BIS-ARYL COMPOUNDS FOR USE AS MEDICAMENTS

Abstract

There is provided compounds of formula I, wherein ring A, D1, D2a, D2b, D3, L1, Y1, L3 and Y3 have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of leukotriene C4 synthase is desired and/or required, and particularly in the treatment of a respiratory disorder and/or inflammation.

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 C₄. 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) B₄ is known to be a strong proinflammatory mediator, while the cysteinyl-containing leukotrienes C₄, D₄ and E₄ (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 CysLT₁ and CysLT₂, 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 CysLT₁. 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 C₄ synthase may be mentioned. However, a 5-LO or a FLAP inhibitor would also decrease the formation of LTB₄. 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 LTC₄ 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,

whereineither one of D_2a and D_2b represents D₂, and the other represents —C(-L²-Y²)═;Y represents —O— or —S(O)_m—;each of D₁, D₂ and D₃ respectively represent —C(R^1a)═, —C(R^1b)═ and —C(R^1c)═, or,each of D₁, D₂ and D₃ 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 -L³-Y³ group, and the others independently represent hydrogen, -L^1a-Y^1a or a substituent selected from X¹;

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 -L³-Y³ 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 X², 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 -L³-Y³ 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 X³, 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, —N₃, —NO₂, —N(R^5g)S(O)₂N(R^6f)R^7f, —OR^5h, —OC(O)N(R^6g)R^7g, —OS(O)₂R⁵ⁱ, —N(R^5k)S(O)₂R^5m, —OC(O)R⁵ⁿ, —OC(O)OR^5p or —OS(O)₂N(R⁶ⁱ)R⁷ⁱ;X¹, X² and X³ 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, —N₃, —NO₂, —N(R^5g)S(O)₂N(R^6f)R^7f, —OR^5h, —OC(O)N(R^6g)R^7g, —OS(O)₂R⁵ⁱ, —N(R^5k)S(O)₂R^5m, —OC(O)R⁵ⁿ, —OC(O)OR^5p or —OS(O)₂N(R⁶ⁱ)R⁷ⁱ;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)_mR^5j or —S(O)₂N(R^6h)R^7h;R^5b to R^5h, R^5j, R^5k, R⁵ⁿ, R^6a to R⁶ⁱ, R^7a, R^7b, R^7d and R^7f to R⁷ⁱ independently represent, on each occasion when used herein, H or R^5a; orany 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 R⁶ⁱ and R⁷ⁱ 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;R⁵ⁱ, 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, —N₃, ═O, —OR^8a, —N(R^8b)R^8c, —S(O)_nR^8d, —S(O)₂N(R^8e)R^8f and/or —OS(O)₂N(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-M¹;R^8c, R^8f and R^8h independently represent H, —S(O)₂CH₃, —S(O)₂CF₃ 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-M²; orR^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;M¹ and M² independently represent —CH₃, —CH₂CH₃, —CF₃ or —N(R^15a)R^15b;R^11a and R^13a independently represent H, —CH₃, —CH₂CH₃, —CF₃ or —CHF₂;R^12a, R^12b, R^14a, R^14b, R^15a and R^15b independently represent H, —CH₃ or —CH₂CH₃,Y¹ and Y^1a independently represent, on each occasion when used herein, —N(H)SO₂R^9a, —C(H)(CF₃)OH, —C(O)CF₃, —C(OH)₂CF₃, —C(O)OR^9b, —S(O)₃R^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(CF₃)₂OH, —S(O)₂N(R¹⁰ⁱ)R⁹ⁱ 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 G¹ and/or Z¹;R^9b to R^9z, R^9aa, R^9ab, R^10f, R^10g, R¹⁰ⁱ 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 G¹ and/or Z¹; orR^9b to R^9z, R^9aa, R^9ab, R^10f, R^10g, R¹⁰ⁱ and R^10j independently represent, on each occasion when used herein, hydrogen; orany pair of R^9f and R^10f, R^9g and R^10g, and R⁹ⁱ and R¹⁰ⁱ, 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;Y² and Y³ 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 G¹ and/or Z¹; orIII) a G¹ group;G¹ represents, on each occasion when used herein, halo, cyano, —N₃, —NO₂, —ONO₂ or -A¹-R^16a;wherein A¹ represents a single bond or a spacer group selected from —C(O)A²-, —S—, —S(O)_rA³-, —N(R^17a)A⁴- or —OA⁵-, in which:A² represents a single bond, —O—, —N(R^17b)— or —C(O)—;A³ represents a single bond, —O— or —N(R^17c)—;A⁴ and A⁵ independently represent a single bond, —C(O)—, —C(O)N(R^17d)—, —C(O)O—, —S(O)_r— or —S(O)_rN(R^17e)—;Z¹ represents, on each occasion when used herein, ═O, ═S, ═NOR^16h, ═NS(O)₂N(R^17f)R^16c, ═NCN or ═C(H)NO₂;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 G²;II) C_1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G² and/or Z²; orIII) a G² group;G² represents, on each occasion when used herein, halo, cyano, —N₃, —NO₂, —ONO₂ or -A⁶-R^18a;wherein A⁶ represents a single bond or a spacer group selected from —C(O)A⁷-, —S—, —S(O)_rA⁸-, —N(R^19a)A⁹- or —OA¹⁰-, in which:A⁷ represents a single bond, —O—, —N(R^19b)— or —C(O)—;A⁸ represents a single bond, —O— or —N(R^19c)—;A⁹ and A¹⁰ independently represent a single bond, —C(O)—, —C(O)N(R^19d)—, —C(O)O—, —S(O)_r— or —S(O)_rN(R^19e)—;Z² represents, on each occasion when used herein, ═O, ═S, ═NOR^18b, ═NS(O)₂N(R^19f)R^18c, ═NCN or ═C(H)NO₂;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 G³;iii) C_1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G³ and/or Z³; orany 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 G³ and/or Z³;G³ represents, on each occasion when used herein, halo, cyano, —N₃, —NO₂, —ONO₂ or -A¹¹-R^20a;wherein A¹¹ represents a single bond or a spacer group selected from —C(O)A¹²-, —S—, —S(O)_rA¹³-, —N(R^21a)A¹⁴- or —OA¹⁵-, in which:A¹² represents a single bond, —O—, —N(R^21b)— or —C(O)—;A¹³ represents a single bond, —O— or —N(R^21c)—;A¹⁴ and A¹⁵ independently represent a single bond, —C(O)—, —C(O)N(R^21d)—, —C(O)O—, —S(O)_r— or —S(O)_rN(R^21e)—;Z³ represents, on each occasion when used herein, ═O, ═S, ═NOR^20b, ═NS(O)₂N(R^21f)R^20c, ═NCN or ═C(H)NO₂;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; andiii) 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; orany 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;L¹ 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 X⁴; orR^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 X⁵;L² and L³ independently represent a single bond or a spacer group selected from —(CH₂)_p—C(R^y3)(R^y4)—(CH₂)_q-A¹⁶-, —(CH₂)_p—C(O)A¹⁷-, —(CH₂)_p—S—, (CH₂)_p—SC(R^y3)(R^y4)—, —(CH₂)_p—S(O)A²¹-, —(CH₂)_p—S(O)₂A¹⁸-, —(CH₂)_p—N(R^w)A¹⁹- or —(CH₂)_p—OA²⁰-, in which:A¹⁶ represents a single bond, —O—, —C(O)—, or —S(O)_m—;A¹⁷, A¹⁸ and A²¹ independently represent a single bond, —C(R^y3)(R^y4)—, —O—, —N(R^w)— or —N(R^w)SO₂—;A¹⁹ and A²⁰ 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)₂N(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 X⁶; orR^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 X⁷;R^w resents, on each occasion when used herein, H or X⁸;X⁴ to X⁸ 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 C₄ 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 X¹ and X² both represent R⁶⁸, 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 X¹ 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 Y² or Y³ represent e.g. an aryl group substituted by G¹ in addition to, for example, C_1-8 alkyl, which latter group is substituted by G¹, the identities of the two G¹ 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 R⁵ group” is referred to herein, we mean any one of R^5a to R^5k, R^5m, R⁵ⁿ 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 G¹ group is present in which G¹ represents -A′-R^16a, A¹ represents —C(O)A² and A² 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 ‘-L³-Y³’ 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 -L³-Y³ group.

