Pyrazolyl acylsulfonamide derivatives as endothelin converting enzyme inhibitors and useful in the treatment of chronic obstructive pulmonary disease

The present invention concerns pyrazolyl acylsulfonamide derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.

Endothelin converting enzyme (ECE-1) is a protease involved in the biosynthesis of endothelin. Endothelin is a strong vasoconstrictor and inhibitors of endothelin have been investigated with a view to developing therapeutic agents of use in treating cardiovascular diseases. For example, EP-0885890 and JP-2000-053649 describe pyrazolyl sulphonyl ureas and suggest that such compounds may be active agents in treating or preventing cardiovascular disease.

Chronic obstructive pulmonary disease (COPD) is a term that refers to a group of lung diseases which can interfere with normal breathing. Current clinical guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases. The most important contributory source of such particles and gases, at least in the western isorld, is tobacco smoke. COPD patients have a variety of symptoms, including cough, shortness of breath, and excessive production of sputum; such symptoms arise from dysfunction of a number of cellular compartments, including neutrophils, macrophages, and epithelial cells. The tiso most important conditions covered by COPD are chronic bronchitis and emphysema.

There is a pressing medical need for new therapies against COPD, in particular for therapies with disease modifying potential. Moreover, there is a need for compounds having improved pharmacological properties.

According to the present invention, the suppression of the biosynthesis of endothelin, by hindering ECE-1, may be effective in the prevention and treatment of chronic obstructive pulmonary disease (for example by reducing mucus secretion).

The present invention provides a compound of formula (I):

wherein:

R ¹ is optionally substituted aryl or optionally substituted heteroaryl; R ² and R ⁴ each independently represent hydrogen, halogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, or C _3-7 cycloalkyl [optionally substituted by halogen or C _1-4 alkyl];

R ³ is optionally substituted aryl, optionally substituted heteroaryl or C _3-7 cycloalkyl [optionally substituted by halogen or C _1-4 alkyl]; aryl and heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, OC(O)NR ⁵ R ⁶ , NR ⁷ R ⁸ , NR ¹⁰ C(O)NR ¹¹ R ¹² , S(O) ₂ NR ¹³ R ¹⁴ ,

NR ¹⁵ S(O) ₂ R ¹⁶ , C(O)NR ¹⁷ R ¹⁸ , CO ₂ R ¹⁹ , NR ²⁰ CO ₂ R ²¹ , S(O) _n R ²² , OS(O) ₂ R ²³ , C _1-6 alkyl (optionally mono-substituted by S(O) ₂ R ²⁴ or C(O)NR ²⁵ R ²⁶ ), C(O)R ²⁷ , NR ²⁸ C(O)R ²⁹ , C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy(C _1-6 )alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, phenyl(C _1-4 )alkyl, phenoxy, phenylthio, phenylS(O), phenylS(O) ₂ , phenyl(C _1-4 )alkoxy, heteroaryl(C _1-4 )alkyl, heteroaryloxy or heteroaryl(C _{1- 4} )alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ ;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and R ²⁹ are, independently, hydrogen, C _1-6 alkyl [optionally substituted by halogen, C _3-6 cycloalkyl or phenyl {optionally substituted by halogen or C _1-4 alkyl}], CH ₂ (C _2-6 alkenyl), phenyl [itself optionally substituted by halogen, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) _2i cyano, C _1-4 alkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or

OCF ₃ ] or heteroaryl [itself optionally substituted by halogen, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ ];

R ¹⁶ , R ²² , R ²³ and R ²⁴ are, independently, C _1-6 alkyl [optionally substituted by halogen, C _3-6 cycloalkyl or phenyl {optionally substituted by halogen or C _1-4 alkyl}], CH ₂ (C _2-6 alkenyl), phenyl [itself optionally substituted by halogen, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ ] or heteroaryl [itself optionally substituted by halogen, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C ₄ alkyl), CF ₃ or OCF ₃ ]; and, n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.

Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate. Salts also include metal salts, such as an alkali metal salt (for example a sodium or potassium salt) or an alkaline earth metal salt (for example magnesium or calcium).

The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.

Halogen is, for example fluorine or chlorine or bromine.

Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl. Alkylene groups may similarly be straight or branched chain.

Cycloalkyl is monocyclic and is, for example, cyclopropyl, cyclopentyl or cyclohexyl.

Haloalkyl is an alkyl group carrying one or more (such as 1 to 6) halogen (such as chloro or fluoro atoms) and is, for example, CF ₃ , CH ₂ CF ₃ or C ₂ F ₅ .

Hydroxyalkyl is an alkyl group carrying one or more (such as 1 to 3) hydroxy, groups. Aryl is, for example, phenyl or naphthyl. Heteroaryl is an aromatic 5- or 6-membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulfur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heteroaryl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benzo[b]thienyl (also known as benz[b]thienyl, benzothienyl or benzo[b]thiophenyl), 2,3-dihydrobenz[b]thienyl (for example in a 1-dioxo-2,3-dihydrobenz[b]thienyl moiety), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl . (such as imidazo[1,2-α]pyridinyl), thieno[3,2-b]pyridin-6-yl, thieno[3,2-b]pyrimidin-6-yl, 1,2,3-benzoxadiazolyl, benzo[1,2,3]thiadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, a pyrazolopyridine (for example 1H- pyrazolo[3,4-b]pyridinyl), quinolinyl, isoquinolinyl, a naphthyridinyl (for example [1,6]naphthyridinyl or [1,8]naphthyridinyl) or abenzothiazinyl; or an N-oxide thereof, or an jS-oxide or S-dioxide thereof. In an embodiment of the invention, R ¹ is aryl or heteroaryl, which aryl or heteroaryl moiety is optionally substituted by one or more of halogen, cyano, nitro, MH ₂ , NH(C _1-4 alkyl), N(C _1-4 atkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ ( C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ .

In an embodiment of the invention, R ¹ is phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl, which phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl moiety is optionally substituted by one or more of halogen, cyano, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy,

C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ .

In an embodiment of the invention, R ¹ is phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl which phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl moiety is optionally substituted by one or more of halogen, cyano, S(C _1-4 alkyl), C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, CF ₃ or OCF ₃ . In an embodiment of the invention, R ¹ is aryl (such as phenyl or naphthyl) optionally substituted by one or more of halogen, cyano, S(C _1-4 alkyl), C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, CF ₃ or OCF ₃ .

In an embodiment of the invention, R ¹ is heteroaryl optionally substituted by one or more of halogen, cyano, S(C _1-4 alkyl), C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, CF ₃ or OCF ₃ . Heteroaryl moieties according to this embodiment include, furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl and benzothienyl. In an aspect of this embodiment, R ¹ is an optionally substituted thienyl, thiazolyl, benzothienyl or indolyl moiety.

In an embodiment of the invention, R ¹ is a group of formula (II)

wherein:

X is O, S, S(O) ₁ , S(O) ₂ , or C _1-6 alkylene; and

Ar ¹ and Ar ² each independently represent phenyl or heteroaryl, which phenyl or heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ . In an embodiment of the invention, R ¹ is a group of formula (II), wherein Ar ¹ and Ar ² each independently represent phenyl, pyridinyl, thienyl or thiazolyl, which phenyl, pyridinyl, thienyl or thiazolyl moiety is optionally substituted by one or more of halogen, cyano, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ .

In an embodiment of the invention, R ¹ is a group of formula (II) wherein X is O, S, or C _1-4 alkylene.

In an embodiment of the invention, R ¹ is a group of formula (II) wherein Ar ¹ and Ar ² each independently represent phenyl, pyridinyl, thienyl or thiazolyl, which phenyl, pyridinyl, thienyl or thiazolyl moiety is optionally substituted by one or more of halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ or OCF ₃ .

In an embodiment of the invention, R ² is hydrogen or C _1-4 alkyl or C _3-7 cycloalkyl [optionally substituted by halogen or C _1-4 alkyl]; and R ⁴ is hydrogen.

In an embodiment of the invention, R ² is hydrogen or C _1-4 alkyl; and R ⁴ is hydrogen. In an embodiment of the invention, R ³ is phenyl optionally substituted by one or more of halogen, cyano, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ . In an aspect of this embodiment, R ³ is phenyl optionally- substituted by one or more of halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ or 0CF ₃ .

In an embodiment of the invention, R ³ is heteroaryl (such as pyridinyl) optionally substituted by one or more of halogen, cyano, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ . In an aspect of this embodiment, R ³ is optionally substituted by one or more of halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ or OCF ₃ .

In an embodiment of the invention, R ³ is C _3-6 cycloalkyl (such as cyclohexyl) optionally substituted by one or more of halogen, cyano, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ . In an aspect of this embodiment, R ³ is optionally substituted by one or more of halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ or OCF ₃ .

In a further aspect, the present invention provides a compound of formula (I) wherein:

R ¹ is aryl or heteroaryl, which aryl or heteroaryl moiety is optionally substituted by one or more of halogen, cyano, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C ₄ alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ , or R ¹ is a group of formula QI):

wherein:

X is O, S, S(O) ₁ , S(O) ₂ , or C _1-6 alkylene and: Ar ¹ and Ar ² each independently represent phenyl or heteroaryl, which phenyl or heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)(C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl),

S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ ;

R ² is hydrogen or C _1-4 alkyl or C _3-7 cycloalkyl [optionally substituted by halogen or C _1-4 alkyl]; and R ⁴ is hydrogen, and

R ³ is phenyl optionally substituted by one or more of halogen, cyano, nitro, NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , S(C _1-4 alkyl), S(O)( C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy,

C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides a compound of formula (I) wherein: R ¹ is phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl, which phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl moiety is optionally substituted by one or more of halogen, cyano, S(C _1-4 alkyl), C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, CF ₃ or OCF ₃ ; or R ¹ is a group of formula (II)

wherein X is O, S, or C _1-4 alkylene;

Ar ¹ and Ar ² each independently represent phenyl, pyridinyl, thienyl, or thiazolyl, which phenyl, pyridinyl, thienyl, or thiazolyl moieties are independently optionally substituted by one or more of halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ or OCF ₃ ;

R is hydrogen or C _1-4 alkyl; R ⁴ is hydrogen; and

R ³ is phenyl, optionally substituted by one or more of halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ or OCF ₃ ; or a pharmaceutically acceptable salt thereof.

