KR100938817B1 - Tricyclic compounds useful as angiotensin ? agonists - Google Patents

Abstract

There is provided a compound of formula 1 Wherein X ₁ , X ₂ , X ₃ , X ₄ , Y ₁ , Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ , R ₄ and R ₅ and their pharmaceutically acceptable salts described herein Is a selective agent of the AT2 receptor, and is particularly useful, for example, in indigestion, gastrointestinal conditions, such as IBS and MOF, and in the treatment of cardiovascular diseases.

[Formula 1]

Description

Tricyclic compounds useful as angiotensin II agonists

The present invention relates to novel and pharmaceutically useful compounds, in particular certain compounds which are angiotensin II (Ang II) agonists, and more particularly to Ang II type 2 receptors (hereinafter referred to as AT2 receptors). ), In particular agents which selectively bind to said receptor. The invention also relates to the use of the compounds as pharmaceutical preparations, to pharmaceutical compositions containing them, and to synthetic routes to their production.

Of; (RAS reninangiotensin system) endogenous hormone Ang II is a linear octa peptide ^{(octapeptide) (Asp 1 -Arg 2} -Val 3 -Tyr 4 -Ile 5 -His 6 -Pro 7 -Phe 8), and, renin angiotensin system Active compound. It is produced by the sequential processing of pro-hormone angiotensinogen by renin and angiotensin converting enzyme (ACE).

The Lenin-Angiotensin System (RAS) plays an important role in the control of blood pressure, body fluid and electrolyte homeostasis. Ang II causes physiological action in many organs, including the kidneys, adrenal glands, heart, blood vessels, brain, gastrointestinal tract and reproductive organs (De Gasparo et al. Pharmacol. Rev. (2000) 52, 415-472).

Two main classes of Ang II receptors have been identified and designated as type 1 receptors (hereinafter referred to as AT1 receptors) and AT2 receptors.

AT1 receptors are expressed in most organs and are believed to be responsible for most biological effects of Ang II. AT2 receptors are more prevalent than AT1 receptors in fetal tissue, adult ovary, adrenal medulla and interest. An equal distribution in the brain and uterus has been reported (Ardaillou, J. Am. Soc. Nephrol. , 10, S30-39 (1999)).

Studies in adult individuals have shown that in the modulation of the response following Ang II stimulation, activation of the AT2 receptor is an opposing effect on the effects modulated by the AT1 receptor. )

AT2 receptors have also been shown to be involved in the suppression of apoptosis and cell proliferation (see de Gasparo et al.). Moreover, it appears to play a blood pressure control role. For example, blood pressure has been shown to be elevated in AT2 receptor deficient transgenic mice. In addition, it has been concluded that AT2 receptors are involved in search behavior, pain sensitivity and thermoregulation.

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

The anticipated pharmaceutical effects of the agonism of the AT2 receptor are outlined in the paper by de Gasparo et al.

Recently, AT2 receptor agonists have been found to be potentially useful for the treatment and / or prevention of digestive tract disorders such as multiple organ failure as well as dyspepsia and irritable bowel syndrome (see International Patent Application WO99 / 43339). .

Ang II antagonists (which bind to AT1 and / or AT2 receptors) are described in particular in European Patent Applications EP 409 332, EP 512 675; International patent applications WO 94/27597, WO 94/02142, WO 95/23792 and WO 94/03435; And US Patents 5,091,390, 5,177,074, 5,412,097, 5,520,521, 5,260,285, 5,376,666, 5,252,574, 5,312,820, 5,330,987, 5,166,206, 5,932,575 and 5,240,928. Ang II agonists, in particular AT2 receptor agonists, are not expected at all in these documents.

International patent application WO 00/68226 and US Pat. No. 6,235,766 disclose substituted imidazolyl groups bound by a methylene bridge to the phenylthiophene moiety as an agent of the angiotensin- (1-7) receptor. compounds, including imidazolyl groups), are described. International patent application WO 01/44239 discloses biphenylsulfonamide compounds as binding angiotensin and endothelin receptor antagonists. The use of such compounds as Ang II receptor agonists is not mentioned or suggested in these documents.

U.S. Patent 5,444,067 describes compounds comprising 5,7-dimethyl-2-ethylpyridinoimidazolyl groups bonded to the phenylthiophene moiety by a methylene bridge. The use of unsubstituted imidazole-containing compounds is not mentioned or suggested in these documents.

Peptides and non-peptide AT2 receptor agonists that are structurally unrelated to those described herein and their potential 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 99/40106, WO 99/39743, WO99 / 26644, WO98 / 33813, WO00 / 02905, and WO 99/46285; U.S. Patent 5,834,432; And Japanese Patent Application JP 143695.

Disclosure of Invention

According to the present invention, there is provided a compound of formula (1) or a pharmaceutically acceptable salt thereof.

Where

(a) Z ₁ and Z ₂ are not the same;

(b) Z ₂ is -CH- or -N- when Z ₁ is -CH = CH-; And

(c) Z ₁ is -CH = CH- and Z ₂ is -CH-, unless Z ₁ and Z ₂ are -CH- and the other is -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 R ² is -N (H) S (O) ₂ N (H) C (O) R ⁷ or -N (H) C (O) N when ₂ R ⁶ or Z ₁ is -CH = CH- (H) S (O) ₂ R ⁷ ;

R ⁵ is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 -alkyl or di-C _1-3 -alkylamino-C _1-4 -alkyl;

R ⁶ is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 -alkyl, C _1-3 alkoxy-C _1-6 -alkyl, C _1-6 alkylamino or di- C _1-6 -alkylamino;

When R ⁷ is C _1-6 -alkyl,

When X ₁ is —C (R ¹ ) —, X ₃ is —C (R ² ) — and X ₄ is —C (R ³ ) —, R ¹ is H;

Y ₁ , Y ₂ , Y ₃ and Y ₄ , are each -CH- or -CF-;

Z ₁ is -CH-, -O-, -S-, -N- or -CH = CH-;

When Z ₂ is -CH-, -O-, -S- or -N-,

_One of X ₁ and X ₂ is —N— and the other is —C (R ¹ ) —;

X ₃ is -N- or -C (R ² )-;

X ₄ is -N- or -C (R ³ )-;

R ¹ , R ² and R ³ are each H, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 -alkyl or halo. Hereinafter, the above compounds and salts will be referred to as "compounds of the present invention".

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be prepared by conventional methods, for example, in the form of free acids or free bases of the free acid or free base of the compounds of the present invention, optionally in a solvent or in a medium in which the salts can dissolve. By reaction with one or more equivalents, after which the solvent or medium is removed using standard techniques (e.g. in vacuo or freeze-drying). do. Salts can also be made by exchanging counter-ions of the compounds of the invention in salt form with other counter-ions, for example using a suitable ion exchange resin.

Unless stated otherwise, the alkyl groups of the present specification and the alkyl portion of the alkoxy group, the alkoxyalkyl group, the alkoxyalkoxy group, the alkylamino group and the alkylaminoalkyl group are straight-chain, or a sufficient number (for example, at least three) In the case of carbon atoms, they are branched-chain and / or cyclic. Moreover, when there are a sufficient number of carbon atoms (eg at least four), such functional groups may be part cyclic / acyclic. Such alkyl groups and the alkyl moieties of alkoxy groups, alkoxyalkyl groups, alkoxyalkoxy groups, alkylamino groups and alkylaminoalkyl groups can also be saturated or unsaturated if there is a sufficient number of (eg at least two) carbon atoms. Unless otherwise stated, such functional groups can also be saturated by one or more halogens, in particular fluorine atoms.

For the avoidance of doubt, alkoxy and alkoxyalkoxy groups are bonded to the rest of the molecule by the oxygen atom of the functional group, alkylamino groups are bonded to the rest of the molecule by the nitrogen atom of the amino portion of the functional group, alkylamino The alkyl group and the alkoxyalkyl group are bonded to the rest of the molecule by the alkyl portion of the functional group.

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

Preferred ring systems comprising substituents Y ₁ , Y ₂ , Y ₃ and Y ₄ include phenyl groups. For the avoidance of doubt, the ring system in the compound of formula 1 is in fact aromatic. In some instances, for example, if one or more of Z ₁ and Z ₂ are —CH— or —N—, one of ordinary skill in the art will know that additional H atoms are necessarily bound to that CH group or nitrogen atom by valence law. Preferred ring systems comprising Z ₁ and Z ₂ include oxazole groups, thiazole groups, phenyl groups, pyridinyl groups, thiophenyl groups and Furanyl groups.

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

Compounds of the present invention may contain one or more asymmetric carbon atoms, with the result that selective and / or diastereoisomerism may occur. Diastereomers can be separated using conventional methods such as, for example, chromatography or fractional crystallisation. The various stereoisomers can be separated by separation of racemic or other mixtures of the compounds using conventional methods such as, for example, fractional crystallization or HPLC methods. Alternatively, derivatization or by reaction of suitable optically activated starting materials under conditions that do not cause racemization or epimerisation with the desired optical isomer, for example with homochiral acid It can be made by derivatisation, followed by the separation of diastereoisomerized derivatives by conventional methods (e.g., high performance liquid chromatography (HPLC), chromatography over silica). All stereoisomers are included within the scope of the present invention.

Preferred compounds of the present invention include the following:

(i) when X ₁ is -C (R ¹ )-

(a) X ₃ is -C (R ² )-and X ₄ is -N-;

(b) X ₃ and X ₄ are both N;

(c) X ₃ is -C (R ² )-and X ₄ is -C (R ³ )-;

(ii) when X ₁ is -N-,

(a) X ₃ is -N-;

(b) X ₃ is -C (R ² ) and X _{4 is} -C (R ³ )-.

In the case of (i) (a) mentioned above, R ¹ is more preferably H.

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

Preferred compounds of formula (I) include the following.

R ¹ is C _1-3 alkyl, such as ethyl, —CF ₃ or in particular H;

R ² is C _1-3 alkyl, such as methyl, halo, or, in particular, H;

R ³ is C _1-3 alkyl, halo or, in particular, H;

Y ₁ , Y ₂ , Y ₃ and Y ₄ are all —CH—;

Z ₁ is -S- or -CH = CH-;

Z ₂ is -CH-;

R ⁴ is S (O) ₂ N (H) C (O) R ⁶ ;

R ⁵ is n -butyl or, in particular, iso-butyl;

R ⁶ is n -butoxymethyl, iso-butoxy and in particular n -butoxy.

Preferred ring systems comprising the substituents X ₁ , X ₂ , X ₃ and X ₄ include pyrazole groups, imidazole groups, 1,2,4-triazole groups and tetra Tetrazole groups.

Compounds of the present invention, when X _1, X ₃ and X ₄ are all -CH-, Y ₁ , Y ₂ , Y ₃ and Y ₄ are all -CH-, Z ₁ is -CH = CH-, In particular, -S-, Z ₂ is -CH- and R ⁵ is n -butyl or, in particular, iso -butyl, and R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ , R ⁶ represents -O- iso-propyl (e.g., -O- iso-propoxy (iso -propoxy), -O- iso -butyl (-O- iso -butyl) [for example, iso-butoxy ( iso -butoxy)], -CH ₂ -O- n -butyl (e.g. n -butoxymethyl) or, in particular, those which are -O- n -butyl (e.g. n -butoxy).

The compounds of the present invention also provide that when X _1, X ₃ and X ₄ are all —CH—, Y ₁ , Y ₂ , Y ₃ and Y ₄ are all —CH—d and Z ₁ is —CH═CH— or -S-, Z ₂ is -CH- and R ⁵ is n -butyl or iso -butyl, then R ⁴ is not -S (O) ₂ N (H) C (O) R ⁶ , R is ⁶ includes those which are -O-iso-propyl, -O-iso-butyl, -CH ₂ -O- n -butyl or -O- n -butyl.

