MXPA00008710A

MXPA00008710A - Benzenesulfonamide-derivatives and their use as medicaments

Info

Publication number: MXPA00008710A
Application number: MXPA/A/2000/008710A
Authority: MX
Inventors: Nowak Thorsten; Roger John Butlin; Jeremy Nicholas Burrows; David Stephen Clarke; Paul Robert Owen Whittamore
Original assignee: Zeneca Limited
Priority date: 1998-03-17
Filing date: 2000-09-06
Publication date: 2002-03-05

Abstract

Compounds of formula (I), pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, wherein:Ring X is phenyl or a six membered heteroaryl ring containing one or two ring nitrogens where said nitrogens are optionally oxidised to form the N-oxide;R1 and R2 are substituents as defined within;R3 and R4 are defined within and are alkyl or halo alkyl or together form a cycloalkyl or halocycloalkyl ring;R5 is a substituent as defined within;Y-Z is a linking group as defined within;are useful in the production of an elevation of PDH activity in a warm-blooded animal such as a human being. Pharmaceutical compositions, methods and processes for preparation of compounds of formula (I) are described.

Description

BENCENSULFONAMIDE DERIVATIVES AND THEIR USE AS MEDICATIONS DESCRIPTION OF THE INVENTION The present invention relates to compounds that increase the activity of pyruvate dehydrogenase (PDH), the processes for their preparation, pharmaceutical compositions containing them as an active ingredient, methods for the treatment of disease states associated with the reduced activity of PDH, its use as medicaments and its use in the manufacture of medicaments for use in elevating PDH activity in warm-blooded animals such as humans. Within tissues, adenosine triphosphate (ATP) provides the energy for the synthesis of complex molecules and, in muscle, for contraction. ATP is generated from the breakdown of energy-rich substrates such as glucose or long-chain free fatty acids. In oxidative tissues such as muscle, the majority of ATP is generated from acetyl CoA which enters the citric acid cycle, thus the supply of acetyl CoA is a critical determinant of the production of ATP in oxidative tissues. Acetyl CoA is produced by ß-oxidation of fatty acids or as a result of glucose metabolism by the glycolytic pathway. The key regulatory enzyme for controlling the rate of acetyl CoA glucose formation is PDH which catalyzes the oxidation of pyruvate to acetyl CoA X carbon dioxide with the concomitant reduction of nicotinamide adenine dinucleotide (NAD) in NADH. In disease states such as non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes (IDDM), lipid oxidation is increased with a concomitant reduction in glucose utilization, which contributes to hyperglycemia. Reduced utilization of glucose in IDDM and NIDDM is associated with a reduction in PDH activity. In addition, an additional consequence of reduced PDH activity may be that an increase in pyruvate concentration results in increased availability of lactate as a substrate for hepatic gluconeogenesis. It is reasonable to expect that the increase in PDH activity may increase the rate of glucose oxidation and consequently the total utilization of glucose, in addition to reducing the production of hepatic glucose. Another factor that contributes to diabetes mellitus is unbalanced insulin secretion, which has been shown to be associated with reduced PDH activity in pancreatic β-cells (in a genetic model of diabetes mellitus rodent Zhou et al. (1996) Diabetes 45: 580-586). The oxidation of glucose is capable of producing more ATP molecules per mole of oxygen than in the oxidation of fatty acids. In conditions where the demand for energy can exceed the energy supply, such as myocardial ischemia, intermittent claudication, cerebral ischemia and reperfusion, (Zaidan et al., 1998, J. Neurochem, 70: 233-241), changing the balance of substrate utilization in favor of glucose metabolism by elevating the activity of PDH can be expected to * improve the ability to maintain ATP levels and consequently function. It can also be expected that an agent that is capable of raising PDH activity will be of benefit in treating conditions in which an excess of circulating lactic acid is manifested, such as in certain cases of asepsis. It has been shown that the dichloroacetic acid (DCA) agent which increases the activity of PDH after acute administration in animals (Vary et al., 1988, Circ.Shock, 24: 3-18), has the predicted effects in the reduction of glycemia, (Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530), and as a therapy for myocardial ischemia (Bersin and Stacpoole 1997; American Heart Journal, 134: 841 -855) and lactic acidemia, (Stacpoole et al., 1983; N. Engl. J. Med. 309: 390-396). PDH is an intramitochondrial multienzyme complex consisting of multiple copies of various subunits that include three enzymatic activities, E2, and E3, required to complete the conversion of pyruvate to acetyl CoA (Patel and Roche 1990; FASEB J., 4: 3224-3233). It catalyzes the non-reversible removal of C02 from pyruvate; E2 forms acetyl CoA and E3 reduces NAD to NADH. Two additional enzymatic activities are associated with the complex: a specific kinase that is capable of phosphorylating El in three serine residues and a specific phosphatase associated with release which reverses phosphorylation. Phosphorylation of only one of the three serine residues produces the inactive El. The proportion of PDH in its active (dephosphorylated) state is determined by a balance between the activity of the kinase and the phosphatase. The activity of the kinase can be immobilized in vivo by the relative concentrations of the metabolic substrates such as NAD, / NADH, CoA / acetylCoA and adenine diphosphate.

(ADP) / ATP as well as for the availability of pyruvate itself. European Patent Publication No. 625516 relates to the compounds that are capable of relaxing the smooth muscle of the bladder and what can be used in the treatment of forced incontinence. It has surprisingly been found that the compounds which also contain a sulfonamide moiety described in the present invention are very good in raising the activity of PDH, a property on no side described in EP 625516. The present invention is based on the surprising discovery that certain compounds elevate PDH activity, a property of value in the treatment of disease states associated with disorders of glucose utilization such as diabetes mellitus, obesity, (Curto et al., 1997; Int. J .

Obes 21: 1137-1142); and lactic acidemia. Additionally, the compounds may be expected to have utility in diseases where the supply of energy-rich substrates to tissues is limited such as in peripheral vascular disease, (which includes intermittent claudication), heart failure and certain cardiac myopathies, muscle weakness, hyperlipidemia and atherosclerosis (Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530). A compound that activates PDH may also be useful for treating the disease Alzheimer's disease (AD) (J Neural Transm (1998) 105: 855-870). Accordingly, the present invention provides a compound of the formula (I): (I) wherein: Ring X is phenyl or a six-membered heteroaryl ring containing one or two ring nitrogens wherein the nitrogens are optionally oxidized to form the α-oxide; R1 and R2 are independently as defined in (a) or (b); R3 and R4 are as defined in (c) or (d); R5 is as defined in (e) or (f); YZ are as defined in (g) or (h) wherein: (a) R1 and R2 are each independently selected from hydrogen, C? _ Alkyl, pyridyl and phenyl which is unsubstituted or substituted by one or two substituents independently selected from C 1 -4 alkyl, C 1-4 alkoxy, C 2-4 alkenyloxy, hydroxy, halo and cyano, or R and R 2 together with the nitrogen atom to which they are attached morpholine, thiomorpholino, piperidinyl, pyrrolidinyl or imidazolyl; (b) R1 and R2 are each independently selected from phenyl substituted by one or more P (wherein P is as defined below), phenyl substituted by one or more groups selected from C? _4 alkyl, C? 4, alkenyloxy, hydroxy, halo and cyano and further substituted by one or more groups selected from P, a heterocyclic group other than unsubstituted pyridyl which is substituted, optionally on a carbon ring by one or more Q (wherein Q is as defined below) and wherein if the heterocyclic group contains an -NH- portion that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined below), naphthyl optionally substituted by one or more Q, C6 alkyl, C3_6 cycloalkyl optionally substituted with one or more Q, C2_6 alkenyl, C2_6 alkynyl, C3 alkyl substituted by one or more V (wherein V is as defined below), R6I- (where R6 and T s on as defined below) and R7alkyl of C? _TT- (wherein R7 is as defined below), or R1 and R2 together with the nitrogen atom to which they are attached, form a heterocyclic group other than unsubstituted morpholino, thiomorpholino unsubstituted, unsubstituted piperidinyl, unsubstituted pyrrolidinyl or unsubstituted imidazolyl which are optionally substituted on a carbon ring by one or more Q (wherein Q is as defined below) and wherein if the heterocyclic group contains • a -NH- that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined below); (c) R3 and R4 are independently Ck alkyl optionally substituted by 1 to 2k + 1 atoms selected from fluorine and chlorine wherein k is 1-3, with the proviso that R and R4 are not both methyl; or R3 and R4 together with the carbon atom to which they are attached form a cycloalkyl ring of Cm optionally substituted from 1 to 2m-2 fluorine atoms wherein m is 3-5; (d) R3 and R4 are both methyl; (e) R5 is hydrogen, C? - alkyl, C? _4 haloalkyl, C? _4 alkoxy, C1_4 haloalkoxy, cyano, nitro, C2_4 alkenyloxy or trifluoromethylthio; (f) R5 is halo, hydroxy, amino, Ci-g alkylamino, (C? -g) 2amino alkyl, C? _6 alkanoylamino, C? -6 alkanoylamino (N-C? _6 alkyl), thiol alkylsulfonylamino of C? -6, alkylsulfonylamino of C? -6 (N-alkyl of C? -6), thiol, alkylsulfanyl of C? _6, alkylsulfinyl of C? -6, alkylsulfonyl of C? _6, sulfa oyl, N - (C?-e) aminosulfonyl, N- (C?-6) -amino-sulfonyl, carboxy, carbamoyl, N- (C ?_6 alkyl) carbamoyl, N- (C? _) 2carbamoyl alkyl, X-6 alkoxycarbonyl, formyl, C1-6 alkanoyl, C2_6 alkenyl, C2_6 alkynyl, C5_6 alkyl, C5_6 haloalkyl, C5_g alkoxy, Cs-g haloalkoxy or Cs_6 alkenyloxy; (g) Y-Z is -? HC (O) -, -OCH2-, -SCH2-, -? HCH2-, trans-vinylene, and ethynylene; (h) Y-Z is -? HC (S) -; • R6 is selected from Ci-β alkyl (optionally substituted with one or more R8), C3-6 cycloalkyl optionally substituted with one or more R8, a heterocyclic group optionally substituted on a carbon ring by one or more R8, and the heterocyclic group contains a -? H- portion that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined below), phenyl optionally substituted by one or more R, naphthyl optionally substituted by one or more R8; R7 is a heterocyclic group optionally substituted on a carbon ring by one or more R8 and if the heterocyclic group contains an -NH- portion that nitrogen may be optionally substituted by a group selected from D (where D is as defined below), phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8; R8 is trifluoromethyl, C6-6alkyl, halo, hydroxy, trifluoromethoxy, cyano, Ci-, alkyloxy, formyl, C6-6 alkanoyl, C6-6 alkanoyloxy, amino, C? _g alkylamino, ? _g) 2amino,. Ci-g alkanoylamino, C6_6 alkanoylamino (C_g_alkyl), nitro, carboxy, carbamoyl, C? -g alkoxycarbonyl, thiol, C? _g alkylsulfanyl, C? _6 alkylsulfinyl, C-alkylsulfonyl β-g, sulfamoyl, N- (C ?_6 alkyl) aminosulfonyl, N- (C?-g) 2-aminosulfonyl, carbamoylalkyl of C?-g, N- (Ci-g alkyl) carbamoylalkyl of Ci-g , N- (Ci-6-alkyl) 2-carbamoylalkyl of C? _g, hydroxyalkyl of Ci-g, Ci-galkyl alkoxy of C? -6, phenylalkyl of Ci-g or phenylalkoxy of Ci-g; P is selected from C2-6_M-alkyl substituted with one or more R9, C2_6-M-alkenyl optionally substituted with one or more R9, C2-gM alkynyl optionally substituted with one or more R9 (with the proviso that that in the three previous groups R9 is not a substituent on the carbon atom bonded to M), R10 -CH2-M-, RX1-M-, thiol, C6-6 alkylsulfanyl, C6-6 alkylsulfinyl, C-alkylsulfonyl ? -6, sulphamoyl, nitro, carboxy, C? G, alkoxycarbonyl, amino, C? _g alkylamino, (C? _6) 2amino alkyl, carbamoyl, N- (Xg alkyl) carbamoyl, N- (C-alkyl) ? -6) 2-carbamoyl, C? _6 alkanoylamino, Ci-g-alkanoylamino (N-Ci-g alkyl), trifluoromethyl, trifluoromethoxy, formyl, C? -6 alkanoyl, Cs_ alkyl, C2-6 alkenyl? . C2-6f alkynyl N- (Ci-6alkyl) aminosulfonyl, hydroxymethyl, hydroxyacetyl, N- (Ci-) 2-aminosulfonyl, C6-6 alkanoylaminosulfonyl, C6-6 alkanoylaminsulfonyl (N-C) alkyl. ? 6), C? _6 alkylsulfonylaminocarbonyl, C? -g alkylsulfonylaminocarbonyl (C? -g N-alkyl), C5-6 alkoxy, C? _6 alkenyloxy, phenyl optionally substituted by one or more R8, optionally substituted naphthyl by one or more R8 and an optionally substituted heterocyclic group or on a carbon ring by one or more R and if the heterocyclic group contains a -? H- portion that nitrogen may be optionally substituted by a group selected from D (where D is as defined later); Q is selected from any of the values defined for P, C? _4 alkyl, Cx-4 alkoxy, C2-4 alkenyloxy, hydroxy, halo, and cyano; V is selected from any of the values defined for Q, phenyl optionally substituted by one or more Q, naphthyl optionally substituted by one or more Q, a heterocyclic group optionally substituted on a carbon ring by one or more Q and if the heterocyclic group contains a portion -NH- that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined below) or cycloalkyl from C3_g optionally substituted with one or more Q; T is selected from -O-, -C (O) -, -NH-, -N (N-C? -6 alkyl) -, --C (0)? H-, -? HC (O) - , -C (O)? (N-C 6 alkyl) -, -? (N-C 1 alkyl -g) C (O) -, -S0 2 -, -C (S) -, -C (S) - H-, -? HC (S) -, -C (S)? (N-C6-alkyl) - and -? (N-C 1-6 alkyl) C (S) -; M is selected from -O-, -? (R12) -, -C (O) -,? (Rx2) C (0) -, -C (0)? (R12) -, -S (0) n- , -OC (O) -, -C (0) 0-,? (Rx2) C (0) 0-, -OC (0)? (R12) -, -C (S)? (R12) -, -? (R12) C (S) -, S02? (R12) -, -? (R12) S02- and -? (R12) C (0)? (R12) -, -? (R12) C (S)? (R12) -, -S02? HC (O) -, -S02? (R12) C (0) -, -C (0)? HSO2-, -C (0)? (R12) S02- or M is a direct link; D is selected from C? _g alkyl, C? _ Alkanoyl, Ci-g alkylsulfonyl, C alco-carbamoyl alkoxycarbonyl, N- (Ci-β) alkylcarbamoyl, N, N- (C alquilo-alkyl) g) 2-carbamoyl, benzoyl, (heterocyclic group) carbonyl, phenylsulfonyl, (heterocyclic group) sulfonyl, phenyl or a heterocyclic group attached to carbon, and wherein any C? -6 alkyl group can be optionally substituted by one or more R9, and wherein any phenyl or heterocyclic group may be optionally substituted on a carbon ring by one or more groups selected from R8 and if a heterocyclic group contains an -NH- portion that nitrogen may be optionally substituted by a group selected from E; E is selected from Ci-g alkyl, Ci-6 alkanoyl, Ci-e alkylsulfonyl, C ± -e alkoxycarbonyl, carbamoyl, N- (C6_6 alkyl) carbamoyl, N, N- (C-alkyl) ? 6) 2-carbamoyl, Ci-galcanoyl alkoxy of C? _6, phenylalkyl of Ci-g, benzoyl, phenylalkanoyl of Ci-g, phenylalkoxycarbonyl of C? _6 and phenylsulfonyl. R9 is selected from hydroxy, amino, Ci-g alkylamino, (C ?g) 2amino alkyl, carboxy, C ?g alkoxy, carbamoyl, N- (C?-6 alkyl) carbamoyl, N- ( C? _ G) 2-carbamoyl, formyl, sulphamoyl, N-alkylaminosulfonyl of C? _g, N- (C? _6) 2-amino-sulfonyl, Ci-g-alkylsulfonylamino, Ci-β-alkanoylamino, a heterocyclic group optionally substituted on a ring carbon per one or more R8 and if the heterocyclic group contains a -H portion-that nitrogen may be optionally substituted by a group selected from D (where D is as defined below), phenyl optionally substituted by one or more R , naphthyl optionally substituted by one or more R, C? -6 alkylsulfanyl, C? _6 alkylsulfinyl and C? -6 alkylsulfonyl; R10 is carboxy, carbamoyl, N- (Ci-β) alkyl carbamoyl, N- (C6_6) alkylcarbamoyl, sulfamoyl, N- (C ?_g) aminosulfonyl alkyl, N- (C ?_6 alkyl) ) 2-aminosulfonyl, C? _6 alkylsulfanyl, C?-6 alkylsulfinyl, Ci-g alkylsulfonyl, Ci-g alkoxycarbonyl, C? _g alkanoylamino, a heterocyclic group optionally substituted on a carbon ring by one or more R8 and if the heterocyclic group contains a -? H- portion that nitrogen - it may be optionally substituted by a group selected from D (where D is as defined above), phenyl optionally substituted by one or more R8 or naphthyl optionally substituted by one or more R8; R11 is a heterocyclic group optionally substituted on a carbon ring by one or more R8 and if the heterocyclic group contains a -? H- portion that nitrogen may be optionally substituted by a group selected from D (where D is as defined above) , phenyl optionally substituted by one or more R8, C3-g cycloalkyl optionally substituted by one or more R8, or naphthyl optionally substituted by one or more R8; R12 is hydrogen or Cx_g alkyl optionally substituted with R13 with the proviso that R13 is not a substituent on the carbon attached to the nitrogen atom of M; R13 is halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C? -g alkyl, Ci-g alkenyl, Ci-g alkynyl, C? G alkylamino, (C? G alkyl) 2-amino , C'6 alkanoylamino, C6-6 alkanoylamino (N-C6-6 alkyl), C6-6 alkylsulfonylamino, C6-6 alkylsulfonylamino (C6-6-alkyl), thiol, C-alkylsulfanyl ? 6, C? _6 alkylsulfinyl, C? _6 alkylsulfonyl, sulfamoyl, N- (C? _ Alkyl) aminosulfonyl, N- (C? _ G) 2-amino-sulfonyl, carboxy, carbamoyl, N- (C-alkyl) ? 6) carbamoyl, N- (C? _ G alkyl) 2-carbamoyl, X-alkoxycarbonyl, C? _6 alkanoyl or formyl; n is 0-2; with the proviso that where R and R are both as defined in (a), R3 and R4 are both as defined in (c), R5 is as defined in (e) and ring X is phenyl, YZ they must be -? HC (S) -; and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, and with the proviso that when R3 and R4 are both methyl, R5 is hydrogen, fluorine or chlorine, YZ is ethynylene, X is phenyl and one of Rx and R2 is hydrogen. and the other is pyrimidyl-? HC (O) - or triazinyl-? HC (O) - (wherein the triazine or pyrimidine is substituted by methyl, methoxy or dimethylamino) then the -SO2? RR portion can not be ortho to YZ; and with the proviso that the compound is not: 4- (3-hydroxy-3-methyl-1-butynyl) -N- (3-methyl-2-pyridinyl) -benzenesulfonamide, N-. { 4- [N, N-bis- (sec-butyl) aminosulfonyl] phenyl} -2-hydroxy-2-methyl-3, 3, 3-trifluoropropanamide, or N-. { 4- [N, N-bis- (iso-butyl) aminosulfonyl] phenyl} -2-hydroxy-2-methyl-3,3,3-trifluoropropanamide. In this specification the term "alkyl" includes straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific only to the straight chain version. For example, "C ?4 alkyl" includes propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as "propyl" are specific only to the straight chain version and references to individual branched chain alkyl groups such as "isopropyl" are specific only to the branched chain version. A similar convention applies to other radicals, for example "haloalkyl of C? -4" includes 1-chloroethyl and 2-fluoroethyl. The term "halo" refers to fluorine, chlorine, bromine and iodine. Wherein a phrase such as "any alkyl group of C? -g can be optionally substituted by one or more groups" to avoid doubt it should be understood that this refers to all groups containing an alkyl group of Ci-g, for example this phrase also refers to an alkanoyl group of C? -g if that was listed in the paragraph. A "heterocyclic group" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen, which, unless otherwise specified , is attached to carbon or nitrogen, wherein a -CH2- group may optionally be replaced by a -C (0) -, a nitrogen atom in the ring may optionally have an alkyl group of Ci-g and form a quaternary compound or a sulfur and / or nitrogen atom in the ring can optionally be oxidized to form the N-oxide and / or the oxides of S. Examples and suitable values of the term "heterocyclic group" are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl , isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, N-methylpyr rolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide. A "six-membered heteroaryl ring containing one or two nitrogens in the ring where the nitrogens are optionally oxidized to form the N-oxide" is an unsaturated monocyclic ring containing six atoms. The examples are pyridine, pyrimidine, pyrazine and N-oxide pyridine. Suitable values when R 1 and R 2 together with the nitrogen atom to which they bind, form a heterocyclic group are morpholino, piperidyl, piperazinyl, indolinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl. , triazolyl, indolyl, isoindolyl and benzimidazolyl. Especially morpholino, piperidyl, piperazinyl, indolinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl and homopiperazinyl. An example of "C? _6 alkanoyloxy" is acetoxy. Examples of "C6-alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n and t-butoxycarbonyl. Examples of "Ci-β alkoxy" include methoxy, ethoxy and propoxy. Examples of "C?-6 alkanoylamino" include formamido, acetamido 'and propionylamino. Examples of "C? -4 alkylsulfanyl" include methylthio and ethylthio. Examples of "C 1-6 alkylsulfinyl" include methylsulfinyl and ethylsulfinyl. Examples of "C? -4 alkylsulfonyl" include mesyl and ethylsulfonyl. Examples of "C?-6 alkanoyl" include propionyl and acetyl. Examples of "C? 6 alkylamino" include methylamino and ethylamino. Examples of "(C? _g) 2amino alkyl" include di-N-methylamino, di- (N-ethyl) amino and N-ethyl-N-methylamino. Examples of "Ci-6alkyl alkoxy of Ci-g" methoxymethyl and propoxyethyl. Examples of "carbamoylalkyl C? _g "are carbamoylmethyl and 2-carbamoylethyl. Examples of" N- (C? G) alkylcarbamoylalkyl of Ci-g "are N- (methyl) aminocarbonylethyl and N- (ethyl) aminocarbonylpropyl.