In an embodiment of the present invention the compound of formula (I) is selected from: N-[(4-chlorophenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol -5-yl)acetamide N-[(4-cyanophenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol- 5-yl)acetamide N-[(4-chlorophenyl)sulfonyl]-2-[1-(4-fluorophenyl)-3-methyl- 1H-pyrazol-5-yl]acetamide

N-[(4-chlorophenyl)sulfonyl]-2-[1-(3-methoxyphenyl)-3-met hyl-1H-pyrazol-5- yl]acetamide N-[(4-tert-butylphenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyr azol-5-yl)acetamide N-({5-[(4-chlorophenyl)thio]-2-thienyl}sulfonyl)-2-(3-methyl -1-phenyl-1H-pyrazol-5- yl)acetamide N-{[5-(butylthio)-2-thienyl}sulfonyl}-2-(3-methyl-1-phenyl-1 H-pyrazol-5-yl)acetamide N- {[5-(isopropylthio)-2-thienyl]sulfonyl} -2-(3-methyl- 1 -phenyl-1H-pyrazol-5- yl)acetamide N-{[4-(4-chlorophenoxy)phenyl]sulfonyl}-2-(3-methyl-1-phenyl -1H-pyrazol-5- yl)acetamide N-({4-[(4-chlorophenyl)thio]phenyl}sulfonyl)-2-(3-methyl-1-p henyl-1H-pyrazol-5- yl)acetamide N-{[5-(4-fluorobenzyl)-2-thienyl]sulfonyl}-2-(3-methyl-1-phe nyl-1H-pyrazol-5- yl)acetamide N-({5-[2-(4-methylphenyl)ethyl]-2-thienyl}sulfonyl)-2-(3-met hyl-1-phenyl-1H-pyrazol-5- yl)acetamide N-({5-[(4-chlorophenyl)thio]-2-thienyl}sulfonyl)-2-[1-(4-flu orophenyl)-3-methyl-1H- pyrazol-5 -yl] acetamide N-[(2,5-dichloro-3-thienyl)sulfonyl]-2-(3-methyl-1-phenyl-1H -pyrazol-5-yl)acetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[5-(2-phenylethyl)- 2- thienyl]sulfonyl}acetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-[(4-phenoxyphenyl )sulfonyl]acetamide

N-[(3,4-dichlorophenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H- pyrazol-5-yl)acetamide N-[(5-bromo-2-thienyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyra zol-5-yl)acetamide

N-({5-[(2-chlorophenyl)thio]-2-thienyl}sulfonyl)-2-(3-met hyl-1-phenyl-1H-pyrazol-5- yl)acetamide methyl 4-{[5-({[(3-methyl-1-phenyl-1H-pyrazol-5-yl)acetyl]amino}sul fonyl)-2- thienyl]thio}benzoate 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[5-(pyridin-4-ylthi o)-2- thienyl] sulfonyl} acetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[5-(pyridin-2-yl thio)-2- thienyl]sulfonyl} acetamide

2-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-[(4-chlor ophenyl)sulfonyl]acetamide N-[(4-chlorophenyl)sulfonyl]-2-(4-iodo-3-methyl-1-phenyl-1H- pyrazol-5-yl)acetamide N-[(4-chlorophenyl)sulfonyl]-2-(3,4-dimethyl-1-phenyl-1H-pyr azol-5-yl)acetamide N-{[4-chloro-5-(phenylthio)-2-thienyl]sulfonyl}-2-(3-methyl- 1-phenyl-1H-pyrazol-5- yl)acetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-({5-[(4-methyl-1, 3-thiazol-2-yl)thio]-2- thienyl}sulfonyl)acetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-({3-[(4-methyl-1, 3-thiazol-2-yl)thio]-2- thienyl}sulfonyl)acetamide N-{[4-chloro-3-(hydroxymethyl)phenyl]sulfonyl}-2-(3-methyl-1 -phenyl-1H-pyrazol-5- yl)acetamide, N-[(4-fluorophenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol -5-yl)acetamide N-[(5-chloro-2-thienyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyr azol-5-yl)acetamide N-[(4-chlorophenyl)sulfonyl]-2-[1-(2-methoxyphenyl)-3-methyl -1H-pyrazol-5- yl]acetamide

N- [(3-methoxyphenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol- 5-yl)acetamide N-[(4-methoxyphenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazo l-5-yl)acetamide N-[(3-chlorophenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol -5-yl)acetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-(phenylsulfonyl)a cetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-[(4-methylphenyl)sul fonyl]acetamide

2-(3-methyl-1-phenyI-1H-pyrazol-5-yl)-N-(2-naphthylsulfon yl)acetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-[(5-methylpyridm- 2-yl)sulfonyl]acetamide

N-[(4-chlorophenyl)sulfonyl]-2-[1-(2-fluorophenyl)-3-meth yl-1H-pyrazol-5-yl]acetamide N-[(4-chlorophenyl)sulfonyl]-2-(1-cyclohexyl-3-methyl-1H-pyr azol-5-yl)acetamide

2-[1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl]-N-[(4-chl orophenyl)sulfonyl]acetamide

N-[(4-chlorophenyl)sulfonyl]-2-(3-methyl-1-pyridin-3-yl-1 H-pyrazol-5-yl)acetamide N-[(4-chlorophenyl)sulfonyl]-2-[1-(3-fluorophenyl)-3-methyl- 1H-pyrazol-5-yl]acetamide

N-[(4-butylphenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyraz ol-5-yl)acetamide N-( {5-[(4-chlorophenyl)sulfonyl]-2-thienyl} sulfonyl)-2-(3-methyl-1-phenyl-1H-pyrazol-5- yl)acetamide

2-[1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl]-N-({5-[(4 -chlorophenyl)thio]-2- thienyl}sulfonyl)acetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{ [4-(2-phenylethyl)phenyl]sulfonyl} acetamide 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[5-(2-thienylthio)- 2- thienyl]sulfonyl} acetamide N-{[4-methyl-3-(2-phenylethyl)phenyl]sulfonyl}-2-(3-methyl-1 -phenyl-1H-pyrazol-5- yl)acetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[5-(phenylthio)- 1,3-thiazol-2-yl]sulfonyl}- acetamide

2-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[2-(phenylthio)- 1,3-thiazol-5-yl]sulfonyl}- acetamide

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[5-(phenylthio)- 2-thienyl]sulfonyl}acetamide

N-({5-[(3-chlorophenyl)thio]-2-thienyl}sulfonyl)-2-(3-met hyl-1-phenyl-1H-pyrazol-5- yl)acetamide

N,N-dimethyl-4-{[5-({[(3-methyl-1-phenyl-1H-pyrazol-5-yl) acetyl]amino}sulfonyl)-2-- thienyl]thio}-benzamide N-(1-benzothien-3-ylsulfony)-2-(3--methyl-1-phenyl-1H-pyrazo l-5-yl)acetamide

N-[(4,5-dichloro-2-thienyl)sulfonyI]-2-(3-methyl-1-phenyl -1H-pyrazol-5-yl)acetamide N-(1-benzothien-2-ylsulfonyl)-2-(3-methyl-1-phenyl-1H-pyrazo l-5-yl)acetamide N-(1H-mdol-2-ylsulfonyl)-2-(3-methyl-1-phenyl-1H-pyrazol-5-y l)acetamide or a pharmaceutically acceptable salt thereof.

Compounds of the present invention can be prepared by methods analogous to those described in the art. In a further aspect of the present invention, there is provided a process for preparing a compound of formula (I), which comprises (a) coupling a compound of formula (III):

with a compound of formula (IV):

(b) where R ¹ represents a group of formula (II) (Ar ² -X-Ar ¹ -) wherein X is C _2-6 alkylene, reacting a compound of formula (V), wherein Y is C _2-6 alkenylene or C _2-6 alkynylene, with a reducing agent

and optionally after (a) or (b) carrying out one or more of the following:

• converting the compound to a further compound of the invention or • forming a pharmaceutically acceptable salt of the compound.

In process (a), the reaction may be performed in a suitable solvent (such as dichloromethane), in the presence of a suitable coupling agent (such as EDCI) and in the presence of one or more suitable bases (such as N,N-dimethylaminopyridine, triethylamine or N,N-diisopropylethylamine) at a suitable temperature (for example 0-35 °C). In process (b) the reaction may be performed in a suitable solvent (such as ethanol), in the presence of a suitable reducing agent (such as hydrogen (2 bar) and Pd/C) at a suitable temperature (for example 0-35 °C).

A compound of the invention wherein R ⁴ is hydrogen may be converted into a compound of the invention wherein R ⁴ is bromine or iodine, by electrophilic substitution

e.g. with. Br ₂ , or a source of electrophilic iodine, e.g. an iodine/silver acetate mixture. A compound of the invention wherein R ⁴ is bromine may be converted into a compound of the invention wherein R ⁴ is C _1-6 alkyl (e.g. methyl) by reaction with a suitable dialkyl metal (e.g dimethyl zinc and a to-phosphino nickel dichloride catalyst). Compounds of formula (III) can be prepared by treatment of a β,δ-diketoester

(Chem. Lett. 1985, 1145-48; Can. J. Chem. 1974, 52(8, pt1), 1343; J. Chem. Soc. 1979, 13, 578) with an appropriate hydrazine in methanol at room temperature (Heterocycles 2000, 55, 1285), followed by hydrolysis of the resulting ester to yield (III).

Compounds of formula (IV) are either commercially available, are known in the literature or may be prepared using known techniques e.g. see (US 2002/0143176; J. Med. Chem. 1981, 24, 959; WO95/29904; TeL Lett. 2002, 43, 8479; J. Med. Chem. 1990, 33, 749; Tet. Lett. 1985, 26, 5935). Compounds of formula (V) maybe prepared by methods analogous to those described herein for the preparation of compounds of formula (I). Examples of preparation methods for certain of these compounds are given hereinafter in the examples. Other examples can be prepared by analogous methods.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl, carboxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve at a certain stage the addition/removal of one or more protecting groups. The protection and deprotection of functional groups is described in 'Protective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991) and 'Protecting Groups', PJ. Kocienski, Georg Thieme Verlag (1994).

The compounds of the invention, or pharmaceutically acceptable salts thereof, have activity as pharmaceuticals, in particular as inhibitors of ECE-1 converting enzyme. According to a further feature of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a warm-blooded animal (such as man) by therapy (including prophylaxis).

According to a further feature of the present invention there is provided a method for modulating ECE- 1 activity in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

In another aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating ECE-1 activity), in a warmblooded animal, such as man).

Diseases and conditions which may be treated with the compounds include:

1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAlD-induced) and dust-induced asthma., both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;

2. bone and joints: arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection- related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome;

systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle- Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;

3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis);

4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses^ and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;

5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;

6. gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative

colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);

7. abdominal, hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;

8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female); 9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;

10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HTV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;

11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome; 12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes;

13. cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and

peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,

15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, mdeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema. .

In particular, compounds of formula (I), or a pharmaceutically acceptable salt thereof. may be effective in the prevention and treatment of chronic obstructive pulmonary disease (COPD). That modulators of ECE-1 activity may be used in treating COPD has not been disclosed previously. .....

Accordingly, in a further aspect the present invention provides a method of treating chronic obstructive pulmonary disease in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of an ECE-1 inhibitor.

The present invention also provides the use of an ECE-1 inhibitor in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).

In a further aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).

The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD). The present invention further provides a method of treating an ECE-1 mediated disease state (such as COPD) in a warm-blooded animal, such as man, which comprises

administering to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of treating chronic obstructive pulmonary disease in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof, for the therapeutic treatment of a warm-blooded animal, such as man, in particular modulating ECE-1 activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will, for example, comprise from 0.05 to 99%w (per cent by weight), such as from 0.05 to 80% w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1mg and 1g of active ingredient

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg ^-1 to 100 mgkg ^-1 of the compound, for example in the range of 0.1 mgkg ^-1 to 20 mgkg ^-1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.

The invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.

In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with agents listed below. Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin-1ike growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline. In addition the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRIl (for the C-C family); CXCRl,

CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX ₃ CRl for the C-X ₃ -

C family. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-

cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof,, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1s such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (M1, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab). The invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed. In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive

pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with agents listed below.

Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofm or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin-1ike growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline. In addition the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B-

Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1,

CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX ₃ CRl for the C-X ₃ -

C family.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially coUagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-Il) and MMP-9 andMMP-12, including agents such as doxycycline. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, arid a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as ZenecaZD-2138; the compound SB-210661; a pyridinyi-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.

