JP4707321B2 - Tricyclic compounds useful as angiotensin II agonists - Google Patents

Description

  The present invention relates to a novel pharmaceutically effective compound, particularly an angiotensin II (Ang II) agonist, more particularly an agonist of Ang II type 2 receptor (hereinafter referred to as AT2 receptor), among them an agonist that selectively binds to this receptor. To a compound that is The invention further relates to the use of such compounds as medicaments, pharmaceutical compositions containing them and the synthetic routes for producing them.

The body hormone AngII is a linear octapeptide (Asp ¹ -Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -Phe ⁸ ) and is an active component of the renin-angiotensin system (RAS). It is produced by sequential treatment of the prohormone angiotensinogen with renin and angiotensin converting enzyme (ACE).

  The renin-angiotensin system (RAS) plays an important role in regulating blood pressure, body fluids, and electrolyte homeostasis. AngII exerts these physiological effects in many organs including the kidney, adrenal gland, heart, blood vessels, brain, gastrointestinal tract and genitals (de Gasparo et al., Pharmacol. Rev. (2000) 52, 415-472) .

  Two main groups of AngII receptors have been identified, referred to as type 1 receptors (AT1 receptors in the following) and AT2 receptors.

  The AT1 receptor is expressed in most organs and is thought to be responsible for most AngII biological effects. In fetal tissue, adult ovary, adrenal medulla and pancreas, AT2 receptors are dominant over AT1 receptors. An even distribution has been reported in the brain and uterus (Ardaillou, J. Am. Soc. Nephrol., 10, S30-39 (1999)).

  Several studies in adult individuals have demonstrated that AT2 receptor activation has the opposite effect on AT1 receptor-mediated effects in modulating responses after AngII stimulation It is.

  The AT2 receptor has also been found to be associated with inhibition of apoptosis and cell proliferation (see de Gasparo et al., Supra). Furthermore, this seems to have a role in blood pressure regulation. For example, transgenic mice lacking the AT2 receptor have been found to increase their blood pressure. Furthermore, it is speculated that AT2 receptors are involved in exploratory behavior, pain sensitivity and thermoregulation.

  AT2 receptor expression has also been found to increase wound healing and heart failure during pathological environments such as vascular injury (see de Gasparo et al., Supra).

  The predicted drug effects of AT2 receptor agonism are generally described in de Gasparo et al., Supra.

  Recently, AT2 receptor agonists have been shown to have potent efficacy in treating and / or preventing gastrointestinal disorders such as dyspepsia and irritable bowel symptoms as well as multiple organ failure (international patents). (See application WO99 / 43339).

  AngII antagonists (binding to the AT1 and / or AT2 receptors) are in particular European patent applications EP 409332, EP 512675; international patent applications WO 94/27597, WO 94/02142, WO 95. / 23792 and WO 94/03435; U.S. Patent Nos. 5091390, 5177707, 5412097, 5250521, 5260285, 5376666, 5252574, and 5312820 No. 5330987, No. 5166206, No. 5932575, No. 5240928. AngII agonists, in particular AT2 receptor agonists, are not considered in any of these documents.

  International Patent Application WO 00/68226 and US Pat. No. 6,235,766 describe compounds containing a substituted imidazolyl group attached to a phenylthiophene moiety via a methylene bridge as an angiotensin- (1-7) receptor agonist. Disclosure. International patent application WO 01/44239 discloses biphenylsulfonamide compounds as combined angiotensin and endothelin receptor antagonists. The use of compounds as AngII receptor agonists is not specified or suggested in any of these documents.

  U.S. Pat. No. 5,440,467 discloses compounds containing a 5,7-dimethyl-2-ethylpyridinoimidazolyl group attached to the phenylthiophene moiety via a methylene bridge as an AT2 receptor agonist. The use of unsubstituted imidazole-containing compounds is not specified or suggested.

Peptide and non-peptide AT2 receptor agonists that are not structurally similar to those described herein and their possible uses are described, for example, in 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 / No. 40106, WO 99/39743, WO 99/26644, WO 98/33813, WO 00/02905 and WO 99/46285; US Pat. No. 5,834,432; and Japanese Patent Application No. 143695 In the issue.
de Gasparo et al., Pharmacol. Rev. (2000) 52, 415-472 Ardaillou, J. Am. Soc. Nephrol., 10, S30-39 (1999) International patent application WO99 / 43339 EP 409332 EP No. 512675 WO 94/27597 WO 94/02142 WO 95/23792 WO 94/03435 US Patent No. 5091390 US Patent No. 577774 US Patent No. 5412097 US Patent No. 5250521 US Patent No. 5260285 US Patent No. 5376666 US Patent No. 5252574 US Patent No. 5312820 US Patent No. 5330987 US Patent No. 5166206 US Patent No. 5932575 US Patent No. 5240928 WO 00/68226 US Patent No. 6235766 WO 01/44239 US Patent No. 544067 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 WO 99/46285 U.S. Pat.No. 5,834,432 Japanese Patent Application No. 143695 UK patent application GB 2281298 "Protective Groups in Organic Chemistry" edited by JWF McOmie (Plenum Press, 1973) "Protective Groups in Organic Synthesis", 3rd edition, TW Greene & PGM Wutz, Wiley-Interscience (1999)

  However, there remains a need for effective and / or selective AT2 receptor agonists that are expected to be particularly useful in the above conditions.

  In the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof

[In the above formula,
One of X ₁ and X ₂ represents -N- and the other represents -C (R ¹ )-;
X ₃ represents -N- or -C (R ² )-;
X ₄ represents -N- or -C (R ³ )-;
R ¹ , R ² and R ³ independently represent H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl or halo;
However, when X ₁ represents -C (R ¹ )-, X ₃ represents -C (R ² )-, and X ₄ represents -C (R ³ )-, R ¹ represents H Represents;
Y ₁ , Y ₂ , Y ₃ and Y ₄ independently represent -CH- or -CF-;
Z ₁ represents -CH-, -O-, -S-, -N- or -CH = CH-;
Z ₂ represents -CH-, -O-, -S- or -N-;
However,
(a) Z ₁ and Z ₂ are not the same;
(b) when Z ₁ represents -CH = CH-, Z ₂ represents only -CH- or -N-;
(c) Z ₁ represents -CH = CH-, with the exception of special cases that represent Z ₂ is -CH-, when one of Z ₁ and Z ₂ represents -CH-, other, -O- Or -S-;
R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ , -S (O) ₂ N (H) S (O) ₂ R ⁶ , -C (O) N (H) S ( O) ₂ R ⁶ or when Z ₁ represents —CH═CH—, R ⁴ represents —N (H) S (O) ₂ N (H) C (O) R ⁷ or —N (H) C (O) N (H) S (O) ₂ R ⁷ may be represented;
R ⁵ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ -alkyl or di-C ₁ -C ₃ -alkylamino-C ₁ -C ₄ alkyl Represents;
R ⁶ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₃ alkoxy-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ alkyl amino or di -C ₁ -C ₆ alkylamino;
R ⁷ represents C ₁ -C ₆ alkyl], and these compounds and salts are referred to hereinafter together as “compounds of the invention”.

  Pharmaceutically acceptable salts include acid addition salts and base addition salts. Any conventional means, for example, reacting the free acid or free base form of a compound of the invention with one or more equivalents of the appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, Subsequently, such salts can be formed by removing the solvent or the medium using standard techniques (eg, in vacuo or by lyophilization). For example, a salt can be prepared by exchanging the counter ion of a salt form of the compound of the present invention with another counter ion using a suitable ion exchange resin.

  Unless otherwise stated, the alkyl group and the alkyl portion of the alkoxy, alkoxyalkyl, alkoxyalkoxy, alkylamino and alkylaminoalkyl groups may be linear or a sufficient number (ie, at least 3), as defined herein. ) Carbon atoms may be branched and / or cyclic. Furthermore, such groups may be partially cyclic / acyclic if there is a sufficient number (ie, a minimum of 4) carbon atoms. Such alkyl groups and the alkyl portion of alkoxy, alkoxyalkyl, alkoxyalkoxy, alkylamino and alkylaminoalkyl groups may be saturated or when there are a sufficient number (ie at least 2) of carbon atoms. May be unsaturated. Unless otherwise stated, such groups may be substituted with one or more halo atoms, especially fluoro atoms.

  Without question, alkoxy and alkoxyalkoxy groups are attached to the rest of the molecule through an oxygen atom in the group, and an alkylamino group is attached to the molecule through a nitrogen atom in the amino portion of the group. The alkylaminoalkyl and alkoxyalkyl groups are attached to the rest of the molecule through the alkyl portion of the group.

  As used herein, the term “halo” includes fluoro, chloro, bromo and iodo.

Preferred ring systems containing substituents Y ₁ , Y ₂ , Y ₃ and Y ₄ include phenyl groups. Without question, the ring system in the compounds of formula I containing the radicals Z ₁ and Z ₂ is indeed aromatic. In some cases, for example, when one or more of Z ₁ and Z ₂ represents -CH- or -N-, an additional H atom must be bonded to the CH group or N atom to provide a valence of One skilled in the art will understand that compliance with the law can be guaranteed. Preferred ring systems containing Z ₁ and Z ₂ include oxazole groups, thiazole groups, phenyl groups, pyridinyl groups, thiophenyl groups and furanyl groups.

  In this context, the compounds of the invention may exhibit tautomerism. All tautomers and mixtures thereof are included within the scope of the present invention.

  The compounds of the present invention also contain one or more asymmetric carbon atoms and may therefore exhibit optical and / or diastereoisomerism. The diastereoisomers can be separated using conventional techniques such as chromatography or fractional crystallization. The various stereoisomers can be isolated by separating racemic or other mixtures of compounds using conventional, eg, fractional crystallization or HPLC techniques. Alternatively, by reacting the appropriate, optionally active starting material under conditions that do not result in racemization or epimerization, or derivatization with, for example, a homochiral acid followed by conventional means (e.g. HPLC, on silica The desired optical isomers can be prepared by separating the diastereoderivatives by chromatography). All stereoisomers are included within the scope of the present invention.

Preferred compounds of the invention include
(i) If X ₁ represents -C (R ¹ )-:
(a) X ₃ represents -C (R ² )-and X ₄ represents -N-;
(b) both X ₃ and X ₄ represent N;
(c) X ₃ represents -C (R ² )-and X ₄ represents -C (R ³ )-; or
(ii) when X ₁ represents -N-
(a) X ₃ represents -N-;
(b) Compounds wherein X ₃ represents —C (R ² ) — and X ₄ represents —C (R ³ ) — are included.

In the case of the above (i) and (a), it is more preferable that R ¹ represents H.

In the case of (ii) (a) above, it is more preferable that R ³ represents H when X ₄ represents —C (R ³ ) —.

Preferred compounds of formula I include:
R ¹ represents C ₁ -C ₃ alkyl, such as ethyl, —CF ₃ or, in particular, H;
R ² represents C ₁ -C ₃ alkyl such as methyl, halo or especially H;
R ³ represents C ₁ -C ₃ alkyl, halo or, in particular, H;
Y ₁ , Y ₂ , Y ₃ and Y ₄ all represent -CH-;
Z ₁ represents -S- or -CH = CH-;
Z ₂ represents -CH-;
R ⁴ represents S (O) ₂ N (H) C (O) R ⁶ ;
R ⁵ represents n-butyl or, in particular, isobutyl;
Included are compounds wherein R ⁶ represents n-butoxymethyl, iso-butoxy and especially n-butoxy.

Preferred ring systems containing substituents X ₁ , X ₂ , X ₃ and X ₄ include pyrazole groups, imidazole groups, 1,2,4-triazole groups and tetrazole groups.

Among the compounds of the invention that may be mentioned, X ₁ , X ₃ and X ₄ all represent —CH—, Y ₁ , Y ₂ , Y ₃ and Y ₄ all represent —CH— and Z ₁ Is —CH═CH— or, in particular, —S—, Z ₂ represents —CH—, and R ⁵ represents n-butyl or, in particular, isobutyl, R ⁴ represents —S (O ) ₂ N (H) C (O) R ⁶ where R ⁶ is —O-isopropyl (ie iso-propoxy), —O-isobutyl (ie iso-butoxy), —CH ₂ — Included are compounds that represent On-butyl (ie, n-butoxymethyl) or, in particular, —On-butyl (ie, n-butoxy).

Among the compounds of the invention that may be mentioned, X ₁ , X ₃ and X ₄ all represent —CH—, Y ₁ , Y ₂ , Y ₃ and Y ₄ all represent —CH— and Z ₁ Represents —CH═CH— or —S—, Z ₂ represents —CH—, and R ⁵ represents n-butyl or isobutyl, R ⁴ represents —S (O) ₂ N ( H) not represent C (O) R ^6, wherein, R ⁶ is, -O- isopropyl, -O- isobutyl, compounds that represent -CH ₂ -On- butyl or -On- butyl.

In addition, the compounds of the present invention that may be mentioned include:
R ⁴ does not represent -S (O) ₂ N (H) S (O) ₂ R ⁶ ;
R ⁵ does not represent di-C ₁ -C ₃ alkylamino-C ₁ -C ₄ -alkyl;
Compounds in which R ⁶ does not represent C ₁ -C ₃ alkoxy-C ₁ -C ₆ alkoxy are included.

  Further preferred compounds of the invention include the compounds of the examples below.

  For example, compounds of formula I can be prepared according to techniques well known to those skilled in the art, such as those described below.

