WO2004046141A1 - New tricyclic angiotensin ii agonists - Google Patents

Abstract

There is provided compounds of formula (I), wherein the dotted lines, XI, X2, X3, X4, A, YI, Y2, Y3, Y4, ZI, Z2, R2 and R3 have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful as selective agonists of the AT2 receptor, and thus, in particular, in the treatment of inter alia gastrointestinal conditions, such as dyspepsia, IBS and MOF, and cardiovascular disorders.

Description

NEW TRICYCLIC ANGIOTENSIN II AGONISTS

Field of the Invention

This invention relates to novel pharmaceutically-use ul compounds, in particular compounds that are angiotensin II (Angll) agonists, more particularly agonists of the Angll type 2 receptor (hereinafter the AT2 receptor), and especially agonists that bind selectively to that receptor. The invention further relates to the use of such compounds as medicaments, to pharmaceutical compositions contaimng them, and to synthetic routes to their production.

Background and Prior Art

The endogenous hormone Angll is a linear octapeptide (Asp -Arg -Val - Tyr⁴-Ile⁵-His⁶-Pro⁷-Phe⁸), and is the active component of the renin- angiotensin system (RAS). It is produced by the sequential processing of the pro-hormone angiotensinogen by renin and angiotensin converting enzyme (ACE).

The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, body fluid and electrolyte homeostasis. Ang II exerts these physiological actions in many organs including the kidneys, the adrenal glands, the heart, blood vessels, the brain, the gastrointestinal tract and the reproductive organs (de Gasparo et al, Pharmacol. Rev. (2000) 52, 415-472).

Two main classes of Angll receptors have been identified, and designated as the type 1 receptor (hereinafter the ATI receptor) and the AT2 receptor. The ATI receptor is expressed in most organs, and is believed to be responsible for the majority of the biological effects of Angll. The AT2 receptor is more prevalent than the ATI receptor in fetal tissues, the adult ovaries, the adrenal medulla and the pancreas. An equal distribution is reported in the brain and uterus (Ardaillou, J. Am. Soc. Nephrol, 10, S30-39 (1999)).

Several studies in adult individuals appear to demonstrate that, in the modulation of the response following Angll stimulation, activation of the AT2 receptor has opposing effects to those mediated by the ATI receptor.

The AT2 receptor has also been shown to be involved in apoptosis and inhibition of cell proliferation (see de Gasparo et al, supra). Further, it seems to play a role in blood pressure control. For example, it has been shown in transgenic mice lacking AT2 receptors that their blood pressure was elevated. Furthermore, it has been concluded that the AT2 receptor is involved in exploratory behaviour, pain sensitivity and theπnoregulation.

The expression of AT2 receptors has also been shown to increase during pathological circumstances, such as vascular injury, wound healing and heart failure (see de Gasparo et al, supra).

The expected pharmacological effects of agonism of the AT2 receptor are described generally in de Gasparo et al, supra.

More recently, AT2 receptor agonists have been shown to be of potential utility in the treatment and/or prophylaxis of disorders of the alimentary tract, such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see international patent application WO 99/43339). International patent application WO 00/68226 and US patent number 6,235,766 disclose compounds comprising substituted imidazolyl groups, which groups are attached, via a methylene bridge, to a phenylthiophene moiety, as agonists of angiotensin-(l-7) receptors. International patent application WO 02/072569 discloses similar compounds as agonists of the same receptors. International patent application WO 01/44239 discloses biphenylsulfonamide compounds as combined angiotensin and endothelin receptor antagonists. The use of the compounds as Ang II receptor agonists is neither mentioned nor suggested in any of these documents.

Angll antagonists (which bind to the ATI and or AT2 receptors) have been disclosed in inter alia European patent applications EP 409 332, EP 512 675, EP 516 392, EP 542 059 and EP 624 583; international patent applications WO 92/20662, WO 93/01177, WO 94/27597, WO 94/02142, WO 95/23792 and WO 94/03435; and US patent numbers 5,091,390, 5,177,074, 5,412,097, 5,250,521, 5,260,285, 5,376,666, 5,252,574, 5,262,412, 5,312,820, 5,330,987, 5,166,206, 5,932,575, 5,240,928 and 6,235,766. In particular, US 5,262,412 discloses 3,5-substituted, 4'-(l-aryl- lH-pyrazol-4-ylmethyl)-5-alkylbiphenyl based compounds. Angll agonists, and particularly AT2 receptor agonists, are not contemplated in any of these documents.

Peptide and non-peptide AT2 receptor agonists, unrelated structurally to those described herein, and potential uses thereof, have been disclosed in, for example, international patent applications WO 00/38676, WO 00/56345, WO 00/09144, WO 99/58140, WO 99/52540, WO 99/46285, WO 99/45945, WO 99/42122, WO 99/40107, WO 99/40106, WO 99/39743, WO 99/26644, WO 98/33813, WO 00/02905 and WO 99/46285; US patent number 5,834,432; and Japanese patent application JP 143695. US patent number 5,444,067 discloses compounds comprising a 5,7- dimemyl-2-e ylpyri(h^oimidazolyl group attached, via a methylene bridge, to a phenylthiophene moiety, as Angll agonists. Further, international patent application WO 02/96883 discloses compounds comprising certain monocyclic heterocyclic groups attached, via a methylene bridge, to substituted phenylthiophene and biphenyl moieties. The compounds disclosed therein are indicated as Angll agonists and in particular as selective AT2 receptor agonists.

However, there remains a need for effective and/or selective AT2 receptor agonists, which are expected to find utility in inter alia the above- mentioned conditions.

Disclosure of the Invention

According to the invention there is provided a compound of formula I,

wherein

Xi represents -C(R^la)- or-N-; X₃ represents -C(R^lc)- or-N-; the dotted lines between the pairs of substituents X₂ and X₃, and X₃ and X , signify the presence of a double bond between one of the relevant pairs of substituents and a single bond between the other pair; and

(i) when the double bond is between X₂ and X₃, then:- X₂ represents -C(R^lb)- or -N-; and

X₄ represents -N(R^ld , -S- or-O-; or

(ii) when the double bond is between X₃ and then:-

X₂ represents -N(R^lb)-, -S- or-O-; and ₄ represents -N- or -C(R^ld)-; R^la, R^lb, R^lc and R^ld independently represent H, C_λ.₆ alkyl, C_μ6 alkoxy- .₆ alkyl, Ar¹, Het¹, Cι_₃ alkyl- Ar², Cμ₃ alkyl-Het², C₁.₃ alkoxy-Ar³ or d.₃ alkoxy-Het³;

Ar¹, Ar² and Ar³ each independently represent a C₆.₁₀ aryl group, which group is optionally substituted by one or more substituents selected from =0, cyano, halo, nitro, Cι_₆ alkyl (optionally terminated by

-N(H)C(0)OR^1,a), d.₆ alkoxy, phenyl, -N(R^12a)R^12b, -C(0)R^12c,

-C(O)0R^12d, -C(0)N(R^12e)R^12f, -N(R^12g)C(0)R^12h, -N(R¹²ⁱ)C(0)N(R^12j)R^12k,

-N(R^12m)S(0)₂R^llb, -S(0)_pR^{l lc}, -OS(0)₂R^{l ld} and -S(0)₂N(R¹²ⁿ)R^12p;

Het¹, Het² and Het³ each independently represent a four- to twelve- membered heterocyclic group containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic group is optionally substituted by one or more substituents selected from =0, cyano, halo, nitro,

Q.₆ alkyl (optionally terminated by -N(H)C(0)OR^lla), C_w alkoxy, phenyl,

-N(R^12a)R^12b, -C(0)R^12c, -C(0)OR^12d, -C(0)N(R^12e)R^12f, -N(R^12g)C(0)R^12h, -N(R¹²ⁱ)C(0)N(R^12j)R^12k, -N(R^12m)S(0)₂R^{l lb}, -S(0)_pR^{l lc}, -OS(0)₂R^{l ld} and

-S(0)₂N(R¹²ⁿ)R^12p;

R^lla to R^lld independently represent Cμ₆ alkyl;

R^12a to R^12p independently represent H or Cμβ alkyl; p represents 0, 1 or 2; provided that: (1) when X₂ or X₄ represents -O- or -S-, then no more than two of the other ring atoms in the ring containing the groups Xi, X₂, X₃ and ₄ may comprise a nitrogen atom; and

(2) when X] represents -C(R^la)-, the double bond is between X₃ and X₄, X₂ represents -N(R^lb)-, X₃ represents -N- and X₄ represents

-C(R^ld)-, then R^lb does not represent a substituted phenyl group; A represents -C(O) or -CH₂-;

Yi, Y₂, Y₃ and Y₄ independently represent -CH- or -CF-; Z1 represents -CH-, -0-, -S-, -N- or -CH=CH-; Z₂ represents -CH-, -0-, -S- or -N-; provided that:

(a) Zi and Z₂ are not the same;

(b) when Z₁ represents -CH=CH-, then Z₂ may only represent -CH- or -N-; and (c) other than in the specific case in which Zi represents -CΗ=CH-, and Z₂ represents -CH-, when one Zi and Z₂ represents -CH-, then the other represents -O- or -S-;

R² represents -S(0)₂N(H)C(0)R⁴, -S(0)₂N(H)S(0)₂R⁴, -C(0)N(H)S(0)₂R⁴, or, when Z_} represents -CH=CH-, R² may represent -N(H)S(0)₂N(H)C(0)R⁵ or -N(H)C(0)N(H)S(0)₂R⁵;

R³ represents Ci_6 alkyl, Cι_₆ alkoxy, C_\.₆ alkoxy-Cι.₆-alkyl or di-Cι_₃-

R⁴ represents Cj_6 alkyl, Cμ₆ alkoxy, C ₆ alkoxy-Cι_₆-alkyl,

C]-₃ alkoxy-Cι-₆-alkoxy, Cι-₆ alkylamino or di-C]-₆ alkylamino; and R⁵ represents C]-₆ alkyl, or a pharmaceutically-acceptable salt thereof, which compounds and salts are referred to together 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 the invention 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 or by freeze-drying). 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.

Unless otherwise specified, alkyl groups, and the alkyl parts of alkoxy, alkoxyalkyl, alkoxyalkoxy, alkylamino, alkylaminoalkyl, alkyl-aryl, alkyl- heterocyclic groups, alkoxy-aryl and alkoxy-heterocyclic groups, as 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. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic/acyclic. Such alkyl groups, and alkyl parts of alkoxy, alkoxyalkyl, alkoxyalkoxy, alkylamino, alkylaminoalkyl, alkyl-aryl, alkyl-heterocyclic, alkoxy-aryl and alkoxy-heterocyclic groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated. Unless otherwise specified, such groups may also be substituted by one or more halo, and especially fluoro, atoms.

For the avoidance of doubt, alkoxy and alkoxyalkoxy groups are attached to the rest of the molecule via the/an oxygen atom in that group, alkylamino groups are attached to the rest of the molecule via the nitrogen atom of the amino part of that group, alkoxyalkyl, alkylaminoalkyl, alkyl-aryl and alkyl- heterocyclic groups are attached to the rest of the molecule via the alkyl part of that group, and alkoxy-aryl and alkoxy-heterocyclic groups are attached to the rest of the molecule via the alkyl part of the alkoxy part of that group.

The term "halo", when used herein, includes fluoro, chloro, bromo and iodo.

For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention (for example any two or more of the substituents R^la, R^lb, R^lc and R^ld) may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which two or more of R^la to R^ld represent Cι-₆ alkyl groups, the alkyl groups in question may be the same or different. Similarly, when aryl and heterocyclic groups are substituted by more than one substituent as defined herein, the identities of the individual substituents are not to be regarded as being interdependent.

C_δ-io aryl groups include phenyl, naphthyl and the like (preferably phenyl). Preferred optional substituents on aromatic groups include Cι_₃ alkyl groups (such as methyl) or Cι_₃ alkoxy groups.

Het (Het to Het ) groups that may be mentioned include those containing 1 to 4 heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) and in which the total number of atoms in the ring system are between five and twelve. Het (Het¹ to Het³) groups may be fully saturated, wholly aromatic, partly aromatic and/or bicyclic in character. Heterocyclic groups that may be mentioned include benzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzomorpholinyl, benzothiophenyl, chromanyl, cinnolinyl, dioxanyl, furanyl, hydantoinyl, imidazolyl, imidazo[l,2-α]pyridinyl, indolyl, isoquinolinyl, isoxazolyl, maleimido, morpholinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimindinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl. 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiophenyl, thiochromanyl, triazolyl, tetrazolyl and the like. Values of Het¹ that may be mentioned include thiophenyl, furanyl, pyridinyl and thiazolyl. Values of Het² that may be mentioned include pyridinyl, furanyl, thiophenyl and thiazolyl. Values of Het³ that may be mentioned include pyridinyl.

Substituents on Het (Het¹ to Het³) groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of Het (Het to Het ) groups may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any fused carbocyclic ring that may be present as part of the ring system. Het (Het¹ to

Het ) groups may also be in the N- or S-oxidised form.

Preferred ring systems comprising the substituents Yi, Y₂, Y₃ and Y₄ include phenyl groups. For the avoidance of doubt, the ring systems in compounds of formula I that comprise the groups ϊ_\ and Z₂, are aromatic in nature. In some instances, for example in cases where one or more of Zj and Z₂ represent -CH- or -Ν- the skilled person will appreciate that an additional H atom may necessarily be bonded to that CH group or Ν atom, in order to ensure that the rules of valency are adhered to. Preferred ring systems comprising Z] and Z₂ include oxazole groups, thiazole groups, phenyl groups, pyridinyl groups, thiophenyl groups and furanyl groups.

In this respect, compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. Compounds of the invention 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, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.

Preferred ring systems comprising the groups Xi, X₂, X₃ and X include those in which:

X] represents -CH- or -N-;

X₃ represents -C(R^lc)- or -N-;

(i) when the double bond is between X₂ and X₃, then:- X₂ represents -CH- or -N-;

X₄ represents -N(R^ld)-, -S- or -0-;

(ii) when the double bond is between X₃ and X₄, then: X₂ represents -N(R^lb , -S- or -0-; X₄ represents -CH- or -N-.

Thus, preferred ring systems comprising the groups Xi, X₂, X₃ and X include thiophenyl (including thiophen-2-yl and thiophen-3-yl) groups, furanyl (including furan-2-yl and furan-3-yl) groups, pyrrolyl (including lH-pyrrol-2-yl and lH-pyrrol-3-yl) groups, pyrazolyl (including 2H- pyrazol-3-yl and lH-pyrazol-4-yl) groups, imidazolyl (including IH- imidazol-2-yl and lH-imidazol-5-yl) groups, thiazolyl (including thiazol-2- yl and thiazol-5-yι) groups, oxazolyl (including oxazol-2-yl and oxazol-5- yl) groups, thiadiazolyl (including [l,3,4]-thiadiazol-2-yl and [1,2,4]- thiadiazol-5-yl) groups, oxadiazolyl (including [l,3,4]-oxadiazol-2-yl and [l,2,4]-oxadiazol-5-yl) groups, triazolyl (including 4H-[l,2,4]-triazol-3-yl and lH-[l,2,4]-triazol-5-yl) groups and tetrazolyl (including lH-tetrazol-5- yl and 2H-tetrazol-5-yl) groups.