When L¹ 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;L² and L³ independently represent a single bond or a spacer group selected from —(CH₂)_p—C(R^y3)(R^y4)—(CH₂)_q-A¹⁶, —(CH₂)_p—C(O)A¹⁷-, —(CH₂)_p—S—, —(CH₂)_p—SC(R^y3)(R^y4)—, —(CH₂)_p—S(O)₂A¹⁸-, —(CH₂)_p—N(R^w)A¹⁹- or —(CH₂)_p—OA²⁰-, 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 D₂; D_2b represents —C(-L²-Y²)═; D₁, D₂ and D₃ 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 -L³-Y³ group, L¹ represents a single bond, Y¹ represents —C(O)OR^9b; R^9b represents methyl or, preferably, hydrogen; L² represents —N(H)-A¹⁹; L³ represents —N(R^w)-A¹⁹-; A¹⁹ represents (in each case) —S(O)₂—, then Y² and Y³ do not both represent 4-methylphenyl when Y represents —O—, R^w represents H, R^2b represents X¹ in which X¹ 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 D₂;D_2b represents —C(-L²-Y²)═;D₁, D₂ and D₃ 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 -L³-Y³ group;when R^2c represents the requisite -L³-Y³ group, then R^2b represents -L^1a-Y^1a, or, preferably hydrogen or a substituent selected from X¹;when R^2b represents the requisite -L³-Y³ group, then R^2b represents -L^1a-Y^1a;X¹ 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;L¹ and L^1a independently represent a single bond; and/orY¹ and Y^1a independently represent —C(O)OR^9b (in which R^9b is preferably hydrogen) or —S(O)₃R^9c (in which R^9c is preferably hydrogen), then preferably:L² and L³ independently represent a single bond or a spacer group selected from —(CH₂)_p—C(R^y3)(R^y4)—(CH₂)_q-A¹⁶-, —(CH₂)_p—C(O)A¹⁷-, (CH₂)_p—S—, —(CH₂)_p—SC(R^y3)(R^y4)—, —(CH₂)_p—S(O)₂A¹⁸- or —(CH₂)_p—OA²⁰-;A¹⁹ 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)₂N(R^w)—;Y² and Y³ 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 G¹ and/or Z¹; or III) a G¹ group;A¹ represents a spacer group selected from —C(O)A²-, —S—, —S(O)₂A³-, —N(R^17a)A⁴- or —OA⁵-;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 G³; iii) a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G³ and/or Z³;A¹⁷ 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)SO₂—;Y² and Y³ 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 G¹ and/or Z¹;G¹ represents, on each occasion when used herein, cyano, —N₃ or —ONO₂ (alternatively, and more preferably, G¹ represents, on each occasion when used herein, halo or cyano);A¹ represents a single bond or a spacer group selected from —C(O)A²-, —S— or —S(O)₂A³-;A⁴ and A⁵ independently represent —C(O)—, —C(O)N(R^17d)—, —C(O)O—, —S(O)₂— or —S(O)₂N(R^17e)—;Y² and Y³ do not independently (e.g. they do not both) represent phenyl substituted by G¹, in which G¹ is preferably halo (e.g. bromo), —NO₂ or -A¹-R^16a, A¹ represents or —N(R^17a)A⁴- or —OA⁵-, in which A⁴ and A⁵ preferably represent single bonds; R^16a represents hydrogen or C_1-8 alkyl (e.g. methyl); and/or R^17a represents hydrogen;A¹⁹ 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)₂N(R^w)—;when A¹⁹ represents —C(O)— (e.g. when p represents 0), the Y² and Y³ do not both represent phenyl substituted e.g. at the para position with A, in which A represents G¹ and G¹ represents —NO₂;G¹ represents halo, cyano, —N₃, —ONO₂ or -A¹-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 D₂;D_2b represents —C(-L²-Y²)═;D₁, D₂ and D₃ 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 -L³-Y³ group and the other (e.g. R^2b) represents -L^1a-Y^1a;-L¹-Y¹ and -L^1a-Y^1a both represent —S(O)₃H, then preferably:A¹⁹ 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)₂N(R^w)—;Y² and Y³ 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 G¹ and/or Z¹;G¹ represents halo, cyano, —N₃ or —ONO₂ (preferably, halo or cyano);A¹ represents a single bond or a spacer group selected from —C(O)A²-, —S—, —S(O)₂A³- or —N(R^17a)A⁴-;A⁵ represents a single bond, —C(O)—, —C(O)N(R^17d)—, —C(O)O— or —S(O)₂N(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 G³ and/or Z³;G³ represents, on each occasion when used herein, halo, cyano, —N₃ or —ONO₂ (preferably, halo or cyano);A¹¹ represents a single bond or a spacer group selected from —C(O)A¹²-, —S—, —S(O)₂A¹³- or —OA¹⁵-;A¹⁴ represents —C(O)—, —C(O)N(R^21d)—, —C(O)O—, —S(O)₂— or —S(O)₂N(R^21e)—.

Compounds of the invention that may be mentioned include those in which, for example, when D₁, D₂ and D₃ 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 Y² and Y³ both represent a heteroaryl (e.g. a 4- to 10-membered heteroaryl) group, then L¹ 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 Y² and Y³ both represent a heteroaryl group, then L² and L³ do not both represent single bonds.

Further compounds of the invention that may be mentioned include those in which in which, for example, when D₁, D₂ and D₃ 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:

L¹ represents a single bond, C_1-6alkylene 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, —N₃, —OR^8a, —N(R^8b)R^8c, —S(O)_nR^8d, —S(O)₂N(R^8e)R^8f or —OS(O)₂N(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, —N₃, ═O, —N(R^8b)R^8c, —S(O)_nR^8d, —S(O)₂N(R^8e)R^8f or —OS(O)₂N(R^8g)R^8h;(e.g. one of) L² and L³ independently represent(s) a spacer group selected from —(CH₂)_p—C(R^y3)(R^y4)—(CH₂)_q-A¹⁶-, —(CH₂)_p—C(O)A¹⁷-, —(CH₂)_p—S—, —(CH₂)_p—SC(R^y3)(R^y4)—, —(CH₂)_p—S(O)₂A¹⁸-, —(CH₂)_p—N(R^w)A¹⁹- or —(CH₂)_p—OA²⁰-;(e.g. one of) Y² and Y³ 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 D₁, D₂ and D₃ 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, X¹ 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, —N₃, ═O, —OR^5a, —N(R^8b)R^8c, —S(O)_nR^8d, —S(O)₂N(R^8e)R^8f or —OS(O)₂N(R^8g)R^8h;R^1a, R^1b, R^1c, X¹, X² and X³ 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, —N₃, —NO₂, —N(R^5g)S(O)₂N(R^6f)R^7f, —OR^5h, —OC(O)N(R^6g)R^7g, —OS(O)₂R⁵ⁱ, —N(R^5k)S(O)₂R^5m, —OC(O)R⁵ⁿ, —OC(O)OR^5p or —OS(O)₂N(R⁶ⁱ)R⁷ⁱ.

Yet further compounds of the invention that may be mentioned include those in which:

when, for example, ring A represents ring (I); L² or L³ represent —N(R^w)A¹⁹-; A¹⁹ represents a single bond; and/or R^w represents H, then:Y² or Y³ (as appropriate) do not represent a benzimidazolyl (such as one attached to the L² or L³ group via the imidazolyl moiety, e.g. benzimidazol-2-yl) group;when Y² or Y³ 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 Y² or Y³ represents a polycyclic (e.g. bicyclic) heteroaryl group, then it is preferably not attached to the L² or L³ group via a ring containing a heteroatom;Y² and/or Y³ (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 D₁ to D₃-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 D₁, D_2b and D₃ 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 L² or L³ represent —C(O)N(H)—, then Y² or Y³ (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′, X², R^z1, X³ or R^z2 substituent present, then:

X¹, X², R^z1, X³ 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, —N₃, —OR^8a, —N(R^8b)R^8c, —S(O)_nR^8d, —S(O)₂N(R^8e)R^8f or —OS(O)₂N(R^8g)R^8h.

Preferred compounds of the invention include those in which:

one (e.g. D₁, D₂ (e.g. D_2a) or D₃) or none of D₁, D₂ and D₃ represent —N═;D₁, D₂ and D₃ 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, —CH₃, —CF₃ or, more preferably, hydrogen;for example when ring A represents ring (II) then, one of R^3a and R^3b represents a substituent X² or, more preferably, H or -L^1a-Y^1a, and the other represents the requisite -L³-Y³ group;R^4b and R^4c independently represent F, Cl, —CH₃, —CF₃ 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 X³ or, more preferably, H or -L^1a-Y^1a, and the other represents the requisite -L³-Y³ 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), X¹, X² and X³ independently represent a group selected from Z^2a, or, halo, —CN, —N(R^6b)R^7b, —N(R^5d)C(O)R^6c, —N₃, —NO₂, —OR^5h or —N(R^5k)S(O)₂R^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)₂R^5m, and each X¹, X² and X³ 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)₂R^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 R⁶ⁱ and R⁷ⁱ are linked together, they form a 5- or 6-membered ring optionally substituted by F, —OCH₃ 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(CH₃)—);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, —N₃, 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)₂CH₃, —S(O)₂CF₃ 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 —CH₃;M¹ and M² independently represent —N(R^15a)R^15b or, preferably, —CH₃ or —CF₃;R^11a, R^12a, R^12b, R^13a, R^14a, R^14b, R^15a and R^15b independently represent —CH₂CH₃, —CF₃ (in the case of R^11a and R^13a) or, preferably, H or —CH₃;Y¹ and Y^1a independently represent —N(H)S(O)₂R^9a, —C(O)OR^9b, —S(O)₂N(R¹⁰ⁱ)R⁹ⁱ or 5-tetrazolyl;when Y¹ and/or Y¹ 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 R⁹ⁱ and R¹⁰ⁱ 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 D₂ 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, R¹⁰ⁱ 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;R¹⁰ⁱ represents H;R⁹ⁱ 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 G¹ and/or Z¹; or G¹;G¹ represents N₃, —NO₂, or, preferably, halo, cyano or -A¹-R^16a;A² represents a single bond or —O—;A⁴ represents —C(O)N(R^17d)—, —C(O)O— or, more preferably, a single bond or —C(O)—;A⁵ represents —C(O)— or, preferably, a single bond;Z¹ 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 G²; C_1-6 alkyl optionally substituted by G² and/or Z²; or, preferably, B represents G²;G² represents cyano, preferably, —NO₂ or, more preferably, halo or -A⁶-R^18a (alternatively, G² represents cyano, or, preferably, halo or -A⁶-R^18a);A⁶ represents a single bond, —N(R^19a)A⁹- or —OA¹⁰-;A⁹ represents —C(O)N(R^19d)—, —C(O)O— or, more preferably, a single bond or —C(O)—;A¹⁰ represents a single bond;Z² 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 G³) or C_1-6 (e.g. C_1-6) alkyl (optionally substituted by G³ and/or Z³), 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 G³ and/or Z³;G³ represents halo or -A¹¹-R^20a;A¹¹ represents a single bond or —O—;A¹² represents a single bond or, preferably, —N(R^21b)—;A¹³ represents a single bond or, preferably, —N(R^21c)—;A¹⁴ and A¹⁵ independently represent a single bond, —C(O)— or —S(O)₂—;Z³ 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)—;L² and L³ independently represent —(CH₂)_p—C(R^y3)(R^y4)—(CH₂)_q-A¹⁶-, —(CH₂)_p—C(O)A¹⁷-, —(CH₂)_p—S—, —SC(R^y3)(R^y4)—, —(CH₂)_p—S(O)₂A¹⁸-, —(CH₂)_p—N(R^w)A¹⁹- or —(CH₂)_p—O—;A¹⁶ represents a single bond or, preferably, —C(O)—;A¹⁸ represents —N(R^w)— or a single bond;A¹⁹ 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)—;A²⁰ represents a single bond or —C(R^y3)(R^y4)—;R^y3 and R^y4 independently represent H or X⁶, or, are linked together to form a 3-membered cyclopropyl group;X⁴ to X⁸ 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;X¹, X² and X³ independently represent halo (e.g. chloro or, especially fluoro), —CN, —NO₂,

—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 D₁ to D₃-containing ring may represent include 2-, 3- or 4-pyridyl or, preferably, phenyl.

Preferred aryl and heteroaryl groups that Y² and Y³ 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 Y² and Y³ 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 Y² and Y³ groups include:

—NO₂; 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;

—OR²⁶;

—SR²⁶;

—C(O)R²⁶;

—C(O)OR²⁶;

—N(R²⁶)R²⁷; and

—S(O)₂R²⁸;

wherein R²⁶ and R²⁷ 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 R²⁶ preferably represents aryl or, particularly C_1-6 alkyl, for example as defined in respect of R²⁶ and R²⁷.

Particularly preferred compounds of the invention include those in which:

D_2b or, preferably, D_2a represents D₂, and the other (i.e. preferably D_2b) represents —C(-L²-Y²);D₁ and D₃ respectively represent —C(R^1a)═ and —C(R^1c)═;D₂ 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 -L³-Y³ group and the other represents a substituent selected from X¹ or, preferably, hydrogen or -L^1a-Y^1a;R^2d represents hydrogen;X¹, X² and X³ independently represent —OR^5h, Z^2a, or, most preferably halo (e.g. chloro or, especially, fluoro) (e.g. X¹ represents fluoro);L¹ 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, —CH₂═CH₂—);L¹ 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;Y¹ and Y^1a independently represent 5-tetrazolyl (e.g. unsubstituted 5-tetrazolyl) or, preferably, —C(O)OR^9b or —N(H)SO₂R^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);Y² and Y³ 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 G¹; or II) G¹;G¹ represents —NO₂, or, more preferably, halo (e.g. fluoro or chloro), cyano or -A¹-R^16a;A¹ represents a single bond, —C(O)A²-, —S—, —S(O)₂A³-, —N(R^17a)A⁴- or —OA⁵-;A², A³, A⁴ and A⁵ 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 G³;R^17a represents hydrogen or, preferably, C_1-6 (e.g. C_1-3) alkyl (such as methyl);G³ represents halo (e.g. fluoro);L² and L³ independently represent a spacer group selected from —(CH₂)_p—C(O)A¹⁷-, —(CH₂)_p—S(O)₂A¹⁸-, —(CH₂)_p—N(R^w)A¹⁹- and —(CH₂)_p—OA²⁰ (e.g. —(CH₂)_p—O—);p represents 0 or 1;when L² or L³ represent —(CH₂)_p—S(O)₂A¹⁸-, —(CH₂)_p—N(R^w)A¹⁹- or —(CH₂)_p—O—, then p preferably represents 0;when L² or L³ represent —(CH₂)_p—C(O)A¹⁷-, then p may represent 0 or 1;A¹⁷ represents —N(R^w)— or, preferably, —N(R^w)SO₂—;A¹⁸ represents —N(R^w)—;A¹⁹ 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)—;A²⁰ represents a single bond;R^w represents hydrogen or X⁸;when A¹⁷ represents —N(R^w)SO₂—, then R^w represents hydrogen;when A¹⁹ represents —C(O)N(R^w)—, then R^w represents hydrogen;R^y3 and R^y4 independently represent hydrogen;X⁸ 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 Y² and Y³ 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 Y² and Y³ groups include isopropyl and, preferably, halo (e.g. fluoro or chloro), —NO₂, cyano, methyl, butyl (e.g. n-butyl or t-butyl), trifluoromethyl (—CF₃), hydroxy (—OH), methoxy, ethoxy, isopropoxy, n-butoxy, trifluoromethoxy, cyclopentyloxy, —C(O)-cyclopropyl, trifluoromethylthio (—S—CF₃), dimethylamino (—N(CH₃)₂) and methanesulfonyl (—S(O)₂CH₃).

Specific L² and L³ groups that may be mentioned include —N(H)—, —N(CH₃)—, —N(n-butyl)-, —N(phenyl)- (e.g. —N(4-cyclopropylcarbonylphenyl)-), —N(H)—CH₂—, —N(H)C(O)—, —N(CH₃)C(O)—, —N(phenyl)-C(O)— (e.g. —N(4-fluorophenyl)-C(O)—), —N(H)S(O)₂—, —N(CH₃)S(O)₂—, —N(H)C(O)CH₂—, —N(H)—C(O)—N(H)—, —S(O)₂—N(H)—, —C(O)N(H)S(O)₂—, —CH₂—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, D₁, D_2a, D_2b, D₃, L¹, L³ and Y³ are as hereinbefore defined, in the presence of a suitable oxidising agent, for example meta chloro per benzoic acid, KMnO₄, 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 L² and/or L³ represents —(CH₂)_p—N(R^w)A¹⁹- 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 D₂ 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 —NH₂ or -L²-Y², L^3a represents —NH₂ or -L³-Y³, provided that at least one of L^2a and L^3a represents —NH₂, and ring A, Y, D₁, D₂, D₃, L¹ and Y¹ are as hereinbefore defined, with:(A) when A¹⁹ 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 CO₂(CO)₈)) or a reagent such as phosgene or triphosgene in the presence of a compound of formula V,

Y^a—NH₂  V

wherein, in both cases, Y^a represents Y² or Y³ (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 -L²-Y² represents —C(O)N(H)—Y² and -L³-Y³ represents —C(O)N(H)—Y³ and Y² and Y³ 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 —NH₂, 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 A¹⁹ represents —S(O)₂N(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, KMnO₄, 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 SO₂ (or a suitable source thereof) or SOCl₂;(C) when A¹⁹ 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)₂CF₃, —OS(O)₂CH₃, —OS(O)₂PhMe 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, Pd₂(dba)₃ or NiCl₂ and an optional additive such as Ph₃P, 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, Et₃N, pyridine, N,N′-dimethylethylenediamine, Na₂CO₃, K₂CO₃, K₃PO₄, Cs₂CO₃, 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 A¹⁹ 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 L² and L³ represents —N(R^w)C(O)N(R^w)— and the other represents —NH₂ (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 D₂ and the other represents —C(-J²)═ (i.e. the J² substituent is attached to either one of D_2ax and D_2bx), one of J¹ or J² represents —N═C═O and the other represents -L²-Y² or -L³-Y³ (as appropriate), —NH₂ (or a protected derivative thereof) or —N═C═O (as appropriate), and ring A, Y, D₁, D₂, D₃, L¹ and Y¹ 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 D₂ 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)₂CF₃, —OS(O)₂CH₃, —OS(O)₂PhMe 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, D₁, D₂, D₃, L¹ and Y¹ 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 L² or L³ (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)₂A¹⁸-, in which A¹⁸ 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 L² and L³ 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)A¹⁹-, followed by reaction with another, separate, compound of formula X in which L^x represents —OA²⁰-) 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 R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵ or R²⁶ 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 R⁵ to R¹⁹ 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. —SnMe₃ or —SnBu₃), 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 R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵ or R²⁶ 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 R⁵ to R¹⁹ 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)₂CF₃, —OS(O)₂CH₃, —OS(O)₂PhMe 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 Y¹ and/or, if present, Y^1a represents —C(O)OR^9b, —S(O)₃R^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 Y¹ 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)₃R^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)₂N(R¹⁰ⁱ)R⁹ⁱ (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 Y¹ and/or, if present, Y^1a represents —C(O)OR^9b, S(O)₃R^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 R⁹ 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^9zaOH  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 H₂SO₄) at elevated temperature, such as at the reflux temperature of the alcohol of formula XIII;(x) for compounds of formula I in which Y¹ and/or, if present, Y^1a represents —C(O)OR^9b, —S(O)₃R^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)₂N(R¹⁰ⁱ)R⁹ⁱ, in which R^9b to R⁹ⁱ, R^10f, R^10g and R¹⁰ⁱ are other than H, and L¹ 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 D₁ to D₃-containing ring is replaced with —O—, reaction of a compound of formula XIV,

wherein at least one of L⁵ 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 -L¹-Y¹ or -L^1a-Y^1a (as appropriate), and ring A, D₁, D_2a, D_2b, D₃, L³ and Y³ are as hereinbefore defined (the skilled person will appreciate that the compound of formula XIV in which L⁵ 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 L⁵ 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,