The.present invention further relates to the combination of a compound of the invention, or a. pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1s such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine,

terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent,, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (M1, M2, and M3) antagonist such as. atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically- applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-1actam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a-comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.

A compound of the present invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-Bl. - or B2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming

growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NKl or NK3 receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Tol1-1ike receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS.

A compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for . example suitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fiuoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, initomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin); (ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as finasteride;

(iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like xnarimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody, cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-a mine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;

(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that isorks by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin);

(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRC A2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2; interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise:

(i) when given, ¹ H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300MHz or 400MHz using perdeuterio DMSO-D6 (CD ₃ SOCD ₃ ) or CDCl ₃ as the solvent unless otherwise stated; (ii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where indicated ionisation was effected by electrospray ionisation (ES) and atmospheric pressure chemical ionisation (APCI); where values for m/z are given, generally only ions which indicate the parent mass are reported, and the mass ions quoted are the positive or negativemass ions — [M+H] ⁺ or [M-H]-; ,

(iii) the title and sub-title compounds of the examples and preparations were named using . the IUPAC name program version 8.00 from Advanced Chemistry Development Inc. Labs; (iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry™,

NovaPak™ or Xterra™ reverse phase silica column, all available from Waters.Corp.; and

(vi) the following abbreviations are used:

INTERMEDIATE 1

This shows the preparation of 5-(1-hydroxy-3-oxo-butylidene)-2,2-dimethyl-[1,3]dioxane- 4,6-dione.

To a stirred O °C solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (9.34 g) and triethylamine (6.56 g) in DCM (100 mL) was added diketene (5.45 g, 5 mL) in DCM (8 rnL) dropwise over 20 min. The reaction was stirred at 0 °C for 20 min then warmed to RT. The reaction was then partitioned between DCM and cold dilute hydrochloric acid, and the organic phase dried over sodium sulfate, and concentrated in vacuo. The orange solid was triturated with ether to give the title compound, 5-(1-hydroxy-3-oxo-butylidene)-2,2- dimethyl-[1,3]dioxane-4,6-dione (9.9 g), as a pale cream solid. ¹ HNMR (400 MHz, CDCl ₃ ) δ 14.99 (s, 1H), 4.14 (s, 2H), 2.33 (s, 3H), 1.75 (d, 6H).

INTERMEDIATE 2 This shows the preparation of (3-methyl-1-phenyl-1H-pyrazol-5-yl)acetic acid.

To a stirred solution of Intermediate 1 (2 g) in methanol (20 mL) was added phenylhydrazine (0.95 g). The mixture was heated at reflux overnight. The reaction mixture was allowed to cool and concentrated in vacuo. The brown oil was subjected to column chromatography (silica, 5% ethyl acetate / iso-hexane then 30% ethyl acetate / iso- hexane). The isolated methyl (3-methyl-1 -phenyl-1H-pyrazol-5-yl)acetate (1.7 g) was dissolved in ethanol (10 mL) and aqueous sodium hydroxide solution (1 M, 7.4 mL) added. After stirring for 1 h the reaction was concentrated in vacuo and water added. Acidification with 10 % v/v aqueous hydrochloric acid precipitated a solid that was extracted into ethyl

acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Trituration of the resulting gum with ether yielded the title compound (3-methyl-1- phenyl-1H-pyrazol-5-yl)acetic acid (1.2 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 - 7.37 (m, 5H), 6.22 (s, 1H), 3.63 (s, 2H), 2.32 (s, 3H).

INTERMEDIATE 3

This shows the preparation of [1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]acetic acid.

To a stirred solution of 4-fluorophenylhydrazine hydrochloride (163 mg) and triethylamine (101 mg) in methanol (5 mL) was added Intermediate 1 (230 g). The reaction mixture was heated at 70 °C for 2 h, then allowed to cool. 5% W/v aqueous sodium hydroxide solution (2 mL) and water (2 mL) were added and the reaction mixture was stirred for a further 2 h at ambient temperature. After this time the mixture was concentrated in vacuo, and partitioned between ether and water. The aqueous phase was acidified and extracted with ethyl acetate and the organic phase dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the resultant gum with diethyl ether gave the title compound [2-(4- fluoro-phenyl)-5-methyl-2H-pyrazol-3-yl]-acetic acid (0.05 g) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 - 7.37 (m, 2H), 7.17 - 7.11 (m, 2H), 6.21 (s, 1H), 3.66 (s, 2H), 2.32 (s, 3H).

INTERMEDIATE 4 [1-(2-Fluorophenyl)-3-methyl-1H-pyrazol-5-yl] acetic acid was prepared analogously to the method for Intermediate 3.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 - 7.38 (m, 2H), 7.28 - 7.18 (m, 2H), 6.25 (s, 1H), 3.59 (s, 2H), 2.33 (s, 3H).

INTERMEDIATE 5 (1-Cyclohexyl-3-methyl-1H-pyrazol-5-yl)acetic acid was prepared analogously to the method for Intermediate 3.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.95 (s, 1H), 3.93 - 3.83 (m, 1H), 3.68 (s, 2H), 2.25 (s, 3H), 2.01 - 1.63 (m, 6H), 1.44 - 1.23 (m, 4H).

INTERMEDIATE 6

This shows the preparation of [1-(3-Methoxyphenyl)-3-methyl-1H-pyrazol-5-yl]acetic acid.

To a stirred solution of Intermediate 1 (400 mg) and triethylamine (260 μL) in methanol (5 mL) was added 3-methoxyphenylhydrazine hydrochloride (300 mg) and the mixture heated at 65 °C for 20 h. Lithium hydroxide (100 mg) was added and the mixture was stirred at 40 °C for 2 h before being concentrated in vacuo. Aqueous hydrochloric acid (1 N) was added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to leave the title compound [2-(3- methoxyphenyl)-5-methyl-2H-pyrazol-3-yl]-acetic acid as an oil (350 mg). APCI+MS: m/z 247 [M+H] ⁺ .

INTERMEDIATE 7 [1-(2-methoxyphenyl)-3-methyl-1H-pyrazol-5-yl]acetic acid was prepared analogously to the method for Intermediate 6.

APCI+MS: m/z 247 [M+H] ⁺ .

INTERMEDIATE 8

(3-Methyl-1-pyridin-3-yl-1H-pyrazol-5-yl)acetic acid was prepared analogously to the method for Intermediate 6.

APCI+MS: m/z 218 [M+H] ⁺

INTERMEDIATE 9 [1-(3-Fluorophenyl)-3-methyl-1H-pyrazol-5-yl]acetic acid was prepared analogously to the method for Intermediate 3.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 - 7.38 (m, 1H), 7.24 - 7.18 (m, 2H), 7.13 - 7.07 (m, 1H), 6.23 (s, 1H), 3.72 (s, 2H), 2.32 (s, 3H).

INTERMEDIATE 10 [1-(3-Chlorophenyl)-3-methyl-1H-pyrazol-5-yl]acetic acid was prepared analogously to the method for Intermediate 3.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.49 (d, 1H), 7.43 - 7.32 (m, 3H), 6.22 (s, 1H), 3.65 (s, 2H), 2.31 (s, 3H).

INTERMEDIATE 11

This shows the preparation of 5-bromo-N-[(1E)-(dimethylamino)methylene]-thiophene-2- sulfonamide.

To a stirred solution of 5-bromόthiophene-2-sulfonamide (2 g) in acetonitrile (20 mL) was added DMF-DMA (2.24 mL) dropwise. After 20 h the mixture was concentrated in vacuo, and the waxy solid slurried in water and collected by filtration. The solid was washed with

water and air dried to give the title compound 5-bromo-N-[(1E)-(dimethylamino) methylene]thiophene-2-sulfonamide (2.3 g).

¹ H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 7.35 (d, 1H), 7.26 (d, 1H), 3.16 (s, 3H), 2.93 (s, 3H).

INTERMEDIATE 12

This shows the preparation of 4-(4-chlorophenoxy)benzenesulfonamide.

To a solution of 4-chlorophenol (128 mg) and 4-fluorobenzenesulfonamide (175 mg) in NMP (1 mL) was added caesium carbonate (326 mg) and the mixture was heated in a CEM Discover microwave at 130 °C for 10 minutes. The reaction mixture was allowed to cool , and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over sodium sulfate. The filtrate was concentrated in vacuo, and the resulting brown oil was dissolved in diethyl ether and flashed through a short plug of silica. Concentration in vacuo gave an oil that was subjected to column chromatography, eluting with 30% ethyl acetate in iso-hexane to give the title compound 4-(4- chlorophenoxy)benzenesulfonamide (100 mg) as a waxy solid.

¹ H NMR (300 MHz, DMSO) δ 7.92 - 7.82 (m, 4H), 7.52 (dd, 2H), 7.47 - 7.40 (m, 2H), 7.34 (br s, 2H).

INTERMEDIATE 13

This shows the preparation of 4-[(4-chlorophenyl)thio]benzenesulfonamide.

To a solution of 4-fluorobenzenesulfonamide (175 mg) and 4-chlorothiophenol (145 mg) in NMP (1 mL) was added cesium carbonate (358 mg). The reaction mixture was stirred at RT for 20 min, then heated to 130°C in a CEM Discover microwave for 1 min. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by column chromatography eluting with 30% ethyl acetate in iso-hexane to give the title compound 4-[(4- chlorophenyl)thio]benzenesulfonamide (85 mg) as a colourless solid. ¹ H NMR (300 MHz, DMSO) δ 7.78 (d, 2H), 7.58 - 7.46 (m, 4H), 7.46 - 7.37 (m, 4H).

INTERMEDIATE 14

This shows the preparation of 2-(4-fluorobenzyl)thiophene.

A stirred solution of (4-fluorophenyl)(2-thienyl)methanone (2 g) and hydrazine monohydrate (0.622 g) in DIGOL (10 mL) was heated to reflux (245 °C) for 1 h. The yellow/orange solution was allowed to cool, and KOH (1.1 g) was added. Upon warming back to reflux the reaction became frothy. After allowing it to cool again, the mixture was warmed gently in stages until the frothing had subsided. After this time the reaction mixture was heated at reflux for 1 h then cooled and diluted with water (200 mL). It was then partitioned between diethyl ether and water, and the organic phase further washed with water, then dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue purified by column chromatography eluting with 10% ethyl acetate in /so-hexane to give the title compound 2-(4-fluorobenzyl)thiophene (0.95 g) as a pale yellow oil. ¹ H NMR (300 MHz, DMSO) δ 7.24 - 7.13 (m, 3H), 7.05 - 6.89 (m, 3H), 6.78 (m, 1H), 4.12 (s, 2H).

INTERMEDIATE 15

This shows the preparation of N-[(1E)-(dimethylamino)methylene]-5-[(4- methylphenyl)ethynyl]thiophene-2-sulfonamide.

To a stirred solution of Intermediate 11 (1.1 g) in triethylamine (4 mL) and NMP (2 mL) was added 1-ethynyl-4-methylbenzene (473 mg), tetrakis(triphenylphosphine)palladium(0) (5 mg) and copper (I) bromide.dimethylsulfide complex (5 mg). The reaction mixture was heated at 90 °C for 20 h, then partitioned between ethyl acetate and 10% v/v aqueous hydrochloric acid, and the organic phase dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and trituration of the residue with ethyl acetate, methanol and DCM gave a pale brown precipitate that was collected by filtration to give clean title compound (300 mg). The washings were concentrated in vacuo and purified by column chromatography, eluting impurities with 30% ethyl acetate in iso-hexane and later the product with 5% methanol in ethyl acetate to give a further crop of title compound (280 mg). The combined solids gave the title compound N-[(1E)-(dimethylamino)methylene]-5- [(4-methylphenyl)ethynyl]thiophene-2-sulfonamide (580 mg). ¹ H NMR (300 MHz, DMSO) δ 8.26 (s, 1H), 7.51 - 7.46 (m, 3H), 7.38 (d, 1H), 7.28 (d, 2H), 3.20 (s, 3H), 2.98 (s, 3H), 2.37 (β, 3H).