Preferred compounds of the invention include those in which: R^lb represents Η or Q.₃ alkyl, such as methyl;

R^lc represents Cι_₃ alkyl, optionally substituted by one or more fluoro atoms, or, more preferably, Η;

R^ld represents Η or Cι_₃ alkyl, such as methyl;

Yi, Y₂, Y₃ and Y₄ all represent -CΗ-; Z_! represents -CH=CH- or, especially, -S-;

Z₂ represents -CH-;

R² represents S(0)₂N(H)C(0)R⁴;

R³ represents w-butyl or, particularly, wo-butyl;

R⁴ represents n-butoxymethyl, wo-butoxy and, especially, «-butoxy.

More preferred compounds of the invention include the compounds of the examples described hereinafter.

Compounds of formula I may be made in accordance with techniques 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 R² represents -S(0)₂N(H)C(0)R⁴ or -S(0)₂N(H)S(0)₂R⁴, and R⁴ is as, hereinbefore defined, reaction of a compound of formula II,

wherein the dotted lines, X_ls X₂, X₃, X , A, Yi, Y₂, Y₃, Y₄, Zj, Z₂ and R³ are as hereinbefore defined with a compound of formula III,

R⁴GL ^J III

wherein G represents C(O) or S(0)₂ (as appropriate), L¹ represents a suitable leaving group, such as halo (e.g. chloro or bromo) and R⁴ is as hereinbefore defined, for example at around room temperature or above (e.g. up to 60-70°C) in the presence of a suitable base (e.g. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, di-z^'so-propylamine, 1 ,8-diazabicyclo[5.4.0]undec- 7-ene, sodium hydroxide, or mixtures thereof) and an appropriate solvent (e.g. pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, trifluoromethylbenzene or triethylamine). Preferred base/solvent systems for compounds of formula III in which G is C(O) include pyrrolidinopyridine/pyridine, pyrrolidinopyridine/triethylamine, dimethylaminopyridine/pyridine or ώmethylaminopyridine/triethylamine. Preferred base/solvent systems for compounds of formula III in which G is S(0)₂ include NaOH/THF;

(ii) for compounds of formula I in which R² represents -S(0)₂N(H)C(0)R and R⁴ represents _₆ alkoxy- -g-alkyl, coupling of a compound of formula II as hereinbefore defined with a compound of formula IV,

R^4aC0₂H rv

wherein R^4a represents Cι_₆ alkoxy-Cι_₆-alkyl, for example under similar conditions to those described under process step (i) above, in the presence of a suitable coupling reagent (e.g. l,r-carbonyl-diimidazole, JV-JV- dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-/V-disuccinimidyl carbonate, benzotriazole-1- yloxytris(dimemylammo)phosphoniumhexafluorophosphate, 2-(lH- benzotriazole- 1 -yl)- 1 , 1 ,3 ,3-tetramethyluronium hexafluorophosphate, benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate, bromo-tris-pyrrolidinophosponium hexafluorophosphate or 2-(lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluorocarbonate), a suitable base (as mentioned in process step (i) above) and an appropriate solvent (as mentioned in process step (i) above);

(iii) for compounds of formula I in which R² represents -C(0)N(H)S(0)₂R⁴ and R⁴ is as hereinbefore defined, coupling of a compound of formula V,

wherein the dotted lines, Xi, X₂, X₃, X₄, A, Y_1? Y₂, Y₃, Y₄, Z_1? Z₂ and R³ are as hereinbefore defined with a compound of formula VI,

R⁴S(0)₂NH₂ VI

wherein R⁴ is as hereinbefore defined, for example in the presence of a suitable coupling reagent (such as those described in process step (ii) hereinbefore), and under similar reaction conditions to those described hereinbefore for preparation of compounds of formula I in which R⁴ represents Cι_₆ alkoxy-C]_₆-alkyl;

(iv) for compounds of formula I in which R² represents -C(0)N(H)S(0)₂R⁴ and R⁴ is as hereinbefore defined, coupling of a compound of formula VII,

wherein the dotted lines, X_l5 X₂, X₃, X₄, A, Y Y₂, Y₃, Y₄, Z_l5 Z₂ and R³ are as hereinbefore defined with a compound of formula VIII,

R⁴S(0)₂C1 VIII

wherein R⁴ is as hereinbefore defined, for example at around 50°C in the presence of a suitable base (e.g. sodium hydride) and an appropriate organic solvent (e.g. THF);

(v) for compounds of formula I in which R² represents -N(H)S(0)₂N(H)C(0)R⁵ and R⁵ is as hereinbefore defined, reaction of a compound of formula IX,

wherein the dotted lines, X X₂, X₃, X₄, A, Yi, Y₂, Y₃, Y₄, Z_ls Z₂ and R³ are as hereinbefore defined with a compound of formula X,

R⁵C(0)N(H)S(0)₂C1 X

wherein R⁵ is as hereinbefore defined, for example at or around room temperature in the presence of a suitable base (e.g. sodium hydroxide or triethylamine) and a suitable organic solvent (e.g. benzene or dichloromethane);

(vi) for compounds of formula I in which R² represents -N(H)C(0)N(H)S(0)₂R⁵ and R⁵ is as hereinbefore defined, reaction of a compound of formula IX as hereinbefore defined with a compound of formula XI,

R⁵S(0)₂N(H)C(0)OR^x XI

wherein R^x represents Cι_₂ alkyl and R⁵ is as hereinbefore defined, for example at or around room temperature in the presence of a suitable organic solvent (e.g. dichloromethane);

(vii) for compounds of formula I in which R represents -N(H)C(0)N(H)S(0)₂R⁵ and R⁵ is as hereinbefore defined, reaction of a compound of formula IX as hereinbefore defined with an isocyanate compound of formula XII,

R⁵S(0)₂NCO XII wherein R⁵ is as hereinbefore defined, for example at or around room temperature in the presence of a suitable organic solvent (e.g. dichloromethane);

(viii) for compounds of formula I in which R² represents -S(0)₂N(H)C(0)R⁴ and R⁴ represents Cι_₆ alkylamino, reaction of a compound of formula II as hereinbefore defined with an isocyanate compound of formula XIII,

R^4bNCO XIII

wherein R^4b is Cι_₆ alkyl, for example at or around room temperature in the presence of a suitable base (e.g. sodium hydroxide or potassium hydroxide and an appropriate organic solvent (e.g. acetone or acetonitrile); or

(ix) for compounds of formula I in which R² represents -S(0)₂N(H)C(0)R⁴ and R⁴ represents di-Cι-₆ alkylamino, reaction of a corresponding compound of formula I in which R² represents -S(0)₂N(H)C(0)R⁴ and R⁴ represents Cμ₆ alkoxy with an amine of formula XIV,

R^4cN(H)R^4d XIV

wherein R^4c and R^4d independently represent Cj_₆ alkyl, for example at above room temperature (e.g. at between 70°C and 100°C) in the presence of an appropriate organic solvent (e.g. toluene).

Compounds of formula V may be prepared by oxidation of a compound of formula XV,

wherein the dotted lines, X], X₂, X₃, X₄, A, Yi, Y₂, Y₃, Y₄, Zi, Z₂ and R³ are as hereinbefore defined, for example under standard oxidation conditions in the presence of a suitable oxidising agent, such as potassium permanganate or chromium (VI) oxide.

Compounds of formulae II, VII, IX and XV may be prepared by way of various techniques. For example:

(a) Compounds of formulae II, VII, IX and XV may be prepared by reaction of a compound of formula XVI,

wherein R^y represents -S0₂NH₂ (in the case of a compound of formula II), -CONH₂ (in the case of a compound of formula VII), -NH₂ (in the case of a compound of formula IX), or -CHO (in the case of a compound of formula XV) and R³, Z¹ and Z² are as hereinbefore defined, or a protected derivative thereof, with a compound of formula XVII,

wherein L² represents a suitable leaving group, such as trimethylsulphonate, or halo, such as iodo or bromo, and the dotted lines, X_ls X₂, X₃, X₄, A, Yi, Y₂, Y₃ and Y₄ are as hereinbefore defined, for example in the presence of an appropriate coupling catalyst system (e.g. a palladium catalyst, such as Pd(PPh₃)₄ or

Pd(OAc)₂/ϋgand (wherein the ligand may be, for example, PPh₃, P(o-Tol)₃ or l,l'-bis(diphenylphospbino)ferrocene)) and a suitable base (e.g. sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, triethylamine or άi-iso- propylethylamine), as well as a suitable solvent system (e.g. toluene, ethanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane or mixtures thereof). This reaction may be carried out at above room temperature (e.g. at a high temperature, such as the reflux temperature of the solvent system that is employed). Preferably, compounds of formula XVI are protected at the R^y position prior to carrying out the reaction with the compound of formula XVII. Suitable protecting groups for different values of R^y are described hereinafter. If a protected version of a compound of formula XVI is employed, this reaction may be followed by deprotection of the R^y group under standard conditions, for example as described hereinafter.

(b) Compounds of formulae II, VII, IX and XV in which A represents -CH₂-, the double bond is between X₂ and X₃, X] and X₂ both represent -N- and X₄ represents -O- may be prepared by way of reaction of a compound of formula XVIII,

XVIII

wherein R^y, Yi, Y₂, Y₃, Y₄, Zi, Z₂ and R³ are as hereinbefore defined, or a protected derivative thereof with NaN₃ and NH₄C1, for example by way of exposure to a microwave reactor at high temperature (e.g. 150°C). The intermediate so formed may then be reacted with a compound of formula XIX,

wherein R ^c is as hereinbefore defined, for example at elevated temperature (e.g. 50°C). (c) Compounds of formulae II, VII, IX and XV wherein A represents -CH₂-, and X_l9 X₂, X₃ and X4 are as hereinbefore defined may be prepared by reaction of a compound of formula XX,

wherein R^y, Yi, Y₂, Y₃, Y₄, Z_1} Z₂, R³ and L¹ are as hereinbefore defined, or a protected derivative thereof with a compound of formula XXI,

wherein M¹ represents, for example, a tin-containing moiety (e.g. a trialkylstannyl such as tributylstannyl), a boron derivative (e.g. a boronic acid), a zinc halide, a magnesium halide or an alkali metal, and the dotted lines, X_ls X₂, X₃ and X₄ are as hereinbefore defined. For example, in the case in which M¹ is a tributylstannyl or a boronic acid moiety, this reaction may be carried out under similar coupling conditions to those described hereinbefore in respect of process (a) above. Further, when M¹ represents a zinc halide, a magnesium halide or an alkali metal, the reaction may be carried out in the presence of diethyl ether or THF at room temperature. Compounds of formula XVI and protected derivatives thereof may be prepared by reaction of a corresponding compound of formula XXII,

wherein R^y, R³, Z₃ and Z₂ are as hereinbefore defined, or an appropriate protected derivative thereof, with a reagent system that will enable the introduction of the -B(OH)₂ into the appropriate ring system. Suitable reagent systems include trialkylborates (e.g. tri-zso-propylborate). Such reactions may be carried out, for example, at low temperature (e.g. between -100°C and 0°C, e.g. between -80°C (such as -78°C) and -10°C (such as -20°C)) in the presence of a suitable base (e.g. n-butyl lithium) and an appropriate organic solvent (e.g. THF), followed by acid hydrolysis (e.g. in the presence of dilute HCl).

Compounds of formula XVII may be prepared by standard techniques.

For example, compounds of formula XVII in 'which A represents -C(O)- may be prepared by way of oxidation of a compound of formula XXIII,

XXIII

wherein the dotted lines, Xi, X₂, X₃, , Yi, Y₂, Y₃, Y₄ and L² are as hereinbefore defined, for example under similar oxidation conditions to those described hereinbefore for preparation of compounds of formula V, or alternatively in the presence of pyridinium chlorochromate in dichloromethane as solvent (as described hereinafter).

Compounds of formula XVII wherein A represents -C(O)- may alternatively be prepared by reaction of a compound of formula XXI, wherein M¹ is an alkali metal with a compound of formula XXIV,

wherein Y_la Y₂, Y₃, Y , L

are as hereinbefore defined under standard conditions.

Compounds of formula XVII in which A represents -CH₂- (provided that, when the double bond is between X₂ and X₃, Xi represents -CH-, X₂ represents -N- and X₃ represents -CH-, then X₄ does not represent O) may be prepared by way of reaction of a corresponding compound of formula XXI, as hereinbefore defined, with a compound of formula XXV,

wherein Yi, Y₂, Y₃, Y₄, L¹ and L² are as hereinbefore defined, for example under similar coupling conditions to those described hereinbefore in respect of the preparation of compounds of formulae II, VII, IX and XV (process step (c)).

Compounds of formula XVII in which A represents -CH₂-, the double bond is between X₂ and X₃, Xi represents -N-, X₂ and X₃ both represent -CH- and X₄ represents -O- may be prepared by way of reaction of a compound of formula XXVI,

wherein Yi, Y₂, Y₃, Y₄ and L² are as hereinbefore defined, with vinylene carbonate, for example at high temperature (e.g. 170°C) in the presence of polyphosphoric acid.

Compounds of formula XVII in which A represents -CH₂- may be prepared by way of reaction of a compound of formula XXVII,

XXVII

wherein the dotted lines, X_l5 X₂, X₃, X₄ and L¹ are as hereinbefore defined, with a compound of formula XXVIII, XXVIII

wherein Yi, Y₂, Y₃, Y and L are as hereinbefore defined, for example under similar conditions to those described hereinbefore in respect of the preparation of compounds of formulae II, VII, IX and XV (process step (a)).

Compounds of formula XVIII and protected derivatives thereof may be prepared by reaction of a compound of formula XXIX,

wherein Y_1} Y₂, Y₃, Y₄ and L are as hereinbefore defined, with a compound of formula XVI as hereinbefore defined, for example under similar coupling conditions to those described hereinbefore in respect of the preparation of compounds of formulae II, VII, IX and XV (process step (a)).

Compounds of foπnula XX may be prepared by conversion of the OH group in a compound of formula XXX,

wherein Yi, Y₂, Y₃, Y₄, Z_ls Z₂, R³ and R^y are as hereinbefore defined to an appropriate leaving group, L¹ (e.g., in the case where L¹ is bromo, conversion may be carried out by reaction with CBr₄, for example at or around room temperature in the presence of a base (e.g. phenylphosphine) and a suitable organic solvent (e.g. DMF)). Compounds of formula XXX may be prepared by reaction of a compound of formula XXXI,

wherein Yi, Y₂, Y₃, Y₄ and L are as hereinbefore defined, with a compound of formula XVI as hereinbefore defined for example under similar coupling conditions to those described hereinbefore in respect of the preparation of compounds of formulae II, VII, IX and XV (process step (a)).

Compounds of formula XXII are available using known techniques. For example:

(a) Compounds of formula XXII in which R^y represents -S(0)₂NH₂, -C(0)NH₂ or -CHO, and protected derivatives thereof, may be prepared by reaction of a compound of formula XXXII,

XXXII

wherein R^ya represents ~S(0)₂NH₂, -C(0)NH₂ or -CHO and Zi and Z₂ are as hereinbefore defined, or a protected derivative thereof, with a compound of formula XXXIII,

R³L³ XXXIII

wherein L³ represents a suitable leaving group (such as toluenesulphonate, benzenesulphonate, methanesulphonate or halo, such as bromo or lodo) and R is as hereinbefore defined, for example at below room temperature (e.g. between around -35°C and around -85°C), in the presence of a suitable base (e.g. «-butyl lithium) and an appropriate solvent (e.g. THF).