In another aspect of the present invention, there is provided a method for preparing a compound of formula I comprising:
(i) in formula R ⁴ represents _{-S (O) 2 N (H} ) C (O) R 6 or _{-S (O) 2 N (H} ) S (O) 2 R 6, R 6 is a For compounds of formula I defined analogously to, for example, at ambient room temperature or above (eg up to 60-70 ° C.), a suitable base (eg pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylamino Pyridine, di-isopropylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, sodium hydroxide or mixtures thereof) and suitable solvents (eg pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, trifluoro) A compound of formula II in the presence of methylbenzene or triethylamine:

[Wherein, X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as described above] III compounds:

R ⁶ GL ¹ III
[Wherein G represents C (O) or S (O) ₂ (suitably), L ¹ represents a suitable leaving group such as halo (eg chloro or bromo), R ⁶ Is defined as above)]. Preferred base / solvent systems for compounds of formula III wherein G is C (O) include pyrrolidinopyridine / pyridine, pyrrolidinopyridine / triethylamine, dimethylaminopyridine / pyridine or dimethylaminopyridine / triethylamine. It is. Preferred base / solvent systems for compounds of formula III where G is S (O) ₂ include NaOH / THF;
(ii) in formula R ⁴ represents _{-S (O) 2 N (H} ) C (O) R 6, R 6 is C ₁ -C ₆ alkoxy -C ₁ -C ₆ - of the formula I represents an alkyl For compounds, for example, under conditions similar to those described in process step (i) above, a suitable coupling agent (e.g., 1,1′-carbonyl-diimidazole, N, N′-dicyclohexylcarbodiimide, N , N'-Disuccinimidyl carbonate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl Uronium hexafluorophosphate, benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate, bromo-tris-pyrrolidinophosphonium hexafluorophosphate or 2- (1H-benzotriazol-1-yl) -1, 1,3,3-tetramethyl Uronium tetrafluorocarbonate), in the presence of a suitable base (as described in process step (i) above) and a suitable solvent (as described in process step (i) above) as above. A compound of formula II as defined in formula IV

R ^6a CO ₂ H IV
Coupling with [wherein R ^6a represents C ₁ -C ₆ alkoxy-C ₁ -C ₆ -alkyl];
(iii) In the compounds of formula I in which R ⁴ represents -C (O) N (H) S (O) ₂ R ⁶ and R ⁶ is as defined above, for example suitable coupling In the presence of an agent (such as that described in process step (ii) above), a compound of formula I is prepared wherein R ⁶ represents C ₁ -C ₆ alkoxy-C ₁ -C ₆ -alkyl. Under reaction conditions similar to those described above for the compound of formula V:

[Wherein, X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as above] VI compounds:

R ⁶ S (O) ₂ NH ₂ VI
Coupling with [wherein R ⁶ is as defined above];
(iv) In compounds of formula I wherein R ⁴ represents -C (O) N (H) S (O) ₂ R ⁶ and R ⁶ is defined as above, for example at about 50 ° C A compound of formula VII in the presence of a suitable base (e.g. sodium hydride) and a suitable organic solvent (e.g. THF):

[Wherein, X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as above] VIII compounds:

R ⁶ S (O) ₂ Cl VIII
Coupling with [wherein R ⁶ is as defined above];
(v) in the compounds of formula I wherein R ⁴ represents -N (H) S (O) ₂ N (H) C (O) R ⁷ and R ⁷ is as defined above, for example at room temperature Or near 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):

[Wherein, X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as described above] X compounds:

R ⁷ C (O) N (H) S (O) ₂ Cl X
Reacting with [wherein R ⁷ is as defined above];
(vi) in the compounds of formula I wherein R ⁴ represents -N (H) C (O) N (H) S (O) ₂ R ⁷ and R ⁷ is defined as above, for example at room temperature Or a compound of formula IX as defined above in the presence of a suitable organic solvent (e.g. dichloromethane) at about room temperature:

R ⁷ S (O) ₂ N (H) C (O) OR ^X XI
Reacting with [wherein R ^x represents C ₁ -C ₂ alkyl and R ⁷ is defined as above];
(vii) In the compounds of formula I wherein R ⁴ represents -N (H) C (O) N (H) S (O) ₂ R ⁷ and R ⁷ is as defined above, for example, room temperature Or near the room temperature in the presence of a suitable organic solvent (for example dichloromethane), the compound of formula IX as defined above is converted to an isocyanate compound of formula XII:

R ⁷ S (O) ₂ NCO XII
Reacting with [wherein R ⁷ is as defined above];
(viii) in formula R ⁴ represents _{-S (O) 2 N (H} ) C (O) R 6, in the compound of formula I in which R ⁶ represents a C ₁ -C ₆ alkylamino, e.g. room temperature or In the vicinity of a compound of formula II as defined above in the presence of a suitable base (eg sodium hydroxide or potassium hydroxide) and a suitable organic solvent (eg acetone or acetonitrile), an isocyanate compound of formula XIII:

R ^6b NCO XIII
Wherein R ^6b represents C ₁ -C ₆ alkyl; or
(ix) in formula R ⁴ represents _{-S (O) 2 N (H} ) C (O) R 6, in the compounds of formula I wherein the R ⁶ is a di -C ₁ -C ₆ alkylamino, for example, at room temperature In the above (for example, 70 to 100 ° C.), in the presence of a suitable organic solvent (for example, toluene), R ⁴ in the formula represents —S (O) ₂ N (H) C (O) R ⁶ , The corresponding compound of formula I, wherein R ⁶ represents C ₁ -C ₆ alkoxy, is an amine of formula XIV:

R ^6c N (H) R ^6d XIV
[Wherein R ^6c and R ^6d independently represent C ₁ -C ₆ alkyl].

Suitable coupling catalyst system (e.g., Pd (PPh _{3) 4} or Pd (OAc) ₂ / ligand (wherein the ligand may for _{example, PPh 3, P (o-} Tol) 3 or 1,1'-bis (diphenylphosphino Palladium catalyst such as phosphino) ferrocene) and a suitable base (e.g. sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or di-isopropylamine), and a suitable solvent system (e.g. A compound of formula XV or an N-protected derivative thereof in the presence of toluene, ethanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane or mixtures thereof)

[In the above formula,
R ⁵ , Z ¹ and Z ² are defined as above] for compounds of formula XVI

[In the above formula,
L ² represents a suitable leaving group such as trimethyl sulfonate or halo such as iodo or bromo, and X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ and Y ₄ are as defined above. The compound of formula II can be prepared by reacting with the same definition. If a protected form of the compound of formula XV is used, this reaction can be followed by deprotection of the SO ₂ NH group, for example, under standard conditions as described below.

  Or a compound of formula XVII in the presence of a suitable base (eg, potassium hydroxide) and a suitable organic solvent (eg, DMSO), eg, near or below room temperature.

[In the above formula,
X ₁ , X ₂ , X ₃ and X ₄ are defined as above] according to formula XVIII or an N-protected derivative thereof

[In the above formula,
By reacting Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ , R ⁵ and L ¹ as defined above (L ¹ may particularly represent bromo), when using a shape that is protected compounds of. formula XVIII which can be prepared a compound of formula II, in the reaction, for example, under standard conditions, such as described below, the deprotection of the sO ₂ NH group In addition, compounds of the formula II in which Z ₁ is —CH═CH— and Z ₂ is —CH—, for example according to the process described in particular in US Pat. In addition, compounds of formula II in which Z ₁ is —S— and Z ₂ is —CH— can be prepared, for example, in particular by the process described in UK patent application GB 2281298 According to or similarly.

  For example, a compound of formula XIX in the presence of a suitable oxidizing agent such as potassium permanganate or chromium (VI) oxide under standard oxidizing conditions.

[In the above formula,
X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as above] to oxidize the formula V Can be prepared.

  For example, under conditions similar to those described above for preparing a compound of formula II (first process), a compound of formula XVI as defined above may be converted (in the case of a compound of formula VII) of formula XX Compound

Or (in the case of a compound of formula IX) a compound of formula XXI

[In the above formula, in any case
Z ₁ , Z ₂ and R ⁵ are as defined above] or compounds of formulas VII and IX can be prepared by reaction with their N-protected derivatives. If protected forms of the compounds of formula XX and XXI are used, these reactions can be followed by deprotection of the NH-group under standard conditions (eg acid hydrolysis).

  The compound of formula XVII as defined above is converted according to standard techniques, for example under conditions similar to those described above for the preparation of compound of formula II (second process)

[In the above formula,
Y _1, Y ₂ , Y ₃ , Y ₄ , L ¹ and L ² are defined as above] to give a compound of formula XVI.

  Compounds of formula XVIII are known in the art. For example, this is defined above in particular according to or similar to the process described in US Pat. No. 5,312,820, UK patent application GB 2281298 and / or with respect to the preparation of compounds of formula II (first process) A compound of formula XXIII as defined above under conditions similar to those of formula XXIII

[In the above formula,
Y _1, Y ₂ , Y ₃ , Y ₄ and L ² are defined as above], followed by reaction of the resulting OH group with an appropriate leaving group L ¹ (eg, L ^{If 1} is bromo, convert to reaction at room temperature or near by reaction with CBr _{4 in} the presence of a base (eg triphenylphosphine) and a suitable organic solvent (eg DMF) Can be prepared.

  Under conditions similar to those described above for the preparation of the compound of formula II (first process), the compound of formula XVI as defined above is converted to the compound of formula XXIV or its protected (with aldehyde moiety) Derivative

[In the above formula,
By reacting Z ₁ , Z ₂ and R ⁵ as defined above, a compound of formula XIX can be prepared. If a protected form of the compound of formula XXIV is used, the reaction can be followed by deprotection of the CHO-group under standard conditions (eg acidic hydrolysis).

  Formula XXV

[In the above formula,
R ^Y represents -S (O) ₂ NH ₂ , -C (O) NH ₂ , -NH ₂ or -CHO (suitably), and R ⁵ , Z ₁ and Z ₂ are as defined above. Or a suitable protected derivative thereof is reacted with a reagent system capable of introducing -B (OH) ₂ into a suitable ring system to produce a compound of formula XV, XX, XXI and XXIV And protected derivatives thereof can be prepared. Suitable reagent systems include trialkyl borate esters (eg, triisopropyl borate). Such a reaction can be performed, for example, at low temperatures (for example, -100 ° C to 0 ° C, such as -80 ° C (such as -78 ° C) and -10 ° C (such as -20 ° C)) with an appropriate base (such as n-butyl It can be carried out in the presence of lithium) and a suitable organic solvent (eg THF) followed by acidic hydrolysis (eg in the presence of dilute HCl).

Compounds of formula XXV can be obtained using known techniques. For example:
(a) Formula XXVI

[In the above formula,
R ^ya represents —S (O) ₂ NH ₂ , —C (O) NH ₂ or —CHO, and Z ₁ and Z ₂ are as defined above] or a protected derivative thereof, Formula XXVII

R ⁵ L ³ XXVII
[In the above formula,
L ³ represents a suitable leaving group (toluenesulfonate, benzenesulfonate, methanesulfonate or bromo, or halo, such as iodo), R ⁵ is a compound of the similarly defined as, for example, below room temperature (e.g. at about -35 ° C. to about -85 ° C.), a suitable base (e.g., by reacting in the presence of butyl lithium) and an appropriate solvent n- (e.g. THF), R ^y in the formula -S ( Compounds of formula XXV representing O) ₂ NH ₂ , —C (O) NH ₂ or —CHO and protected derivatives thereof can be prepared.

  (b) Formula XXVIII

A suitable reagent for introducing a suitable compound of [wherein R ⁵ , Z ₁ and Z ₂ are as defined above] into a suitable ring system, a —S (O) ₂ NH ₂ group (E.g. chlorosulfonic acid or thionyl chloride in the presence of a suitable strong base (e.g. butyllithium)) and subsequently the resulting intermediate is reacted with ammonia or a protected derivative thereof (e.g. t-butylamine). The compounds of formula XXV and protected derivatives thereof can be prepared by reacting under conditions well known to those skilled in the art, wherein R ^y represents —S (O) ₂ NH ₂ .

  (c) a compound of formula XXVIII as defined above is represented by formula XXIX

R ^Z N = C = O XXIX
[In the above formula,
R ^z represents a suitable protecting group such as C ₁ -C ₆ alkyl, for example alkyl containing t-butyl, etc.] and a low temperature (eg −78 ° C. to about 0 ° C.) and a suitable base (eg n Specific protected derivatives of compounds of formula XXV in which R ^y represents -C (O) NH ₂ by reaction in the presence of -butyl lithium) and a suitable solvent (THF) (e.g. C it can be prepared ₁ -C ₆ alkyl, for example t- butyl alkyl protected derivative), such as.

  (d) Formula XXX

[In the above formula,
R ⁵ , Z ₁ and Z ₂ are as defined above] with a protected derivative of ammonia (eg protected with (eg C ₁ -C ₆ ) alkyl, t-butyl etc.) and standard Reacting under appropriate coupling conditions (e.g. see conditions described for the preparation of compounds of formula I (process step (iii))), wherein R ^y represents -C (O) NH ₂ Certain protected derivatives of compounds of XXV can be prepared (eg, alkyl protected derivatives such as C ₁ -C ₆ alkyl, eg, t-butyl). Compounds of formula XXX are known in the art or are prepared by standard techniques, for example to prepare the corresponding compounds of formula XXV where R ^y is —CHO, eg, compounds of formula V It can be prepared by oxidizing under the conditions described above.

(e) a compound of formula XXVIII, wherein Z ₁ represents -CH = CH- and Z ₂ represents -CH-, with an appropriate reagent system for introducing an aldehyde group into the benzene ring (e.g., TiCl ₍₄ / CHCl ₃ , SnCl ₄ / CH ₂ Cl ₂ or 1,3,5,7-azaadamantane / TFA) react under standard reaction conditions and then (if appropriate) the resulting benzaldehyde as standard The compounds of formula XXV and protected derivatives thereof, wherein R ^y is —CHO, Z ₁ represents —CH═CH—, and Z ₂ represents —CH— Can be prepared.

(f) nitration of a compound of formula XXVIII, wherein Z ₁ represents -CH = CH- and Z ₂ represents -CH-, followed by reduction of the resulting nitrobenzene (if appropriate) Protecting the resulting aminobenzene, but by carrying out all this step under standard conditions, R ^{y in} the formula is —NH ₂ and Z ₁ represents —CH═CH—. A compound of formula XXV and its N-protected derivative can be prepared, wherein Z ₂ represents —CH—.

  Compounds of formula III, IV, VI, VIII, X, XI, XII, XIII, XIV, XVII, XXII, XXIII, XXVI, XXVII, XXVIII and XXIX are either commercially available or known in the literature, here Similar to the described process, or in conventional synthetic procedures, can be obtained from readily available starting materials with the appropriate reagents and reaction conditions by standard techniques.

  The compounds of the present invention can be isolated from the reaction mixture using conventional techniques.

  It will be apparent to those skilled in the art that in the processes described above and below, the functional group of the intermediate compound may need to be protected with a protecting group.

  Functional groups that it is desirable to protect include sulfonamides, amides, aminos and aldehydes. Suitable protecting groups for sulfonamide, amide and amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc) or t-butyl. Suitable protecting groups for aldehydes include alcohols such as methanol or ethanol and diols such as 1,3-propanediol or preferably 1,2-ethanediol (forming a cyclic acetal).

  Functional group protection and deprotection can be performed before or after the reaction in the above scheme.

  As is well known to those skilled in the art, protecting groups can be removed according to the techniques described below. For example, a protected compound / intermediate described herein can be converted to a chemically unprotected compound using standard deprotection techniques (e.g., trifluoroacetic acid, sulfuric acid, toluene sulfone). Using acid or boron trichloride).

  In order to obtain the compounds of the invention, in other cases and in some cases, the individual process steps can also be carried out in a different order and / or individual reactions can be carried out throughout the course. It can be carried out at different stages (i.e. by adding substituents and / or carrying out chemical transformations on intermediates different from those mentioned above in connection with a particular reaction). If you can understand it. This eliminates or necessitates the need for protecting groups.

  Depending on the type of chemistry involved, the need to protect the group and its type further require an order to complete the synthesis.

The use of protecting groups, JWF McOmie (Plenum Press, 1973 ) edited by "Protective Groups in Organic Chemistry", and "Protective Groups in Organic Synthesis", 3 rd edition, TW Greene & PGM Wutz, Wiley-Interscience (1999) Is fully described.