L⁶-L^xy-Y^b  XV

wherein L^xy represents L¹ or L^1a (as appropriate) and Y^b represents —C(O)OR^9b, —S(O)₃R^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)₂N(R¹⁰ⁱ)R⁹ⁱ, in which R^9b to R⁹ⁱ, R^10f, R^10g and R¹⁰ⁱ are other than H, and L⁶ 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)₃R^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 L¹ represents a single bond and Y¹ 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 L⁵ represents —B(OH)₂ are also compounds of formula I;(xi) compounds of formula I in which L¹ and/or, if present, L^1a represent a single bond, and Y¹ and/or, if present, Y^1a represent either: B(OR^9h)₂ in which R^9h represents H; —S(O)₃R^9c; or any one of the following groups:

in which R^9j, R^9k, R^9m, R⁹ⁿ, 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 L¹ 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 L¹ and/or L^1a group represents —C≡N, in the presence of an appropriate reagent that effects the conversion, e.g. NaN₃, 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 L¹ and/or, if present, L^1a represent a single bond, and Y¹ 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 Y¹ and/or, if present, Y^1a represents —CN, with hydroxylamine (so forming a corresponding hydroxyamidino compound) and then with SOCl₂, 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*OEt₂), 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 L¹ and/or, if present, L^1a represent a single bond, and Y¹ 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 L⁵ 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 -L¹-Y¹ or -L^1a-Y^1a (as appropriate), and ring A, D₁, D_2a, D_2b, D₃, L³ and Y³ are as hereinbefore defined (the skilled person will appreciate that the compound of formula XIV in which L⁵ 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 L⁵ 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. K₂CO₃). The skilled person will appreciate that compounds of formula XIV in which L⁵ represents —B(OH)₂ are also compounds of formula I;(xiv) for compounds of formula I in which L¹ and/or, if present, L^1a represent a single bond, and Y¹ 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 L⁵ 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 L¹ and/or, if present, L^1a represent a single bond, and Y¹ 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 L⁵ 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 CO₂(CO)₈)), in the presence of a compound of formula XVII,

R^9bOH  XVII

wherein R^9b is as hereinbefore defined, and an appropriate catalyst system (e.g. a palladium catalyst, such as PdCl₂, Pd(OAc)₂, Pd(Ph₃P)₂Cl₂, Pd(Ph₃P)₄, Pd₂(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, D₁, D_2a, D_2b, D₃, L¹, Y¹, L³ and Y³ 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 L¹ or, if present, L^1a represents C_1-6 alkylene, and Y¹ 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, D₁, D_2a, D_2b, D₃, L³ and Y³ 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 Y¹ (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 AlCl₃ under Friedel-Crafts conditions;(xviii) for compounds of formula I in which L¹ represents —CH═CH—, reaction of a compound of formula XXIV,

wherein ring A, Y, D₁, D_2a, D_2b, D₃, L³ and Y³ are as hereinbefore defined, with a compound of formula XXV,

(EtO)₂P(O)CH₂—Y¹  XXV

or the like, or a compound of formula XXVI,

(Ph)₃P═CH—Y¹  XXVI

wherein (in both cases), Y¹ 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 L² and/or L³ represent —(CH₂)_p—C(O)A¹⁷- in which A¹⁷ represents —N(R^w)— or —N(R^w)SO₂—, 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 D₂ 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 —(CH₂)_p—C(O)OH or -L²-Y², L^3b represents —(CH₂)_p—C(O)OH or -L³-Y³, provided that at least one of L^2b and L^3b represents —(CH₂)_p—C(O)OH, and ring A, Y, D₁, D₂, D₃, L¹ and Y¹ 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 SOCl₂ 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 L¹-Y¹ represents —C(O)N(H)SO₂R^9a, reaction of a corresponding compound of formula XXIX,

wherein ring A, Y, D₁, D_2a, D_2b, D₃, L³ and Y³ are as hereinbefore defined, with a compound of formula XXX,

H₂N—SO₂R^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 SOCl₂ 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 L¹-Y¹ represents —C(O)N(H)SO₂R^9a, reaction of a corresponding compound of formula XXXI,

wherein ring A, Y, D₁, D_2a, D_2b, D₃, L³ and Y³ are as hereinbefore defined, with a compound of formula XXXII,

Cl—SO₂R^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 L² or L³ represent —N(H)—CH₂—, 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 LiAlH₄.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 D₂ 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 —N₃, —NO₂, -L³-Y³ or a protected —NH₂ group, Z^z2 represents —N₃, —NO₂, -L²-Y² or a protected —NH₂ group, provided that at least one of Z^z1 and Z^z2 represents —N₃ or —NO₂, 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 —NH₂ (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 Ph₂C═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 L¹ represents a single bond, and Y¹ 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, D₁, D_2ax, D_2bx, D_2az, D_2bz, D₃, 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)Cl₃ and DMF, followed by oxidation under standard conditions;(III) reaction of a compound of formula XXXVI,

wherein W¹ represents a suitable leaving group such as one defined by Z^x and Z^y above, and ring A, Y, D₁, D_2a1, D_2b1, D₃, 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 CO₂(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 W² 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, D₁, D_2a1, D_2b1, D₃, Z^q1 and Z^q2 are as hereinbefore defined, with e.g. CO₂ (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 L⁶ 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 —NH₂, L¹ represents a single bond and Y¹ represents —C(O)OH, may alternatively be prepared by reaction of a compound of formula XXXVIII,

wherein L^3a, D₁, D₂, D₃, 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 H₂O₂, which is preferably in the presence of an alkaline solution. Similarly, compounds of formula III in which L³ represents —NH₂, 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, D₁, D_2ax, D_2bx, D₃, L^2a, Y, L¹ and Y¹ 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 —NH₂, L¹ represents a single bond and Y¹ represents —C(O)OR^9b, may be prepared by reaction of a compound of formula XL,

wherein X^q represents —OH, —NH₂ or —N₃, and L^3a, D₁, D₂, D₃, 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 HN₃ (which may be formed in by contacting NaN₃ with a strong acid such as H₂SO₄). Variants include reaction with diphenyl phosphoryl azide ((PhO)₂P(O)N₃) 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 —NH₂, under Hoffmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br₂) which may result in the formation of a carbamate intermediate;(iii) when X^q represents —N₃ (which compound itself may be prepared from the corresponding acyl hydrazide under standard diazotization reaction conditions, e.g. in the presence of NaNO₂ and a strong acid such as H₂SO₄ 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 —NH₂, 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 K₃PO₄ 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 —NO₂ and the other represents -L²-Y² or -L³-Y³ (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 D₂ and the other (preferably D_2bq) represents —C(—NO₂)═, and Z^ab, D₁, D₂, D₃, D₄, L¹, Y¹ 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 W² 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 —NH₂ 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 W¹ 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 W² represents —Mg-halide may be prepared from a corresponding compound of formula XXXVI in which W¹ represents halo (e.g. bromo), for example optionally in the presence of a catalyst (e.g. FeCl₃) 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 W² represents a zinc-based group (e.g. using ZnCl₂).