(b) Compounds of formula XXII in which R^y is -S(0)₂NH₂ and N- protected derivatives thereof, may be prepared by reaction of an appropriate compound of formula XXXIV,

XXXIV

wherein R³, Zj and Z₂ are as hereinbefore defined with an appropriate reagent for introduction of a -S(0)₂NH₂ group into the appropriate ring system (for example chlorosulphonic acid, or thionyl chloride in the presence of a suitable strong base (e.g. butyl lithium)), followed by reaction of the resultant intermediate with ammonia, or a protected derivative thereof (e.g. tert-butylamine), under conditions that are well known to those skilled in the art. (c) Certain protected derivatives (e.g. alkyl, such as Cι_₆ alkyl, for example tert-butyl, protected derivatives) of compounds of formula XXII in which R^y represents -C(0)NH₂ may be prepared by reaction of a compound of formula XXXIV as hereinbefore defined, with a compound of formula XXXV,

R^zN=C=0 XXXV

wherein R^z represents an appropriate protecting group, such as an alkyl group, including Cμ₆ alkyl, e.g. tert-butyl, for example at low temperature (e.g. -78°C to around 0°C), in the presence of a suitable base (e.g. «-butyl lithium) and an appropriate solvent (e.g. THF).

(d) Certain protected derivatives (e.g. alkyl, such as Cι_₆ alkyl, for example tert-butyl, protected derivatives) of compounds of formula

XXII in which R^y represents -C(0)NH₂ may also be prepared by reaction of a compound of formula XXXVI,

XXXVI

wherein R³, Z_! and Z₂ are as hereinbefore defined with a protected (e.g. an (e.g. C .₆) alkyl, such as tert-butyl-protected) derivative of ammonia (e.g. tert-butylamine) under standard coupling conditions (see, for example, those described hereinbefore for preparation of compounds of formula I (process step (iii))). Compounds of formula

XXXVI are known in the art or may be prepared by way of standard techniques, for example oxidation of a corresponding compound of formula XXII in which R^y is -CHO e.g. under those conditions described hereinbefore for preparation of compounds of formula V.

(e) Compounds of formula XXII in which R^y is -CHO, Zj represents -CH=CH- and Z₂ represents -CH-, and protected derivatives thereof, may be prepared by reaction of a compound of formula XXXIV in which Zi represents -CH=CH- and Z₂ represents -CH- with an appropriate reagent system for the introduction of an aldehyde group into the benzene ring (e.g. TiCl₄/CHCl₃, SnCl₄/CH₂Cl₂ or 1,3,5,7- azaadamantane/TFA) under standard reaction conditions, followed by (if appropriate) protection of the resultant benzaldehyde under standard conditions.

(f) Compounds of formula XXII in which R^y is -NH₂, Zj represents -CH=CH- and Z₂ represents -CH-, and N-protected derivatives thereof, may be prepared by nitration of a compound of formula XXXIV in which Zi represents -CH=CH- and Z₂ represents -CH-, followed by reduction of the resultant nitrobenzene and (if appropriate) protection of the resultant aminobenzene, all of which steps may be carried out under standard conditions.

Compounds of formula XXIII may be prepared by:

(1) standard Grignard reaction of a compound of formula XXXVII,

XXXVII

wherein Hal represents a non-fluoro halo atom, such as Br, and Yi, Y₂, Y3, Y₄ and L² are as hereinbefore defined with an appropriate metal, such as Mg, followed by reaction of the resultant Grignard reagent with a compound of formula XXXVIII,

XXXVIII

wherein the dotted lines, X X₂, X₃ and ₄ are as hereinbefore defined under standard conditions;

(2) reaction of a compound of formula XXXIX,

XXXIX

wherein Yi, Y₂, Y₃, Y₄ and L are as hereinbefore defined with a compound of formula XXI as hereinbefore defined, wherein M¹ represents magnesium halide or an alkali metal, for example under standard conditions.

Compounds of formula XXVII may be prepared by conversion of the OH group in a compound of formula XL, 31

wherein the dotted lines, Xj, X₂, X₃ and X₄ are as hereinbefore defined to an appropriate leaving group, L¹, for example under similar conditions to those described hereinbefore in respect of formation of compounds of formula XX. Compounds of formula XL may be prepared from corresponding compounds of formula XXXVIII under standard reduction conditions.

Compounds of formulae III, IV, VI, VIII, X, XI, XII, XIII, XIV, XIX, XXI, XXIV, XXV, XXVI, XXVIII, XXIX, XXXI, XXXII, XXXIII, xxxrv, XXXV, XXXVII, XXXVIII and XXXIX 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 readily available starting materials using appropriate reagents and reaction conditions.

Compounds of the invention may be isolated from their reaction mixtures using conventional techniques.

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.

Functional groups that it is desirable to protect include sulphonamido, amido, amino and aldehyde. Suitable protecting groups for sulphonamido, amido and amino include tert-butyloxycarbonyl, benzyloxycarbonyl, 2- trimethylsilylethoxycarbonyl (Teoc) or tert-butyl. Suitable protecting groups for aldehyde include alcohols, such as methanol or ethanol, and diols, such as 1,3-propanediol or, preferably, 1,2-ethanediol (so forming a cyclic acetal).

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 (e.g. using trifiuoroacetic acid, sulfuric acid, toluenesulfonic acid or boron trichloride).

Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This may negate, or render necessary, the need for protecting groups.

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 Orgamc Chemistry", edited by J W F McOmie, Plenum Press (1973), and "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. The compounds of the invention are therefore indicated as pharmaceuticals.

According to a further aspect of the invention there is thus provided the compounds of the invention for use as pharmaceuticals.

In particular, compounds of the invention are agonists of Angll, more particularly, are agonists of the AT2 receptor, and, especially, are selective agonists of that sub-receptor, for example as may be demonstrated in the tests described below.

The compounds of the invention are thus expected to be useful in those conditions in which endogenous production of Angll is deficient and/or where an increase in the effect of Angll is desired or required.

The compounds of the invention are further expected to be useful in those conditions where AT2 receptors are expressed and their stimulation is desired or required.

The compounds of the invention are further indicated in the treatment of conditions characterised by vasoconstriction, increased cell growth and or differentiation, increased cardiac contractility, increased cardiovascular hypertrophy, and/or increased fluid and electrolyte retention. The compounds of the invention are further indicated in the treatment of stress-related disorders, and/or in the improvement of microcirculation and/or mucosa-protective mechanisms.

Thus, compounds of the invention are expected to be useful in the treatment of disorders, which may be characterised as indicated above, and which are of, for example, the gastrointestinal tract, the cardiovascular system, the respiratory tract, the kidneys, the eyes, the female reproductive (ovulation) system and the central nervous system (CNS).

Disorders of the gastrointestinal tract that may be mentioned include oesophagitis, Barrett's oesophagus, gastric ulcers, duodenal ulcers, dyspepsia (including non-ulcer dyspepsia), gastro-oesophageal reflux, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatitis, hepatic disorders (such as hepatitis), gall bladder disease, multiple organ failure (MOF) and sepsis. Other gastrointestinal disorders that may be mentioned include xerostomia, gastritis, gastroparesis, hyperacidity, disorders of the bilary tract, coelicia, Crohn's disease, ulcerative colitis, diarrhoea, constipation, colic, dysphagia, vomiting, nausea, indigestion and Sjδgren's syndrome.

Disorders of the respiratory tract that may be mentioned include inflammatory disorders, such as asthma, obstructive lung diseases (such as chronic obstructive lung disease), pneumonitis, pulmonary hypertension and adult respiratory distress syndrome.

Disorders of the kidneys that may be mentioned include renal failure, nephritis and renal hypertension. Disorders of the eyes that may be mentioned include diabetic retinopathy, premature retinopathy and retinal microvascularisation.

Disorders of the female reproductive system that may be mentioned include ovulatory dysfunction.

Cardiovascular disorders that may be mentioned include hypertension, cardiac hypertrophy, cardiac failure, artherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, post- balloon dilatation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina, cardiac arrhythmias, claudicatio intermittens, preeclampsia, myocardial infarction, reinfarction, ischaemic lesions, erectile dysfunction and neointima proliferation.

Disorders of the CNS that may be mentioned mclude cognitive dysfunctions, dysfunctions of food intake (hunger/satiety) and thirst, stroke, cerebral bleeding, cerebral embolus and cerebral infarction.

Compounds of the invention may also be useful in the modulation of growth metabolism and proliferation, for example in the treatment of hypertrophic disorders, prostate hyperplasia, autoimmune disorders, psoriasis, obesity, neuronal regeneration, the healing of ulcers, inhibition of adipose tissue hyperplasia, stem cell differentiation and proliferation, cancer (e.g. in the gastrointestinal tract, lung cancer, etc), apoptosis, tumours (generally) and hypertrophy, diabetes, neuronal lesions and organ rejection.

The compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above conditions. . - < ~ v

36 According to a further aspect of the present invention, there is provided a method of treatment of a condition in which endogenous production of Angll is deficient, and/or a condition where an increase in the effect of Angll is desired or required, and/or a condition where AT2 receptors are expressed and their stimulation is desired or required, which method comprises administration of a therapeutically effective amount of a compound of the invention to a person suffering from, or susceptible to, such a condition.

The compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.

When the condition to be treated is multiple organ failure, preferred routes of aclministration are parenteral (e.g. by injection). Otherwise, the preferred route of administration for compounds of the invention is oral.

The compounds of the invention may be administered alone, but are preferably aώ inistered 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, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Compounds of the invention may also be administered in combination with other AT2 agonists that are known in the art, as well as in combination with ATI receptor antagonists that are known in the art, such as losartan, or in combination with an inhibitor of angiotensin converting enzyme (ACE).

According to a further aspect of the invention, there is provided a combination product comprising:

(A) a compound of the invention; and

(B) an ATI receptor antagonist, or an ACE inhibitor, 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 compound of the invention in conjunction with an ATI receptor antagonist, or an ACE inhibitor, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of the invention, and at least one comprises ATI receptor antagonist, or ACE inhibitor, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including compound of the invention and ATI receptor antagonist or ACE inhibitor).

Thus, there is further provided:

(1) a pharmaceutical formulation including a compound of the invention and an ATI receptor antagonist, or an ACE inhibitor, in admixture with 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, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including an ATI receptor antagonist, or an ACE inhibitor, 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.

Depending upon the disorder and patient to be treated and the route of administration, the compounds of the invention may be admimstered at varying doses.

Although doses will vary from patient to patient, suitable daily doses are in the range of about 1 to 1000 mg per patient, admimstered in single or multiple doses. More preferred daily doses are in the range 2.5 to 250 mg per patient.

Individual doses of compounds of the invention may be in the range 1 to 100 mg.

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 condition that is to be treated, as well as the age, weight, sex 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 have the advantage that they bind selectively to, and exhibit agonist activity at, the AT2 receptor. By compounds which "bind selectively" to the AT2 receptor, we include that the affinity ratio for the relevant compound (AT2:AT1) is at least 5:1, preferably at least 10:1 and more preferably at least 20:1.

The 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.

Biological Tests The following test procedures may be employed.

Test A

Rat liver membranes were prepared according to the method of Dudley et al (Mol Pharmacol. (1990) 38, 370). Binding of [¹²⁵I]Ang II to membranes was conducted in a final volume of 0.5 mL containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, 10 mM MgCl_2s 1 mM EDTA, 0.025% bacitracin, 0.2% BSA (bovine serum albumin), liver homogenate corresponding to 5 mg of the original tissue weight, [¹²⁵I]Ang II (70 000 cpm, 0.03 nM) and variable concentrations of test substance. Samples were incubated at 25°C for 1 h, and binding was terminated by filtration through Whatman GF/B glass-fiber filter sheets using a Brandel cell harvester. The filters were washed with 4 x 2 mL of Tris-HCl (pH 7.4) and transferred to tubes. The radioactivity was measured in a gamma counter. The characteristics of the Ang II binding AT] receptor were determined by using six different concentrations (0.03-5 nmol/L) of the labeled [¹² I] Angll. Non-specific binding was determined in the presence of 1 μM Ang II. The specific binding was determined by subtracting the non-specific binding from the total bound [¹²⁵I]AngII. The dissociation constant (K_d = 1.7 ± 0.1 nM, [L] = 0.057 nM) was determined by Scatchard analysis of data obtained with Ang II by using GraFit (Erithacus Software, UK). The binding data were best fitted with a one-site fit. All experiments were performed at least in triplicate.

Test B Receptor Binding Assay using Porcine Myometrial Membrane AT₂ Receptor

Myometrial membranes were prepared from porcine uteri according to the method by Nielsen et al (Clin. Exp. Pharm. Phys. (1997) 24, 309). Any possible interference that may be exhibited by binding of compound to ATj receptors was blocked by addition of 1 μM of a selective ATI inhibitor. Binding of [ I]Ang II to membranes was conducted in a final volume of 0.5 mL containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, 10 mM MgCl₂, 1 mM EDTA, 0.025% bacitracin, 0.2% BSA, homogenate corresponding to 10 mg of the original tissue weight, [¹²⁵I]Ang II (70 000 cpm, 0.03 nM) and variable concentrations of test substance. Samples were incubated at 25°C for 1 h, and binding was terminated by filtration through Whatman GF/B glass-fiber filter sheets using a Brandel cell harvester. The filters were washed with 3 3 mL of Tris-HCl (pH 7.4) and transferred to tubes. The radioactivity was measured using a gamma counter. The characteristics of the Ang II binding AT₂ receptor was determined by using six different concentrations (0.03-5 nmol/L) of the labeled [¹²⁵I]Ang II. Non-specific binding was determined in the presence of 1 μM Ang II. The specific binding was determined by subtracting the non-specific binding from the total bound [ I] Ang II. The dissociation constant (K_d = 0.7 ± 0.1 nM, [L] = 0.057 nM) was determined by Scatchard analysis of data obtained with Ang II by using GraFit (Erithacus Software, UK). The binding data were best fitted with a one-site fit. All experiments were performed at least in triplicate .

Test C

Duodenal Mucosal Alkaline Secretion Assay

Compounds were exposed to the duodenal mucosa in barbiturate- anaesthetised rats prepared for in situ titration of duodenal mucosal alkaline secretion, according to the methodology described by Flemstrδm et al in Am. J. Physiol. (1982) 243, G348.

The invention is illustrated by way of the following examples.

Example 1 N-Butyloxycarbonyl-3-(4-tMazol-2-ylmethylphenyl -5-feo-butyl1iLiophene- 2-sulfonamide

(a) N-tert-Butylthiophene-2-sulfonamide

Thiophene-2-sulfonyl chloride (15 g, 0.082 mol) was dissolved in CHC1₃ (200 mL) under Ν₂ atmosphere and then cooled to 0°C. tert-Butylamine (25.9 mL, 0.246 mol) dissolved in CHC1₃ (50 mL) was then added dropwise to the reaction mixture. The reaction mixture was stirred for 1 h at room temperature and then at reflux for 10 min. Toluene (700 mL) was added and the organic phase was washed with water (3 x 50 mL), dried, and concentrated in vacuo. The sub-title product was used without further purification in the next step.

