, J = 2.2 Hz) 
               
               
                   
                 8.18-8.09 (4H, m) 8.06-7.94 (6H, m) 
               
               
                 16:1 
                 12.5-12.4 (2H, br s) 8.85 (2H, d, J = 8.5 Hz) 8.51 (2H, d, J = 2.5 Hz) 
               
               
                   
                 8.23 (2H, dd, J = 8.8 and 2.2 Hz) 7.99-7.86 (4H, m) 7.80-7.59 (4H, m) 
               
               
                 16:2 
                 12.6-12.5 (2H, br s) 8.87 (2H, d, J = 9.0 Hz) 8.53 (2H, d, J = 2.3 Hz) 
               
               
                   
                 8.27 (2H, dd, J = 9.0 and 2.3 Hz) 8.16-8.12 (4H, m) 8.02-7.97 (4H, m) 
               
               
                 17:1 
                 10.66 (1H, s) 10.11 (1H, s) 8.0-7.83 (4H, m) 7.81-7.51 (5H, m) 7.37 (1H, 
               
               
                   
                 d, J = 8.3 Hz) 7.16-7.04 (2H, m) 7.01 (1H, d, J = 2.9 Hz) 6.92 (1H, dd, 
               
               
                   
                 J = 8.4 and 2.7 Hz) 3.63 (2H, s) 
               
               
                 17:2 
                 10.30 (1H, s) 10.2-10.1 (1H, br s) 7.95 (2H, dd, J = 7.8 and 1.8 Hz) 
               
               
                   
                 7.86-7.72 (3H, m) 7.62-7.40 (6H, m) 7.11-6.90 (4H, m) 3.67 (2H, s) 
               
               
                 17:3 
                 10.29 (1H, s) 9.7-9.8 (1H, br s) 8.02-7.76 (6H, m) 7.65-7.35 (4H, m) 
               
               
                   
                 7.14-6.97 (5H, m) 6.92 (1h, d, J = 2.9 Hz) 4.74 (1H, septet, J = 5.9 Hz) 
               
               
                   
                 3.62 (2H, s) 1.29 (6H, d, J = 5.9 Hz) 
               
               
                 17:4 
                 12.5-12.1 (1H, br s) 10.66 (1H, s) 9.90 (1H, s) 7.96-7.82 (4H, m) 
               
               
                   
                 7.80-7.70 (3H, m) 7.40 (1H, d, J = 8.7 Hz) 7.37-7.29 (2H, m) 7.13-7.04 (2H, m) 
               
               
                   
                 7.00 (1H, d, J = 2.8 Hz) 6.93 (1H, dd, J = 8.6 and 2.7 Hz) 3.63 (2H, s) 
               
               
                   
                 2.66 (2H, t, J = 6.7 Hz) 1.67-1.50 (2H, m) 1.42-1.21 (2H, m) 0.91 (3H, t, J = 7.3 Hz) 
               
               
                 17:5 
                 10.25-10.18 (1H, br s) 10.2-9.9 (1H, br s) 8.00-7.72 (5H, m) 
               
               
                   
                 7.68-7.52 (2H, m) 7.50-7.29 (3H, m) 7.13-6.87 (4H, m) 3.66 (2H, s) 2.66 (2H, t, 
               
               
                   
                 J = 7.5 Hz) 1.67-1.50 (2H, m) 1.42-1.21 (2H, m) 0.91 (3H, t, J = 7.2 Hz) 
               
               
                 17:6 
                 10.21 (1H, s) 9.59 (1H, s) 9.2-9.0 (2H, br s) 7.92-7.73 (4H, m) 
               
               
                   
                 7.65-7.56 (1H, m) 7.56-7.51 (1H, m) 7.44 (1H, d, J = 8.1 Hz) 7.39-7.30 (2H, m) 
               
               
                   
                 7.07-6.96 (2H, m) 6.92 (1H, d, J = 2.1 Hz) 6.76-6.64 (2H, m) 4.36-4.27 (2H, m) 
               
               
                   
                 3.60 (2H, s) 3.51-3.33 (2H, m) 3.12-3.00 (2H, m) 2.66 (2H, t, J = 7.5 Hz), 
               
               
                   
                 1.67-1.49 (2H, m) 1.41-1.20 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 17:7 
                 10.28-10.26 (1H, br s) 7.97-7.92 (2H, m) 7.81-7.76 (2H, m) 
               
               
                   
                 7.62-7.50 (5H, m) 7.08-7.03 (2H, m) 7.03-6.98 (2H, m) 6.89 (1H, d, J = 2.5 Hz) 
               
               
                   
                 6.71 (1H, dd, J = 8.7 and 2.7 Hz) 6.68-6.63 (1H, m) 4.03 (2H, t, J = 6.5 Hz) 
               
               
                   
                 3.56 (2H, s) 1.74-1.66 (2H, m) 1.47-1.37 (2H, m) 0.92 (3H, t, J = 7.4 Hz) 
               
               
                 18:1 
                 10.8-10.5 (1H, br s) 7.95 (1H, dd, J = 8.1 and 1.8 Hz) 7.90 (1H, dd, J = 8.1 
               
               
                   
                 and 1.8 Hz) 7.52 (1H, t, J = 8.1 Hz) 7.45-7.17 (2H, m) 7.16-7.04 (3H, m) 
               
               
                   
                 7.03-6.89 (3H, m) 6.78-6.73 (1H, m), 6.70 (1H, t, J = 1.8 Hz) 3.20 (3H, s) 
               
               
                 18:2 
                 13.1-12.8 (1H, br s) 8.7-8.5 (1H, br s) 8.3-8.2 (1H, br s) 7.42-7.18 (4H, m) 
               
               
                   
                 7.17-6.95 (7H, m) 6.93-6.72 (3H, m) 
               
               
                 18:3 
                 13.1-12.9 (1H, br s) 8.79 (1H, s) 7.99-7.85 (2H, m) 7.48-7.29 (1H, m) 
               
               
                   
                 7.29-7.17 (3H, m) 7.17-7.11 (1H, m) 7.10-6.91 (5H, m) 6.91-6.85 (1H, m) 
               
               
                   
                 6.82-6.75 (1H, m) 3.25 (3H, s) 2.86-2.67 (1H, m) 0.92 (4H, d, J = 6.3 Hz) 
               
               
                 18:4 
                 13.5-12.6 (1H, br s) 11.1-10.2 (1H, br s) 8.58 (1H, s) 7.82 (1H, dd, J = 7.8 
               
               
                   
                 and 1.5 Hz) 7.69 (1H, dd, J = 7.8 and 1.5 Hz) 7.42-7.21 (3H, m) 
               
               
                   
                 7.13-6.93 (5H, m) 6.90-6.69 (3H, m) 2.61 (3H, s) 
               
               
                 18:5 
                 13.1-12.9 (1H, br s) 10.40 (1H, s) 8.62 (1H, s) 8.03-7.96 (1H, m) 7.90 (1H, 
               
               
                   
                 dd, J = 7.8 and 1.8 Hz) 7.85-7.74 (2H, m) 7.66 (1H, dd, J = 7.8 and 1.8 Hz) 
               
               
                   
                 7.55 (1H, t, J = 7.8 Hz) 7.40-7.22 (2H, m) 7.18-6.99 (3H, m) 6.95-6.83 (2H, 
               
               
                   
                 m) 6.82 (1H, d, J = 1.8 Hz) 
               
               
                 18:6 
                 13.1-12.9 (1H, br s) 10.39 (1H, s) 7.99 (1H, t, J = 2.0 Hz) 7.90 (1H, dt, 
               
               
                   
                 J = 7.8 and 2.0 Hz) 7.84-7.74 (2H, m) 7.56 (1H, t, J = 7.8 Hz) 7.66 (1H, dt, 
               
               
                   