Examples of "N- (C? -6-alkyl) 2-carbamoylalkyl of C? -6" are N, N- (dimethyl) aminocarbonylethyl and N- (methyl) -N- (ethyl) aminocarbonylpropyl. Examples of "C2_4 alkenyloxy" are vinyloxy and allyloxy. Examples of "C3_4 cycloalkyl" are cyclopropyl and cyclohexyl. Examples of "C2-g alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C2-6 alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of "haloalkoxy of C? _4" are 2-fluoroethoxy and 1-bromopropoxy. Examples of "C alca alkanoylamino- (N-C alquilo5 alkyl)" is (N-methyl) formamido and (N-propyl) acetamido. Examples of "C alqu-g alkylsulfonylamino" are methylsulfonylamino and ethylsulfonylamino. Examples of "C 1 -C 6 alkylsulfonylamino (C 6 -C 6 -alkyl)" are methylsulfonyl- (N-ethyl) -amino and ethylsulfonyl (N-butyl) -amino. Examples of "N- (C 1-6 alkyl) aminosulfonyl" are N- (methyl) aminosulfonyl and N- (ethyl) aminosulfonyl. Example of "N- (C 1-6 alkyl) 2aminosulfonyl" are N, N- (dimethyl) aminosulfonyl and N- (methyl) -N- (ethyl) aminosulfonyl. Examples of "N- (C? _6 alkyl) carbamoyl" are methylaminocarbonyl nyl and ethylaminocarbonyl.

Examples of "N- (C? _6) 2-carbamoyl" alkyl are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "Cx-g phenylalkyl" are benzyl and phenethyl. Examples of "Ci-g phenylalkoxy" are benzyloxy and phenylethoxy. Examples of "C ?_6 alkanoylaminosulfonyl" are acetylaminosulfonyl and propionylaminosulfonyl. Examples of "C 1- (N-C 1-6 alkyl) alkanoylaminsulfonyl" are acetyl (N-methyl) aminosulfonyl and propionyl (N-ethyl) aminosulfonyl. Examples of "C 1 -C 6 alkylsulfonylaminocarbonyl" are mesylaminocarbonyl and ethanesulfonylaminocarbonyl. Examples of "alkylsulfonylaminocarbonyl of C? -g (N-alkyl of C? 6) aminocarbonyl "are N- (methyl) mesylaminocarbonyl and N- (methyl) ethanesulphonylaminocarbonyl." Examples of "C?-Galcanoyl alkoxy of C6-6" are methyoxyacetyl and ethoxypropionyl Examples of "Ci-g phenylalkanoyl" are phenylacetyl and phenylpropionyl Examples of "(heterocyclic group) carbonyl" are pyrid-3-ylcarbonyl and pyrimid-2-ylcarbonyl Examples of "(heterocyclic group) alkanoyl of C? _g" are pyrid-3-ylacetyl and pyrimid-2-ylpropionyl. Examples of "C6-6 phenylalkoxycarbonyl" are benzyloxycarbonyl and phenethyloxycarbonyl Another aspect of the invention provides a compound of formula (I) as depicted above wherein Ring X is phenyl or a six-membered heteroaryl ring containing one or two nitrogens in the ring where the nitrogens are optionally oxidized to form the N-oxide, R1 and R2 are independently as defined in (a) or (b): R3 and R4 are as defined in (c) or (d) ); R5 is as defined in (e) or (f); -Z are as defined in (g) or (h) wherein: (a) R1 and R2 are each independently selected from hydrogen, C3_3 alkyl, pyridyl and phenyl which is unsubstituted or substituted by one or two substituents independently selected from C? -4 alquiloalkyl, C? -4 alcoalkoxy, C 2-4 alkenyloxy, hydroxy, halo and cyano, or Rx and R2 together with the nitrogen atom to which they are attached, form morpholino, thiomorpholino, piperidinyl, pyrrolidinyl or imidazolyl; (b) R1 and R2 are each independently selected from phenyl substituted by one or more P (wherein P is as defined below), a heterocyclic group other than unsubstituted pyridyl which is optionally substituted by one or more Q (in where Q is as defined below), naphthyl optionally substituted by one or more Q, C4- alkyl, C3-g cycloalkyl, C2-g alkenyl, C2-6 alkynyl, C? -g alkyl substituted by one or more V (where V is as defined later), R6T- (where R6 and T are as defined below) and R7alkyl of C? _gT- (where R7 is as defined below), _ or R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic group other than morpholino, thiomorpholino, piperidinyl, pyrrolidinyl or imidazolyl; (c) R3 and R4 are independently Ck alkyl optionally substituted by 1 to 2k + 1 atoms selected from fluorine and chlorine wherein k is 1-3, provided that R3 and R4 are not both methyl; or R3 and R4 together with the carbon atom to which they are attached form a cycloalkyl ring of Cm optionally substituted by 1 to 2m-2 fluorine atoms wherein m is 3-5; (d) R3 and R4 are both methyl; (e) R5 is hydrogen, C4-4alkyl, Cl-4 haloalkyl, C4-4alkoxy, C4-4 haloalkoxy, cyano, nitro, C2-4alkenyloxy or trifluoromethylthio; (f) R5 is halo, hydroxy, amino, C? _g alkylamino, (C? _6) 2amino alkyl, C? -g alkanoylamino, C? _g alkanoylamino (N? _6 alkyl), alkylsulfonylamino C? _g, Ci-g alkylsulfonylamino, Ci-β-N-alkyl, thiol, C! -6 alkylsulfanyl, C? _6 alkylsulfinyl, Ci-g alkylsulfonyl, sulphamoyl, N- (C? g) aminosulfonyl, N- (Ci-g) 2-aminosulfonyl, carboxy, carbamoyl, N- (C6_6 alkyl) carbamoyl, N- (C6_6) alkylcarbamoyl, C6_g alkoxycarbonyl, formyl , Ci-g alkanoyl, C2-g alkenyl, C2-g alkynyl, C5-6 alkyl, C5_ghaloalkyl, C5-6alkoxy, C5_alkoxy-alkenyloxy of Cs_; (g) Y-Z is -? HC (O) -, -OCH2-, -SCH2-, -? HCH2-, trans-vinylene, and ethynylene; (h) Y-Z is -? HC (S) -; R is selected from C? -6 alkyl, C3_ cycloalkyl, a heterocyclic group optionally substituted by one or more R8, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8; R7 is a heterocyclic group optionally substituted by one or more R8, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8; R8 is trifluoromethyl, C? -6 alkyl, halo, hydroxy, trifluoromethoxy, cyano, Ci-g alkoxy, C? -6 alkanoyl, C? _6 alkanoyloxy, amino, C? _6 alkylamino, (C ? g) 2-amino, C? _g alkanoylamino, C? -g alkanoylamino (N-C? -g alkyl), nitro, carboxy, carbamoyl, Cx-g alkoxycarbonyl, thiol, Ca-6 alkylsulfanyl, alkylsulfinyl C? -g, C? -g alkylsulfonyl, sulfamoyl, N- (Ci-s alkyl) aminosulfonyl, N- (Ci-g) 2-aminosulfonyl, carbamoylalkyl of C? _6, N- (Ci-g alkyl) ) carbamoylalkyl of Ci-g, N- (C? _g) alkylcarbamoylalkyl of C? _6, hydroxyalkyl of C? -6 or C? -6alkyl of C? _6; P is selected from R9-C-6-M- alkyl, R9-C2-alkenyl-gM-, R9-alkynyl from -C2-6-M-, R10-CH2-M-, R11-M-, thiol / C? _g alkylsulfanyl, C? _6 alkylsulfinyl, C?-g alkylsulfonyl, sulfamoyl, nitro, carboxy, C? _6 alkoxycarbonyl, amino, C_g alkylamino, (Cg) 2amino alkyl, carbamoyl, N- (alkyl) of C? _g) carbamoyl, N- (C? -6) 2-carbamoyl, C? _g alkanoylamino, C? -6 alkanoylamino (N-C? -g alkyl), trifluoromethyl, trifluoromethoxy, C? alkanoyl? _g, C5_6 alkyl, C2_g alkenyl, C2_g alkynyl, N- (Cj-g alkyl) aminosulfonyl, N- (C_-g) 2-aminosulfonyl alkyl, C5_6 alkoxy, alkenyloxy C5-6, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8 and a heterocyclic group optionally substituted by one or more R8; Q is selected from any of the values defined for P, C? -4 alkyl, C? _4 alkoxy, C2_4 alkenyloxy, hydroxy, halo, and cyano; V is selected from any of the values defined for Q, phenyl optionally substituted by one or more Q, naphthyl optionally substituted by one or more Q or a heterocyclic group optionally substituted by one or more Q; T is selected from -O-, -C (O) -, -? H-, -? (N-alkyl of C? _6) -, -C (0)? H-, -C (O)? (N-C 1-6 alkyl) -, -S02-, -C (S) -, -C (S) NH-, -C (S) N (N-C alquilo-alkyl) -; M is selected from -0-, -? (R12) -, -? (R12) C (0) -, -C (0)? (R12) -, -S (0) n-, -0C (0) -, -C (0) 0-, -? (R12) C (0) 0-, OC (0)? (R12) -, -C (S)? (R12) -, -? (R12) C (S) -, -S02? (R12) -, ? (R12) S02- and -? (R12) C (0)? (R12) -, -? (R12) C (S)? (R12) -, -S02? HC (O) -, -C (0)? HSO2- or M is a direct link; R9 is selected from hydroxy, C? -g alkylamino, (C? -g) alkyl amino, carboxy, C? -6 alkoxy, carbamoyl, N- (C_6 alkyl) carbamoyl, N- (C? -g) 2-carbamoyl, sulfamoyl, N-alkylaminosulfonyl of C? _6, N- (C? _6 alkyl) 2-amino sulfonyl, a heterocyclic group optionally substituted by one or more R8, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8, C? _6 alkylsulfanyl, C? -6 alkylsulfinyl and C-6 alkylsulfonyl; R 10 is carboxy, carbamoyl, N- (C 1 6 alkyl) carbamoyl, N- (C 1 -g) 2 -carbamoyl alkyl, sulfamoyl, N- (C 1 -β) aminosulfonyl alkyl, N- (C 1 alkyl) g) 2-amino-sulfonyl, C 1 -g alkylsulfonyl, a heterocyclic group optionally substituted by one or more R 8, phenyl optionally substituted by one or more R or naphthyl optionally substituted by one or more R 8; R11 is a heterocyclic group optionally substituted by one or more R8, phenyl optionally substituted by one or more R8, or naphthyl optionally substituted by one or more R; R > 12 is hydrogen or C? -g alkyl; n is 0-2; • with the proviso that when R1 and R2 are both as defined in (a), R3 and R4 are both as defined in (c), R5 is as defined in (e) and the X ring is phenyl, YZ it must be -NHC (S) -; and pharmaceutically acceptable salts or hydrolysable esters in vivo thereof, with the proviso that the compound is not: 4- (3-hydroxy-3-methyl-l-butynyl) -N- (3-methyl-2-pyridinyl) -benzenesulfonamide; N-. { 4- [N, N-bis- (sec-butyl) aminosulfonyl] phenyl} -2-hydroxy-2-methyl-3, 3, 3-trifluoropropanamide, or _ N-. { 4- [N, N-bis- (iso-butyl) aminosulfonyl] phenyl} -2-hydroxy-2-methyl-3,3,3-trifluoropropanamide. A further aspect of the invention provides a compound of the formula (I) as depicted above wherein: Ring X is phenyl or a six-membered heteroaryl ring containing one or two nitrogens in the ring wherein the nitrogens are optionally oxidized to form the N-oxide; R1 and R2 are each independently selected from hydrogen, phenyl optionally substituted by one or more P, a heterocyclic group optionally substituted on a carbon ring by one or more P and wherein if the heterocyclic group contains a portion -NH- that nitrogen it may be optionally substituted by a group selected from D, naphthyl optionally substituted by one more P, cycloalkyl of C3g optionally substituted by one or more P, alkenyl of C2-6, alkynyl of C-6 substituted by one or more V, R6T- and R7alkyl of C6-6T-, or R1 and R together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted on a carbon ring by one or more P and wherein if the heterocyclic group contains a portion - NH- that nitrogen may be optionally substituted by a group selected from D; R3 and R4 are independently Ck alkyl optionally substituted by 1 to 2k + 1 selected fluorine and chlorine atoms wherein k is 1-3, or R3 and R4 together with the carbon atom to which they are attached, form a cycloalkyl ring of Cm optionally substituted by 1 to 2m-2 fluorine atoms where m is 3-5; R5 is halo, hydroxy, C? _g alkylamino, (C? -g) 2amino alkyl, CX alkanoylamino, C? -g alkanoylamino (N? -C6 alkyl), C? -d alkylsulfonylamino, alkylsulfonyl of C-6 (N-C 1-6 alkyl), thiol, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, Cg-alkylsulfonyl, sulfamoylsulfonamino, N- (C? -6) aminosulfonyl, N- (C-alkyl) ? 6) 2-aminosulfonyl, carboxy, carbamoyl, N- (C? -6-alkyl) carbamoyl, N- (C? -6-alkyl) 2-carbamoyl, C? _6-alkoxyalkyloxycarbonyl, formyl, C? -g alkanoyl, alkenyl C2-6, C2-6 alkynyl, C5_6 alkyl, C5-6 haloalkyl, Cs-g alkoxy, C5_6 haloalkoxy or C5_6 alkenyloxy; Y-Z is -? HC (O) -, -? HC (S) -, -0CH2-, -SCH2-, -? HCH2-, trans-vinylene, and ethynylene; R6 is selected from C? -g alkyl (optionally substituted with one or more R8), C3.g cycloalkyl optionally substituted with one or more R8, a heterocyclic group optionally substituted on a carbon ring by one or more R8 and if the heterocyclic group contains a -? H- portion that nitrogen may be optionally substituted by a group selected from D, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8; R7 is a heterocyclic group optionally substituted on a carbon ring by one or more R8 and if the heterocyclic group contains a -? H- portion that nitrogen may be optionally substituted by a group selected from D, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8; R8 is trifluoromethyl, C? _g alkyl, halo, hydroxy, trifluoromethoxy, cyano, C? _6 alkoxy, formyl, C? _g alkanoyl, C? _6 alkanoyloxy, amino, C? _g alkylamino, C alquilo _ alkyl; ? 6) 2-amino, C? -g alkanoylamino, C? _6 alkanoylamino (N? -C6 alkyl), nitro, carboxy, carbamoyl, C? -6 alkoxycarbonyl, thiol, C? -6 alkylsulfanyl, C-6 alkylsulfinyl, C? -6 alkylsulfonyl, sulfamoyl, N- (C? -6) aminosulfonyl alkyl, N- (C? 6 alkyl) 2-amino sulfonyl, carbamoylalkyl of Cg, N- (C6 alkyl) ) carbamoylalkyl of C? _6, N- (C? -g) alkylcarbamoylalkyl of C? _6, hydroxyalkyl of C? -g, C? -alkyl of C? gg, phenylalkyl of C_6 or phenylalkoxy of C? _g; P is selected from C2-6 alkyl-M- substituted with one or more R9, C2-gM alkenyl optionally substituted with one or more R9, C2_6-M alkynyl optionally substituted with one or more R9 (with the proviso that in the three previous groups R9 is not a substituent on the carbon atom attached to M), R10 -CH2-M-, RX1-M-, thiol, alkylsulfanyl of C_6, alkylsulfinyl of C? -6, alkylsulfonyl of C_6 , sulfamoyl, nitro, carboxy, hydroxy, halo, cyano, C? -6 alkoxycarbonyl, amino, C? _6 alkylamino, (C? -6) alkyl, 2-amino, carbamoyl, N- (C? _6 alkyl) ) carbamoyl, N- (C? _g) 2carbamoyl alkyl, C? _6 alkanoylamino, C? _6 alkanoylamino (N-C? -6 alkyl), trifluoromethyl, trifluoromethoxy, formyl, C? -g alkanoyl, alkyl of C? -6, C2-6 alkenyl, C2-g alkynyl, N- (C? _6 alkyl) aminosulfonyl, hydroxymethyl, hydroxyacetyl, N- (C? _g) 2-aminosulfonyl, C? _g alkanoylaminosulfonyl , C-6 alkanoylamino (N-alkyl) sulfonyl, a C 1-6 -alkylsulfonylaminocarbonyl, C 1-6 alkylsulfonyl (C 1-6 alkyl) aminocarbonyl, C 1-6 alkoxy, C 2-6 alkenyloxy phenyl optionally substituted by one or more R 8, naphthyl optionally substituted by one or more R8 and an optionally substituted heterocyclic group on a carbon ring by one or more R8 and if the heterocyclic group contains a -? H- portion that nitrogen may be optionally substituted by a group selected from D; V is selected from any of the values defined for P, phenyl optionally substituted by one or more P, naphthyl optionally substituted by one or more P, a heterocyclic group optionally substituted on a carbon ring by one or more P and if the group heterocyclic contains a -? H- portion that nitrogen may be optionally substituted by a group selected from D or C3_g cycloalkyl optionally substituted with one or more P; T is selected from -O-, -C (O) -, -? H-, -? (N-C? -6 alkyl) -, -C (0)? H-, -? HC (O) -, -C (O)? (N-C6 alkyl) -, -? (N-C 1 -) - C (O) -, -S02-, -C (S) -, -C (S) - H-, -? HC (S) -, -C (S)? (N-alkyl of C? _6) - and -? (N-C 1-6 alkyl) C (S) -; M is selected from -O-, -? (R12) -, -C (O) -,? (R12) C (0) '-, -C (0)? (R12) -, -S (0) " -, -OC (O) -, -C (0) 0-, N (R12) C (0) 0-, -OC (0) N (R12) -, -C (S) N (R12) -, -N (R12) C (S) -, S02N (R12) -, -N (R12) S02 and -N (R12) C (0) N (R12) -, -N (R12) C (S) N ( R12.} -, -S02NHC (O) -, -S02N (R12) C (0) -, -C (0) NHSO2-, -C (0) N (R12) S02- or M is a direct bond; D is selected from C6_6alkyl, C6_6alkanoyl, C6_6alkylsulfonyl, C1_g alkoxycarbonyl, carbamoyl, N- (C6 alkyl) carbamoyl, N, N- (C6_6 alkyl) 2carbamoyl, benzoyl, (heterocyclic group) carbonyl, phenylsulfonyl, (heterocyclic group) sulfonyl, phenyl or a heterocyclic group attached to carbon, and wherein any C? -6 alkyl group can be optionally substituted by one or more R9, and in wherein any phenyl or heterocyclic group can be optionally substituted on a carbon ring by one or more groups selected from R8 and if the heterocyclic group contains a -? H- portion that nitrogen can be substituted. optionally be replaced by a selected group of E; E is selected from C? -g alkyl, C? 6 alkanoyl, C? -g alkylsulfonyl, C? _g alkoxycarbonyl, carbamoylb, N- (C? _6 alkyl,) carbamoyl, N, N- ( C? _6) 2carbamoyl alkyl, C? -galcanoyl alkoxy of C? _g, phenylalkyl of C-6, benzoyl, phenylalkanoyl of C? -g, phenylalkoxycarbonyl of C? -gy phenylsulfonyl. R9 is selected from hydroxy, amino, C? -g alkylamino, (C6 alkyl)? Amino, carboxy, C? G alkoxy, carbamoyl, N- (C? -6 alkyl) carbamoyl, N- (alkyl) C? _6) 2-carbamoyl, formyl, sulphamoyl, C? _6 N-alkylaminosulfonyl, N- (C? _6) aminosulfonyl alkyl, C? _g alkylsulfonylamino, C? _g alkanoylamino, an optionally substituted heterocyclic group on a carbon ring for one or more R8 and if the heterocyclic group contains a portion -? H - that nitrogen may be optionally substituted by a group selected from D, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8 alkylsulfanyl of C? -6, alkylsulfinyl of C? _6 and alkylsulfonyl of C? -6; R 10 is carboxy, carbamoyl, N- (C 1 6 alkyl) carbamoyl, N- (C 1 -g) 2 -carbamoyl alkyl, sulfamoyl, N- (C 1 -d) aminosulfonyl alkyl, N- (C 1 alkyl) 6) 2-amino-sulfonyl, C 1 -g alkylsulphanyl, C 1 -g alkylsulfinyl, C 1 -g alkylsulfonyl, C 1 -g alkoxycarbonyl, C 1 -g alkanoylamino, an optionally substituted heterocyclic group on a carbon ring by one or more R8 and if the heterocyclic group contains a -? H- portion that nitrogen may be optionally substituted by a group selected from D, phenyl optionally substituted by one or more R8 or naphthyl optionally substituted by one or more R8; R11 is a heterocyclic group optionally substituted on a carbon ring by one or more R8 and if the "heterocyclic" group contains a -? H- portion that nitrogen may be optionally substituted by a group selected from D, phenyl optionally substituted by one or more R8 C3-6 cycloalkyl optionally substituted by one or more R8, or naphthyl optionally substituted by one or more R8; R12 is hydrogen or C? -alkyl optionally substituted with R13 with the proviso that R13 is not a substituent on the carbon bonded to the nitrogen atom of M; R13 is halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C? _g alkyl, C? _6 alkenyl, C? _6 alkynyl, C? _6 alkylamino, ( Ci-gXamino alkyl, C? -g alkanoylamino, Cl-6 alkanoylamino (N-alkyl of Cl-6), C? -6 alkylsulfonylamino, C? -g alkylsulfonylamino (N-alkyl of C? _g) , thiol, alkylsulfanyl of C? _g, alkylsulfinyl of C? -g, alkylsulfonyl of C? _g, sulfamoyl d e C? _6, N- (C? 6 alkyl) aminosulfonyl, N- (C? -6) 2-aminosulfonyl, carboxy, carbamoyl, N- (C? _6 alkyl) carbamoyl, N- (C? ? g) 2carbamoyl, C? -g alkoxycarbonyl, C? .go formyl alkanoyl; n is 0-2; and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof. Preferred values for R1, R2, R3, R4, R5, X and Y-Z are as follows. Preferably R.sup.1 and R.sup.2 are each independently selected from hydrogen, C? -6 alkyl, C2_6 alkenyl, C3-g cycloalkyl, C? _g alkyl substituted by a heterocyclic group, C? -g alkyl substituted by phenyl ( which phenyl is optionally substituted by one or more substituents selected from halo, trifluoromethoxy, a heterocyclic and trifluoromethyl group), and phenyl which is substituted by one or more substituents selected from halo, C4 alkoxy, carbamoyl, trifluoromethyl, C? -6, nitro, hydroxy, cyano, C6-6 alkanoylamino, C6-6 alkylsulfonyl, C6-C6 alkanoyl and sulfamoyl, or R1 and R2 together with the nitrogen group to which they are attached, form morpholino or piperazine . More preferably R1 and R2 are each independently selected from hydrogen, C5-5 alkyl, C3 alkenyl, C3_6 cycloalkyl, pyridylCH2-, thienylCH2-, 1,3-benzodioxylCH2-, phenylCH2- (which phenyl is optionally substituted by one or more substituents selected from fluorine, chloro, trifluoromethoxy, thiadiazole, and trifluoromethyl) and phenyl which is optionally substituted by one or more substituents selected from fluoro, chloro, bromo, iodo, methoxy, hydroxy, carbamoyl, C? -4 alkyl, trifluoromethyl, nitro, cyano , sulfamoyl, C2-2 alkanolyl, mesyl and C2-2 alkanoyl, or R1 and R2 together with the nitrogen group to which they bind, form morpholino or piperazine.