In addition, the compounds of the present invention

R ⁴ is not —S (O) ₂ N (H) S (O) ₂ R ⁶ ;

R ⁵ is not di-C _1-3 alkylamino-C _1-4 -alkyl;

R ⁶ includes those other than C _1-3 alkoxy-C _1-6 alkoxy.

More preferred compounds of the present invention include compounds of the embodiments to be described below.

Compounds of formula (1) can be made according to methods well known to those skilled in the art, for example the methods described below.

According to another aspect of the present invention, there is provided a process for preparing a compound of formula 1, comprising:

(i) wherein R ⁴ is —S (O) ₂ N (H) C (O) R ⁶ or —S (O) ₂ N (H) S (O) ₂ R ⁶ and R ⁶ is as defined above Reacting a compound of Formula 1 with a compound of Formula 3 for a compound of Formula 1;

(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 above.)

R ⁶ GL ¹

Wherein G is [as appropriate] C (O) or S (O) ₂ , L ¹ is a suitable leaving group such as halo (eg chloro or bromo), R ⁶ is defined above and is a suitable base [eg pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethyl, for example at approximately room temperature or higher (eg up to 60-70 ° C.). Amine, dimethylaminopyridine, di-iso-propylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, sodium hydroxide, or mixtures thereof ] In the presence of a suitable solvent (e.g. pyridine, dichloromethane, coloform, tetrahydrofuran, dimethylformamide, trifluoromethylbenzene or triethylamine) and G is C (O) Preferred base / solvent systems of the compounds of formula 3 are pyrrolidinopyridine / pyridine, Preferred base / solvent systems of the compounds of the formula (3) which comprise Ralidinopyridine / triethylamine, dimethylaminopyridine / pyridine or dimethylaminopyridine / triethylamine, and G is S (O) ₂ , comprise NaOH / THF do.)

(ii) for compounds of formula 1 above, wherein R ⁴ is —S (O) ₂ N (H) C (O) R ⁶ and R ⁶ is C _1-6 alkoxy-C _1-6 -alkyl Combining the compound of Formula 2 with a compound of Formula 4;

R ^6a CO ₂ H

Wherein R ^6a is C _1-6 alkoxy-C _1-6 -alkyl, for example under similar conditions as described in step (i) above, a suitable binder [1,1′-carbonyl-diimine Dazole, N, N'-dicyclohexylcarbodiimide, N, N'-disuccinimidyl carbonate, benzotriazole-1-yloxytris (dimethylamino) phosphonium hexa Fluorophosphate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluromium hexafluorophosphate, benzotriazol-1-yl-oxy-tris-pyrrolidino -Phosphonium hexafluorofluorophosphate, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, bromo-tris-pyrrolidinophosphonium hexafluorophosphate or 2- (1H- Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluorocarbonate] and a suitable base [in step (i) above And the reaction in the presence of a suitable solvent [described in step (i) above).

(iii) For the compound of Formula 1, wherein R ⁴ is -C (O) N (H) S (O) ₂ R ⁶ and R ⁶ is defined above, the compound of Formula 5 is a compound of Formula 6 Combining with;

(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 above.)

R ⁶ S (O) ₂ NH ₂

Wherein R ⁶ is as defined above, for example in the presence of a suitable binder [as described in step (ii) above], and R ⁶ is C _1-6 alkoxy-C _1-6 -alkyl The reaction proceeds under reaction conditions similar to those described above for the preparation of the compound of Formula 1.)

(iv) For a compound of Formula 1 wherein R ⁴ is -C (O) N (H) S (O) ₂ R ⁶ and R ⁶ is defined above, the compound of Formula 7 is a compound of Formula 8 Combining with;

(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 above.)

R ⁶ S (O) ₂ Cl

(Wherein R ⁶ is defined above and proceeds for example at about 50 ° C. in the presence of a suitable base (eg sodium hydroxide) and a suitable organic solvent (eg THF).)

(v) For a compound of Formula 1 wherein R ⁴ is -N (H) S (O) ₂ N (H) C (O) R ⁷ and R ⁷ is defined above, the compound of Formula 9 is Reacting with a compound of Formula 10;

(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 above.)

R ⁷ C (O) N (H) S (O) ₂ Cl

Wherein R ⁷ is as defined above and proceeds in the presence of a suitable base (sodium hydroxide or triethylamine) and a suitable organic solvent (eg benzene or dichloromethane), for example at room temperature or approximately room temperature. )

(vi) a compound of formula 9 as defined above for the compound of formula 1 above, wherein R ⁴ is -N (H) C (O) N (H) S (O) ₂ R ⁷ and R ⁷ is defined above Reacting with a compound represented by Formula 11;

R ⁷ S (O) ₂ N (H) C (O) OR ^x

(Wherein R ^x is C _1-2 alkyl and R ⁷ is as defined above and proceeds for example in the presence of a suitable organic solvent (eg dichloromethane) at or about room temperature.)

(vii) a compound of formula 9 as defined above for compounds of formula 1 above wherein R ⁴ is -N (H) C (O) N (H) S (O) ₂ R ⁷ and R ⁷ is as defined above; Reacting with an isocyanate compound of Formula 12;

R ⁷ S (O) ₂ NCO

(Wherein R ⁷ is defined above and proceeds the reaction in the presence of a suitable organic solvent (eg dichloromethane), for example at or about room temperature.)

(viii) For the compound of formula 1 wherein R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ and R ⁶ is C _1-6 alkylamino, the compound of formula 2 as defined above Reacting with an isocyanate compound of Formula 13;

R ^6b NCO

Wherein R ^6b is C _1-6 alkyl and reacts in the presence of a suitable base (eg sodium hydroxide or potassium hydroxide) with a suitable organic solvent (eg acetone or acetonitrile), for example at room temperature or approximately room temperature Proceed.)

or

(ix) For compounds of Formula 1 wherein R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ and R ⁶ is di-C _1-6 alkylamino, R ⁴ is -S (O Reacting the corresponding compound of Formula 1 with an amine of Formula 14 wherein ₂ N (H) C (O) R ⁶ and R ⁶ is C _1-6 alkoxy.

R ^6c N (H) R ^6d

Wherein R ^6c and R ^6d are each C _1-6 alkyl and react the reaction in the presence of a suitable organic solvent (eg toluene) at a temperature above room temperature (eg between 70 ° C. and 100 ° C.). Proceed.)

The compound of formula 2 may be prepared by the reaction of a compound of formula 15 with a compound of formula 16:

(Wherein R ⁵ , Z ¹ and Z ² are those defined above or N-protected derivatives thereof)

Wherein L ² is a suitable leaving group such as trimethylsulfonate, 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, for example, suitable coupling systems as well as suitable solvent catalysts (e.g. toluene, ethanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane or mixtures thereof) Palladium catalysts such as Pd (PPh ₃ ) ₄ or Pd (OAc) ₂ / ligand wherein the ligands are for example PPh ₃ , P (o-Tol) ₃ or 1,1′-bis (diphenyl Phosphino) ferrocene)] and a suitable base (e.g. sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or iso -propylamine). At approximately room temperature (for example at the reflux temperature of this solvent system) If a protected version of the compound of formula 15 is used, this reaction may be followed by deprotection of the SO ₂ NH- group under standard conditions, for example, which will be described later. deprotection).

The compound of Formula 2 may also be prepared by the reaction of a compound of Formula 17 with a compound of Formula 18.

(Wherein X ₁ , X ₂ , X ₃ and X ₄ are defined above).

Wherein Y ₁ , Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ , R ⁵ and L ¹ are as defined above (L ¹ may in particular be bromo), or their N- N-protected derivatives, which are reacted in the presence of a suitable base (e.g. potassium hydroxide) and a suitable organic solvent (e.g. DMSO) at approximately room temperature or lower than room temperature. If the protective suited version of the compound of formula 18 used, the reaction may be followed by all the de-protection of the SO ₂ NH- group under standard conditions to be described as such hereinafter. Further, Z ₁ is -CH = CH- And compounds of formula (2) wherein Z ₂ is -CH- can be prepared, for example, according to or similarly to those described in particular in US Pat. No. 5,312,820. Furthermore, Z ₁ is -S- and Z ₂ is -CH- compound of formula 2, for example, particularly the United Kingdom Patent Application No. GB It may be prepared according to the method described in 2281298 or in a similar manner.)

The compound of Formula 5 may be prepared by oxidation of the compound of Formula 19.                 

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 above, for example potassium permanganate or chromium oxide The reaction proceeds under standard oxidizing conditions in the presence of a suitable oxidizing agent such as (VI).)

The compounds of Formulas 7 and 9 may be different from the compounds of Formula 20 (for compounds of Formula 7) or the compounds of Formula 21 (for compounds of Formula 9) Can be prepared by reaction.

[In both formulas above, Z ₁ , Z ₂ and R ⁵ are those defined above or their N-protected derivatives, for example described above for the preparation of the compound of formula 2 (first step) The reaction proceeds under similar conditions. If protected versions of the compounds of formulas 20 and 21 are used, these reactions can be followed by deprotection of the NH-group under standard conditions (eg acid degradation).

The compound of formula 16 may be prepared by standard techniques, for example, by the reaction of a compound of formula 17 as defined above with a compound of formula 22 below.

Wherein Y ₁ , Y ₂ , Y ₃ , Y ₄ , L ¹ and L ² are defined above, for example similar to those described above with respect to the preparation of the compound of formula 2 (second process) The reaction proceeds under conditions.)

Compounds of Formula 18 are known in the art. For example, they may in particular be subjected to or in accordance with the method described in US Pat. No. 5,312,820, UK Patent Application GB 2281298, and / or the reaction of the compound of formula 15 as defined above with the compound of formula 23 Can be prepared by                 

Wherein Y ₁ , Y ₂ , Y ₃ , Y ₄ and L ² are as defined above, for example, the reaction proceeds under conditions similar to those described above with respect to the preparation of the compound of formula 2 (first step) Conversion of an OH group to a suitable leaving group, L ¹ , in its intermediate (e.g., when L ¹ is bromo, the conversion may be a base (e.g. For example triphenylphosphine) and CBr ₄ in the presence of a suitable organic solvent (eg DMF).)

The compound of Formula 19 may be prepared by the reaction of the compound of Formula 16 with the compound of Formula 24 below.

[Wherein Z ₁ , Z ₂ and R ⁵ are those defined above or their protected (in the aldehyde moiety) derivatives, for example described above for the preparation of the compound of formula 2 (first process) The reaction proceeds under similar conditions. If a protected version of the compound of formula 24 is used, this reaction may be followed by deprotection of the CHO- group under standard conditions (eg acid degradation).]

The compounds of Formulas 15, 20, 21, and 24 and their protected derivatives may be prepared by the reaction of the corresponding compounds of Formula 25 below.

Wherein R ^y is —S (O) ₂ NH ₂ , —C (O) NH ₂ , —NH ₂ or —CHO (as appropriate), and R ⁵ , Z ₁ and Z ₂ are as defined above Or their suitable protected derivatives, and having a reagent system for introducing -B (OH) ₂ into a suitable ring system. Suitable reagent systems include trialkylborates (eg tri- iso -propylborate). Such reactions may be carried out at low temperatures (eg between -100 ° C. and 0 ° C., for example between −80 ° C. (eg −78 ° C.) and −10 ° C. (eg −20 ° C.)) (eg n − Butyl lithium) and a suitable organic solvent (eg THF), followed by acid decomposition (eg in the presence of dilute HCl).]