                 J = 7.8 and 2.0 Hz) 7.47-7.19 (2H, m) 7.17-7.05 (3H, m) 7.02-6.91 (1H, m) 
               
               
                   
                 6.88-6.79 (2H, m) 3.25 (3H, s) 
               
               
                 19:1 
                 10.85 (1H, br s) 10.38 (1H, s) 7.75-7.65 (2H, m) 7.59-7.38 (4H, m) 
               
               
                   
                 7.30-7.19 (4H, m) 7.16-7.09 (1H, m) 7.09-6.95 (4H, m) 3.98 (2H, t, J = 6.4 Hz) 
               
               
                   
                 1.73-1.56 (2H, m) 1.47-1.27 (2H, m) 0.88 (3H, t, J = 7.3 Hz) 
               
               
                 19:2 
                 10.87 (1H, s) 10.46 (1H, s) 7.75-7.64 (2H, m) 7.59-7.39 (4H, m) 
               
               
                   
                 7.32-6.94 (7H, m) 6.83-6.72 (1H, m) 3.98 (2H, t, J = 6.3 Hz) 1.74-1.56 (2H, m) 
               
               
                   
                 1.47-1.27 (2H, m) 0.88 (3H, t, J = 7.3 Hz) 
               
               
                 19:3 
                 14.2-13.7 (1H, br s) 11.50 (1H, s) 10.50 (1H, s) 8.53 (1H, d, J = 9.0 Hz) 
               
               
                   
                 7.81 (1H, d, J = 2.0 Hz) 7.73 (1H, d, J = 8.2 Hz) 7.65-7.17 (8H, m) 7.11-6.98 (1H, 
               
               
                   
                 m) 6.87-6.76 (1H, m) 
               
               
                 20:1 
                 10.8-10.6 (1H, br s) 7.95-7.78 (2H, m) 7.73-7.25 (9H, m) 7.24-7.15 (1H, m) 
               
               
                   
                 7.11-6.99 (2H, m) 4.02 (2H, t, J = 6.5 Hz) 1.76-1.60 (2H, m) 1.49-1.31 (2H, 
               
               
                   
                 m) 0.90 (3H, t, J = 7.4 Hz) 
               
               
                 20:2 
                 9.44 (1H, s) 8.06-7.92 (1H, m) 7.91-7.79 (1H, m) 7.77-7.58 (2H, m) 
               
               
                   
                 7.55-7.16 (10H, m) 
               
               
                 20:3 
                 13.5-13.2 (1H, br s) 7.96-7.81 (2H, m) 7.68-7.58 (1H, m) 7.54-7.50 (1H, m) 
               
               
                   
                 7.49-7.15 (10H, m) 
               
               
                 20:4 
                 10.94 (1H, s) 8.14-8.02 (2H, m) 7.75-7.57 (3H, m) 7.56-7.38 (6H, m) 
               
               
                   
                 7.34-7.21 (2H, m) 7.13-6.89 (2H, m) 4.01 (2H, d, J = 6.7 Hz) 1.74-1.60 (2H, m) 
               
               
                   
                 1.52-1.30 (2H, m) 1.46 (9H, s) 0.90 (3H, t, J = 7.2 Hz) 
               
               
                 20:5 
                 10.8-10.6 (1H, br s) 8.07-7.91 (1H, m) 7.90-7.78 (1H, m) 7.77-7.19 (10H, 
               
               
                   
                 m) 7.17-6.98 (2H, m) 4.02 (2H, t, J = 6.4 Hz) 1.77-1.59 (2H, m) 
               
               
                   
                 1.50-1.29 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 26:6 
                 9.12 (1H, s) 8.02-7.87 (1H, m) 7.86-7.74 (1H, m) 7.72-7.56 (2H, m) 
               
               
                   
                 7.53-7.12 (10H, m) 1.50 (9H, s) 
               
               
                 20:7 
                 10.8-10.6 (1H, br s) 8.16-7.96 (2H, m) 7.77-7.60 (3H, m) 7.59-7.39 (6H, m) 
               
               
                   
                 7.37-7.20 (2H, m) 7.16-6.98 (2H, m) 4.02 (2H, t, J = 6.2 Hz) 1.77-1.58 (2H, 
               
               
                   
                 m) 1.51-1.32 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 20:8 
                 13.6-13.2 (1H, br s) 9.44 (1H, s) 8.11-7.98 (2H, m) 7.66-7.57 (1H, m) 
               
               
                   
                 7.55-7.16 (12H, m) 
               
               
                 20:9 
                 13.5-13.2 (1H, br s) 12.6-12.3 (1H, br s) 9.45 (1H, s) 7.96-7.83 (2H, m) 
               
               
                   
                 7.65-7.56 (1H, m) 7.55-7.42 (2H, m) 7.41-7.08 (10H, m) 4.06 (2H, t, J = 6.4 Hz) 
               
               
                   
                 1.78-1.63 (2H, m) 1.51-1.35 (2H, m) 0.92 (3H, t, J = 7.4 Hz) 
               
               
                 21:1 
                 (DMSO-d 6  + CF 3 COOH) 10.6 (1H, br s) 10.7-10.5 (1H, br s) 8.16 (1H, d, 
               
               
                   
                 J = 7.9 Hz) 7.94 (1H, dd, J = 6.6 Hz, J = 1.5 Hz) 7.86 (1H, d, J = 7.9 Hz) 
               
               
                   
                 7.80-7.67 (3H, m) 7.66-7.54 (1H, m) 7.46 (1H, d, J = 8.8 Hz) 7.37-7.22 (2H, m) 
               
               
                   
                 7.10-6.99 (2H, m) 2.62 (3H, s) 
               
               
                 21:2 
                 (DMSO-d 6  + CF 3 COOH) 11.2 (1H, br s) 10.63 (1H, s) 8.16 (1H, d, J = 7.8 Hz) 
               
               
                   
                 7.90-7.66 (5H, m) 7.51-7.37 (2H, m) 7.23 (1H, dd, J = 9.0 Hz, J = 2.9 Hz) 
               
               
                   
                 7.08-6.98 (2H, m) 2.61 (3H, s) 
               
               
                 21:3 
                 7.72-7.60 (2H, m) 7.44-7.34 (2H, m) 7.32-7.09 (6H, m) 7.07-6.90 (3H, m) 
               
               
                   
                 6.87-6.77 (2H, m) 3.78 (3H, s) 3.33 (3H, s) 1.21 (9H, s) 
               
               
                 21:4 
                 10.69 (1H, s) 10.28 (1H, s) 7.98-7.88 (2H, m) 7.84-7.73 (2H, m) 
               
               
                   
                 7.71-7.62 (2H, m) 7.59-7.46 (4H, m) 7.37-7.22 (2H, m) 7.10-6.95 (4H, m) 4.00 (2H, 
               
               
                   
                 t, J = 6.5 Hz) 1.75-1.59 (2H, m) 1.49-1.29 (2H, m) 0.89 (3H, t, J = 7.4 Hz) 
               
               
                 22:1 
                 12.5-12.2 (1H, br s) 10.30 (1H, s) 9.73 (1H, s) 7.95 (2H, dd, J = 8.3, 1.5 Hz) 
               
               
                   
                 7.86-7.77 (2H, m) 7.72 (1H, d, J = 16.0 Hz) 7.61-7.45 (5H, m) 7.36 (1H, d, 
               
               
                   
                 J = 2.4 Hz) 7.10-6.97 (4H, m) 6.96-6.82 (2H, m) 6.22 (1H, d, J = 16.0 Hz) 
               
               
                   