Compounds of formula XXXVIII and XXXIX may be prepared by reaction of a compound of formula XLIII,

wherein L^3a, D₁, D₂, D₃, Y and ring A are as hereinbefore defined, or a compound of formula XLIV

respectively, wherein ring A, D₁, D_2ax, D_2bx, D₃, L^2a, Y, L¹ and Y¹ 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 -L¹-Y¹ 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, D₁, D_2a, D_2b, D_2aq, D_2bq and D₃ 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, D₁, D_2a, D_2b, D_2aq, D_2bq and D₃ 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 D₁, D_2a, D_2b, D₃, L¹, Y¹, L³ and Y³ (as well as L² and Y²) 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 Y¹ (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 D₁ to D₃-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 & 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 & 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 D₂; D_2b represents —C(-L²-Y²)═; D₁, D₂ and D₃ 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 -L³-Y³ group, -L¹-Y¹ represents —C(O)OR^9b; L² represents —N(H)S(O)₂—; L³ represents —(CH₂)_pN(R^w)-A¹⁹-:(1) A¹⁹ represents —S(O)₂—, p represents 0, then Y² and Y³ 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 X¹ in which X¹ represents —OR^5h, and R^5h represents n-pentyl, isobutyl, n-propyl, ethyl or methyl;
    • (iii) R^w represents H, R^2b represents X¹ in which X¹ 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 X¹, X¹ represents Z^2a, in which Z^2a represents R^5a, and R^5a represents methyl, —CF₃, —CH₂OH, —CH═CH₂, ethyl or n-propyl;
    • (v) R^w represents H, R^2b represents X¹, in which X¹ 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 X¹, X¹ represents Z^2a and Z^2a represents —C(O)NH₂;(2) p represents 1, Y represents —O—, R^2b and R^w both represent H, then Y² does not represent 4-methylphenyl when:
  • (A) R^9b represents H; or
  • (B) R^9b represents methyl, and (in both cases):
    • (i) A¹⁹ represents —S(O)₂— and Y³ represents 4-methylphenyl, 4-acetylphenyl (i.e. 4-(C(O)CH₃)phenyl) or 4-nitrophenyl;
    • (ii) A¹⁹ represents —C(O)—, and Y³ represents 4-pyridyl;(II) L¹ represents a single bond, Y¹ represents —C(O)OR^9b, R^9b represents H:
  • (A) L² and L³ both represent —C(O)N(H)—, R^2c represents the requisite -L³-Y³ group, R^2b represents -L¹-Y^1a, -L^1a-Y^1a represents —COOH, then:
    • (i) when Y represents —S(O)₂—, then Y² and Y³ do not both represent 4-methoxyphenyl, 3-nitro-4-aminophenyl or 3-nitro-4-hydroxyphenyl;
    • (ii) when Y represents —O—, then Y² and Y³ do not both represent 4-methoxyphenyl, 4-bromophenyl, 3-nitro-4-aminophenyl, 3-nitro-4-hydroxyphenyl or 2-carboxyphenyl;
  • (B) L² and L³ both represent —C(O)N(H)—, R^2b represents the requisite -L³-Y³ group, R^2c represents -L¹-Y^1a, -L^1a-Y^1a represents —COOH, when Y represents —O— or —S(O)₂, then Y² and Y³ do not both represent 4-methoxyphenyl;
  • (C) L² and L³ both represent —N(H)C(O)—, R^2c represents the requisite -L³-Y³ group, R^2b represents -L¹-Y^1a, -L^1a-Y^1a represents —COOH, when Y represents —O—, then Y² and Y³ do not both represent 4-nitrophenyl;(III) R^2c represents the requisite -L³-Y³ group, R^2b represents -L¹-Y^1a, -L¹-Y¹ and -L^1a-Y^1a both represent —S(O)₃H, L² and L³ both represent —OS(O)₂—, Y represents —S(O)₂—:
  • (A) Y² and Y³ do not both represent phenyl, each of which are substituted at the 4-position with A, in which A represents G¹, G¹ represents -A¹-R^16a, A¹ represents —N(H)S(O)₂—, and R^16a represents either 3-nitrophenyl or 3-aminophenyl;
  • (B) Y² and Y³ do not both represent 4-nitrophenyl;(IV) R^2c represents the requisite -L³-Y³ group, -L¹-Y¹ represents —C(O)OH, L² represents —O—CH₂—, L³ represents —(CH₂)₂N(R^w)—CH₂—, R^w represents methyl substituted by ═O and —O-tert-butyl, Y represents —S(O)₂—, then Y² and Y³ do not both represent unsubstituted phenyl groups;(V) Y represents —O—, R^2b represents -L^1a-Y^1a, -L¹-Y¹ and -L^1a-Y^1a represent —COOH, R^2c represents the requisite -L³-Y³ group, L² and L³ both represent —N(H)S(O)₂—, then:
  • (i) Y² and Y³ do not both represent 4-nitrophenyl, 4-(methanesulfonyl)phenyl (i.e. 4-(-S(O)₂CH₃)phenyl), 4-cyanophenyl, 4-(acetamido)phenyl, 4-acetylphenyl (i.e. 4-C(O)CH₃)phenyl) or 4-methoxyphenyl;(VI) Y represents —O—, R^2b represents hydrogen, -L¹-Y¹ represents —COOH, R² represents the requisite -L³-Y³ group, L² represents —N(H)S(O)₂—:
  • (i) L³ represents —CH₂—N(H)S(O)₂—, then Y² and Y³ 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)CH₃) or 2,5-dimethoxyphenyl;
  • (ii) L³ represents —CH₂—N(H)S(O)₂—, then Y² does not represent 4-nitrophenyl when Y³ represents 4-(acetamido)phenyl, 2,5-dimethoxyphenyl, 4-carboxyphenyl, 4-cyanophenyl, 2,4-dinitrophenyl, 2-(ethoxycarbonyl)phenyl (i.e. 2-COOCH₃)phenyl), 4-methoxyphenyl, bromo-6-chloro-pyrid-3-yl or 4-(methanesulfonyl)phenyl;
  • (iii) L³ represents —N(H)S(O)₂—, then Y² and Y³ do not both represent 4-nitrophenyl;(VII) Y represents —O—, R^2c represents hydrogen, -L¹-Y¹ represents —COOH, R^2b represents the requisite -L³-Y³ group:
  • (i) L² represents —N(H)S(O)₂—, Y² represents 4-carboxyphenyl:
    • (a) then when L³ represents —CH₂—N(H)—C(O)—CH₂—, Y³ does not represent unsubstituted phenyl;
    • (b) then when L³ represents —CH₂—N(H)—C(O)—, Y³ does not represent unsubstituted 2-furanyl;
  • (ii) then when L² represents —N(H)C(O)CH₂—, L³ represents —CH₂—N(H)—C(O)—CH₂—, Y² and Y³ 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 D₂; D_2b represents —C(-L²-Y²)═; D₁, D₂ and D₃ 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 -L³-Y³ group, -L¹-Y¹ represents —C(O)OR^9b; L² represents —N(H)S(O)₂—; L³ represents —(CH₂)_pN(R^w)-A¹⁹-:(1) A¹⁹ represents —S(O)₂—, p represents 0, then Y² and Y³ 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 X¹ in which X¹ represents —OR^5h, and R^5h represents n-pentyl, isobutyl, n-propyl, ethyl or methyl;
    • (iii) R^w represents H, R^2b represents X¹ in which X¹ 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 X¹, X¹ represents Z^2a, in which Z^2a represents R^5a, and R^5a represents methyl, —CF₃, —CH₂OH, —CH═CH₂, ethyl or n-propyl;
    • (v) Fr represents H, R^2b represents X¹, in which X¹ 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 Y² does not represent 4-methylphenyl when:
  • (A) R^9b represents H:
    • (i) A¹⁹ represents —S(O)₂— and Y³ represents 4-methylphenyl, 4-acetylphenyl (i.e. 4-(C(O)CH₃)phenyl) or 4-nitrophenyl;
    • (ii) A¹⁹ represents —C(O)—, and Y³ represents 4-pyridyl;(V) Y represents —O—, R^2b represents -L^1a-Y^1a, -L¹-Y¹ and -L^1a-Y^1a represent —COOH, R^2c represents the requisite -L³-Y³ group, L² and L³ both represent —N(H)S(O)₂—, then:
  • (i) Y² and Y³ do not both represent 4-nitrophenyl, 4-(methanesulfonyl)phenyl (i.e. 4-(-S(O)₂CH₃)phenyl), 4-cyanophenyl, 4-(acetamido)phenyl, 4-acetylphenyl (i.e. 4-C(O)CH₃)phenyl) or 4-methoxyphenyl;(VI) Y represents —O—, R^2b represents hydrogen, -L¹-Y¹ represents —COOH, R^2c represents the requisite -L³-Y³ group, L² represents —N(H)S(O)₂—:
  • (i) L³ represents —CH₂—N(H)S(O)₂—, then Y² and Y³ 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)CH₃) or 2,5-dimethoxyphenyl;
  • (ii) L³ represents —CH₂—N(H)S(O)₂—, then Y² does not represent 4-nitrophenyl when Y³ represents 4-(acetamido)phenyl, 2,5-dimethoxyphenyl, 4-carboxyphenyl, 4-cyanophenyl, 2,4-dinitrophenyl, 2-(ethoxycarbonyl)phenyl (i.e. 2-COOCH₃)phenyl), 4-methoxyphenyl, 5-bromo-6-chloro-pyrid-3-yl or 4-(methanesulfonyl)phenyl;
  • (iii) L³ represents —N(H)S(O)₂—, then Y² and Y³ do not both represent 4-nitrophenyl;(VII) Y represents —O—, R² represents hydrogen, -L¹-Y¹ represents —COOH, R^2b represents the requisite -L³-Y³ group:
  • (i) L² represents —N(H)S(O)₂—, Y² represents 4-carboxyphenyl:
    • (a) then when L³ represents —CH₂—N(H)—C(O)—CH₂—, Y³ does not represent unsubstituted phenyl;
    • (b) then when L³ represents —CH₂—N(H)—C(O)—, Y³ does not represent unsubstituted 2-furanyl;
  • (ii) then when L² represents —N(H)C(O)CH₂—, L³ represents —CH₂—N(H)—C(O)—CH₂—, Y² and Y³ 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 Y¹ (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 Y¹ (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) C₄ 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. LTC₄, LTD₄ or LTE₄ is inhibited or decreased, or where it is required that the activation of a Cys-LT receptor (e.g. Cys-LT, or Cys-LT₂) 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 LTD₄, LTE₄ or, especially, LTC₄.