The compound of formula 25 is available using known methods. For example:                 

(a) R ^y is -S (O) ₂ NH ₂ , -C (O) NH ₂ or -CHO, and the compounds of the above-mentioned protected derivatives thereof are compounds of the formula (27) It can be prepared by reaction with.

( ^Wherein R ^ya is -S (O) ₂ NH ₂ , -C (O) NH ₂ or -CHO and Z ₁ and Z ₂ are those defined above or their protected derivatives.)

R ⁵ L ³

Wherein L ³ is a suitable leaving group (e.g. toluenesulfonate, benzenesulfonate, methanesulfonate or halo such as bromo or iodo) and R ⁵ is defined above, e.g. The reaction proceeds in the presence of a suitable base (e.g. n -butyl lithium) and a suitable solvent (e.g. THF).

(b) The compound of formula 25, wherein R ^y is -S (O) ₂ NH ₂ and an N-protected derivative thereof, can be prepared by the reaction of a suitable compound of formula (28).

Wherein R ⁵ , Z ₁ and Z ₂ are as defined above and the -S (O) ₂ NH ₂ group is selected from the appropriate ring system [e.g. chlorosulfonic acid in the presence of a suitable strong base (for example butyl lithium), or Having a suitable reagent system for introduction into thionyl chloride, which can be followed by reaction with ammonia of the intermediate, or its protected derivative (e.g. tert -butylamine), under conditions well known to those skilled in the art.)

(c) any protected derivative of the compound of formula 25 wherein R ^y is -C (O) NH ₂ (eg alkyl protected derivatives such as C _1-6 alkyl, which is tert -butyl) , A compound of formula 28 as defined above may be prepared by reaction with a compound of formula 29.

R ^Z N = C = O

Wherein R ^Z is a suitable protecting group such as, for example, an alkyl group comprising C _1-6 alkyl (such as tert -butyl), for example at low temperatures (e.g. at -78 ° C) To 0 ° C.), the reaction proceeds in the presence of a suitable base (eg n -butyl lithium) and a suitable solvent (eg THF).)

(d) any unprotected derivative of the compound of formula 25 wherein R ^y is -C (O) NH ₂ (e.g., unprotected derivative of alkyl such as C _1-6 alkyl (eg tert -butyl)), Also, under standard binding conditions [e.g., those described above for the preparation of compounds of formula 1 above (step (iii))), R ⁵ , Z ₁ and Z ₂ are defined above, By protection with ammonia (eg tert -butylamine), for example (protected with (C _1-6 ) alkyl (such as for example tert -butyl)) derivatives.

The compound of formula 30 is known in the art or can be prepared by standard techniques, for example by oxidation of the corresponding compound of formula 25 wherein R ^y is -CHO under the conditions described above for the preparation of the compound of formula 5 above. Can be.

(e) wherein the compound of Formula 25 wherein R ^y is -CHOd, Z ₁ is -CH = CH- and Z ₂ is -CH- and its protected derivative, Z ₁ is -CH = CH- under standard conditions; Suitable reagent systems for the introduction of aldehyde groups into the benzene ring of the above formula (28) wherein Z ₂ is -CH- (e.g. TiCl ₄ / CHCl ₃ , SnCl ₄ / CH ₂ Cl ₂ or 1,3,5, 7-azaadamantane / TFA), followed by protection (if appropriate) of benzaldehyde made as above under standard conditions.

(f) The compound of Formula 25 wherein R ^y is -NH ₂ , Z ₁ is -CH = CH- and Z ₂ is -CH- and its N-protected derivative, wherein Z ₁ is -CH = CH- and Z and ₂ can be prepared by nitrification of the compound of formula 28 -CH-, the number (if appropriate) protection of the reduced and aminobenzene that is made and followed by the reaction step of the nitrobenzene after the nitrification These can all be performed under standard conditions.

The compounds of Formulas 3, 4, 6, 8, 10, 11, 12, 13, 14, 17, 22, 23, 26, 27, 28 and 29 are commercially available or known in the literature or described herein It is possible to obtain from readily available starting materials using suitable reagents and reaction conditions by methods analogous to the methods described or by conventional synthesis methods according to standard techniques.

The compounds of the present invention can be separated from their reaction mixtures using conventional techniques.

Those skilled in the art will appreciate that in the methods described above and later, functional groups of intermediate compounds need to be protected by protecting groups.

Functional groups that require protection include sulfonamido, amido, amino and aldehydes. Suitable protecting groups for sulfonamido, amido and amino include tert -butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilethoxycarbonyl (Teoc) or tert -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 (which forms a cyclic acetal). .

Protection and deprotection of functional groups can occur before or after the reaction in the schemes described above.

Protecting groups can be removed by methods that are well known in the art and will be described later. For example, the protected compound-intermediates described herein may be prepared using standard deprotection methods (eg using trifluoroacetic acid, sulfonic acid, toluenesulfonic acid or boron trichloride). Can be chemically converted into an unprotected compound.

One of ordinary skill in the art would appreciate that in order to obtain the compounds of the invention differently and in some cases, in a more convenient way, each process step described above is carried out in a different order and / or each reaction is carried out in the overall route. It will be appreciated that other steps may be performed (e.g., substituents are added to other intermediates than those described above in connection with the particular reaction and / or chemical transformations are applied to such other intermediates). Can be run for This may obviate or eliminate the need for a protector.

This type of chemistry involved will define the need and type of protecting group as well as the sequence to complete the synthesis.

The use of protecting groups is described in JWF McOmie's Protective Groups in Organic Chemistry (Plenum Press (1973)) and T. W. TW Greene and Blood. G. M. PGM Wutz's Protective Groups in Organic Synthesis (3rd edition, Wiley-Interscience (1999)) is fully described.

Medical and Pharmaceutical Uses

The compounds of the present invention are useful because they have pharmaceutical activity. The compounds of the present invention thus act as medicaments.

According to another aspect of the invention, there is provided a compound of the invention for use as a medicament.

In particular, the compounds of the present invention are agents of Ang II, more specifically agents of AT2 receptors, and more particularly, selective agents of their sub-receptors that can be seen in the tests described below.

Therefore, the compounds of the present invention are expected to be useful for conditions in which endogenous production of Ang II is lacking and / or enhanced effect of Ang II is required.

The compounds of the present invention are also expected to be useful for conditions in which AT2 receptors are expressed and their stimulation is required.

Compounds of the present invention may also be used for vasoconstriction, increased cell growth and / or differentiation, increased cardiac contractility, increased cardiovascular hypertrophy, and / or humoral hyperactivity. (indicated in the treatment of conditions characterized by increased fluid and electrolyte retention).

The compounds of the invention also stand out in the treatment of stress-related disorders, and / or in improving microcirculation and / or mucosa-protective mechanisms.

Thus, the compounds of the present invention are as described above and for example, the gastrointestinal tract, cardiovascular system, respiratory tract, kidneys, eyes, female reproductive (ovulation) It is expected to be useful for the treatment of diseases of the system and central nervous system (CNS).

Diseases of the gastrointestinal tract are gastroesophageal (oesophagitis), Barrett-s oesophagus, gastric ulcers, duodenal ulcers, indigestion (including non-ulcer dyspepsia), gastroesophageal reflux (gastro-oesophageal) reflux), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatitis, liver disease (such as hepatitis), gallbladder disease, multiple organ failure (MOF), and pulmonary sepsis. Other gastrointestinal diseases include dry mouth (xerostomia), gastritis, gastroparesis, hyperacidity, biliary tract diseases, coelicia, Crohn-s disease, ulcerative colitis ( ulcerative colitis, diarrhea, constipation, abdominal pain, dysphagia, vomiting, nausea, placebo, and Sjogren-s syndrome.

Diseases of the airways include inflammatory disorders such as asthma, obstructive pulmonary disease (eg chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension and adult respiratory distress syndrome.

Kidney diseases include renal failure, nephritis and renal hypertension.

Diseases of the eye include diabetic retinopathy, premature retinopathy and retinal microvascularisation.

Female reproductive diseases include ovulation disorders.

Renal vascular diseases include hypertension, cardiac hypertrophy, heart failure, artherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, and post-balloons. Post-balloon dilatation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, cardiac arrhythmias, cardiac arrhythmias, claudicatiointermittens, preeclampsia preeclampsia, myocardial infarction, reinfarction, ischemic lesions, erectile dysfunction and neointima proliferation.

CNS diseases include cognitive dysfunction, dysfunction of food intake (hunger / hunger), thirst, stroke, cerebral hemorrhage, cerebral embolus and cerebral infarction.                 

The compounds of the present invention may also be useful for the regulation of growth metabolism and proliferation, for example hypertrophic disorders, prostate hyperplasia, autoimmune disorders, psoriasis, obesity , Neuronal regeneration, ulcer treatment, adipose tissue hyperplasia, period cell differentiation and proliferation, cancer (eg in gastrointestinal tract, lung cancer, etc.), apoptosis, tumors (usually) and hypertrophy, It is the treatment of diabetes mellitus, neuronal lesions and organ rejection.

Compounds of the present invention stand out in both therapeutic and / or prophylactic treatment of the above conditions.

According to another aspect of the present invention, a condition in which endogenous production of Ang II is insufficient and / or conditions in which an increase in the effect of Ang II is required, and / or a condition in which an AT2 receptor is expressed and its stimulation is required A method of treatment is provided, the method comprising administering a therapeutically effective amount of a compound of the invention to a person suffering from or susceptible to such conditions.

The compounds of the present invention are usually orally, intravenously, subcutaneously, orally, rectally, skinly, nasal, tracheally, bronchically, in other parenteral routes, or in inhalation. By pharmaceutically acceptable dosage form.

When the condition to be treated is multiple organ failure, the preferred route of administration is parenteral (eg by injection). Otherwise, the preferred route of administration of the compounds of the invention is mouth.

The compounds of the present invention may be administered alone, but may be tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration. It is preferably administered in the form of a known pharmaceutical formulation, including the like.

Such pharmaceutical preparations may be prepared according to standard and / or accepted pharmaceutical practices.

According to another aspect of the invention, there is provided as an example a pharmaceutical formulation comprising a compound of the invention and mixed with a pharmaceutically acceptable adjuvant, diluent or carrier.

The compounds of the present invention may also be administered with AT1 receptor antagonists known in the art, such as losartan or with inhibitors of angiotensin converting enzymes, as well as with other AT2 agonists known in the art.

According to another aspect of the present invention,

(A) a compound of the present invention; And

(B) comprises an AT1 receptor antagonist, or an ACE inhibitor,

There is provided a combination product wherein (A) and (B) elements are each mixed with a pharmaceutically acceptable adjuvant, diluent or carrier.

Such binding products are provided for co-administration of a compound of the invention with an AT1 receptor antagonist, or an ACE inhibitor, and thus

At least one of such formulations may be comprised comprising a compound of the invention, at least one may be comprised of an AT1 receptor, or an ACE inhibitor, or may be provided (eg, formulated) as a combined preparation. Provided in a single dosage form comprising a compound of the invention and an AT1 receptor antagonist or ACE inhibitor.

Therefore, the following is further provided:

(1) a pharmaceutical formulation comprising a compound of the invention and an AT1 receptor antagonist, or an ACE inhibitor, mixed with a pharmaceutically acceptable adjuvant, diluent or carrier; And

(2) (a) a pharmaceutical formulation comprising a compound of the invention, admixed with a pharmaceutically acceptable adjuvant, diluent or carrier; And

(b) a pharmaceutical formulation comprising an AT1 receptor antagonist, or an ACE inhibitor, mixed with a pharmaceutically acceptable adjuvant, diluent or carrier; Composed of ingredients,

A kit of parts, wherein the components (a) and (b) are each provided in a form suitable for administration together.