1H NMR δ(CDCl₃): 7.60 (IH, dd, J= 1.3, 3.8 Hz), 7.53 (IH, dd, J= 1.3, 5.0 Hz), 7.02 (IH, dd, J= 5.0, 3.8 Hz), 5.13 (IH, m), 1.24 (9H, m) ¹³C NMR δ(CDCl₃): 145.0, 131.7, 131.2, 127.0, 55.1, 29.9 (b) S-t 'o-Butyl-N-tert-butylthiophene^-sulfonamide N-tert-Butylthiophene-2-sulfonamide (10 g, 0.046 mol; see step (a) above) was dissolved in THF (85 mL) under N₂ and then cooled to -78°C. n-BuLi (1.6 M, 76.9 mL, 0.12 mol) was added via a syringe. The reaction mixture was stirred at -78°C for 30 min. and then at -40°C for 2 h. Iodo-2- methylpropane (10.5 mL, 0.09 mol) was added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with NH₄C1 (aq.) and extracted with EtOAc. The combined organic phase was washed with brine and dried and concentrated in vacuo. The crude product was purified on column chromatography (hexanes:EtOAc (10:1)) to give the sub-title compound in 55% yield (7.0 g, 0.025 mol).

1H NMR δ(CDCl₃): 7.43 (IH, d, J= 3.6 Hz), 6.67 (IH, ά, J= 3.8 Hz), 4.83 (IH, m), 2.67 (2H, d, J= 7 Hz), 1.88 (IH, m), 1.26 (9H, ), 0.93 (6H, J = 6.6 Hz). ¹³C NMR δ(CDCl₃): 145.0, 131.7, 131.2, 127.0, 55.1, 29.9

(c) 5-^o-Butyl-2-(N-tert-butylantinosulfonyl)thiophene-3-boronic acid 5-wo-Butyl-N-tert-butylthiophene-2-sulfonamide (10.6 g, 0.039 mol; see step (b) above) was dissolved in THF (165 mL) under Ν₂ and then cooled to -78°C. «~BuLi ( 1.6 M, 60.19 mL, 0.096 mol) was added via a syringe. The reaction mixture was stirred at -20°C for 4 h. Tri-ώo-propylborate (13.3 mL, 0.058 mol) was then added via a syringe and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with 2 M HCl (20 mL). The organic phase was separated and the water phase was extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine, dried and concentrated in vacuo. The product may be used without further purification. MS(ESI⁺) m/z: 236.8 (ά) 2-(4-Bromobenzy thiazole

4-Bromobenzylbrornide (150 mg, 0.6 mmol), 2-tributylstannylthiazole (336.8 mg, 0.9 mmol; Frontier Scientific), ώ-zrø-propyletiiylamine (160 μL), Pd(PPh₃)₄ (20 mg, 0.017 mmol) and DMF (2 mL) were mixed and heated to 80°C for 6 h. After cooling to room temperature, water (50 mL) was added and the resultant extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with water and brine and dried over MgS0 . After removing the solvents, the residue was purified by column chromatography using hexane:EtOAc (5:1) as eluent to give the sub-title compound (46.7 mg, 0.18 mmol, 31 % yield). MS (EΫ) m/z: 255.9, 253.9 (M⁺)

1H NMR (CDC1₃, 270 MHz): δ 7.72 (d, J= 3.3 Hz, IH), 7.47 (d, J= 8.4 Hz, 2H), 7.24 (d, J= 3.3 Hz, IH), 7.21 (d, J= 8.4 Hz, 2H), 4.32 (s, 2H) ¹³C NMR (CDC1₃, 67.5 MHz): δ 169.5, 143.9, 142.4, 136.7, 131.9, 130.7, 121.1, 120.9, 119.2, 38.7

(e) 3-(4-TMazol-2-yl-methylphenyl)-5-f o-butyl-N-tert-butylthiophene-2- sulfonamide

5-wo-Butyl-2-(N-tert-butylann^osulfonyl)thiophene-3-boronic acid (100 mg, 0.313 mmol; see step (c) above), 2-(4-bromobenzyl)thiazole (40 mg,

0.157 mmol; see step (d) above), Pd(PPh₃)₄ (15 mg, 0.013 mmol), ΝaOH

(2.5 mL, 1M, 2.5 mmol), toluene (20 mL) and ethanol (1.5 mL) were mixed together under Ν₂. The mixture was warmed to reflux for 2 h, diluted with

EtOAc (150 mL), washed with water, and then brine, and dried over MgS0₄. The solvent was evaporated and the residue was purified by flash chromatography using CHCl₃:MeOH (40:1) as eluent to give the sub-title compound in 60% yield (42.5 mg, 0.095 mmol).

MS (EI⁺) m/z: 449.0 (M⁺)

1H NMR (CDC1₃, 270 MHz): δ 7.72 (d, J= 3.3 Hz, IH), 7.60 (d, J= 8.1 Hz, 2H), 7.40 (d, J= 8.1 Hz, 2H), 7.24 (d, J= 3.2 Hz, IH), 6.74 (s, IH), 4.40 (s, 2H), 2.66 (d, J = 7.1 Hz, 2H), 1.90 (m, IH), 0.97 (s, 9H), 0.94 (d, /= 6.6 Hz, 6H)

¹³C NMR (CDC1₃, 67.5 MHz): δ 148.3, 142.6, 137.9, 136.3, 133.8, 129.9, 129.1, 128.8, 119.2, 54.5, 39.2, 38.9, 30.5, 29.4, 22.1 IR (neat): 3290, 3117, 2959, 1512, 1314 cm^"1

Anal. Calcd for C₂₂H₂₈N₂0₂S₃: C, 58.9; H, 6.3; N, 6.2. Found: C, 59.0; H, 6.6; N, 6.2

(f) 3-(4-T azol-2-ylmethylphenyl)-5-t-fo-butyllMophene-2-sulfonamide BC1₃ (1 mL, 1M in hexane) was added to a solution of 3-(4-thiazol-2-yl- metiιylphenyl)-5-t^'-?o-butyl-N-tert-butyltbiophene-2-sulfonamide (42.5 mg, 0.0947 mmol; see step (e) above) in CH₂C1₂ and the mixture was stirred under a N₂ atmosphere for 40 minutes at ambient temperature. The reaction mixture was then diluted with EtOAc (50 mL) and washed with water and then brine, dried over MgS0₄ and concentrated to give crude sub-title product.

(g) N-Butyloxycarbonyl-3-(4-tMazol-2-ylmethylphenyl)-5-z^'-7o-butylthio- phene-2-sulfonamide The crude product from step (f) above was dissolved in pyridine (2 mL). Pyrrolidinopyridine (32 mg, 0.17 mmol) followed by «-butyl chloroformate (276 μL, 2.17 mmol) were added. The reaction mixture was stirred overnight at room temperature under a Ν₂ atmosphere. The reaction mixture was evaporated and co-evaporated. The residue was purified by preparative LC/MS chromatography using acetonitrile:water (0.1% formic acid) as eluent to give the title compound in 19% yield (8.9 mg, 0.018 mmol). MS (EI⁺) m z: 493.0 (M⁺)

1H NMR (CDC1₃, 270 MHz): δ 7.71 (d, J= 3.3 Hz, IH), 7.44 (d, J= 8.1 Hz, 2H), 7.27 (d, /= 8.1 Hz, 2H), 7.21 (d, J= 3.2 Hz, IH), 6.76 (s, IH), 4.33 (s, 2H), 4.04 (t, J= 6.6 Hz, 2H), 2.71 (d, = 6.9 Hz, 2H), 1.94 (m, IH), 1.50 (m, 2H), 1.25 (m, 2H), 1.00 (d, J= 6.6 Hz, 6H), 0.86 (t, J = 7.1 Hz, 3H) ¹³C NMR (CDC1₃, 67.5 MHz): δ 169.8, 151.3, 150.2, 146.0, 142.5, 138.8, 132.9, 129.4, 128.9, 119.0, 66.7, 39.3, 38.9, 30.5, 30.4, 22.2, 18.8, 13.6 IR (neat): 2957, 2872, 1740, 1511 cm ¹

Anal. Calcd for C₂₃H₂₈N₂0₄S₃: C, 56.1; H, 5.7; N, 5.7. Found: C, 55.8; H, 6.0; N, 5.4

Example 2 N-Butyloxycarbonyl-3-[4-(tMazole-2-carbonyl)phenyl]-5-? 'Q-butylthio- phene-2-sulfonamide

(a) (4-Bromophenyl)thiazol-2-ylmethanol n-BuLi (1.6 M in hexane, 2.0 mL, 3.20 mmol) was slowly added to a cooled (-78°C) solution of 2-bromothiazole (500 mg, 3.05 mmol; Aldrich) in THF (7 mL). The mixture was stirred for 15 minutes at the same temperature, then slowly warmed to -20°C and stirred for 1 hour. The mixture was cooled back to -78°C and 4-bromobenzaldehyde (0.564 g, 3.05 mmol; Acros Organics) in THF (3 mL) was added. After this addition, the temperature of the reaction mixture was slowly raised to room temperature. The mixture was stirred for about 3 h. The reaction was quenched with aqueous NH₄C1 (satd.) and diluted with ether (30 mL). The separated aqueous layer was extracted with ether (10 mL). The combined organic layers were washed with brine, dried over MgS0₄ and evaporated under reduced pressure. The crude product was purified by flash chromatography using acetone:petroleum ether (1:4) to give the sub-title compound (220 mg, 0.814 mmol, yield: 27 %). MS (ESf ) m/z: 270 (M^1") 1H NMR (CDCI₃, 270 MHz): δ 7.69 (d, J= 3.3 Hz, IH), 7.49 (d, J= 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 3.3 Hz, IH), 6.02 (s, IH), 3.61(bs, IH)

¹³C NMR (CDC1₃, 67.5 MHz): δ 142.2, 140.2, 131.8, 128.2, 122.5, 119.8, 73.1 ^'

(b) (4-Bromophenyl)thiazol-2-ylmethanone

Pyridiniumchlorochromate (PCC, 180 mg, 0.844 mmol) was added to a stirred solution of (4-bromoρhenyl)thiazol-2-ylmethanol (152 mg, 0.563 mmol; see step (a) above) in DCM (5 mL) at ambient temperature. The stirring was continued for 30 minutes. The solvent was evaporated and the residue passed through a silica-gel column using dimethylether as the eluting solvent, to give the sub-title compound (120 mg, 0.448 mmol, yield: 80%). 1H NMR (CDC1₃, 270 MHz): δ 8.38 (d, J= 8.6 Hz, 2H), 8.08 (d, /= 3.0 Hz, IH), 7.73 (d, J= 3.0 Hz, IH), 7.65 (d, J- 8.6 Hz, 2H) ¹³C NMR (CDC1₃, 67.5 MHz): δ 144.8, 133.9, 132.5, 131.6, 129.0, 126.5

(c) 3-[4-(TMazole-2-carbonyl)phenyl]-5-z^{' ,}o-butyl-N-tert-butylthiophene-2- sulfonamide

5-wo-Butyl-2-(N-tert-butylanήnosulfonyl)tlιiophene-3-boronic acid (170 mg, 0.533 mmol; see Example 1(c) above), (4-bromophenyl)thiazol-2-yl- methanone (110 mg, 0.410 mmol; see step (b) above), toluene (4 mL), ethanol (1 mL), ΝaOH (1.0 M, 1.65 mL, 1.641 mmol) and Pd(PPh₃)₄ (14 mg, 0.012 mmol) were mixed under Ν₂. The mixture was heated at 100°C for 2 h. The mixture was diluted with EtOAc (20 mL), washed with water, brine and dried over MgS0₄. The solvent was evaporated and the residue was purified by flash chromatography using petroleum etheπacetone as an eluent to give the sub-title compound (149 mg, 0.322 mmol, yield: 79%). MS (ESI⁺) m/z: 463 (M⁺) 1H NMR (CDCI₃, 270 MHz): δ 8.58 (d, J= 8.6 Hz, 2H), 8.11 (d, J = 3.0 Hz, IH), 7.76 (d, /= 8.6 Hz, 2H), 7.74 (s, IH), 6.80 (s, IH), 4.17 (s, IH), 2.70 (d, J= 7.3 Hz, 2H), 1.93 (m, IH), 1.01 (s, 9H), 0.98 (d, J = 6.6 Hz, 6H) ¹³C NMR (CDC1₃, 67.5 MHz): δ 148.7, 144.9, 141.9, 140.0, 134.6, 131.1, 129.0, 128.7, 126.4, 54.6, 39.1, 30.5, 29.5, 22.1

(d) 3-[4-(TMazole-2-carbony phenyll-5-røo-butyltMoρhene-2-sulfonamide Trifluoroacetic acid (10 mL) was added to 3-[4-(thiazole-2- carbonyl)phenyl]-5-wo-butyl-N-tert-butyltMophene-2-sulfonamide (142 mg, 0.307 mmol; see step (c) above). Two drops (ca. 0.05 mL) of anisole were also added and the mixture was stirred under a N₂ atmosphere for 14 h at ambient temperature. The reaction mixture was evaporated and co- evaporated with acetonitrile (10 mL x 3) to give crude sub-title product.

(e) N-Bu1yloxycarbonyl-3-[4-(t azole-2-carbonyl)phenyl]-5-z^'-fo-butyll3ιio- phene-2-sulfonamide

The crude product from step (d) above was dissolved in pyridine (5 mL). Pyrrolidinopyridine (46 mg, 0.307 mmol) followed by n-butyl chloroformate (390 μL, 3.069 mmol) were added. The reaction mixture was stirred overnight at room temperature under a N₂ atmosphere. The mixture was evaporated and co-evaporated with acetonitrile. The residue was taken up in chloroform (30 mL), washed with citric acid (10% aq.) followed by water and then brine, and dried over MgS0₄. The residue was purified by flash chromatography using petroleum ether: acetone as eluent to give the title compound (73 mg, 0.144 mmol, yield: 47%). MS (ESI⁺) m/z: 507 (M^1")

1H NMR (CDC1₃, 270 MHz): δ 8.51 (d, /= 8.3 Hz, 2H), 8.08 (d, J= 3.0 Hz, IH), 7.75 (d, J= 3.3 Hz, IH), 6.63 (d, J= 8.3 Hz, 2H), 6.18 (s, IH), 4.04 (t, J= 6.3 Hz, 2H), 2.73 (d, J= 6.9 Hz, 2H), 1.96 (m, IH), 1.54-1.44 (m, 2H), 1.30-1.17 (m, 2H), 1.00 (d, J= 6.6 Hz, 6H), 0.86 (t, J= 7.3 Hz, 3H) ¹³C NMR (CDCI₃, 67.5 MHz): δ 151.9, 150.0, 144.8, 139.2, 135.0, 130.8, 129.1, 126.6, 67.0, 39.3, 30.3, 22.2, 18.7, 13.4 IR (neat): 2957, 2356, 2326, 1747, 1711, 1154 cm^"1

Example 3

N-Butyloxycarbonyl-3-[4-(l-methyl-lH-imidazole-2-carbonyl phenyl]-5- t-?o-butylthiophene-2-sulfonamide

(a) ( -Bromophenyι)-( 1 -methyl- lH-imidazol-2-yl)methanol n-BuLi (1.6 M in hexane, 4.77 mL, 6.99 mmol) was slowly added to a cooled (-78°C) solution of 1 -methyl- lH-imidazole (574 mg, 6.99 mmol;

Acros Organics) in TΗF (10 mL). The mixture was stirred for 15 minutes at the same temperature, then slowly warmed to -20°C and stirred for 1 hour. The mixture was cooled to -78°C and 4-bromobenzaldehyde (1.293 g, 6.99 mmol) in TΗF (4 mL) was added. After this addition, the temperature was slowly raised to room temperature and the mixture stirred for about 3 h. The reaction was quenched with aqueous ΝΗ₄C1 (satd.) and diluted with ether (30 mL). The separated aqueous layer was extracted with ether (10 mL). The combined organic layers were washed with brine and dried over MgS0₄. The solvent was slowly evaporated at a low temperature and the precipitated solid was filtered and dried under vacuum to give the sub-title compound (1.23 g,4.60 mmol, yield: 66%).