Medical and Pharmaceutical Uses The compounds of the present invention are useful because they possess pharmacological activity. Accordingly, the compounds of the present invention are referred to as drugs.

  Another aspect of the present invention therefore provides a compound of the present invention for use as a medicament.

  In particular, the compounds of the invention are agonists of AngII, in particular agonists of the AT2 receptor, more particularly selective sub-receptors, as demonstrated in the following tests, for example. An agonist.

  Accordingly, the compounds of the present invention are expected to be useful in situations where AngII is deficient in the body and / or an increased effect of AngII is desired or required.

  Furthermore, the compounds of the present invention are expected to be useful in situations where the AT2 receptor is expressed and its stimulation is desirable or required.

  Furthermore, the compounds of the invention are needed in the treatment of conditions characterized by increased vasoconstriction, increased cell growth and / or differentiation, increased cardiovascular contractility, increased cardiovascular hypertrophy and / or increased fluid and electrolyte stagnation. Is done.

  Furthermore, the compounds of the invention are required in the treatment of stress related diseases and / or in the improvement of microcirculation and / or mucosal protection mechanisms.

  Accordingly, the compounds of the present invention have the characteristics as described above, for example, those of the gastrointestinal tract, cardiovascular system, respiratory organ, kidney, eye, female genital (ovulation) system or central nervous system (CNS). Expected to be useful in treating disorders.

  Disorders of the gastrointestinal tract include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastro-esophageal reflux, irritable bowel syndrome (IBS), inflammatory bowel disease ( IBD), pancreatitis, liver damage (such as hepatitis), gallbladder disease, multiple organ failure (MOF) and sepsis. Other gastrointestinal diseases that may be mentioned include xerostomia, gastritis, gastric insufficiency, hyperacidity, bilary tract disorders, coelicia, Crohn's disease, ulcerative colitis, diarrhea, constipation, Includes colic, dysphagia, vomiting, nausea, dyspepsia and Sjogren's syndrome.

  Respiratory disorders include inflammatory disorders such as asthma, obstructive pulmonary disease (such as chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, and adult respiratory distress syndrome.

  Kidney disorders that may be mentioned include renal failure, nephritis and renal hypertension.

  Eye disorders that may be mentioned include diabetic retinopathy, premature retinopathy and retinal microangiogenesis.

  Among the female reproductive disorders that may be mentioned are ovulation disorders.

  Examples of cardiovascular diseases include hypertension, cardiac hypertrophy, heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial damage, endothelial injury, stenosis after balloon dilatation, angiogenesis, diabetic complications, Includes microvascular disorders, tonsillitis, cardiac arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic disorder, erectile dysfunction and neointimal proliferation.

  CNS disorders that may be mentioned include cognitive impairment, eating disorders (hunger / fullness) and dry mouth, stroke, intracerebral hemorrhage, cerebral embolism and cerebral infarction.

  The compounds of the present invention can modulate growth metabolism and proliferation, such as hypertrophic disorders, prostate hypertrophy, autoimmune disorders, psoriasis, obesity, neuronal regeneration, ulcer healing, inhibition of adipose tissue hyperplasia, stem cell differentiation and proliferation, It is also useful in the treatment of cancer (eg, gastrointestinal tract, lung cancer, etc.), apoptosis, tumor (generally) and hypertrophy, diabetes, neuronal damage or organ rejection.

  The compounds of the invention are required for both therapeutic and / or prophylactic treatment of the aforementioned conditions.

  In another embodiment of the present invention, a condition in which AngII is in vivo production and / or an increase in the effect of AngII is desirable, or a condition and / or AT2 receptor is expressed and stimulation thereof is desirable Or a method for the treatment of a required condition comprising administering a therapeutically effective amount of a compound of the invention to a human suffering from or suspected of such a condition. including.

  The compounds of the invention are usually orally, intravenously, subcutaneously, buccal, rectal, dermal, nasal, tracheal, bronchial, by other parenteral routes, or via inhalation. As an acceptable dosage form.

  When the condition to be treated is multiple organ failure, the preferred route of administration is parenteral (eg, by infusion). Alternatively, the preferred route of administration of the compounds of the invention is oral.

  The compounds of the present invention can be administered alone, but preferably include tablets, capsules, elixirs for oral administration, suppositories for rectal administration, and sterile solutions or suspensions for parenteral or intramuscular administration. The drug formulation is administered.

  Such formulations can be prepared with standard and / or acceptable pharmaceutical practices.

  In another aspect of the present invention there is provided a pharmaceutical formulation comprising a compound of the present invention mixed with a pharmaceutically acceptable adjuvant, diluent or carrier.

  The compounds of the present invention may be combined with other AT2 agonists known in the art, further in combination with AT1 receptor antagonists such as losartan known in the art, and angiotensin converting enzyme (ACE) It can also be administered in combination with other inhibitors.

In another aspect of the invention,
(A) a compound of the invention; and
(B) A combination comprising an AT1 receptor antagonist or ACE inhibitor, wherein components (A) and (B) are each formulated in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier Providing products.

  Such combination products are provided for administering a compound of the present invention in combination with an AT1 receptor antagonist or ACE inhibitor, wherein at least one of these formulations comprises a compound of the present invention and at least 1 The species may exist as a separate formulation containing an AT1 receptor antagonist or ACE inhibitor, or may exist as a combination formulation (i.e., formulated) (i.e., a compound of the invention and an AT1 receptor antagonist or ACE). Present as a single formulation containing the inhibitor).

Therefore,
(1) a pharmaceutical formulation containing a compound of the invention and an AT1 receptor antagonist or ACE inhibitor mixed with a pharmaceutically acceptable adjuvant, diluent or carrier; and
(2) Ingredients:
(a) a pharmaceutical formulation containing a compound of the invention mixed with a pharmaceutically acceptable adjuvant, diluent or carrier; and
(b) a pharmaceutical formulation containing an AT1 receptor antagonist or ACE inhibitor mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein each of components (a) and (b) is the other A kit comprising parts provided in a form suitable for administration in combination with is provided.

  Depending on the disorder to be treated and the patient and route of administration, the compounds of the invention can be administered at various doses.

  Suitable doses range from about 1 to 1000 mg per patient, administered in single or multiple doses, although the dose will vary from patient to patient. A more preferred daily dose is in the range of 2.5 to 250 mg per patient.

  Individual doses of the compounds of the invention range from 1 to 100 mg.

  In any case, the physician or skilled person can determine the actual dose that is most appropriate for an individual patient, which is the condition to be treated, and the age, weight of the individual patient to be treated. , May vary with gender and response. The above doses are examples of average cases; of course, there are individual cases where higher or lower dose ranges are reasonable, and such cases are also within the scope of the invention.

  The compounds of the present invention have the advantage of selectively binding to the AT2 receptor and exhibiting agonist activity thereto. For compounds that "selectively bind" to the AT2 receptor, the affinity ratio for the related compound (AT2: AT1) should be at least 5: 1, preferably at least 10: 1 and more preferably at least 20: 1. pointing.

  More than the compounds known in the prior art, the compounds of the invention are effective, less toxic, active over the long term, powerful, with few side effects, are easily absorbed, and / or Or have the advantage of having a good pharmacokinetic profile (e.g. higher oral bioavailability and / or low clearance) and / or having other effective pharmacological, physical or chemical properties .

Biological tests The following test procedures can be used.

Exam A
Receptor binding assays using rat liver plasma membrane AT ₁ receptor
Rat hepatocyte membranes were prepared according to the method of Dudley et al (Mol. Pharmacol. (1990) 38, 370). Tris-HCl 50 mM (pH 7.4), NaCl 100 mM, MgCl ₂ 10 mM, EDTA 1 mM, bacitracin 0.025%, BSA 0.2% (bovine serum albumin), liver homogenate corresponding to the original tissue weight of 5 mg, [ ¹²⁵ I] Ang II [ ¹²⁵ I] AngII binding to the membrane was performed in a final volume of 0.5 mL containing (70000 cpm, 0.03 nM) and various concentrations of test substances. Binding was terminated by incubating the samples for 1 hour at 25 ° C. and filtering through Whatman GF / B glass fiber filter sheets using a Brandel cell harvester. The filter was washed with 4 × 2 mL of Tris-HCl (pH 7.4) and transferred to a tube. Radioactivity was measured with a gamma counter. Six different concentrations (0.03-5 nmol / L) of labeled [ ¹²⁵ I] AngII were used to characterize the AngII-bound AT ₁ receptor. Nonspecific binding was determined in the presence of 1 μM AngII. Specific binding was determined by subtracting nonspecific binding from the entire bound [ ¹²⁵ I] AngII. The dissociation constant (K _d = 1.7 ± 0.1 nM, [L] = 0.057 nM) was determined by Scatchard analysis of the data obtained with AngII using GraFit (Erithacus Software, UK). The binding data was optimized with a one-site fit. All experiments were performed at least 3 times.

Exam B
Receptor binding assay using porcine myometrial membranes AT ₂ receptors
Porcine myometrium was prepared from porcine uterus according to the method by Nielsen et al (Clin. Exp. Pharm. Phys. (1997) 24, 309). Possible interference that could be shown by binding of the compound to the AT ₁ receptor was blocked by adding 1 μM of the selective AT1 inhibitor. Tris-HCl 50 mM (pH 7.4), NaCl 100 mM, MgCl ₂ 10 mM, EDTA 1 mM, bacitracin 0.025%, BSA 0.2%, homogenate corresponding to the original tissue weight 10 mg, [ ¹²⁵ I] AngII (70000 cpm, 0.03 nM) and Binding of [ ¹²⁵ I] AngII to the membrane was done in a final volume of 0.5 mL containing various concentrations of test substances. Binding was terminated by incubating the samples for 1 hour at 25 ° C. and filtering through Whatman GF / B glass fiber filter sheets using a Brandel cell harvester. The filter was washed with 3 × 3 mL of Tris-HCl (pH 7.4) and transferred to a tube. Radioactivity was measured using a gamma counter. Six different concentrations (0.03-5 nmol / L) of labeled [ ¹²⁵ I] AngII were used to characterize the AngII-bound AT ₂ receptor. Non-specific binding was determined in the presence of 1 μM AngII. Specific binding was determined by subtracting nonspecific binding from the entire bound [ ¹²⁵ I] AngII. The dissociation constants (K _d = 0.7 ± 0.1 nM, [L] = 0.057 nM) were determined by Scatchard analysis of the data obtained with Ang II using GraFit (Erithacus Software, UK). The binding data was optimized with a one-site fit. All experiments were performed at least 3 times.

Test C
Duodenal mucosa alkaline secretion assay
According to the methodology described by Flemstroem et al. (Am. J. Physiol. (1982) 243, G348), the duodenal mucosa of barbiturate anesthetized rats prepared for in situ titration of duodenal mucosa alkaline secretion was applied. The compound was exposed.

  The invention is described in detail in the following examples.

Example 1
N-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
(a) Nt-Butylthiophene-2-sulfonamide Thiophene-2-sulfonyl chloride (15 g, 0.082 mol) was dissolved in CHCl ₃ (200 mL) under N ₂ atmosphere and then cooled to 0 ° C. Then t-butylamine (25.9 mL, 0.246 mol) dissolved in CHCl ₃ (50 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour and then at reflux for 10 minutes. Toluene (700 mL) was added and the organic phase was washed with water (3 × 50 mL), dried and concentrated in vacuo. The subtitle product was used in the next step without further purification.
¹ H NMR δ (CDCl ₃ ): 7.60 (1H, dd, J = 1.3, 3.8Hz), 7.53 (1H, dd, J = 1.3, 5.0Hz), 7.02 (1H, dd, J = 5.0, 3.8Hz) 5.13 (1H, m), 1.24 (9H, m)
¹³ C NMR δ (CDCl ₃ ): 145.0, 131.7, 131.2, 127.0, 55.1, 29.9

(b) 5-Isobutyl-Nt-butylthiophene-2-sulfonamide
Nt- butyl-2-sulfonamide was dissolved (10 g, 0.046 mol, wherein the step (a) refer) to THF (85 mL) under N _2, then cooled to -78 ° C.. N-BuLi (1.6M, 76.9 mL, 0.12 mol) was added via syringe. The reaction mixture was stirred at −78 ° C. for 30 minutes and then at −40 ° C. for 2 hours. Iodo-2-methylpropane (10.5 mL, 0.09 mol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with NH ₄ Cl (aq) and extracted with EtOAc. The combined organic phases were washed with brine, dried and concentrated in vacuo. The crude product was purified by column chromatography (hexane: EtOAc (10: 1)) to give the subtitle compound in 55% yield (7.0 g, 0.025 mol).
¹ H NMR δ (CDCl ₃ ): 7.43 (1H, d, J = 3.6Hz), 6.67 (1H, d, J = 3.8Hz), 4.83 (1H, m), 2.67 (2H, d, J = 7Hz) 1.88 (1H, m), 1.26 (9H, m), 0.93 (6H, J = 6.6Hz).
¹³ C NMR δ (CDCl ₃ ): 145.0, 131.7, 131.2, 127.0, 55.1, 29.9

(c) 5-isobutyl-2- (Nt-butylaminosulfonyl) thiophene-3-boronic acid
5-Isobutyl-Nt-butylthiophene-2-sulfonamide (10.6 g, 0.039 mol, see step (b) above) was dissolved in THF (165 mL) under N ₂ and then cooled to -78 ° C. N-BuLi (1.6M, 60.19 mL, 0.096 mol) was added via syringe. The reaction mixture was stirred at −20 ° C. for 4 hours. Then triisopropyl borate (13.3 mL, 0.058 mol) was added via syringe and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 2M HCl (20 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine, dried and concentrated in vacuo. The product was used without further purification.
MS (ESI ⁺ ) m / z: 236.8

(d) 1- (4-Bromobenzyl) -1H-imidazole dimethyl sulfoxide (20 mL; dried over 4A molecular sieves) is added to potassium hydroxide (2.24 g, 0.04 mol, ground pellet) and the mixture is stirred for 5 minutes. did. Imidazole (0.5718 g, 0.0084 mol) was then added and the mixture was stirred for 2 hours. 4-Bromobenzyl bromide (3.25 g, 0.013 mol) was added and the mixture was briefly cooled and stirred for an additional hour, after which water (20 mL) was added. The mixture was extracted with ether (3 × 100 mL) and each extract was washed with water (3 × 50 mL). The combined ether layers were dried over CaCl ₂ and the solvent was removed in vacuo. The residue was chromatographed on silica gel using CHCl ₃ : MeOH (30: 1) + formic acid 0.05% as eluent to give the subtitle product (1.275 g, yield: 53%).
¹ H NMR δ (CDCl ₃ ): 7.73 (3H, m), 7.28 (3H, m), 7.15 (1H, m), 5.30 (2H, s)
¹³ C NMR δ (CDCl ₃ ): 136.8, 134.8, 131.5, 129.3, 128.4, 121.5, 118.7, 49.4. MS (ESI ⁺ ) m / z: 236.8