                 4.01 (2H, t, J = 6.8 Hz) 1.78-1.60 (2H, m) 1.52-1.31 (2H, m) 0.92 (3H, t, 
               
               
                   
                 J = 7.3 Hz) 
               
               
                 22:2 
                 10.28 (1H, s) 9.5-9.3 (1H, br s) 7.99-7.88 (2H, m) 7.83-7.73 (2H, m) 
               
               
                   
                 7.64-7.48 (5H, m) 7.11-6.95 (4H, m) 6.88 (1H, d, J = 2.4 Hz) 6.76 (1H, d, J = 8.8 Hz) 
               
               
                   
                 6.67 (1H, dd, J = 8.8, 2.4 Hz) 4.03 (2H, t, J = 6.8 Hz) 2.76-2.63 (2H, m) 
               
               
                   
                 2.39-2.25 (2H, m) 1.79-1.60 (2H, m) 1.53-1.34 (2H, m) 0.92 (3H, t, J = 7.3 Hz) 
               
               
                 22:3 
                 10.31 (1H, s) 10.06 (1H, s) 8.02-7.91 (4H, m) 7.88-7.78 (2H, m) 
               
               
                   
                 7.69-7.47 (5H, m) 7.34 (1H, d, J = 8.3 Hz) 7.14-7.00 (5H, m) 6.44 (1H, d, J = 16.0 Hz) 
               
               
                   
                 4.74 (1H, septet, J = 5.9 Hz) 1.30 (6H, d, J = 5.9 Hz) 
               
               
                 22:4 
                 12.5-12.2 (2H, br s) 12.1-11.9 (1H, br s) 9.75 (1H, s) 8.71 (1H, d, J = 9.2 Hz) 
               
               
                   
                 7.94-7.94 (2H, m) 7.70 (1H, d, J = 16.0 Hz) 7.57-7.34 (5H, m) 
               
               
                   
                 7.14-6.94 (5H, m) 6.87 (1H, d, J = 8.8 Hz) 6.27 (1H, d, J = 16.0 Hz) 4.75 (1H, 
               
               
                   
                 septet, J = 6.0 Hz) 4.00 (2H, t, J = 6.4 Hz) 1.77-1.59 (2H, m) 1.51-1.34 (2H, 
               
               
                   
                 m) 1.30 (6H, d, J = 6.0 Hz) 0.91 (3H, t, J = 7.3 Hz) 
               
               
                 23:1 
                 11.1-10.7 (1H, br s) 7.73-7.62 (2H, m) 7.50 (1H, d, J = 8.3 Hz) 
               
               
                   
                 7.36-6.97 (8H, m) 6.59-6.33 (1H, br s) 6.36 (1H, d, J = 8.3 Hz) 6.18-6.05 (2H, m) 
               
               
                   
                 4.28 (2H, s) 3.99 (2H, t, J = 6.3 Hz) 1.75-1.57 (2H, m) 1.49-1.28 (2H, m) 
               
               
                   
                 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 23:2 
                 10.8-10.6 (1H, br s) 7.74-7.61 (2H, m) 7.49 (1H, d, J = 8.8 Hz) 7.33 (1H, d, 
               
               
                   
                 J = 2.9 Hz) 7.21 (1H, dd, J = 8.8 and 2.9 Hz) 7.10-6.76 (6H, m) 6.35 (1H, d, 
               
               
                   
                 J = 8.8 Hz) 6.16-6.01 (2H, m) 4.17 (2H, s) 4.00 (2H, t, J = 6.3 Hz) 3.78 (3H, 
               
               
                   
                 s) 3.67 (3H, s) 1.76-1.58 (2H, m) 1.50-1.28 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 23:3 
                 10.8-10.6 (1H, br s) 7.74-7.62 (2H, m) 7.56-7.46 (2H, m) 7.36-7.18 (4H, 
               
               
                   
                 m) 7.09-6.98 (3H, m) 6.7-6.5 (1H, br s) 6.32 (1H, d, J = 8.8 Hz) 
               
               
                   
                 6.15-6.07 (2H, m) 4.31 (2H, s) 4.00 (2H, t, J = 6.3 Hz) 1.75-1.58 (2H, m) 
               
               
                   
                 1.49-1.28 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 23:4 
                 10.72 (1H, s) 7.74-7.63 (2H, m) 7.57-7.38 (2H, m) 7.37-6.96 (7H, m) 
               
               
                   
                 6.7-6.3 (1H, br s) 6.37 (1H, d, J = 8.8 Hz) 6.19-6.06 (2H, m) 4.29 (2H, s) 
               
               
                   
                 3.99 (2H, t, J = 6.3 Hz) 1.76-1.57 (2H, m) 1.50-1.28 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 23:5 
                 12.9-12.1 (1H, br s) 8.12 (1H, d, J = 8.3 Hz) 7.86 (1H, d, J = 2.0 Hz) 
               
               
                   
                 7.64 (1H, dd, J = 8.3 and 2.0 Hz) 7.49-6.97 (7H, m) 6.6-6.3 (1H, br s) 6.35 (1H, 
               
               
                   
                 dd, J = 7.8 and 1.5 Hz) 6.18-6.06 (2H, m) 4.28 (2H, s) 
               
               
                 24:1 
                 9.4-9.3 (1H, br s) 7.50 (1H, d, J = 2.4 Hz) 7.46-7.15 (5H, m) 7.12-6.93 (5H, 
               
               
                   
                 m) 6.79-6.63 (1H, m) 6.56-6.39 (1H, m) 3.57 (2H, t, J = 7.3 Hz) 
               
               
                   
                 1.60-1.40 (2H, m) 1.37-1.21 (2H, m) 0.84 (3H, t, J = 7.0 Hz) 
               
               
                 24:2 
                 9.6-9.1 (1H, br s) 7.51 (1H, d, J = 2.4 Hz) 7.42-7.14 (7H, m) 7.14-7.03 (2H, 
               
               
                   
                 m) 7.03-6.88 (2H, m) 6.80-6.62 (1H, m) 6.56-6.38 (1H, m) 3.57 (2H, t, 
               
               
                   
                 J = 7.3 Hz) 1.59-1.39 (2H, m) 1.39-1.18 (2H, m) 0.84 (3H, t, J = 7.0 Hz) 
               
               
                 24:3 
                 7.66-7.58 (1H, m) 7.49-7.16 (7H, m) 7.15-7.00 (2H, m) 6.47-6.30 (1H, m) 
               
               
                   
                 6.20-6.06 (1H, m) 3.47 (2H, t, J = 7.4 Hz) 1.62-1.43 (2H, m) 1.41-1.20 (2H, 
               
               
                   
                 m) 0.87 (3H, t, J = 7.4 Hz) 
               
               
                 25:1 
                 13.8-13.5 (1H, br s) 10.38 (2H, s) 10.23 (1H, s) 8.40 (1H, d, J = 9.2 Hz) 
               
               
                   
                 7.78-7.54 (7H, m) 7.38 (1H, dd, J = 9.2 and 3.1 Hz) 7.33-7.23 (2H, m) 
               
               
                   
                 7.13-7.01 (4H, m) 
               
               
                 25:2 
                 10.9-10.8 (1H, br s) 10.37 (1H, s) 7.75-7.64 (4H, m) 7.53 (1H, d, J = 9.1 Hz) 
               
               
                   
                 7.48 (1H, d, J = 2.9 Hz) 7.34 (1H, dd, J = 9.1 and 2.9 Hz) 7.31-7.23 (2H, 
               
               
                   
                 m) 7.10-6.97 (6H, m) 3.99 (2H, t, J = 6.4 Hz) 1.74-1.57 (2H, m) 
               
               
                   
                 1.48-1.28 (2H, m) 0.88 (3H, t, J = 7.3 Hz) 
               