Particularly R1 and R2 are each independently selected from hydrogen, methyl, ethyl, propenyl and phenyl which is substituted by a substituent selected from methoxy, chloro, iodo, hydroxy, carbamoyl, cyano, acetylamino, mesyl, acetyl and sulfamoyl,, or R1 and R2 together with the nitrogen group to which they bind, form morpholino. More particularly R1 and R2 are each independently selected from hydrogen and phenyl which is replaced by a substituent selected from methoxy, hydroxy, carbamoyl, cyano, acetyl, mesyl and sulfamoyl. The preferred combinations of R1 and R2 are as follows. Preferably R1 and R2 are both methyl or ethyl, or one of R1 and R2 is methyl, ethyl or optionally substituted phenyl and the other is hydrogen, or R1 and R2 together with the nitrogen to which they bind, form morpholino. More preferably one of R1 and R2 is hydrogen and the other is phenyl substituted with a substituent selected from methoxy, hydroxy, carbamoyl, cyano, acetyl, mesyl and sulfamoyl. In another aspect of the invention, preferably R1 and R2 are each independently selected from i) hydrogen; ii) C? -alkyl optionally substituted with one or more hydroxy, halo, C? -alkoxy (optionally substituted with one or more hydroxy), C? -6 alkoxycarbonyl, C? -6 alkanoylamino, N / N- (C? _6 alkyl) amino, C? -6 alkylsulfanyl, N- (Ci-b) alkylcarbamoyl, (optionally substituted with one or more C? -6 alkoxycarbonyl), phenyl (optionally substituted with one or more halo, trifluoromethyl, C? g alkoxy, C? -6 alkyl, trifluoromethoxy, thiadiazolyl or sulfamoyl), pyridyl, thienyl, 1,3-benzodioxolyl, morpholino, piperidinyl, tetrahydrofuran and imidazolyl; iii) phenyl optionally substituted with one or more halo, trifluoromethyl, nitro, cyano, hydroxy, sulfamoyl, carbamoyl, amino, formyl, carboxy, C? _6 alkyl (optionally substituted with one or more hydroxy), C? alkoxy (optionally substituted with one or more phenyl), C? _6 alkanoyl, C? _6 alkoxycarbonyl, C? alkanoylamino? 6, C? -6 alkylsulfanyl (optionally substituted with one or more C? -g hydroxy or alkoxy), Ci-g alkylsulfonyl (optionally substituted with one or more hydroxy or alkoxy Ci-g), N- (Cx-e alkyl) amino (optionally substituted with one or more hydroxy), N- (C? _6 alkyl) carbamoyl (optionally substituted with one or more C? _6 alkoxy), N, N- (C? -6-alkyl) 2-amino, hydroxy or tetrahydrofuran), N, N- (C? _g) 2-carbamoyl alkyl (optionally substituted with one or more hydroxy or C6-alkoxy), N- (C2-6 alkenyl,) carbamoyl, N- (C6-6 cycloalkyl) carbamoyl (optionally substituted with one or more hydroxy), N- (C-alkenyl) ? -6) aminosulfonyl, N- (C3. G) aminosulfonyl cycloalkyl (optionally substituted with one or more hydroxy), N- (C? -6) aminosulfonyl alkyl (optionally substituted with one or more hydroxy, amino or N, N- (C-alkyl) 6) 2amino), N, N- (C? -6) 2-aminosulfonyl alkyl (optionally substituted with one or more hydroxy), alkanoylaminosulfonyl C? -6, C? _g alkylsulfonylaminocarbonyl, morpholinosulfonyl, piperazinylcarbonyl (optionally substituted on a ring nitrogen by C? _6 alkyl), morpholinocarbonyl, pyrrolidinylsulfonyl (optionally substituted with one or more hydroxy); iv) C3_6 cycloalkyl, (optionally substituted with one or more hydroxy); v) C2-6 alkenyl, vi) C6-C6 alkanoyl, [optionally substituted with one or more amino or phenyl (where phenyl is optionally substituted with one or more halo)]; .vii) benzoyl (optionally substituted with one or more halo, C6-6 alkylsulfanyl, Cg alkylsulfonyl, cyano, benzyloxy, C6-6 alkoxy, trifluoromethyl, N, N- (C6-6 alkyl) 2-aminosulfonyl, hydroxy ); viii) N-phenylcarbamoyl; or ix) a heterocyclic group selected from tetrahydrofuran, piperidinyl (optionally substituted on a nitrogen in the ring with C? _6 alkyl), pyridyl (optionally substituted with one or more trifluoromethyl, C? -go halo), pyrimidinyl (optionally substituted with one or more C? _g alkyl or N, N- (C? _Xamino alkyl), thienyl (optionally substituted with one or more carbamoyl), isoxazolyl (optionally substituted with one or more C? -6 alkyl) and pyrazinyl (optionally substituted with one or more Ci-β alkyl); or R1 and R2 together with the nitrogen atom to which they are attached, form morpholino, piperidinyl [optionally substituted with one or more hydroxy, Ci-g alkyl (wherein C6-6 alkyl is optionally substituted with hydroxy) or pyrrolidinyl ], piperazinyl [optionally substituted on a nitrogen in the ring by C? -6 alkoxycarbon, C? -6 alkanoyl, (wherein the C? _6 alkanoyl is optionally substituted with one or more C? -g alkoxy, C? _6 alkanoylamino, hydroxy or amino), C?-C alquilo alkyl (wherein the C?-6 alkyl is optionally substituted with one or more hydroxy), C? _6 alkylsulfonyl, phenylsulfonyl (wherein the phenylsulfonyl is optionally substituted with one or more C?-6 alkylsulfonyl) or morpholinocarbonyl], indolinyl, thiazolidinyl, pyrrolidinyl (optionally substituted with one or more hydroxy), thiomorpholino, or 3-pyrrolinyl or homopiperazinyl (optionally substituted on a nitrogen in the ring with - C-6 alkyl).

Most preferably R1 and R2 are each independently selected from: i) hydrogen; ii) C? -6 alkyl optionally substituted with one or more hydroxy, halo, C? -6 alkoxy (optionally substituted with one or more hydroxy) C6-6 alkoxycarbonyl, N, N- (C? -6 alkyl) ) 2-amino, C? _6 alkylsulfanyl, N- (C?-E) alkylcarbamoyl (optionally substituted with one or more Ci-e alkoxycarbonyl), phenyl (optionally substituted with one or more halo or sulfamoyl), pyridyl, thienyl , 1,3-benzodioxolyl, morpholino, piperidinyl, tetrahydrofuran and imidazolyl; iii) phenyl optionally substituted with one or more halo, trifluoromethyl, nitro, cyano, hydroxy, sulfamoyl, carbamoyl, amino, formyl, carboxy, C? _4 alkyl, (optionally substituted with one or more hydroxy), alkoxy C? -4, (optionally substituted with one or more phenyl), C? _6 alkanoyl, C? -6 alkoxycarbonyl, C? _? Alkanoylamino, C? _6 alkylsulfanyl (optionally substituted with one or more hydroxy or alkoxy) of C? -6), C? -6 alkylsulfonyl (optionally substituted with one or more hydroxy or alkoxy C? -6), N- (C? -e) amino) alkyl (optionally substituted with one or more hydroxy), N- (C? -6 alkyl) carbamoyl (optionally substituted with one or more C alco _g, N, N- (C?-6) alkyl 2amino hydroxy or tetrahydrofuran) alkoxy, N, N- (C? _6) alkylcarbamoyl (optionally substituted with one or more hydroxy or C ?g alkoxy), N- (C2-g alkenyl) carbamoyl, N- (C3_6 cycloalkyl) carbamoyl (optionally substituted with one or more hydroxy), N- (C2_6 alkenyl) aminosulfonyl, N- (C3_6 cycloalkyl) aminosulfonyl (optionally substituted with one or more hydroxy, or N, N- (C6-C6-alkyl) 2-amino), N, N- (C6-alkyl) 2-aminosulfonyl, (optionally substituted with one or more hydroxy), C? _g alkanoylaminsulfonyl, C? -g alkylsulfonylaminocarbonyl, morpholinosulfonyl, piperazinylcarbonyl (optionally substituted on a ring nitrogen by C? _6 alkyl), morpholinocarbonyl, pyrrolidinylsulfonyl (optionally substituted with one or more hydroxy ); iv) C3-6 cycloalkyl, (optionally substituted with one or more hydroxy); v) C2-g alkenyl, vi) C? -6 alkanoyl, [optionally substituted with one or more phenyl (wherein the phenyl is optionally substituted with one or more halo)]; vii) benzoyl (optionally substituted with one or more halo, C? -g alkylsulfanyl, C? --6 alkylsulfonyl, cyano, C? _6 alkoxy, trifluoromethyl, N, N- (C? 6) 2-amino-sulfonyl, hydroxy); viii) a heterocyclic group selected from tetrahydrofuran, pyridyl (optionally substituted with one or more trifluoromethyl, C-6 alkyl or halo), pyrimidinyl (optionally substituted with one or more C? _g alkyl or N, N- (C ? _g) 2 amino), thienyl (optionally substituted with one or more carbamoyl), isoxazolyl (optionally substituted with one or more C? _6 alkyl) and pyrazinyl (optionally substituted with one or more C? _g alkyl); or R 1 and R? With the nitrogen atom to which they bind, they form morpholino, piperidinyl [optionally substituted with one or more hydroxy, C6-6 alkyl (wherein the C6-alkyl is optionally substituted with hydroxy) or pyrrolidinyl] , piperazinyl [optionally substituted on a nitrogen in the ring by C6-6 alkoxycarbonyl, C6-6 alkanoyl, (wherein the C6-6 alkanoyl is optionally substituted with one or more C6-alkoxy, C6-alkanoylamino) ? -g, hydroxy or amino), C? _g alkyl (wherein C? -g alkyl is optionally substituted with one or more hydroxy), C? _6 alkyl sulphonyl, phenylsulfonyl (where phenylsulfonyl is substituted optionally with one or more C alqu _g) alkylsulfonyl or morpholinocarbonyl], indolinyl, thiazolidinyl, pyrrolidinyl (optionally substituted with one or more hydroxy), thiomorpholino, or 3-pyrrolinyl. Particularly R1 and R2 are independently selected from: i) hydrogen; ii) C alquilo _g alkyl optionally substituted with one or more hydroxy, C?-g alkoxy, Ci-g alkylsulfanyl alkoxycarbonyl, N- (C?-6 alkyl) carbamoyl(optionally substituted with one or more C6-6 alkoxycarbonyl) phenyl (optionally substituted with one or more sulfamoyl), morpholino and tetrahydrofuran. iii) phenyl optionally substituted with one or more halo, trifluoromethyl, hydroxy, sulfamoyl, amino, alkyl C1-4, C? _4 alkoxy, C? -6 alkoxycarbonyl, C? _6 alkylsulfanyl (optionally substituted with one or more hydroxy or C? _g alkoxy), C? -6 alkylsulphonyl (optionally substituted with one or more hydroxy or C? _g alkoxy), N- (C? -g) amino) alkyl (optionally substituted with one or more hydroxy), N- (C? _6 alkyl) carbamoyl (optionally substituted with one or more hydroxy or tetrahydrofuran), N, N- (C? -6) alkylcarbamoyl, (optionally substituted with one or more hydroxy), N- (C2-g alkenyl) carbamoyl, N- (C2-T alkenyl) aminosulfonyl, N - (alkyl of C? _ 6) aminosulfonyl (optionally substituted with one or more hydroxy or N, N- (C? _6 alkyl) 2-amino), N, N- (C? 6) C 2 -6 alkylsulfonyl-alkylsulfonylaminocarbonyl, morpholinosulfonyl, pyrrolidinylsulfonyl (optionally substituted with one or more hydroxy); iv) C3_6 cycloalkyl, (optionally substituted with one or more hydroxy); v) C2_g alkenyl, vi) C6_6 alkanoyl, [optionally substituted with one or more phenyl vii) benzoyl (optionally substituted with one or more halo, cyano, C6_6 alkoxy, hydroxy; .viii) a heterocyclic group selected from pyridyl (optionally substituted with one or more trifluoromethyl, C? -goalkyl halo), pyrimidinyl (optionally substituted with one or more C? _6 alkyl, N, N- (C? _g) 2amino alkyl, thienyl ( optionally substituted with one or more carbamoyl), isoxazolyl (optionally substituted with one or more C_6 alkyl) and pyrazinyl (optionally substituted with one or more C? -6 alkyl); or R1 and R2 together with the nitrogen atom to which bind, form morpholino, piperidinyl [optionally substituted with one or more hydroxy or C? _g alkyl (wherein C? _6 alkyl is optionally substituted with hydroxy], pyrrolidinyl], piperazinyl [optionally substituted on a nitrogen in the ring by alkoxycarbonyl of C? _6, alkanoyl of C? _6, (wherein the C? _6 alkanoyl is optionally substituted with one or more C? -g alkoxy, C? _g alkanoylamino, hydroxy or? Amino), C? -6 alkylsulphonyl or morpholinocarbonyl], indolinyl or 3-pyrrolinyl. More particularly R1 and R2 are each independently selected from hydrogen, methyl, cyclopropyl, 4-hydroxycyclohexyl, 2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 4- (morpholin-sulfonyl) phenyl, pyrid-3-yl, 2- carbamoylthien-3-yl, 2-chloropyrid-3-yl, 5-chloropyrid-2-yl, 5-methylpyrid-2-yl, pyrimid-2-yl, 4,6-dimethylpyrimid-2-yl or 5-6- dimethylpyrazin-2-yl; or R1 and R2 together with the nitrogen atom to which they bind, form 4-hydroxypiperidinyl or 1- (hydroxyacetyl) piperazin-4-yl. In a further aspect of the invention, preferably R1 and R2 are independently selected from i) hydrogen ii) C? -g "alkyl, C3-g cycloalkyl, optionally substituted with one or more C? _g alkyl, C-alkoxy ? -g, C2-g alkenyloxy, hydroxy, halo, cyano, C? -g alkylsulfanyl, C? -6 alkylsulfinyl, C? -6 alkylsulfonyl, sulfamoyl, carboxy, C? -g, aminocarbonyl, amino, alkylamino of C? _g, (Cx-X2amino alkyl, carbamoyl, N- (C6_6 alkyl) carbamoyl, C6_6 alkanoylamino, C6_6 alkanoylamino (N-C6_6 alkyl) , C alca _g alkanoyl, C 2-6 alkenyl, C 2-6 alkynyl, N- (C--6 alkyl) aminosulfonyl, hydroxymethyl, hydroxyacetyl or N- (C?-6-alkyl) 2-aminosulfonyl; heterocyclic selected from pyridyl, pyrimidyl, pyridazinyl or pyrazinyl wherein the heterocycle group is optionally substituted with one or more C? _6 alkyl, C? -6 alkoxy, C? _6 alkenyloxy, hydroxy, halo, cyano, C-alkylsulfanyl ? _6, alq C? -6 alkylsulfinyl, C? _6 alkylsulfonyl, sulfamoyl, carboxy, C? -6 alkoxycarbonyl, amino, C? -6 alkylamino, (C? -6) 2-amino alkyl, carbamoyl, N- (alkyl) C? -6) carbamoyl, N- (C? G alkyl) 2-carbamoyl, "C? -6 alkanoylamino, C? _6 alkanoylamino (C? _g alkyl), trifluoromethyl, trifluoromethoxy, C? Alkanoyl? 6, C? _6 alkenyl, C? _6 alkynyl, N- (C? _6 alkyl) aminosulfonyl, hydroxymethyl, hydroxyacetyl or N- (C? _g) 2-aminosulfonyl; or R1 and R2 together with the nitrogen atom to which they bind, form piperidinyl or piperazinyl; wherein the piperidinyl and piperazinyl can be optionally substituted on a carbon ring by one or more groups selected from C? _g alkyl, C? -6 alkoxy, C? _g alkenyloxy, hydroxy, halo, cyano, C-alkylsulfanyl? -g, C?-g alkylsulfinyl, C? _6 alkylsulfonyl, sulfamoyl, carboxy, C? _6 alkoxycarbonyl, amino, C?-g alkylamino, C alquilo _6 alkyl 2amino, carbamoyl, N- (alkyl) of C? _ g) carbamoyl, N- (C? -6) 2-carbamoyl, C? _6-alkanoylamino, C? _6-alkanoylamino (N-C? _g alkyl), C? _6-alkanoyl, C-alkenyl? -g, alkynyl of C? -g, N- (C? _?) alminosulfinyl, hydroxymethyl, hydroxyacetyl or N- (C? _6 alkyl) aminosulfinyl; and the piperazinyl can be optionally substituted on the nitrogen • in the ring by a group selected from C? _g alkanoyl, C? -g alkylsulfonyl, C? _g alkoxycarbonyl, carbamoyl, N- (C? _ alkyl) carbamoyl and N, N- (C? _s alkyl) carbamoyl; and wherein any C? -g alkyl group can be optionally substituted by one or more groups selected from hydroxy, amino, C? -6 alkylamino, (C? _6) 2 amino, carboxy, C? -g alkoxy, carbamoyl, N- (C? _g) carbamoyl, N- (C? -g) 2-carbamoyl, sulfamoyl, N-alkylaminosulfinyl of C? _6, N- (C? _6) 2-aminosulfinyl, alkylsulfonylamino of C ? -6, C? _g alkanoylamino, C? -6 alkylsulfanyl / C? _g alkylsulfinyl, C? _6 alkylsulfonyl. Preferably the group RXR2? S02- is for Y-Z. In one aspect of the invention R3 and R4 are independently Ck alkyl optionally substituted by 1 to 2k + 1 atoms selected from fluorine and chlorine, wherein k is 1-3. Preferably R3 and R4 are independently Ck alkyl optionally substituted from 1 to 2k + 1 atoms selected from fluorine and chlorine, wherein k is 1-3, • or R3 and R4, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by 1 to 4 fluorine atoms. More preferably R3 and R4 are independently Ck alkyl optionally substituted by 1 to 2k + 1 fluorine atoms, wherein k is 1-2, or R3 and R4, together with the carbon atom to which they are attached, form a cyclopropa ring .no optionally substituted by 1 to 4 fluorine atoms. Particularly R3 and R4 are independently methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and perfluoroethyl, or R3 and R4, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by 1 to 4. fluorine atoms. More particularly R3 and R4 are independently methyl, fluoromethyl, difluoromethyl and trifluoromethyl, or R3 and R4, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by 1 to 4 fluorine atoms. Preferred combinations of R3 and R4 are as follows Preferably R and R4 are both methyl or one of R "and R is methyl and the other is trifluoromethyl, More preferably one of R3 and R4 is methyl and the other is trifluoromethyl. , the R configuration generally represents a preferred stereochemistry for the compounds of the formula (I).

Preferably R5 is ortho for Y-Z. Preferably R5 is selected from halo, nitro, C? _4 alkyl, C? -4 alkoxy, hydroxy, hydrogen, amino, carboxy and sulfamoyl. More preferably R5 is selected from fluorine, chlorine, bromine, nitro, methyl, ethyl, methoxy, ethoxy, hydroxy, hydrogen, amino, carboxy and sulfamoyl. . Particularly R5 is selected from fluorine, chlorine, nitro and methyl. More particularly R5 is selected from fluorine and chlorine. Particularly preferred R 5 is chloro ortho for Y-Z. In another aspect of the invention, preferably R is selected from halo, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, hydroxy, hydrogen, amino, carboxy and sulfamoyl . More preferably R5 is selected from fluorine, chlorine, bromine, nitro, methyl, ethyl, methoxy, ethoxy, ethenyl, ethynyl, hydroxy, hydrogen, amino, carboxy and sulfamoyl. Particularly R5 is selected from fluorine, chlorine, nitro, methyl, ethenyl and ethynyl. Preferably X is phenyl. Preferably Y-Z is selected from -NHC (O) -, NHC (S) -, trans-vinylene and ethynylene.

More preferably Y-Z is selected from -NHC (O) - and -NHC (S) -. Particularly Y-Z is -NHC (O) -. In a particular embodiment of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof (as defined herein). The particular and preferred values are those mentioned above. According to another aspect of the present invention there is provided a compound of the formula (la) O) wherein: R a and R 2a- is independently selected from hydrogen, C? -6 alkyl, C? _6 alkenyl, C3-6 cycloalkyl, C? -6 alkyl substituted by a heterocyclic group, C? _6 substituted by phenyl (phenyl which is optionally substituted by one or more halo, trifluoromethoxy, a heterocyclic or trifluoromethyl group) and phenyl which is optionally substituted by one or more halo, C? _6 alkoxy, carbamoyl, trifluoromethyl, C? -4, nitro, hydroxy, cyano, C6-6 alkanoylamino, C? _6 alkylsulfonyl, C? -6 alkanoyl or sulfamoyl, or Rla and R2a together with the nitrogen group to which they bind, form morpholino or piperazine; R3a and Ra are independently methyl optionally substituted by 1-3 fluoro; 'R5a is selected from halo, nitro, C? --6 alkyl, C? _g alkoxy, hydroxy, hydrogen, amino, carboxy and sulfamoyl; G is 0 or S; with the proviso that wherein Rla and R2a are selected from hydrogen, C? _3 alkyl or phenyl (which phenyl is optionally substituted by one or two substituents selected from halo, C? -4 alkoxy, C? -4 alkyl) , hydroxy or cyano), R5a is nitro, C? -4 alkyl, C? -4 alkoxy or hydrogen and R3a and R4a are not both methyl, G must be S; and pharmaceutically acceptable salts or esters hydrolyzable in vivo thereof. Where relevant, the R configuration generally represents a preferred stereochemistry for the compounds of the formula (la).