MS (ESI⁺) m/z: 268 (M⁺+l)

1H NMR (CDCI₃, 270 MHz): δ 7.36 (d, J= 8.6 Hz, 2H), 7.12 (d, J= 8.6 Hz, 2H), 6.78 (s, IH), 6.71 (s, IH), 5.81 (s, IH), 3.36 (s, 3H)

¹³C NMR (CDCI₃, 67.5 MHz): δ 148.2, 139.5, 131.2, 127.4, 125.9, 122.3,

121.2, 68.1, 33.1

IR (neat): 3113, 2839, 1487, 1070, 1010 cm^"1 (b) (4-BromophenylV(l-methyl-lH-imidazol-2-yl)methanone

PCC (242 mg, 1.12 mmol) was added to a stirred solution of (4- bromophenyl)-(l -methyl- lH-imidazol-2-yl)methanol (200 mg, 0.748 mmol; see step (a) above) in DCM (5 mL) at ambient temperature. The mixture was stirred for 30 minutes. The solvent was evaporated and the residue was passed through a silica gel column using ether as eluent to give the sub-title compound (174 mg, 0.656 mmol, yield: 88%).

1H NMR (CDC1₃, 270 MHz): δ 8.15 (d, J= 8.6 Hz, 2H), 7.60 (d, J= 8.6 Hz, 2H), 7.20 (s, IH), 4.05 (s, 3H) ¹³C NMR (CDC1₃, 67.5 MHz): δ 135.9, 132.3, 131.3, 129.2, 127.9, 127.0, 36.5 IR (neat): 2345, 1762, 1649, 1404 cm^-1

(c) 3-[4-(l-Methyl-lH-imidazole-2-carbonyl)phenyl]-5-t-?o-butyl-N-tert- butylthiophene-2-sulfonamide

5-wo-Butyl-2-(N-tert-butylannnosulfonyl)thiophene-3-boronic acid (156.5 mg, 0.490 mmol; see Example 1(c) above), (4-bromophenyl)-(l-methyl-lH- imidazol-2-yl)methanone (100 n g, 0.377 mmol; see step (b) above), toluene (4 mL), ethanol (1 mL), ΝaOΗ (1.0 M, 1.5 mL, 1.5 mmol) and Pd(PPh₃)₄ (13 mg, 0.011 mmol) were mixed under Ν₂. The mixture was heated at 100°C for 3 h. The mixture was diluted with EtOAc (30 mL), washed with water and brine, and dried over MgS0₄. The solvent was evaporated and the residue was purified by flash chromatography using petroleum etheπacetone as eluent to give the sub-title compound (130 mg, 0.277 mmol, yield: 75%).

1H NMR (CDC1₃, 270 MHz): δ 8.35 (d, J= 8.3 Hz, 2H), 7.71 (d, J= 8.3 Hz, 2H), 7.22 (s, IH), 7.12 (s, IH), 6.76 (s, IH), 4.24 (bs, IH), 4.08 (s, 3H), 2.67 (d, J= 6.9 Hz, 2H), 1.90 (m, IH), 0.98 (s, 9H), 0.95 (d, J= 6.6 Hz, 6H) ¹³C NMR (CDC1₃, 67.5 MHz): δ 148.6, 142.3, 139.1, 136.8, 130.9, 129.2, 128.8, 127.0, 54.5, 39.1, 36.5, 30.5, 29.5, 22.1 IR (neat): 3224, 2966, 1732, 1634, 1542, 1142 cm^-1

(d) 3-[4-(l-Methyl-lH-inn^azole-2-carbonyl phenyl1-5-z o-butylthiophene- 2-sulfonamide Trifluoroacetic acid (5 mL) was added to 3-[4-(l-methyl-lH-imidazole-2- carbonyl)phenyl]-5-wo-butyl-N-tert-butylthiophene-2-sulfonamide (125 mg, 0.271 mmol; see step (c) above). Two drops (ca. 0.05 mL) of anisole were also added and the mixture was stirred under N2 atmosphere for 18 h at ambient temperature. The reaction mixture was evaporated and co- evaporated with acetonitrile (5 mL x 3) to give crude sub-title product.

(e) N-Butyloxycarbonyl-3-[4-(l-metbyl-lH-imidazole-2-carbonyl)phenyl]- 5-z^'-?o-butylthiophene-2-sulfonamide

The crude product from step (d) above was dissolved in pyridine (5 mL). Pyrrolidinopyridine (44 mg, 0.297 mmol) followed by «-butyl chloroformate (384 μL, 2.97 mmol) were added. The reaction mixture was stirred overnight at room temperature under a N₂ atmosphere. The mixture was evaporated and co-evaporated with acetonitrile. The residue was taken up in chloroform (30 mL), washed with 10% aqueous citric acid followed by water and brine, and dried over MgS0₄. The residue was purified by flash chromatography using petroleum ether:acetone as eluent to give the title compound (104 mg, 0.206 mmol, yield: 75%).

1H NMR (CDCI₃, 270 MHz): δ 8.22 (d, J= 8.3 Hz, 2H), 7.55 (d, J= 8.3 Hz, 2H), 7.15 (s, IH), 7.10 (s, IH), 6.76 (s, IH), 4.06 (s, 3H), 3.99 (t, J = 6.3 Hz, 2H), 2.69 (d, J = 6.9 Hz, 2H), 1.92 (m, IH), 1.52-1.41 (m, 2H), 1.27- 1.14 (m, 2H), 0.97 (d, J= 6.6 Hz, 6H), 0.82 (t, /= 7.3 Hz, 3H) ¹³C NMR (CDC1₃, 67.5 MHz): δ 142.8, 138.3, 137.1, 130.6, 129.2, 129.1, 128.7, 126.9, 66.7, 39.2, 36.4, 30.5, 30.3, 22.2, 18.7, 13.5 IR (neat): 2958, 1747, 1650, 1396, 1157 cm^-1 Example 4

N-Butyloxycarbonyl-3-[4-(oxazole-2-carbonyl phenyl]-5-t-?o-bu1ylthio- phene-2-sulfonamide

(a) (4-Bromophenyl)oxazol-2-ylmethanol

To a solution of oxazole (96 mg, 1.43 mmol; Aldrich) in THF (5 mL) at room temperature under N₂ was added BH₃-THF (1M in THF, 1.5 mL, 1.50 mmol). After 30 minutes, the solution was cooled to -78°C and rc-BuLi (1.6 M in hexane, 0.94 mL, 1.50 mmol) was added dropwise. After a further 30 minutes, 4-bromobenzaldehyde (265 mg, 1.43 mmol) in THF (3 mL) was added. The mixture was stirred for 1 h and HO Ac (5% in ethanol, 3.4 mL) was added. The temperature of the reaction was raised to room temperature and stirred for 24 h. The mixture was partitioned between ether (20 mL) and NaHC0₃ (5% aq., 20 mL). The organic layer was washed with water, and then brine, and dried over MgS0₄. The solvent was evaporated and purified by flash chromatography using acetone:petroleum ether (1:4) as eluent to give the sub-title compound (40 mg, 0.16 mmol, yield: 11%). MS (ESI⁺) m/z: 253, 255 (M⁺+l) 1H NMR (CDC1₃, 270 MHz): δ 7.62 (s, IH), 7.49 (d, J= 8.3 Hz, 2H), 7.32 (d, J= 8.3 Hz, 2H), 7.12 (s, IH), 5.93 (s, IH), 5.00 (bs, IH)

¹³C NMR (CDC1₃, 67.5 MHz): δ 139.7, 137.6, 131.8, 128.3, 125.9, 122.6, 69.1

(b) (4-Bromophenyl)oxazol-2-ylmethanone PCC (51.0 mg, 0.236 mmol) was added to a stirred solution of (4- bromophenyl)oxazol-2-ylmethanol (40.0 g, 0.157 mmol; see step (a) above) in DCM (5 mL) at ambient temperature and the mixture stirred for 30 minutes. The solvent was evaporated and the residue was passed through a silica gel column using ether as eluent to give the sub-title compound (34 mg, 0.13 mmol, yield: 87%). MS (ESI⁺) m/z: 251, 253 (M'+l)

1H NMR (CDC1₃, 270 MHz): δ 8.39 (d, J- 8.6 Hz, 2H), 7.92 (s, IH), 7.66 (d, J= 8.6 Hz, 2H), 7.42 (s, IH)

¹³C NMR (CDC1₃, 67.5 MHz): δ 157.4, 141.7, 133.5, 132.3, 131.8, 129.6, 129.1

IR (neat): 3132, 1661, 1583, 1473, 1175 cm^"1

(c) 3-[4-(Oxazole-2-carbonyl)phenyl]-5-z' C'-butyl-N-te^butylthiophene-2- sulfonamide 5-wo-Butyl-2-(N-tert-butylam osulfonyl)thiophene-3-boronic acid (53 mg, 0.17 mmol; see Example 1(c) above), (4-bromophenyι)oxazol-2-yl- methanone (32 mg, 0.13 mmol; see step (b) above), toluene (2 mL), ethanol (0.5 mL), ΝaOH (1.0 M, 0.5 mL, 0.51 mmol) and Pd(PPh₃)₄ (5.0 mg, 4.0 μmol) were mixed under Ν₂. The mixture was heated at 100°C for 3 h. The mixture was diluted with EtOAc (15 mL), washed with water and then brine and dried over MgS0₄. The solvent was evaporated and the residue was purified by flash chromatography using petroleum ether: acetone as eluent to give the sub-title compound (50 mg, 0.11 mmol, yield: 88%). MS (ESI⁺) m/z: 447 (M^1") 1H NMR (CDC1₃, 270 MHz): δ 8.56 (d, J= 8.6 Hz, 2H), 7.92 (s, IH), 7.76 (d, J= 8.6 Hz, 2H), 7.43 (s, IH), 6.78 (s, IH), 4.14 (s, IH), 2.68 (d, 7= 6.9 Hz, 2H), 1.91 (m, IH), 0.99 (s, 9H), 0.95 (d, J= 6.6 Hz, 6H) ¹³C NMR (CDC1₃, 67.5 MHz): δ 178.0, 157.6, 148.8, 141.6, 140.4, 137.5, 134.4, 130.9, 129.2, 128.7, 54.7, 39.1, 30.5, 29.5, 22.1 IR (neat): 2960, 1664, 1605, 1145 cm^-1

(d) 3-[4-(Oxazole-2-carbonylphenyl ]-5-z^'-?o-butyltMophene-2-sulfonamide Trifluoroacetic acid (3 mL) was added to 3-[4-(oxazole-2-carbonyl)phenyl]- 5-z5O-butyl-N-tert-butylthiophene-2-sulfonamide (44 mg, 0.098 mmol; see step (c) above). Two drops (ca 0.05 mL) of anisole were then added and the mixture stirred under a N₂ atmosphere for 18 h at ambient temperature. The reaction mixture was evaporated and co-evaporated with acetonitrile (5 mL x 3) to give crude sub-title product.

(e) N-Butyloxycarbonyl-3-f4-(oxazole-2-carbonyl)phenyl]-5-z'-?o-butyll3ιio- phene-2-sulfonamide

The crude product from step (d) above was dissolved^" in pyridine (3 mL). Pyrrolidinopyridine (15 mg, 0.097 mmol) and n-butyl chloroformate (123 μL, 0.973 mmol) were added. The reaction mixture was stirred overnight at room temperature under a N₂ atmosphere. The mixture was evaporated and co-evaporated with acetonitrile. The residue was taken up in chloroform (20 mL), washed with 1 % aqueous citric acid followed by water and brine, and dried over MgS0 . The residue was purified by flash chromatography using petroleum ether: acetone as eluent to give the title compound (36 mg, 0.073 mmol, yield: 77%).

1H NMR (CDC1₃, 270 MHz): δ 8.56 (d, J= 8.6 Hz, 2H), 7.91 (s, IH), 7.62 (d, J= 8.6 Hz, 2H), 7.41 (s, IH), 6.79 (s, IH), 4.02 (t, J= 6.6 Hz, 2H), 2.71 (d, = 6.9 Hz, 2H), 1.93 (m, IH), 1.52-1.42 (m, 2H), 1.30-1.15 (m, 2H), 0.98 (ά, J= 6.6 Hz, 6H), 0.84 (t, J= 13 Hz, 3H) ¹³C NMR (CDCI₃, 67.5 MHz): δ 178.1, 157.6, 152.0, 150.0, 144.9, 141.7, 139.6, 134.7, 130.7, 129.1, 66.9, 39.2, 30.5, 30.3, 22.2, 18.7, 13.5 IR (neat): 2960, 1751, 1664, 1474, 1159 cm^-1

Example 5 N-Butyloxycarbonyl-3-(4-oxazol-2-ylme1faylphenyl)-5-z5(3-butylthiophene- 2-sulfonamide

(a) 2-(4-Bromobenzyl oxazole

A mixture of 4-bromobenzeneacetamide (0.5 g, 2.3 mmol) and vinylene carbonate (241 mg, 2.80 mmol) in polyphosphoric acid (1.5 g) was heated at 170°C for 3 h. The residue was added to water (25 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic extracts were washed with water and brine, dried and evaporated. The residue was purified by column chromatography using petroleum ether:ethyl acetate (4:1) as eluent to give the sub-title compound (165 mg, 0.693 mmol, yield: 30%).

1H NMR (CDC1₃, 270 MHz): δ 7.54 (s, IH), 7.44 (d, = 8.6 Hz, 2H), 7.15 (d, /= 8.6 Hz, 2H), 7.01(s, IH), 4.04 (s, 2H)

¹³C NMR (CDCI₃, 67.5 MHz): δ 162.5, 138.8, 134.2, 131.7, 130.4, 127.1, 121.0, 33.9 IR (neat): 2356, 1571, 1489, 1071 cm^'1

(b) 3-(4-Oxazol-2-ylmethylphenyl)-5-z^'-fo-butyl-N-tert-butylthiophene-2- sulfonamide 5-z5^,o-Butyl-2-(N-tert-butylanamosulfonyl)thiophene-3-boronic acid (218 mg, 0.683 mmol; see Example 1(c) above), 2-(4-bromobenzyl)oxazole (125 mg, 0.525 mmol; see step (a) above), toluene (5 mL), ethanol (1.5 mL), NaOH (1.0 M, 2.1 mL, 2.1 mmol) and Pd(PPh₃)₄ (18 mg, 16 μmol) were mixed under N₂. The mixture was heated at 100°C for 3 h. The mixture was diluted with EtOAc (30 mL), washed with water and brine, and dried over MgS0₄. The solvent was evaporated and the residue was purified by flash chromatography using petroleum etheπacetone as eluent to give the sub-title compound (89 mg, 0.21 mmol, yield: 40%). 1H NMR (CDCI₃, 270 MHz): δ 7.62 (s, IH), 7.55 (d, J= 8.3 Hz, 2H), 7.38 (d, = 8.3 Hz, 2H), 7.14(s, IH), 6.70 (s, IH), 4.26 (s, 2H), 4.12 (bs, IH), 2.65 (d, J= 6.9 Hz, 2H), 1.88 (m, IH), 0.95 (s, 9H), 0.93 (d, J= 6.6 Hz, 6H) ¹³C NMR (CDC1₃, 67.5 MHz): δ 163.5, 148.4, 142.5, 139.4, 136.4, 134.5, 134.1, 129.5, 129.0, 128.8, 126.7, 125.4, 54.5, 39.1, 33.9, 30.5, 29.4, 22.1 IR (neat): 2958, 2344, 1313, 1146 cm^"1 (c) 3-(4-Oxazol-2-ylmetfaylphenyl)-5-røo-butylτIu^phene-2-sulfonamide Trifluoroacetic acid (4 mL) was added to 3-(4-oxazol-2-ylmethylphenyl)-5- z^'λo-butyl-N-tert-butylthiophene-2-sulfonamide (81 mg, 0.19 mmol; see step (b) above). Two drops (ca. 0.05 mL) of anisole were also added and the mixture stirred under a N₂ atmosphere for 18 h at ambient temperature. The reaction mixture was evaporated and co-evaporated with acetonitrile (5 mL x 3) to give crude sub-title product.