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

Although the dosage varies from patient to patient, suitable daily dosages range from about 1 to 1000 mg per patient and are administered in single or multiple doses, with more preferred daily dosages ranging from 2.5 to 250 mg per patient.

Individual dosages of the compounds of the present invention may range from 1 to 100 mg.

In any event, the physician or person skilled in the art will be able to determine the actual dosage best suited for each patient, which dosage will depend on the age, weight, sex and response of the particular patient to be treated as well as the condition to be treated. The above dosages are illustrative of the usual cases, and there may be unusual cases where more or less ranges of dosage are desired and are of course within the scope of the present invention.

The compounds of the present invention have the advantage of selectively binding to AT2 receptors and exhibiting agonist activity. With compounds that selectively bind to AT2 receptors, the affinity ratio [AT2: AT1] to the corresponding compound is at least 5: 1, preferably at least 10: 1, more preferably Thinks it is at least 20: 1.

The compounds of the present invention are also more effective, less toxic, longer acting, more potent, produce less byproducts, more easily absorbed and / or better than compounds known in the prior art. Have a pharmacokinetic profile (eg, higher oral bioavailability and / or lower clearance), and / or other useful pharmaceutical, physical, or chemical properties. There is an advantage.

Biological test

The following test procedures may be used.

Exam A

Receptor Binding Assay Using Rat Membrane AT1 Receptor

Mice were prepared according to the method of Dudley et al . ( Mol. Pharmacol. (1990) 38 , 370). 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, 10 mM MgCl ₂ , 1 mM EDTA, 0.025% bacitracin, 0.2% BSA (bovine serum albumin), In a final volume of 0.5 mL solution containing [ ¹²⁵ I] Ang II (70 000 cpm, 0.03 nM) and various concentrations of test substance in a liver homogenate corresponding to 5 mg of the original tissue weight [ ¹²⁵ I] Ang II was bound to the membrane. Samples were incubated at 25 ° C. for 1 hour and filtered by filtration through Whatman GF / B glass-fiber filter sheets using a Brandel cell harvester. The binding has ended. The filters were washed with 4 × 2 mL of Tris-HCl (pH 7.4) and then transferred to the tube. Radioactivity was measured on a gamma counter. The properties of Ang II binding AT ₁ receptors were measured (determined) using labeled [ ¹²⁵ I] Ang II at six different concentrations (0.03-5 nmol / L). Non-specific binding was measured in the presence of 1 μM Ang II. Specific binding was measured by subtracting non-specific binding from the total bound [ ¹²⁵ I] Ang II. Dissociation constant ( K _d = 1.7 ± 0.1 nM, [L] = 0.057 by Scatchard analysis of data obtained with Ang II using GraFit (Erithacus software, UK) nM) was measured. The binding data best matched the one-site fit. All tests were run at least three times.

Exam B

Receptor binding assay using porcine myometrial membrane AT2 receptor

Clin, Nielsen et al. Exp. Pharm. Phys. [1997] 24 , 309] was prepared according to the method according to the method according to the [[1997] 24 , 309]. Potential interference that may be manifested by the binding of the compound to the AT1 receptor was blocked by the addition of 1 μM of a selective AT1 inhibitor. 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 10 mM MgCl ₂ , 1 mM EDTA, 0.025% Bacitracin, 0.2% BSA, homogenate equivalent to 10 mg of original tissue weight And [ ¹²⁵ I] Ang II (70 000 cpm, 0.03 nM) and [ ¹²⁵ I] Ang II in a final volume of 0.5 mL solution containing various concentrations of test substances. Samples were incubated at 25 ° C. for 1 hour, and filtered by filtration through Whatman GF / B glass-fiber filter sheets using a Brandel cell harvester. The bond is terminated. The filters were washed with 3 × 3 mL of Tris-HCl (pH 7.4) and then transferred to the tube. Radioactivity was measured on a gamma counter. The properties of Ang II binding AT ₂ receptors were measured using labeled [ ¹²⁵ I] Ang II at six different concentrations (0.03-5 nmol / L). Non-specific binding was measured in the presence of 1 μM Ang II. Specific binding was measured by subtracting non-specific binding from the total bound [ ¹²⁵ I] Ang II. Dissociation constant ( K _d = 0.7 ± 0.1 nM, [L] = 0.057 by Scatchard analysis of data obtained with Ang II using GraFit (Erithacus software, UK) nM) was measured. The binding data best matched the one-site fit. All tests were run at least three times.

Exam C

Duodenal Mucosal Alkaline Secretion Assay

Flemstrom et al. Am. Barbiturate-anaesthetised rats prepared for in situ titration of duodenal mucosal alkaline secretion according to the systematic method described in J. Physiol . [(1982) 243 , G348]. Compounds were exposed to the duodenum mucosa.

The invention is illustrated by the following examples.

Example 1

N -Butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-iso-butylthio-phene-2-sulfonamide

(a) N -tetra-tert-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 tert-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 for 1 hour at room temperature and then for 10 minutes in reflux. Toluene (700 mL) was added and the organic phase was washed with water (3 × 50 mL), dried and concentrated in vacuo. Sub-title product was used without further purification in the next step.

¹ H NMR δ (CDCl ₃ ): 7.60 (1H, dd, J = 1.3, 3.8 Hz), 7.53 (1H, dd, J = 1.3, 5.0 Hz), 7.02 (1H, dd, J = 5.0, 3.8 Hz) , 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-iso-butyl- N -tert-butylthiophene-2-sulfonamide

N-tert-butylthiophene-2-sulfonamide (10 g, 0.046 mol, see step (a) above) was dissolved in THF (85 mL) under N ₂ atmosphere and then cooled to -78 ° C. n- BuLi (1.6 M, 76.9 mL, 0.12 mol) was added by 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 mixture was quenched with NH ₄ Cl (solution) and extracted with EtOAc. The combined organic phase was washed with brine, dried and concentrated in vacuo. The crude product was purified by column chromatography [hexanes: EtOAc (10: 1)] to afford the side product in 55% yield (7.0 g, 0.025 mol).

¹ H NMR δ (CDCl ₃ ): 7.43 (1H, d, J = 3.6 Hz), 6.67 (1H, d, J = 3.8 Hz), 4.83 (1H, m), 2.67 (2H, d, J = 7 Hz ), 1.88 (1H, m), 1.26 (9H, m), 0.93 (6H, J = 6.6 Hz). ¹³ C NMR δ (CDCl ₃ ): 145.0, 131.7, 131.2, 127.0, 55.1, 29.9

(c) 5- iso -butyl-2- (N-tert-butylaminosulfonyl) thiophene-3-boronic acid

5-iso-butyl - N EtOAc (3 x 100 mL ) -EtOAc (3 x 100 mL) EtOAc (3 x 100 mL) tert t-butyl-thiophene-2-sulfonamide (10.6 g, 0.039 mol, (b ) Was dissolved in THF (165 mL) under N ₂ atmosphere and then cooled to -78 ° C. n- BuLi (1.6 M, 60.19 mL, 0.096 mol) was added by syringe. The reaction mixture was stirred for 4 h at -20 ° C. Tri-iso-propylborate (13.3 mL, 0.058 mol) was then added by syringe and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 2 M HCl (20 mL). The organic phase was separated and the water phase was extracted with EtOAc (3 × 100 mL). This combined organic phase was 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; Dryied over 4A molecular sieve] was added to potassium hydroxide [2.24 g, 0.04 moles, ground pellets] 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 cooled briefly and stirred for an additional hour before adding water (20 mL). The mixture was extracted with ether (3 X 100 mL) and each extract was washed with water (3 X 50 mL). This combined ether layer was dried over CaCl ₂ and the solvent was removed in vacuo. The residue was chromatographed with silica gel as eluent CHCl ₃ : MeOH (30: 1) plus 0.05% formic acid to give the side 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-iso-butyl- N -tert-butylthiophene-2-sulfonamide

5- iso -butyl-2- (N- tert -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), sodium chloride (1.0M, 1.5 mL, 1.5 mmol) and Pd (PPh ₃ ) ₄ (14.5 mg, 0.125 mmol) was mixed under N ₂ atmosphere. The mixture was heated at 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 to obtain 113.9 mg of the side product (yield: 63.27%) and the residue was separated by column chromatography with chloroform: methanol (20: 1) as eluent.

IR (neat): 3060, 2996, 1507 cm ^-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 = 7.1 Hz), 1.64 (1H, m) , 0.73 (9H, s), 0.72 (6H, d, J = 6.9 Hz)

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 Anal. Calcd. for C ₂₂ H ₂₉ N ₃ O ₂ S ₂ : 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-iso-butylthiophene-2-sulfonamide

Trifluoroacetic acid (2 mL) was added 3- (4-imidazol-1-ylmethylphenyl) -5- iso -butyl- N - tert -butylthiophene-2-sulfonamide (113 mg, 0.2618 mmol, To step (e)) and a drop of anisole (about 0.05 mL) was added to the mixture. The reaction mixture was stirred for 30 hours under N ₂ atmosphere and then evaporated and co-evaporated with acetonitrile until TLC showed that it was pure. The crude product was used directly 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 = 7.1 Hz), 2.62 (H, brs), 1.94 (1H, m), 0.97 (6H, d, J = 6.6 Hz)

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-imidazol-1-ylmethylphenyl) -5-iso-butylthio-phene-2-sulfonamide

The crude 3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophene-2-sulfonamide of step (f) was dissolved in pyridine (2 mL, dried with 4 'molecular sieve). 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 min crisis. Evaporation to remove solvent and cross-evaporation with acetonitrile and column chromatography using 10% MeOH in chloroform as eluent gave the title compound 46.5% yield [over the last two steps] (57.8). mg, 0.1217 mmol).

IR (neat): 3555.8, 3120.3, 2955.9, 1694.2, 1268.5 cm ^-1

¹ H NMR δ (CDCl ₃ ): 7.96 (1 H, 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 = 6.6 Hz), 2.71 (2H, d, J = 7.1 Hz), 1.94 (1H, m), 1.51 (2H, m), 1.25 (2H, m), 0.98 (6H, d, J = 6.6 Hz), 0.87 (3H, t, J = 7.4 Hz)

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 Anal. Calcd 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 -Iso-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-iso-butyl-thiophen-2-sulfonamide

30 mg of crude 3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophen-2-sulfonamide (see Example 1 (f) above) was converted to pyridine (1 mL, 4 ′ molecules). Sieve) and cooled with ice. Then pyrrolidinopyridine (11.8 mg, 0.080 mmol) and iso -butyl chloroformate (103.6 µL, 0.80 mmol) were added to the mixture. The mixture was stirred overnight at 50 ° C. N ₂ atmosphere. Evaporation to remove the solvent and cross-evaporation with acetonitrile followed by purification by column chromatography using 10% MeOH in chloroform as eluent yielded 71% of the title compound (27 mg, 0.057 m). Mole).