INTERMEDIATE 16

This shows the preparation of 5-[(4-methylphenyl)ethynyl]thiophene-2-sulfonamide.

To a stirred solution of Intermediate 15 (290 mg) in methanol (5 mL) was added aqueous sodium hydroxide (10 %, 4 mL). The reaction mixture was heated at reflux for 2 h, before the methanol was removed in vacuo. The residue was diluted with water then acidified with 10 % aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase

was dried over sodium sulfate, and concentrated in vacuo to give the title compound 5-[(4- methylphenyl)-ethynyl]thiophene-2-sulfonamide (130 mg) as a tan solid. ¹ H NMR (300 MHz, DMSO) δ 7.85 (s, 2H), 7.54 - 7.48 (m, 3H), 7.41 (d, 1H), 7.29 (d, 2H), 2.37 (s, 3H).

INTERMEDIATE 17

This shows the preparation of N-({5-[(4-methylphenyl)ethynyl]-2-thienyl}sulfonyl)-2-(3- methyl-1-phenyl-1H-pyrazoI-5-yl)acetamide.

To a stirred solution of Intermediate 2 (55 mg) and Intermediate 16 (70 mg) in DCM (4 mL) was added EDCI (63 mg) and DMAP (6 mg). After 1 h, the reaction mixture was concentrated in vacuo and purified by RPHPLC (Xterra, 45% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound N-({5-[(4-methylphenyl)ethynyl]-2- thienyl}sulfonyl)-2-(3-methyl-1-phenyl-1H-pyrazoI-5-yl)aceta mide (45 mg) as an off- white solid.

¹ H NMR (300 MHz, DMSO) δ 7.67 (d, 1H), 7.53 (d, 2H), 7.47 - 7.37 (m, 4H), 7.30 (d, 4H), 6.11 (s, 1H), 3.77 (s, 2H), 2.38 (s, 3H), 2.20 (s, 3H).

INTERMEDIATE 18 N-[(1E)-(Dimethylamino)methylene]-5-(phenylethynyl)thiophene -2-sulfonamide was prepared from Intermediate 11 analogously to the method for Intermediate 15.

¹ H NMR (300 MHz, DMSO) δ 8.25 (s, 1H), 7.62 - 7.54 (m, 2H), 7.52 - 7.41 (m, 4H), 7.39 (d, J = 3.8 Hz, 1H), 3.18 (s, 3H), 2.96 (s, 3H).

INTERMEDIATE 19

This shows the preparation of N-[(1E)-(dimethylamino)methylene]-5-(2- phen.ylethyl)thiophene-2-sulfonamide.

To a solution of Intermediate 18 (350 mg) in EtOH (10 mL) was added 10 % PtO ₂ on carbon (20 mg). The reaction was stirred under 2 bar of hydrogen pressure for 1 h. The reaction mixture was filtered through Celite, and concentrated in vacuo to give the title compound N-[(1E)-(dimethylamino)methylene]-5-(2-phenylethyl)thiophene -2-sulfonamide

(320 mg).

¹ H NMR (300 MHz, DMSO) δ 8.17 (s, 1H), 7.33 - 7.15 (m, 6H), 6.84 (dd, 1H), 3.18 - 3.09 (m, 5H), 2.97-2.90 (m, 5H).

INTERMEDIATE 20

This shows the preparation of 5-(2-phenylethyl)thiophene-2-sulfonamide.

To a stirred solution of Intermediate 19 (320 mg) in methanol (5 mL) was added 10 % aqueous sodium hydroxide (3 mL). The reaction mixture was heated at reflux for 1 h then concentrated in vacuo, and water added. The aqueous solution was acidified to neutral pH, and the precipitate extracted into ethyl acetate. The organic phase was dried over sodium

sulfate, filtered, and concentrated in vacuo to give the title compound 5-(2- phenylethyl)thiophene-2-sulfonamide (240 mg).

¹ H NMR (300 MHz, DMSO) δ 7.59 - 7.53 (m, 2H), 7.38 - 7.16 (m, 6H), 6.90 - 6.85 (m, 1H), 3.22 - 3.10 (m, 2H), 3.01 - 2.90 (m, 2H).

INTERMEDIATE 21

4-Bromo-N-[(1E)-(dirnethylamino)methylene]benzenesulfonam ide was prepared analogously to the method for Intermediate 11.

¹ H NMR (300 MHz, DMSO) δ 8.23 (s, 1H), 7.79 - 7.69 (m, 4H), 3.16 (s, 3H), 2.93 (s, 3H).

INTERMEDIATE 22 N-[(1E)-(Dimethylamino)methylene]-4-(phenylethynyl)benzenesu lfonamide was prepared analogously to the method for Intermediate 15.

¹ H NMR (300 MHz, DMSO) δ 8.24 (s, 1H), 7.80 (d, 2H), 7.70 (d, 2H), 7.63 - 7.55 (m, 2H), 7.53 - 7.39 (m, 3H), 3.16 (s, 3H), 2.93 (s, 3H),

INTERMEDIATE 23

N-[(1E)-(Dimethylamino)methylene]-4-(2-phenylethyl)benzenesu lfonamide was prepared analogously to the method for Intermediate 19.

¹ H NMR (300 MHz, DMSO) δ 8.20 (s, 1H), 7.66 (d, 2H), 7.38 (d, 2H), 7.32 - 7.13 (m, 5H), 3.14 (s, 3H), 2.99 - 2.84 (m, 7H).

INTERMEDIATE 24

4-(2-Phenylethyl)benzenesulfonamide was prepared analogously to the method for Intermediate 20.

¹ H NMR (300 MHz, DMSO) δ 7.71 (d, 2H), 7.41 (d, 2H), 7.32 - 7.13 (m, 7H), 3.01 - 2.84 (m, 4H).

INTERMEDIATE 25

This shows the preparation of 3-bromo-4-chlorobenzenesulfonamide.

Concentrated hydrochloric acid (25 mL) was added to a stirred solution of 3-bromo-4- chloroaniline (7.24 g) in THF (60 mL) forming a cream-coloured precipitate. Further THF was added until the precipitate had fully dissolved. The reaction mixture was cooled to -5 °C before the addition of sodium nitrite (2.54 g) in water (15 mL) at a rate such that the temperature of the reaction mixture did not exceed - 5 °C. Once the addition was complete, magnesium chloride (5.25 g) was added portionwise, maintaining the temperature below -3 °C.

To a saturated solution of sulfur dioxide gas in acetic acid (40 mL) was added cupric chloride (1.76 g). To this was added the solution of the diazonium salt resulting in effervescence and an exotherm to 30 °C. The green solution was stirred for 40 rain, before being poured into saturated brine (300 mL) and this mixture was then stirred at RT for 2 h. The solution was extracted with ethyl acetate three times. The combined organic extracts were washed with saturated aqueous sodium bicarbonate then with saturated brine, and dried over magnesium sulfate, filtered, and concentrated in vacuo to leave an orange oil. The oil was dissolved with stirring in THF (60 mL), and aqueous ammonia (60 mL) was added. The mixture was stirred at room temperature for 30 min before being concentrated in vacuo. The residue was partitioned between ethyl acetate and water, and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to give a pale orange solid. The solid was triturated with 4 : 1 iso-hexzne I diethyl ether to give a beige solid (7.26 g).

¹ H NMR (300 MHz, DMSO) δ 8.13 (d, 1H), 7.87-7.79 (m, 2H), 7.58 (s, 2H).INTERMEDIATE 26

3-Bromo-N-[(1E)-(dimethylammo)methylene]-4-methylbenzenes ulfonamide was prepared analogously to the method for Intermediate 11.

¹ H NMR (300 MHz, DMSO) δ 8.22 (s, 1H), 7.89 (d, 1H), 7.67 (dd, 1H), 7.51 (d, 1H), 3.15 (s, 3H), 2.91 (s, 3H), 2.40 (s, 3H).

INTERMEDIATE 27 N-[(1E)-(Dimethylamino)methylene]-4-methyl-3-(phenylethynyl) benzenesulfona prepared analogously to the method for Intermediate 15.

¹ H NMR (300 MHz, DMSO) δ 8.23 (s, 1H), 7.84 (d, 1H), 7.73 - 7.57 (m, 3H), 7.54 - 7.40 (m, 4H), 3.15 (s, 3H), 2.91 (s, 3H), 2.52 (s, 3H).

INTERMEDIATE 28

This shows the preparation of 4-methyl-3-(2-phenylethyl)benzenesuifonaniide.

To a solution of Intermediate 27 (52 mg) in EtOH (10 mL) was added 20 % Pd(OH) ₂ on carbon (10 mg) and the mixture was stirred under hydrogen at 3 bar pressure for 5 h. The reaction mixture was filtered through Celite, washing the plug with DCM. The solution was concentrated in vacuo to give a brown oil that was dissolved in methanol (20 mL) and 10% sodium hydroxide (5 mL). The solution was stirred at reflux temperature for 6 h, cooled, and the solvent removed in vacuo. The residue was taken up in water and acidified with 1 N hydrochloric acid drop wise to precipitate a brown solid that was collected by filtration, washed with water and IPA to give the title compound 4-methyl-3-(2- phenylethyl)benzenesulfonamide (120 mg).

¹ H NMR (300 MHz, DMSO) δ 7.69 (d, 1H), 7.56 (dd, 1H), 7.36 - 7.17 (m, 8H), 2.96 - 2.78 (m, 4H), 2.31 (s, 3H).

INTERMEDIATE 29

This shows the preparation of 5-[(3-chlorophenyl)thio]thiophene-2-sulfonamide,

To a solution of 3-chlorobenzenethiol (87 mg) and 5-bromothiophene-2-sulfonamide (121 mg) in DMF (1 mL) was added aqueous 2 N sodium hydroxide solution (100 μL) and water (1 mL). The reaction was heated in a CEM Discover microwave for 15 rain at 130 °C, then for a further 30 min at 150 °C. The dark solution was partitioned between diethyl ether and water, and the organic phase was dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound 5-[(3- chlorophenyl)thio]thiophene-2-sulfonamide (35 mg).

¹ H NMR (300 MHz, DMSO) δ 7.79 (s, 2H), 7.56 (d, 1H), 7.47 (d, 1H), 7.44 - 7.35 (m, 3H), 7.30 - 7.26 (m, 1H).

INTERMEDIATE 30

This shows the preparation of 4-{[5-(aminosulfonyl)-2-thienyl]thio}benzoic acid.

To a solution of 5-bromothiophene-2-sulfonamide (242 mg) and 4-mercaptobenzoic acid (154 mg) in DMF (1 mL) was added aqueous 2 N sodium hydroxide solution (1 mL). The reaction mixture was heated in a CEM Discover microwave at 150°C for 25 min. After this time it was allowed to cool, then it was diluted with water (20 mL) and acidified with 10 % v/v aqueous hydrochloric acid. The fine precipitate that formed was difficult to filter so the

majority of the liquid was decanted from the solid, and the gelatinous residue concentrated to dryness in vacuo to give the title compound 4-{[5-(aminosulfonyl)-2- thienyl]thio}benzoic acid (280mg).