(d) N-Butyloxycarbonyl-3-(4-oxazol-2-ylmethylphenyl)-5-z'-?o-butylthio- phene-2-sulfonamide

The crude product from step (c) above was dissolved in pyridine (3.0 mL). Pyrrolidinopyridine (27 mg, 0.19 mmol) and n-butyl chloroformate (237 mg, 1.87 mmol) were added. The reaction mixture was stirred overnight at room temperature under a N₂ atmosphere. The mixture was evaporated and co-evaporated with acetonitrile and the residue was taken up in chloroform (30 mL), washed with 10% aqueous citric acid, followed by water and brine, and dried over MgS0 . The residue was purified by flash chromatography using petroleum etheπacetone as eluent to give the title compound (46 mg, 0.097 mmol, yield: 52%). 1H NMR (CDC1₃, 270 MHz): δ 10.0 (bs, IH), 7.51 (s, IH), 7.40 (d, J = 8.3 Hz, 2H), 7.17 (d, J= 8.3 Hz, 2H), 6.95 (s, IH), 6.69 (s, IH), 4.04 (s, IH), 4.00 (t, J = 6.6 Hz, 2H), 2.66 (d, / = 7.3 Hz, 2H), 1.90 (m, IH), 1.50-1.38 (m, 2H), 1.28-1.15 (m, 2H), 0.95 (d, / = 6.6 Hz, 6H), 0.83 (t, J = 7.3 Hz, 3H) ¹³C NMR (CDCI₃, 67.5 MHz): δ 151.0, 150.7, 145.6, 138.8, 135.2, 133.0, 131.1, 129.4, 129.2, 128.6, 126.3, 66.4, 53.6, 39.2, 33.6, 30.4, 29.1, 22.1, 18.7, 13.5 IR (neat): 2959, 1747, 1345, 1158 cm^-1 Example 6

N-Butyloxycarbonyl-3-[4-(thiophene-2-carbonyl^')phenyl]-5-z^'-?o-butyl- thiophene-2-sulfonamide

fa) r4-Bromophenyl)thiophen-2-ylmethanol n-Butyl lithium (1.6 M in hexane, 1.78 mL, 2.85 mmol) was slowly added to a cooled (-78°C) solution of thiophene (0.2 g, 2.37 mmol) in THF (5 mL) and stirred for 15 minutes at the same temperature. The resultant was then slowly warmed to -20°C and stirred for 1 hour. The mixture was cooled to -78°C and 4-bromobenzaldehyde (0.439 g, 2.37 mmol) in THF (4 mL) was added. After this addition, the temperature was slowly raised to room temperature and stirred for about 2 hours. The reaction was quenched with satd. ΝH₄C1 (aq.) and diluted with ether (20 mL), and the separated aqueous layer was extracted with ether (10 mL). The combined organic layer was washed with brine and dried over MgS0₄. The solvents were evaporated at a low temperature and the crude product was purified by flash chromatography using acetone :petroleum ether as eluent to afford the subtitle compound in 83% (0.53 g) yield. MS (ESI*) m z: 270 (M⁺+l) 1H NMR (CDCI₃, 270 MHz): δ 7.47 (d, J= 8.3 Hz, 2H), 7.31-7.22 (m, 3H), 6.93 (m, IH), 6.86 (s, IH), 5.98 (d, J = 5.3 Hz, IH)

¹³C NMR (CDCI₃, 67.5 MHz): δ 147.4, 141.9, 131.5, 127.9, 126.7, 125.7, 125.0,121.8,71.6

IR (neat): 3283, 2889, 2292, 1898, 1591, 1488, 1229, 1044 cm -1

(b) (4-Bromophenyl)thiophen-2-ylmethanone

PCC (0.3 g, 1.39 mmol) was added to a stirred solution of (4-bromophenyl)- thiophen-2-ylmethanol (0.25 g, 0.93 mmol; see step (a) above) in DCM (10 mL) at ambient temperature and the resultant was stirred for 30 minutes. The solvent was evaporated and residue was passed through a silica-gel column using ether as the eluting solvent to give the sub-title compound in 80% (0.198 g) yield. MS (ESf) m/z: 268 (M⁺+l)

1H NMR (CDC1₃, 270 MHz): δ 7.70-7.75 (m, 3H), 7.65-7.59 (m, 3H), 7.17- 7.13 (m, lH)

¹³C NMR (CDC1₃, 67.5 MHz): δ 187.0, 143.1, 136.8, 134.7, 134.5, 131.6,

130.6, 128.0, 127.2

IR (neat): 3087, 1634, 1620, 1565, 1393, 1279, 1110 cm^"1

(c) 3-[4-(TMophene-2-carbonyl phenyl]-5-z' (?-butyl-N-tert-butyltfaiophene- 2-sulfonamide

5-z50-Butyl-2-(N-tert-butylam osulfonyl)thiophene-3-boronic acid (0.233 g, 0.73 mmol; see Example 1(c) above), (4-bromophenyl)thiophen-2- ylmethanone (0.15 g, 0.56 mmol; see step (b) above), toluene (5 mL), ethanol (1.5 mL), NaOH (1.0 M, 2.2 mL, 2.24 mmol) and Pd(PPh₃)₄ (0.019 g, 0.016 mmol) were mixed under N₂. The mixture was heated at 80°C for 3 hours and then diluted with EtOAc (25 mL), washed with water and then brine, and dried over MgS0₄. The solvent was evaporated and the residue was purified by flash chromatography using petroleum ether:acetone as eluent to give 0.123 g of the sub-title compound in 86% yield. MS (ESI⁺) m z: 462 (M⁺)

1H NMR (CDC1₃, 270 MHz): δ 7.92 (d, J= 8.6 Hz, 2H), 7.76-7.72 (m, 3H), 7.65 (m, IH), 7.16 (m, IH), 6.79 (s, IH), 4.18 (brs, IH), 2.68 (d, J = 7.3 Hz, 2H), 1.92 (m, IH), 1.01 (s, 9H), 0.96 (d, J = 6.60 Hz, 6H) ¹³C NMR (CDC1₃, 67.5 MHz): δ 187.4, 148.8, 143.3, 141.9, 138.8, 137.7, 137.2, 134.8, 134.4, 129.2, 1.29.1, 128.6, 128.0, 54.7, 39.1, 30.5, 29.5, 22.1. IR (neat): 3283, 2958, 2360, 1635, 1414, 1313, 1145 cm^"1 (d) 3-r4-(Thioρhene-2-carbonyl phenyll-5- 'o-butylthioρhene-2-sulfon- amide

Trifluoroacetic acid (10 mL) was added to 3-[4-(thiophene-2-carbonyl)- phenyl]-5-wo-butyl-N-tert-butylthiophene-2-sulfonamide (0.2 g, 0.43 mmol; see step (c) above). Two drops (ca. 0.05 mL) of anisole were then added and the mixture stirred under a N₂ atmosphere for 18 hours at ambient temperature. The reaction mixture was evaporated and co- evaporated with acetonitrile to give crude sub-title compound.

(e) N-Butyloxycarbonyl-3-[4-(thiophene-2-carbonyπphenyl1-5-z^c>-butyl- thiophene-2-sulfonamide

The crude product from step (d) above was dissolved in pyridine (4 mL). Pyrrolidinopyridine (0.064 g, 0.43 mmol) and w-butyl chloroformate (0.59 g, 4.33 mmol) were added. The reaction mixture was stirred overnight at room temperature under a N₂ atmosphere. The mixture was evaporated and co-evaporated with acetonitrile and the residue was taken up in chloroform (20 mL), washed with 10% aqueous citric acid, followed by water and brine, and dried over MgS0 . The residue was purified by flash chromatography using petroleum ether.acetone as an eluent to give 0.175 g of the title compound in 80% yield. MS (ESI⁺) m z: 506 (M⁺+l)

1H NMR (CDC1₃, 270 MHz): δ 8.16 (brs, IH), 7.84 (d, J = 7.92 Hz, 2H), 7.72 (d, J = 4.62 Hz, IH), 7.65 (d, J = 2.97 Hz, IH), 7.60 (d, J = 7.92 Hz, 2H), 7.13 (s, IH), 6.81 (s, IH), 4.03 (t, J = 6.60 Hz, 2H), 2.72 (d, J = 6.93 Hz, 2H), 1.95 (m, IH), 1.49 (m, 2H), 1.25 (m, 2H), 0.99 (d, J = 6.60 Hz, 6H), 0.84 (t, J = 7.26 Hz, 3H)

¹³C NMR (CDCI₃, 67.5 MHz): δ 187.6, 151.7, 150.2, 145.1, 143.0, 137.8, 137.7, 135.1, 134.5, 131.3, 129.0, 128.0, 66.8, 39.1, 30.4, 30.2, 22.1, 18.6, 13.4 IR (neat): 3208, 2960, 1751, 1630, 1410, 1158 cm^"1 Example 7

N-Butyloxycarbonyl-3-[4-(l-methyl-lH-pyrazole-5-carbonyl)phenyl1-5-z-?o- butylthiophene-2-sulfonamide

(a) (4-Bromophenyl)-( 1 -methyl- lH-pyrazol-5-yl)methanol n-Butyl lithium (1.6 M in hexane, 1.83 mL, 2.92 mmol) was slowly added to a cooled (-78°C) solution of 1-methylρyrazole (0.2 g, 2.43 mmol) in TΗF (5 mL). The resultant was stirred for 15 minutes at the same temperature, and then slowly warmed to -20°C and stirred for 1 hour. The mixture was cooled to -78°C and 4-bromobenzaldehyde (0.45 g, 2.43 mmol) in TΗF (4 mL) was added. After this addition, the temperature was slowly raised to room temperature and stirred about 2 hours. The reaction was quenched with satd. NΗ₄C1 (aq.) and diluted with ether (20 mL). The separated aqueous layer was extracted with ether (10 mL). The combined organic layer was washed with brine and dried over MgS0₄. The solvents were evaporated at a low temperature and the crude product was purified by flash chromatography using acetone:petroleum ether as eluent to afford the subtitle compound in 69% (0.45 g) yield. MS (ESI⁺) m/z: 268 (M⁺+l) 1H NMR (CDC1₃, 270 MHz): δ 7.50 (d, J= 8.6 Hz, 2H), 7.37 (d, J= 2.0 Hz, IH), 7.24 (d, J= 8.6 Hz, 2H), 6.04 (d, J= 2.0 Hz, IH), 5.88 (s, IH), 3.79 (s, 3H), 2.93 (brs, IH)

¹³C NMR (CDC1₃, 67.5 MHz): δ 144.1, 139.3, 131.7, 128.0, 122.2, 106.1, 77.1, 67.6, 37.1 IR (neat): 3220, 2943, 2353, 1487, 1396, 1201 cm^"1

(b) (4-Bromophenyiy ( 1 -methyl- lH-pyrazol-5-yl)methanone PCC (0.24 g, 1.12 mmol) was added to a stirred solution of (4- bromophenyl)-(l-methyl-lH-pyrazol-5-yl)methanol (0.2 g, 0.75 mmol; see step (a) above) in DCM (5 mL) at ambient temperature. The resultant was stirred for 30 minutes. The solvent was evaporated and residue was passed through a silica-gel column using ether as the eluting solvent to give the sub-title compound in 84% (0.166 g) yield.

MS (ESI⁺) m/z: 265 (M'+l) 1H NMR (CDC1₃, 270 MHz): δ 7.73 (ά, J= 8.6 Hz, 2H), 7.61 (d, J= 8.6 Hz,

2H), 7.49 (d, J= 2.0 Hz, IH), 6.61 (d, J= 2.0 Hz, IH), 4.19 (s, 3H)

¹³C NMR (CDC1₃, 67.5 MHz): δ 184.6, 137.6, 137.4, 136.7, 130.8, 130.3,

128.0, 113.4, 39.7

IR (neat): 3125, 2954, 1644, 1582, 1395 cm^"1

(c) 3-[4-(l-Methyl-lH-pyrazole-5-carbonyl)phenyl]-5-z_ts^,o-butyl-N-tert- butylthiophene-2-sulfonamide

5-z^'-?o-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (0.235 g, 0.73 mmol; see Example 1(c) above), (4-bromophenyl)-(l -methyl- 1H- pyrazol-5-yl)methanone (0.15 g, 0.56 mmol; see step (b) above), toluene (5 mL), ethanol (1.5 mL), ΝaOH (1.0 M, 2.3 mL, 2.26 mmol) and Pd(PPh₃)₄

(0.019 g, 0.016 mmol) were mixed under Ν₂. The mixture was heated at

100°C for 3 hours. The mixture was then diluted with EtOAc (25 mL), washed with water and then brine, and dried over MgS0₄. The solvent was evaporated and the residue was purified by flash chromatography using petroleum etheπacetone as eluent to give 0.182 g of sub-title compound in

70% yield.

MS (ESI⁺) m z: 460 (M⁺)

1H NMR (CDC1₃, 270 MHz): δ 7.93 (d, J= 8.6 Hz, 2H), 7.74 (d, J= 8.6 Hz, 2H), 7.49 (d, J = 2.0 Hz, IH), 6.80 (s, IH), 6.67 (d, J = 2.0 Hz, IH), 4.47

(brs, IH), 4.21 (s, 3H) 2.69 (ά, J= 6.9 Hz, 2H), 1.92 (m, IH), 1.02 (s, 9H),

0.97 (d, J= 6.6 Hz, 6H)

¹³C NMR (CDC1₃, 67.5 MHz): δ 185.1, 144.8, 141.7, 139.4, 137.8, 137.5,

137.4, 137.3, 129.4, 129.1, 128.7, 113.6, 54.6, 39.1, 30.4, 29.5, 22.1 IR (neat): 3165, 2967, 1644, 1391, 1137, 1049 cm^"1 (d) 3-r4-(l-Methyl-lH-pwazole-5-carbonyl phenyll-5-iso-butylthiophene- 2-sulfonamide

Trifluoroacetic acid (10 mL) was added to 3-[4-(l-methyl-lH-pyrazole-5- carbonyl)phenyl]-5-z^'j'o-bu1yl-N-tert-butylthiophene-2-sulfonamide (0.15 g, 0.32 mmol; see step (c) above). Two drops (ca. 0.05 mL) of anisole were then added and the resultant mixture stirred under a N₂ atmosphere for 18 hours at ambient temperature. The reaction mixture was evaporated and co- evaporated with acetonitrile (5 mL x 3) to give crude sub-title compound.