(e) 3- (4-imidazol-1-ylmethylphenyl) -5-isobutyl-Nt-butylthiophene-2-sulfonamide
5-isobutyl-2- (Nt-butylaminosulfonyl) thiophene-3-boronic acid (200.5 mg, 0.628 mmol, see step (c) above), 1- (4-bromobenzyl) -1H-imidazole (98.8 mg 0.416 mmol, see step (d) above), toluene (15 mL), ethanol (15 mL), NaOH (1.0 M, 1.5 mL, 1.5 mmol) and Pd (PPh ₃ ) ₄ (14.5 mg, 0.125 mmol) in N ₂ mixed under. The mixture was heated under reflux for 2 hours. The mixture was diluted with EtOAc (50 mL), washed with water and brine, and dried over MgSO ₄ . The solvent was removed and the residue was separated by column chromatography using chloroform: methanol (20: 1) as eluent to give the subtitle compound 113.9 mg (63.27% yield). IR (Neat): 3060, 2996, 1507cm- ¹ .
¹ H NMR δ (CDCl ₃ ): 7.39 (1H, s), 7.35 (2H, d, J = 8.1 Hz), 6.98 (2H, d, J = 8.1 Hz), 6.96 (1H, s), 6.84 (H , s), 6.47 (H, s), 4.91 (2H, s), 3.96 (1H, s), 2.72 (H, brs), 2.42 (2H, d, J = 7.1Hz), 1.64 (1H, m) , 0.73 (9H, s), 0.72 (6H, d, J = 6.9Hz)
¹³ C NMR δ (CDCl ₃ ): 148.6, 142.3, 137.2, 136.2, 135.1, 129.7, 129.4, 128.8, 127.4, 119.2, 54.6, 50.6, 39.2, 30.5, 29.5, 22.1
MS (ESI ^<+> ) m / z: 431.9. Elemental _{analysis: C 22 H 29 N 3 O} 2 S 2 Calculated: C, 58.8; H, 7.0 ; N, 9.4. Found: C, 58.7.0; H, 6.7; N, 9.1

(f) 3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide trifluoroacetic acid (2 mL) was replaced with 3- (4-imidazol-1-ylmethylphenyl) -5- Isobutyl-Nt-butylthiophene-2-sulfonamide (113 mg, 0.2618 mmol, see step (e) above) was added and 1 drop (about 0.05 mL) of anisole (about 0.05 mL) was added to the mixture. The reaction mixture was stirred under N ₂ atmosphere for 30 hours, then evaporated and co-evaporated with acetonitrile until found to be pure by TLC. The crude product was used as such in the next step without further purification.
¹ H NMR δ (CDCl ₃ ): 7.70 (1H, s), 7.57 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.10 (1H, s), 6.93 (H , s), 6.73 (H, s), 5.14 (2H, s), 2.67 (2H, d, J = 7.1Hz), 2.62 (H, brs), 1.94 (1H, m), 0.97 (6H, d, (J = 6.6Hz)
¹³ C NMR δ (CDCl ₃ ): 148.4, 142.9, 137.2, 136.2, 134.6, 129.7, 129.3, 128.8, 127.3, 119.2, 50.6, 39.2, 30.5 22.1
MS (EI ⁺ ) m / z: 375.9

(g) N-butyloxycarbonyl-3- (4-indazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide Crude 3- (4-imidazol-1-yl from step (f) above (Ilmethylphenyl) -5-isobutylthiophene-2-sulfonamide was dissolved in pyridine (2 mL, dried over 4 molecular sieves). Pyrrolidinopyridine (40.52 mg, 0.2618 mmol) and butyl chloroformate (363.5 mg, 0.339 mL) were added to the mixture. The mixture was stirred overnight at room temperature under N ₂ atmosphere. Evaporate and co-evaporate with acetonitrile to remove the solvent and purify by column chromatography using 10% MeOH in chloroform as eluent to give the title compound (57.8 mg, 0.1217 mmol) in 46.5% yield (final In 2 steps overall). IR (neat): 3555.8, 3120.3, 2955.9, 1694.2, 1268.5 cm ⁻¹ .
¹ H NMR δ (CDCl ₃ ): 7.96 (1H, s), 7.57 (2H, d, J = 7.9 Hz), 7.10 (2H, d, J = 7.9 Hz), 6.89 (H, s), 6.85 (H , s), 6.74 (H, s), 5.16 (2H, s), 4.03 (2H, t, J = 6.6Hz), 2.71 (2H, d, J = 7.1Hz), 1.94 (1H, m), 1.51 (2H, m), 1.25 (2H, m), 0.98 (6H, d, J = 6.6Hz), 0.87 (3H, t, J = 7.4Hz)
¹³ C NMR δ (CDCl ₃ ): 152.5, 158.4, 143.9, 136.4, 134.6, 133.0, 129.8, 128.9, 127.3, 125.6, 119.6, 65.9, 51.2, 39.3, 30.6, 30.4, 22.3, 18.9, 13.7
MS (EI ⁺ ) m / z: 476.0 Elemental analysis: Calculated for C ₂₃ H ₂₉ N ₃ O ₄ S ₂ H ₂ O: C, 56.0; H, 6.3; N, 8.5. Found: C, 56.4; H, 6.2; N, 8.6

Example 2
N-isobutyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylnothiophene-2-sulfonamide Crude 3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene- 30 mg of 2-sulfonamide (see Example 1 (f) above) was dissolved in pyridine (1 mL, dried over 4 molecular sieves) and cooled on ice. Pyrrolidinopyridine (11.8 mg, 0.080 mmol) and isobutyl chloroformate (103.6 μL, 0.80 mmol) were then added to the mixture. The mixture was stirred overnight at 50 ° C. under N ₂ atmosphere. Evaporation and co-evaporation with acetonitrile to remove the solvent followed by purification by column chromatography using 10% MeOH in CHCl ₃ as eluent gave the title compound (27 mg, 0.057 mmol) in 71% yield. Obtained.
¹ H NMR δ (CD ₃ OD): 8.18 (brs, 1H), 7.58 (d, J = 7.9Hz, 2H), 7.32 (d, J = 7.9Hz, 2H), 7.29 (brs, 1H), 7.17 ( brs, 1H), 6.82 (s, 1H), 5.30 (s, 2H), 3.70 (d, J = 6.6Hz, 2H), 2.72 (d, J = 7.1Hz, 2H), 1.93 (m, 1H), 1.76 (m, 1H), 0.99 (d, J = 6.6Hz, 6H), 0.81 (d, J = 7.4Hz, 6H)
¹³ C NMR δ (CD ₃ OD): 155.7, 150.5, 145.2, 137.0, 136.4, 135.6, 131.0, 130.5, 128.9, 126.6, 121.8, 73.0, 52.2, 40.0, 31.9, 29.1, 22.6, 19.3
MS (ESI ⁺ ) m / z: 476.0

Example 3
N-isopropyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide Crude 3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2 -100 mg of the sulfonamide (see Example 1 (f) above) was dissolved in pyridine (4 mL, dried over 4 molecular sieves) and cooled on ice. Pyrrolidinopyridine (39.5 mg, 0.266 mmol) and isopropyl chloroformate (1M in toluene, 2.66 mL, 2.66 mmol) were then added to the mixture. The mixture was stirred overnight at 50 ° C. under N ₂ atmosphere. Evaporate and coevaporate with acetonitrile to remove the solvent followed by purification using preparative LC / MS (30% acetonitrile to pure acetonitrile, reverse phase) to give the title compound (52.6 mg, 0.114 mmol) was obtained.
¹ H NMR δ (CD ₃ OD): 8.16 (brs, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.32 (s, 1H), 7.18 ( s, 1H), 6.84 (s, 1H), 5.32 (s, 2H), 4.72 (Sevent, J = 6.3Hz, 1H), 2.73 (d, J = 7.1Hz, 2H), 1.94 (m, 1H) , 1.09 (d, J = 6.3Hz, 6H), 1.00 (d, J = 6.6Hz, 6H)
¹³ C NMR δ (CD ₃ OD): 155.5, 151.0, 145.6, 137.2, 136.2, 135.0, 131.0, 130.5, 128.9, 126.8, 122.0, 70.5, 52.1, 40.0, 31.9, 22.6, 22.1
MS (ESI ⁺ ) m / z: 462.0

Example 4
N- (Butoxyacetyl) -3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
CDI (1,1′-carbonyl-diimidazole, 129.5 mg, 0.80 mmol) was added to a solution of butoxyacetic acid (103.8 μL, 0.80 mmol) in anhydrous THF (4 mL). The mixture was stirred at 50 ° C. for 2.5 hours. 3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide (see Example 1 (f) above; 100 mg) and DBU (1,8--) in anhydrous THF (4 mL). Diazabicyclo [5.4.0] undec-7-ene, 19.9 μL, 0.133 mmol) was added to the reaction mixture. The reaction mixture was then stirred at 50 ° C. overnight. MeOH (20 mL) was added to the reaction mixture which was then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and then washed with water (3 × 50 mL). The organic phase was dried and evaporated. The crude product was purified by column chromatography using 10% MeOH in CHCl ₃ as eluent to give the title compound (27 mg, 0.057 mmol).
¹ H NMR δ (CD ₃ OD): 7.96 (brs, 1H), 7.66 (d, J = 8.3Hz, 2H), 7.30 (d, J = 8.3Hz, 2H), 7.21 (brs, 1H), 7.07 ( brs, 1H), 6.79 (s, 1H), 5.26 (s, 2H,), 3.67 (s, 2H,), 3.40 (t, J = 6.8Hz, 2H), 2.66 (d, J = 6.9Hz, 2H ), 1.88 (m, 1H), 1.48 (m, 2H), 1.29 (m, 4H), 0.96 (d, J = 6.6Hz, 6H), 0.82 (t, J = 7.3Hz, 3H)
¹³ C NMR δ (CD ₃ OD): 178.3, 148.3, 143.4, 138.0, 137.3, 136.6, 131.1, 130.3, 128.5, 128.2, 127.6, 121.4, 72.4, 72.3, 51.7, 39.9, 32.2, 31.8, 30.7, 22.6, 20.1, 14.3
MS (ESI ⁺ ) m / z: 490.1

Example 5
N-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-butylthiophene-2-sulfonamide
(a) 5-Butylthiophene-2-sulfonic acid t-butylamide
Nt-butylthiophene-2-sulfonamide (5 g, 0.0228 mol, see Example 1 (a) above) was dissolved in THF (43 mL) under N ₂ and then cooled to −78 ° C. N-BuLi (1.6M, 38.5 mL, 0.062 mol) was added via syringe. The reaction mixture was stirred at −78 ° C. for 30 minutes and then at −40 ° C. for 2 hours. Iodobutane (5.19 mL, 0.046 mol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature overnight, quenched with NH ₄ Cl (aq) and extracted with EtOAc. The combined organic phases were washed with brine, dried and concentrated in vacuo. The crude product was purified by column chromatography (Hex: EtOAc 10: 1) to give the subtitle compound in 46% yield (2.92 g, 0.011 mol).
¹ H NMR δ (CDCl ₃ ): 7.41 (d, J = 3.6Hz, 1H), 6.69 (d, J = 3.8Hz, 1H), 4.96 (m, 1H), 2.80 (d, J = 7.6Hz, 2H ), 1.65 (m, 2H), 1.37 (m, 2H), 1.26 (s, 9H), 0.92 (t, J = 7.26Hz, 3H)
¹³ C NMR δ (CDCl ₃ ): 153.0, 141.7, 131.9, 124.0, 54.9, 33.4, 29.9, 22.0, 13.6.

(b) 5-Butyl-2- (Nt-butylaminosulfonyl) thiophene-3-boronic acid
5-Butylthiophene-2-sulfonic acid t-butylamide (2.9 g, 0.010 mol, see step (a) above) was dissolved in THF (40 mL) under N ₂ and then cooled to −78 ° C. N-BuLi (1.6 M, 16.2 mL, 0.026 mol) was added via syringe. The reaction mixture was stirred at −20 ° C. for 4 hours. Then triisopropyl borate (13.3 mL, 0.058 mol) was added via syringe and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 2M HCl (20 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine, dried and concentrated in vacuo. The product was used in the next step without further purification. MS (ESI ⁺ ) m / z: 320.1

(c) 3- (4-imidazol-1-ylmethylphenyl) -5-butyl-Nt-butylthiophene-2-sulfonamide
5-Butyl-2- (Nt-butylaminosulfonyl) thiophene-3-boronic acid (300 mg, 1.27 mmol, see step (b) above), 1- (4-bromobenzyl) -1H-imidazole (606 mg, 1.90 mmol, see Example 1 (d) above), toluene (15 mL), ethanol (4 mL), NaOH (1.0 M, 4.0 mL, 5.1 mmol) and Pd (PPh ₃ ) ₄ (43.9 mg, 0.038 mmol) in N ₂ mixed under. The mixture was heated to reflux for 2 hours, diluted with EtOAc (50 mL), washed with water and brine and dried over MgSO ₄ . The solvent was removed and the residue was separated by column chromatography using chloroform: methanol (20: 1) as the eluent. The product was not completely pure but was used in the next step without further purification.