¹ H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 7.91 (d, 2H), 7.85 (s, 2H), 7.59 (d, 1H), 7.50 (d, 1H), 7.34 (d, 2H).

INTERMEDIATE 31

This shows the preparation of methyl 4-{[5-(ammosulfonyl)-2-thienyl]thio}benzoate.

To a solution of Intermediate 30 (280 mg) in methanol (10 mL) was added chloro- trimethylsilane (1 mL). The solution was stirred for 24 h then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound 4-{[5-(aminosulfonyl)-2-thienyl]thio}benzoate (120 mg) as a gum that solidified on standing.

¹ H NMR (300 MHz, DMSO) δ 7.93 (d, 2H), 7.86 (s, 2H), 7.60 (d, 1H), 7.51 (d, 1H), 7.35 (d, 2H), 3.84 (s, 3H).

INTERMEDIATE 32 This shows the preparation of N-(tert-butyl)-5-(pyridin-4-ylthio)thiophene-2-sulfonamide.

To a solution of n-BuLi in hexanes (2.5 M, 2.4 mL) in THF (20 mL) at -78 °C was added 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide (895 mg) in THF (3 mL) dropwise. The reaction mixture was stirred at this temperature for 30 min then 4,4'-dithiodipyridine (661

mg) in THF (3 mL) was added which caused the formation of a precipitate. The mixture was allowed to warm to RT and stirred for 20 h. The reaction was then partitioned between ethyl acetate and water, and the organic phase washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting impurities with 2 : 1 iso-hexane in ethyl acetate to give the title compound N-(tert-butyl)-5-(pyridin-4-ylthio)thiophene-2-sulfonamide (297 mg) with 1:1 iso-hexane/ethyl acetate.

¹ H NMR (400 MHz, DMSO) δ 8.43 (s, 2H), 7.61 (d, 1H), 7.27 - 7.26 (m, 1H), 7.00 (d, 2H), 4.62 (s, 1H), 1.34 (s, 9H).

INTERMEDIATE 33

This shows the preparation of 5-(pyridin-4-ylthio)thiophene-2-sulforiamide.

To a stirred solution of Intermediate 32 (290 mg) in DCE (4 mL) was added methanesulfonic acid (255 mg). The reaction mixture was heated to 80 °C for 3 h. After cooling, saturated aqueous sodium bicarbonate solution was added slowly until a neutral pH was observed, and the reaction mixture was partitioned between water and DCM. The organic phase was dried over sodium sulfate and concentrated in vacuo to give the title compound 5-(pyridin-4-ylthio)thiophene-2-sulfonamide (159 mg).

¹ HNMR (300 MHz, DMSO) δ 8.46 (dd, 2H), 7.90 (s, 2H), 7.65 (d, 1H), 7.56 (d, 1H), 7.14 (dd, 2H).

INTERMEDIATE 34 This shows the preparation of N-(tert-butyl)-5-(pyridin-2-ylthio)thiophene-2-sulfonamide.

To a stirred solution of n-BuLi in hexanes (2.5 M, 2.4 mL) in THF (20 mL) at -78 °C was added 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide (895 mg) in THF (3 mL) dropwise. The reaction was stirred at this temperature for 30 min then 2,2'-dithiodipyridine (661 mg) in THF (3 mL) was added. The precipitous mixture was allowed to warm to RT and stirred for 20 h. The reaction mixture was then partitioned between ethyl acetate and water, and the organic phase was washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo and purification by column chromatography, eluting with 30 % ethyl acetate in iso-hexane gave the protected sulfonamide. This was taken up in DCE (4 mL), methanesulfonic acid (369 mg) was added and the solution heated at reflux for 3 h. After cooling, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and DCM, and the organic phase was concentrated in vacuo. The gum was purified by RPHPLC (Xterra, 5% to 95% acetonitrile in NH ₄ OAc (0.2% aq.)) to give the title compound N-(tert-butyl)-5-(pyridin-2-ylthio)thiophene-2-sulfonamide (132 mg). ¹ H NMR (300 MHz, DMSO) δ 8.46 (ddd, 1H), 7.82 (s, 2H), 7.76 (td, 1H), 7.58 (d, 1H), 7.45 (d, 1H), 7.25 (ddd, 1H), 7.18 (d, 1H).

INTERMEDIATE 35

This shows the preparation of a mixture of 5-[(4-methyl-1,3-thiazol-2-yl)thio]thiophene-2- sulfonamide and 3-[(4-methyl-1 ,3-thiazol-2-yl)thio]thiophene-2-sulfonamide.

To a stirred solution of n-BuLi in hexanes (2.5 M, 3.1 mL) in THF (25 mL) at -78 °C was added a solution of N-(tert-butyl)thiophene-2-sulfonamide (842 mg) in THF (5 mL) dropwise. The reaction mixture was stirred at this temperature for 1 h prior to the addition of 2,2'-dithiobis(4-methyl-1 ,3-thiazole) (1.0 g) in THF (5 mL). After 30 min, the reaction

mixture was allowed to warm to -50 °C and stirred thereafter for 30 min. It was then poured into dilute aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, before being filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1 : 9 to 1 : 4 ethyl acetate / iso-hexane to leave a yellow oil. This was dissolved in DCE (15 mL) and treated with methanesulfonic acid (1 mL) and heated at reflux for 4 h. Further methanesulfonic acid (1 mL) was added and the reaction mixture heated at reflux for a further 2 h. The cooled reaction mixture was partitioned between DCM and aqueous saturated sodium bicarbonate, and the aqueous phase further extracted three times with DCM. The combined organics were dried over sodium sulfate, before being filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1 : 5 to 1 : 3 ethyl acetate / iso-hexane then 3 : 97 methanol / ethyl acetate to leave a yellow gum (470 mg) as a 0.63 to 0.37 mixture of the tiso isomers 5-[(4-methyl-1,3-thiazol-2- yl)thio]thiophene-2-sulfonamide and 3-[(4-methyl-1,3-thiazol-2-yl)thio]thiophene-2- sulfonamide respectively.

¹ HNMR (400 MHz, DMSO) δ 7.91 (0.74H, s), 7.88 (1.26H, s), 7.85 (0.63H, d), 7.58 - 7.55 (1H, m), 7.36 - 7.35 (0.37H, m), 7.31 - 7.30 (0.63H, m), 7.04 (0.37H, d), 2.36 (1.11H, d), 2.33 (1.89H, d) as a 0.63 : 0:37 mixture of isomers; ES+ and ES-MS: m/z 293 [M+H] ⁺ and 291 [M-H]-.

INTERMEDIATE 36

4- {[5-({[(1E)-(dimethylamino)methylene]amino} sulfonyl)-2-thienyl]thio}benzoic acid was prepared from Intermediate 30 analogously to the method for Intermediate 11.

APCI+MS: m/z 370 [M+H] ⁺ .

INTERMEDIATE 37

This shows the preparation of 4-{[5-(aminosulfonyl)-2-thienyl]thio}-N,N- dimethylbenzamide.

To a solution of Intermediate 36 (200 mg) in THF (5 mL) was added CDI (96 mg). The solution was stirred for 20 min, then dimethylamine in THF (2.0 M, 297 μL) was added. After 20 h, the reaction was concentrated in vacuo and the residue partitioned between 2 N aqueous sodium hydroxide and ethyl acetate. The aqueous phase was acidified and extracted with ethyl acetate, and the organics dried over sodium sulfate, filtered, and concentrated in vacuo. The clear gum was taken up in methanol (5 mL) and 2 N aqueous sodium hydroxide (1 mL) and refluxed for 2 h. After allowing to cool, the reaction was concentrated in vacuo and the residue diluted with water, acidified, and extracted with ethyl acetate. The organic phase was dried, then concentrated in vacuo to give the title compound 4- {[5-(aminosulfonyl)-2-thienyl]thio} -N,N-dimethylbenzamide (50 mg). APCI-MS: m/z 341 [M-H]-.

INTERMEDIATE 38

This shows the preparation of 4-chloro-3-formylbenzenesulfonamide.

To a stirred solution of Intermediate 25 (4 g) in THF (30 mL) at RT was added a solution of isopropylmagnesium chloride in THF (2.0 M, 23 mL) dropwise. The reaction mixture was stirred for 30 min, and then DMF (6 mL) was added rapidly, causing an exo therm to 45 °C. After 30 min, water was added. To the mixture was added aqueous dilute hydrochloric acid and saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1 : 5 to

2 : 5 ethyl acetate / iso-hexane to give 4-chloro-3-formylbenzenesulfonamide as a colourless solid (2.0 g).

¹ H NMR (DMSO) δ 4.94 (s, 2H), 7.64 (d, 1H), 8.07 (d, 1H), 8.46 (s, 1H), 10.50 (s, 1H).

EXAMPLE 1

This Example illustrates the preparation of N-[(4-chlorophenyl)sulfonyl]-2-(3-methyl-1- phenyl-1H-pyrazol-5-yl)acetamide.

To a solution of Intermediate 2 (160 mg) in DCM (1 mL) at RT was added EDCI (90 nig), DMAP (60 mg), and 4-chlorobenzenesulfonamide (90 mg). The reaction was stirred for 19 h and then partitioned between 10 % v/v aqueous hydrochloric acid and DCM. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give an off-white solid. Trituration with ethyl acetate yielded the title compound N- [(4- chlorophenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl) acetamide (94 mg) as a colourless solid.

¹ H NMR (400 MHz, DMSO) δ12.4 (br s, 1H), 7.85 (d, 2H), 7.69 (d, 2H), 7.32 - 7.79 (m, 3H), 7.22 (d, 2H), 6.02 (s, 1H), 3.72 (s, 2H), 2.16 (s, 3H); APCI-MS: m/z 388 [M-H]-.

EXAMPLE 2

This Example illustrates the preparation of N-[(4.-cyanophenyl)sulfonyl]-2-(3-methyl-1- phenyl-1H-pyrazol-5-yl)acetamide.

To a solution of Intermediate 2 (108 mg) in DCM (10 ml) was added EDCI (105 mg), DMAP (6 mg), triethylamine (50 mg) and 4-cyanobenzenesulfonamide (91 mg). The reaction was stirred for 1 h at RT, then partitioned between DCM and 10 % v/v aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo and the recovered gum was purified by RPHPLC (Xterra, 25 % to 75% acetonitrile in aqueous formic acid (0.2%)) to yield the title compound N-[(4- cyanophenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)a cetamide (28 mg) as a solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.11 (d, 2H), 7.83 (d, 2H), 7.43 - 7.34 (m, 3H), 7.30 - 7.23 (m, 2H), 6.08 (s, 1H), 3.56 (s, 2H), 2.27 (s, 3H); APCI+MS: m/z 381 [M+H] ⁺ .

EXAMPLE 3

This Example illustrates the preparation of N-[(4-chlorophenyl)sulfonyl]-2-[1-(4- fluorophenyl)-3-methyl-1H-pyrazol-5-yl]acetamide.