(e) N-Butyloxycarbonyl-3-[4-(l-methyl-lH-pyrazole-5-carbonyl)phenyl]-5- t^'-rø-butylτhiophene-2-sulfonanride

The crude product from step (d) above was dissolved in pyridine (4 mL). Pyrrolidinopyridine (0.048 g, 0.32 mmol) and n-butyl chloroformate (0.45 g, 3.26 mmol) were added. The reaction mixture was stirred overnight at room temperature under a Ν₂ atmosphere. The mixture was evaporated and co-evaporated with acetonitrile and the residue was taken up in chloroform (20 mL), washed with 10% aqueous citric acid, followed by water and then brine, and dried over MgS0 . The residue was purified by flash chromatography using petroleum etheπacetone as eluent to give 0.118 g of the title compound in 72% yield. MS (ESI⁺) m/z: 504 (M⁺)

1H NMR (CDC1₃, 270 MHz): δ 10.69 (brs, IH), 7.57 (m, 5H), 6.79 (s, IH), 6.59 (s, IH), 4.07 (t, J = 6.60 Hz, 2H), 3.86 (s, 3H), 2.73 (d, J= 7.26 Hz, 2H), 1.96 (m, IH), 1.53 (m, 2H), 1.28 (m, 2H), 1.00 (d, J = 6.60 Hz, 6H), 0.89 (t, J= 7.26 Hz, 3H)

¹³C NMR (CDCI₃, 67.5 MHz): δ 184.5, 151.4, 150.6, 143.9, 138.7, 137.5, 137.2, 132.4, 129.2, 128.9, 128.8, 113.5, 66.5, 39.2, 30.4, 22.1, 18.7, 13.5. IR (neat): 2959, 2871, 1747, 1656, 1346, 1259, 1159 cm^"1 Example 8

N-Butyloxycarbonyl-3-r4-(5-trifluoromethyl[^" 3.4]oxadiazol-2-ylmethyl)- phenyll-5-røo-butylτhiophene-2-sulfonamide

(a) 3-(4-Cvanomethylphenyl)-5-zi'o-butyl-N-fert-butylthiophene-2-sulfon- amide

5-z5^,o-Bu1yl-2-(N-tert-butylanήnosulfonyl)thiophene-3-boronic acid (200.5 mg, 0.628 mmol; see Example 1 (c) above), 4-bromophenylacetonitrile (81.7 mg, 0.416 mmol), toluene (15 mL), ethanol (2.5 mL), ΝaOH (1.0 M, 1.5 mL, 1.5 mmol) and Pd(PPh₃)₄ (18 mg, 0.016 mmol) were mixed together under Ν₂. The mixture was heated at reflux for 2 hours and then diluted with EtOAc (50 mL). The organic phase was washed with water and brine, then dried over MgS0 . The solvent was removed in vacuo and the residue was separated by column chromatography using hexane:acetone (4:1) to give the sub-title compound (92.5 mg, 0.237 mmol, yield: 57%). IR (neat): 3291, 2996, 2868, 2243, 1510, 1464, 1425 cm^"1. 1H MR δ(CDCl₃): 7.65 (2H, d, J= 8.2), 7.42 (2H, d, J= 8.2), 6.75 (IH, s), 3.81 (2H, s), 2.70 (2H, d, J= 7.1), 1.97 (IH, m), 1.01 (9H, s), 0.98 (6H, d, J = 6.9). ¹³C NMR δ(CDCl₃): 148.6, 142.3, 134.8, 130.1, 129.8, 128.8, 128.0, 117.6, 54.6, 39.2, 30.6, 29.6, 23.5, 22.1. MS (ESI⁺) m/z: 390.8

Anal. Calcd. for C₂oH₂₆N₂θ₂S₂. ^x/2xH₂0: C, 60.12; H, 6.81; N, 7.01. Found: C, 60.5; H, 6.6; N, 6.9.

(b) 3-[4-(5-Trifluoromethyl[ 3.4]oxadiazol-2-ylmethyl)phenyl]-5-z.yo- butyl-N-tert-butylthiophene-2-sulfonamide

A dried heavy-walled Pyrex tube was charged with 3-(4- cyanometiiylphenyl)-5-z5'o-butyl-N-tert-butyltlnophene-2-sulfonamide (0.3 g, 0.77 mmol; see step (a) above), NaN₃ (0.06 g, 0.92 mmol) and NH₄C1 (0.05 g, 0.92 mmol) in DMF (1 mL). The reaction mixture was flushed with N₂ and sealed tightly before mixing with a Whirlimixer. The reaction mixture was subjected to a microwave reacter at 150°C for 2 hours. The mixture was diluted with saturated NaHC0₃ (aq.) (50 mL) and washed with ether (10 mL x 3, to remove unreacted starting material). The aqueous phase was acidified with cone. HCl to pH < 1 and extracted with chloroform (10 mL x 3). The combined organic phase was dried, the solvent evaporated in vacuo and the residue was redissolved in trifluoroacetic anhydride (4 mL, excess) and heated at 50°C for 30 min. The mixture was evaporated and purified by flash chromatography using acetone: petroleum ether as eluent to afford the sub-title compound in a yield of 30% (116 mg, 0.231 mmol). IR (neat): 3291, 2962, 1558, 1313, 1210, 1170 cm^"1. 1H NMR (CDC1₃, 270 MHz): δ 7.65 (d, J= 8.25 Hz, 2H), 7.42 (ά, J= 8.25 Hz, 2H), 6.77 (s, IH), 4.37 (s, 2H), 4.13 (br s, IH), 2.70 (d, J = 7.26 Hz, 2H), 1.94 (m, IH), 1.00 (s, 9H), 0.98 (d, J= 6.60 Hz, 6H).

¹³C NMR (CDCI₃, 67.5 MHz): δ 167.2, 155.9, 155.2, 154.6, 148.5, 142.2, 136.6, 134.8, 132.4, 129.8, 128.9, 128.7, 127.9, 122.0, 118.1, 114.0, 77.0, 54.5, 39.1, 31.4, 30.5, 29.4, 22.1. MS (ESI⁺) m/z: 502 Qs/ +1).

(c) 3-[4-(5-Trifluoromeτhyl[ 3.4]oxadiazol-2-ylmeτhyl)phenyl]-5-t^".s'o-but- ylthiophene-2-sulfonamide

Trifluoroacetic acid (5 mL) was added to 3-[4-(5-trifluoro- methyl[ 1 ,3 ,4]oxadi azol-2-ylmethyl)phenyl]-5- z^'-rø-butyl-N-tert-butylthio- phene-2-sulfonamide (100 mg, 0.19 mmol; see step (b) above). Two drops (ca. 0.05 mL) of anisole were added and the mixture was stirred under a N₂ atmosphere for 18 h at ambient temperature. The reaction mixture was concentrated under reduced pressure and then co-evaporated with acetonitrile (10 mL x 3) to give crude sub-title product. (d) N-Butyloxycarbonyl-3-[4- 5-trifluoromethvir 1.3.4]oxadiazol-2-yl- methyl)phenyl]-5-z'^o-butylthiophene-2-sulfonamide

The crude product from step (c) above was dissolved in pyridine (3 mL).

Pyrrolidinopyridine (29 mg, 0.19 mmol) was added, followed by w-butyl chloroformate (253 μL, 1.99 mmol). The reaction mixture was stirred overnight at room temperature under a N₂ atmosphere. The reaction mixture was concentrated under reduced pressure and then co-evaporated with acetonitrile. The residue was dissolved in chloroform (20 mL), washed with citric acid (10% aq.), water and brine, and then dried over MgS0₄. The residue was purified by flash chromatography using petroleum ether: acetone as eluent to give the title compound (76 mg, 0.139 mmol, 70% yield).

IR (neat): 3227, 2961, 1750, 1346, 1212, 1160 cm^"1.

^!H NMR (CDC1₃, 270 MHz): δ 7.81 (br s, IH), 7.45 (d, J= 8.25 Hz, 2H), 7.36 (d, J = 8.25 Hz, 2H), 6.75 (s, IH), 4.33 (s, 2H), 4.05 (t, J= 6.60 Hz,

2H), 2.70 (d, J= 6.93 Hz, 2H), 1.93 (m, IH), 1.50 (m, 2H), 1.26 (m, 2H),

0.98 (d, J= 6.60 Hz, 6H), 0.87 (t, J= 7.26 Hz, 3H).

¹³C NMR (CDC1₃, 67.5 MHz): δ 167.3, 156.5, 155.9, 155.2, 154.5, 151.7,

150.1, 145.7, 133.8, 132.7, 130.7, 129.6, 129.3, 128.8, 128.5, 118.1, 114.1, 66.8, 39.2, 31.3, 30.4, 30.3, 22.1, 18.6, 13.5.

MS (ESI^"1 m/z: 546 (W).

Example 9

N-Butyloxycarbonyl-3-r4-(tMophene-3-ylmethyl)phenyl]-5-z5'Q-butyltlιio- phene-2-sulfonamide

(a) 3-(4-Hydroxymethylρhenyl -5-z-?(9-butyl-N-tert-butylthiophene-2-sulfon- amide

5-z-?o-Butyl-2-(N-tert-butylammosulfonyl)thiophene-3-boronic acid (319.3 mg, 1.00 mmol; see Example 1(c) above), 4-bromobenzyl alcohol (374.1 mg, 2.00 mmol), toluene (20 mL), ethanol (4 mL), NaOH (1.0M, 4 mL, 4 mmol) and Pd(PPh₃)₄ (34 mg, 0.030mmol) were mixed together under N₂.

The mixture was warmed to reflux for 2 hours and was then diluted with

EtOAc (50 mL), washed with water and brine and dried over MgS0₄. The solvent was removed and the residue was separated by column chromatography using CHCl₃:MeOH (40:1) as eluent to give 289 mg of the sub-title compound (yield: 76%).

IR (neat): 3465, 3162, 2952, 2867, 1441 cm^"1

1H NMR δ(CD₃OD): 7.59(2H, d, /= 8.2 Hz), 7.45 (2H, d, J= 8.2 Hz), 6.75 (IH, s), 4.75 (2H, s), 4.11 (IH, brs), 2.69 (2H, d, J= 7.1 Hz), 1.92 (IH, m),

0.99 (6H, d, J= 7.2 Hz), 0.98 (9H, s)

¹³C NMR δ(CD₃OD): 148.3, 142.9, 141.1, 134.2, 130.3, 128.9, 127.6,

126.8, 64.8, 54.5, 39.2, 30.5, 29.5, 22.1

MS (EI⁺) m/z: 382.0 Anal. Calcd. for C₁₉H₂₇N0₃S₂: C, 59.8; H, 7.3; N, 3.7. Found: C, 59.6; H,

7.0; N, 3.5

(b) 3-(4-Bromomethylphenyl -5-z o-butyl-N-tert-butylthiophene-2-sulfon- amide 3-(4-Hydroxymethylphenyl)-5-z^'-fo-butyl-N-tert-butylthiophene-2-sulfon- amide (280 mg, 0.734 mmol; see step (a) above) was dissolved in DMF (10 mL). PPh₃ (459.2 mg, 1.75 mmol) and CBr₄ (580.3, 1.75 mmol) were added to the resultant solution. The mixture was stirred for 24 h at room temperature and then diluted with ethyl acetate. The organic phase was washed with water (50 mL) and brine (50 mL) and then dried over MgS0₄. After removing the solvents, the residue was purified by column chromatography using hexane:acetone (5:1) as eluent to give the sub-title compound (314.9 mg, 0.709 mmol, 76% yield). IR (neat): 3302, 2952, 2866, 1442 cm^"1 1H NMR δ(CDCl₃): 7.62(2H, d, J= 8.4 Hz), 7.48(2H, d, J= 8.4 Hz), 6.75 (IH, s), 4.56 (2H, s), 4.11 (IH, brs), 2.69 (2H, d, J= 7.1 Hz), 1.92 (IH, m), 0.99 (6H, d, J= 7.2 Hz), 0.98 (9H, s)

¹³C NMR δ( CDC1₃): 148.5, 142.4, 138.2, 136.9, 135.1, 129.5, 129.1, 128.7, 54.6, 39.2, 32.8, 30.5, 29.5, 22.1 MS (El⁴) m z: 445.8

(c) 3-[4-(TMophene-3-ylmethyl)phenyl]-5-z^o-butyl-N-tert-butylthiophene- 2-sulfonamide 3-(4-Bromometiιylphenyl)-5-z^'-?o-butyl-N-tert-butylt ophene-2-sulfonamide (100 mg, 0.23 mmol; see step (b) above), 3-thiopheneboronic acid (36 mg, 0.33 mmol), toluene (2.5 mL), ethanol (0.7 mL), NaOH (1.0 M, 1.0 mL, 1.0 mmol), Pd(PPh₃) (10 mg, 0.01 mmol) were mixed under N₂. The mixture was heated to 80°C for 3 hours and then diluted with EtOAc (20 mL), washed with water and brine, and then dried over MgS0₄. The solvent was evaporated and the residue was purified by flash chromatography using petroleum etheπacetone (5:1) as eluent to give the sub-title compound (81 mg, 0.18 mmol, 78 % yield). IR (neat): 3293, 2960, 1310, 1144 cm^"1. 1H NMR (CDC1₃, 270 MHz): δ 7.54 (d, J = 8.25 Hz, 2H), 7.31-7.24 (m, 3H), 6.96 (m, IH), 6.89 (m, IH), 6.75 (s, IH), 4.05 (s, IH), 4.01 (s, 2H), 2.67 (d, J= 6.93 Hz, 2H), 1.91 (m, IH), 1.00-0.93 (m, 15H). ¹³C NMR (CDC1₃, 67.5 MHz): δ 148.2, 142.9, 141.1, 140.9, 132.8, 129.1, 128.9, 128.8, 128.1, 125.8, 121.2, 54.4, 39.1, 36.2, 30.5, 29.4, 22.1. MS (ESI⁺) m/z: 448 (M⁴).

(d) 3-[4-(TMophene-3-ylmethyl)phenyll-5-z-?o-butylthiophene-2-sulfon- amide

Trifluoroacetic acid (3 mL) was added to 3-[4-(thiophene-3- ylmethyl)phenyl]-5-z^'-?o-butyl-N-tert-butyll ophene-2-sulfonamide (60 mg, 0.13 mmol; see step (c) above). Two drops (ca. 0.05 mL) of anisole were added and the mixture was stirred under a N₂ atmosphere for 12 h at ambient temperature. The reaction mixture was evaporated and co- evaporated with acetonitrile (10 mL x 3) to give crude sub-title product.

(e) N-Butyloxycarbonyl-3-f4-(thiophene-3-ylmethyl phenyll-5-z-?o-butyl- thiophene-2-sulfonamide

The crude product from step (d) above was dissolved in pyridine (3 mL).

Pyrrolidinopyridine (20 mg, 0.134 mmol) and n-bυtyl chloroformate (170 μL, 1.34 mmol) were added. The reaction mixture was stirred overnight at room temperature under a N₂ atmosphere. The mixture was evaporated and co-evaporated with acetonitrile. The residue was dissolved in chloroform (20 mL), washed with citric acid (10% aq.), water and brine, and then dried over MgS0 . The residue was purified by flash chromatography using petroleum ether: acetone (2:1) as eluent to give the title compound (43 mg, 0.087 mmol, 65 % yield). IR (neat): 3233, 2958, 1753, 1346, 1160 cm^"1.

1H NMR (CDC1₃, 270 MHz): δ 7.40 (d, J = 8.25 Hz, 2H), 7.30-7.21 (m, 3H), 7.10 (s, IH), 6.97-6.91 (m, 2H), 6.76 (s, IH), 4.05-4.00 (m, 4H), 2.70 (d, J= 7.26 Hz, 2H), 1.94 (m, IH), 1.47 (m, 2H), 1.23 (m, 2H), 0.99 (d, J= 6.60 Hz, 6H), 0.87 (t, J= 7.26 Hz, 3H).