               
                 25:3 
                 11.0-10.8 (1H, br s) 10.44 (1H, s) 7.75-7.63 (4H, m) 7.53 (1H, d, J = 8.9 Hz) 
               
               
                   
                 7.49 (1H, d, J = 2.9 Hz) 7.39-7.22 (2H, m) 7.13-6.97 (5H, m) 
               
               
                   
                 6.89-6.78 (1H, m) 3.99 (2H, t, J = 6.3 Hz) 1.74-1.57 (2H, m) 1.45-1.28 (2H, m) 
               
               
                   
                 0.88 (3H, t, J = 7.4 Hz) 
               
               
                 25:4 
                 14.2-13.4 (1H, br s) 11.50 (1H, s) 10.45 (1H, s) 8.52 (1H, d, J = 8.9 Hz) 
               
               
                   
                 7.83-7.68 (4H, m) 7.64-7.52 (2H, m) 7.46 (1H, dd, J = 8.9 and 3.0 Hz) 
               
               
                   
                 7.40-7.24 (1H, m) 7.15-7.02 (3H, m) 6.90-6.80 (1H, m) 
               
               
                 25:5 
                 14.2-13.5 (1H, br s) 11.46 (1H, s) 10.45 (1H, s) 8.49 (1H, d, J = 8.9 Hz) 
               
               
                   
                 7.81 (1H, dd, J = 8.0 and 1.6 Hz) 7.77-7.69 (2H, m) 7.68-7.60 (2H, m) 
               
               
                   
                 7.56-7.42 (2H, m) 7.40-7.24 (1H, m) 7.16-7.02 (3H, m) 6.90-6.80 (1H, m) 
               
               
                 25:6 
                 14.2-13.6 (1H, br s) 11.98 (1H, s) 10.45 (1H, s) 8.74 (1H, d, J = 8.9 Hz) 
               
               
                   
                 7.95-7.82 (2H, m) 7.78-7.62 (3H, m) 7.46 (1H, dd, J = 9.1 and 2.8 Hz) 
               
               
                   
                 7.40-7.24 (1H, m) 7.16-7.02 (5H, m) 6.91-6.80 (1H, m) 4.73 (1H, septet, J = 5.9 Hz) 
               
               
                   
                 1.28 (6H, d, J = 5.9 Hz) 
               
               
                 25:7 
                 13.6-13.0 (1H, br s) 10.37 (1H, s) 9.6-9.3 (1H, br s) 7.75-7.64 (2H, m) 
               
               
                   
                 7.58-7.50 (1H, m) 7.46-7.17 (6H, m) 7.14-6.97 (5H, m) 
               
               
                 26:1 
                 9.3-9.6 (1H, br s) 7.85-7.73 (2H, m) 7.49 (1H, d, J = 2.6 Hz) 7.42-7.02 (9H, 
               
               
                   
                 m) 6.91-6.74 (3H, m) 4.03 (2H, t, J = 6.4 Hz) 3.50 (2H, s) 1.77-1.60 (2H, m) 
               
               
                   
                 1.51-1.31 (2H, m) 0.91 (3H, t, J = 7.2 Hz) 
               
               
                 26:2 
                 13.5-13.1 (1H, br s) 12.8-12.3 (1H, br s) 9.47-9.37 (1H, br s) 
               
               
                   
                 7.97-7.85 (1H, m) 7.83-7.62 (2H, m) 7.49 (1H, d, J = 2.8 Hz) 7.42-7.12 (7H, m) 
               
               
                   
                 6.92-6.76 (3H, m) 3.55 (2H, s) 
               
               
                 26:3 
                 12.7-12.3 (1H, br s) 10.08 (1H, s) 7.95-7.83 (1H, m) 7.82-7.57 (4H, m) 
               
               
                   
                 7.44 (1H, d, J = 9.0 Hz) 7.36 (1H, d, J = 2.9 Hz) 7.34-7.24 (1H, m) 7.21 (1H, 
               
               
                   
                 dd, J = 9.0 and 2.9 Hz) 7.09-6.99 (2H, m) 6.94 (1H, d, J = 7.7 Hz) 
               
               
                   
                 6.88-6.78 (2H, m) 4.01 (2H, t, J = 6.5 Hz) 3.56 (2H, s) 1.75-1.60 (2H, m) 
               
               
                   
                 1.54-1.29 (2H, m) 1.46 (9H, s) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 26:4 
                 13.2-11.9 (2H, br s) 11.1-10.5 (1H, br s) 7.98-7.84 (1H, m) 7.83-7.62 (4H, 
               
               
                   
                 m) 7.54 (1H, d, J = 8.8 Hz) 7.39 (1H, d, J = 2.6 Hz) 7.34-7.20 (2H, m) 
               
               
                   
                 7.12-7.00 (2H, m) 6.93 (1H, d, J = 7.7 Hz) 6.88-6.76 (2H, m) 4.01 (2H, t, J = 6.2 Hz) 
               
               
                   
                 3.57 (2H, s) 1.77-1.59 (2H, m) 1.50-1.29 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 26:5 
                 13.7-12.2 (2H, br s) 11.1-10.6 (1H, br s) 7.99-7.78 (2H, m) 7.75-7.63 (2H, 
               
               
                   
                 m) 7.53 (1H, d, J = 9.0 Hz) 7.48-7.36 (2H, m) 7.33-7.20 (2H, m) 
               
               
                   
                 7.10-7.00 (2H, m) 6.93 (1H, d, J = 7.6 Hz) 6.87-6.78 (2H, m) 4.01 (2H, t, J = 6.3 Hz) 
               
               
                   
                 3.58 (2H, s) 1.77-1.58 (2H, m) 1.50-1.29 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 27:1 
                 7.67-7.58 (2H, m) 7.43 (1H, d, J = 2.8 Hz) 7.38 (1H, d, J = 8.8 Hz) 7.18 (1H, 
               
               
                   
                 q, J = 9.4 Hz) 7.08-6.93 (5H, m) 6.91-6.82 (2H, m) 6.78-6.64 (1H, m) 
               
               
                   
                 6.52-6.41 (1H, m) 3.95 (2H, t, J = 6.3 Hz) 3.62-3.50 (2H, m) 1.72-1.56 (2H, m) 
               
               
                   
                 1.53-1.19 (6H, m) 0.87 (3H, t, J = 6.9 Hz) 0.84 (3H, t, J = 6.9 Hz) 
               
               
                 27:2 
                 7.52 (1H, d, J = 8.8 Hz) 7.38 (1H, d, J = 2.8 Hz) 7.35-7.12 (4H, m) 
               
               
                   
                 7.10-7.01 (3H, m) 6.97-6.90 (2H, m) 6.85-6.70 (1H, m) 6.59-6.48 (1H, m) 3.77 (3H, 
               
               
                   
                 s) 3.72 (3H, s) 3.58 (2H, t, J = 7.3 Hz) 1.57-1.39 (2H, m) 1.38-1.18 (2H, m) 
               
               
                   
                 0.84 (3H, t, J = 7.3 Hz) 
               
               
                 27:3 
                 8.27 (1H, s) 7.72-7.60 (2H, m) 7.47 (1H, d, J = 8.8 Hz) 7.33 (1H, d, J = 2.8 Hz) 
               
               
                   
                 7.32-6.85 (10H, m) 6.81-6.70 (1H, m) 4.04-3.92 (2H, m) 
               
               
                   
                 1.74-1.57 (2H, m) 1.48-1.27 (2H, m) 0.89 (3H, t, J = 7.4 Hz) 
               
               
                 27:4 
                 8.26 (1H, s) 7.72-7.61 (2H, m) 7.45 (1H, d, J = 8.8 Hz) 7.33 (1H, d, J = 2.8 Hz) 
               