To a solution of Intermediate 3 (50 mg) in DCM (5 mL) was added EDCI (40 mg), DIPEA (35 μL), DMAP (3 mg) and 4-chlorobenzenesulfonamide (41 mg). The reaction mixture was stirred for 2 h at RT and then partitioned between DCM and 10 % v/v aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, filtered, and

concentrated in vacuo to give a clear gum which was purified by RPHPLC (Xterra, 5% to

50% acetonitrile in aqueous ammonia (0.2% aq.)), to give the title compound N-[(4- chlorophenyl)sulfonyl]-2-[1-(4-fluorophenyl)-3-methyl-1H-pyr azol-5-yl]acetamide (20 mg) as a solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88 (d, 2H), 7.47 (d, 2H), 7.32 - 7.25 (m, 2H), 7.04 (t, 2H),

6.06 (s, 1H), 3.51 (s, 2H), 2.27 (s, 3H); APCI+MS: m/z 408 [M+H] ⁺ .

EXAMPLE 4

This Example illustrates the preparation of N-[(4-chlorophenyl)sulfonyl]-2-[1-(3- methoxyphenyl)-3-methyl-1H-pyrazol-5-yl]acetamide.

To a stirred solution of Intermediate 6 (300 mg), 4-chlorobenzenesulfonamide (300 mg), DMAP (200 mg) in DCM (6 mL) at RT was added EDCI (300 mg) and the mixture was stirred for 20 h. The reaction mixture was concentrated in vacuo, methanol was added and this solution was purified by RPΗPLC (Xterra, 5% to 50% acetonitrile in formic acid (0.2% aq.)) to leave, after diethyl ether trituration, the title compound N-[(4- chlorophenyl)sulfonyl]-2-[1-(3-methoxyphenyl)-3-methyl-1H-py razol-5-yl]acetamide (20 mg) as a solid. ¹ H NMR (300 MHz, DMSO) δ 12.43 (s, 1H), 7.84 (d, 2H), 7.68 (d, 2H), 7.26 (t, 1H), 6.90 (dd, 1H), 6.83 (t, 1H), 6.82 - 6.78 (m, 1H), 6.03 (s, 1H), 3.74 (s, 3H), 3.73 (s, 2H), 2.16 (s, 3H); APCI+MS: m/z 420, 422 [M+H] ⁺ .

EXAMPLE 5 This Example illustrates the preparation of N-[(4-tert-butylphenyl)sulfonyl]-2-(3-methyl-1- phenyl-1H-pyrazol-5-yl)acet amide.

To a stirred solution of Intermediate 2 (100 mg) and 4-tert-butyl-benzenesuIfonamide (98 mg) in DCM (4 mL) at RT was added EDCI (97 mg) followed by DMAP (16 mg). The reaction mixture was stirred overnight and then partitioned between DCM and 10% v/v aqueous hydrochloric acid. The organic phase was concentrated in vacuo and triturated with ethyl acetate to give the title compound N-[(4-tert-butylphenyl)sulfonyl]-2-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)acetamide (38 mg) as a colourless solid.

¹ H NMR (300 MHz, DMSO) δ 12.27 (s, 1H), 7.81 (d, 2H), 7.67 (d, 2H), 7.43 - 7.34 (m, 3H), 7.29 - 7.19 (m, 2H), 6.02 (s, 1H), 3.70 (s, 2H), 2.17 (s, 3H), 1.34 (s, 9H); APCI+MS: m/z 412 [M+H] ⁺ .

EXAMPLE 6

This Example illustrates the preparation of N-({5-[(4-chlorophenyl)thio]-2- thienyl}sulfonyl)-2-(3-methyl-1-phenyl-1H-pyrazoI-5-yl)aceta mide.

To a stirred solution of Intermediate 2 (45 mg) and 5-[(4-chlorophenyl)thio]thiophene-2- sulfonamide (64 mg) in DCM (4 mL) at RT was added EDCI (44 mg) then DMAP (5 mg). The mixture was stirred for 4 h, then partitioned between DCM and 10 % v/v aqueous hydrochloric acid, the organic phase dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the gum obtained purified by RPΗPLC (Xterra column, 25% to 95% acetonitrile in aqueous TFA (0.1%)), to give the title compound N-({5-[(4-

chlorophenyl)thio]-2-thienyl}sulfonyl)-2-(3-methyl-1-phenyl- 1H-pyrazol-5-yl)acetamide (15 mg) as a colourless solid.

¹ H NMR (300 MHz, DMSO) δ 7.66 (dt, 1H), 7.51 - 7.31 (m, 8H), 7.29 - 7.24 (m, 2H), 6.08 (s, 1H), 3.73 (s, 2H), 2.18 (s, 3H); APCI+MS: rn/z 504, 506 [M+H] ⁺ .

EXAMPLE 7

This Example illustrates the preparation ofN-{[5-(butylthio)-2-thienyl]sulfonyl}-2-(3- methyl-1-phenyl- 1H-pyrazol-5-yl)acetamide.

To a stirred solution of 1-butanethiol (91 mg) in DMF (5 mL) was added sodium hydride in mineral oil (55%, 52 mg). After 5 min, Intermediate 11 (300 mg) was added and the mixture was heated for 20 h at 70 °C. Water (5 mL) and 10 % w/v aqueous sodium hydroxide (1.6 mL) were then added. The resulting mixture was stirred at RT for 1 h, then heated to reflux for 1 h. The reaction was cooled and concentrated in vacuo. Water was added, the solution was acidified and then extracted into ethyl acetate. The organic phase was separated and dried over sodium sulfate, filtered and concentrated in vacuo to give a gum that was purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)). To a stirred solution of the resultant oil and Intermediate 2 (68 mg) in DCM (3 mL) at RT was added EDCI (73 mg) and DMAP (8 mg). After 20 h, the reaction mixture was concentrated in vacuo and the gum was purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound N-{[5-(butylthio)-2-thienyl]sulfonyl}-2-(3-methyl- 1-phenyl-1ϋ/-pyrazol-5-yl)acetamide (80 mg) as a colourless solid. ¹ H NMR (400 MHz, DMSO) δ 7.58 (d, 1H), 7.41 - 7.31 (m, 3H), 7.26 (td, 2H), 7.17 (d, 1H), 6.06 (s, 1H), 3.71 (s, 2H), 3.02 (t, 2H), 2.17 (s, 3H), 1.61 - 1.53 (m, 2H), 1.38 (sextet, 2H), 0.85 (t, 3H); APCI+MS : m/z 450 [M+H]\

EXAMPLE 8

This Example illustrates the preparation of N-{[5-(isopropylthio)-2-thienyl]sulfonyl}-2-(3- methyl-1-phenyl- 1H-pyrazol-5 -yl)acetamide.

To a stirred solution of 2-propanethiol (77 mg) in THF (10 mL) was added sodium hydride in mineral oil (55%, 57 mg). After 5 min, Intermediate 11 (300 mg) was added and the reaction mixture was heated at reflux for 28 h. The mixture was concentrated in vacuo, and methanol (5 mL) and 2 N aqueous sodium hydroxide (1.6 mL) were added. The mixture was heated at reflux for 1 h, concentrated in vacuo and partitioned between diethyl ether and water. The aqueous phase was acidified with 10% v/v aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was concentrated in vacuo and purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)). The resultant oil and Intermediate 2 (55 mg) were dissolved in DCM (3 mL) and EDCI (53 mg) and DMAP (6 mg) added. After 1 h, the reaction was concentrated in vacuo and the gum purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound N- {[5-(isopropylthio)-2-thienyl]sulfonyl}-2-(3-methyl-1-phenyl -ΪH ^" -pyrazol-5-yl)acetamide (23 mg) as a colourless solid.

¹ H ΝMR (400 MHz, DMSO) δ 7.61 (d, 1H), 7.41 - 7.32 (m, 3H), 7.26 (dd, 2H), 7.23 (d, 1H), 6.04 (s, 1H), 3.71 (s, 2H), 3.44 - 3.36 (m, 1H), 2.16 (s, 3H), 1.25 (d, 6H); APCI+MS: m/z 436 [M+H] ⁺ .

EXAMPLE 9

This Example illustrates the preparation of N-{[4-(4-chlorophenoxy)phenyl]sulfonyl}-2-(3- methyl-1-phenyl-1H-pyrazol-5-yl)acetamide.

To a stirred solution of Intermediate 2 (37 mg) and Intermediate 12 (75 mg) in DCM (4 ml) at RT was added EDCI (36 mg) and DMAP (2 mg). The mixture was stirred for 3 d. It was then concentrated in vacuo and purified by RPHPLC (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound N-{[4-(4-chlorophenoxy)phenyl]sulfonyl}- 2-(3-m ethyl- 1 -phenyl- 1H-pyrazol-5-yl)acetamide (32 mg).

¹ H NMR (300 MHz, DMSQ) δ 12.29 (s, 1H), 7.87 (dd, 2H), 7.55 (dd, 2H), 7.45 - 7.36 (m, 3H), 7.29 - 7.14 (m, 6H), 6.06 (s, 1H), 3.71 (s, 2H), 2.16 (s, 3H); APCI+MS: m/z 482 (M+H ⁺ ); APCI+MS: m/z 482, 484 [M+H] ⁺ .

EXAMPLE 10

This Example illustrates the preparation of N-({4-[(4-chlorophenyI)thio]phenyl}sulfonyl)- 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)acetamide.

To a stirred solution of Intermediate 13 (45 mg) and Intermediate 2 (33 mg) in DCM (3 mL) at RT was added EDCI (35 mg) and DMAP (3.7 mg). The reaction was stirred for 3 d, then concentrated in vacuo and purified by RPΗPLC (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound N-({4-[(4-chlorophenyl)thio]phenyl}sulfonyl)- 2-(3 -methyl-1-phenyl-1H-pyrazol-5-yl)acetamide (36 mg) as a colourless solid.

¹ H NMR (300 MHz, DMSQ) δ 12.34 (s, 1H), 7.77 (d, 2H), 7.59 (s, 4H), 7.44 - 7.31 (m, 5H), 7.25 (d, 2H), 6.04 (s, 1H), 3.70 (s, 2H), 2.18 (s, 3H); APCI+MS: m/z 498, 500 [M+H] ⁺ .

EXAMPLE 11

This Example illustrates the preparation ofN-{[5-(4-fluorobenzyl)-2-thienyl]sulfonyl}-2- (3-methyl-1-phenyl-1H-pyrazol-5- yl)acetamide.

Phosphorus pentachloride (1.95 g) was added in small portions to stirred chlorosulfonic acid (1.1 g) at RT. The dark solution was then cooled using an ice bath. Slowly, Intermediate 14 (0.9 g) was added dropwise. After complete addition the reaction was poured onto ice, and extracted with DCM. The organic phase was washed with water, dried over sodium sulfate, and filtered. Concentration in vacuo gave an oil, which was dissolved in THF (5 mL), and aqueous ammonia (1 mL) was added. The mixture was stirred for 20 min then concentrated in vacuo to give a brown gum (60 mg) that was dissolved in DCM (5 mL). To this was added Intermediate 2 (50 mg), EDCI (55 mg) and DMAP (5 mg). The reaction mixture was stirred for 1 h, then concentrated in vacuo and purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound N-{[5-(4- fluorobenzyl)-2-thienyl]sulfonyl}-2-(3-methyl-1-phenyl-1H-py razol-5-yl)acetamide (19 mg).

¹ H NMR (300 MHz, DMSQ) δ 12.41 (s, 1H), 7.59 (s, 1H), 7.44 - 7.12 (m, 9H), 7.02 (s, 1H), 6.07 (S, 1H), 4.26 (s, 2H), 3.70 (s, 2H), 2.19 (s, 3H); APCI+MS: m/z 470 [M+H] ⁺ .