(d) 3- (4-imidazol-1-ylmethylphenyl) -5-butylthiophene-2-sulfonamide trifluoroacetic acid (10 mL) was purified from crude 3- (4-imidazole- In addition to 1-ylmethylphenyl) -5-butyl-Nt-butylthiophene-2-sulfonamide, 1 drop of anisole (about 0.05 mL) was added to the mixture. The reaction mixture was stirred under N ₂ atmosphere for 30 hours, then evaporated and co-evaporated with acetonitrile. The crude product was purified by column chromatography (CH ₂ Cl ₂ : MeOH (20: 1)) to give the subtitle compound (232 mg, 0.62 mmol) in 49% yield (1- (4-bromobenzyl) -1H-imidazole). From).
¹ H NMR δ (CDCl ₃ , CD ₃ OD): 8.97 (1H, s), 7.64-7.40 (m, 6H), 6.82 (s, 1H), 5.44 (s, 2H), 2.83 (t, J = 7.6 Hz, 2H), 1.68 (m, 1H), 1.39 (m, 1H), 0.95 (t, J = 7.26Hz, 1H)
¹³ C NMR δ (CDCl ₃ , CD ₃ OD): 150.3, 143.8, 136.9, 136.2, 134.9, 131.1, 129.7, 129.3, 123.1, 121.5, 53.3, 34.4, 30.3, 22.9, 14.0
MS (ESI ⁺ ) m / z: 376.1

(e) N-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-butylthiophene-2-sulfonamide
3- (4-imidazol-1-ylmethylphenyl) -5-butylthiophene-2-sulfonamide (232 mg, 0.62 mmol; see step (d) above) to pyridine (3 mL, dried over 4 molecular sieves) Melted. Pyrrolidinopyridine (91.6 mg, 0.618 mmol) and butyl chloroformate (785.7 mg, 0.618 mL) were added to the mixture. The mixture was stirred overnight at room temperature under N ₂ atmosphere. Evaporation and co-evaporation with acetonitrile to remove the solvent followed by purification by column chromatography using 10% MeOH in chloroform as eluent gave the title compound (29 mg, 0.061 mmol) in 10% yield. Obtained.
¹ H NMR δ (CD ₃ OD): 7.94 (s, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.20 (s, 1H), 7.06 ( s, 1H), 6.8 (s, 1H), 5.25 (s, 2H), 3.88 (t, J = 6.3Hz, 2H), 2.84 (t, J = 7.4Hz, 2H), 1.68 (m, 1H), 1.44 (m, 4H), 1.26 (m, 2H), 0.96 (t, J = 7.3Hz, 3H), 0.87 (t, J = 7.3Hz, 3H)
¹³ C NMR δ (CD ₃ OD): 159.5, 150.2, 143.9, 138.4, 137.2, 136.6, 131.0, 129.5, 128.5, 128.0, 121.4, 66.5, 51.7, 49.0, 34.7, 32.1, 30.5, 23.2, 20.1, 14.1
MS (ESI ⁺ ) m / z: 476.1

Example 6
N-butyloxycarbonyl-2- (4-imidazol-1-ylmethylphenyl) -4-isobutylbenzenesulfonamide
(a) Nt-Butyl-4-isobutylbenzenesulfonamide Chlorosulfonic acid (28.6 mL, 0.43 mol) was added dropwise at 0 ° C. to stirred isobutylbenzene (11.14 g, 0.083 mol). The reaction mixture was then heated to 40 ° C. for 0.5 h, poured into ice water (150 mL) and extracted with ethyl acetate (400 mL). The organic phase was washed with water and brine and dried over MgSO ₄ . The solvent was removed in vacuo and the residue was dissolved in CHCl ₃ (50 mL). To this stirred solution was added t-butylamine (43.7 mL, 0.416 mol) dropwise. The reaction was heated to reflux for 10 minutes and then cooled to room temperature. The reaction mixture was then diluted with toluene (200 mL) and washed with water and brine. The organic phase was dried over MgSO ₄ and the solvent was removed in vacuo. Purification using column chromatography with hexane: acetone (4: 1) as eluent afforded the subtitle compound as a white solid (12.0 mg, 0.045 mol) in 54% yield. IR (neat, cm ⁻¹ ) ν 3266, 2960, 2925, 2871, 1597, 1455.
¹ H NMR δ (CDCl ₃ ): 7.84 (d, J = 8.4Hz, 2H), 7.27 (d, J = 8.3Hz, 2H), 5.11 (brs, 1H), 2.55 (d, J = 7.3Hz, 2H ), 1.90 (m, 1H), 1.65 (m, 2H), 1.21 (s, 9H), 0.92 (d, J = 6.6Hz, 6H)
¹³ C NMR δ (CDCl ₃ ): 146.4, 140.7, 129.9, 129.5, 126.8, 54.5, 45.1, 30.1, 22.3
MS (ESI ⁺ ) m / z: 270.0
Elemental analysis: Calculated for C ₁₄ H ₂₃ NO ₂ S: C, 62.42; H, 8.61; N, 5.20; O, 11.88; S, 11.90; Found: C, 62.2; H, 8.5; N, 5.2

(b) 4-Isobutyl-2- (Nt-butylaminosulfonyl) benzene-3-boronic acid
To a THF (50 mL) solution of Nt-butyl-4-isobutyl-benzenesulfonamide (2.69 g, 10 mmol, see step (a)) was added n-BuLi (15.6 mL, 1.6 M, 25 mmol) at −78 ° C., N ₂ (g) Added dropwise under atmosphere. The temperature was gradually raised to 0 ° C. over 2 hours and then this temperature was held for 30 minutes. The reaction mixture was then cooled to −40 ° C. and triisopropyl borate (4.6 mL, 20 mmol) was added. The reaction mixture was stirred at ambient temperature overnight and quenched with 2M HCl (20 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine, dried and concentrated in vacuo. The crude product was used in the next step without further purification. MS (ESI ⁺ ) m / z: 314.0

(c) 2- (4-imidazol-1-ylmethylphenyl) -4-isobutyl-Nt-butylbenzenesulfonamide Crude product from step (b) above (1.2 g, 3.83 mmol), 1- (4 -Bromobenzyl) -1H-imidazole (98.8 mg, 0.416 mmol, see Example 1 (d) above), Pd (PPh ₃ ) ₄ (29 mg, 0.25 mmol), NaOH (3 mL, 1M, 3 mmol), toluene ( 15 mL) and ethanol (3 mL) were mixed under N ₂ (g). The mixture was heated to reflux for 2 hours. The reaction mixture was then diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over MgSO ₄ and the solvent was removed in vacuo. Purification using column chromatography with CHCl ₃ : MeOH (20: 1) as eluent afforded the subtitle compound (93.7 mg, 0.220 mmol) in 53% yield. IR (neat, cm ^-1 ) ν 3379, 3293, 3153, 2955, 2868, 1701, 1596, 1505
¹ H NMR δ (CDCl ₃ ): 8.05 (d, J = 8.1 Hz, 1H), 7.80 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.30 (m, 3H), 7.07 (m , 3H), 5.24 (s, 2H), 2.56 (d, J = 7.1Hz, 2H), 1.90 (m, 1H), 1.01 (s, 9H), 0.93 (d, J = 6.6Hz, 6H)
¹³ C NMR δ (CDCl ₃ ): 146.2, 139.9, 138.9, 138.8, 136.7, 135.5, 132.8, 130.3, 128.4, 128.2, 127.9, 126.6, 119.5, 54.0, 50.6, 44.7, 29.8, 29.4, 22.0
MS (ESI ⁺ ) m / z: 426.1

(d) 2- (4-imidazol-1-ylmethylphenyl) -4-isobutylbenzene-sulfonamide
To a solution of 2- (4-imidazol-1-ylmethylphenyl) -4-isobutyl-Nt-butylbenzene-sulfonamide (0.211 mmol, 90.0 mg, see step (c) above) in CH ₂ Cl ₂ (5 mL) , BCl ₃ (1.5 mL, 1M, 1.5 mmol) was added under N ₂ (g). The mixture was stirred for 0.5 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine, dried over MgSO ₄ and the solvent removed in vacuo. The crude product was used as such in the next step without further purification.

(e) N-Butyloxycarbonyl-2- (4-imidazol-1-ylmethylphenyl) -4-isobutylbenzenesulfonamide The crude product from step (d) above was purified on pyridine (2 mL, 4Å molecular sieves). Dissolved in dry). Pyrrolidinopyridine (36 mg, 0.024 mmol) and butyl chloroformate (276 μL, 2.23 mmol) were added to the mixture, which was then stirred at room temperature for 30 hours under N ₂ (g). The solvent was removed in vacuo and then co-evaporated with acetonitrile. Purification using column chromatography with CHCl ₃ : MeOH (10: 1) as eluent gave the title compound (66.7 mg, 0.142 mmol) in 68% yield (2- (4-imidazol-1-ylmethyl). Phenyl) -4-isobutyl-Nt-butylbenzenesulfonamide). IR (neat, cm ^-1 ) ν 3129, 3058, 2956, 2869, 1737, 1658, 1466
¹ H NMR δ (CDCl ₃ , CH ₃ OD): 8.14 (d, J = 8.1 Hz, 1H), 7.72 (s, 1H), 7.36-7.19 (m, 6H), 7.04 (m, 3H), 5.19 ( s, 2H), 3.98 (t, J = 6.5Hz, 2H), 2.56 (d, J = 7.1Hz, 2H), 1.93 (m, 1H), 1.41 (m, 2H), 1.21 (m, 2H), 0.93 (d, J = 6.6Hz, 6H), 0.85 (t, J = 7.1Hz, 3H)
¹³ C NMR δ (CDCl ₃ , CH ₃ OD): 151.8, 147.7, 140.4, 139.6, 137.1, 135.3, 134.9, 133.2, 130.5, 129.9, 128.6, 128.0, 127.0, 119.9, 66.3, 45.1, 30.6, 30.1, 22.4 , 18.9, 13.6
^{MS (ESI +) m / z} : 470.1

Example 7
N-Butyloxycarbonyl-5-isobutyl-3- (4-tetrazol-2-ylmethylphenyl) thiophene-2-sulfonamide
(a) 3- (4-Hydroxymethylphenyl) -5-isobutyl-Nt-butylthiophene-2-sulfonamide
5-isobutyl-2- (Nt-butylaminosulfonyl) 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 (1.0 M, 4 mL, 4 mmol) and Pd (PPh ₃ ) ₄ (34 mg, 0.030 mmol) are mixed together under N ₂ . The mixture was heated to reflux for 2 hours, then diluted with EtOAc (50 mL), washed with water and brine, and dried over MgSO ₄ . The solvent was removed and the residue was separated by column chromatography using CHCl ₃ : MeOH (4: 1) as eluent to give the subtitle compound 289 mg (yield: 76%). IR (Neat) ν3465, 3162, 2952, 2867, 1441cm ^-1
1 H NMR δ (CD ₃ OD): 7.59 (2H, d, J = 8.2 Hz), 7.45 (2H, d, J = 8.2 Hz), 6.75 (1H, s), 4.75 (2H, s), 4.11 ( 1H, brs), 2.69 (2H, d, J = 7.1Hz), 1.92 (1H, m), 0.99 (6H, d, J = 7.2Hz), 0.98 (9H, s)
¹³ C NMR δ (CD ₃ OD): 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
Elemental analysis: Calculated for _{C 19 H 27 NO3 S2: C} , 59.8; H, 7.3; N, 3.7. Found: C, 59.6; H, 7.0; N, 3.5

(b) 3- (4-Bromomethylphenyl) -5-isobutyl-Nt-butylthiophene-2-sulfonamide
3- (4-Hydroxymethylphenyl) -5-isobutyl-Nt-butylthiophene-2-sulfonamide (280 mg, 0.734 mmol, see step (a) above) was dissolved in DMF (10 mL). PPh ₃ (459.2 mg, 1.75 mmol) and CBr ₄ (580.3, 1.75 mmol) were added to the resulting solution. The mixture was diluted at room temperature for 24 hours and then diluted with ethyl acetate. The organic phase was washed with water (50 mL) and brine (50 mL) and then dried over MgSO ₄ . After removal of the solvent, the residue was purified by column chromatography using hexane: acetone (5: 1) as eluent to give the subtitle compound (314.9 mg, 0.709 mmol, 76% yield). IR (Neat): 3302, 2952, 2866, 1442cm ^-1
1 H NMR δ (CDCl ₃ ): 7.62 (2H, d, J = 8.4Hz), 7.48 (2H, d, J = 8.4Hz), 6.75 (1H, s), 4.56 (2H, s), 4.11 (1H , brs), 2.69 (2H, d, J = 7.1Hz), 1.92 (1H, m), 0.99 (6H, d, J = 7.2Hz), 0.98 (9H, s)
¹³ C NMR δ (CDCl ₃ ): 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 (EI ⁺ ) m / z: 445.8

(c) 5-isobutyl-Nt-butyl-3- (4-tetrazol-2-ylmethylphenyl) thiophene-2-sulfonamide
KOH (112.2 mg, 2.00 mmol, ground pellet) was added to DMSO (10 mL, dried over 4 molecular sieves) and stirred for 5 minutes. Tetrazole (28.0 mg, 0.4 mmol) was added to the mixture, which was then stirred for 2 hours. 3- (4-Bromomethylphenyl) -5-isobutyl-Nt-butylthiophene-2-sulfonamide (130 mg, 0.292 mmol, see step (b) above) was added and the mixture was allowed to cool briefly and further 1 Stir for hours, then add water (50 mL). The reaction mixture was extracted with ethyl acetate (250 mL) and the extract was washed with water (2 × 50 mL) and brine (50 mL). The organic phase was dried over MgSO ₄ and the solvent was removed in vacuo. The residue was purified by column chromatography using hexane: acetone (3: 1) as eluent to give the subtitle compound (28.6 mg, 0.066 mmol, 23% yield). IR (Neat): 3328, 3134, 2980, 1501, 1466cm ^-1
1 H NMR δ (CDCl ₃ ): 8.52 (1H, s), 7.64 (2H, d, J = 8.3 Hz), 7.46 (2H, d, J = 8.3 Hz), 6.73 (1H, s), 5.85 (2H , s), 2.69 (2H, d, J = 7.1Hz), 1.91 (1H, m), 1.58 (1H, s), 0.98 (15H, brs)
¹³ C NMR δ (CDCl ₃ ): 153.2, 148.5, 142.4, 136.8, 135.8, 133.2, 129.7, 128.8, 128.5, 56.3, 54.6, 39.2, 30.5, 29.5, 22.1
MS (EI ⁺ ) m / z: 434.0
Elemental _{analysis: C 20 H 27 N 5 O} 2 S 2 × H 2 O Calculated: C, 53.2; H, 6.5 ; N, 15.5. Found: C, 53.7; H, 6.1; N, 15.2

(d) 5-isobutyl-3- (4-tetrazol-2-ylmethylphenyl) thiophene-2-sulfonamide
CH ₂ Cl ₂ (10 mL) of 5-isobutyl-Nt-butyl-3- (4-tetrazol-2-ylmethylphenyl) thiophene-2-sulfonamide (42.1 mg, 0.111 mmol, see step (c) above) To the solution, BCl ₃ (0.5 mL, 1 M, 0.5 mmol) was added under N ₂ (g). The reaction mixture was stirred for 0.5 hour. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine, dried over MgSO ₄ and the solvent removed in vacuo. The crude product was used as such in the next step without further purification.