               
                   
                 7.32-6.83 (10H, m) 6.81-6.69 (1H, m) 3.77 (3H, s) 
               
               
                 27:5 
                 11.4-11.1 (1H, br s) 7.85 (1H, t, J = 8.1 Hz) 7.72 (1H, dd, J = 10.3, 1.8 Hz) 
               
               
                   
                 7.51-7.38 (3H, m) 7.29-7.13 (2H, m) 7.10-7.02 (2H, m) 7.01-6.91 (2H, m) 
               
               
                   
                 6.86-6.71 (1H, m) 6.61-6.50 (1H, m) 3.58 (2H, t, J = 7.3 Hz) 1.57-1.40 (2H, 
               
               
                   
                 m) 1.38-1.22 (2H, m) 0.84 (3H, t, J = 7.0 Hz) 
               
               
                 28:1 
                 11.4-10.6 (1H, br s) 7.75-7.61 (2H, m) 7.59-7.17 (6H, m) 7.10-6.97 (2H, 
               
               
                   
                 m) 6.95-6.83 (1H, m) 6.82-6.60 (3H, m) 4.00 (2H, t, J = 6.5 Hz) 
               
               
                   
                 1.76-1.56 (2H, m) 1.50-1.28 (2H, m) 0.90 (3H, t, J = 7.3 Hz) 
               
               
                 28:2 
                 14.1-13.7 (1H, br s) 12.1-11.9 (1H, br s) 8.72 (1H, d, J = 9.3 Hz) 
               
               
                   
                 7.96-7.82 (2H, m) 7.63 (1H, d, J = 2.9 Hz) 7.56-7.16 (4H, m) 7.15-7.00 (2H, m) 
               
               
                   
                 6.98-6.84 (1H, m) 6.85-6.65 (3H, m) 5.00-4.85 (1H, m) 2.10-1.45 (8H, m) 
               
               
                 28:3 
                 13.8-12.5 (1H, br s) 9.9-9.0 (1H, br s) 7.60-7.16 (8H, m) 7.13-7.00 (1H, m) 
               
               
                   
                 6.97-6.84 (1H, m) 6.80-6.58 (3H, m) 
               
               
                 28:4 
                 8.13 (1H, d, J = 8.6 Hz) 7.91-7.84 (1H, m) 7.70-7.60 (1H, m) 7.54-7.16 (6H, 
               
               
                   
                 m) 6.96-6.83 (1H, m) 6.81-6.61 (3H, m) 
               
               
                 28:5 
                 11.9-10.9 (1H, br s) 7.76-7.64 (2H, m) 7.57-7.18 (6H, m) 7.10-7.00 (2H, 
               
               
                   
                 m) 6.95-6.84 (1H, m) 6.81-6.62 (3H, m) 3.79 (3H, s) 
               
               
                 29:1 
                 11.0-10.8 (1H, br s) 10.21 (1H, s) 7.88-7.76 (2H, m) 7.75-7.65 (2H, m) 
               
               
                   
                 7.61-7.39 (8H, m) 7.37-7.25 (2H, m) 6.70 (1H, dd, J = 7.8 2.0 Hz) 1.29 (9H, 
               
               
                   
                 s) 1.21 (9H, s) 
               
               
                 29:2 
                 11.7-11.5 (1H, br s) 10.09 (1H, s) 8.12 (1H, d, J = 8.8 Hz) 7.90 (1H, d, 
               
               
                   
                 J = 2.0 Hz) 7.93-7.83 (2H, m) 7.65 (1H, dd, J = 8.8 2.0 Hz) 7.56 (1H, d, 
               
               
                   
                 J = 7.8 Hz) 7.50-7.20 (5H, m) 7.07-6.95 (2H, m) 6.69 (1H, dd, J = 7.8 2.0 Hz) 
               
               
                   
                 4.03 (2H, t, J = 6.3 Hz) 1.78-1.61 (2H, m) 1.52-1.31 (2H, m) 0.92 (3H, t, 
               
               
                   
                 J = 7.3 Hz) 
               
               
                 29:3 
                 12.4-11.8 (1H, br s) 10.20 (1H, s) 8.12 (1H, d, J = 8.8 Hz) 7.90 (1H, d, 
               
               
                   
                 J = 1.8 Hz) 7.89-7.80 (2H, m) 7.67 (1H, d, J = 8.8 1.8 Hz) 7.63-7.28 (7H, m) 
               
               
                   
                 7.25 (1H, dd, J = 8.8 and 2.9 Hz) 6.70 (1H, dd, J = 7.8 2.0 Hz) 1.29 (9H, s) 
               
               
                 30:1 
                 13.7-13.4 (1H, br s) 10.27 (1H, s) 9.98 (1H, s) 8.89 (1H, s) 8.79 (1H, s) 
               
               
                   
                 8.33 (1H, d, J = 9.2 Hz) 7.79-7.67 (2H, m) 7.54-7.22 (8H, m) 7.10-6.94 (4H, 
               
               
                   
                 m) 
               
               
                 30:2 
                 12.4-12.0 (1H, br s) 9.97 (1H, s) 9.74 (1H, s) 9.46 (1H, s) 8.23 (1H, d, 
               
               
                   
                 J = 9.0 Hz) 7.92-7.35 (11H, m) 7.09 (1H, dd, J = 9.0 and 2.9 Hz) 
               
               
                   
                 7.04-6.90 (2H, m) 5.76 (1H, s) 
               
               
                 30:3 
                 16.69-15.40 (1H, br s) 10.25 (1H, s) 7.91-7.75 (4H, m) 7.61-7.43 (4H, m) 
               
               
                   
                 7.39-7.31 (2H, m) 7.06-6.91 (3H, m) 6.86-6.76 (2H, m) 
               
               
                 31:1 
                 7.51-7.26 (6H, m) 7.25-7.12 (2H, m) 7.05 (2H, dd, J = 9.2, and 2.9 Hz) 
               
               
                   
                 6.62 (2H, d, J = 9.2 Hz) 4.44 (4H, s) 
               
               
                 31:2 
                 7.41-7.22 (4H, m) 7.21-7.11 (4H, m) 7.06 (2H, dd, J = 9.1 and 3.1 Hz) 
               
               
                   
                 6.69 (2H, d, J = 9.1 Hz) 4.56 (4H, s) 
               
               
                 32:1 
                 10.6 (1H, br s) 10.4-10.3 (1H, br s) 7.78-7.38 (9H, m) 7.34-7.25 (2H, m) 
               
               
                   
                 7.16 (1H, dd, J = 9.0 and 2.8 Hz) 7.11-7.00 (2H, m) 2.88 (1H, septet, J = 7.0 Hz) 
               
               
                   
                 1.13 (6H, d, J = 7.0 Hz) 
               
               
                 32:2 
                 10.4-10.3 (1H, br s) 10.13 (1H, s) 8.00-7.87 (2H, m) 7.86-7.74 (2H, m) 
               
               
                   
                 7.60-7.40 (4H, m) 7.38-7.26 (2H, m) 7.18 (1H, dd, J = 9.1 and 2.8 Hz) 
               
               
                   
                 7.12-6.97 (4H, m) 4.74 (1H, septet, J = 6.1 Hz) 2.90 (1H, septet, J = 7.0 Hz) 
               
               
                   
                 1.30 (6H, d, J = 6.1 Hz) 1.16 (6H, d, J = 7.0 Hz) 
               
               
                 32:3 
                 10.29 (1H, s) 8.30 (1H, s) 7.53-7.35 (4H, m) 7.33-7.16 (1H, m) 
               
               
                   