¹ H NMR δ (CD ₃ OD): 8.18 (brs, 1 H), 7.58 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 7.29 (brs, 1H), 7.17 ( brs, 1H), 6.82 (s, 1H), 5.30 (s, 2H), 3.70 (d, J = 6.6 Hz, 2H), 2.72 (d, J = 7.1 Hz, 2H), 1.93 (m, 1H), 1.76 (m, 1H), 0.99 (d, J = 6.6 Hz, 6H), 0.81 (d, J = 7.4 Hz, 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 -Iso-propyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-iso-butyl-thiophene-2-sulfonamide

100 mg of crude 3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophen-2-sulfonamide (see Example 1 (f) above) was converted to pyridine (4 mL, 4 ′ molecules). Sieve) and cooled with ice. Then pyrrolidinopyridine (39.5 mg, 0.266 mmol) and iso -propyl chloroformate (1M in toluene, 2.66 mL, 2.66 mmol) were added to the mixture. The mixture was stirred overnight at 50 ° C. N ₂ atmosphere.

Co-evaporation with evaporation and acetonitrile to remove solvent followed by preparative LC / MS [30% acetonitrile to pure acetonitrile, reverse phase] This obtained the target compound (52.6 mg, 0.114 mmol).

¹ H NMR δ (CD ₃ OD): 8.16 (brs, 1 H), 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 (sep, J = 6.3 Hz, 1H), 2.73 (d, J = 7.1 Hz, 2H), 1.94 (m, 1H), 1.09 (d, J = 6.3 Hz, 6H), 1.00 (d, J = 6.6 Hz, 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-iso-butylthiophene-2-sulfonamide

CDI (1,1′-carbonyl-diimidazole, 129.5 mg, 0.80 mmol) was added to a butoxyacetic acid solution (103.8 μL, 0.80 mmol) of dry THF (4 mL). The mixture was stirred at 50 ° C. for 2.5 hours. DBU of 3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophene-2-sulfonamide solution (see Example 1 (f) above; 100 mg) solution and dry THF (4 mL) (1,8-diazabicyclo [5.4.0] undec-7-ene, 19.9 (L, 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 and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with water (3 X 50 mL). The organic phase was dried and evaporated. The crude product was purified by column chromatography using CHCl ₃ with 10% MeOH as eluent to afford the desired product (27 mg, 0.057 mmol).

¹ H NMR δ (CD ₃ OD): 7.96 (brs, 1 H), 7.66 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 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 = 6.8 Hz, 2H), 2.66 (d, J = 6.9 Hz, 2H ), 1.88 (m, 1H), 1.48 (m, 2H), 1.29 (m, 4H), 0.96 (d, J = 6.6 Hz, 6H), 0.82 (t, J = 7.3 Hz, 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 tert-butylamide

N - tert -butylthiophene-2-sulfonamide (5 g, 0.0228 mol, see Example 1 (a) above) was dissolved in THF (43 mL) under N ₂ atmosphere and then cooled to -78 ° C. n- BuLi (1.6 M, 38.5 mL, 0.062 mol) was added using a syringe. The reaction mixture was stirred at −78 ° C. for 30 minutes and then at −40 ° C. for 2 hours. Iodo-butane [5.19 mL, 0.046 mol] was added dropwise to the reaction mixture. The reaction mixture was stirred at rt overnight, quenched with NH ₄ Cl (solution) and extracted with EtOAc. This combined organic phase was washed with brine, dried and concentrated in vacuo. The crude product was purified by column chromatography (Hex: EtOAc 10: 1) to afford the desired compound (2.92 g, 0.011 mol) in 46% yield.

¹ H NMR δ (CDCl ₃ ): 7.41 (d, J = 3.6 Hz, 1H), 6.69 (d, J = 3.8 Hz, 1H), 4.96 (m, 1H), 2.80 (d, J = 7.6 Hz, 2H ), 1.65 (m, 2H), 1.37 (m, 2H), 1.26 (s, 9H), 0.92 (t, J = 7.26 Hz, 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- ( N-tert -butylaminosulfonyl) thiophene-3-boronic acid

5- butylthiophene -2-sulfonic acid tert -butylamide (2.9 g, 0.010 mol, see step (a) above) was dissolved in THF (40 mL) under N ₂ atmosphere and then cooled to -78 ° C. n- BuLi (1.6 M, 16.2 mL, 0.026 mol) was added by syringe. The reaction mixture was stirred at -20 ° C for 4 hours. Tri- iso -propylborate (13.3 mL, 0.058 mol) was then added by syringe and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 2 M HCl (20 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 X 100 mL). This combined organic phase was 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- N -tert-butylthiophene-2-sulfonamide

5-Butyl-2- ( N-tert -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), sodium hydroxide (1.0 M, 4.0 mL, 5.1 mmol) and Pd (PPh ₃ ) ₄ (43.9 mg, 0.038 mmol) were mixed under N ₂ atmosphere. 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 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 added to crude 3- (4-imidazol-1-ylmethylphenyl) -5-butyl- N - tert - butylthiophene -2- from step (c). To the sulfonamide was added and a drop of anisole (about 0.05 mL) was added to the mixture. The reaction mixture was stirred for 30 h under N ₂ atmosphere and then evaporated and co-evaporated with acetonitrile. The crude product was purified by column chromatography to give [CH ₂ Cl ₂ : MeOH (20: 1)] side product (232 mg, 0.62 mmol) from [1- (4-bromobenzyl) -1H-imidazole. ] Obtained at 49% yield.

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 = 7.26 Hz, 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-butylthio-phen-2-sulfonamide

3- (4-imidazol-1-ylmethylphenyl) -5-butylthiophene-2-sulfonamide (232 mg, 0.62 mmol, see step (d) above) pyridine (3 mL, dried with 4 'molecular sieve) Dissolved in. Pyrrolidinopyridine (91.6 mg, 0.618 mmol) and butyl chloroformate (785.7 μL, 0.618 mmol) were added to the mixture. The mixture was stirred overnight under room temperature N ₂ atmosphere. 10% yield of the desired product by evaporation to remove solvent and cross-evaporation with acetonitrile followed by column chromatography using 10% MeOH as eluent in chloroform as the eluent. Got it.

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 = 6.3 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 1.68 (m, 1H), 1.44 (m, 4H), 1.26 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H), 0.87 (t, J = 7.3 Hz, 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-iso-butylbenzene-sulfonamide

(a) N -tert-butyl-4-iso-butylbenzenesulfonamide

Chlorosulfonic acid (28.6 mL, 0.43 mol) was added dropwise to iso-butylbenzene (11.14 g, 0.083 mol) stirred at 0 ° C. The reaction mixture was heated at 40 ° C. for 0.5 h and then 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 was added tert-butylamine was added drop becomes a (43.7 mL, 0.416 mol). The reaction was heated for 10 minutes to reflux 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 by column chromatography using hexanes: acetone (4: 1) as eluent gave the sub-purpose compound as a white solid (12.0 mg, 0.045 mol) in 54% yield.

IR (neat, cm ^-1 ) ν3266, 2960, 2925, 2871, 1597, 1455

¹ H NMR δ (CDCl ₃ ): 7.84 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 5.11 (brs, 1H), 2.55 (d, J = 7.3 Hz, 2H ), 1.90 (m, 1H), 1.65 (m, 2H), 1.21 (s, 9H), 0.92 (d, J = 6.6 Hz, 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

Anal. Cald for C ₁₄ H ₂₃ NO ₂ S: C, 62.42; H, 8.61; N, 5.20; 0, 11.88; S, 11.90; Found: C, 62.2; H, 8.5; N, 5.2

(b) 4-iso-butyl-2- ( N -tert-butylaminosulfonyl) benzene-3-boronic acid

To a solution of N - tert -butyl-4- iso -butyl-benzenesulfonamide [2.69 g, 10 mmol, see step (a) above] in THF (50 mL) under N ₂ (g) atmosphere at −78 ° C., n- BuLi (15.6 mL, 1.6 M, 25 mmol) was added dropwise. The temperature was gradually raised to 0 ° C. over 2 hours and then held at that temperature for 30 minutes. The reaction mixture was then cooled to −40 ° C. and tri- iso -propylborate (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 water 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- iso -butyl- N - tert -butylbenzene-sulfonamide

See crude product (1.2 g, 3.83 mmol) of step (b) and 1- (4-bromo-benzyl) -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) in N ₂ (g) min. Mix under crisis. 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 by column chromatography using CHCl ₃ : MeOH (20: 1) as eluent gave the sub-object compound (93.7 mg, 0.220 mmol) in 53% yield.

IR (neat, cm ^-1 ) v3379, 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 = 7.1 Hz, 2H), 1.90 (m, 1H), 1.01 (s, 9H), 0.93 (d, J = 6.6 Hz, 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- iso -butylbenzene-sulfonamide

2- (4-imidazol-1-ylmethylphenyl) -4- iso -butyl- N - tert -butylbenzene-sulfonamide (0.211 mmol) of CH ₂ Cl ₂ (5 mL) under N ₂ (g) atmosphere. , 90.0 mg, see step (c) above) was added BCl ₃ (1.5 mL, 1M, 1.5 mmol). The mixture was stirred for 0.5 hour. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine, dried over MgSO ₄ and the solvent was removed in vacuo. The crude product was used directly in the next step without further purification.

(e) N -butyloxycarbonyl-2- (4-imidazol-1-ylmethylphenyl) -4- iso -butyl-benzenesulfonamide

The crude product of step (d) was dissolved in pyridine (2 mL, dried with 4 cc molecular sieve). Pyrrolidinopyridine (36 mg, 0.024 mmol) and butyl chloroformate (276 μL, 2.23 mmol) were added to the mixture and stirred for 30 hours under an atmosphere of N ₂ (g) at room temperature. The solvent was removed in vacuo and then co-evaporated with acetonitrile. CHCl ₃ : Purified by column chromatography using MeOH (10: 1) as eluent to afford the desired product (66.7 mg, 0.142 mmol) [2- (4-imidazol-1-ylmethylphenyl) -4- iso- From butyl- N - tert -butylbenzene-sulfonamide].

IR (neat, cm ^-1 ) ν3129, 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 = 6.5 Hz, 2H), 2.56 (d, J = 7.1 Hz, 2H), 1.93 (m, 1H), 1.41 (m, 2H), 1.21 (m, 2H), 0.93 (d, J = 6.6 Hz, 6H), 0.85 (t, J = 7.1 Hz, 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- Iso -Butyl-3- (4-tetrazol-2-ylmethylphenyl) thio-phen-2-sulfonamide

(a) 3- (4-hydroxymethylphenyl) -5- iso -butyl- N - tert - butylthiophene -2-sulfon-amide

5- iso -butyl-2- (N- tert -butylaminosulfonyl) thiophene-3-boronic acid (319.3 mg, 1.00 mmol, see Example 1 (c) above) and 4-bromobenzyl alcohol (374.1 mg, 2.00 mmol), toluene (20 mL), ethanol (4 mL), NaOH (1.0M, 4 mL, 4 mmol) and Pd (PPh ₃ ) ₄ (34 mg, 0.030 mmol) ) Were mixed with each other under a nitrogen atmosphere. The mixture was heated to reflux for 2 hours and 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 (40: 1) as eluent to afford 289 mg of sub-purpose compound (yield: 76%).

IR (neat): 3465, 3162, 2952, 2867, 1441 cm ^-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 = 7.1 Hz), 1.92 (1H, m), 0.99 (6H, d, J = 7.2 Hz), 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

Anal. Calcd for C ₁₉ H ₂₇ NO ₃ S ₂ : C, 59.8; H, 7.3; N, 3.7. Found: C, 59.6; H, 7.0; N, 3.5

(b) 3- (4-bromomethylphenyl) -5- iso -butyl- N - tert - butylthiophene -2-sulfon-amide

3- (4-hydroxymethylphenyl) -5- iso -butyl- N - tert - butylthiophene -2-sulfon-amide (280 mg, 0.734 mmol, see step (a) above) in DMF (10 mL) Dissolved in. PPh ₃ (459.2 mg, 1.75 mmol) and CBr ₄ (580.3, 1.75 mmol) were added to this solution. The mixture was stirred 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 . The solvent was removed and the residue was purified by column chromatography using hexanes: acetone (5: 1) as eluent to afford the sub-target compound (314.9 mg, 0.709 mmol, 76% yield).