(e) N-butyloxycarbonyl-5-isobutyl-3- (4-tetrazol-2-ylmethylphenyl) thiophene-2-sulfonamide The crude product from step (d) above was converted to pyridine (1 mL, 4 、 molecule Dissolved in the dry on the sieve). Pyrrolidinopyridine (14 mg, 0.0095 mmol) and butyl chloroformate (120 μL, 0.97 mmol) were added to the mixture which was then stirred at room temperature for 30 hours under N ₂ (g). The solvent was removed in vacuo and then coevaporated with acetonitrile. Purification using column chromatography with CHCl ₃ : MeOH (35: 1) as eluent gave the title compound (24.9 mg, 0.052 mmol) in 54% yield (5-isobutyl-Nt-butyl-3- ( 4-tetrazol-2-ylmethylphenyl) thiophene-2-sulfonamide). IR (Neat): 3330, 2961, 2875, 1743, 1466cm ^-1
1 H NMR δ (CDCl ₃ ): 8.49 (1H, s), 7.68 (1H, s), 7.48 (2H, d, J = 8.2 Hz), 7.40 (2H, d, J = 8.2 Hz), 6.73 (1H , s), 5.82 (2H, s), 4.07 (2H, t, J = 6.6Hz), 2.70 (2H, d, J = 7.1Hz), 1.91 (1H, m), 1.50 (2H, m), 1.24 (2H, m), 0.98 (6H, d, J = 6.9Hz), 0.87 (3H, J = 7.4Hz)
¹³ C NMR δ (CDCl ₃ ): 153.2, 151.8, 150.1, 145.6, 134.8, 133.4, 129.6, 129.3, 128.3, 66.9, 56.3, 39.2, 30.5, 30.4, 22.2, 18.7, 13.6
MS (EI ⁺ ) m / z: 478.0
Elemental _{analysis: C 21 H 27 N 5 O} 4 S 2 Calculated: C, 52.8; H, 5.7 ; N, 14.7. Found: C, 53.0; H, 5.8; N, 14.1

Example 8
N-Butyloxycarbonyl-5-isobutyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide
(a) 1- (4-Bromobenzyl) -1H-tetrazole dimethyl sulfoxide (10 mL, dried over 4 molecular sieves) is added to potassium hydroxide (1.12 g, 0.02 mol, ground pellet) and the mixture is stirred for 5 minutes did. 1H-tetrazole (0.35 g, 0.005 mol) was then added and the mixture was stirred for 2 hours. 4-Bromobenzyl bromide (1.87 g, 0.0075 mol) was added and the mixture was briefly cooled and stirred for an additional hour, after which water (50 mL) was added. The mixture was extracted with ether (3 × 80 mL) and each extract was washed with water (3 × 50 mL). The combined ether layers were dried over MgSO ₄ and the solvent was removed in vacuo. The residue was chromatographed on silica gel using CHCl ₃ : MeOH (40: 1) as eluent to give the subtitle compound (0.98 g, yield: 82%).
¹ H NMR δ (CDCl ₃ ): 8.64 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4), 5.56 (2H, s)
¹³ C NMR δ (CDCl ₃ ): 142.4, 132.4, 131.8, 129.9, 123.4, 51.3
MS (ESI ⁺ ) m / z: 238.8
Elemental analysis: Calculated for _{C 8 H 7 BrN 4: C} , 40.2; H, 3.0; N, 23.4. Found: C, 40.3; H, 3.0; N, 23.4

(b) 5-Isobutyl-Nt-butyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide
5-isobutyl-2- (Nt-butylaminosulfonyl) thiophene-3-boronic acid (401.0 mg, 1.256 mmol, see Example 1 (c) above), 1- (4-bromobenzyl) -1H-tetrazole ( 199.4 mg, 0.834 mmol, see step (a) above), toluene (20 mL), ethanol (3.0 mL), NaOH (1.0 M, 5.0 mL, 5.0 mmol) and Pd (PPh ₃ ) ₄ (29.0 mg, 0.25 mmol) ) were mixed under N _2. The mixture was heated to reflux for 2 hours. The mixture was diluted with EtOAc (20 mL), washed with water and brine, and dried over MgSO ₄ . The solvent was removed and the residue was separated by column chromatography using CHCl ₃ : MeOH (40: 1) as eluent to give the subtitle compound 222.4 mg (yield: 62%). IR (Neat): 3284, 3134, 2958, 2870, 1513, 1436cm ^-1
1 H NMR δ (CDCl ₃ ): 8.71 (1H, s), 7.64 (2H, d, J = 8.3Hz), 7.40 (2H, d, J = 8.3Hz), 6.74 (1H, s), 5.65 (2H , s), 2.67 (2H, d, J = 7.1Hz), 1.94 (1H, m), 0.99 (15H, m)
¹³ C NMR δ (CDCl ₃ ): 148.5, 142.6, 142.2, 136.8, 135.9, 133.1, 129.9, 128.8, 128.3, 54.6, 51.7, 39.2, 30.5, 29.5, 22.1
MS (ESI ⁺ ) m / z: 433

(c) 5-isobutyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide
BCl ₃ (1.0 mL, 1 M, 1.0 mmol) was added to 5-isobutyl-Nt-butyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide (177.0 mg, 0.408 mmol, previous step). (See (b)) in CH ₂ Cl ₂ (10 mL) under N ₂ (g) and the reaction mixture was stirred for 0.5 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine, dried over MgSO ₄ and the solvent removed in vacuo. The crude product was used as such in the next step without further purification.

(d) N-butyloxycarbonyl-5-isobutyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide Similar to the procedure described in Example 7 (e) above, The title compound was prepared from the crude 5-isobutyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide from step (c) (89.6 mg, 0.188 mmol, 46% yield ( 5-isobutyl-Nt-butyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide))). IR (Neat): 3135, 2959, 2875, 1747, 1464cm ^-1
1 H NMR δ (CDCl ₃ ): 8.73 (1H, s), 7.43 (2H, d, J = 7.7Hz), 7.24 (2H, d, J = 7.7Hz), 6.72 (1H, s), 5.59 (2H , s), 4.00 (2H, brs), 2.69 (2H, brs), 1.91 (1H, m), 1.46 (2H, m), 1.19 (2H, m), 0.95 (6H, d, J = 6.9Hz) , 0.83 (3H, J = 6.8Hz)
¹³ C NMR δ (CDCl ₃ ): 151.8, 151.4, 145.3, 143.0, 134.8, 133.5, 129.6, 129.1, 127.8, 66.9, 51.4, 39.2, 30.9, 30.4, 22.2, 18.7, 13.6
MS (EI ⁺ ) m / z: 478.0
Elemental analysis: calculated for C ₂₁ H ₂₇ N ₅ O ₄ S ₂ × 1/2 H ₂ O: C, 51.8; H, 5.8; N, 14.4. Found: C, 51.4; H, 5.6; N, 14.1

Example 9
N-butyloxycarbonyl-3- (4- [1,2,4] triazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
(a) 1- (4-Bromobenzyl) -1H- [1,2,4] triazole
DMF and KOH (3.3 g, 58 mmol) were stirred together at room temperature for 5 minutes, after which 1,2,4-triazole (1 g, 14.5 mmol) was added. After an additional 30 minutes, the reaction mixture was cooled to 0 ° C. and 1-bromo-4-bromomethylbenzene (7.2 g, 29 mmol) was added dropwise over 5 minutes. The reaction mixture was heated to 60 ° C., then cooled to room temperature, extracted with ethyl acetate and water, followed by drying over K ₂ CO ₃ . Evaporation of the solvent gave yellow-white crystals, which were repeatedly recrystallized (ethyl acetate / isohexane) to give the subtitle compound 0.60 g as white crystals (isolated yield 62%). It was.
¹ H NMR δ (270 MHz, CDCl ₃ ): 8.11 (s, 1H), 7.96 (s, 1H), 7.51 to 7.38 (m, 2H), 7.15 to 7.10 (m, 2H), 5.29 (S, 2H)
¹³ C NMR δ (67.8 MHz, CDCl ₃ ): 152.2, 143.0, 133.5, 132.1, 129.5, 122.7, 52.8
^{MS m / z 238 (M +} + 1)

(b) 3- (4- [1,2,4] Triazol-1-ylmethylphenyl) -5-isobutyl-Nt-butylthiophene-2-sulfonamide
5-isobutyl-2- (Nt-butylaminosulfonyl) thiophene-3-boronic acid (0.479 g, 1.5 mmol, see Example 1 (c) above), 1- (4-bromobenzyl) -1H- [1 , 2,4] triazole (0.238 g, 1 mmol, see step (a) above), Pd (OAc) ₂ (15.7 mg, 0.03 mmol), triphenylphosphine (15.7 mg, 0.06 mmol) and NaOH (0.16 g, 4 mmol) was dissolved in 4 mL of toluene / ethanol (4: 1) in a thick glass tube and then heated to 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water followed by drying over K ₂ CO ₃ . The solvent was evaporated and the reaction mixture was separated on a silica column (dichloromethane + methanol 1% to dichloromethane + methanol 4%) to give the subtitle compound 0.288 g (65% yield).
¹ H NMR δ (270 MHz, CDCl ₃ ): 8.13 (s, 1H), 7.94 (s, 1H), 7.60-7.57 (m, 2H), 7.33-7.30 (m, 2H), 6.72 (s, 1H) , 5.37 (s, 2H), 4.47 (s, 1H), 2.65, (d, J = 7Hz, 2H), 1.89 (sevent J = 7Hz, 1H), 0.96 (s, 9H), 0.94 (d, J = 7Hz, 6H)
¹³ C NMR δ (67.8 MHz, CDCl ₃ ): 152.1, 148.5, 143.1, 142.3, 136.6, 135.2, 134.8, 129.6, 128.8, 128.0, 54.5, 53.1, 39.1, 30.4, 29.4, 22.1
^{MS m / z 433 (M +} + 1)

(c) 3- (4- [1,2,4] triazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
3- (4- [1,2,4] triazol-1-ylmethylphenyl) -5-isobutyl-Nt-butylthiophene-2-sulfonamide (146.4 mg, 0.34 mmol, see step (b) above) , Mixed with BCl ₃ (1M solution in hexane) (2 mL, 1.7 mmol) in 5 mL of dichloromethane at room temperature and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate and water followed by drying over K ₂ CO ₃ . Upon evaporation of the solvent, the resulting product was pure enough to be used as such in the next step.

(d) N-butyloxycarbonyl-3- (4- [1,2,4] triazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide Crude 3-step from step (c) above 59 mg (0.16 mmol) of (4- [1,2,4] triazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide was added to butyl chloroformate (31 μL, 0.24 mmol) and 4 in 5 mL of triethylamine. -Mixed with dimethylaminopyridine (2 mg, 16 μmol) at 0 ° C. The reaction mixture was stirred overnight, then diluted with ethyl acetate, washed with water, dried over K ₂ CO _3. The reaction mixture was then separated by silica column (dichloromethane + methanol 15%), circular chromatography (dichloromethane + methanol 10-15%) and preparative LC-MS to yield 7.0 mg (9% isolated yield) of the title compound. Obtained.
¹ H NMR δ (270 MHz, CDCl ₃ ): 8.11 (s, 1H), 7.98 (s, 1H), 7.50-7.47 (m, 2H), 7.29-7.26 (m, 2H), 6.74 (s, 1H) , 5.39 (s, 2H), 4.05 (t, J = 7Hz, 2H), 2.71 (d, J = 7Hz, 2H), 1.95 (sevent, J = 7Hz, 1H), 1.52 (quintet, J = 7Hz, 2H), 1.26 (hex wire, J = 7Hz, 2H), 0.99 (d, J = 7Hz, 6H), 0.88 (t, J = 7Hz, 3H)
¹³ C NMR δ (67.8 MHz, CDCl ₃ ): 151.9, 151.1, 145.1, 143.4, 134.7, 134.2, 131.6, 129.7, 129.0, 127.8, 66.3, 53.2, 39.2, 30.4, 30.3, 22.1, 18.7, 13.5
MS m / z (relative strength 30 eV) 477 (M ⁺ + 1)

Example 10
N- (Butylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
(a) 1- (4-Bromobenzyl) -1H-imidazole dimethyl sulfoxide (20 mL, dried over 4 molecular sieves) was added to potassium hydroxide (2.24 g, 0.04 mol, ground pellet) and the mixture was stirred for 5 minutes. . Imidazole (0.5718 g, 0.0084 mol) was then added and the mixture was stirred for 2 hours. 4-Bromobenzyl bromide (3.25 g, 0.013 mol) was added and the mixture was briefly cooled and stirred for an additional hour, after which water (20 ml) was added. The mixture was extracted with ether (3 × 100 mL) and each extract was washed with water (3 × 50 mL). The combined ether layers were dried over CaCl ₂ and the solvent was removed in vacuo. The residue was chromatographed on silica gel using CHCl ₃ / MeOH (30: 1) + 0.05% formic acid as eluent to give the subtitle compound (1.275 g, yield: 53%).
¹ H NMR δ (CDCl ₃ ): 7.73 (m, 3H), 7.28 (m, 3H), 7.15 (m, 1H), 5.30 (s, 2H)
¹³ C NMR δ (CDCl ₃ ): 136.8, 134.8, 131.5, 129.3, 128.4, 121.5, 118.7, 49.4
MS (ESI ⁺ ) m / z: 236.8

(b) 3- (4-Imidazol-1-ylmethylphenyl) -5-isobutyl-Nt-butylthiophene-2-sulfonamide
5-isobutyl-2- (Nt-butylaminosulfonyl) thiophene-3-boronic acid (200.5 mg, 0.628 mmol, see Example 1 (c) above), 1- (4-bromobenzyl) -1H-imidazole ( 98.8 mg, 0.416 mmol, see step (a) above), toluene (15 mL), ethanol (15 mL), NaOH (1.0 M, 1.5 mL, 1.5 mmol) and Pd (PPh ₃ ) ₄ (14.5 mg, 0.125 mmol) Were mixed under N ₂ . The mixture was heated to reflux for 2 hours. The mixture was diluted with EtOAc (50 mL), washed with water and brine, and dried over MgSO ₄ . The solvent was removed and the residue was separated by column chromatography using chloroform: methanol (20: 1) as eluent to give the subtitle compound 113.9 mg (yield: 63.27%). IR (neat, cm ^-1 ) ν3060, 2996, 1507
¹ H NMR δ (CDCl ₃ ): 7.39 (s, 1H), 7.35 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 6.96 (s, 1H), 6.84 (s , 1H), 6.47 (s, 1H), 4.91 (s, 2H), 3.96 (s, 1H), 2.72 (brs, 1H), 2.42 (d, J = 7.1Hz, 2H), 1.64 (m, 1H) , 0.73 (s, 9H), 0.72 (d, J = 6.9Hz, 6H)
¹³ C NMR δ (CDCl ₃ ): 148.6, 142.3, 137.2, 136.2, 135.1, 129.7, 129.4, 128.8, 127.4, 119.2, 54.6, 50.6, 39.2, 30.5, 29.5, 22.1
MS (ESI ⁺ ) m / z: 431.9
Elemental _{analysis: C 22 H 29 N 3 O} 2 S 2 Calculated: C, 58.8; H, 7.0 ; N, 9.4. Found: C, 58.7.0; H, 6.7; N, 9.1

(c) 3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
CH ₂ Cl ₂ (10 ml) of 3- (4-imidazol-1-ylmethylphenyl) -5-isobutyl-Nt-butylthiophene-2-sulfonamide (0.097 mmol, 42.0 mg, see step (b) above) To the solution, BCl ₃ (0.5 mL, 1 M, 0.5 mmol) was added under N ₂ (g). The mixture was stirred for 0.5 h, water (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine, dried over MgSO ₄ and the solvent removed in vacuo. The crude product was used as such in the next step without further purification.