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 LTE₄.

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 LTC₄), 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'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, LTC₄ synthase and/or a method of treatment of a disease in which inhibition of the synthesis of LTC₄ 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 PDE₄ 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 LTC₄ 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, LTC₄ synthase catalyses the reaction where the substrate LTA₄ methyl ester is converted to the corresponding LTC₄ methyl ester. Recombinant human LTC₄ 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 LTC₄ methyl ester is performed with reversed phase HPLC (Waters 2795 utilizing an Onyx Monolithic C18 column). The mobile phase consists of acetonitrile/MeOH/H₂O (32.5/30/37.5) with 1% acetic acid pH adjusted with NH₃ 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 LTC₄ 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 LTA₄ 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 LTC₄ can be used:

In the assay, LTC₄ synthase catalyses the reaction where the substrate LTA₄ is converted to LTC₄. Recombinant human LTC₄ 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 LTC₄ 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 LTA₄ (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 aqueousBINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthylBoc tert-butoxycarbonylbrine saturated aqueous solution of NaClconc concentratedDCM dichloromethane

DMAP 4-N,N-dimethylaminopyridine

DMF N,N-dimethylformamide

EDCl (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideEtOAc ethyl acetateEtOH ethanoleq equivalentsMeOH methanolNMR nuclear magnetic resonancePd—C palladium on charcoal (10%)Pd₂dba₃ tris(dibenzylideneacetone)dipalladium(0)rt room temperaturerx temperaturesat saturatedTEA triethylamineTFA trifluoroacetic acidTLC thin layer chromatographyxantphos 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 NaHCO₃ (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 (Na₂SO₄), 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), K₂CO₃ (2.87 g, 16.21 mmol), (CH₃)₂SO₄ (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 NH₄OH, extractive workup (EtOAc), drying (Na₂SO₄), 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 K₂CO₃ (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 (NaHCO₃ (sat), HCl (0.1 M)), drying (Na₂SO₄), 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 (Na₂SO₄) 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 CH₂Cl₂. 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, NaHCO₃ (sat)), drying (Na₂SO₄), 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), Cs₂CO₃, (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), Cs₂CO₃, (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 (Na₂SO₄), 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), K₂CO₃ (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, NaHCO₃ (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, NaHCO₃ (5%), water, brine), drying (Na₂SO₄) 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 (NaHCO₃ (5%), water, brine), drying (Na₂SO₄), 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), Na₂SO₄ (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 NaHCO₃. 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), NaHCO₃ (10%), water and brine. The organic layer was dried (Na₂SO₄), filtered and concentrated to give the ester XIV which was used without further purification. Yields are given in Table 4.

Step 2: LiOHxH₂O (104 mg, 2.48 mmol) was added to XIV (0.827 mmol) in H₂O (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 H₂O, brine, dried (Na₂SO₄) 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), NaHCO₃ (10%), H₂O and brine. The organic layer was dried (Na₂SO₄), 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), NaHCO₃ (10%), H₂O and brine. The organic layer was dried (Na₂SO₄), 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 (KHSO₄, 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), K₂CO₃ (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 (KHSO₄, 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, NaHCO₃ (aq), brine), drying (Na₂SO₄) 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), NaHCO₃ (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. Na₂SO₄ 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 (CH₂Cl₂, HCl (conc), H₂O, brine, NaHCO₃ (sat)), drying (Na₂SO₄) 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

H₂SO₄ (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 NaHCO₃ and concentrated. Water (1.5 L) was added and the pH was adjusted ˜8 with solid NaHCO₃. 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 (Na₂SO₄), 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 K₂CO₃ (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 (Na₂SO₄), 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 (Na₂SO₄) 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), K₂CO₃ (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 (NaHCO₃ (sat), HCl (0.1 M), water, brine) drying (Na₂SO₄) 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 NaHCO₃ and the mixture was concentrated. Extractive workup (EtOAc, water, brine), drying (Na₂SO₄) 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), K₂CO₃ (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 (Na₂SO₄) 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 CH₃CN (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), K₂CO₃ (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 (Na₂SO₄) 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), K₂CO₃ (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 (Na₂SO₄), 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 (Na₂SO₄), 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), K₂CO₃ (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 (Na₂SO₄), 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), CH₃I (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, NaHCO₃ (sat), citric acid (10%), brine), drying (Na₂SO₄), 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, NaHCO₃ (sat)), drying (Na₂SO₄) 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), Cs₂CO₃ (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), K₂CO₃ (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, NaHCO₃ (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), Cs₂CO₃ (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), FeCl₃ (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 (Na₂SO₄), 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 NaHCO₃ (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), Na₂CO₃ (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 (Na₂SO₄) 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), K₂CO₃ (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 (Na₂SO₄), 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), Pd₂ dba₃ (60 mg, 0.065 mmol), BINAP (61 mg, 0.098 mmol), Cs₂CO₃ (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 (Na₂SO₄), 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 H₂SO₄ (0.4 g, 2.5 mmol), K₂CO₃ (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 (CH₂Cl₂, water, brine), drying (Na₂SO₄), 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 (Na₂SO₄), 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), K₂CO₃ (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, NaHCO₃ (sat), HCl (0.1 M), brine), drying (Na₂SO₄), 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 (NaHCO₃, brine), drying (Na₂SO₄), 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 (Na₂SO₄), concentration and chromatography gave the sub-title compounds.

Step 2: N-(aryl)-3-hydroxybenzenesulfonamide

BBr₃ (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 (Na₂SO₄) 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), K₂CO₃ (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 (Na₂SO₄), 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 (Na₂SO₄), 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%), NaHCO₃ (2 M)), drying (Na₂SO₄), 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), K₂CO₃ (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, NaHCO₃ (sat), brine), drying (Na₂SO₄), 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), Cs₂CO₃ (1.32 g, 4.1 mmol), Pd₂dba₃ (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%), NaHCO₃ (sat)), drying (Na₂SO₄), 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), Et₃SiH (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, NaHCO₃ (sat), water, brine), drying (Na₂SO₄) 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 (Na₂SO₄), 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), K₂CO₃ (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 (Na₂SO₄), 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 CH₂Cl₂ was stirred at rt for 24 h. Concentration, extractive workup (EtOAc, water, brine), drying (Na₂SO₄), 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

NH₄Cl (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 (Na₂SO₄), 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), K₂CO₃ (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 (Na₂SO₄) 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, NaHCO₃ (sat), H₂O, brine), drying (Na₂SO₄) 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, H₂O, brine), drying (Na₂SO₄) 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), Cs₂CO₃ (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, H₂O, brine), drying (Na₂SO₄) 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 (Na₂SO₄) and concentration gave the sub-title compounds.

Step 2: N-(aryl)-4-hydroxybenzenesulfonamide

BBr₃ 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, NaHCO₃ (10%), water, brine), drying (Na₂SO₄), 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

FeCl₃.6H₂O (0.82 g, 3.0 mmol) in H₂O (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 (Na₂SO₄), 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 (Na₂SO₄), 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), Pd₂(dba)₃ (10 mg, 0.011 mmol), xantphos (10 mg, 0.017 mmol), Cs₂CO₃ (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 (CH₂Cl₂), 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), K₂CO₃ (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 (Na₂SO₄), 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, NaHCO₃ (sat), citric acid (10%), water, brine), drying (Na₂SO₄) 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), Na₂CO₃ (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 (Na₂SO₄), 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), K₂CO₃ (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 (Na₂SO₄) 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, NaHCO₃ (sat), water, brine), drying (Na₂SO₄) 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), NaN₃ (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, NaHCO₃ (sat) water, brine), drying (Na₂SO₄) 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, KHCO₃ (sat), water, brine), drying (Na₂SO₄) 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), Cs₂CO₃ (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), K₂CO₃ (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 Na₂CO₃ (147 mg, 1.38 mmol) in H₂O (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, NaHCO₃ (sat), water, brine), drying (Na₂SO₄) 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.   1H NMR (DMSO-d6, 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-d6 + CF3COOH) 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-d6 + CF3COOH) 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-d6 + CF3COOH) 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 LTC₄ synthase at a concentration of 10 μM or below. For example, the following representative compounds of the examples exhibited the following IC₅₀ values.