») A preferred additional class of compounds is that of the formula (Ib): (Ib) wherein Rlb and R2 are independently selected from hydrogen, methyl, ethyl, C3_3 alkenyl or phenyl which is substituted by one of methoxy, chloro, iodo, hydroxy, carbamoyl, cyano, acetylamino, mesyl, acetyl or sulfamoyl. or Rlb and R2b together with the nitrogen group to which they bind, form morpholino. and pharmaceutically acceptable salts or esters hydrolyzable in vivo thereof. In a further aspect of the invention there is provided a compound of the formula (Ib) wherein R 1b and R 2b are independently selected from: i) hydrogen; ii) C3-6 cycloalkyl alkyl optionally substituted with one or more C? _g alkyl, C? -6 alkoxy, C2-6 alkenyloxy, hydroxy, halo, cyano, C1-6 alkylsulfanyl, C? -6 alkylsulfinyl, C? _6 alkylsulfonyl, sulfamoyl, carboxy, C 1-6 alkylcarbonyl, amino, C? -6 alkylamino, Ci-g) alkyl, carbamoyl, N- (C? -6) carbamoyl, N- (C? 6 alkyl) 2-carbamoyl, C? -g alkanoylamino, C? -g alkanoylamino (C? _6 alkyl), C? -6 alkanoyl, C2-g alkenyl , C2-g alkynyl, N- (C? -g) aminosulfonyl, hydroxymethyl, hydroxyacetyl or N- (C? 6 alkyl) aminosulfonyl; iii) a heterocyclic group selected from pyridyl, pyrimidyl, pyridacyl, or pyrazinyl, wherein the heterocyclic group is optionally substituted with one or more C? -g alkyl, C? _6 alkoxy, C? -g alkynyloxy, hydroxy, halo, cyano, C? _6 alkylsulfanyl, C? _6 alkylsulfinyl, C? _6 alkylsulfonyl, sulfamoyl, carboxy, C?-6 alkoxycarbonyl, amino, C? _6 alkylamino, (Cx-gXamino alkyl, carbamoyl, N- (Ci-β) alkylcarbamoyl, N- (Ci-6-alkyl) 2-carbamoyl, C-6-alkanoylamino, C-6-alkanoylamino (N-C 6 alkyl), trifluoromethyl, trifluoromethoxy, C-alkanoyl ? -6, C2-6 alkenyl, C2_6 alkynyl, N- (C? _6 alkyl) aminosulfinyl, hydroxymethyl, hydroxyacetyl or N- (C? _6 alkyl) aminosulfinyl; or Rlb and R2b together with the nitrogen to which they are attached, form piperidinyl or piperazinyl, wherein the piperidinyl and piperazinyl can be optionally substituted on a carbon ring by one or more groups selected from C? -6 alkyl, C? _6 alkoxy, C? -6 alkenyloxy, hydroxy, halo, cyano, C? -6 alkylsulfanyl, C? -6 alkylsulfinyl, C? -6 alkylsulfonyl, sulfamoyl, carboxy , C6_6 alkoxycarbonyl, amino, C6_6 alkylamino, C6_6 alkylamino, carbamoyl, N- (C6 alkyl) carbamoyl, N- (C_-g) 2-carbamoyl alkyl, alkanoylamino of C? -6, C? _6 alkanoylamino (N? -C6 alkyl), C? _6 alkanoyl, C2-6 alkenyl, C2-6 alkynyl, N- (C? _ alkyl) aminosulfinyl , hydroxymethyl, hydroxyacetyl or N- (C? _6 alkyl) aminosulfinyl; and the piperazinyl can be optionally substituted on the nitrogen in the ring by a group selected from C? _g alkanoyl, C? -6 alkylsulfonyl, C? -6 alkoxycarbonyl, carbamoyl, N- (C? _6 alkyl) carbamoyl and N, N- (C? -g) alkyl carbamoyl; and wherein any C? _g alkyl group may be optionally substituted by one or more groups selected from hydroxy, amino, C? _6 alkylamino, (C? -g) 2-amino alkyl, carboxy, C? -g alkoxy, carbamoyl , N- (C-6 alkyl) carbamoyl, N- (C? -e) 2-carbamoyl, sulfamoyl, N-alkylaminosulfinyl of C? _6, N- (C? 6 alkyl) 2-amino silofinyl, alkylsulfonylamino of C? -6, C? _g alkanoylamino, C? _6 alkylsulfanyl, C? _6 alkylsulfinyl and C? _6 alkylsulfonyl, and a pharmaceutically acceptable salt or in vivo hydrolysable esters thereof. Where relevant, the R configuration generally represents a preferred stereochemistry for the compounds of the formula (Ib) A further preferred class of compounds is that of the formula (le): Cl 0 OH (le) wherein: K is methoxy, hydroxy, carbamoyl, cyano, acetyl, mesyl, or sulfamoyl, and pharmaceutically acceptable salts or esters hydrolysable in vivo thereof. Where relevant, the R configuration generally represents a preferred stereochemistry for the compounds of the formula (le). Preferred compounds having the formula (I) are Examples 1-37, 61-94 and 270 and the pharmaceutically acceptable salts or esters hydrolysable in vivo thereof. The most preferred compounds having the formula (I) are Examples 17, 34, 35, 36, 62, 78, 81 and 270 and the pharmaceutically acceptable salts or hydrolysable esters in vivo thereof. In another aspect of the invention, preferred compounds of the invention are any of Examples 1-272 and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof. In a further aspect of the invention the preferred compounds of the invention are Examples 27, 43, 44, 123, 143, 144, 145, 150, 166, 251, 252, 253, 255, 258, 259 ,. 263 and 261 and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof. In a further aspect of the invention, the preferred compounds of the invention are Examples 143, 145, 251, 252 and 258 and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof. Preferred aspects of the invention are those which relate to the compound or a pharmaceutically acceptable salt thereof. Within the present invention it is to be understood that a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the drawings of the formula within this specification may represent only one of the possible 'tautomeric forms. It should be understood that the invention encompasses any tautomeric form that elevates PDH activity and is not limited merely to any tautomeric form used within the formula drawings. The drawings of the formulas within this specification can only represent one of the possible tautomeric forms and it should be understood that the specification encompasses all the possible tautomeric forms of the drawn compounds not only those forms which it has been possible to graphically show in the present. It will be appreciated by those skilled in the art that certain compounds of the formula (I) contain one or more asymmetrically substituted carbon and / or sulfur atoms, and consequently may exist in, and be isolated as an enantiomerically pure mixture of diastereoisomers or as a racemate. . Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, enantiomerically pure mixture of diastereoisomers, polymorphic or stereoisomeric form, or mixtures thereof, which forms possess useful properties in enhancing the activity of PDH, being well known in the art. technique how prepares the optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis of optically active starting materials, by chiral synthesis, by enzymatic resolution, (for example WO 9738124), by biotransformation, or by chromatographic separation using a chiral stationary phase) and how to determine the efficiency for the elevation of PDH activity by the standard methods described below. It should also be understood that certain compounds of the formula (I) and salts thereof can exist in solvated as well as non-solvated forms, for example, hydrated forms. It should be understood that the invention encompasses all such solvated forms which elevate the activity of the PDH. A compound of the formula (I), or salts thereof, and other compounds of the invention (as defined hereafter) can be prepared by any process known to be pertinent to the preparation of the chemically-referred compounds. Such processes include, for example, those illustrated in European Patent Applications Publication Nos. 0524781, 0617010, 0625516, and in GB 2278054, WO 9323358 and WO 9738124. Another aspect of the present invention provides a process for preparing a compound of the formula I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, which process (in which the variable groups are as defined for formula (I) unless otherwise stated) comprises: (a) deprotect a protected compound of the formula (II) wherein Pg is an alcohol protecting group; (b) for a compound of the formula (I) in which Y-Z is -NHC (O) -, coupling an aniline of the formula (III) (III) with an acid of the formula (IV): wherein G is a hydroxyl group; (c) coupling an aniline of the formula (III) with an activated acid derivative of the formula (IV). wherein G is a hydroxyl group, which can be protected as an ester or ether; (d) for a compound of the formula (I) in which Y-Z is ethynylene, by reacting an alkyne of the formula (V): with a base, followed by treatment with a ketone of the formula (VI): (i); (e) for a compound of the formula (I) in which Y-Z is trans-vinylene, reducing a compound of the formula (I) in which Y-Z is ethynylene; (f) for a compound of the formula (I) in which Y-Z is trans-vinylene, by dehydration of a diol of the formula (VII): (g) for a compound of the formula (I) in which Y-Z is trans-vinylene, by base catalyzed opening of an epoxide of the formula (VIII): (VIII); (h) for a compound of the formula (I) in which Y-Z is -NHCH2-, reducing a compound of the formula (I) in which Y-Z is -NHC (O) -; (i) for a compound of the formula (I) in which Y-Z is -QCH2-, -SCH2- or -NHCH2- by reacting an ethylene oxide of the formula (IX): (IX) with a compound of the formula (III) or a compound of the formula (X): (X) where J is -OH-, -NH2 or LSH; (j) by reacting a compound of the formula (XI): (XI). wherein K is an atom or leaving group, and in which Y-Z is OCH2, SCH2 or NHCH2 or -NHC (O) - with an amine of the formula RXR2NH; (k) for a compound of the formula (I) in which YZ is -NHC (S) -, by reacting a compound of the formula (I) in which YZ is -NHC (O) - with a sulfur reagent; and after that if necessary: i) converting a compound of the formula (I) into another compound- of the formula (I); ii) eliminate any protective groups; or iii) forming a pharmaceutically acceptable salt or a hydrolysable ester in vivo. Suitable values for Pg are a benzyl group, a silyl group or an acetyl protector. K is an atom or leaving group, the values suitable for K are for example a halogen atom such as fluorine or chlorine. The specific conditions of the above reactions are as follows: a) Suitable reagents for deprotecting an alcohol of formula (II) are for example: 1) when Pg is benzyl: (i) hydrogen in the presence of palladium / carbon catalyst , ie hydrogenolysis; or (ii) hydrogen bromide or hydrogen iodide; 2) when Pg is a silyl protecting group: (i) tetrabutylammonium fluoride; or (ii) aqueous hydrofluoric acid; 3) when Pg is acetyl: i) the soft aqueous base; for example, lithium hydroxide. The reaction can be conducted in a suitable solvent such as ethanol, methanol, acetonitrile or dimethyl sulfoxide and can be conveniently carried out at a temperature in the range of -40 to 100 ° C. (b) An aniline of the formula (III) and an acid of the formula (IV) can be coupled together in the presence of a suitable coupling reagent. The standard peptide coupling reagents known in the art can be used as suitable coupling reagents, for example thionyl chloride (or oxalyl chloride), carbonyldiimidazole and dicyclohexylcarbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, pyridine, or 2,6-di-alkyl-pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. The coupling reaction can. performed conveniently at a temperature in the range of -40 to 40 ° C. (c) An aniline of the formula (III) can be coupled with an activated acid derivative of the formula (IV) for example acid chlorides, acidic anhydrides, or phenylesters, wherein G is a hydroxyl group which can be suitably protected as a stable ester or ether. This coupling can optionally be achieved in the presence of a base for example triethylamine, pyridine, or 2,6-di-a-guyl-pyridines such. such as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. The coupling reaction can be suitably carried out at a temperature in the range of -40 to 40 ° C; (d) suitable bases for reacting with a corresponding alkyne of the formula (V) are for example lithium diisopropylamide (LDA), n-butyllithium or tert-butyllithium. The reaction with a ketone of the formula (IV) can be carried out at a temperature in the range of -100 to -40 ° C preferably at a temperature in the range of -70 to -40 ° C and in a solvent such as tetrahydrofuran , diethyl ether, or 1,2-dimethoxyethane. (e) a suitable reducing agent for a compound of the formula (I) in which Y-Z is trans-vinylene is, for example, lithium aluminum hydride or sodium bis (methoxyethoxy) aluminum hydride. The reaction can be conducted in a suitable solvent such as tetrahydrofuran or diethyl ether, and at a temperature in the range of 0 to 50 ° C. (f) Dehydration of a diol of the formula (VII) can be conducted in the presence of an acid catalyst (for example p-toluenesulfonic acid), neat or with a solvent such as toluene or dichloromethane at a temperature in the range of 0 to 200 ° C preferably at a temperature in the range of 20 to 100 ° C. (g) Base-catalyzed aperture of an epoxide of the formula (VIII) can be carried out in a suitable organic solvent for example, ethers or toluene. Ethers such as tetrahydrofuran are preferred. Suitable bases include potassium tert-butoxide or sodium hydride. The opening can be carried out at a temperature in the range of -50 to 100 ° C, preferably at a temperature in the range of 0 to 50 ° C for example at room temperature. (h) A compound of the formula (I) in which YZ is -NHC (O) - can be reduced with a suitable reducing agent such as aluminum hydride and lithium or borane.The reaction can be conveniently carried out at a temperature in the range of 0 ° C to reflux, in solvents such as for example diethyl ether, tetrahydrofuran, or 1,2-dimethoxyethane (i) An ethylene oxide of the formula (IX) can be reacted with a corresponding compound of the formula (III) or a compound of the formula (X) in the presence of a base for example sodium hydride or triethylamine The reaction may be conducted to reflux in a solvent such as dichloromethane, tetrahydrofuran, or diethylether. (j) A compound of the formula (XI) wherein K is a leaving atom or group, for example a halogen atom such as fluorine or chlorine and in which YZ is OCH2, SCH2 or NHCH2 or -NHC (O) - can be reacted with a amine of the formula R1R2NH in the presence of a base, for example an amine to tertiary, such as triethylamine and in the presence of a catalyst for example dimethylaminopyridine. Suitable solvents for the reaction include nitriles such as acetonitrile and amides such as dimethylformamide. The reaction is conveniently carried out at a temperature in the range of 0 to 120 ° C. (k) A compound of the formula (I) in which YZ is -NHC (O) - can be reacted with a reagent such as for example phosphorus pentasulfide or Lawesson's reagent (2,4-bis (4-methoxyphenyl)) -1,3-dithia-2,4-diphosphetane-2,4-disulfide '), optionally in the presence of a suitable base such as for example pyridine or triethylamine. Suitable solvents for the reaction include, for example, toluene, tetrahydrofuran, 1,3-dioxane or acetonitrile. The reaction is conveniently carried out at a temperature in the range of 0 to reflux. If they are not commercially available, the starting materials necessary for the procedures such as those described above can be made by methods that are selected from the techniques of standard organic chemistry, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the process described above or the methods described in the examples. For example, it will be appreciated that certain optional aromatic substituents on the compounds of the present invention can be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications before or immediately after the processes mentioned above, and as such are included in the aspect of the process of the invention. Such reactions and modifications include, for example, the introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and the reaction conditions for such processes are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid, (such as aluminum trichloride) under Friedel conditions. -Crafts; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminum trichloride) under Friedel-Crafts conditions and the introduction of a halogen group. Particular examples of the modifications include the reduction of a nitro group to an amino group by, for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or 'alkylsulfonyl using, for example, hydrogen peroxide in acetic acid with heating or 3-chloroperbenzoic acid. Specific examples of the techniques used to make the starting materials described above are illustrated, but not limited by, the following examples in which the variable groups are as defined for formula (I) unless stated otherwise. 1) Preparation of compounds of the formula (II). a) compounds of the formula (II) in which YZ is 0CH2, SCH2 or NHCH2 can be made by treating the corresponding compound of the formula (X) wherein J is -OH, -SH, -NH2 or a compound of the formula ( III) with a compound of the formula (XII): (XII) where Y is a leaving group for example mesylate; in the presence of a base such as an alkali metal hydride (e.g., sodium hydride), in a solvent such as' tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, or 1,3-Dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone, and at a temperature of 20 ° C under reflux. b) A compound of the formula (II), wherein YZ is -NHC (O) -, can be made by coupling a compound of the formula (III) with a compound of the formula (IV) (where G is hydroxy protected with a protective group) in a manner analogous to that described for process (b) of the preparations of a compound of formula (I) above. The compounds of the formula (IV) wherein G is hydroxy protected with a protecting group can be made by conventional procedures. For example, cleavage of the ester group of a compound of the formula (XIII): (XIII) wherein E is a protective carboxy group (for example Me); under standard conditions such as mild alkaline conditions, for example, aqueous lithium hydroxide. Compounds of the formula (XIII) wherein G is protected hydroxy are prepared by protecting a compound of formula (XIII) wherein G is hydroxy by reaction with a compound such as benzyl chloride or benzyl bromide (in the presence of a suitable base such as sodium hydride and optionally with a lyst such as sodium iodide, to provide a benzyl protecting group) or any of the conventional silylating agents known and used for such a purpose (for example 2-trimethylsilylethoxymethyl chloride, in the presence of a base suitable such as triethylamine optionally in the presence of a lyst such as dimethylaminopyridine). Compounds of the formula (XIII) wherein G is hydroxy are prepared by esterifying an acid of the formula (IV) by a conventional esterifion process such as the reaction with an alcohol of C? -g (for example methanol) in the presence of a acid lyst (for example sulfuric acid). c) A compound of the formula (II), wherein Y-Z is ethynylene, can be made by reacting a compound of the formula (XIV): (XIV) wherein L is a leaving group such as bromine, iodine, or triflate, with an acetylene of the formula (XV) (XV) in the presence of a lyst such as a combination of copper (I) iodide and bis (triphenylphosphine) palladium dichloride or palladium (II) acetate. The reaction can be conducted in an inert solvent such as tetrahydrofuran, benzene, or toluene, or in a basic solvent such as diethylamine or triethylamine, and at a temperature in the range of -20 to 110 ° C. A compound of the formula (XV) can be made by reacting a compound of the formula (XVI). with an agent such as: i) benzyl bromide (to provide a benzyl protecting group), this reaction can be conveniently conducted in the presence of a base such as sodium hydride and optionally in the presence of a lyst such as sodium iodide in a solvent such as tetrahydrofuran at a temperature of about -78 to about 100 ° C; or ii) any of the conventional silylating agents known and used for such a purpose (such as for example tert-butyl dimethylsilylchloride or triflate, - in the presence of a suitable base such as 1,8-diazabicyclo [5.4.0] undec. 7-ene or triethylamine optionally in the presence of a lyst such as dimethylaminopyridine) at a temperature of about -78 to about 100 ° C. d) A compound of the formula (II), wherein YZ is trans-vinylene, can be made by reacting a compound of the formula (XVII): wherein M is an alkyl metal group such as a trialkyltin (for example tributyl- or trimethyl-tin) ) or a bisalkyloxyborane (for example cholborane); with a compound of the formula (X), wherein J can be a leaving group for example iodide, bromide, or triflate in the presence of a lyst such as bis (triphenylphosphine) palladium dichloride or tetrakis (triphenylphosphine) -palladium (0) ). The reaction may conveniently be conducted in a suitable inert solvent such as tetrahydrofuran or dimethylformamide at a temperature of O-150 ° C. A compound of the formula (XVII) can be made by reacting a compound of the formula (XV). i) with an agent such as cholborane, to form the vinylborane compound; or ii) a trialkyltin hydride in the presence of a catalytic amount of a radical chain initiator such as, for example, aza-jbis-isobutyronitrile or using trialkyltin hydride pre-treated with a strong base (such as an alkyl lithium) and copper cyanide (I), or using a transition metal catalyst such as, for example, tetrakis (triphenylphosphine) palladium (O) to form a compound of the formula (XVII) wherein M is trialkyltin. These reactions can be conveniently conducted in a suitable inert solvent such as tetrahydrofuran, toluene or xylene at a temperature of O-150 ° C. The compounds of the formula (XVI) can be made by reacting a compound of the formula (VI) with an alkali metal acetylide (for example lithium acetylide) or alkaline earth metal acetylide (for example magnesium acetylide). The reaction can be conducted in a solvent such as tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane and at a temperature of -100 to 25 ° C. 2) Preparation of compounds of the formula (III). A compound of the formula (III) can be prepared: i) of a compound of the formula (XVIII) (XVIII) wherein Pg is a protective group such as for example acetyl; a) by treatment with chlorosulfonic acid under standard conditions, and then b) the formation of the sulfonamide under standard conditions as described above in the process (j) for the preparation of a compound of the formula (I) and then c) unfolding of the protecting group under mild alkaline conditions (for example when Pg is acetyl with a base such as aqueous sodium hydroxide); or ii) reducing a compound of the formula (XIX): (XIX) under standard conditions for example by a reducing agent such as tin (II) chloride or iron powder together with concentrated acid to give a compound of the formula (III). A compound of the formula (XIX) can be made by reacting a compound of the formula (XX): (XX) with an amine of the formula R1R2NH- in a process analogous to that used in the process (j) for the preparation of a compound of the formula (I) above. A compound of the formula (XX) can be prepared by: a) oxidizing a compound of the formula (XXI): (XXI) under standard conditions for example with chlorine in a suitable solvent such as acetic acid at a temperature of from -78 to about 100 ° C; or b) diazotizing a compound of the formula (XXII): (XXII) under standard conditions for example with nitrous acid and sulfuric acid followed by reaction with a mixture of sulfur dioxide and copper (II) chloride in a suitable solvent such as water or a water / acetic acid solution. 3) Resolution of compounds of the formula (IV) If the resolved acid is required it can be prepared by any of the known methods for the preparation of optically active forms (for example, by recrystallization of the chiral salt. {For example WO 9738124) , by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase). For example if a result acid is required (R) - (+) it can be prepared by the method of Scheme 2 in the publication of the World Patent Application No. WO 9738124 for the preparation of the acid (S) - (-), it is say using the classical resolution method described in European Patent Application Publication No. EP 0524781, also for the preparation of (S) - (-) acid, except that (IS, 2R) -norephedrine can be used instead of (S) - (-) -1-phenylethylamine. 4) Preparation of compounds of the formula (V). A compound of the formula (V) can be prepared by reacting a compound of the formula (XIV), wherein L is bromine, iodine or triflate with trimethylsilylacetylene in the presence of a catalyst such as a combination of bis (triphenylphosphine) palladium dichloride and copper iodide (I) in diethylamine? triethylamine, followed by treatment with a base (e.g., potassium carbonate) in an alcohol of C? _g (such as methanol) as the solvent to remove the trimethylsilyl group. 5) Preparation of compounds of the formula (VII). A compound of the formula (VII) can be prepared from a compound of the formula (XXIII): by reduction under standard conditions for example using a hydride, such as sodium borohydride. A compound of the formula (XXIII) can be prepared by deprotonation of a compound of the formula (XXIV), (xxrv with a strong base, for example lithium diisopropylamide in an organic solvent, for example tetrahydrofuran at a temperature of -78 to 100 ° C followed by the addition of an amide of the formula (XXV): wherein R19 and R20 are each independently C? -g alkyl or together with the atoms to which they are attached form a 5-7 membered ring. An amide of the formula (XXV) can be prepared from an acid of the formula (IV), or a reactive derivative thereof, by reaction with an amine of the formula R19 (R200) NH under standard conditions such as those described in process (b) for the preparation of a compound of the formula (I) above. 6) Preparation of compounds of the formula (VIII). A compound of the formula (VIII) can be prepared from a diol of the formula (V11) using a suitable dehydrating agent, for example bis [a, bis (trifluoromethyl) benzenemetholate] diphenyl sulfide. 7) Preparation of compounds of the formula (IX). A compound of the formula (IX) can be made by treating a compound of the formula (VI) with a detrimethylsulfonium salt (such as trimethylsulfonium iodide) and a base (such as an alkali metal hydroxide) in a solvent such as dichloromethane. 8) Preparation of compounds of the formula (X). • a) A compound of the formula (X) where J is -OH, can be prepared by diazotizing a compound of the formula (III) under standard conditions such as those described above in 2 (ii) above followed by heating the resulting compound in dilute sulfuric acid. b) A compound of the formula (X), wherein J is -SH, can be prepared by reacting a compound of the formula (XIV) wherein L is a leaving group (for example chlorine) with an excess of methanethiol in the presence of sodium hydride. 9) Preparation of compounds of the formula (XI). A compound of the formula (XI) wherein K is chloro, in which Y-Z is OCH2, SCH2, NHCH2 or -NHC (O) can be prepared by 1) either a) coupling a compound of the formula (XXVI) (XXVI) wherein J is -OH, -SH or NH2 with a compound of the formula (XII) wherein Y is a leaving group for example mesylate; in the presence of a base such as an alkali metal hydride (e.g., sodium hydride), in a solvent such as tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, or 1,3-Dimethyl-3, 4, 5, 6- tetrahydro-2 (1H) -pyrimidinone, and at a temperature of 20 ° C under reflux; or b) where YZ is -NHC (O) -coupling with a compound of the formula (XXVI) where J is NH2 with a compound of the formula (IV), following a method analogous to that of the process (b) for the preparation of a compound of the formula (I) above.