IR (neat): 3302, 2952, 2866, 1442 cm ^-1

¹ H NMR δ (CDCl ₃ ): 7.62 (2H, d, J = 8.4 Hz), 7.48 (2H, d, J = 8.4 Hz), 6.75 (1H, s), 4.56 (2H, s), 4.11 (1H) , brs), 2.69 (2H, d, J = 7.1 Hz), 1.92 (1H, m), 0.99 (6H, d, J = 7.2 Hz), 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- iso -butyl- N - tert -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 4A molecular sieve) and stirred for 5 minutes. Tetrazole (28.0 mg, 0.4 mmol) was added to the mixture and then stirred for 2 hours. 3- (4-bromomethylphenyl) -5- iso -butyl- N - tert - butylthiophene -2-sulfonamide [130 mg, 0.292 mmol, see step (b) above] was added and the mixture was briefly stirred. Cool and stir for an additional hour before adding water (50 mL). The reaction mixture was extracted with ethyl acetate (250 mL) and the extract was washed with water (2 X 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 hexanes: acetone (3: 1) as eluent to afford the sub-object compound (28.6 mg, 0.066 mmol, 23% yield).

IR (neat): 3328, 3134, 2980, 1501, 1466 cm ^-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 = 7.1 Hz), 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

Anal. Calcd for C ₂₀ H ₂₇ N ₅ O ₂ S ₂ (H ₂ O: C, 53.2; H, 6.5; N, 15.5.Found: C, 53.7; H, 6.1; N, 15.2

(d) 5- iso -butyl-3- (4-tetrazol-2-ylmethylphenyl) thiophene-2-sulfonamide

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

(e) N -butyloxycarbonyl-5- iso -butyl-3- (4-tetrazol-2-ylmethylphenyl) thio-phen-2-sulfonamide

The crude product of step (d) was dissolved in pyridine (1 mL, dried with 4 cc molecular sieve). Pyrrolidinopyridine (14 mg, 0.0095 mmol) and butyl chloroformate (120 μL, 0.97 mmol) were added to the mixture and then stirred at room temperature under N ₂ (g) atmosphere for 30 hours. The solvent was removed in vacuo and then co-evaporated with acetonitrile. Purification by column chromatography using CHCl ₃ : MeOH (35: 1) as eluent gave the desired product (24.9 mg, 0.052 mmol) (5- iso -butyl- N - tert -butyl-3- (4-tetrazole). From -2-ylmethylphenyl) thiophen-2-sulfonamide).

IR (neat): 3330, 2961, 2875, 1743, 1466 cm ^-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 = 6.6 Hz), 2.70 (2H, d, J = 7.1 Hz), 1.91 (1H, m), 1.50 (2H, m), 1.24 (2H, m), 0.98 (6H, d, J = 6.9 Hz), 0.87 (3H, J = 7.4 Hz)

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

Anal. Calcd for C ₂₁ H ₂₇ N ₅ O ₄ S ₂ : C, 52.8; H, 5.7; N, 14.7. Found: C, 53.0; H, 5.8; N, 14.1

Example 8

N -Butyloxycarbonyl-5- Iso -Butyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide

(a) 1- (4-bromobenzyl) -1 H -tetrazole

Dimethyl sulfoxide (10 mL, dried over 4A molecular sieve) was added to potassium hydroxide (1.12 g, 0.02 mol, ground pellet) and the mixture was stirred for 5 minutes. 1 H -tetrazole (0.35 g, 0.005 mol) was added and the mixture was stirred for 2 hours. 4-bromobenzyl bromide (1.87 g, 0.0075 moles) was added and the mixture was cooled for a while and stirred further before adding water (50 mL). The mixture was extracted with ether (3 X 80 mL) and each extract was washed with water (3 X 50 mL). The combined ether layer was dried over MgSO ₄ and the solvent was removed in vacuo. The residue was chromatographed on silica gel with CHCl ₃ : MeOH (40: 1) as eluent to afford the sub-purpose 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

Anal. Calcd. 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- iso -butyl- N - tert -butyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide

5- iso -butyl-2- (N- tert -butylaminosulfonyl) thiophene-3-boronic acid (401.0 mg, 1.256 mmol, see Example 1 (c) above), and 1- (4-bro Mobenzyl) -1 H -tetrazole (199.4 mg, 0.834 mmol, see step (a) above), toluene (20 mL), ethanol (3.0 mL), NaOH (1.0M, 5.0 mL, 5.0 m) Moles) and Pd (PPh ₃ ) ₄ (29.0 mg, 0.25 mmol) were mixed under N ₂ atmosphere. 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 afford 222.4 mg of sub-purpose compound (yield: 62%).

IR (neat): 3284, 3134, 2958, 2870, 1513, 1436 cm ^-1

¹ H NMR δ (CDCl ₃ ): 8.71 (1H, s), 7.64 (2H, d, J = 8.3 Hz), 7.40 (2H, d, J = 8.3 Hz), 6.74 (1H, s), 5.65 (2H , s), 2.67 (2H, d, J = 7.1 Hz), 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- iso -butyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide

BCl ₃ (1.0 mL, 1M, 1.0 mmol) in N ₂ (g) atmosphere was dissolved with 5 iso -butyl- N - tert -butyl-3- (4-tetrazol-1) in CH ₂ Cl ₂ (10 mL). -Ylmethylphenyl) thiophene-2-sulfonamide (177.0 mg, 0.408 mmol, see step (b) above) was added to the solution and the reaction mixture was stirred for 0.5 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3 X 50 mL). The combined organic phases were washed with brine, dried over MgSO ₄ and the solvent was removed in vacuo. The crude product was used directly in the next step without further purification.

(d) N -butyloxycarbonyl-5- iso -butyl-3- (4-tetrazol-1-ylmethylphenyl) thio-phen-2-sulfonamide

The desired compound was prepared in the same manner as described in Example 7 (e) from crude 5- iso -butyl-3- (4-tetrazol-1-ylmethylphenyl) -thiophene-2-sulfonamide in step (c). Prepared similarly to [89.6 mg, 0.188 mmol, (from 5- iso -butyl- N - tert -butyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide) 46% Yield].

IR (neat): 3135, 2959, 2875, 1747, 1464 cm ^-1

¹ H NMR δ (CDCl ₃ ): 8.73 (1H, s), 7.43 (2H, d, J = 7.7 Hz), 7.24 (2H, d, J = 7.7 Hz), 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 = 6.9 Hz) , 0.83 (3H, J = 6.8 Hz)

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

Anal. Calcd for C ₂₁ H ₂₇ N ₅ O ₄ S ₂ x½H 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- Iso -Butyl-thiophene-2-sulfonamide

(a) 1- (4-bromobenzyl) -1 H- [1,2,4] triazole

DMF and KOH (3.3 g, 58 mmol) were stirred each other for 5 minutes before 1,2,4-triazole (1 g, 14.5 mmol) was added. After 30 minutes more, the reaction mixture was cooled to 0 ° C. and 1-bromo-4-bromomethyl-benzene (7.2 g, 29 mmol) was added dropwise for 5 minutes. The reaction mixture was heated to 60 ° C., cooled, extracted with ethyl acetate and water, and dried over K ₂ CO ₃ . The solvent was evaporated to yield yellow-white crystals, and 0.60 g of the sub-purpose compound was obtained as a white crystal with repeated recrystallization (ethyl acetate / isohexane) (62% yield).

¹ H NMR δ (270 MHz, CDCl ₃ ): 8.11 (s, 1H), 7.96 (s, 1H), 7.51-7.38 (m, 2H), 7.15-7.10 (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- iso -butyl- N - tert -butylthio- phen -2-sulfonamide

5- iso -butyl-2- (N- tert -butylaminosulfonyl) thiophene-3-boronic acid (0.479 g, 1.5 mmol, see Example 1 (c) above) and 1- (4-bro Mobenzyl) -1 H- [1,2,4] triazole (0.238 g, 1 mmol, see step (a) above), Pd (OAc) ₂ (15.7 mg, 0.03 mmol), triphenyl Phosphine (15.7 mg, 0.06 mmol) and NaOH (0.16 g, 4 mmol) were dissolved in 4 mL of toluene / ethanol (4: 1) in a thick walled glass tube and then 80 ° C. for 1 hour. Heated to The reaction mixture was cooled, extracted with ethyl acetate and water and dried over K ₂ CO ₃ . The solvent was evaporated and the reaction mixture was separated by silica column [dichloromethane + 1% methanol to (to) dichloromethane + 4% methanol] to yield 0.288 g of sub-purpose product (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 (7 Hz, 2H), 1.89 (sept J (7 Hz, 1H), 0.96 (s, 9H), 0.94 (d, J (7 Hz, 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- iso -butylthiophen-2-sulfon-amide

3- (4- [1,2,4] triazol-1-ylmethylphenyl) -5- iso -butyl- N - tert -butylthiophene-2-sulfonamide (146.4 mg, 0.34 mmol, (b) Step)) was mixed with BCl ₃ (1M hexane solution) (2 mL, 1.7 mmol) in 5 mL of dichloromethane and stirred for 1 h. The reaction mixture was extracted with ethyl acetate and water and dried over K ₂ CO ₃ . The product which evaporated the solvent was pure enough to be used directly in the next step.

(d) N -butyloxycarbonyl-3- (4- [1,2,4] triazol-1-ylmethylphenyl) -5- iso -butyl-thiophene-2-sulfonamide

59 mg (0.16 mmol) of crude 3- (4- [1,2,4] triazol-1-ylmethylphenyl) -5- iso -butylthiophene-2-sulfonamide in step (c) Mix with butyl chloroformate (31 μL, 0.24 mmol), 5 mL of triethylamine 4-dimethylaminopyridine (2 mg, 16 μmol) at ° C. The reaction mixture was stirred overnight and then diluted with ethyl acetate, washed with water and dried over K ₂ CO ₃ . The reaction mixture was then separated by silica column (dichloromethane + 15% methanol), circulation chromatography (dichloromethane + 10-15% methanol) and preparative LC-MS to give 7.0 mg of the desired compound (9% yield yield). ).