EXAMPLE 12

This Example illustrates the preparation of N-({5-[2-(4-methylphenyl)ethyl]-2- thienyl}sulfonyl)-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)aceta mide.

To a stirred solution of Intermediate 17 (30 mg) in EtOH (10 mL) was added 10% Pd/C (10 mg) at RT. The reaction mixture was stirred for 20 h at 2 bar hydrogen pressure. The reaction was filtered through Celite then concentrated in vacuo to give the title compound N-({5-[2-(4-methylphenyl)ethyl]-2-thienyl}sulfonyl)-2-(3-met hyl-1-phenyl-1H-pyrazol-5- yl)acetamide (21 mg) as a colourless solid.

¹ HNMR (300 MHz, DMSQ) δ 12.42 (s, 1H), 7.53 (d, 1H), 7.46 - 7.25 (m, 5H), 7.18 -. 7.06 (m, 4H), 6.95 (d, 1H), 6.09 (s, 1H), 3.68 (s, 2H), 3.18 (t, 2H), 2.92 (t, 2H), 2.27 (s, 3H), 2.20 (s, 3H); APCI+MS: m/z 480 [M+H] ⁺ .

EXAMPLE 13

This example illustrates the preparation of N-({5-[(4-chlorophenyl)thio]-2- thienyl}sulfonyl)-2-[1-(4-fluorophenyl)-3-methyl-1H-pyrazol- 5-yl] acetamide.

To a stirred solution of 5-[(4-chlorophenyl)thio]thiophene-2-sulfonamide (91 mg) and

Intermediate 3 (70 mg) in DCM (3 mL) at RT was added EDCI (63 mg) and DMAP (2 mg). The reaction mixture was stirred for 1 h, then concentrated in vacuo and purified by

RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound N-

({5-[(4-chlorophenyl)thio]-2-thienyl}sulfonyl)-2-[1-(4-fl uorophenyl)-3-methyl-1H- pyrazol-5-yl]acetamide (54 mg).

¹ H NMR (400 MHz, DMSO) δ 7.65 (d, 1H), 7.49 - 7.41 (m, 4H), 7.38 (d, 1H), 7.35 - 7.29

(m, 2H), 7.19 (t, 2H), 6.07 (s, 1H), 3.72 (s, 2H), 2.16 (s, 3H); APCI-MS: m/z 520, 522

[M-H]-.

EXAMPLE 14

This example illustrates the preparation of N-[(2,5-dichloro-3-thienyl)sulfonyl]-2-(3- methyl-1-phenyl-1H-pyrazol-5-yl)acetamide.

To a stirred solution of Intermediate 2 (48 mg) and 2,5-dichlorothiophene-3-sulfonamide (52 mg) in DCM (4 mL) at RT was added EDCI (51 mg) and DMAP (2 mg). The reaction mixture was stirred for 1 h then concentrated in vacuo and purified by RPHPLC (Xterra,

5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound N-[(2,5-dichloro-3- thienyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)aceta mide (21 mg). ¹ H NMR (300 MHz, DMSCO δ 7.49 - 7.36 (m, 3H), 7.35 - 7.28 (m, 3H), 6.12 (s, 1H), 3.77 (s,. 2H), 2.19 (s, 3H); APCI-MS: m/z 428, 430 [M-H]-.

EXAMPLE 15

This example illustrates the preparation of 2-(3-methyl-1 -phenyl- 1H-pyrazol-5-yl)-N-{ [5- (2-phenylethyl)-2-thienyl] sulfonyl} acetamide.

To a stirred solution of Intermediate 2 (5 mg) and Intermediate 20 (62 mg) in DCM (4 mL) at RT was added EDCI (53 mg) and DMAP (4 mg). The reaction mixture was stirred for 1 h then concentrated in vacuo and purified by RPΗPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[5- (2-phenylethyl)-2-thienyl]sulfonyl} acetamide (35 mg). ¹ H NMR (300 MHz, DMSO) δ 12.40 (s, 1H), 7.57 - 7.53 (m, 1H), 7.46 - 7.35 (m, 4H), 7.34 - 7.16 (m, 6H), 7.02 - 6.93 (m, 1H), 6.07 (s, 1H), 3.69 (s, 2H), 3.24 - 3.14 (m, 2H), 3.01 - 2.91 (m, 2H), 2.18 (s, 3H); APCI-MS: m/z 464 [M-H]-.

EXAMPLE 16 This example illustrates the preparation of 2-(3 -methyl- 1 -phenyl- 1H-pyrazol-5-yl)-N- [(4- phenoxyphenyl)sulfonyl] acetamide.

To a stirred solution of 4-phenoxybenzenesulfonyl chloride (75 mg) in THF (4 mL) was added aqueous ammonia (2 mL). The solution was stirred for 10 min then concentrated in vacuo. The solid residue was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM (4 mL) and Intermediate 2 (50 mg), EDCI (53 mg) and DMAP (3 mg) were added. The reaction was stirred for 20 h, then concentrated in vacuo and purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound 2- (3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-[(4-phenoxyphenyl)sulf onyl]acetamide (51 mg). ¹ H NMR (300 MHz, DMSO) δ 12.26 (s, 1H), 7.84 (d, 2H), 7.50 (t, 2H), 7.44 - 7.34 (m, 2H), 7.33 - 7.21 (m, 4H), 7.19 - 7.09 (m, 4H), 6.03 (s, 1H), 3.69 (s, 2H), 2.17 (s, 3H); APCI+MS: m/z 448 [M+H] ⁺ .

EXAMPLE 17 This example illustrates the preparation of N-[(3,4-dichlorophenyl)sulfonyl]-2-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)acetamide.

To a solution of 3,4-dichlorobenzenesulfonyl chloride (68 mg) in TΗF (4 mL) was added aqueous ammonia (2 mL) and the reaction mixture was stirred for 5 min. It was then concentrated in vacuo to dryness. The residue was dissolved in DCM (4 mL) with Intermediate 2 (50 mg), EDCI (58 mg) and DMAP (3 mg), stirred for 1 h then concentrated in vacuo and purified by RPΗPLC (Xterra, 5% to 95% acetonitrile in TFA

(0.2% aq.)) to give the title compound N-[(3,4-dichlorophenyl)sulfonyl]-2-(3-methyl-1- phenyl-1H-pyrazol-5-yl)acetamid.e (44 mg).

¹ HNMR (300 MHz, DMSQ) δ 8.01 - 7.87 (m, 2H), 7.77 (d, 1H), 7.41 - 7.21 (m, 5H), 6.06 (s, 1H), 3.76 (s, 2H), 2.17 (s, 3H); APCI-MS: ra/z 422, 424 [M-H]-.

EXAMPLE 18

This example illustrates the preparation of N-[(5-bromo-2-thienyl)sulfonyl]-2-(3-methyl- 1 -phenyl- 1H-pyrazol-5-yl)acetamide.

To a stirred solution of 5-bromothiophene-2-sulfonamide (2.42 g) and Intermediate 2 (2.16 g) in DCM (50 mL) was added EDCI (2.49 g) and DMAP (2 mg). The reaction was stirred for 4 h at RT and more EDCI (500 mg) and DMAP (10 mg) were added. The reaction was stirred for 20 h then partitioned between DCM and 0.5% v/v aqueous hydrochloric acid. The organic phase was dried over sodium sulfate and concentrated in vacuo to give a foam. Ethyl acetate was added until the foam had just dissolved, and iso-hexane added dropwise until a solid began to form. Trituration yielded the title compound N-[(5-bromo-2- thienyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)aceta mide (2.4 g). ¹ H NMR (300 MHz, DMSQ) δ 7.53 (d, 1H), 7.43 - 7.31 (m, 4H), 7.30 - 7.25 (m, 2H), 6.09 (s, 1H), 3.76 (s, 2H), 2.18 (s, 3H); APCI-MS: m/z 438, 440 [M-H]-.

EXAMPLE 19

This example illustrates the preparation of N-({5-[(2-chlorophenyl)thio]-2- thienyl}sulfonyl)-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)aceta mide.

To a solution of 2-chlorothiophenol (87 mg) and 5-bromothiophene-2-sulfonamide (121 mg) in DMF (1 mL) was added 2 N aqueous sodium hydroxide (100μL) and water (1 mL). The reaction mixture was heated in a CEM Discover microwave at 130 °C for 5 min, then 150 °C for 20 min. The mixture was partitioned between diethyl ether and water, and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant oil was purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)> to give a small amount of 5-[(2-chlorophenyl)thio]thiophene-2-sulfonamide (22 mg) that was dissolved in DCM (2 mL). To this solution was added Intermediate 2 (15 mg), EDCI (17 mg) and DMAP (3 mg). The reaction mixture was stirred for 3 h, then concentrated in vacuo and the residue purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound N-( {5-[(2-chlorophenyl)thio]-2-thienyl} sulfonyl)-2-(3 - methyl- 1 -phenyl-1H-pyrazol-5-yl)acetamide (17 mg). ¹ H NMR (300 MHz, DMSQ) δ 7.70 (d, 1H), 7.59 (dd, 1H), 7.46 (d, 1H), 7.41 - 7.25 (m, 7H), 7.16 (d, 1H), 6.08 (s, 1H), 3.73 (s, 2H), 2.17 (s, 3H); APCI-MS: m/z 502, 504 [M- H]-.

EXAMPLE 20

This example illustrates the preparation of methyl 4-{[5-({[(3-methyl-1-phenyl-1H- pyrazol-5-yl)acetyl]amino} sulfonyl)-2-thienyl]thio}benzoate..

To a stirred solution of Intermediate 31 (100 mg) and Intermediate 2 (66 mg) in DCM (4 mL) at RT was added EDCI (75 mg) and DMAP (3 mg). The reaction mixture was stirred for 2 h then partitioned between DCM and water. The organic phase was dried over sodium sulfate and concentrated in vacuo to give a crude sample of the title compound methyl 4- {[5-( {[(3-methyl-1-phenyl-1H-pyrazol-5-yl)acetyl]amino} sulfρnyl)-2- thienyl]thio}benzoate (120 mg). Some (60 mg) of this sample was purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give an analytically pure sample of the title compound (45 mg). ¹ H NMR (300 MHz, DMSO) δ 7.92 (d, 2H), 7.76 - 7.71 (m, 1H), 7.54 - 7.50 (m, 1H), 7.44 - 7.25 (m, 7H), 6.09 (s, 1H), 3.84 (s, 3H), 3.75 (s, 2H), 2.18 (s, 3H); APCI-MS: m/z 526 [M-H]-.

EXAMPLE 21 This example illustrates the preparation of 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[5- (pyridin-4-ylthio)-2-thienyl]sulfonyl} acetamide hydrochloride.

To a stirred solution of Intermediate 33 (63 mg) and Intermediate 2 (50 mg) in DCM (4 mL) at RT was added EDCI (58 mg) and DMAP (7 mg). The reaction mixture was stirred for 20 h, concentrated in vacuo and purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) then RPHPLC (Xterra, 5% to 50% acetonitrile in NH ₄ OAc (0.2% aq.)).