Route a or b is then followed by: 2) treatment with chlorosulfonic acid. 10) Preparation of compounds of the formula (XII). A compound of the formula (XII), wherein Y is mesylate can be prepared by reacting a compound of the formula (XXVII): (XXVII) with methanesulfonic acid chloride in the presence of a base such as triethylamine, in a solvent, such as dichloromethane, and at a temperature of about -78 to 25 ° C. The compounds of the formula (XXVII) are prepared by reducing a compound of the formula (XIII) with a suitable reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or THF and at a temperature of about 0 to about 25 °. C. It is noted that many of the starting materials for the synthetic methods - as described above are commercially available and / or widely reported in the scientific literature, or can be made from commercially available compounds using adaptations of the processes reported in the scientific literature.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary / desirable to protect any sensitive groups in the compounds. Cases where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Thus, if the reagents include such amino, carboxy or hydroxy groups it may be desirable to protect the group in any of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or a t-butoxycarbonyl group, an arylmethoxycarbonyl group, example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups will necessarily vary with the selection of the protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example tris (boron trifluoroacetate). An alternative protecting group suitable for a primary amino group is, for example, a group of the phthaloyl which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the selection of the protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a group of the butyl which can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon . The protecting groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. In cases where the compounds of formula (I) are sufficiently basic or acidic to form acidic or basic-stable salts, administration of the compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described in the following. Examples of suitable pharmaceutically acceptable salts are the organic acid addition salts formed with acids which form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, tartrate, citrate, succinate, benzoate, ascorbate, α-ketoglutarate, and -glycerophosphate. Suitable inorganic salts such as sulfate, nitrate, and hydrochloride can also be formed. The pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound of the formula (I) (or its ester) with a suitable acid which produces a physiologically acceptable anion. It is also possible with the majority of the compounds of the invention to make a corresponding alkali metal salt (for example sodium, potassium, or lithium) or an alkaline earth metal salt (for example calcium) by treating a compound of the formula (I) ( and in some cases the ester) with one equivalent of an alkali metal hydroxide or alkaline earth metal or alkoxide (eg, ethoxide or methoxide) in aqueous medium followed by conventional purification techniques. Esters capable of in vivo cleavage of the compounds of the invention can be made by coupling with a pharmaceutically acceptable carboxylic acid or an activated derivative thereof. For example, the coupling can be carried out by treating a compound of the formula (I) with an appropriate acid chloride (for example, acetyl chloride, propionyl chloride, or benzoyl chloride) or an acid anhydride (e.g. acetic anhydride, propionic anhydride, or benzoic anhydride) in the presence of a suitable base such as triethylamine. Those skilled in the art will appreciate that other suitable carboxylic acids (including their activated derivatives) for the formation of esters capable of in vivo cleavage are known in the art and these are also intended to be included within the scope of the invention. Catalysts such as 4-dimethylaminopyridine can also be usefully employed. Many of the intermediates defined herein are novel and these are provided as a further feature of the invention. The identification of compounds that enhance the activity of PDH is the object of the present invention. These properties can be evaluated, for example, using one or more of the procedures subsequently arranged: (a) Elevation of PDH activity viin This test determines the ability of a test compound to elevate the activity of PDH. The cDNA encoding the PDH kinase can be obtained by polymerase chain reaction (PCR) and subsequent cloning. This can be expressed in a suitable expression system to obtain a polypeptide with PDH kinase activity. For example rat PDH kinase II (rPDHKII) obtained by the expression of recombinant protein in Escherichia coli (E. coli), was found to exhibit PDH kinase activity. In the case of rPDHKII (accession to gene bank U10357) and a 1.3kb fragment encoding the protein was isolated by PCR from rat liver cDNA and cloned into a vector (e.g. pQE32-Quiagen Ltd .). The recombinant construct was transformed into E. coli (for example M15pRep4-Quiagen Ltd.). Recombinant clones were identified, the DNA plasmid was isolated and subjected to DNA sequence analysis. A clone that had the expected nucleic acid sequence was selected for the expression work. Details of the methods for the assembly of recombinant DNA molecules and the expression of recombinant proteins in bacterial systems can be found in standard texts for example Sambrook et al, 1989, Molecular Cloning - A Laboratory Manual, 2nd edition, Cold Spring Harbor Laboratory Press. Other PDH kinases known for use in tests can be cloned and expressed in a similar way. For the expression of the rPDHKI1 activity, cells of the E. coli strain M15pRep4 were transformed with the vector pQE32 vector containing rPDHKIl cDNA. This vector incorporates a 6-His tag on the protein at its N-terminus. It was cultured in E. coli to an optical density of 0.6 (600 nM) and the expression of the protein was induced by the addition of 10 μM of isopropylthio-β-galactosidase. The cells were cultured for 18 hours at 18 ° C and harvested by centrifugation. The paste of resuspended cells was smooth by homogenization and the insoluble material was removed by centrifugation at 24000xg for 1 hour. The 6-His-labeled protein was removed from the supernatant using a nickel-chelating nitrile triacetic acid (Ni-NTA: Quiagen Ltd.) matrix resin (Quiagen) which was washed with 20 mM tris (hydroxymethyl) aminomethane-chlo ride. hydrogen, 20 mM imidazole, 0.5 M sodium chloride pH 8.0, before elution of the bound protein using a regulator containing 20 mM tris (hydroxymethyl) aminomethane-hydrogen chloride, 200 mM imidazole, 0.15 M Sodium chloride pH 8.0. The eluted fractions containing the 6-His protein were pooled and stored in aliquots at 80 ° C in 10% glycerol. Each new batch of standard enzyme was titrated in the test to determine a concentration that gives approximately 90% inhibition of PDH under the conditions of the test. For-a typical batch, the standard enzyme was diluted to 7.5 μg / ml. To test the activity of the novel compounds, the compounds were diluted with 10% dimethylsulfoxide (DMSO) and lOμl was transferred to the individual wells of 96-well test plates. The control wells contain 20 μl of 10% DMSO instead of the compound. 40μl of the Regulator containing 50mM of potassium phosphate regulator pH 7.0, lOmM of ethylene glycol-bis (ß-aminoethyl ether) -N, N, N, N-tetracetic acid (EGTA), 1 mM of benzamidiha, 1 mM of fluoride of phenylmethylsulfonyl (PMSF), 0.3mM tosyl-L-lysine chloromethylketone (TLCK), 2mM dithiothreitol (DTT), recombinant rPDHKIl and the compounds were incubated in the presence of PDH kinase at room temperature for 45 minutes. To determine the maximum rate of the PDH reaction, a second series of control wells containing 10% DMSO was included in place of the compound and omitting rPDHKII. Then PDH kinase activity was initiated by the addition of 5 μM of ATP, 2 mM magnesium chloride and 0.04 U / ml PDH (porcine heart PDH Sigma P7032) in a total volume of 50 μl and the plates were incubated at room temperature for an additional 45 minutes. The residual activity of the PDH was then determined by the addition of substrates (2.5 mM coenzyme A, 2.5 mM thiamine pyrophosphate (cocarboxylase), 2.5 mM sodium pyruvate, 6 mM NAD in a total volume of 80 μl and the plates were incubated for 90 minutes at room temperature.The production of reduced NAD (NADH) was established by optical density measured at 340 nm using a plate reading spectrophotometer.The ED50 for a test compound was determined in the usual way using the results of 12 concentrations of the compound. (b) Elevation of PDH activity in vitro in isolated primary cells This test determines the ability of the compounds to stimulate the oxidation of puribate in primary rat hepatocytes.Hepatocytes were isolated by the procedure of two-stage collagenase digestion described by Seglen (Methods Cell Biol. (1976) 13, 29-33) and seeded in 6-well culture plates (Falcon Primary) at 600,000 cell Viable per well in Dulbecco's Modified Eagless Medium (DMEM, Gibco BRL) containing 10% fetal calf serum (FCS), 10% penicillin / streptomycin (Gibco BRL) and 10% non-essential amino acids (NEAA, Gibco BRL). After 4 hours of incubation at 37 ° C in 5% C02, the medium was replaced with Minimum Essential Medium (MEM, Gibco BRL) containing NEAA and penicillin / streptomycin as above, in addition to 10 nM dexamethasone and 10 nM. of insulin. The next day the cells were washed with phosphate buffered saline (PBS) and the medium was replaced with 1 ml of KREBS solution regulated with HEPES (25 mM HEPES, 0.15M sodium chloride, 25 mM sodium acid carbonate, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium sulfate, 1 mM potassium dihydrogen phosphate) containing the compound to be tested at the required concentration in 0.1% DMSO. The control wells contain only 0.1% DMSO and a maximum response was determined using a 10 μM treatment of a known active compound. After a preincubation period of 40 minutes at 37 ° C in 5% C02, the cells were pulsed with sodium pyruvate to a final concentration of 0.5 mM (containing sodium pyrubate 1-14C (product Amersham CFA85) for 12 hours). minutes, then the medium was removed and transferred to a tube which was immediately sealed with a stopper containing a suspended central well The absorber inside the central well was saturated with 50% phenylethylamine, and the C02 in the medium was released by the addition of 0.2μl of 60% (w / v) perchloric acid (PCA), the released 14C02 trapped in the absorbent was counted by liquid scintillation.The ED50 for a test compound was determined in the usual way using results of 7 compound concentrations (c) Elevation of PDH activity in vivo The ability of compounds to increase PDH activity in relevant rat tissues can be measured using the test described below. an increase in the proportion of PDH in its non-phosphorylated active form can be detected in muscle, heart, liver and adipose tissue after a simple administration of an active compound. It can be expected that this will lead to a decrease in blood glucose after repeated administration of the compound. For example, a simple administration of DCA, a compound known to activate PDH by the inhibition of PDH kinase (Whitehouse, Cooper and Randle (1974) Biochem. J. 141, 761-774) 150 mg / kg, intraperitoneally, increased the proportion of PDH in its active form (Vary et al (1988) Circ. Shock 24, 3-18) and after repeated administration resulted in a significant decrease in plasma glucose (Evans and Stacpoole (1982) Biochem. .31, 1295-1300). Groups of rats (weight range 140-180g) are treated with a single dose or multiple doses of the compound of interest by forced oral feeding in an appropriate vehicle. A control group of rats was treated only with vehicle. At a fixed time after the final administration of the compound, the animals are terminally anaesthetized, the tissues are removed and frozen in liquid nitrogen. For the determination of PDH activity, the muscle samples are broken under liquid nitrogen before homogenization by a burst of 30 seconds in a Polytron homogenizer in 4 volumes of a regulator containing 40 mM potassium phosphate pH 7.0, 5 mM EDTA, 2 mM DTT, 1% Triton X-100, 10 nM sodium pyruvate, 10 μM phenylmethylsulfonyl chloride (PMSF) and 2 μg / ml each of leupeptin, peptain A and aprotinin. The extracts were centrifuged before the test. A portion of the extract is treated with PDH phosphatase prepared from porcine hearts by the method of Siess and Wieland (Eur. J. Biochem (1972) 26, 96): 20 μl of extract, 40 μl of phosphatase (dilution 1:20) , in a final volume of 125 μl containing 25 mM magnesium chloride, 1 mM calcium chloride. The activity of the untreated sample is compared with the activity of the phosphorylated extract thus prepared. The activity of PDH is tested by the method of Stansbie et al., (Biochem J. (1976) 154, 225). An extract of 50 μl is incubated with 0.75 mM of NAD, 0.2 mM of CoA, 1.5 mM of thiamine pyrophosphate (TPP) and 1.5 mM of sodium pyruvate in the presence of 20 μg / ml of p- (p-aminophenylazo) acid benzene sulfonic acid (AABS) and 50 mU / ml arylamintransferase • (AAT) in a buffer containing 100 mM tris (hydroxymethyl) aminomethane, 0.5 mM EDTA, 50 mM sodium fluoride, 5 mM 2-mercaptoethanol and 1 mM magnesium chloride pH 7.8. The AAT is prepared from pigeon livers by the method of Tabor et al. (J. Biol. Chem. (1953) 204, 127). The rate of formation of acetyl CoA is determined by the rate of reduction of AABS which is indicated by a decrease in optical density at 460 nm. The liver samples are prepared by an essentially similar method, except that sodium pyruvate is excluded from the extraction buffer and added to the phosphatase incubation at a final concentration of 5 mM. The treatment of an animal with an active compound resolved in an increase in the activity of the PDH complex in the tissues. This is indicated by an increase in the amount of active PDH (determined by the activity of untreated extract as a percentage of the total activity of PDH in the same extract after phosphatase treatment). According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) as defined above or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, in association with an excipient or carrier. pharmaceutically acceptable. According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) which is selected from: i) a compound of the formula (I) wherein R3 and R4 are both methyl, R5 is hydrogen, fluorine or chlorine, YZ is ethynylene, X is phenyl and one of R1 and R2 is hydrogen and the other is pyrimidyl-NH-C (O) - or triazinyl-NH-C (O) - (wherein the triazine or pyrimidine is replaced by methyl, methoxy or dimethylamino) and the -S-? 2NR1R2 portion is ortho to YZ; ii) 4- (3-hydroxy-3-methyl-1-butynyl) -N- (3-methyl-2-pyridinyl) -benzenesulfonamide; iii) N-. { 4- [N, N-bis- (sec-butyl) aminosulfonyl] phenyl} -2-hydroxy-2-methyl-3,3,3-trifluoropropanamide; or iv) N-. { 4- [N, N-bis- (iso-butyl) aminosulfonyl] phenyl} -2-hydroxy-2-methyl-3,3,3-trifluoropropanamide; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, in association with a pharmaceutically acceptable carrier or excipient. The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for local administration for example as an ointment or cream or for rectal administration for example as a suppository. In general, the above compositions can be prepared in a conventional manner using conventional excipients. The compositions of the present invention are advantageously presented in the unit dosage form. The compound will normally be administered to a warm-blooded animal at a unit dose within the range of 5-5000 mg per square meter of animal body area, i.e. about 0.1-100 mg / kg. A unit dose in the range, for example, 1-100 mg / kg, preferably 1-50 mg / kg is contemplated and this usually provides a therapeutically effective dose. A unit dosage form such as a tablet or capsule will usually contain, for example, 1-250 mg of active ingredient. According to a further aspect of the present invention there is provided a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as defined above for use in a method of treating the human or animal body by therapy. It has been found that the compounds of the present invention elevate PDH activity and are therefore of interest for their blood glucose lowering effects. A further feature of the present invention is a compound of the formula (I) and the pharmaceutically acceptable salts or in vivo hydrolysable esters thereof for use as a medicament. Conveniently this is a compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, for use as a medicament for producing an elevation of PDH activity in a warm-blooded animal such as a human. Thus according to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof in the manufacture of a medicament for use in the production of a elevation of PDH activity in a warm-blooded animal such as a human. . According to a further feature of the invention there is provided a method for producing an elevation of PDH activity in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to the animal an amount effective of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as defined above. • To avoid doubt, in aspects of the invention which concern the use of compounds of the formula (I) or pharmaceutically acceptable salts or in vivo hydrolysable ester thereof in medicine, the definition of the compounds includes compounds selected from: i) a compound of the formula (I) wherein R3 and R4 are both methyl, R5 is hydrogen, fluorine or chlorine, YZ is ethylene, X is phenyl and one of R1 and R2 is hydrogen and the other is pyrimidyl-NH-C ( O) - or triazinyl-NH-C (O) - (wherein the triazine or pyrimidine is substituted by methyl, methoxy or dimethylamino) and the -S-? 2NR1R2 portion is ortho to YZ; _ ii) 4- (3-hydroxy-3-methyl-l-butynyl) -N- (3-methyl-2-pyridinyl) -benzenesulfonamide; iii) N-. { 4- [α, β-bis- (sec-butyl) aminosulfonyl] phenyl} -2-hydroxy-2-methyl-3,3,3-trifluoropropanamide; or iv) N-. { 4- [α, β-bis- (iso-butyl) aminosulfonyl] phenyl} -2-hydroxy-2-methyl-3,3,3-trifluoropropanamide; and its pharmaceutically acceptable salts and ester hydrolyzables in vivo. As stated above, the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily vary depending on the host treated, the route of administration and the severity of the disease in question. Preferably a daily dose in the range of 1-50 mg / kg is employed. However, the daily dose will necessarily vary depending on the host treated, the particular route of administration, and the severity of the disease in question. Accordingly, the optimal dosage can be determined by the practitioner who is treating any particular patient. The elevation of the PDH activity described herein may be applied as a single therapy or may involve, in addition to the subject matter of the present invention, one or more other substances and / or treatment. Such joint treatment may be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. For example in the treatment of diabetes mellitus, chemotherapy may include the following main categories of treatment: i) insulin; ii) insulin secretagogue agents designed to stimulate insulin secretion (eg glibenclamide, tolbutamide, other sulfonylureas); iii) oral hypoglycemic agents such as metformin, thiazolidinediones; iv) agents designed to reduce the absorption of glucose from the intestine (for example acarbose); v) agents designed to treat the complications of prolonged hyperglycemia; vi) other agents used to treat lactic acidemia; vii) inhibitors of fatty acid oxidation; viii) agents that decrease lipids; ix) agents used to treat coronary heart disease and peripheral vascular disease such as aspirin, pentoxifylline, cilostazol; and / or x) thiamin As set forth above the compounds defined in the present invention are of interest for their ability to elevate PDH activity. Such compounds of the invention can therefore be useful in a range of disease states including diabetes mellitus, peripheral vascular disease, (including intermittent claudication), heart failure and certain cardiac myopathies, myocardial ischemia, cerebral ischemia and reperfusion, weakness muscle, hyperlipidemias, Alzheimer's disease and / or atherosclerosis. In addition to their use in therapeutic medicine, the compounds of the formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of elevators of PDH activity in laboratory animals such as cats, dogs, rabbits, monkeys rats and mice as part of the search for new therapeutic agents. The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise: (i) temperatures are given in Celcius degrees (° C); the operations were carried out at room or ambient temperature, that is at a temperature in the range of 18-25 ° C; (ii) the organic solutions were dried over anhydrous magnesium sulfate; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascal, 4.5-30 mm Hg) with a bath at a temperature of up to 60 ° C; (iii) chromatography means unless otherwise indicated flash chromatography on silica gel; Thin layer chromatography (TLC) was carried out on silica gel plates; where it refers to a "Bond Elut" column, this means a column containing 10 g or 20 g of silica with a particle size of 40 microns, containing the silica in a 60 ml disposable syringe and supported by a porous disk, obtained from Varian, Harbor City, California, USA under the name "Mega Bond Elut SI" (iv) in general, the course of the reactions was followed by TLC and the reaction times are given only for illustration; (v) the returns are given only for illustration and are not necessarily those which can be obtained by the diligent development of the process; the preparations were repeated if more material was required; (vi) when given, 1E NMR data are cited and are in the form of delta values for primary proton diagnostics, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulfoxide (DMSO-dg) unless otherwise stated; the coupling constants (J) are given in Hz; (vii) chemical symbols have their usual meaning; SI units and symbols are used; (viii) the solvent ratios are given as a percentage by volume; (ix) the mass spectrum (MS) was run with an electron energy of 70 electron volts in the chemical ionization mode (Cl) using a direct exposure probe; where the indicated ionization is carried out by electron impact (El) or fast atom bombardment (FAB) where values are given for m / z, generally only the ions that indicate the relative mass are reported, and unless it is said so otherwise the mass of ion cited is the mass of the negative ion - (MH) X y '(x) The following abbreviations are used: DMSO dimethylsulfoxide DMF N, N-dimethylformamide DCM dichloromethane; and EtOAc ethylacetate. Example 1 N- [2-chloro-4- (morpholinosulfonyl) phenyl] -2-hydroxy-2-methylpropanamide 2-Acetoxyisobutyryl chloride (660 mg, 3. 6 mmol) was added to a stirred mixture of 2-chloro-4- (morpholinosulfonyl) anilino (Method A) (1.0 g, 3.6 mmol) and pyridine (0.34 mL, 4.2 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight, and then washed with 1 M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved 1% aqueous ethanol (10 ml) and lithium hydroxide monohydrate (300 mg, 7.5 mmol) was added. The mixture was stirred for 2 h at room temperature, then EtOAc (25 ml) was added and the resulting organic layer was washed with water, dried and evaporated to dryness to yield the title compound (226 mg, 0.6 mmol). ? MR: 1.4 (s, 6H), 2.9 (m, 4H), 3. 6 (m, 4H), 6.3 (s, 1H), 7.7 (d, 1H), 7.8 (m, 1H), 8.6 (d, 1H), 9.8 (s, 1H); MS: 363 (M + H) +.