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 = 7 Hz, 2H), 2.71 (d, J = 7 Hz, 2H), 1.95 (sept, J = 7 Hz, 1H), 1.52 (pent, J = 7 Hz, 2H), 1.26 (sext, J = 7 Hz, 2H), 0.99 (d, J = 7 Hz, 6H), 0.88 (t, J = 7 Hz, 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 intensity 30 eV] 477 (M ⁺ + 1)

Example 10

N -(Butylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- Iso -Butyl-thiophene-2-sulfonamide

(a) 1- (4-bromobenzyl) -1H-imidazole

Dimethyl sulfoxide (20 mL, dried with 4 μg molecular sieve) 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 allowed to cool for a while and stirred for an additional time before adding water (20 mL). The mixture was extracted with ether (3 × 100 mL) and each extract was washed with water (3 × 50 mL). The combined ether layer was dried over CaCl ₂ and the solvent was removed in vacuo. The residue was chromatographed on silica gel with CHCl ₃ / MeOH (30: 1) plus 0.05% formic acid as eluent to afford the sub-purpose 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- iso -butyl-N-tert- butylthiophene -2-sulfonamide

5- iso -butyl-2- ( N - tert -butylaminosulfonyl) thiophene-3-boronic acid (200.5 mg, 0.628 mmol, see Example 1 (c) above), 1- (4-bromo Benzyl) -1H-imidazole (98.8 mg, 0.416 mmol, see step (a) above), toluene (15 mL), ethanol (15 mL), NaOH (1.0M, 1.5 mL, 1.5 mmol) and Pd ( PPh ₃ ) ₄ (14.5 mg, 0.125 mmol) was mixed under N ₂ atmosphere. 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 afford 113.9 mg of sub-purpose compound (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 = 7.1 Hz, 2H), 1.64 (m, 1H) , 0.73 (s, 9H), 0.72 (d, J = 6.9 Hz, 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

Anal. Calcd for C ₂₂ H ₂₉ N ₃ O ₂ S ₂ : 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- iso -butylthiophene-2-sulfonamide

3- (4-imidazol-1-ylmethylphenyl) -5- iso -butyl-N-tert- butylthiophene -2-sulfonamide (0.097) of CH ₂ Cl ₂ (10 mL) under N ₂ (g) atmosphere. mmol, 42.0 mg, see step (b) above) was added BCl ₃ (0.5 mL, 1M, 0.5 mmol). The mixture was stirred for 0.5 hour. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine, dried over MgSO ₄ and the solvent was removed in vacuo. The crude product was used directly in the next step without further purification.

(d) N- (butylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butyl-thiophene-2-sulfonamide

The crude product of step (c) was dissolved in acetone (5 mL) under N ₂ (g) atmosphere. NaOH (0.20 mL, 1M, 0.20 mmol) was added to the mixture and then stirred for 10 minutes. Butyl isocyanate (109 μL, 0.97 mmol) was added and the mixture was stirred at room temperature overnight. 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 by column chromatography using CHCl ₃ : MeOH (10: 1) as eluent gave [3- (4-imidazol-1-ylmethylphenyl) -5- iso - butylthiophene -2-sulfonic acid tert -butylamide From 33% yield of the title compound (15.1 mg, 0.032 mmol).

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 = 7.1 Hz, 2H), 1.92 (m , 1H), 1.20 (m, 4H), 0.99 (d, J = 6.6, 6H), 0.86 (t, J = 7.1 Hz, 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- Iso Butylthiophene-2-sulfonamide

Crude 3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophen-2-sulfon-amide under N ₂ (g) atmosphere (according to the procedure described in Example 10 (c) above) Prepared) was dissolved in THF (3 mL). NaOH (1.0 mL, 1M, 1.0 mmol) was added to the mixture and then stirred for 10 minutes. Butanesulfonyl chloride (45 μL, 0.35 mmol) was then 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. This crude product was recrystallized from acetone to give the desired product (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 (d, J = 7.1 Hz, 2H), 1.67 (m, 1H), 1.65 (m, 2H), 1.29 (m, 2H), 0.89-0.79 (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- Iso Butylthiophene-2-carboxamide

(a) 2- iso -butylthiophene

A solution of thiophene (6.00 g, 0.0714 mol) in THF (80 mL) at −78 ° C. was treated with n- BuLi (1.6 M in hexane, 54 mL, 0.0864 mol). The mixture was stirred at −40 ° C. for about 2 hours. The solution was then cooled back to -78 ° C and treated with 2-methylpropyliodide (16.04 g, 0.0871 mol). The solution was stirred at 0 ° C. for 2 hours and then overnight at room temperature for about 16 hours. The solution was treated with water (25 mL) and extracted with petroleum ether (3 x 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 sub-object compound (3.0 g, 0.0213 mole) in 30% yield.

¹ H NMR δ (CDCl ₃ ): 7.14 (dd, J = 5.1, 1.2 Hz, 1H), 6.95 (dd, J = 5.1, 3.3 Hz, 1H), 6.79 (dd, J = 3.3, 1.2 Hz, 1H) , 2.72 (d, J = 7.1 Hz, 2H), 1.92 (m, 1H), 0.97 (d, J = 6.7 Hz, 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- iso -butyl- N - tert - butylthiophene -2-carboxamide

2-isopropyl of THF (15mL) at -78 ℃ - butyl-thiophene was added (1 g, 7.143 m mol reference, the step (a)), n -BuLi (in hexane 1.6 M, 5.3 mL, 8.48 m mol) of And the reaction mixture was stirred at 0 ° C. for 2 hours. Then tert -butyl-isocyanate (897 μL, 7.86 mmol) at −78 ° C. was added to the mixture. The stirred solution was further stirred at 0 ° C. for 2 hours. The reaction mixture was then quenched with H ₂ O (15 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was dried over MgSO ₄ , concentrated and purified by silica gel column chromatography (10:90 petroleum ether-EtOAc) to afford white needles of the sub-purpose product (1.2 g, 5.01 mmol). Obtained in% yield.

¹ H NMR δ (CDCl ₃ ): 7.24 (d, J = 3.6 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 5.72 (brs, 1H), 2.65 (d, J = 7.2 Hz, 2H ), 1.88 (m, 1H), 1.44 (s, 9H), 0.93 (d, J = 6.6 Hz, 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

Anal. Calcd. 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- iso -butyl- N - tert - butylthiophene -2-carboxamide-3-boronic acid

5- iso -butyl- N - tert - butylthiophene -2-carboxamide of THF (50 mL) at −78 ° C., obtained from step (b) above; 0.5 g, 2.1 mmol] 3.3 mL of n -BuLi (1.6M in hexane, 3.3 mL, 5.28 mmol) was added. The reaction mixture was slowly heated to -20 ° C and stirred for 4 hours. Tri- iso -propylborate (0.59 g, 3.14 mmol) at -78 ° C was added to the mixture. This solution was slowly heated to room temperature and stirred overnight. The reaction was quenched with HCl (solution) (2M, 2 mL) and extracted with EtOAc (2 × 25 mL), washed with brine, dried over MgSO ₄ and concentrated. This crude product was used in the next step without further purification.

MS (EI ⁺ ) m / z: 284

(d) 3- (4-imidazol-1-ylmethylphenyl) -5- iso -butyl- N - tert - butylthiophene -2-carboxamide

5- iso -butyl- N - tert - butylthiophene -2-carboxamide-3-boronic acid under N ₂ atmosphere (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 with each other. 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 purified by column chromatography using chloroform: methanol (95: 5) as eluent to afford 99 mg of sub-purpose compound (yield: 74%).

¹ H NMR δ (CDCl ₃ ): 7.55 (br s, 1 H), 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 = 6.9 Hz, 2H), 1.89 (m, 1H), 1.13 ( s, 9H), 0.95 (d, J = 6.6 Hz, 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

Anal. Calcd. for C ₂₃ H ₂₉ N ₃ OS + H ₂ O: 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- iso -butylthiophene-2-carboxamide

Trifluoroacetic acid (2.5 mL) was added 3- (4-imidazol-1-ylmethylphenyl) -5- iso -butyl- N - tert - butylthiophene -2-carboxamide (165 mg, 0.417 mmol, To step (d) above), a drop of anisol (about 0.05 mL) was added to the reaction mixture. The mixture was stirred for 30 minutes under N ₂ atmosphere and 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 sub-target compound (117 mg, 0.345 mmol) in 73% yield.

¹ H NMR δ (CD ₃ OD): 9.05 (br s, 1 H), 7.63 (br s, 1 H), 7.55 (br s, 1 H), 7.51 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 5.47 (s, 2H), 2.68 (d, J = 7.1 Hz, 2H), 1.90 (m, 1H), 0.96 (d, J = 6.6 Hz, 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

Anal. Calcd. 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- iso -butylthio-phen-2-carboxamide

NaH (55%, 12 mg, 0.28 mmol) was dissolved in THF (1 mL) 3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophene-2-carboxamide (46 mg, 0.136 mmol, see step (e) above). The mixture was stirred at 50 ° C. for 0.5 h. 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 desired 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 = 7.4 Hz, 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 = 6.9 Hz, 2H), 1.90 (m, 1H), 1.65 (br s, 2H), 1.29 (m, 2H), 0.95 (d, J = 6.5 Hz, 6H), 0.81 (t, J = 6.6 Hz, 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

Anal. Calcd. for C ₂₃ H ₂₉ N ₃ O ₃ S ₂ + H ₂ O: 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 methods described herein.

(i) N -butyloxycarbonyl-4-butyl-2- (4-imidazol-1-ylmethylphenyl) benzene-sulfonamide

¹ H NMR δ (CDCl ₃ ) ,: 8.95 (brs, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.66 (brs, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.34 ( dd, J = 8.3, 1.6 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H,), 7.05 (d, J = 1.6 Hz, 1H), 6.83 (brs, 2H), 5.10 (s, 2H) , 4.00 (t, J = 6.5, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.62 (m, 2H), 1.48 (m, 2H), 1.36 (m, 2H), 1.22 (m, 2H ), 0.92 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.3 Hz, 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- iso -butylthiophen-2-sulfonamide

¹ H NMR δ (20% CD ₃ OD in CDCl ₃ ): 8.00 (brs, 1H), 7.56 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 7.7 Hz, 2H), 7.07 (brs, 2H), 6.75 (s, 1H), 5.20 (s, 2H), 4.14 (brt, J = 4.5 Hz, 2H), 3.52 (brt, J = 6.9 Hz, 2H), 3.32 (s, 3H), 2.70 ( d, J = 7.1 Hz, 2H), 1.94 (m, 1H), 0.99 (d, J = 6.4 Hz, 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- iso -butylthio-phen-2-sulfonamide

¹ H NMR δ (20% CD ₃ OD in CDCl ₃ ): 7.78 (brs, 1 H), 7.55 (d, J = 7.8 Hz ,. 2H), 7.24 (d, J = 7.8 Hz, 2H), 7.07 (brs , 2H), 6.77 (s, 1H), 5.22 (s, 2H), 4.06 (q, J = 7.1 Hz, 2H), 2.71 (d, J = 7.1 Hz, 2H), 1.95 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 6.4 Hz, 6H)

¹³ C NMR ((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) N - tert -butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butyl-thiophene-2-sulfonamide

¹ H NMR δ (10% CD ₃ OD in CDCl ₃ ): 7.65 (brs, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.94 (brs, 2H), 6.65 (s, 1H), 5.09 (s, 2H), 2.59 (d, J = 7.1 Hz, 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- iso -butylthiophen-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 = 6.6 Hz, 2H), 2.71 (d, J = 6.9 Hz, 2H), 2.24 (s, 3H), 1.94 (m, 1H), 1.51 (m, 2H), 1.28 (m, 2H), 1.00 (d, J = 6.6 Hz, 6H), 0.87 (t, J = 7.4 Hz, 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- iso -butyl-thiophene-2-sulfonamide

¹ H NMR δ (CDCl ₃ ): 0.84 (t, J = 7.3 Hz, 3H), 0.95 (d, J = 6.6 Hz, 6H), 1.22 (m, 2H), 1.48 (m, 2H), 1,90 (m, 1H), 2.66 (d, J = 6.9 Hz, 2H), 4,01 (t, J = 6.6 Hz, 2H), 5.26 (s, 2H), 6.23 (s, 1H), 6.69 (s, 1H), 7.02 (d, J = 8.3 Hz, 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- iso -butylthiophene-2-sulfonamide

¹ H NMR δ (CDCl ₃ ): 7.66 (s, 1H), 7.50 (s, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.74 (s , 1H), 6.59 (d, J = 2.1 Hz, 1H), 5.40 (s, 2H), 4.03 (t, J = 6.6 Hz, 2H), 2.71 (d, J = 6.9 Hz, 2H), 1.96 (m , 1H), 1.49 (m, 2H), 1.25 (m, 2H), 0.99 (d, J = 6.6 Hz, 6H), 0.87 (t, J = 7.4 Hz, 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-ylmethyl-phenyl) -5- iso -butylthiophen-2-sulfonamide

¹ H NMR δ (CDCl ₃ ): 8.18 (brs, 1H), 7.84 (brs, 1 H), 7.46 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.06 (brs , 1H), 6.99 (brs, 1H), 6.68 (s, 1H), 3.07 (brt, 2H), 2.67 (d, J = 7.1 Hz, 2H), 2.56 (brs, 3H), 1.91 (m, 1H) , 1.35 (m, 2H), 1.19 (m, 2H), 0.96 (d, J = 6.6 Hz, 6H), 0.84 (t, J = 7.2 Hz, 3H)

¹³ C NMR ((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-methoxy-ethyl) thiophen-2-sulfonamide

¹ H NMR δ (5% CD ₃ OD in CDCl ₃ ): 7.86 (brs, 1H), 7.51 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 7.05 (brs, 1H), 6.99 (brs, 1H), 6.83 (s, 1H), 5.18 (s, 2H), 4.03 (t, J = 6.5 Hz, 2H), 3.67 (t, J = 6.2 Hz, 2H), 3.10 ( t, J = 6.2 Hz, 2H), 1.52 (m, 2H), 1.26 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H)

¹³ C NMR δ (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 target compounds of the examples were tested in Tests A and B, with affinity for the AT2 receptor smaller than Ki = 100 nM (e.g. less than 50 nM) and greater than Ki = 500 nM (e.g. 1 Was found to show affinity for the AT1 receptor (greater than μm).