                 7.15-7.04 (3H, m) 7.02-6.88 (5H, m) 6.83-6.72 (1H, m) 3.96 (2H, t, J = 6.6 Hz) 
               
               
                   
                 1.73-1.55 (2H, m) 1.47-1.26 (2H, m) 0.88 (3H, t, J = 7.4 Hz) 
               
               
                 33:1 
                 9.4-9.2 (1H, br s) 8.27 (1H, s) 7.91 (1H, d, J = 2.8 Hz) 7.65-7.53 (2H, m) 
               
               
                   
                 7.44-7.15 (5H, m) 7.10-7.00 (1H, m) 6.99-6.92 (1H, m) 6.91-6.82 (1H, m) 
               
               
                   
                 6.76-6.66 (1H, m) 
               
               
                 33:2 
                 9.6-9.2 (1H, br s) 7.95 (1H, d, J = 8.4 Hz) 7.87 (1H, d, J = 2.3 Hz) 7.69 (1H, 
               
               
                   
                 d, J = 8.4 Hz) 7.46-7.25 (5H, m) 7.24-7.19 (1H, m) 7.14 (1H, dd, J = 8.4 and 
               
               
                   
                 2.3 Hz) 7.08-6.99 (2H, m) 2.63 (3H, s) 
               
               
                 34:1 
                 13.38 (1H, s) 9.40 (1H, s) 7.97 (1H, s) 7.53 (1H, d, J = 2.7 Hz) 
               
               
                   
                 7.44-7.13 (9H, m) 6.98 (1H, dd, J = 12.2 and 2.7 Hz) 6.89-6.73 (3H, m) 
               
               
                 34:2 
                 14.1-13.6 (1H, br s) 11.9-11.5 (1H, br s) 8.48 (1H, d, J = 9.1 Hz) 8.04 (1H, 
               
               
                   
                 s) 7.73-7.58 (1H, m) 7.57 (1H, d, J = 3.1 Hz) 7.41 (1H, dd, J = 9.1 and 3.1 Hz) 
               
               
                   
                 7.36-7.17 (5H, m) 7.09 (1H, dd, J = 11.9 and 2.8 Hz) 6.95-6.79 (3H, 
               
               
                   
                 m) 
               
               
                 34:3 
                 13.35 (1H, s) 9.43 (1H, s) 7.97 (1H, s) 7.53 (1H, dd, J = 2.5 and 0.6 Hz) 
               
               
                   
                 7.51-7.39 (1H, m) 7.36-7.14 (6H, m) 6.97 (1H, dd J = 12.2 and 2.7 Hz) 
               
               
                   
                 6.89-6.71 (3H, m) 3.84 (3H, s) 
               
               
                 34:4 
                 13.5-13.1 (1H, br s) 9.46 (1H, s) 7.97 (1H, s) 7.53 (1H, d, J = 2.4 Hz) 
               
               
                   
                 7.39 (1H, d, J = 8.6 Hz) 7.34-7.10 (6H, m) 6.99 (1H, d, J = 2.2 Hz) 
               
               
                   
                 6.96-6.91 (1H, m) 6.89-6.71 (3H, m) 3.87 (3H, s) 
               
               
                 34:5 
                 13.6-13.5 (1H, br s) 9.83 (1H, s) 7.98 (1H, s) 7.74 (1H, d, J = 7.9 Hz) 
               
               
                   
                 7.68-7.53 (3H, m) 7.35-7.14 (6H, m) 7.00 (1H, dd, J = 12.2 and 2.7 Hz) 
               
               
                   
                 6.91-6.73 (3H, m) 
               
               
                 34:6 
                 14.0-13.7 (1H, br s) 11.55 (1H, s) 8.45 (1H, d, J = 9.0 Hz) 7.70-7.54 (1H, 
               
               
                   
                 m) 7.53 (1H, d, J = 3.0 Hz) 7.37 (1H, dd, J = 3.0 and 9.0 Hz) 7.34-7.21 (2H, 
               
               
                   
                 m) 7.14 (1H, t, J = 9.0 Hz) 7.05 (1H, dd, 12.0 and 2.6 Hz) 7.00-6.91 (2H, 
               
               
                   
                 m) 6.88-6.75 (4H, m) 3.80 (3H, s) 
               
               
                 34:7 
                 9.8-9.2 (1H, br s) 7.48 (1H, d, J = 2.9 Hz) 7.40-7.15 (6H, m) 
               
               
                   
                 7.09-6.69 (7H, m) 3.67 (3H, s) 3.12 (3H, s) 
               
               
                 34:8 
                 9.9-9.3 (1H, br s) 7.59-7.44 (3H, m) 7.29-7.12 (3H, m) 7.09-6.69 (7H, m) 
               
               
                   
                 3.67 (3H, s) 3.12 (3H, s) 
               
               
                 34:9 
                 13.5-13.3 (1H, br s) 9.7-9.5 (1H, br s) 7.57-7.47 (3H, m) 7.36-7.18 (3H, 
               
               
                   
                 m) 7.10-6.70 (8H, m) 3.67 (3H, s) 3.12 (3H, s) 
               
               
                  34:10 
                 14.0-13.7 (1H, br s) 11.5 (1H, br s) 8.47 (1H, d, J = 9.1 Hz) 7.80 (1H, d, 
               
               
                   
                 J = 1.9 Hz) 7.73 (1H, d, J = 8.3 Hz) 7.60 (1H, dd, J = 8.3 1.9 Hz) 7.51 (1H, d, 
               
               
                   
                 J = 3.0 Hz) 7.37 (1H, dd, J = 9.1 3.0 Hz) 7.11-6.91 (5H, m) 6.89-6.77 (2H, 
               
               
                   
                 m) 3.68 (3H, s) 3.14 (3H, s) 
               
               
                 35:1 
                 14.2-13.5 (1H, br s) 11.9-11.6 (1H, br s) 10.7-10.5 (1H, br s) 8.49 (1H, d, 
               
               
                   
                 J = 8.7 Hz) 8.18-8.07 (2H, m) 7.96-7.77 (6H, m) 8.72 (1H, d, J = 8.7 Hz) 
               
               
                   
                 7.65-7.54 (2H, m) 7.46-7.35 (2H, m) 
               
               
                 35:2 
                 10.6-10.5 (1H, br s) 8.17-8.06 (2H, m) 7.96-7.84 (3H, m) 7.84-7.71 (3H, 
               
               
                   
                 m) 7.64 (1H, dd, J = 8.7 and 1.9 Hz) 7.43 (1H, dd, J = 8.7 and 1.9 Hz) 
               
               
                   
                 7.39-7.24 (4H, m) 
               
               
                 36:1 
                 10.79 (s, 1H), 10.05 (s, 1H), 7.72-7.61 (m, 5H), 7.57-7.50 (m, 3H), 
               
               
                   
                 7.42-7.31 (m, 4H), 7.30-7.21 (m, 3H), 3.70 (s, 3H), 2.62 (t, J = 7.7 Hz, 2H), 
               
               
                   
                 1.55-1.48 (m, 2H), 1.29-1.19 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H) 
               
               
                 36:2 
                 10.79 (s, 1H), 10.74 (s, 1H), 7.76-7-73 (m, 2H), 7.67-7.62 (m, 3H), 
               
               
                   
                 7.58-7.49 (m, 4H), 7.38-7.30 (m, 4H), 7.27-7.23 (m, 2H), 2.61 (t, J = 7.7 Hz, 2H), 
               
               
                   
                 1.55-1.47 (m, 2H), 1.26-1.19 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H) 
               
               
                 36:3 
                 10.85 (s, 1H), 10.80 (s, 1H), 7.90-7.86 (m, 2H), 7.77-7.73 (m, 2H), 
               
               
                   