¹³C NMR (CDCI₃, 67.5 MHz): δ 151.4, 149.9, 146.4, 141.3, 140.7, 131.8, 130.2, 129.4, 128.9, 128.7, 128.3, 125.7, 121.4, 66.8, 39.2, 36.1, 30.4, 30.3, 22.2, 18.7, 13.5. MS (ESI j m/z: 492 (M⁺).

Example 10

Title compounds of the Examples were tested in Tests A and B above and were found to exhibit an affinity for AT2 receptors of less than Ki = 100 nM (e.g. less than 50 nM). The title compounds of the Examples were found to exhibit an affinity to ATI receptors of more than Ki = 500 nM (e.g. more than 1 μM).

Example 11 Title compounds of the Examples are tested in Test C above and are found to stimulate markedly mucosal alkalisation. This effect is blocked by co- administration of the selective AT2 receptor antagomst PD123319 (Sigma Chemical Company).

Claims

Claims

1. A compound of formula I,

wherein

Xi represents -C(R^la)- or-N-;

X₃ represents -C(R^lc)- or -N-; the dotted lines between the pairs of substituents X₂ and X , and X₃ and X-_f, signify the presence of a double bond between one of the relevant pairs of substituents and a single bond between the other pair; and

(i) when the double bond is between X₂ and X₃, then:-

X₂ represents -C(R )- or -N-; and X₄ represents -N(R^ld)-, -S- or -0-; or

(ii) when the double bond is between X₃ and X₄ then:-

X₂ represents -N(R^lb)-, -S- or-O-; and

X₄ represents -N- or -C(R^ld)-;

R^la, R^lb, R^lc and R^ld independently represent H, Cι_₆ alkyl, Cι.₆ alkoxy-Cι_₆ alkyl, Ar¹, Het¹, .₃ alkyl-Ar², C₁-₃ alkyl-Het², C,_₃ alkoxy-Ar³ or d_₃ alkoxy-Het³;

Ar¹, Ar² and Ar³ each independently represent a Cβ-io aryl group, which group is optionally substituted by one or more substituents selected from =0, cyano, halo, nitro, Cι_₆ alkyl (optionally terminated by -N(H)C(0)OR^lla), d.₆ alkoxy, phenyl, -N(R^12a)R^{1 b}, -C(0)R^12c, -C(0)OR^12d, -C(0)N(R^12e)R^12f, -N(R^12g)C(0)R^12h, -N(R¹²ⁱ)C(0)N(R^12j)R^12k, -N(R^12m)S(0)₂R^llb, -S(0)_pR^llc, -OS(0)₂R^lld and -S(0)₂N(R¹²ⁿ)R^12p; Het¹, Het² and Het³ each independently represent a four- to twelve- membered heterocyclic group containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic group is optionally substituted by one or more substituents selected from =0, cyano, halo, nitro, d.₆ alkyl (optionally terminated by -N(H)C(0)OR^lla), d_₆ alkoxy, phenyl, -N(R^12a)R^12b, -C(0)R^12c, -C(0)OR^12d, -C(0)N(R^12e)R^12f, -N(R^12g)C(0)R^12h, -N(R¹²ⁱ)C(0)N(R^12j)R^12k, -N(R^12m)S(0)₂R^{l lb}, -S(0)_pR^{l lc}, -OS(0)₂R^lld and -S(0)₂N(R¹²ⁿ)R^12p;

R^lla to R^lld independently represent C]_₆ alkyl; R^12a to R^12p independently represent H or Cι.₆ alkyl; p represents 0, 1 or 2; provided that:

(1) when X₂ or X₄ represents -O- or -S-, then no more than two of the other ring atoms in the ring containing the groups Xi, X₂, X₃ and X may comprise a nitrogen atom; and (2) when Xi represents -C(R^la)-, the double bond is between X₃ and X₄, X₂ represents -N(R^lb)-, X₃ represents -N- and X₄ represents -C(R^ld)-, then R^Ib does not represent a substituted phenyl group; A represents -C(O) or -CH₂-;

Yi, Y₂, Y₃ and Y independently represent -CH- or -CF-; Z_! represents -CH-, -0-, -S-, -N- or -CH-CH-; Z₂ represents -CH-, -0-, -S- or -N-; provided that:

(a) Z] and Z₂ are not the same;

(b) when Zi represents -CH=CH-, then Z₂ may only represent -CH- or -N-; and (c) other than in the specific case in which Z_λ represents -CH=CH-, and Z₂ represents -CH-, when one Zi and Z₂ represents -CH-, then the other represents -O- or -S-; R² represents -S(0)₂N(H)C(0)R⁴, -S(0)₂N(H)S(0)₂R⁴, -C(0)N(H)S(0)₂R⁴, or, when Z_\ represents -CH=CH-, R may represent -N(H)S(0)₂N(H)C(0)R⁵ or -N(H)C(0)N(H)S(0)₂R⁵; R³ represents d-₆ alkyl, Cμ₆ alkoxy, C].₆ alkoxy-Cι_₆-alkyl or di-Cι_₃- alkylamino-Ci-₄-alkyl;

R⁴ represents d_₆ alkyl, Cι_₆ alkoxy, Cι-₆ alkoxy-Cι-₆-alkyl, C₁-₃ alkoxy-Cι_₆-alkoxy, d_₆ alkylamino or di-Cι_₆ alkylamino; and R⁵ represents d-₆ alkyl, or a pharmaceutically-acceptable salt thereof.

2. A compound as claimed in Claim 1 wherein X_\ represents -CH- or -N-.

3. A compound as claimed in Claim 1 or Claim 2 wherein, when the double bond is between X₂ and X₃, then X₂ represents -CH- or -N.

4. A compound as claimed in Claim 1 or Claim 2 wherein, when the double bond is between X₃ and X₄, then X₄ represents -CH- or

-N-.

5. A compound as claimed in any one of the preceding claims wherein the ring system comprising the groups Xj, X₂, X₃ and X₄ is a thiophenyl, a furanyl, a pyrrolyl, a pyrazolyl, an imidazolyl, a thiazolyl, an oxazolyl, a thiadiazolyl, an oxadiazolyl, a triazolyl, or a tetrazolyl, group.

6. A compound as claimed in Claim 5 wherein the ring system is an imidazolyl, a pyrazolyl, an oxadiazolyl, a thiophenyl, a thiazolyl or an oxazolyl group.

7. A compound as claimed in Claim 6 wherein the ring system is an imidazolyl, a pyrazolyl, an oxazolyl or a thiazolyl group.

8. A compound as claimed in any one of Claims 1, 2 or 4 to 7 wherein R^lb represents H or d_₃ alkyl.

9. A compound as claimed in Claim 8 wherein R^lb represents H or methyl.

10. A compound as claimed in any one of the preceding claims wherein R^lc represents H or Cι_₃ alkyl optionally substituted by one or more fluoro atoms.

11. A compound as claimed in Claim 10 wherein R^lc represents trifluoromethyl.

12. A compound as claimed in Claim 10 wherein R^lc represents H.

13. A compound as claimed in any one of Claims 1 to 3 or 5 to 12 wherein R^ld represents H or d_₃ alkyl.

14. A compound as claimed in Claim 13 wherein R^Id represents H or methyl.

15. A compound as claimed in any one of the preceding claims wherein Yi, Y₂, Y₃ and Y₄ all represent -CH-.

16. A compound as claimed in any one of the preceding claims wherein Z_\ represents -S- or -CH=CH~.

17. A compound as claimed in Claim 16 wherein Z_\ represents -S-.

18. A compound as claimed in any one of the preceding claims wherein Z₂ represents -CH-.

19. A compound as claimed in any one of the preceding claims wherein R represents « -butyl or zjø-butyl.

20. A compound as claimed in Claim 19 wherein R³ represents z-rø-butyl.

21. A compound as claimed in any one of the preceding claims wherein, when R² represents -S(0)₂N(H)C(0)R⁴, -S(0)₂N(H)S(0)₂R⁴ or -C(0)N(H)S(0)₂R⁴, R⁴ represents n-butyl, n-butoxymethyl, z^'so-butoxy or n-butoxy.

22. A compound as claimed in any one of the preceding claims wherein R² represents -S(0)₂N(H)C(0)R⁴.

23. A compound as claimed in Claim 22 wherein R⁴ represents n- butoxymethyl, iso-butoxy or w-butoxy.

24. A compound as claimed in any one of Claims 21 to 23 wherein R⁴ represents n-butoxy.

25. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

26. A compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

27. A compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition in which selective agonism of the AT2 receptor is desired and/or required.

28. A compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition in which endogenous production of Angll is deficient.

29. A compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition in which an increase in the effect of Angll is desired or required.

30. A compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition where AT2 receptors are expressed and their stimulation is desired or required.

31. The use of a compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition in which selective agonism of the AT2 receptor is desired and/or required.

32. The use of a compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition in which endogenous production of Angll is deficient.

33. The use of a compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition in which an increase in the effect of Angll is desired or required.

34. The use of a compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition where AT2 receptors are expressed and their stimulation is desired or required.

35. The use as claimed in any one of Claims 31 to 34, wherein the condition is of the gastrointestinal tract, the cardiovascular system, the respiratory tract, the kidneys, the eyes, the female reproductive (ovulation) system, or the central nervous system.

36. The use as claimed in Claim 35, wherein the condition is oesophagitis, Barrett's oesophagus, a gastric ulcer, a duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastro-oesophageal reflux, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, hepatic disorders (including hepatitis), gall bladder disease, multiple organ failure, sepsis, xerostomia, gastritis, gastroparesis, hyperacidity, a disorder of the bilary tract, coelicia, Crohn's disease, ulcerative colitis, diarrhoea, constipation, colic, dysphagia, vomiting, nausea, indigestion, Sjogren's syndrome, inflammatory disorders, asthma, an obstructive lung disease (including chronic obstructive lung disease), pneumonitis, pulmonary hypertension, adult respiratory distress syndrome, renal failure, nephritis, renal hypertension, diabetic retinopathy, premature retinopathy, retinal microvascularisation, ovulatory dysfunction, hypertension, cardiac hypertrophy, cardiac failure, artherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, post baloon dilatation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina, cardiac arrhythmias, claudicatio intermittens, preeclampsia, myocardial infarction, reinfarction, ischaemic lesions, erectile dysfunction, neointima proliferation, cognitive dysfunctions, dysfunctions of food intake (hunger/satiety), thirst, stroke, cerebral bleeding, cerebral embolus, cerebral infarction, hypertrophic disorders, prostate hyperplasia, autoimmune disorders, psoriasis, obesity, neuronal regeneration, an ulcer, adipose tissue hyperplasia, stem cell differentiation and proliferation, cancer, apoptosis, tumours, hypertrophy diabetes, neuronal lesions or organ rejection.

37. The use as claimed in Claim 36, wherein the condition is non-ulcer dyspepsia, irritable bowel syndrome, multiple organ failure, hypertension or cardiac failure.

38. A method of treatment of a condition in which selective agonism of the AT2 receptor is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, to a person suffering from, or susceptible to, such a condition.

39. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, and an ATI receptor antagonist, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

40. A kit of parts comprising components:

(a) a pharmaceutical formulation including a compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including an ATI receptor antagonist, 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.

41. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, and an angiotensin converting enzyme inhibitor, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

42. A kit of parts comprising components:

(a) a pharmaceutical formulation including a compound as defined in any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including an angiotensin converting enzyme inhibitor, 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.

43. A process for the preparation of a compound as defined in Claim 1, which comprises: (i) for compounds of formula I in which R² represents -S(0)₂N(H)C(0)R⁴ or -S(0)₂N(H)S(0)₂R⁴, and R⁴ is as defined in Claim 1, reaction of a compound of formula II,

wherein the dotted lines, X_l5 X₂, X₃, X₄, A, Yi, Y₂, Y₃, Y₄, Z_\, Z₂ and R are as defined in Claim 1 with a compound of formula III,

R⁴GL ¹ III wherein G represents C(O) or S(0)₂ (as appropriate), L¹ represents a suitable leaving group and R⁴ is as defined in Claim 1; (ii) for compounds of formula I in which R² represents -S(0)₂N(H)C(0)R⁴ and R⁴ represents Cι_₆ alkoxy-Cι_₆-alkyl, coupling of a compound of formula II as defined above with a compound of formula IV,

R^4aC0₂H IV wherein R^4a represents Cι_₆ alkoxy-d_₆-alkyl; (iii) for compounds of formula I in which R² represents -C(0)N(H)S(0)₂R⁴ and R is as defined in Claim 1, coupling of a compound of formula V,

wherein the dotted lines, X_1} X₂, X₃, X₄, A, Yi, Y₂, Y₃, Y₄, Z_1? Z₂ and R³ are as defined in Claim 1 with a compound of formula VI,

R⁴S(0)₂NH₂ VI wherein R⁴ is as defined in Claim 1;

(iv) for compounds of formula I in which R represents -C(0)N(H)S(0)₂R and R⁴ is as defined in Claim 1, coupling of a compound of formula VII,

wherein the dotted lines, X_l5 X₂, X₃, X₄, A, Y_l9 Y₂, Y₃, Y , Z_\, Z₂ and R are as defined in Claim 1 with a compound of formula VIII,

R⁴S(0)₂C1 VIII wherein R⁴ is as defined in Claim 1;

(v) for compounds of formula I in which R represents

-N(H)S(0)₂N(H)C(0)R⁵ and R⁵ is as defined in Claim 1, reaction of a compound of formula IX,

wherein the dotted lines, X_1} X₂, X₃, X₄, A, Y_1} Y₂, Y₃, Y₄, Z_l5 Z₂ and R³ are as defined in Claim 1 with a compound of formula X,

R⁵C(0)N(H)S(0)₂C1 X wherein R⁵ is as defined in Claim 1 ;

(vi) for compounds of formula I in which R represents -N(H)C(0)N(H)S(0)₂R⁵ and R⁵ is as defined in Claim 1, reaction of a compound of formula IX as defined above with a compound of formula XI,

R⁵S(0)₂N(H)C(0)OR^x XI wherein R^x represents Cι_₂ alkyl and R⁵ is as defined in Claim 1;

(vii) for compounds of formula I in which R represents -N(H)C(0)N(H)S(0)₂R⁵ and R⁵ is as defined in Claim 1, reaction of a compound of formula IX as defined above with a compound of formula XII,

R⁵S(0)₂NCO XII wherein R⁵ is as defined in Claim 1 ;

(viii) for compounds of formula I in which R represents -S(0)₂N(H)C(0)R⁴ and R⁴ represents Cμ₆ alkylamino, reaction of a compound of formula II as defined above with a compound of formula XIII,

R^4bNCO XIII

Ah wherein R is Cι_₆ alkyl; or

(ix) for compounds of formula I in which R² represents -S(0)₂N(H)C(0)R⁴ and R⁴ represents di-d_₆ alkylamino, reaction of a corresponding compound of formula I in which R represents -S(0)₂N(H)C(0)R⁴ and R⁴ represents Cι-₆ alkoxy with a compound of formula XIV,

R^4cN(H)R^4d XIV wherein R^4c and R^4d independently represent Cι_₆ alkyl.

44. A compound of formula II as defined in Claim 43 or a protected derivative thereof.

45. A compound of formula V as defined in Claim 43 or a protected derivative thereof.

46. A compound of formula VII as defined in Claim 43 or a protected derivative thereof.

47. A compound of formula IX as defined in Claim 43 or a protected derivative thereof.