TABLE 39
Selected compound data
Compound (Table:Number) IC50 [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 LTC₄ 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

Claims

1. A compound of formula I,

2. A compound as claimed in claim 1, wherein D1, D2 and D3 respectively represent —C(R1a)═, —C(R1b)═ and —C(R1c)═.

3. A compound as claimed in claim 1, wherein ring A represents ring (I).

4. A compound as claimed in claim 1, wherein Ea1 and Ea5 independently represent —C(H)═ and Ea2, Ea3 and Ea4 respectively represent —C(R2b)═, —C(R2c)═ and —C(R2d)═.

5. A compound as claimed in claim 1, wherein one of R2b or R2c represents the requisite -L3-Y3 group and the other represents halo, hydrogen or -L1a-Y1a.

6. A compound as claimed in claim 1, wherein R2d represents hydrogen.

7. A compound as claimed in claim 1, wherein L1 and L1a independently represent a single bond or C1-4 alkylene.

8. A compound as claimed in claim 1, wherein Y1 and Y1a independently represent —C(O)OR9b.

9. A compound as claimed in claim 1, wherein R9b represents C1-6 alkyl or H.

10. A compound as claimed in claim 1, wherein A represents I) C1-8 alkyl optionally substituted by one or more substituents selected from G1; or II) G1.

11. A compound as claimed in claim 1, wherein G1 represents halo (e.g. fluoro or chloro), cyano, —NO2 or -A1-R16a.

12. A compound as claimed in claim 1, wherein A1 represents a single bond, —C(O)A2-, —S—, —S(O)2A3-, —N(R17a)A4- or —OA5-.

13. A compound as claimed in claim 1, wherein L2 and L3 independently represent a spacer group selected from —(CH2)p—C(O)A17-, —(CH2)p—S(O)2A18-, —(CH2)p—N(Rw)A19- and —(CH2)p—O—.

14. A compound as claimed in claim 1, wherein A17 represents —N(Rw)SO2—; A18 represents —N(Rw)—; and/or A19 represents a single bond, —C(Ry3)(Ry4)—, —C(O)—, —C(O)C(Ry3)(Ry4)—, —S(O)2— or —C(O)N(Rw)—.

15. A compound as claimed in claim 1, wherein Rw represents hydrogen or X8.

16. A compound as claimed in claim 1, wherein X8 represents C1-4 alkyl or aryl optionally substituted by one or more substituents selected from halo and —C(O)R26d, in which R26d represents C1-4 alkyl.

17. A compound as claimed in claim 1, wherein Y2 and Y3 independently represent optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, 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.

18. A compound as claimed in claim 17, wherein Y2 and Y3 independently represent optionally substituted pyridyl, benzofuranyl, isoquinolinyl and/or phenyl.

19. A compound as claimed in claim 17, wherein the optional substituents are selected from halo; cyano; —NO2; C1-6 alkyl optionally substituted with one or more halo groups; heterocycloalkyl optionally substituted by one or more substituents selected from C1-3 alkyl and ═O; —OR26; —SR26; —C(O)R26; —C(O)OR26; —N(R26)R27; and —S(O)2R28; wherein R26 and R27 independently represent H, C1-6 alkyl optionally substituted by one or more halo groups or aryl optionally substituted by one or more halo or C1-3 alkyl groups (which alkyl group is optionally substituted by one or more halo atoms); and R28 represents aryl or, particularly C1-6 alkyl.

20. Use of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease in which inhibition of the synthesis of leukotriene C4 is desired and/or required.

21. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, provided that: when D2a represents D2; D2b represents —C(-L2-Y2)═; D1, D2 and D3 respectively represent —C(R1a)═, —C(R1b)═ and —C(R1c)═; ring A represents ring (I); Ea1, Ea2, Ea3, Ea4 and Ea5 respectively represent —C(H)═, —C(R2b)═, —C(R2c)═, —C(R2d)═ and —C(H)═; R1a, R1b, R1c and R2d all represent hydrogen:(I) R2c represents the requisite -L3-Y3 group, -L1-Y1 represents —C(O)OR9b; L2 represents —N(H)S(O)2—; L3 represents —(CH2)pN(Rw)-A19-:(1) A19 represents —S(O)2—, p represents 0, then Y2 and Y3 do not both represent 4-methylphenyl when: (A) Y represents —O— and R9b represents H;(B) Y represents —O— and R9b represents methyl, and (in both cases): (i) Rw represents H or n-hexyl, and R2b represents H;(ii) Rw represents H, R2b represents X1 in which X1 represents —OR5h, and R5h represents n-pentyl, isobutyl, n-propyl, ethyl or methyl;(iii) Rw represents H, R2b represents X1 in which X1 represents —N(R6b)R7b, one of R6b or R7b represents H, and the other represents methyl, ethyl, n-propyl and n-butyl;(iv) Rw represents H, R2b represents X1, X1 represents Z2a, in which Z2a represents R5a, and R5a represents methyl, —CF3, —CH2OH, —CH═CH2, ethyl or n-propyl;(v) Rw represents H, R2b represents X1, in which X1 represents fluoro, chloro or cyano;(c) Rw represents H, R2b represents -L1a-Y1a, -L1a-Y1a represents —C(O)OR9b, and: (i) both R9b substituents represent hydrogen;(ii) both R9b substituents represent methyl;(D) Y represents —S— and R9b, Rw and R2b all represent H;(E) Y represents —S—, R9b represents methyl, and Rw and R2b represent H;(F) Y represents —O—, R9b represents methyl, Rw represents H, R2b represents X1, X1 represents Z2a and Z2a represents —C(O)NH2;(2) p represents 1, Y represents —O—, R2b and Rw both represent H, then Y2 does not represent 4-methylphenyl when: (A) R9b represents H; or(B) R9b represents methyl, and (in both cases): (i) A19 represents —S(O)2— and Y3 represents 4-methylphenyl, 4-acetylphenyl (i.e. 4-(C(O)CH3)phenyl) or 4-nitrophenyl;(ii) A19 represents —C(O)—, and Y3 represents 4-pyridyl;(II) L1 represents a single bond, Y1 represents —C(O)OR9b, R9b represents H: (A) L2 and L3 both represent —C(O)N(H)—, R2c represents the requisite -L3-Y3 group, R2b represents -L1-Y1a, -L1a-Y1a represents —COOH, then: (i) when Y represents —S(O)2—, then Y2 and Y3 do not both represent 4-methoxyphenyl, 3-nitro-4-aminophenyl or 3-nitro-4-hydroxyphenyl;(ii) when Y represents —O—, then Y2 and Y3 do not both represent 4-methoxyphenyl, 4-bromophenyl, 3-nitro-4-aminophenyl, 3-nitro-4-hydroxyphenyl or 2-carboxyphenyl;(B) L2 and L3 both represent —C(O)N(H)—, R2b represents the requisite -L3-Y3 group, R2c represents -L1-Y1a, -L1a-Y1a represents —COOH, when Y represents —O— or —S(O)2, then Y2 and Y3 do not both represent 4-methoxyphenyl;(C) L2 and L3 both represent —N(H)C(O)—, R2c represents the requisite -L3-Y3 group, R2b represents -L1-Y1a, -L1a-Y1a represents —COOH, when Y represents —O—, then Y2 and Y3 do not both represent 4-nitrophenyl;(III) R2c represents the requisite -L3-Y3 group, R2b represents -L1-Y1a, -L1-Y1 and -L1a-Y1a both represent —S(O)3H, L2 and L3 both represent —OS(O)2—, Y represents —S(O)2—: (A) Y2 and Y3 do not both represent phenyl, each of which are substituted at the 4-position with A, in which A represents G1, G1 represents -A1-R16a, A1 represents —N(H)S(O)2—, and R16a represents either 3-nitrophenyl or 3-aminophenyl;(B) Y2 and Y3 do not both represent 4-nitrophenyl;(IV) R2c represents the requisite -L3-Y3 group, -L1-Y1 represents —C(O)OH, L2 represents —O—CH2, L3 represents —(CH2)2N(Rw)—CH2—, Rw represents methyl substituted by ═O and —O-tert-butyl, Y represents —S(O)2—, then Y2 and Y3 do not both represent unsubstituted phenyl groups;(V) Y represents —O—, R2b represents -L1a-Y1a, -L1-Y1 and -L1a-Y1a represent —COOH, R2c represents the requisite -L3-Y3 group, L2 and L3 both represent —N(H)S(O)2—, then: (i) Y2 and Y3 do not both represent 4-nitrophenyl, 4-(methanesulfonyl)phenyl (i.e. 4-(-S(O)2CH3)phenyl), 4-cyanophenyl, 4-(acetamido)phenyl, 4-acetylphenyl (i.e. 4-C(O)CH3)phenyl) or 4-methoxyphenyl;(VI) Y represents —O—, R2b represents hydrogen, -L1-Y1 represents —COOH, R2 represents the requisite -L3-Y3 group, L2 represents —N(H)S(O)2—: (i) L3 represents —CH2—N(H)S(O)2—, then Y2 and Y3 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)CH3) or 2,5-dimethoxyphenyl;(ii) L3 represents —CH2—N(H)S(O)2—, then Y2 does not represent 4-nitrophenyl when Y3 represents 4-(acetamido)phenyl, 2,5-dimethoxyphenyl, 4-carboxyphenyl, 4-cyanophenyl, 2,4-dinitrophenyl, 2-(ethoxycarbonyl)phenyl (i.e. 2-COOCH3)phenyl), 4-methoxyphenyl, 5-bromo-6-chloro-pyrid-3-yl or 4-(methanesulfonyl)phenyl;(iii) L3 represents —N(H)S(O)2—, then Y2 and Y3 do not both represent 4-nitrophenyl;(VII) Y represents —O—, R2c represents hydrogen, -L1-Y1 represents —COOH, R2b represents the requisite -L3-Y3 group: (i) L2 represents —N(H)S(O)2—, Y2 represents 4-carboxyphenyl: (a) then when L3 represents —CH2—N(H)—C(O)—CH2—, Y3 does not represent unsubstituted phenyl;(b) then when L3 represents —CH2—N(H)—C(O)—, Y3 does not represent unsubstituted 2-furanyl;(ii) then when L2 represents —N(H)C(O)CH2—, L3 represents —CH2—N(H)—C(O)—CH2—, Y2 and Y3 do not both represent unsubstituted phenyl.

22. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, provided that: when D2a represents D2; D2b represents —C(-L2-Y2)═; D1, D2 and D3 respectively represent —C(R1a)═, —C(R1b)═ and —C(R1c)═; ring A represents ring (I); Ea1, Ea2, Ea3, Ea4 and Ea5 respectively represent —C(H)═, —C(R2b)═, —C(R2c)═, —C(R2d)═, and —C(H)═; R1a, R1b, R1c and R2d all represent hydrogen:(I) R2c represents the requisite -L3-Y3 group, -L1-Y1 represents —C(O)OR9b; L2 represents —N(H)S(O)2—; L3 represents —(CH2)pN(Rw)-A19-:(1) A19 represents —S(O)2—, p represents 0, then Y2 and Y3 do not both represent 4-methylphenyl when: (A) Y represents —O— and R9b represents H: (i) Rw represents H or n-hexyl, and R2b represents H;(ii) Rw represents H, R2b represents X1 in which X1 represents —OR5h, and R5h represents n-pentyl, isobutyl, n-propyl, ethyl or methyl;(iii) Rw represents H, R2b represents X1 in which X1 represents —N(R6b)R7b, one of R6b or R7b represents H, and the other represents methyl, ethyl, n-propyl and n-butyl;(iv) Rw represents H, R2b represents X1, X1 represents Z2a, in which Z2a represents R5a, and R5a represents methyl, —CF3, —CH2OH, —CH═CH2, ethyl or n-propyl;(v) Rw represents H, R2b represents X1, in which X1 represents fluoro, chloro or cyano;(B) Y represents —O—, R9b represents methyl, and Rw and R2b represent H;(C) Rw represents H, R2b represents -L1a-Y1a, -L1a-Y1a represents —C(O)OR9b, and both R9b substituents represent hydrogen;(D) Y represents —S— and R9b, Rw and R2b all represent H;(2) p represents 1, Y represents —O—, R2b and Rw both represent H, then Y2 does not represent 4-methylphenyl when: (A) R9b represents H: (i) A19 represents —S(O)2— and Y3 represents 4-methylphenyl, 4-acetylphenyl (i.e. 4-(C(O)CH3)phenyl) or 4-nitrophenyl;(ii) A19 represents —C(O)—, and Y3 represents 4-pyridyl;(V) Y represents —O—, R2b represents -L1a-Y1a, -L1-Y1 and -L1a-Y1a represent —COOH, R2c represents the requisite -L3-Y3 group, L2 and L3 both represent —N(H)S(O)2—, then: (i) Y2 and Y3 do not both represent 4-nitrophenyl, 4-(methanesulfonyl)phenyl (i.e. 4-(-S(O)2CH3)phenyl), 4-cyanophenyl, 4-(acetamido)phenyl, 4-acetylphenyl (i.e. 4-C(O)CH3)phenyl) or 4-methoxyphenyl;(VI) Y represents —O—, R2b represents hydrogen, -L1-Y1 represents —COOH, R2c represents the requisite -L3-Y3 group, L2 represents —N(H)S(O)2—: (i) L3 represents —CH2—N(H)S(O)2—, then Y2 and Y3 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)CH3) or 2,5-dimethoxyphenyl;(ii) L3 represents —CH2—N(H)S(O)2—, then Y2 does not represent 4-nitrophenyl when Y3 represents 4-(acetamido)phenyl, 2,5-dimethoxyphenyl, 4-carboxyphenyl, 4-cyanophenyl, 2,4-dinitrophenyl, 2-(ethoxycarbonyl)phenyl (i.e. 2-COOCH3)phenyl), 4-methoxyphenyl, 5-bromo-6-chloro-pyrid-3-yl or 4-(methanesulfonyl)phenyl;(iii) L3 represents —N(H)S(O)2—, then Y2 and Y3 do not both represent 4-nitrophenyl;(VII) Y represents —O—, R2c represents hydrogen, -L1-Y1 represents —COOH, R2b represents the requisite -L3-Y3 group: (i) L2 represents —N(H)S(O)2—, Y2 represents 4-carboxyphenyl: (a) then when L3 represents —CH2—N(H)—C(O)—CH2—, Y3 does not represent unsubstituted phenyl;(b) then when L3 represents —CH2—N(H)—C(O)—, Y3 does not represent unsubstituted 2-furanyl;(ii) then when L2 represents —N(H)C(O)CH2—, L3 represents —CH2—N(H)—C(O)—CH2—, Y2 and Y3 do not both represent unsubstituted phenyl, for use as a pharmaceutical.

23. A compound as claimed in claim 21, wherein L2 and L3 independently represent a single bond or a spacer group selected from —(CH2)p—C(Ry3)(Ry4)—(CH2)q-A16-, —(CH2)p—C(O)A17-, —(CH2)p—S—, —(CH2)p—SC(Ry3)(Ry4)—, —(CH2)p—S(O)2A18- or —(CH2)p—OA20-.

24. A compound as claimed in claim 21, wherein A19 represents a single bond, —C(Ry3)(Ry4)—, —C(O)—, —C(O)C(Ry3)(Ry4)—, —C(O)N(Rw)—, —C(O)O— or —S(O)2N(Rw)—.

25. A pharmaceutical formulation including a compound of formula I, as defined in claim 22, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

26. The use as claimed in claim 20, wherein the disease is a respiratory disease, inflammation and/or has an inflammatory component.

27. The use as claimed in claim 26 wherein the disease is an allergic disorder, asthma, childhood wheezing, a chronic obstructive pulmonary disease, bronchopulmonary dysplasia, cystic fibrosis, an interstitial lung disease, an ear nose and throat disease, an eye disease, a skin diseases, a rheumatic disease, vasculitis, a cardiovascular disease, a gastrointestinal disease, a urologic disease, a disease of the central nervous system, an endocrine disease, urticaria, anaphylaxis, angioedema, oedema in Kwashiorkor, dysmenorrhoea, a burn-induced oxidative injury, multiple trauma, pain, toxic oil syndrome, endotoxin chock, sepsis, a bacterial infection, a fungal infection, a viral infection, sickle cell anaemia, hypereosinofilic syndrome, or a malignancy.

28. The use as claimed in claim 27, wherein the disease is an allergic disorder, asthma, rhinitis, conjunctivitis, COPD, cystic fibrosis, dermatitis, urticaria, an eosinophilic gastrointestinal disease, an inflammatory bowel disease, rheumatoid arthritis, osteoarthritis or pain.

29. A method of treatment of a disease in which inhibition of the synthesis of leukotriene C4 is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.

30. A combination product comprising: (A) a compound of formula I as defined in claim 1, or a pharmaceutically-acceptable salt thereof; 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.

31. A combination product as claimed in claim 30 which comprises a pharmaceutical formulation including a compound of formula I as defined in claim 1, or a pharmaceutically-acceptable salt thereof, another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.

32. A combination product as claimed in claim 30 which comprises a kit of parts comprising components: (a) a pharmaceutical formulation including a compound of formula I as defined in claim 1, or a pharmaceutically-acceptable salt thereof, 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,

33. A process for the preparation of a compound of formula I as defined in claim 1, 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,

34. A process for the preparation of a pharmaceutical formulation as defined in claim 25, which process comprises bringing into association a compound of formula I, as defined in claim 22, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.

35. A process for the preparation of a combination product as defined in claim 30, which process comprises bringing into association a compound of formula I, as defined in claim 1, 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.

36. A compound as claimed in claim 22, wherein L2 and L3 independently represent a single bond or a spacer group selected from —(CH2)p—C(Ry3)(Ry4)—(CH2)q-A16-, —(CH2)p—C(O)A17-, —(CH2)p—S—, —(CH2)p—SC(Ry3)(Ry4)—, —(CH2)p—S(O)2A18- or —(CH2)p—OA20-.

37. A compound as claimed in claim 22, wherein A19 represents a single bond, —C(Ry3)(Ry4)—, —C(O)—, —C(O)C(Ry3)(Ry4)—, —C(O)N(Rw)—, —C(O)O— or —S(O)2N(Rw)—.