(d) N- (butylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide The crude product from step (c) above was acetone (5 mL) Dissolved under N ₂ (g). NaOH (0.20 mL, 1M, 0.20 mmol) was added to the mixture, which was then stirred for 10 minutes. Then butyl isocyanate (109 μL, 0.97 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was then diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over MgSO ₄ and the solvent was removed in vacuo. Purification using column chromatography with CHCl ₃ : MeOH (10: 1) as eluent gave the title compound (15.1 mg, 0.032 mmol) in 33% yield (3- (4-imidazol-1-ylmethyl). Phenyl) -5-isobutylthiophene-2-sulfonic acid t-butylamide). IR (neat, cm ^-1 ) ν3261, 3120, 2957, 2869, 1701, 1514
¹ H NMR δ (CDCl ₃ , CH ₃ OD): 7.64 (s, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.97 (brs 1H), 6.90 (brs, 1), 6.72 (s, 1H), 6.24 (brs, 1H), 5.10 (s, 2H), 3.08 (m, 2H), 2.62 (d, J = 7.1Hz, 2H), 1.92 (m , 1H), 1.20 (m, 4H), 0.99 (d, J = 6.6, 6H), 0.86 (t, J = 7.1Hz, 3H)
¹³ C NMR δ (CDCl ₃ , CH ₃ OD): 152.2, 150.0, 144.5, 137.0, 135.9, 134.4, 133.0, 129.7, 129.5, 128.1, 127.1, 119.5, 50.7, 39.9, 39.2, 31.6, 30.5, 22.2, 19.8 , 13.7
MS (ESI ⁺ ) m / z: 475.2

Example 11
N-butylsulfonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide Crude 3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2 -Sulfonamide (prepared according to the procedure described in Example 10 (c) above) was dissolved in THF (3 mL) under N ₂ (g). NaOH (1.0 mL, 1M, 1.0 mmol) was added to the mixture, which was then stirred for 10 minutes. Then butanesulfonyl chloride (45 μL, 0.35 mmol) was added and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over MgSO ₄ and the solvent was removed in vacuo. The crude product was recrystallized from acetone to give the title compound (31.7 mg, 0.064 mmol). IR (neat, cm ^-1 ) ν3133, 2959, 2871, 1576, 1543, 1514
¹ H NMR δ (CDCl ₃ , CH ₃ OD): 8.70 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.08-7.20 (m, 5H), 6.59 (s, 1H), 5.06 ( s, 2H), 3.08 (m, 2H), 2.57 (a, J = 7.1Hz, 2H), 1.67 (m, 1H), 1.65 (m, 2H), 1.29 (m, 2H), 0.89 to 0.79 (m , 9H)
¹³ C NMR δ (CDCl ₃ , CH ₃ OD): 146.8, 140.9, 138.2, 136.8, 135.0, 131.9, 130.4, 128.6, 127.9, 121.2, 119.8, 54.0, 52.5, 38.9, 30.3, 25.6, 21.9, 21.4, 13.4
MS (ESI ⁺ ) m / z: 496.1

Example 12
N-butylsulfonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-carboxamide
(a) A solution of 2-isobutylthiophene thiophene (6.00 g, 0.0714 mol) in THF 80 mL (80 mL) was treated with n-BuLi (1.6 M in hexane, 54 mL, 0.0864 mol) at −78 ° C. The mixture was stirred at −40 ° C. for about 2 hours. The solution was then cooled again to −78 ° C. and treated with 2-methylpropyl iodide (16.04 g, 0.0871 mol). The solution was stirred at 0 ° C. for 2 hours and then at room temperature overnight for about 16 hours. The solution was treated with water (25 mL) and extracted with petroleum ether (3 × 25 mL). The organic layer was dried over magnesium sulfate and filtered. The crude product was purified by distillation (54-55 ° C. at 12 mmHg) to give the subtitle compound (3.0 g, 0.0213 mol) in 30% yield.
¹ H NMR δ (CDCl ₃ ): 7.14 (dd, J = 5.1, 1.2Hz, 1H), 6.95 (dd, J = 5.1, 3.3Hz, 1H), 6.79 (dd, J = 3.3, 1.2Hz, 1H) 2.72 (d, J = 7.1Hz, 2H), 1.92 (m, 1H), 0.97 (d, J = 6.7Hz, 3H)
¹³ C NMR δ (CDCl ₃ ): 144.3, 126.5, 124.8, 123.0, 39.1, 30.8, 22.2
MS (EI ⁺ ) m / z: 140

(b) 5-Isobutyl-Nt-butylthiophene-2-carboxamide
To 2-isobutylthiophene (1 g, 7.143 mmol, see step (a) above) in THF (15 mL) was added n-BuLi (1.6 M in hexane, 5.3 mL, 8.48 mmol) at −78 ° C. and the reaction mixture Was stirred at 0 ° C. for 2 hours. Then t-butyl isocyanate (897 μL, 7.86 mmol) was added to the mixture at −78 ° C. The stirred solution was held at 0 ° C. for an additional 2 hours. The reaction mixture was then quenched with H ₂ O (15 mL) and extracted with EtOAc (3 × 20 mL). The organic phase was dried over MgSO ₄ , concentrated and purified using silica gel column chromatography (petroleum ether-EtOAc 10:90) to yield the subtitle compound (1.2 g, 5.01 mmol) as white needles. Obtained at a rate of 70%.
¹ H NMR δ (CDCl ₃ ): 7.24 (d, J = 3.6Hz, 1H), 6.69 (d, J = 3.6Hz, 1H), 5.72 (brs, 1H), 2.65 (d, J = 7.2Hz, 2H ), 1.88 (m, 1H), 1.44 (s, 9H), 0.93 (d, J = 6.6Hz, 3H)
¹³ C NMR δ (CDCl ₃ ): 161.4, 149.2, 137.6, 127.5, 125.5, 51.8, 39.5, 30.7, 28.9, 22.1
IR (Neat): 3215, 2924, 1620, 1550, 1464, cm ^-1
Elemental analysis: Calculated for _{C 13 H 21 NOS: C,} 65.2; H, 8.8; N, 5.9. Found: C, 65.5; H, 8.9; N, 5.9.
MS (EI ⁺ ) m / z: 239

(c) 5-Isobutyl-Nt-butylthiophene-2-carboxamide-3-boronic acid
To a solution of 5-isobutyl-Nt-butylthiophene-2-carboxamide (from step (b) above; 0.5 g, 2.1 mmol) in THF (50 mL), n-BuLi (1.6 M in hexane, 3.3 mL, 5.28 mmol) Was added at -78 ° C. The reaction mixture was gradually warmed to −20 ° C. and stirred for 4 hours. Triisopropyl borate (0.59 g, 3.14 mmol) was added to the mixture at −78 ° C. The solution was gradually heated to room temperature and stirred overnight. The reaction was quenched with HCl (aq) (2M, 2 mL), extracted with EtOAc (2 × 25 mL), washed with brine, dried over MgSO ₄ and concentrated. The crude product was used in the next step without further purification. ^{MS (EI +) m / z} : 284

(d) 3- (4-imidazol-1-ylmethylphenyl) -5-isobutyl-Nt-butylthiophene-2-carboxamide
5-isobutyl-Nt-butylthiophene-2-carboxamido-3-boronic acid (200 mg, 0.706 mmol, see step (c) above), 1- (4-bromobenzyl) -1H-imidazole (80 mg, 0.337 mmol) , Toluene (5 mL), ethanol (2 mL), NaOH (1.63 M, 0.84 mL, 1.38 mmol) and Pd (PPh ₃ ) ₄ (16.3 mg, 0.014 mmol) were mixed together under N ₂ . The resulting mixture was heated to reflux for 2 hours. The mixture was diluted with EtOAc (50 mL), washed with water and brine, and dried over MgSO ₄ . The solvent was removed and the residue was separated by column chromatography using chloroform: methanol (95: 5) as eluent to give the subtitle compound 99 mg (yield: 74%).
¹ H NMR δ (CDCl ₃ ): 7.55 (br s, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.09 (br s, 1H), 6.89 (br s, 1H), 6.63 (s, 1H), 5.25 (br s, 1H), 5.16 (s, 2H), 2.63 (d, J = 6.9Hz, 2H), 1.89 (m, 1H), 1.13 ( s, 9H), 0.95 (d, J = 6.6Hz, 3H)
¹³ C NMR δ (CDCl ₃ ): 161.4, 147.4, 140.2, 137.3, 136.3, 136.1, 133.9, 130.0, 129.8, 128.3, 127.6, 119.0, 51.4, 50.4, 39.3, 30.5, 28.4, 22.2
IR (Neat): 3113, 2930, 1645, 1512 cm ^-1
MS (EI ⁺ ) m / z: 396
Elemental _{analysis: C 23 H 29 N 3 OS} + H 2 O Calculated: C, 66.8; H, 7.6 ; N, 10.2. Found: C, 67.0; H, 7.6; N, 9.9.

(e) 3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-carboxamide trifluoroacetic acid (2.5 mL) was replaced with 3- (4-imidazol-1-ylmethylphenyl) -5- In addition to isobutyl-Nt-butylthiophene-2-carboxamide (165 mg, 0.417 mmol, see step (d) above), 1 drop of anisole (about 0.05 mL) was added to the reaction mixture. The mixture was stirred for 30 h under N ₂ atmosphere, then evaporated and co-evaporated with acetonitrile. The crude product was purified by column chromatography (CH ₂ Cl ₂ : MeOH (85:15)) to give the subtitle compound (117 mg, 0.345 mmol) in 73% yield.
¹ H NMR δ (CD ₃ OD): 9.05 (br s, 1H), 7.63 (br s, 1H), 7.55 (br s, 1H), 7.51 (d, J = 8.4Hz, 2H), 7.45 (d, J = 8.4Hz, 2H), 6.81 (s, 1H), 5.47 (s, 2H), 2.68 (d, J = 7.1Hz, 2H), 1.90 (m, 1H), 0.96 (d, J = 6.6Hz, 3H)
¹³ C NMR δ (CD ₃ OD): 167.1, 148.9, 144.1, 137.9, 136.6, 135.1, 131.2, 130.8, 130.1, 129.8, 123.3, 121.6, 53.4, 40.0, 31.8, 22.5
IR (Neat): 3308, 2957, 1657, 1509, 1461
MS (EI ⁺ ) m / z: 340
Elemental analysis: Calculated for C ₁₉ H ₂₁ N ₃ OS: C, 67.2; H, 6.2; N, 12.4. Found: C, 67.5; H, 6.4; N, 12.3.

(f) N-butylsulfonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-carboxamide
NaH (55%, 12 mg, 0.28 mmol) was added to THF of 3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-carboxamide (46 mg, 0.136 mmol, see step (e) above). (1 mL) was added to the solution. The mixture was stirred at 50 ° C. for 0.5 hour. Butanesulfonyl chloride (29 μL, 0.223 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified by silica gel chromatography (CH ₂ Cl ₂ : MeOH, 9: 1)) to give 31 mg of the title compound as a white powder (yield: 50%).
¹ H NMR δ (CDCl ₃ ): 7.82 (br s, 1H), 7.32 (br s, 2H), 7.06 (d, J = 7.4Hz, 2H), 6.95 (br s, 2H), 6.64 (s, 1H ), 5.09 (br s, 2H), 4.79 (br s, 1H), 2.97 (br s, 2H), 2.62 (d, J = 6.9Hz, 2H), 1.90 (m, 1H), 1.65 (br s, 2H), 1.29 (m, 2H), 0.95 (d, J = 6.5Hz, 6H), 0.81 (t, J = 6.6Hz, 3H)
¹³ C NMR δ (CDCl ₃ ): 166.4, 148.9, 144.3, 137.3, 136.4, 134.8, 132.2, 130.0, 129.4, 127.2, 119.9, 53.2, 51.0, 39.5, 30.5, 25.4, 22.3, 21.5, 13.6
MS (EI ⁺ ) m / z: 460
Elemental _{analysis: C 23 H 29 N 3 O} 3 S 2 + H 2 O Calculated: C, 57.8; H, 6.5 ; N, 8.8. Found: C, 58.1; H, 6.4; N, 8.3.
IR (Neat): 3482, 3118, 2958, 1558, 1456 cm ^-1