The recovered gum was dissolved in DCM (2 mL) with a few drops of methanol, and hydrochloric acid in dioxane (4 M, 200 μL) was added. The precipitous solution was concentrated in vacuo to give the title compound 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)- N-{[5-(pyridin-4-ylthio)-2-thienyl]sulfonyl}acetamide hydrochloride (40 mg). ¹ H NMR (400 MHz, DMSQ) δ 8.64 (d, 2H), 7.86 (d, 1H), 7.71 (d, 1H), 7.61 (d, 2H), 7.45 7.24 (m, 5H), 6.13 (s, 1H), 3.84 (s, 2H), 2.18 (s, 3H); APCI-MS: m/z 469 [M-H]-.

EXAMPLE 22

This example illustrates the preparation of 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[5- (pyridin-2-y lthio)-2-thienyl]sulfonyl} acetamide.

To a stirred solution of Intermediate 2 (50 mg) and Intermediate 34 (63 mg) in DCM (4 mL) at RT was added EDCI (58 mg) and DMAP (4 mg). The mixture was stirred for 3 h, concentrated in vacuo and purified by RPHPLC (Xterra, 5% to 50% acetonitrile in NH ₄ OAc (0.2% aq.)) then by RPHPLC (Xterra, 5% to 50% acetonitrile in TFA (0.2% aq.)) to give the title compound 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-{[5-(pyridin-2- ylthio)-2-thienyl]sulfonyl} acetamide (25 mg).

¹ H NMR (400 MHz, DMSQ) δ 8.48 (d, 1H), 7.76 (t, 1H), 7.70 (d, 1H), 7.47 (d, 1H), 7.40 - 7.24 (m, 7H), 6.08 (s, 1H), 3.73 (s, 2H), 2.16 (s, 3H); APCI+MS: rn/z 471 [M+H] ⁺ .

EXAMPLE 23

This example illustrates the preparation of 2-(4-bromo-3 -methyl- 1 -phenyl- 1H-pyrazol-5- yl)-N-[(4-chlorophenyl)sulfonyl]acetamide.

To a stirred solution of Example 1 (40 mg) in acetic acid (5 mL) at RT was added bromine (10 μL). The reaction was stirred for 1 h then concentrated in vacuo and triturated with diethyl ether to give the title compound 2-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)- N-[(4-chlorophenyl)sulfonyl]acetamide (10 mg).

¹ H NMR (300 MHz, DMSQ) δ 10.08 (s, 1H), 7.92 (d, 2H), 7.49 (d, 2H), 7.46 - 7.30 (m, 5H), 3.88 (s, 2H), 2.45 (s, 3H); APCI+MS: m/z 468, 470 [M+H] ⁺ .

EXAMPLE 24 This example illustrates the preparation of N-[(4-chlorophenyl)sulfonyl]-2-(4-iodo-3- memyl-1-phenyl-1H-pyrazol-5-yl)acetamide.

Iodine (285 mg) was added slowly to a stirred solution of Example 1 (190 mg) and silver acetate (100 mg) in DCM (10 mL) at RT. After 1 h, the reaction mixture was filtered, washing the residue with DCM and acetonitrile. The filtrate was concentrated in vacuo and the residue subjected to flash column chromatography, eluting with 3 : 7 ethyl acetate / iso- hexane. The appropriate fractions were evaporated and the resulting solid triturated with 1 : 1 ethyl acetate / diethyl ether to leave the title compound as a colourless solid (160 mg). ¹ H NMR (400 MHz, DMSO) δ 2.15 (3H, s), 3.72 (2H, s), 7.18 - 7.23 (2H, m), 7.37 - 7.41 (3H, m), 7.70 (2H, d), 7.85 (2H, d), 12.62 (1H, br s); ES+MS: m/z 516, 518 [M+H] ⁺ , ES-

MS 514, 516 [M-H]-.

EXAMPLE 25

This example illustrates the preparation of N-[(4-chlorophenyl)sulfonyl]-2-(3,4-dimethyl- 1 -phenyl-1H-pyrazol-5-yl)acetamide.

To a stirred solution of Example 23 (100 mg) and [1,3-bis-(diphenylphosphino)-ρropane] nickel dichloride (2 mg) in THF (4 mL) was added dimethylzinc (2.0 M in toluene, 213 μL). The mixture was then heated at 80 °C for 3 h. Having been allowed to cool, the reaction mixture was poured into saturated aqueous ammonium chloride solution, and extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was redissolved in 4 : 1 acetonitrile / water, and subjected to RPHPLC (Novapak, 5% to 50% acetonitrile in NH ₄ OAc (0.2% aq.)) to give the title compound N-[(4-chlorophenyl)sulfonyl]-2-(3,4- dimethyl-1 -phenyl- 1H-pyrazol-5-yl)acetamide (10 mg).

¹ H NMR (400 MHz, DMSO) δ 1.80 (3H, s), 2.09 (3H, s), 3.66 (2H, s), 7.12 (2H, dd), 7.29 - 7.37 (3H, m), 7.70 (2H, dm), 7.84 (2H, dm), 12.47 (1H, br s); ES+MS: m/z 404, 406 [M+H] ⁺ , ES-MS 402, 404 [M-H]-.

EXAMPLE 26

This example illustrates the preparation of N-{[4-chloro-5-(phenylthio)-2- thienyl]sulfonyl}-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)aceta mide.

To a stirred solution of Intermediate 2 (91 mg) and 4-chloro-5-(phenylthio)thiophene-2- sulfonamide (160 mg) in DCM (2 mL) at RT was added EDCI (104 mg) and DMAP (3 mg). The reaction mixture was stirred for 3 h, then concentrated in vacuo and the residue purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound N-{[4-chloro-5-(phenylthio)-2-thienyl]sulfonyl}-2-(3-methyl- 1-phenyl-1H- pyrazoI-5-yl)acetamide (65 mg).

¹ H NMR (300 MHz, DMSQ) δ 7.74 (s, 1H), 7.49 - 7.42 (m, 5H), 7.40 - 7.25 (m, 5H), 6.10 (s, 1H), 3.77 (s, 2H), 2.18 (s, 3H); APCH-MS: m/z 504, 506 [M+H] ⁺ .

EXAMPLES 27&28

This example illustrates the preparation of 2-(3 -methyl-1-phenyl-1H-pyrazol-5-yl)-N-( {5-

[(4-methyl-1,3-thiazol-2-yl)thio]-2-thienyl}sulfonyl)acet amide and 2-(3-methyl-1-phenyl- 1H-pyrazol-5-yl)-N-({3-[(4-methyl-1,3-thiazol-2-yl)thio]-2-t hienyl}sulfonyl)acetamide.

To a stirred solution of Intermediate 2 (178 mg) and Intermediate 35 (240 mg) in DCM (5 mL) was added EDCI (220 mg) and DMAP (7 mg). The reaction mixture was stirred for 2 h, concentrated in vacuo, and purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-({3-[(4-methyl-1,3-t hiazol-

2-yl)thio]-2-thienyl}sulfonyl)acetamide (35 mg) eluting as the first peak, and 2-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)-N-({5-[(4-methyl-1,3-thiazol-2-yl) thio]-2-thienyl}sulfonyl)- acetamide (100 mg) eluting as the second peak.

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-({3-[(4-niethyl-1 ,3-thiazol-2-yl)thio]-2- thienyl}sulfonyl)acetamide: ¹ H NMR (400 MHz, DMSQ) δ 8.08 (d, 1H), 7.48 - 7.41 (m, 2H), 7.41 - 7.36 (m, 2H), 7.33 - 7.27 (m, 2H), 7.09 (d, 1H), 6.08 (s, 1H), 3.67 (s, 2H), 2.36 (d, 3H), 2.17 (s, 3H); APCI+MS: m/z 491 [M+H] ⁺ .

2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-({5-[(4-methyl-1, 3-thiazol-2-yl)thio]-2- thienyl}sulfonyl)acetamide: 1H NMR (400 MHz, DMSCO δ 7.71 (d, 1H), 7.57 (d, 1H), 7.40 - 7.30 (m, 4H), 7.28 - 7.25 (m, 2H), 6.08 (s, 1H), 3.76 (s, 2H), 2.34 - 2.33 (m, 3H), 2.17 (s, 3H); APCI+MS: m/z 491 [M+H] ⁺ .

EXAMPLE 29

This example illustrates the preparation of N-{[4-chloro-3- (bydroxymethyl)phenyl]sulfonyl}-2-(3-methyl-1-phenyl-1H-pyra zol-5-yl)acstamide.

To a stirred solution of Intermediate 2 (500 mg), Intermediate 38 (500 mg), and DMAP (280 mg) in DCM (5 mL) at RT was added EDCI (370 mg). The reaction mixture was stirred for 24 h, concentrated in vacuo, and the residue was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give, after trituration with diethyl ether, the intermediate N-[(4-chloro-3- formylphenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl) acetamide as a solid (1.1

g). To a stirred solution of this solid (200 mg), and dimethylamine solution in THF (2.0 M, 0.5 mL), in THF (5 mL) at RT was added sodium triacetoxyborohydride (101 mg). The reaction mixture was stirred for 2 h, methanol added, then concentrated in vacuo, and purified by RPHPLC (Symmetry, 5% to 95% acetonitrile in NH ₄ OAc (0.2% aq.)) and by RPHPLC (Symmetry, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give, after trituration with diethyl ether, the title compound, N-{[4-chloro-3-(hydroxymethyl)phenyl]sulfonyl}- 2-(3-methyl-1 -phenyl- 1H-pyrazol-5-yl)acetamide (48 mg).

¹ H NMR (300 MHz, DMSO) δ 12.38 (s, 1H), 8.05 (s, 1H), 7.75 - 7.63 (m, 2H), 7.40 - 7.31 (m, 3H), 7.26 - 7.21 (m, 2H), 6.04 (s, 1H), 5.74 (s, 1H), 4.62 (s, 2H), 3.70 (s, 2H), 2.16 (s, 3H); APCI+MS: m/z 420 [M+H] ⁺ .

EXAMPLE 30

This example illustrates the preparation of N-(1H-indol-2-ylsulfonyl)-2-(3-methyl-1- phenyl-1H-pyrazol-5-yl)acetamide.

To a stirred solution of 1H-indole-2-sulfonamide (91 mg), Intermediate 2 (100 mg), and DMAP (6 mg) in DCM (5 mL) at RT was added EDCI (115 mg). The reaction mixture was stirred for 24 h, and the precipitate was collected by filtration, washed with water and diethyl ether, then dried to give the title compound N-(1H-mdol-2-ylsulfonyl)-2-(3-methyl- 1 -phenyl- 1H-pyrazol-5-yl)acetamide as a colourless solid (60 mg). ¹ HNMR (400 MHz, DMSO) δ 12.41 (s, 1H), 12.08 (s, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.33 (t, 1H), 7.30 - 7.19 (m, 5H), 7.15 (t, 1H), 7.09 (s, 1H), 6.03 (s, 1H), 3.71 (s, 2H), 2.12 (s, 3H); APCI+MS: m/z 395 [M+H] ⁺ . The examples in the following table were prepared using methods analogous to those described herein above.

Pharmacological Data

Exemplified compounds were tested to determine inhibition of endothelin-converting enzyme-1 (ECE-1) using the method of Johnson and Ahn (Anal. Biochem. 2000, 286,112- 118): with analysis being conducted at either ambient temperature using 50 mM Tris Maleate pH6.0 assay buffer and samples prepared in a 384 wel1-plate format (Conditions A); or alternatively at 37 °C using 50 mM Tris Maleate pH6.0 assay buffer and samples prepared in a 96 wel1-plate format (Conditions B).

The compounds of the examples have a pIC ₅₀ of least 4.0. pIC ₅₀ values for a representative selection of compounds are given in the Table below.