Example 2 N- [2-Chloro-4- (piperidinesulfonyl) phenyl] -2-hydroxy-2-methylpropanamide A solution of N- [2-chloro-4- (fluorosulfonyl) phenyl] -2-acetoxy-2-methylpropanamide ( Method B) (340 mg, 1 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and piperidine (0.1 mL, 1 mmol) in acetonitrile (5 mL) was heated under reflux for 18 h. After evaporation to dryness, the residue was dissolved in 1% aqueous ethanol (10 ml) and lithium hydroxide monohydrate (84 mg, 2 mmol) was added. The mixture was stirred for 2 h at room temperature, then EtOAc (25 ml) was added. The resulting solution was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography using 50% EtOAc / isohexane to yield the title compound as an oil (226 mg, 0.6 mmol). RM? : 1.4 (s, 6H), 1.5 (m, 6H), 2.9 (m, 4H), 6.2 (d, 1H), 7.7 (d, 1H), 7.8 (m, 1H), 8.6 (d, 1H), 9.8 (s, 1H); MS: 361 (M + H) +. Examples 3-21 The procedures described in Examples 1 and 2 were repeated using appropriate sheet to replace the morpholine or piperidine to obtain the compounds described below in 30-65% yields. "Meth" refers to whether the Example was made by the procedure of Example 1 or 2. aminosulfonyl) phenyl] -2- 2H), 6.2 (broad, 1H), hydroxy-2-methyl- 7.2 (m, 5H), 7.7 (m, propanamide 1H), 7.8 (m, 1H), 8.2 (broad, 1H) ), 8.4 (d, 1H), 9.7 (s, 1H) N- [2-chloro-4- (pyrid-3-382 1.4 (s, 6H), 3.9 (m, 1-methylaminosulfonyl) -1H), 4.0 (d, 2H), 6.2 phenyl] -2-hydroxy-2- (s, 1H), 7.3 (broad, methylpropanamide 1H), 7.4 (m, 1H), 7.6 (d, 1H), 7.8 (m, 1H ), 8.3 (m, 1H), 8.4 (m, 2H), 9.7 (m, 1H) N- (2-Chloro-4-anilino- 367 1.4 (s, 6H), 6.2 (s, 1 sulfonylphenyl) -2 - 1H), 7.0 (m, 3H), 7.2 hydroxy-2- (m, 3H), 7.7 (c, 1H), methylpropanamide 7.8 (d, 1H), 8.4 (d, 1H), 9.7 (s, 1H) . N- [2-Chloro-4- (2-chloro-401 1.4 (s, 6H), 6.2 (s, 1 anilinosulfonyl) phenyl] -1H), 7.2 (m, 3H), 7.4 2-hydroxy-2- (m, 2H), 7.6 (c, 1H), methylpropanamide 7.8 (d, 1H), 8.4 (d, 1H), 9.8 (s, 1H). N- [2-Chloro-4- (3-iodo-493 1.4 (s, 6H), 6.2 (s, 1 anilino-sulfonyl) phenyl] -1H), 7.1 (m, 2H), 7.4 2-hydroxy-2 - (m, 3H), 7.7 (c, 1H), methylpropanamide 7.8 (s, 1H), 8.4 (d, 1H), 9.8 (s, 1H). N- [2-Chloro-4- (4-chloro-401 1.4 (s, 6H), 6.2 (s, 1 anilino-sulfonyl) phenyl] -1H), 7.1 (d, 2H), 7.3 2-hydroxy-2- (d, 2H), 7.7 (m, 2H), methylpropanamide 7.8 (d, 1H), 8.4 (d, 1H), 9.7 (s, 1H). N- [2-chloro-4 - (4-methoxy-397 1.4 (s, 6H), 3.6 (s, 1 aminosulfonyl) phenyl] -2- 3H), 6.2 (broad, 1H), hydroxy-2- '6.8 (d, 2H), 7.0 (d, methylpropanamide 2H), 7.6 (m, 2H), 7.7 (d, 1H), 8.4 (d, 1H), 9.7 (s, 1H). N- [2-Chloro-4- (2-chloro-4-527 1.4, (s, 6H), 6.3 (s, 1-iodoanilinosulfonyl) -1H), 7.0 (d, 1H), 7.6 phenyl] -2-hydroxy -2- (m, 3H), 7.8 (d, 2H), methylpropanamide 8.4 (d, 1H), 9.8 (s, 1H). N- [2-Chloro-4- (2-fluoro-511 1.4 (s, 6H), 6.3 (s, 1 4-iodoanilinosulfonyl) - 1H), 7.0 (m, 1H), 7.5 phenyl] -2-hydroxy-2- * (m, 1H), 7.6 (m, 2H), methylpropanamide 7.8 (m, 2H), 8.5 (m , 1H), 9.8 (s, 1H).

N- [2-Chloro-4 - (2, 4 - 523 / 1.4 (s, 6H), 6.2 (s, 1 dibromoanilinosulfonyl) - 525 1H), 7.6 (m, 3H), 7.8 phenyl] -2-hydroxy-2- (m, 2H), 8.2 (d, 2H), methylpropanamide 9.6 (s, 1H). 21 N- [2-Chloro-4- (3-bromo-4,479 / '1.4 (s, 6H), 6.2 (s, 1-chloroanilinosulfonyl) -481 1H), 7.1 (m, 1H), 7.5 phenyl] - 2-hydroxy-2- (m, 3H), 7.8 (m, 2H), methylpropanamide. 8.3 (m, 1H), 9.8 (m, 1H) Example 22 R / SN- [Chloro-4- (3-bromo-4-chloroanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2- methy1propanamide A solution of R / S-3, 3, 3, trifluoro-2-hydroxy-2-methylpropanoylchloride (Method El) (110 mg, 0.62 mmol) in DCM (5 mL) was added to a stirred mixture of 2-chloro -4- (3-Bromo-4-chloroanilinosulfonyl) aniline (Method C) (270 mg, 0.68 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight and was then washed with aqueous sodium hydrogen carbonate solution and water, dried and evaporated to dryness. The residue was purified by column chromatography using 50% EtOAc / isohexane to yield the title compound as a foam (100 mg, 0.19 mmol). RM? : 1.9 (s, 3H), 6.2 (s, 1H), 7.1 (m, 1H), 7.5 (m, 3H), 7.8 (m, 2H), 8.4 (d, 1H), 9.6 (s, 1H); MS: 533/535.

EXAMPLE 23 RN- [2-Chloro-4- (-methoxyanesilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of S-3, 3, 3-trifluoro-2-hydroxy- 2-methylpropanoylchloride (Method P) (446 mg 2.5 mmol) in DCM (15 ml) was added to a stirred mixture of 2-chloro-4- (4-methoxyanilino-sulfonyl) aniline (Method D) (650 mg, 2.1 mmol) and 2,6-di-t-butylpyridine (0.56 ml, 2.5 mmoles) in DCM (50 ml). The resulting mixture was stirred at room temperature overnight and then washed with 1M aqueous hydrochloric acid, aqueous sodium hydrogen carbonate solution and brine, dried and evaporated to dryness. The residue was purified by column chromatography using 5% EtOAc in DCM to yield the title compound as a foam (680 mg, 1.5 mmol). EA: found: C, 45.1; H, 3.8; ?, 5.8%; C? 7H? G? 2F3ClSO, requires: C, 45.1; H, 3.5; ?, 6.2%; R? M (CDC13): 1.9 (s, 3H), 3.75 (s, 3H), 3.8 (s, 1H), 6.4 (s, 1H), 6.8 (d, 2H), 7.0 (d, 2H), 7.6 (dd, 1H), 7.8 (d, 1H), 8.5 (d, 1H), 9.3"(s, 1H); MS: 451. Examples 24-105 The procedure described in Example 23 was repeated using appropriate 4-aminobenzenesulfonamide to replace 2-chloro-4- [(4-methoxyanilino) sulfonyl] aniline to obtain the compounds described below. "Meth" refers to the Method (section on Subsequent Starting Materials) used to make the appropriate sulfonamide. , 3-trifluoro-2-1H), 4.4 (m, 1H), 7.8 hydroxy-2-methyl- (dd, 1H), 7.9 (d, 1H), propanamide 8.6 (d, 1H), 9.3 (s, 1H) RN- [2-Chloro-4- (dimethyl-373 (CDC13): 1.8 (s, 3H), E aminosulfonyl) phenyl] -2.7 (s, 6H), 3.8 (s, 3,3, -3-trifluoro-2H), 7.7 (dd, 1H), 7.9 hydroxy-2-methyl- '(d, 1H), 8.6 (d, 1H), propanamide 9.3 (s, 1H). R-N- [2-Chloro-4 -415 (CDCl3) 1.8 (s, 3H), E (morpholino-3.0 (m, 4H), 3.6 (s, sulfonyl) phenyl] -3.3, 3-1H), 3.8 (ra, 4H), 7.7 trifluoro-2-hydroxy-2- (dd, 1H), 7.9 (d, 1H), methylpropanamide 8.6 (d, 1H), 9.3 (s, 1H) RN- [2-Chloro-4-401 (CDCL3): 1.2 (t 6H), E (diethylamino- 1.8 (s, 3H), 3.2 (c, sulfonyl) phenyl] -3,3, 3-4H), 3.8 (s, 1H), 7.7 trifluoro-2-hydroxy-2- • (dd, 1H) 7.9 (d, 1H), methylpropanamide 8.6 (d, 1H), 9.3 (s, 1H). RN- [2-Chloro-4- (4-t-477 IX (s, 9H), 1.6 (s, F-butyl-anilinosulfonyl) -3H), 7.0 (d, 2H), 7.3 phenyl] -3.3, 3-trifluoro- (d, 2H), 7.7 (d, 1H), 2-hydroxy-2-methyl-7.9 (s, 1H), 8.2 (d, propanamide * • 1H), 9.8 (s, 1H). RN- [2-Chloro-4- (anilino-421 1.6 (s, 3H), 7.0 (m, F-sulfonyl) phenyl] -3,3,3-2H), 7.2 (m, 3H), 7.7 trifluoro-2 -hydroxy-2- (m, 1H), 7.9 (m, 1H), methylpropanamide 8.2 (d, 1H), 9.8 (s, 1H). RN- [2-Chloro-4 - (4- 439 1.6 (s, 3H), 7.1 (m, F fluoro-anilinosulfonyl) -4H), 7.7 (m, 1H), 7.9 phenyl] -3.3, 3- trifluoro- (s, 1H), 8.2 (d, 1H), 2-hydroxy-2-methyl9.8 (d, 1H). propanamide * RN- [2-Chloro-4- (4- 478 .1.6. (s, 3H), 2.0 (s, F acetamido-aillin-3H), 7.0 (m, 2H), 7.4 sulfonyl) phenyl] -3 , 3.3- (ra, 2H), 7.7 (m, 1H), trifluoro-2-hydroxy-2- 7.9 (s, 1H), 8.2 (d, methyl-propanamide 1H), 9.8 (d, 1H). RN- [2-Chloro-4 - (4 - 499 1.6 (s, 3H), 3.1 (s, F mesylanilino-sulfonyl) -3H), 7.3 (d, 2H), 7.8 phenyl] -3, 3, 3- trifluoro- (d, 2H), 7.85 (dd, 2 - . 2-hydroxy-2-methyl1H), 7.95 (d, 1H), 8.2 propanamide * (d, 1H) RN- [2-Chloro-4- (4-500 1.6 (s, 3H), 7.2 (s, F sulfamoyl) naphyl - 2H), 7.3 (d, 2H), 7.7 fonyl) phenyl] -3,3,3- (d, 2H), 7.8 (dd, 1H), trifluoro-2-hydroxy-2- 7.95 (d, 1H) , 8.2 (d, methyl-propanamide 1H) RN- [2-Chloro-4 - (3- 547 1.6 (s, 3H), 7.0 (m, F-iodoanilinosulfonyl) -2H), 7.4 (m, 2H), 7.7 phenyl ] "- 3, 3, 3-trifluoro- (m, 1H), 7.9 (s, 1H), 2-hydroxy-2-methyl-, 8 * 2 (d, 1H), 9.8 (s, propanamide * 1H). RN- [2-Chloro-4 (4- 467 1.6 (s, 3H), 2.4 (s, D-methylthio-aninosulfonyl) -3H), 7.0 (d, 2H), 7.2 phenyl] -3,3,3-trifluoro - (d, 2H), 7.7 (dd, 1H), 2-hydroxy-2-methyl-7.8 (d, 1H), 8.2 (d, propanamide 1H). RN- [2-Chloro-4 - (4-527 1.6 (s, 3H), 5.0 (s, D benzyloxy-anilino-2H), 6.85> (d, 2H), 7.0 sulfonyl) phenyl] -3.3 , 3- (d, 2H), 7.4 (m, 5H), trifluoro-2-hydroxy-2-7.6 (dd, 1H) 7.8 (d, methyl-propanamide 1H), 8.5 (d, 1H). RN- (2-Chloro-4-345 1.6 (s, 3H), 7.4 (s, D-sulfanoyl-phenyl) -3,3,3-2H), 7.8 (dd, 1H), 7.9 trifluoro-2-hydroxy- 2- (d, 1H), 8.2 (d, 1H). Methylpropanamide R-N-. { 2-Chloro-4 - [N, N-bis-433 1.6 (s, 3H), 3.2 (t, D (2-hydroxyethyl) amino-4H), 3.5 (m, 4H), 4.8 sulfonyl] phenyl} -3.3.3- (t, 2H), 7.8 (dd, 1H), trifluoro-2-hydroxy-2- 7.9 (d, 1H), 8.25 (d, methyl-propanamide 1H). RN- (2-Chloro-4-. {4- [N, N- 588 1.6 (s, 3H), 3.1 (t, D bis- (2-hydroxyethyl) -4H), 3.5 (m, 4H), 4.8 aminosulfonyl] -anilino- (t, 2H), 7.25 (d, 2H), sulfonyl, phenyl) -3,3,3-7,7 (d, 2H), 7.8 (dd, trifluoro-2-hydroxy-2) - 1H), 7.9 (d, 1H), 8.2 methylpropanamide (t, 1H). R-N- { 2-Chloro-4 - [4- 570 1.6 (s, 3H), 2.95 (m, D # (morpholinosulfonyl) - 4H), 3.75 (m, 4H), 7.2 anilinosulfonyl] phenyl} - (d, 2H), 7.7 (d, 2H), 3,3,3-trifluoro-2- '7.8 (dd, 1H), 7.9 (d, hydroxy-2-methyl-1H), 8.6 (d, 1H). propanamide RN- [2-chloro-4- (R, S-2,3- 419 1.6 (s, 3H), 2.6 (ra, D-dihydroxy-propylamino-1H), 2.9 (m, 1H), 3.2-sulfonyl) phenyl] - 3, 3, 3- (m, 2H), 3.5 (ra, 1H), trifluoro-2-hydroxy-2- 4.5 (t, 1H), 4.75 (d, methylpropanamide 1H), 7.8 (dd, 1H), 7.9 (d, 1H), 8.2 (d, 1H). RN- [2-Fluoro-4- (2- 423 CDC1 3: 1 .75 (s, 3H), G fluoro- 6.75 (s, 1H), 6.9 -7.0 anilinosulfonyl) phenyl] - '(m, 1H), 1 . 1.-7.2 (m, * indicates that 2, 6-di-b-butylpyridine was not used in the reaction, t indicates that no aqueous work was used for the final stage; Instead of the reaction mixture being concentrated, DCM (5 ml) was added and the solution was charged to a Bond Elut column. This was then eluted with iso-hexane (50 ml) followed by 10% EtOAc / DCM to produce the product # indicates that this sulfonamide was obtained as a by-product of the preparation of Example 42. Example 106 RN- [2-Fluoro -4- (3-hydroxyanilinosulphenyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- [2-fluoro-4- (3-benzyloxyanilinosulphenyl) phenyl] -3,3, 3- trifluoro-2-hydroxy-2-methylpropanamide (Example 57) (0.36 g, 0.7 mmol) in ethanol (15 ml) was hydrogenated over 10% Pd / C for 4 h at room temperature. The catalyst was removed by filtration and the ethanol was evaporated to yield the title compound as a solid (0.18 g, 0.4 mmol). RM? : 1.6 (s, 3H), 6.4 (d, 1H), 6.5 (d, 1H), 6.6 (s, 1H), 7.0 (t, lH), 7.6 (d, 2H), 7.7 (s, lH), -7.95 (t, lH), 9.45 (s, lH). 9.8 (s, lH); MS 421 Example 107 RN- [2-Fluoro-4- (4-hydroxyanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide The procedure of Example 106 was repeated using RN-2-fluoro-4- (4-benzyloxyanilinesulfonyl) phenyl] 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 53) (039g, 0.8 mmol) as the starting material to produce the title compound, as a solid (0.26g) , 0.6 mmol). RM? : 1.6 (s, 3H) 6.6 (d, 2H), 6.85 (d, 2H); 7.05-7.15 (m, lH), 7.4-7.5 (m, 2H), 7.7 (S, 1H), 7.9 (t, lH), 9.2 (s, lH), 9.8 (s, lH); MS: 421. Example 108 RN [2-Fluoro-4- (3-mesylanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide • A solution of RN- [2-fluoro-4- (3-methylthioanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 50) (360 mg, 0.8 mmol) and 70% 3-of 3-chloroperoxy benzoic acid (390 mg, 1.6 mmoles) in DCM (20 ml) was stirred at room temperature overnight and then evaporated to dryness and the residue was treated with aqueous sodium hydrogen carbonate solution (25 ml). The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to yield the title compound as a solid (O.lg 0.2 mmol). RM ?: 1.6 (s, 3H), 3.05 (s, 3H), 7.2-7.7 (m, 8H), 7.95 (t, 1H), 9.8 (s, 1H); MS: 483 Example 109 RN- [2-Fluoro-4- (2-mesylanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide The procedure of Example 108 was repeated using RN- [2-fluoro-4 - (2-methylthioanilino-sulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 47) (290 mg, 0.6, mmole) as the starting material for producing the compound, title as a solid (100 mg, 0.2 mmol). RM ?: 1.6 (s, 3H), 3.25 (s, 3H), 7.25 (d, 1H), 7.4 (t, 1H), 7.5 (t, 1H), 7.6-7.8 (m, 3H), 7.85-7.95 (m, 2H), 8.05 (t, 1H), 9.85 (s, 1H); MS: 483. Example 110 R-N-. { 2-Chloro-4- [4- (2-hydroxyethylthio) anilinosulfonyl] phenyl} -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of S-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl chloride (Method P) (700 mg, 3.92 mmol) in DCM (25 mL) was added to a stirred mixture of 2-chloro- [4- (2-hydroxyethylthio) anilinosulfonyl] aniline (Method R) (630 mg;, 1.76 mmol) and 2,6-di-t-butyl. pyridine (0.9, ml, 4.0 mmol) in DCM (50 ml). The resulting mixture was stirred at room temperature overnight and then washed with 1M aqueous hydrochloric acid, aqueous sodium hydrogen carbonate solution, and brine then dried and evaporated to dryness. The residue was purified by column chromatography using 20% EtOAc in DCM to afford the title compound as a foam (330 mg, 0.66 mmol). NMR: 1.6 (s, 3H), 2.9 (t, 2H), 3.5 (m, 2H), 4.8 (t, 1H), 7.0 (d, 2H), 7.2 (d, 2H), 7.7 (dd, 1H) 7.8 (d, 1H), 8.2 (d, 1H); MS: 497. Example 111 R-N-. { 2-Chloro-4- [4- (2-hydroxyethylsulfonyl) anilinosulfonyl] -phenyl} -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of R-N-. { 2-Chloro-4- [4- (2-hydroxyethylsulfonyl) anilinosulfonyl] phenyl} -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 110) (270 mg, 0.54 mmol) and 55% of 3-chloroperoxybenzoic acid (340 mg, 1.08 mmol) in DCM (25S ml) was stirred at room temperature overnight and then evaporated to dryness and the residue was treated with aqueous sodium hydrogen carbonate solution (25 ml). The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated. The residue was purified by column chromatography using 50% EtOAc in DCM to yield the title compound as a foam (144 mg, 0.27 mmol). RM ?: 1.6 (s, 3H), 3.35 (t, 2H), 3.6 (m, 2H), 4.8 (t, 1H), 7.3 (d, 2H), 7.75 (d, 2H), 7.85 (dd, 1H) ), 7.95 (d, 1H), 8.25 (d, 1H); MS: 529. Example 112 R-N-. { 2-Chloro-4- [4- (2-ethoxyethylthio) anilinosulfonyl] phenyl} -3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide A solution of S-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide chloride (Method P) (393 mg, 2.2 mmol) in DCM (25 ml) was added to a stirred mixture of 2-chloro-4- [4- (2-ethoxyethylthio) anilinosulfonyl] aniline (Method S) (770 mg, 2.0 mmol) and 2,6-di-t-butylpyridine. (0.51 mL 2.2 mmol) in DCM (25 mL). The resulting mixture was stirred at room temperature for 6 h and then washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was purified by column chromatography using 10% EtOAc in DCM to give the title compound of the title as a foam (520 mg, 0.99 mm'ol). NMR: 1.0 (t, 3H), 1.6 (s, 3H), 3.0 (t, 2H), 3.3-3.5 (m, 4H), 7.0 (d, 2H), 7.2 (d, 2H), 7.7 (dd, 1H), 7.8 (d, 1H), 8.2 (d, 1H); MS: 525. Example 113 R-N-. { 2-Chloro-4 - [4- (2-ethoxy-ethylsulfonyl) anilinosulfonyl] -phenyl} 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide The procedure of Example 111 was repeated using R-N- { 2-Chloro-4- [4- (2-ethoxyethylthio) anilinosulfonyl] phenyl} - 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Example 112) (460 mg, 0.87 mmol) as the starting material to obtain the title compound as a foam (260 mg, 0.46 mmol). RM ?: 0.7 (t, 3H), 1.6 (s "3H), 3.1 (t, 2H), 3.45 (t, 2H), 3.55 (t, 2H), 7.3 (d, 2H), 7.75 (d, 2H) ), 7.85 (dd, 1H), 8.0 (d, 1H), 8.3 (t, 1H); 557. Example 114 RN- [2-Chloro-4- (4-methoxycarbonylaminosilonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of S-3, 3, 3-trifluoride chloride -2-hydroxy-2-methylpropanoyl (Method P) (8.24 g, 46.2 mmol) in DCM (200 mL) was added to a stirred mixture of 2-chloro-4- (4-methoxycarbilanilinosulfonyl) aniline (Method T) ( 13.6 g, 40.0 mmol) and 2,6-di-butylpyridine (10.3 mL, 46.2 mmol) in DCM (200 mL). The resulting mixture was stirred at room temperature overnight and then washed with 1M aqueous hydrochloric acid, the aqueous sodium hydrogen carbonate solution and brine, dried and evaporated to dryness. The residue was purified by column chromatography using 10% EtOAc in DCM to yield the title compound as a solid (16.6 g, 34.5 mmol). NMR: 1.6 (s, 3H), 3.8 (s, 3H), '7.2 (d, 2H), 7.8 (dd, 1H), 7.85 (d, 2H), 7.9 (d, 1H), 8.2 (d, 1H) ); MS: 479. EXAMPLE 115 RN- [2-Chloro-4- (4-carboxyanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of lithium hydroxide (428 mg, 11.6 mmol. ) in water (10 ml) were added to a solution of RN- [2-chloro-4- (4-methoxycarbilanilinosulphenyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 114) ( 610 mg, 1.27 mmol) in methanol (20 ml). The resulting mixture was stirred at room temperature overnight and evaporated to dryness. The residue was dissolved in 1M aqueous hydrochloric acid (15 ml), the aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with the brine, dried and evaporated to yield the title compound as a foam (560 mg, 1.2 mmol ); the microanalysis found: C, 43.8; H, 3.0; N, 5.7%; C? 7H? 4N2F3ClSOg requires: C, 43.7; H, 3.0; N, 6.0%; NMR: 1.6 (s, 3H), 7.2 (d, 2H), 7.8 (d, 2H), 7.8 (dd, 1H), 7.95 (d, 1H), 8.2 (d, 1H); MS: 465. EXAMPLE 116 RN- [2-Chloro-4-piperazin-1-ylsulphonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of S-3, 3 chloride, 3-trifluoro-2-hydroxy-2-methylpropanoyl (Method P) (5.6 g, 31.2 mmol) in DCM (250 mL) was added to a stirred mixture of 2-chloro-4- [1- (-butoxycarbonyl) piperazin-4-ylsulfonyl] aniline (Method U) (10.7 g, 28.4 mmol) and 2,6-di-t-butylpyridine (7.1 mL, 31.2 mmol) in EtOAc (750 mL). The resulting mixture was stirred at room temperature overnight, the DCM was evaporated and the EtOAc layer was washed with aqueous sodium hydrogen carbonate solution and brine, dried and evaporated to dryness. The residue was dissolved in 3M hydrogen chloride in EtOAc (70 ml), stirred at room temperature overnight and evaporated to dryness. The residue was treated with saturated sodium hydrogen carbonate solution, the aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated. The residue was crystallized from EtOAc to yield the title compound as a solid (7.5 g, 18.0 mmol). NMR: 1.6 (s, 3H), 2.7 (m, 4H), 2.8 (m, 4H), 7.7 (dd, 1H), 7.85 (d, 1H), 8.3 (d, 1H); MS: 414. EXAMPLE 117 R-N- [2-Chloro-4- (l-acetylpiperazin-4-ylsulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide. A solution of RN- [2-chloro-4- (piperazin-1-ylsulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 116) (330 mg, 0.8 mmol) and triethylamine (0.33 ml) in DCM (20 ml) was added to a stirred solution of acetyl chloride (0.13 ml, 1.8 mmol) in DCM (15 ml). The resulting mixture was stirred at room temperature overnight and evaporated to dryness. The residue was dissolved in methanol (10 ml) and added to a stirred solution of lithium hydroxide (150 mg, 3.75 mmol) in water (5 ml). The resulting mixture was stirred at room temperature for 4 h and then evaporated to dryness and the residue was treated with 1M aqueous hydrochloric acid (15 ml). The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to yield the title compound, as a foam (81 mg, 0.18 mmol). RM ?: 1.6 (s, 3H), 2.0 (s, 3H), 3.0 (m, 4H), 3.6 (m, 4H), 7.8 (dd, 1H), 7.9 (d, 1H), 8.4 (d, 1H) ); MS: 456. Examples 118-125 The procedure of Example 117 was repeated using the appropriate acid chloride or sulfonyl chloride to replace the acetyl chloride to obtain the compounds described below. Ex Compound MS XH RM? 118 RN- [2-Chloro-4 - (1- 492 1.6 (s, 3H), 2.9 (s, mesylpiperazin-4-yl-3H), 3.0 (m, 4H), 3.2 sulfonyl) phenyl] -3.3 , 3- (m, 4H), 7.8 (dd, 1H), trifluoro-2-hydroxy-2- • 7.9 (d, 1H), 8.4 (d, methylpropanamide 1H). 119 R-N-. { 2-Chloro-4- [1- (4-632-1.6 (s, 3H), 3.0 (m, mesylphenylsulphonyl) -8H), 3.3 (s, 3H), 7.7 piperazin-4-ylsulfonyl] - (dd, 1H), 7.8 (d, 1H), phenyl} -3,3, 3-trifluoro-2-7.95 (d, 2H), 8.15 (d, hydroxy-2-methyl2H), 8.4 (d, 1H). Propanamide 120 R-N-. { 2-Chloro-4 - [1- (methoxy-486 1.6 (s, 3H), 2.95 (m, acetyl) -piperazin-4-yl-4H), 3.2 (s, 3H), 3,5-sulfonyl] phenyl} -3.3.3- (m, 4H), 4.0 (s, 2H). trifluoro-2-hydroxy-2- • 7.8 (dd, 1H), 7.9 (d, methylpropanamide 1H), 8.4 (d, 1H). 121 R-N-. { 2-Chloro-4 - [1- (methoxy-500 1.6 (s, 3H), 2.5 (t, propionyl) -piperazin-4-yl-2H), 2.9E) (m, 4H), 3.2 sulfonyl] phenyl} -3.3.3- (s, 3H), 3.5 (m, 4H), trifluoro-2-hydroxy-2- 3.6 (t, 2H), 7.8 (dd, methylpropanamide * 1H), 7.9 (d, 1H) 8.4 (d, 1H). 122 R-N-. { 2-Chloro-4 - [1- (aceta- 513 1.6. (S, 3H), 1.9 (s, midoacetyl) -piperazin-4- 3H), 3.0 (m, 4H), 3.6-ylsulfonyl] phenyl} -3.3, 3- (m, 4H), 3.9. (d, 2H), trifluoro-2-hydroxy-2-7.8 (dd, 1H), 7.9 (d, methylpropanamide 1H), 8.4 (d, 1H). 123 R-N-. { 2 -Cloro-4 - [1- 472 1.6 (s, 3H), 2.8 (m, (hydroxyacetyl) -piperazine- • 2H), 3.0 (m, 4H), 3 .45- 4 -ylsul fonyl] phenyl} -3, 3.3- 3.6 (m, 4H), 7.8 (dd, trifluoro-2-hydroxy-2H), 7.9 (d, 1H), 8.4 methylpropanamide. (d, 1H). 124 R-N-. { 2 -Cloro-4 - [l-R. S-512 1.6 (s, 3H), 1.9 (m, tetrahydrofuran-3-2H), 3.0 (m, 4H), 3.2-ylcarbonyl) piperazine-4- (m, 1H), 3.5-3.6 (m, ylsulfonyl) phenyl .3., -3.3, 3-8H), 7.8 (dd, 1H), 7.9 trifluoro-2-hydroxy-2- (d, 1H), 3.4 (d, 1H) • methyl-propanamide 125 RN-. { 2-Chloro-4 - [l-527 1.6 (s, 3H), 2.9 (m, (morpholinocarbonyl) -4H), 3.1 (m, 4H), 3.2 piperazin-4-ylsulfonyl] - (m, 4H), 3.5 (m, 4H), phenyl} -3,3,3-trifluoro-2-7,8 (dd, 1H), 7.9 (d, hydroxy-2-methylpropanamide 1H), 8.4 (d, 1H). Example 126 R-N-. { 2-Chloro-4 - [(1-aminoacetylpipe'razin-4-yl) sulfonyl] phenyl} -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- [2-chloro-4-piperazin-l-ylsulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2 methylpropanamide (Example 116) (330 mg, 0.8 mmol) in tetrahydrofuran (3 ml) was added to a stirred solution of (-butoxycarbonyl) glycine (149 mg, 0.85 mmol) and carbonyldiimidazole (139 mg, 0.85 mmol) in tetrahydrofuran ( 8 ml). The resulting mixture was stirred at room temperature overnight and evaporated to dryness. The residue was dissolved in 0.7M aqueous citric acid (30 ml); The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with saturated aqueous sodium acid carbonate solution and brine, dried and evaporated to dryness. The residue was dissolved in 3M hydrogen chloride in EtOAc (10 ml), stirred at room temperature for 3 h and evaporated to dryness. The residue was treated with saturated sodium acid carbonate solution, the aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to yield the title compound as a foam (230 mg, 0.49 mmol ). NMR: 1.6 (s, 3H), 3.0 (m, 4H), 3.4 (m, 2H), 3.45-3.6 (, 4H), 7.8 (dd, 1H), 7.9 (d, 1H), 8.4 (d, 1H) ); MS: 471. Example 127 RN- [2-Chloro-4- (N-acetylsulfamoyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- (2-chloro-4-) sulfamoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 40) (150 mg, 0.43 mmol) acetic acid (62.4 mg, 1.04 mmol) and 4-dimethylaminopyridine (380 mg, 3.12 mmol) in DCM (25 ml) was stirred on a 4A molecular bed at room temperature for 3 h. To this mixture was then added 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (300 mg, 1.57 mmol). The resulting mixture was stirred at room temperature overnight and was filtered, washed with 1M aqueous hydrochloric acid, dried and evaporated to dryness. The residue was dissolved in methanol (10 ml) and added to a stirred solution of lithium hydroxide (92 mg, 2.3 mmol) in water (5 ml). The resulting mixture was stirred at room temperature for 4h and then evaporated to dryness and the residue was treated with 1M aqueous hydrochloric acid (15 ml). The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to yield the title compound as a foam (118 mg, 0.3 mmol), the microanalysis found: C, 38.5; H, 3.6; N, 6.6%; Ci2H? 2N2F3ClS? 5, 0.5 EtOAc requires: C, 38.8; H, 3.7; N, 6.5%; NMR (CDC13): 1.8 (s, 3H), 2.1 (s, 3H), 7.9 (dd, 1H), 8.2 (d, 1H), 8.7 (s, 1H); MS: 387. Examples 128-138 The procedure described in Example 127 was repeated using the appropriate acid to replace the acetic acid to obtain the compounds described below.