Example 13
The following compounds were also prepared according to the techniques described here:
(i) N-butyloxycarbonyl-4-butyl-2- (4-imidazol-1-ylmethylphenyl) benzenesulfonamide
¹ H NMR δ (CDCl ₃ ): 8.95 (brs, 1H), 8.20 (d, J = 8.3Hz, 1H), 7.66 (brs, 1H), 7.38 (d, J = 8.0Hz, 2H), 7.34 ( dd, J = 8.3, 1.6Hz, 1H), 7.11 (d, J = 8.0Hz, 2H), 7.05 (d, J = 1.6Hz, 1H), 6.83 (brs, 2H), 5.10 (s, 2H), 4.00 (t, J = 6.5, 2H), 2.67 (t, J = 7.5Hz, 2H), 1.62 (m, 2H), 1.48 (m, 2H), 1.36 (m, 2H), 1.22 (m, 2H) , 0.92 (t, J = 7.2Hz, 3H), 0.86 (t, J = 7.3Hz, 3H)
¹³ C NMR δ (CDCl ₃ ): 151.9, 148.5, 140.2, 139.9, 136.7, 135.1, 134.7, 132.3, 130.8, 129.9, 127.7, 127.2, 126.9, 119.2, 65.9, 50.9, 35.4, 33.0, 30.5, 22.4, 18.8 , 13.8, 13.6
(ii) N- (2-methoxyethyloxy) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
¹ H NMR δ (20% CD ₃ OD in CDCl ₃ ): 8.00 (brs, 1H), 7.56 (d, J = 7.7Hz, 2H), 7.19 (d, J = 7.7Hz, 2H), 7.07 (brs, 2H), 6.75 (s, 1H), 5.20 (s, 2H), 4.14 (brt, J = 4.5Hz, 2H), 3.52 (brt, J = 6.9Hz, 2H), 3.32 (s, 3H), 2.70 ( d, J = 7.1Hz, 2H), 1.94 (m, 1H), 0.99 (d, J = 6.4Hz, 6H)
¹³ C NMR δ (20% CD ₃ OD in CDCl ₃ ): 153.1, 149.7, 144.0, 136.1, 134.8, 134.6, 132.8, 129.6, 128.8, 127.0, 125.6, 119.8, 70.0, 64.1, 58.2, 50.9, 38.9, 30.2 , 21.8
(iii) N-ethyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
¹ H NMR δ (20% CD ₃ OD in CDCl ₃ ): 7.78 (brs, 1H), 7.55 (d, J = 7.8Hz, 2H), 7.24 (d, J = 7.8Hz, 2H), 7.07 (brs, 2H), 6.77 (s, 1H), 5.22 (s, 2H), 4.06 (q, J = 7.1Hz, 2H), 2.71 (d, J = 7.1Hz, 2H), 1.95 (m, 1H), 1.17 ( t, J = 7.1Hz, 3H), 0.99 (d, J = 6.4Hz, 6H)
¹³ C NMR δ (20% CD ₃ OD in CDCl ₃ ): 153.0, 150.7, 145.1, 137.2, 135.9, 135.0, 132.7, 130.1, 129.5, 127.9, 127.6, 120.2, 62.6, 49.6, 39.5, 30.8, 22.3, 14.3
(iv) Nt-Butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
¹ H NMR δ (10% CD ₃ OD in CDCl ₃ ): 7.65 (brs, 1H), 7.39 (d, J = 7.9Hz, 2H), 7.11 (d, J = 7.9Hz, 2H), 6.94 (brs, 2H), 6.65 (s, 1H), 5.09 (s, 2H), 2.59 (d, J = 7.1Hz, 2H), 1.82 (m, 1H), 1.22 (s, 9H), 0.87 (d, J = 6.6 Hz, 6H)
¹³ C NMR δ (10% CD ₃ OD in CDCl ₃ ): 150.5, 149.5, 144.6, 136.6, 135.5, 134.2, 131.7, 129.5, 129.0, 128.0, 127.1, 119.6, 83.0, 50.6, 39.0, 30.3, 27.5, 21.9
(v) N-butyloxycarbonyl-3- [4- (4-methylimidazol-1-ylmethyl) phenyl] -5-isobutylthiophene-2-sulfonamide
¹ H NMR δ (CDCl ₃ ): 8.22 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 6.84 (s, 1H), 6.74 (s , 1H), 5.18 (s, 2H), 4.03 (t, J = 6.6Hz, 2H), 2.71 (d, J = 6.9Hz, 2H), 2.24 (s, 3H), 1.94 (m, 1H), 1.51 (m, 2H), 1.28 (m, 2H), 1.00 (d, J = 6.6Hz, 6H), 0.87 (t, J = 7.4Hz, 3H)
¹³ C NMR δ (CDCl ₃ ): 152.4, 150.5, 144.6, 135.2, 134.5, 132.6, 130.0, 129.1, 127.8, 117.1, 116.9, 66.3, 51.7, 39.3, 30.6, 22.3, 18.9, 13.6, 11.5
(vi) N-butyloxycarbonyl-3- (4-pyrazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
¹ H NMR δ (CDCl ₃ ): 0.84 (t, J = 7.3Hz, 3H), 0.95 (d, J = 6.6Hz, 6H), 1.22 (m, 2H), 1.48 (m, 2H), 1,90 (m, 1H), 2.66 (d, J = 6.9Hz, 2H), 4,01 (t, J = 6.6Hz, 2H), 5.26 (s, 2H), 6.23 (s, 1H), 6.69 (s, 1H), 7.02 (d, J = 8.3Hz, 2H), 7,37 (m, 3H), 7.48 (s, 1H)
¹³ C NMR δ (CDCl ₃ ): 13.6, 18.7, 22.2, 30.4, 39.2, 55.1, 66.5, 106.0, 127.3, 129.3, 129.6, 133.7, 136.9, 139.4, 145.7, 150.6, 151.3
(vii) N-butyloxycarbonyl-3- [4- (3-trifluoromethylpyrazol-1-ylmethyl) phenyl] -5-isobutylthiophene-2-sulfonamide
¹ H NMR δ (CDCl ₃ ): 7.66 (s, 1H), 7.50 (s, 1H), 7.42 (d, J = 8.1Hz, 2H), 7.23 (d, J = 8.2Hz, 2H), 6.74 (s , 1H), 6.59 (d, J = 2.1Hz, 1H), 5.40 (s, 2H), 4.03 (t, J = 6.6Hz, 2H), 2.71 (d, J = 6.9Hz, 2H), 1.96 (m , 1H), 1.49 (m, 2H), 1.25 (m, 2H), 0.99 (d, J = 6.6Hz, 6H), 0.87 (t, J = 7.4Hz, 3H)
¹³ C NMR δ (CDCl ₃ ): 151.8, 150.2, 146.0, 143.6, 142.5, 141.8, 139.4, 136.0, 134.0, 131.1, 130.6, 129.4, 127.5, 123.2, 119.2, 66.9, 56.1, 39.3, 30.5, 22.2, 18.7 , 13.5
(viii) N- (N-butyl-N-methylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide
¹ H NMR δ (CDCl ₃ ): 8.18 (brs, 1H), 7.84 (brs, 1H), 7.46 (d, J = 8.2Hz, 2H), 7.16 (d, J = 8.2Hz, 2H), 7.06 (brs , 1H), 6.99 (brs, 1H), 6.68 (s, 1H), 3.07 (brt, 2H), 2.67 (d, J = 7.1Hz, 2H), 2.56 (brs, 3H), 1.91 (m, 1H) 1.35 (m, 2H), 1.19 (m, 2H), 0.96 (d, J = 6.6Hz, 6H), 0.84 (t, J = 7.2Hz, 3H)
¹³ C NMR δ (CDCl ₃ ): 153.6, 149.8, 143.3, 136.9, 135.5, 135.1, 134.2, 129.6, 128.7, 127.2, 126.8, 119.8, 51.0, 48.5, 39.3, 34.3, 30.4, 29.7, 22.3, 19.8, 13.8
(ix) N-Butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- (2-methoxyethyl) thiophene-2-sulfonamide
¹ H NMR δ (5% CD ₃ OD in CDCl ₃ ): 7.86 (brs, 1H), 7.51 (d, J = 7.9Hz, 2H), 7.18 (d, J = 7.9Hz, 2H), 7.05 (brs, 1H), 6.99 (brs, 1H), 6.83 (s, 1H), 5.18 (s, 2H), 4.03 (t, J = 6.5Hz, 2H), 3.67 (t, J = 6.2Hz, 2H), 3.10 ( t, J = 6.2Hz, 2H), 1.52 (m, 2H), 1.26 (m, 2H), 0.88 (t, J = 7.3Hz, 3H)
¹³ C NMR δ (5% CD ₃ OD in CDCl ₃ ): 151.7, 148.1, 144.7, 136.9, 135.2, 134.8, 133.0, 129.9, 129.4, 127.4, 127.2, 119.8, 72.0, 66.3, 58.8, 51.1, 30.7, 30.5 , 18.8, 13.6

Example 14
The example title compounds were tested in Tests A and B above, which show that Ki = less than 100 nM (e.g., less than 50 nM) affinity for the AT2 receptor and Ki = 500 nM (e.g., greater than 1 μM). It was found to show affinity for the AT1 receptor.

Example 15
The title compounds of the Examples were tested in Test C above, and they were found to significantly stimulate mucosal alkalinization. This effect was blocked by co-administration of the selective AT2 receptor antagonist PD123319 (Sigma Chemical Company).

Claims (31)

A compound of formula I or a pharmaceutically acceptable salt thereof

[In the above formula,
One of X ₁ and X ₂ represents —N— and the other represents —C (R ¹ ) —;
X ₃ represents —N— or —C (R ² ) —;
X ₄ represents -N- or -C (R ³ )-;
R ¹ , R ² and R ³ independently represent H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl or halo;
However, when X ₁ represents -C (R ¹ )-, X ₃ represents -C (R ² )-, and X ₄ represents -C (R ³ )-, R ¹ represents H Represents;
Y ₁ , Y ₂ , Y ₃ and Y ₄ independently represent —CH— or —CF—;
Z ₁ represents -S- or -CH = CH-;
Z ₂ represents —CH—;
R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ , -S (O) ₂ N (H) S (O) ₂ R ⁶ or -C (O) N (H) S ( O) represents ₂ R ^6;
R ⁵ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ -alkyl or di-C ₁ -C ₃ -alkylamino-C ₁ -C ₄ alkyl Represents;
R ⁶ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₃ alkoxy-C ₁ -C ₆ -alkoxy, C ₁ -C represents a ₆ alkylamino or di -C ₁ -C ₆ alkylamino. The compound according to claim 1, wherein when X ₁ represents -C (R ¹ )-, X ₃ represents -C (R ² )-and X ₄ represents -N-. 3. A compound according to claim 2, wherein R < ¹ > represents H. The compound of claim 1, wherein when X ₁ represents —C (R ¹ ) —, both X ₃ and X ₄ represent N. The compound according to claim 1, wherein when X ₁ represents -C (R ¹ )-, X ₃ represents -C (R ² )-and X ₄ represents -C (R ³ )-. . When the X ₁ represents -N-, X ₃ is represents -N-, A compound according to claim 1. X ₄ is -C (R ³⁾ - in the case of representing a, R ³ is represents H, compound of Claim 6. The compound according to claim 1, wherein when X ₁ represents -N-, X ₃ represents -C (R ² ) and X ₄ represents -C (R ³ )-. R ¹ is, H, represents a C ₁ -C ₃ alkyl or CF _3, A compound according to any one of claims 1, 2, 4 or 6 8. 10. A compound according to claim 9, wherein R < ¹ > represents H or ethyl. R ² is, C ₁ -C ₃ alkyl, represents halo or H, A compound according to any one of 10 claims 1 to 3, 5 or 8. R ² is H or methyl, A compound according to claim 11. R ² is represents H, compound of claim 12. R ³ is, C ₁ -C ₃ alkyl, represents halo or H, A compound according to any one of claims 1, 5, 6 or 8 13. R ³ is represents H, compound of claim 14. Y _1, Y _2, Y ₃ and Y ₄ are all represent -CH-, A compound according to any one of claims 1 to 15. R ⁴ is, -S (O) represents a _{2 N (H) C (O} ) R 6, A compound according to any one of claims 1 to 16. R ⁵ is representative of the n- butyl or isobutyl, A compound according to any one of claims 1 to 17. R ⁵ is represents isobutyl, compounds of claim 18. R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ , -S (O) ₂ N (H) S (O) ₂ R ⁶ or -C (O) N (H) S ( O) represents ₂ R ^6, R ⁶ is, n- butoxymethyl, iso - represents a butoxy or n- butoxy, compounds according to any one of claims 1 19. R ⁶ is, represents a n- butoxy, compound of claim 20. When X ₁ , X ₃ and X ₄ all represent —CH—, Y ₁ , Y ₂ , Y ₃ and Y ₄ all represent —CH—, and R ⁵ represents n-butyl or isobutyl. , R ⁴ represents -S (O) ₂ N (H) C (O) R ⁶ , where R ⁶ is -On-butyl, -O-isopropyl, -O-isobutyl or -CH _2- 2. A compound according to claim 1, which represents On-butyl. N-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-isobutyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-isopropyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N- (butoxyacetyl) -3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-butylthiophene-2-sulfonamide;
N-butyloxycarbonyl-2- (4-imidazol-1-ylmethylphenyl) -4-isobutylbenzene-sulfonamide;
N-butyloxycarbonyl-5-isobutyl-3- (4-tetrazol-2-ylmethylphenyl) thiophene-2-sulfonamide;
N-butyloxycarbonyl-5-isobutyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide;
N-butyloxycarbonyl-3- (4- [1,2,4] triazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N- (butylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-butylsulfonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-butylsulfonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-carboxamide;
N-butyloxycarbonyl-4-butyl-2- (4-imidazol-1-ylmethylphenyl) benzene-sulfonamide;
N- (2-methoxyethyloxy) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-ethyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
Nt-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-butyloxycarbonyl-3- [4- (4-methylimidazol-1-ylmethyl) phenyl] -5-isobutylthiophene-2-sulfonamide;
N-butyloxycarbonyl-3- (4-pyrazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-butyloxycarbonyl-3- [4- (3-trifluoromethylpyrazol-1-ylmethyl) phenyl] -5-isobutylthiophene-2-sulfonamide;
N- (N-butyl-N-methylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide; or
N-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- (2-methoxyethyl) -thiophene-2-sulfonamide. A process for preparing the compound of claim 1
(i) R ⁴ in the formula represents -S (O) ₂ N (H) C (O) R ⁶ or -S (O) ₂ N (H) S (O) ₂ R ⁶ and R ⁶ claims To prepare a compound of formula I as defined in paragraph 1, a compound of formula II:

[Wherein X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as in claim 1]
A compound of formula III:
R ⁶ GL ¹ III
[In the above formula, G represents C (O) or S (O) ₂ , L ¹ represents a leaving group, and R ⁶ is defined as in claim 1)]
Or react with
R ⁴ in (ii) wherein represents _{-S (O) 2 N (H} ) C (O) R 6, compounds of formula I in which R ⁶ represents a C ₁ -C ₆ alkoxy -C ₁ -C ₆ alkyl In order to prepare a compound of formula II, as defined above, a compound of formula IV
R ^6a CO ₂ H IV
[Wherein R ^6a represents C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl]
Coupled with; or
(iii) in formula R ⁴ represents _{-S (O) 2 N (H} ) C (O) R 6, in order to prepare compounds of formula I where R ⁶ represents C ₁ -C ₆ alkylamino, A compound of formula II as defined above is converted to a compound of formula XIII:
R ^6b NCO XIII
[Wherein R ^6b represents C ₁ -C ₆ alkyl]
A method comprising reacting with. A process for preparing the compound of claim 1
In order to prepare compounds of formula I wherein R ⁴ represents -C (O) N (H) S (O) ₂ R ⁶ and R ⁶ is defined as in claim 1, Compound:

[Wherein X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as in claim 1]
A compound of formula VI:
R ⁶ S (O) ₂ NH ₂ VI
[Wherein R ⁶ is defined as in claim 1]
A method comprising coupling with. A process for preparing the compound of claim 1
In order to prepare compounds of formula I wherein R ⁴ represents -C (O) N (H) S (O) ₂ R ⁶ and R ⁶ is defined as in claim 1, Compound:

[Wherein X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as in claim 1]
A compound of formula VIII:
R ⁶ S (O) ₂ Cl VIII
[Wherein R ⁶ is defined as in claim 1]
A method comprising coupling with. A process for preparing the compound of claim 1
For R ⁴ in the formula represents a _{-S (O) 2 N (H} ) C (O) R 6, for preparing a compound of formula I representative of the R ⁶ a di -C ₁ -C ₆ alkylamino, wherein R ⁴ represents _{-S (O) 2 N (H} ) C (O) R 6, the corresponding compound of formula I in which R ⁶ represents a C ₁ -C ₆ alkoxy in the formula XIV:
R ^6c N (H) R ^6d XIV
[Wherein R ^6c and R ^6d independently represent C ₁ -C ₆ alkyl]
A method comprising reacting with.   25. A compound of formula II as defined in claim 24 or a sulfonamide group thereof protected with t-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc) or a t-butyl group. Wherein X ₁ , X ₃ and X ₄ all represent —CH—, Y ₁ , Y ₂ , Y ₃ and Y ₄ all represent —CH—, and R ⁵ represents n-butyl or isobutyl. Item 28. The compound of formula II according to item 28.   26. A compound of formula V as defined in claim 25.   27. A compound of formula VII as defined in claim 26 or an amide group protected with t-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc) or a t-butyl group.