                 7.67-7.62 (m, 1H), 7.58-7.46 (m, 6H), 7.37 (d, J = 3.0 Hz, 1H), 7.32 (d, J = 3.0 Hz, 
               
               
                   
                 1H), 7.27 (d, J = 3.0 Hz, 1H), 7.25 (d, J = 3.0 Hz, 1H) 
               
               
                 36:4 
                 10.80 (s, 1H), 10.71 (s, 1H), 7.77-7.72 (m, 2H), 7.71-7.67 (m, 2H), 
               
               
                   
                 7.66-7.62 (m, 1H), 7.58-7.50 (m, 4H), 7.35 (d, J = 3.0 Hz, 1H), 7.33 (d, J = 3.0 Hz, 
               
               
                   
                 1H), 7.29-7.23 (m, 2H), 7.08-7.03 (m, 2H), 3.80 (s, 3H) 
               
               
                 36:5 
                 10.81 (s, 1H), 10.71 (s, 1H), 7.77-7.72 (m, 2H), 7.69-7.62 (m, 3H), 
               
               
                   
                 7.57-7.49 (m, 4H), 7.35 (d, J = 3 Hz, 1H), 7.32 (d, J = 3 Hz, 1H), 3.65-3.61 (m, 
               
               
                   
                 2H), 7.07-7.01 (m, 2H), 4.00 (t, J = 6.5 Hz, 2H), 1.71-1.63 (m, 2H), 
               
               
                   
                 1.45-1.34 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H) 
               
               
                 37:1 
                 13.6-13.1 (1H, br s) 9.6-9.2 (1H, br s) 7.52 (1H, d, J = 2.8 Hz) 
               
               
                   
                 7.49-7.27 (7H, m) 7.24 (1H, dd, J = 9.0 Hz) 7.16-7.05 (4H, m) 7.00-6.91 (2H, m) 
               
               
                   
                 3.81 (3H, s) 3.05 (3H, s) 
               
               
                 37:2 
                 9.6-9.3 (1H, br s) 7.82-7.66 (1H, m) 7.65-7.53 (1H, m) 7.52-7.10 (11H, m) 
               
               
                   
                 6.97-6.82 (2H, m) 3.22 (3H, d, J = 1.8 Hz) 
               
               
                 37:3 
                 13.5-13.1 (1H, br s) 9.6-9.3 (1H, br s) 7.84-7.64 (3H, m) 7.47 (1H, d, 
               
               
                   
                 J = 2.8 Hz) 7.39-7.14 (8H, m,) 7.00-6.85 (2H, m) 3.29 (3H, s) 
               
               
                 37:4 
                 9.8-9.2 (1H, br s) 7.56-7.46 (2H, m) 7.41-7.21 (7H, m) 7.12-7.04 (3H, m) 
               
               
                   
                 6.97-6.89 (3H, m,) 3.75 (3H, s) 3.11 (3H, s) 
               
               
                 37:5 
                 13.5-13.1 (1H, br s) 9.6-9.2 (1H, br s) 7.70-7.61 (2H, m) 7.60-7.51 (2H, m) 
               
               
                   
                 7.49 (1H, d, J = 2.8 Hz) 7.42-7.15 (6H, m) 7.11-7.05 (2H, m) 6.97-6.86 (2H, 
               
               
                   
                 m) 3.12 (3H, s) 
               
               
                 37:6 
                 13.5-13.2 (1H, br s) 9.6-9.3 (1H, br s) 7.70 (1H, dd, J = 9.0 Hz) 
               
               
                   
                 7.57-7.45 (2H, m) 7.39-7.30 (2H, m) 7.31-7.14 (7H, m,) 6.95-6.87 (2H, m) 3.83 (3H, 
               
               
                   
                 s) 3.27 (3H, s) 
               
               
                   
               
            
           
         
       
     
     Example 38 
     The following compounds were/are prepared by analogy to the processes described above:
     38:1 N-{5-[4-(3,4-Difluorophenylamino)phenoxy]pyridine-3-carbonyl}-3,4-difluoro-benzenesulfonamide;   38:2 N-(5-{4-[(3,4-Difluorophenyl)methylamino]phenoxy}pyridine-3-carbonyl)-3,4-difluorobenzenesulfonamide; and   38:3 2-(3,4-Difluorophenylamino)-5-[6-(3,4-difluorophenylamino)pyridin-3-yloxy]-benzoic acid.   

     Example 39 
     Title compounds of the examples were tested in the biological test described above (HPLC method) and were found to exhibit 50% inhibition of LTC 4  synthase at a concentration of 10 μM or below. For example, the following representative compounds of the examples exhibited the following IC 50  values. 
     
       
         
           
               
             
               
                 TABLE 39 
               
             
            
               
                   
               
               
                 Selected compound data 
               
            
           
           
               
               
               
            
               
                   
                 Compound (Table:Number) 
                 IC 50  [nM] 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                  1:2 
                 845 
               
               
                   
                 19:1 
                 1160 
               
               
                   
                 14:6 
                 449 
               
               
                   
                 22:3 
                 5110 
               
               
                   
                 28:1 
                 629 
               
               
                   
                 29:1 
                 802 
               
               
                   
                   
               
            
           
         
       
     
     Example 40 
     Title compounds of the Examples were tested in the biological in vitro assay described above (HTRF method) and were found to inhibit LTC 4  synthase. Thus, when the total concentration of title compounds in the assay was 10 μM (unless otherwise specified), the following %-inhibition values where obtained. 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Ex. 
                 % inh. 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                  1:1 
                 98 
               
               
                   
                  1:2 
                 97 
               
               
                   
                  1:3 
                 100 
               
               
                   
                  1:4 
                 100 
               
               
                   
                  1:5 
                 99 
               
               
                   
                  1:6 
                 100 
               
               
                   
                  1:7 
                 97 (3 μM) 
               
               
                   
                  1:8 
                 99 (3 μM) 
               
               
                   
                  1:9 
                 100 
               
               
                   
                  2:1 
                 98 
               
               
                   
                  2:2 
                 100 
               
               
                   
                  2:3 
                 100 
               
               
                   
                  2:4 
                 99 
               
               
                   
                  2:5 
                 100 
               
               
                   
                  2:6 
                 100 
               
               
                   
                  2:7 
                 100 
               
               
                   
                  2:8 
                 100 
               
               
                   
                  2:9 
                 99 
               
               
                   
                  3:1 
                 65 
               
               
                   
                  3:2 
                 86 
               
               
                   
                  4:1 
                 99 
               
               
                   
                  4:2 
                 93 
               
               
                   
                  4:3 
                 97 
               
               
                   
                  4:4 
                 99 
               
               
                   
                  5:1 
                 100 
               
               
                   
                  5:2 
                 99 
               
               
                   
                  5:3 
                 100 
               
               
                   
                  6:1 
                 99 
               
               
                   
                  6:2 
                 98 
               
               
                   
                  6:3 
                 100 
               
               
                   
                  6:4 
                 96 
               
               
                   
                  6:5 
                 96 
               
               
                   
                  6:6 
                 98 
               
               
                   
                  6:7 
                 100 
               
               
                   
                  7:1 
                 95 
               
               
                   
                  7:2 
                 100 
               
               
                   
                  8:1 
                 100 
               
               
                   
                  8:2 
                 93 
               
               
                   
                  8:3 
                 96 
               
               
                   
                  8:4 
                 89 
               
               
                   
                  8:5 
                 83 (3 μM) 
               
               
                   
                  8:6 
                 97 
               
               
                   
                  8:7 
                 64 (1 μM) 
               
               
                   
                  8:8 
                 89 (3 μM) 
               
               
                   
                  8:9 
                 88 
               
               
                   
                  8:10 
                 67 
               
               
                   