Example 15

The target compound of the example was tested in Test C above and found to significantly promote mucosal alkalisation. This effect was blocked by co-administration of the selective AT2 receptor antagonist PD123319 [Sigma Chemical Company].

Claims (50)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof; [Formula 1]

Where (a) Z ₁ and Z ₂ are not the same; (b) Z ₂ is -CH- or -N- when Z ₁ is -CH = CH-; And (c) Z ₁ is -CH = CH- and Z ₂ is -CH-, unless Z ₁ and Z ₂ are -CH- and the other is -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 R ² is -N (H) S (O) ₂ N (H) C (O) R ⁷ or -N (H) C (O) N when ₂ R ⁶ or Z ₁ is -CH = CH- (H) S (O) ₂ R ⁷ ; R ⁵ is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 -alkyl or di-C _1-3 -alkylamino-C _1-4 -alkyl; R ⁶ is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 -alkyl, C _1-3 alkoxy-C _1-6 -alkyl, C _1-6 alkylamino or di- C _1-6 -alkylamino; When R ⁷ is C _1-6 -alkyl, When X ₁ is —C (R ¹ ) —, X ₃ is —C (R ² ) — and X ₄ is —C (R ³ ) —, R ¹ is H; Y ₁ , Y ₂ , Y ₃ and Y ₄ , are each -CH- or -CF-; Z ₁ is -CH-, -O-, -S-, -N- or -CH = CH-; When Z ₂ is -CH-, -O-, -S- or -N-, _One of X ₁ and X ₂ is —N— and the other is —C (R ¹ ) —; X ₃ is -N- or -C (R ² )-; X ₄ is -N- or -C (R ³ )-; R ¹ , R ² and R ³ are each H, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 -alkyl or halo. The compound of claim 1, wherein when X ₁ is —C (R ¹ ) —, X ₃ is —C (R ² ) — and X ₄ is —N—. The compound of claim 2, wherein R ¹ is H. 4. The compound of claim 1, wherein when X ₁ is —C (R ¹ ) —, both X ₃ and X ₄ are N. 7. The compound of claim 1, wherein when X ₁ is —C (R ¹ ) —, X ₃ is —C (R ² ) — and X ₄ is —C (R ³ ) —. The compound of claim 1, wherein when X ₁ is -N-, X ₃ is -N-. The compound of claim 6, wherein when X ₄ is —C (R ³ ) —, R ³ is H. 8. The compound of claim 1, wherein when X ₁ is -N-, X ₃ is -C (R ² ) and X ₄ is -C (R ³ )-. The compound of any one of claims 1, 2, 4 or 6 to 8, wherein R ¹ is H, C _1-3 alkyl or CF ₃ . The compound of claim 9, wherein R ¹ is H or ethyl. The compound of claim 1, wherein R ² is C _1-3 alkyl, halo or H. 10. The compound of claim 11, wherein R ² is H or methyl. 13. The compound of claim 12, wherein R ² is H. The compound of claim 1, wherein R ³ is C _1-3 alkyl, halo or H. 15. The compound of claim 14, wherein R ³ is H. The compound of claim ₁ , wherein Y ₁ , Y ₂ , Y ₃ and Y ₄ are all —CH—. The compound of claim 1, wherein Z ₁ is —S— or —CH═CH—. 18. The compound of claim 17, wherein Z ₁ is -S-. The compound of claim 1, wherein Z ₂ is —CH—. The compound of claim 1, wherein R ⁴ is —S (O) ₂ N (H) C (O) R ⁶ . The compound of claim 1, wherein R ⁵ is n -butyl or iso -butyl. The compound of claim 21, wherein R ⁵ is iso -butyl. The compound of claim 1, wherein 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) _{2 When} R ⁶ , R ⁶ is n -butoxymethyl, iso -butoxy or n -butoxy. The compound of claim 23, wherein R ⁶ is n -butoxy. The compound of claim _1, wherein X _1, X ₃ and X ₄ are all —CH—, Y ₁ , Y ₂ , Y ₃ and Y ₄ are all —CH— and Z ₁ is —S— or —CH═CH When R ₂ is -CH- and R ⁵ is n -butyl or iso -butyl, then R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ , wherein R ⁶ is -O n- butyl, -O- iso -propyl, -O- iso -butyl or -CH ₂ -O- n -butyl. The method of claim 1, N -butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthio-phen-2-sulfonamide; N - iso -butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butyl-thiophen-2-sulfonamide; N - iso -propyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butyl-thiophen-2-sulfonamide; N- (butoxyacetyl) -3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophen-2-sulfonamide; N -butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-butylthiophene-2-sulfonamide; N -butyloxycarbonyl-2- (4-imidazol-1-ylmethylphenyl) -4- iso -butylbenzene-sulfonamide; N -butyloxycarbonyl-5- iso -butyl-3- (4-tetrazol-2-ylmethylphenyl) thiophene-2-sulfonamide; N-butyloxycarbonyl-5- iso -butyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide; N -butyloxycarbonyl-3- (4- [1,2,4] triazol-1-ylmethylphenyl) -5- iso -butyl-thiophen-2-sulfonamide; N- (butylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butyl-thiophen-2-sulfonamide; N -butylsulfonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophen-2-sulfonamide; N -butylsulfonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophene-2-carboxamide; N -butyloxycarbonyl-4-butyl-2- (4-imidazol-1-ylmethylphenyl) benzene-sulfonamide; N- (2-methoxyethyloxy) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophen-2-sulfonamide; N -ethyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophen-2-sulfonamide; N - tert -butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butyl-thiophen-2-sulfonamide; N -butyloxycarbonyl-3- [4- (4-methylimidazol-1-ylmethyl) phenyl] -5- iso -butylthiophen-2-sulfonamide; N -butyloxycarbonyl-3- (4-pyrazol-1-ylmethylphenyl) -5- iso -butylthiophen-2-sulfonamide; N -butyloxycarbonyl-3- [4- (3-trifluoromethylpyrazol-1-ylmethyl) phenyl] -5- iso -butylthiophen-2-sulfonamide; N- ( N -butyl- N -methylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- iso -butylthiophen-2-sulfonamide; or N -butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- (2-methoxyethyl) -thiophene-2-sulfonamide. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete (i) R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ or -S (O) ₂ N (H) S (O) ₂ R ⁶ , and R ⁶ is defined in claim 1 Reacting the compound of Formula 2 with a compound of Formula 3 for the compound of Formula 1; [Formula 2]

(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 in claim 1). [Formula 3] R ⁶ GL ¹ (Wherein G is C (O) or S (O) ₂ , L ¹ is a leaving group and R ⁶ is defined in claim 1.) (ii) for compounds of formula 1 above, wherein R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ and R ⁶ is C _1-6 alkoxy-C _1-6 -alkyl Coupling a compound of Formula 2 to a compound of Formula 4; [Formula 4] R ^6a CO ₂ H Wherein R ^6a is C _1-6 alkoxy-C _1-6 -alkyl. (iii) For a compound of Formula 1 wherein R ⁴ is -C (O) N (H) S (O) ₂ R ⁶ and R ⁶ is defined in claim 1, the compound of Formula 5 is Combining with a compound; [Formula 5]

(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 in claim 1). [Formula 6] R ⁶ S (O) ₂ NH ₂ (Wherein R ⁶ is defined in claim 1) (iv) For the compound of Formula 1, wherein R ⁴ is -C (O) N (H) S (O) ₂ R ⁶ and R ⁶ is defined in claim 1, the compound of Formula 7 Binding to a compound of 8; [Formula 7]

(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 in claim 1). [Formula 8] R ⁶ S (O) ₂ Cl (Wherein R ⁶ is defined in claim 1) (v) for the compound of formula 1 wherein R ⁴ is -N (H) S (O) ₂ N (H) C (O) R ⁷ and R ⁷ is defined in claim 1; Reacting with a compound of Formula 10, [Formula 9]

(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 in claim 1). [Formula 10] R ⁷ C (O) N (H) S (O) ₂ Cl (Wherein R ⁷ is defined in claim 1) (vi) a compound as defined above for the compound of formula 1 wherein R ⁴ is -N (H) C (O) N (H) S (O) ₂ R ⁷ and R ⁷ is as defined in claim 1 Reacting the compound of 9 with the compound of formula 11; [Formula 11] R ⁷ S (O) ₂ N (H) C (O) OR ^x (Wherein R ^x is C _1-2 alkyl and R ⁷ is defined in claim 1). (vii) for the compounds of formula 1 above, wherein R ⁴ is -N (H) C (O) N (H) S (O) ₂ R ⁷ and R ⁷ is as defined in claim 1 Reacting the compound of 9 with the compound of formula 12; [Formula 12] R ⁷ S (O) ₂ NCO (Wherein R ⁷ is defined in claim 1) (viii) For the compound of formula 1 wherein R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ and R ⁶ is C _1-6 alkylamino, the compound of formula 2 as defined above is Reacting with a compound of Formula 13; [Formula 13] R ^6b NCO (Wherein R ^6b is C _1-6 alkyl) or (ix) For compounds of Formula 1 wherein R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ and R ⁶ is di-C _1-6 alkylamino, R ⁴ is -S (O ₂ ) reacting a corresponding compound of formula 1, wherein ₂ N (H) C (O) R ⁶ and R ^{6 is} C _1-6 alkoxy, with a compound of formula 14; Method of Preparation of the Defined Compound. [Formula 14] R ^6c N (H) R ^6d (Wherein R ^6c and R ^6d are each C _1-6 alkyl) A compound of formula 2, 5, 7 or 9 as defined in claim 45. X ₁ , X ₃ and X ₄ are all -CH-, Y ₁ , Y ₂ , Y ₃ and Y ₄ are all -CH-, Z ₁ is -S- or -CH = CH- and Z ₂ is The compound of formula (2) as defined in claim 45, wherein -CH- and R ⁵ is n -butyl or iso -butyl. delete delete delete