Example 139 R-N- Hydrochloride. { 2-Chloro-4- [N- (aminoacetyl) sulfamoyl] -phenyl} -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- (2-chloro-4-sulfamoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 40) (345 mg, 1.0 mmol), (tert-butoxycarbonyl) glycine (420 mg, 2.4 mmol) and 4-dimethylaminopyridine (878 mg, 7.2 mmol) in DCM (35 mL) was stirred on a 4A molecular bed at room temperature for 3 h . then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (688 mg, 3.6 mmol) was added to this mixture. The resulting mixture was stirred at room temperature overnight and then filtered, washed with 0.7M aqueous citric acid and brine, dried and evaporated to dryness. The residue was dissolved in methanol (20 ml) and added to a stirred solution of lithium hydroxide (125 mg, 3.0 mmol) in water (10 ml). The resulting mixture was stirred at room temperature for 4 h and then evaporated to dryness and the residue was treated with 0.7 M aqueous citric acid (15 ml). The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated. The residue was dissolved in 3M hydrogen chloride in EtOAc (5 mL), stirred at room temperature overnight and the solid was filtered to give the title compound (245 mg, 0.6 mmol); MS: 402. Example 140 R-N-. { 2-chloro-4- [N- (4-hydroxybenzoyl) sulfamoyl] phenyl} -3, 3,3-trifluoro-2-hydroxy-2-methyldropanamide A solution of R-N-. { 2-Chloro-4- [N- (4-benzyloxybenzoyl) sulfamoyl] phenyl} -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 133) (750 mg, 1.35 mmol) in EtOAc (40 mL) was hydrogenated over 10% Pd / C for 4h at room temperature. The catalyst was removed by filtration and the EtOAc was evaporated to yield the title compound as a foam (480 mg, 1.03 mmol). RM ?: 1.6 (s, 3H), 6.7 (d, 2H), 7.7 (d, 2H), 7.8 (dd, 1H), 7.9 (d, 1H), 8.1 (d, 1H); MS: 465.

Example 141 RN- [2-Chloro-4- (pyrrol-1-ylsulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- (2-chloro-4-sulfamoylphenyl) 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Example 40) (345 mg, 1.0 mmol), 2, 5-diethoxytetrahydrofuran (320 mg, 2.0 mmol) and 4-toluenesulfonic acid (190 mg, 1.0 mmoles) in toluene (15 ml) was heated at 100 ° C overnight and evaporated to dryness. The residue was dissolved in EtOAc (50 ml) and washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated to dryness. The residue was purified by column chromatography using 30% EtOAc in hexane to give the title compound as a solid, (200 mg, 0.5 mmol). RM ?: 1.6 (s, 3H), 6.35 (s, 2H), 7.35 (s, 2H), 7.9 (dd, 1H), 8.2 (d, 1H), 8.3 (d, 1H); MS: 395. Example 142 R-N-. { 2-Chloro-4- [(2-morpholinoethylamino) sulfonyl] phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- [2-chloro-4- (chlorosulfonyl) phenyl) ] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Method Y) (366 mg, 1.0 mmol) in DCM (10 mL) was added to a stirred solution of 4- (2-aminoethyl) morpholine (286 mg, 2.2 mmol) in DCM (15 ml). The resulting mixture was stirred at room temperature overnight and then washed with aqueous sodium hydrogen carbonate solution and brine, dried and evaporated to dryness. The residue was purified by column chromatography using EtOAc to yield the title compound as a foam (384 mg, 0.84 mmol). NMR: 1.6 (s, 3H), 2.3 (m, 6H), 2.9 (m, 2H), 3.5 (m, 4H), 7.8 (dd, 1H), 7.9 (d, 1H), 8.2 (d, 1H); MS: 458. Examples 143-208 The procedure described in Example 142 was repeated using the appropriate amine to replace 4- (2-aminoethyl) morphine using DCM or EtOAc as solvent to obtain the compounds described below. f1 The melting point for Example 145 was 117-118 ° C and [a] D20 + 1.46 ° (c, 10.2 in EtOH). F2 The melting point for Example 146 was 110-111 ° C and [a] D20 + 0.85 ° (c, 10.0 in EtOH). F3 The melting point for Example 147 was 134-135 ° C and [a] D20 + 1.75 ° (c, 10.7 in EtOH). EXAMPLE 209 RN- [2-Chloro-4- (2-aminoethylaminosulfonyl) -phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanapride hydrochloride A solution of RN- [2-chloro-4- ( chlorosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Method Y) (366 mg, 1.0 mmol) in DCM (15 ml) was added to a stirred solution of N-t-butoxycarbonyl ethylenediamine (350 mg, 2.2 mmol) in DCM (10 ml). The resulting mixture was stirred at room temperature for 4 h, washed with 1M aqueous citric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated to dryness. The residue was dissolved in 3M hydrogen chloride in EtOAc (5 mL) and stirred at room temperature overnight. The precipitated solid was filtered, washed with EtOAc (5 ml) and dried to yield the title compound as a solid (362 mg, 0.63 mmol). RM ?: 1.6 (s, 3H, 2.85 (m, 2H), 3.0 (m, 2H), 7.8 (dd, 1H), 8.0 (d, lH), 8.3 (d, 1H), MS: 388. Example 210 RN- [2-Chloro-4- (2-dimethylaminoethyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methyl-ropanamide hydrochloride A solution of RN- [2-chloro-4- (chlorosulfonyl ) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylprop'anamide (Method Y) (366 mg, 1.0 mmol) in DCM (10 ml) was added to a stirred solution of N, N-dimethylaminoethylamine (194 mg, 2.2 mmol) in DCM (15 ml). The resulting mixture was stirred at room temperature overnight and then washed with aqueous sodium hydrogen carbonate solution and brine, evaporated to dryness. The residue was purified by conversion to the hydrochloride salt and recrystallization from EtOAc to yield the title compound (300 mg, 0.72 mmol): RM ?: 1.6 (s, 3H), 2.75 (s, 6H), 3.1 (s, 4H), 7.8 (dd, 1H), 8.0 (d, 1H), 8.3 (d, 1H); MS:, 416. EXAMPLE 211 RN- [2-chloro-4-aminoanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- [2-chloro-4- (chlorosulfonyl ) phenyl] -3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Method Y) (275 mg, 0.75 mmol) in DCM (15 ml) was added to a stirred solution of N-t-butoxycarbonyl-1,4-phenylenediamine ( 156 mg, 0.75 mmol) and pyridine (0.18 mL, 2.2 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 4 h, washed with 1M aqueous citric acid, saturated sodium hydrogen carbonate solution and brine then dried and evaporated to dryness. The residue was dissolved in 3M hydrogen chloride in EtOAc (12 mL), stirred at room temperature overnight and evaporated to dryness. The residue was treated with saturated sodium acid carbonate solution, the aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated. The residue was purified by column chromatography using 25% EtOAc in DCM to afford the title compound as a foam (275 mg, 0.63 mmol). RM ?: 1.6 (s, 3H), 5.0 (s, 2H), 6.4 (d, 2H), 6.7 (d, 2H), 7. (dd, 1H), 7.7 (d, 1H), 8.2 (d, 1 HOUR); MS: 436. EXAMPLE 212 RN-2- [Chloro-4- (-formylanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- [2-chloro-4- ( chlorosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Method Y) (1.2 g, 3.28 mmol) in EtOAc (20 mL) was added to a stirred solution of 2- (4-aminophenyl) ) -1, 3-dioxolane (Method V) (800 mg, 4.85 mmole) and pyridine (0.4 ml, 4.8 mmole) in EtOAc (80 ml). The resulting mixture was stirred at room temperature overnight, washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was purified by column chromatography using 10% EtOAc in DCM to yield the title compound as a solid (1.1 g, 2.5 mmol). RM ?: 1.6 (s, 3H), 7.3 (d, 2H), 7.8 (d, 2H), 7.85 (dd, 1H), 7.95 (d, 1H), 8.2 (d, 1H), 9.8 (s, 1H) ); MS: 449. EXAMPLE 213 RN- [2-Chloro-4- (4-hydroxymethylanilinesulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide Sodium borohydride (38 mg, 1.0 mmol) was added to a solution of RN- [2-chloro-4- (4-formylanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 212) (225 mg, 0.5 mmol) in ethanol ( 15 ml). The resulting mixture was stirred at room temperature overnight and evaporated to dryness. The residue was dissolved in 1M aqueous hydrochloric acid (15 ml). The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to yield the title compound as a foam (220 mg, 0.5 mmol). NMR: 1.6 (s, 3H), 4.4 (s, 2H), 7.0 (d, 2H), 7.2 (d, 2H), 7.7 (dd, 1H), 7.85 (d, 1H) and 8.2 (d, 1H); MS: 451. Example 214 R-N-. { 2-; Chloro-4 - [N- (2-hydroxyethyl) -N- (4-aminophenyl) aminosulfonyl] phenyl} 3, 3, 3-trifluoro-2-hydroxy-2-ethylpropanamide A solution of RN- [2-chloro-4- (chlorosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Method Y) (580 mg, 1.58 mmol) in DCM (15 ml) was added to a stirred solution of 4- (2-hydroxyethylamino) aniline (Method W) (285 mg, 1.9 mmol) and pyridine (0.31 ml, 3.7 mmol). in DCM (15 ml). The resulting mixture was stirred at room temperature overnight, washed with 1M aqueous hydrochloric acid, dried and evaporated to dryness. The residue was dissolved in methanol (20 ml) and added to a stirred solution of lithium hydroxide (332 mg, 8.0 mmol) in water (10 ml). The resulting mixture was stirred at room temperature overnight and then evaporated to dryness and the residue treated with 1M aqueous hydrochloric acid until pH 7.0. The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated; The residue was purified by column chromatography using 50% EtOAc in DCM to afford the title compound as a foam (156 mg, 0.3 mmol). NMR: 1.6 (s, 3H), 3.35 (t, 2H), 3.5 (t, 2H), 4.7 (t, 1H), 5.2 (s, 2H), 6.4 (d, 2H), 6.7 (d, 2H) , 7.6 (dd, 1H), 7.65 (d, 1H), 8.3 (d, 1H); MS: 480. Example 215 R-N-. { -Cloro-4- [4- (2-hydroxyethylamino) anilinosulfonyl] phenyl} -3,3,3-trifluoro-2-hydroxy-2-methylp'ropanamide A solution of RN- [2-chloro-4- (chlorosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2- Methylpropanamide (Method Y) (770 mg, 2.1 mmol) in DCM (20 mL) was added to a stirred solution of 4- (N-2-tetrahydropyranyloxyethyl-t-butoxycarbonylamino) aniline (Method X) (620 mg, 1.85 mmol) and pyridine (0.34 ml, 4.08 mmol) in DCM (20 ml). The resulting mixture was stirred at room temperature overnight, washed with 1M aqueous citric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated to dryness. The residue was dissolved in 3M hydrogen chloride in EtOAc (12 mL), stirred at room temperature for 4 h and evaporated to dryness. The residue was treated with saturated sodium hydrogen carbonate solution, the aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated. The residue was purified by column chromatography using 25% EtOAC in DCM to afford the title compound as a foam (260 mg, 0.45 mmol). RM ?: 1.6 (s, 3H), 3.0 (m, 2H), 3.5 (m, 2H), 4.6 (t, 1H), 5.4 (t, 1H), 6.4 (d, 2H), 6.7 (d, 2H) ), 7.6 (dd, 1H), 7.7 (d, 1H), 8.2 (d, 1H); MS: 480. Example 216 R-N-. { 2-Chloro-4 - [4- (acetamidosulfonyl) anilinosulfonyl] phenyl} -3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- [2-chloro-4- (4-sulfamoylanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2- methylpropanamide (Method 36) (175 mg, 0.35 mmol), acetic acid (50 mg, 0.84 mmol) and 4-dimethylaminopyridine (306 mg, 2.51 mmol s) in DCM (25 mL) was stirred on a 4A molecular bed at room temperature during _3h. To this mixture was added 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (242 mg, 126 mmol). The resulting mixture was stirred at room temperature overnight, and then filtered, washed with 1M aqueous hydrochloric acid, dried and evaporated to dryness. The residue was dissolved in methanol (10 ml) and added to a stirred solution of lithium hydroxide (147 mg, 3.5 mmol) in water (5 ml). The resulting mixture was stirred at room temperature for 4 h, evaporated to dryness and the residue treated with 1M aqueous hydrochloric acid (15 ml). The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to yield the title compound as a foam (140 mg, 0.26 mmol). RM ?: 1.6 (s, 3H), 1.9 (s, 3H), 7.3 (d, 2H), 7.75 (d, 2H), 7.85 (dd, 1H), 7.95 (d, 1H), 8.25 (d, 1H) ); MS: 542.