                  8:11 
                 70 (3 μM) 
               
               
                   
                  8:12 
                 99 
               
               
                   
                  8:13 
                 98 
               
               
                   
                  8:14 
                 100 
               
               
                   
                  8:15 
                 98 
               
               
                   
                  8:16 
                 99 
               
               
                   
                  8:17 
                 98 
               
               
                   
                  8:18 
                 99 
               
               
                   
                  8:19 
                 99 
               
               
                   
                  8:20 
                 96 
               
               
                   
                  8:21 
                 98 
               
               
                   
                  9:1 
                 100 
               
               
                   
                  9:2 
                 96 
               
               
                   
                  9:3 
                 99 
               
               
                   
                  9:4 
                 99 
               
               
                   
                  9:5 
                 98 
               
               
                   
                 10:1 
                 98 
               
               
                   
                 10:2 
                 88 
               
               
                   
                 10:3 
                 95 
               
               
                   
                 10:4 
                 95 
               
               
                   
                 10:5 
                 98 
               
               
                   
                 10:6 
                 98 
               
               
                   
                 11:1 
                 99 
               
               
                   
                 11:2 
                 97 
               
               
                   
                 11:3 
                 98 
               
               
                   
                 11:4 
                 98 
               
               
                   
                 11:5 
                 99 
               
               
                   
                 11:6 
                 96 
               
               
                   
                 11:7 
                 100 
               
               
                   
                 11:8 
                 98 
               
               
                   
                 11:9 
                 89 
               
               
                   
                 11:10 
                 95 
               
               
                   
                 11:11 
                 72 
               
               
                   
                 11:12 
                 92 
               
               
                   
                 11:13 
                 99 
               
               
                   
                 11:14 
                 100 
               
               
                   
                 11:15 
                 99 
               
               
                   
                 11:16 
                 94 
               
               
                   
                 11:17 
                 97 
               
               
                   
                 11:18 
                 96 
               
               
                   
                 11:19 
                 97 
               
               
                   
                 11:20 
                 76 
               
               
                   
                 11:21 
                 96 
               
               
                   
                 11:22 
                 95 
               
               
                   
                 12:1 
                 96 
               
               
                   
                 12:2 
                 94 
               
               
                   
                 12:3 
                 83 
               
               
                   
                 12:4 
                 87 
               
               
                   
                 12:5 
                 96 
               
               
                   
                 13:1 
                 98 
               
               
                   
                 13:2 
                 100 
               
               
                   
                 13:3 
                 99 
               
               
                   
                 14:1 
                 98 
               
               
                   
                 14:2 
                 99 
               
               
                   
                 14:3 
                 98 
               
               
                   
                 14:4 
                 100 
               
               
                   
                 14:5 
                 97 
               
               
                   
                 14:6 
                 80 (3 μM) 
               
               
                   
                 15:1 
                 99 
               
               
                   
                 15:2 
                 100 
               
               
                   
                 15:3 
                 99 
               
               
                   
                 16:1 
                 98 
               
               
                   
                 16:2 
                 97 
               
               
                   
                 17:1 
                 96 
               
               
                   
                 17:2 
                 99 
               
               
                   
                 17:3 
                 87 
               
               
                   
                 17:4 
                 79 
               
               
                   
                 17:5 
                 94 
               
               
                   
                 17:6 
                 23 
               
               
                   
                 17:7 
                 95 
               
               
                   
                 18:1 
                 97 
               
               
                   
                 18:2 
                 97 
               
               
                   
                 18:3 
                 95 
               
               
                   
                 18:4 
                 98 
               
               
                   
                 18:5 
                 100 
               
               
                   
                 18:6 
                 96 
               
               
                   
                 19:1 
                 100 
               
               
                   
                 19:2 
                 100 
               
               
                   
                 19:3 
                 100 
               
               
                   
                 20:1 
                 99 
               
               
                   
                 20:2 
                 96 
               
               
                   
                 20:3 
                 97 
               
               
                   
                 20:4 
                 99 
               
               
                   
                 20:5 
                 97 
               
               
                   
                 20:6 
                 100 
               
               
                   
                 20:7 
                 94 
               
               
                   
                 20:8 
                 96 
               
               
                   
                 20:9 
                 100 
               
               
                   
                 21:1 
                 100 
               
               
                   
                 21:2 
                 98 
               
               
                   
                 21:3 
                 99 
               
               
                   
                 21:4 
                 100 
               
               
                   
                 22:1 
                 96 
               
               
                   
                 22:2 
                 99 
               
               
                   
                 22:3 
                 72 
               
               
                   
                 22:4 
                 100 
               
               
                   
                 23:1 
                 100 
               
               
                   
                 23:2 
                 99 
               
               
                   
                 23:3 
                 98 
               
               
                   
                 23:4 
                 99 
               
               
                   
                 23:5 
                 98 
               
               
                   
                 24:1 
                 93 
               
               
                   
                 24:2 
                 95 
               
               
                   
                 24:3 
                 97 
               
               
                   
                 25:1 
                 98 
               
               
                   
                 25:2 
                 100 
               
               
                   
                 25:3 
                 100 
               
               
                   
                 25:4 
                 100 
               
               
                   
                 25:5 
                 100 
               
               
                   
                 25:6 
                 100 
               
               
                   
                 25:7 
                 100 
               
               
                   
                 26:1 
                 94 (3 μM) 
               
               
                   
                 26:2 
                 93 
               
               
                   
                 26:3 
                 95 
               
               
                   
                 26:4 
                 95 
               
               
                   
                 26:5 
                 99 
               
               
                   
                 27:1 
                 100 
               
               
                   
                 27:2 
                 100 
               
               
                   
                 27:3 
                 100 
               
               
                   
                 27:4 
                 100 
               
               
                   
                 27:5 
                 98 
               
               
                   
                 28:1 
                 98 
               
               
                   
                 28:2 
                 94 
               
               
                   
                 28:3 
                 96 
               
               
                   
                 28:4 
                 98 
               
               
                   
                 28:5 
                 99 
               
               
                   
                 29:1 
                 97 
               
               
                   
                 29:2 
                 99 
               
               
                   
                 29:3 
                 99 
               
               
                   
                 30:1 
                 98 
               
               
                   
                 30:2 
                 93 
               
               
                   
                 30:3 
                 100 
               
               
                   
                 31:1 
                 66 
               
               
                   
                 31:2 
                 98 
               
               
                   
                 32:1 
                 98 
               
               
                   
                 32:2 
                 94 
               
               
                   
                 32:3 
                 98 
               
               
                   
                 33:1 
                 97 
               
               
                   
                 33:2 
                 99 
               
               
                   
                 34:1 
                 97 
               
               
                   
                 34:2 
                 98 
               
               
                   
                 34:3 
                 97 
               
               
                   
                 34:4 
                 97 
               
               
                   
                 34:5 
                 98 
               
               
                   
                 34:6 
                 96 
               
               
                   
                 34:7 
                 94 
               
               
                   
                 34:8 
                 97 
               
               
                   
                 34:9 
                 96 
               
               
                   
                 34:10 
                 98 
               
               
                   
                 35:1 
                 99 
               
               
                   
                 35:2 
                 100 
               
               
                   
                 36:1 
                 97 
               
               
                   
                 36:2 
                 100 
               
               
                   
                 36:3 
                 100 
               
               
                   
                 36:4 
                 95 
               
               
                   
                 36:5 
                 100 
               
               
                   
                 37:1 
                 95 
               
               
                   
                 37:2 
                 92 
               
               
                   
                 37:3 
                 91 
               
               
                   
                 37:4 
                 92 
               
               
                   
                 37:5 
                 94 
               
               
                   
                 37:6 
                 94