Example 217 R-N-. { 2-Chloro-4 - [4- (mesylaminocarbonyl) anilinosulfonyl] phenyl} -3,3,3-trifluoro-2-hydroxy-2-methylpronamide • 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (195 mg, 1.02 mmol) was added to a solution of RN- [2-chloro] -4- (4-carboxyanoylsulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Example 115) (320 mg, 0.69 mmol), methane sulfonamide (79 mg, 0.82 mmol) and 4- dimethylaminopyridine (250 mg, 2.06 mmol) in DCM (25 ml). The resulting mixture was stirred at room temperature overnight, evaporated to dryness and the residue treated with 1M aqueous hydrochloric acid (15 ml). The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to yield the title compound as a foam (130 mg, 0.24 mmol). RM ?: 1.6 (s, 3H), 2.8 (s, 3H), 7.0 (d, 2H), 7.7 (d, 2H), 7.8 (dd, 1H), 7.9 (d, 1H), 8.2 (d, 1H) ); MS: 542. Example 218 R-N-. { 2-Chloro-4- [4- (l-methyl-piperazin-4-ylcarbonyl) anilinosulfonyl] phenyl} -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide Oxalyl chloride (0.07ml, 0.8 mmol) was added to a solution of RN- [2-chloro-4- (4-carboxynylaminosulfenyl) phenyl] -3 , 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Example 115) (314 mg, 0.67 mmol) in DCM (15 ml). The resulting mixture was stirred at room temperature overnight and evaporated to dryness. The residue was dissolved in EtOAc (5 mL) and added to a solution of 1-methylpiperazine (150 mg, 1.5 mmol) in EtOAc (5 mL). The resulting mixture was stirred at room temperature overnight, washed with 1M aqueous hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated to yield the title compound as a foam. (355 mg, 0.65 mmol); MS: 547. Examples 219-238 The procedure of Example 218 was repeated using the appropriate amine to replace the 1-methylpiperazine to obtain the compounds described below. 233 R-N-. { 2-Chloro-4- [4- 562 1.6 (s, 3H), 1.3-1.9 (m, (trans / cis-4-hydroxycyclo-8H), 3.8 (m, 2H), 7.2-hexylaminocarbonyl) anilino (d, 2H), 7.8 (d, 2H), sulfonyl] phenyl} -3.3, 3-7.85 (dd, 1H), 8.0 (d, trifluoro-2-hydroxy-2H), 8.3 (d, 1H). methylpropanamide 234 R-N-. { 2-Chloro-4- [4- (R, S-548 1.6 (s, 3H), 1.8 (m, tetrahydrofur-2-ylmethyl-4H), 3.25 (t, 2H), 3.6 aminocarbonyl) anilinosulfo (m, 1H ), 3.75 (m, 1H), nil] phenyl} -3.3.3- 3.9 (m, 1H), 7.2 (t, trifluoro-2-hydroxy-2H), 7.8 (d, 2H), 7.85 methylpropanamide (dd, 1H), 8.0 (d, 1H) , 8.3 (d, 1H). 235 R-N-. { 2-Chloro-4- [4- (R, Sl- 522 1.1 (d, 3H), 1.6 (s, methyl-2-hydroxyethylamino3H), 3.4 (m, 2H), 3.9 carbonyl) anilinosulfonyl] - (m, 1H ), 7.2 (d, 2H), phenyl} -3,3,3-trifluoro-2-7,8 (d, 2H), 7.85 (dd, hydroxy-2-methylpropanamide 1H), 8.0 (d, 1H), 8.3 (d, 1H). 236 R-N-. { 2 -Cloro-4 - [4 - (R, Sl- 536 1.1 (d, 3H), 1.6 (s, methyl-2-methoxyethylamino-3H), 3.2 (s, 3H), 3.4 carbonyl) anilinosulfonyl] - (m , 2H), 4.1 (m, 1H), phenyl} -3,3, 3-trifluoro-2- 7.2 (d, 2H), 7.8 (d, hydroxy-2-methylpropanamide 2H), 7.85 (dd, 1H), 8.0 (d, 1H), 8 .3 (d, 1 HOUR) . 237 RN- (2-Chloro-4 -. {4 - [N-522 1.6 (s, 3H), 2.9 (s, methyl-N- (2-hydroxyethyl) -3H), 3.4 (m, 2H), 3.5 aminocarbonyl] anilinosulfo (m, 2H), 1.2 (d, 2H) 7.8 nil.} Phenyl) -3,3,3- (d, 2H), 7.85 (dd, 1H), trifluoro-2-hydroxy -2- 8.0 (d, 1H), 8.3 (d, methylpropanamide 1H). 238 RN- (2-Chloro-4-. {4- [N- 536 1.6 (s, 3H)? 2.9 (s, methyl-N- (2-methoxyethyl) -3H), 3.3 (s, 3H), 3.4 aminocarbonyl] anilino (m, 2H), 3.5 (m, 2H), sulfonyl, phenyl) -3,3,3-7.2 (d, 2H), 7.8 (d, trifluoro-2-hydroxy-2H) ), 7.85 (dd, 1H). 8.0 methylpropanamide (d, 1H), 8 .3 (d, 1H). Example 239 R-N-. { 2-Chloro-4 - [4- (2-hydroxyethylaminosulfonyl] anilinosulfonyl] phenyl] -3,3,3-tri? Uoro-2-hydroxy-2-methylpropanamide A solution of RN- [2-chloro-4- ( 4-fluorosulfenylanilinosulphenyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Method O) (250 mg, 0.5 mmol), ethanolamine (92 mg, 1.5 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) in ethanol (25 ml) was heated at 78 ° C overnight and evaporated to dryness. The residue was treated with 1M aqueous hydrochloric acid (10 ml). The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to yield the title compound as a foam (200 mg, 0.37 mmol). NMR: 1.6 (s, 3H), 2.8 (m, 2H), 3.3 (m, 2H), 4.6 (t, 1H), 7.3 (d, 2H), 7.7 (d, 2H), 7.8 (dd, 1H) , 7.9 (d, 1H), 8.2 (d, 1H); MS: 544. Examples 240-248 The procedure of Example 239 was repeated using the appropriate amine to replace the ethanolamine to obtain the compounds described below. Ex Compound MS RM? 240 R-N-. { 2 -Cloro-4 - [4 - (R, S-2- 574 1.6 (s, 3H), 2.8 (m, 3-dihydroxypropylamino-1H), 3.2 (m, 2H), 3.4-sulfonyl) anilinosulfonyl] - (m, 2H), 7.3 (d, 2H), phenyl} -3, 3, 3-trifluoro-2-7.6 (d, 2H), 7.8 (dd, hydroxy-2-methylpropanamide 1H), 7.9 (d, 1H), 8.2 (d, 1H). 245 RN- ('2-Chloro-4 - [4- (allyl-540 1.6 (s, 3H), 3.4 (d, aminosulfonyl) anilinosulfo. 2H), 5.0 -5.2 (m, 2H), nil] phenyl. -3.3.3- 5.65 (m, 1H), 7.3 (d, trifluoro-2-hydroxy-2H), 7.6 (d, 2H), 7.8 methylpropanamide (dd, 1H), 7.9 (d, 1H ), 8.2 (d, 1H) 246 RN-. {2-Chloro-4 - [4-528 1.6 (s, 3H), 2.5 (s, (dimethylaminosulfonyl) -6H), 7.3 (d, 2H), 7.6 anilinosulfonyl] phenyl} - (d, 2H), 7.8 (dd, 1H), 3,3, 3-trifluoro-2-hydroxy-7.9 (d, 1H), 8.2 (d, 2 - . 2 - . 2-methylpropanamide 1H). 247 RN- [2-Chloro-4- [4- (R, S-570 1.6 (s, 3H), 1.65 (m, hydroxy-pyrrolidin-1-yl-2H), 2.9 (d, 1H), 3.2 sulfonyl ) anilinosulfonyl] - (m, 3H), 4.1 (ra, 1H), phenyl} -3, 3, 3-trifluoro-2- 7.3 (d, 2H), 7.6 (d, hydroxy-2-methylpropanamide 2H), 7.8 (dd, 1H), 7.9 (d, 1H), 3.2 (d, 1H) 248 RN-. { 2 -Cloro-4- [4-598-1.1-1.5 (ti, 8H), 1.6 > (s, (trans / cis-4-hydroxycyclo-3H), 2.9 (d, 1H), 4.5 hexylaminosulfonyl) anilino (m, 1H), 7.3 (d, 2H), sulfonyl] phenyl} -3.3.3-7.7 (d, 2H), 7.9 (dd, trifluoro-2-hydroxy-2H), 8.1 (d, 1H), 8.3 methylpropanamide (d, 1H). Example 249 RN- [2-Chloro-4- (5-trifluoromethylpyrid-2-ylaminosulfonyl) -phenyl] -3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide RN- (2-chloro-4-chlorosulfonylphenyl) -3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Method M) (293 mg, 0.80 mmol) and 2-amino-5-trifluoromethylpyridine (130 mg, 0.80 mmol) were dissolved in pyridine (2 ml) . The resulting mixture was stirred at 85 ° C for 20 h. The mixture was then cooled to room temperature and concentrated under vacuum to yield an oil, which was purified on a Bond Elut column to yield the title compound as a solid (285 mg, 0.58 mmol). RM ?: 1.55 (s, 3H), 7.15 (d, 1H) 7.90 (m, 2H), 8.02 (m, 2H), 8.21 (d, 1H), 8.51 (s, 1H), 9.84 (s, 1H) 12.09 (broad s, 1H); MS: 490. Examples 250-264 The procedure of Example 249 was repeated using the appropriate aminoheterocycle to replace the 2-amino-5-trifluoromethyl pyridine to obtain the compounds described below, in 18-92% yields. 263 RN- [2-Chloro-4- (4,6-451 1.59 (s, 3H), 2.25 (s, dimethylpyrimidin-2- 6H), 6.72 (s, 1H), 7.91 ilaminosulfonyl) phenyl] - (m, 2H), 8.12 (s, 1H), 3, 3, 3-trifluoro-2-hydroxy- 8.17 (d, 1H), 9.83 (s, 2-methylpropanamide 1H). 264 R-N- [2-Chloro-4- (piperazine- 423 1.58 (s, 3H), 7.93 (m, 2-ylaminosulfonyl) phenyl] -2H), 8.08 (s, 1H), 8.24 3,3, 3-trifluoro-2-hydroxy- (m, 3H), 8.34 (s, 1H), 2-methylpropanamide 9.87 (s, 1H). + 1 The starting aminoheterocycle for Example 255, 2-amino-3-carbamoylthiophene, was prepared according to the procedure described in J. Med Chem. , 1996, 39 (8), pl635. t2 The starting aminoheterocycle for Example 260, 2-amino-4-dimethylamino-6-methyl-pyrimidine, was prepared according to the procedure described in the North American Patent Application: US 77-769475 770217. + 3 The starting aminoheterocycle for Example 261, 2-amino-5,6-dimethylpyrazine was prepared according to the procedure described in Chem. Ber. , 1967, 100 (2), p560-563. t4 The starting aminoheterocycle for Example 262, 4-amino-3-5-dimethylisoxazole, was prepared according to the procedure described in Hel v. Chim. Acta, 1991, 74 (3), p531. Example 265 RN- [2-Chloro-4- (N'-phenylureidosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- (2-chlorosulfamoylphenyl) - 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Example 40) (345 mg, 1.0 mmol), phenyl isocyanate (122 mg, 1.02 mmol) and copper (I) chloride (5 mg, 0.052 mmol) DMF (5 ml) was stirred at room temperature for 24 h. The solution was poured into water and acidified with 1M aqueous hydrochloric acid (1 ml). The solid precipitate was extracted with diethyl ether (25 ml) and the ether extract was dried and evaporated. The residue was purified or column chromatography using 10% EtOAc in DCM to yield the title compound as a solid (70 mg, 0.15 mmol). RM ?: 1.9 (s, 3H), 7.0 (t, 1H), 7.3 (t, 2H), 7.5 (m, 4H), 7.6 (d, 1H), 7.8 (dd, 1H), 7.9 (d, 1H) ); MS: 464. Example 266 R-N-. { 2-Chloro-4- [N-methyl-N- (pyrazin-2-yl) aminosulfonyl] phenyl} -3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide Potassium carbonate (65 mg, 0.47 mmol) and RN- [2-chloro-4- (pyrazin-2-ylamino-sulfonyl) phenyl] -3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Example 264) (200 mg, 0.47 mmol) was added to acetone (10 ml). Methyl iodide (0.03 ml, 0.48 mmol) was added to the resulting suspension and the mixture was stirred at room temperature for 22 h before being concentrated under vacuum. Water (15 ml) was added to the residue, which was acidified with 2M HCl and extracted with DCM (2 x 40 ml). The combined extracts were washed with brine (25 ml), dried and concentrated under vacuum to leave a foam, which was purified by column chromatography to yield the title compound as a foam (100 mg, 0.23 mmol.). NMR: 1.60 (s, 3H), 3.25 (s, 3H), 7.66 (d, 1H), 7.82 (s, 1H), 8.27 (d, 1H); 8.42 (s, 1H), 8.52 (s, 1H), 8.80 (s, 1H); MS: 437. Example 267 R-N-. { 2-Chloro-4- [N-methyl-N- (5-trifluoromethylpyrid-2-yl) aminosulfonyl] phenyl} -3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide Potassium carbonate (51 mg, 0.52 mmol) and RN- [2-chloro-4- (5-trifluoromethylpyridid-2-ylaminosulfonyl) phenyl] -3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Example 249) (180 mg, 0.37 mmol) was added to acetone (10 ml). Then methyl iodide (0.023 ml, 0.37 mmol) was added to the resulting suspension and the mixture was stirred at room temperature for 22 h before being concentrated under vacuum. Water (2 ml) was added to the residue which was acidified with 2M HCl and DCM (1 ml) was added. The mixture was absorbed on a Bond Elut column and all the organic components of the mixture were washed with DCM. This resulting solution was concentrated under vacuum to yield a residue which was purified by column chromatography to yield the title compound as a foam (66 mg, 0.13 mmol). RM ?: 1.60 (s, 3H), 3.38 (s, 3H), 7.74 (d, 1H), 7.78 (d, 1H), 7.93 (s, 1H), 8.05 (s broad, 1H), 8.26 (d, 1H), 8.29 (d, 1H), 8.73 (s, 1H), 9. 90 (broad s, 1H); MS: 504. Example 268 R-N-. { 2-Chloro-4 - [N-ethyl-N- (pyrazin-2-yl) aminosulfonyl] phenyl} - 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide Potassium carbonate (64 mg, 0.65 mmol) and RN- [2-chloro-4- (pyrazin-2-ylamino-sulfonyl) phenyl] -3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Example 264) (203 mg, 0.47 mmol) was added to acetone (10 ml). Ethyl iodide was added (0.078 ml, 0.98 mmol) was added to the resulting suspension and the mixture was stirred at room temperature for 96 h before being concentrated under vacuum. 1M HCl (15 ml) was added to the residue which was then extracted with EtOAc (2 x 15). The combined extracts were washed with brine (25 ml), dried and concentrated in vacuo to leave a foam which was purified by column chromatography to yield the title compound as a foam (78 mg, 0.17 mmol).

RM ?: 1.04 (t, 3H), 1.60 (s, 3H), 3.80 (c, 2H), 7.67 (d, 1H), 7.85 (s, 1H), 8.05 (s broad, 1H), 8.28 (d, 1H), 8.48 (s, 1H), 8.57 (s, 1H), 8.78 (s, 1H), 9.89 (broad s, 1H); MS: 451. Example 269 R-N-. { 2-Chloro-4- [N-ethyl-N- (5-trifluoromethylpyrid-2-yl) aminosulfonyl] phenyl} -3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide Potassium carbonate (74 mg, 0.75 mmol) and RN- [2-chloro-4- (5-trifluoromethylpyrid-2-ylaminosulfonyl) phenyl] -3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Example 249) (246 mg, 0.51 mmol) was added to acetone (10 ml). Ethyl iodide (0.045 ml, 0.055 mmol) was added to the resulting suspension and the mixture was stirred at room temperature for 22 h. Ethyl iodide (0.045 ml, 0.055 mmol) was added to the mixture which was then stirred at room temperature for an additional 46 h and concentrated under vacuum. 1M HCl (5 ml) and EtOAc (1 ml) were added to the residue which was absorbed onto a Bond Elut column and all the organic components of the mixture were washed with EtOAc. This resulting solution was concentrated under vacuum to leave a residue which was purified by column chromatography to yield the title compound as a foam (81 mg, 0.16 mmol). RM ?: 1.18 (m, 3H), 1.60 (s, 3H), 4.00 (m, 2H), 7.68 (d, 1H), 7.80 (d, 1H), 7.96 (s, 1H), 8.25 (d, 1H) ), 8.29 (d, 1H), 8.76 (s, 1H), 9.85 (s broad, 1H); MS: 518. Example. 270 RN- [2-Chloro-4- (-hydroxyanilinesulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- [2-chloro-4- (4-benzyloxyanilinosulfonyl) phenyl] 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Example 39) (1.85 g, 3.5 mmol) in EtOAc (200 mL) was hydrogenated over 10% Pd / C for 4 h at room temperature. The catalyst was removed by filtration and the EtOAc was evaporated. The residue was purified by column chromatography using 10% EtOAc in DCM to afford the title compound as a foam (1.55 g, 3.5 mmol). NMR: 1.6 (s, 3H), 6.6 (d, 2H), 6.8 (d, 2H), 7.6 (dd, 1H), 7.75 (d, IH), 8.2 (d, 1H); MS: 437. Example 271 S-N-. { 2-Chloro-4- [(4-sulfamoylanilino) sulfonyl] phenyl} -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of R-3, 3, 3-trifluoro-2-hydroxy-2-methylpropanoylchloride (Method Cl) (223 mg, 1.25 mmol) in DCM ( 10 ml) was added to a stirred mixture of 2-chloro-4- [(4-sulfamoylanilino) sulfonyl] aniline (Method Al) (362 mg, 1.0 mmol) and .2,6-di-tert-butylpyridine (0.28 ml, 1.25 mmol). ) in EtOAc (25 ml). The resulting mixture was stirred at room temperature overnight, evaporated to dryness, the residue was dissolved in EtOAc and washed with 1M aqueous hydrochloric acid, aqueous sodium hydrogen carbonate solution and brine, dried and evaporated to dryness. The residue was purified by column chromatography using 25% EtOAc in hexane to give, as a foam, the title compound (270 mg, 0.54 mmol). EA found: C, 39.4; H, 3.4; ?, 7.4; S, 11. 5%; C? GH? 5? 3F3ClS206 0.5 EtOAc requires: C, 39.6; H, 3.5; ?, 7.7; S, 11.7%; RM ?: 1.6 (s, 3H), 7.2 (s, 2H), 7.25 (d, 2H), 7.65 (d, 2H), 7.8 (dd, 1H), 7.95 (d, 1H), 8.2 (d, 1H) ); MS: 500. Example 272 RN- [2-Chloro-5- (2-chloroanilinosulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of S-3, 3, 3-trifluoro -2-hydroxy-2-methylpropanoylchloride (Method P) (95 mg, 0.53 mmol) in DCM (5 mL) was added to a stirred mixture of 2-chloro-5- (2-chloroanilinosulfonyl) aniline (Method Bl) (140 mg, 0.44 mmol) and 2,6-di-t-butylpyridine (0.12 mL, 0.53 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight, evaporated to dryness, the residue was dissolved in EtOAc and washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was purified by column chromatography using 5% EtOAc in DCM to give, as a foam, the title compound (178 mg, 0.39 mmol). RM ?: 1.6 (s, 3H), 7.2 (m, 3H), 7.4 (d, 1H), 7.45 (dd, 1H), 7.75 (d, 1H), 8.4 (d, 1H); MS: 455. Preparation of Starting Materials Starting materials for the above Examples are commercially available or are easily prepared by standard methods of known materials. For example, the following reactions (Methods A-Bl) are illustrations but not limitations of the preparation of some of the initial materials used in the above reactions. Method A 2-Chloro-4- (morpholinosulfonyl) aniline A solution of N-acyl-2-chloro-chlorosul phonaniline (536 mg, 2 mmol), morpholine (0.2 ml, 2.3 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmoles) and pyridine (0.19 ml, 2.3 mmoles) in DCM (25 ml) was stirred at room temperature for 4 h. The mixture was washed with water and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (25 ml) and 2M aqueous sodium hydroxide (5 ml) was added. The mixture was refluxed for 4 h and then cooled to room temperature, evaporated to dryness and water (25 ml) was added to the residue. The aqueous solution was extracted with EtOAc; the organic phase was separated then washed with water, dried and evaporated to dryness to yield the title compound (500 mg, 1.8 mmol). MS: 275. Method B N- (2-Chloro-4-fluorosulfoniiphenyl) -2-acetoxy-2-methylpropanamide A solution of 2-chloro-4-fluorosulfonylaniline (2.5 g, 12 mmol), 2-acetoxyisobutyryl chloride (2.35 g, 14 mmol) and pyridine (1.2 ml, 14.5 mmol), in DCM (50 ml) was stirred at room temperature for 18 h. The mixture was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography using 25% EtOAc / isohexane and the oily product, the title compound (2.0 g, 5.9 mmol), solidified on standing. MS: 336. Method C 2-Chloro-4- (3-bromo-4-chloroanilinosulfonyl) aniline A solution of N-acyl-2-chloro-4-chlorosulfonylaniline (370 mg, 1.38 mmol), 3-bromo-4- Chloroaniline (250 mg, 1.2 mmol), 4-dimethylaminopyridine (10 mg) and pyridine (0.11 ml, 1.3 mmol) in DCM (10 ml) was stirred at room temperature for 4 h. The solution was washed with water and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (25 ml) and 2M aqueous sodium hydroxide (5 ml) was added. The mixture was refluxed for 4 h and then cooled to room temperature, evaporated to dryness and water (25 ml) was added to the residue. The aqueous solution was extracted with EtOAc; The separated organic phase was washed with water, dried and evaporated to dryness to yield the title compound (500 mg, 1.1 mmol). MS: 435. Method D 2-Chloro-4- (4-methoxyanilinosulfonyl) aniline A solution of N-acyl-2-chloro-4-chlorosulfonylaniline (536 mg, 2 mmol), 4-methoxyaniline (246 mg, 2 mmol) , 4-dimethylaminopyridine (10 mg, 0.08 mmol) and pyridine (0.19 ml, 2.3 mmol) in DCM (25 ml) was stirred at room temperature for 4 h. The solution was washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (25 ml) and 2M aqueous sodium hydroxide (5 ml) was added. The mixture was refluxed for 4 h and then cooled to room temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralized to pH 7.0 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to dryness to yield the title compound (620 mg, 1.98 mmol). MS: 311. Method E 2-Chloro-4- (allylaminosulfonyl) aniline A solution of N-acyl-2-chloro-4-chlorosulfonylaniline (670 mg, 2.5 mmol) and allylamine (342 mg, 5.7 mmol), in DCM ( 25 ml) was stirred at room temperature for 4 h. The mixture was washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (25 ml) and 2M aqueous sodium hydroxide (5 ml) was added. The mixture was refluxed for 4 h and then cooled to room temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralized to pH 7.0 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc. The EtOAc extracts were washed with brine, dried and evaporated to dryness to yield the title compound (550 mg, 2.2 mmol). MS: 245. Method F 2-Chloro-4- (thien-2-ylmethylaminosulfonyl) aniline A solution of N-acyl-2-chloro-4-chlorosulfonylaniline '(320 mg, 1.2 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol), pyrridine (0.1 ml, 1. 2 mmole) and 2-thiophenemethylamine (120 mg, 1.08 mmole) in DCM (8 ml;) was stirred at room temperature for 18 h. The mixture was washed with 1M aqueous hydrochloric acid and then the organic phase was concentrated. The residue was dissolved in ethanol (7 ml), 2M aqueous sodium hydroxide (2 ml) was added and the mixture was heated at 60 ° C for 6 h. The solvent was evaporated and the residue was dissolved in EtOAc, washed with water and the solvent phase was concentrated to yield the title compound which was used, without further purification. Method G 2-Fluoro-4- (2-fluoroanilinosulfonyl) aniline Method D was followed except that N-acyl-2-fluoro-chlorosulfonylaniline (Method H) was used in place of N-acyl-2-chloro-4-chlorosulfonylaniline , was used instead of 4-methoxyaniline and 4-dimethylaminopyridine was not used to produce the title compound.

Method H N-Acyl-2-fluoro-4-chlorosulfonylaniline Salt of N-acyl-2-fluoro-4-sulfoaniline triethylamine (1: 1) (Method I) (39 g, 0.12 mol) was added in portions, for 30 minutes, at POC13 (60 ml) at 0 ° C. The reaction mixture was stirred at room temperature for 15 h and then poured slowly onto a stirred ice water solution. After stirring for 15 minutes the mixture was filtered to yield the title compound as a solid (26 g, 0.10 mol). RM? (CDC13): 2.25 (s, 3H), 7.55 (broad s, 1H), 7.7 (dd, 1H), 7.75-7.80 (m, IH), 8.65 (t, 1H); MS: 190. Method I Salt of N-Acyl-2-fluoro-4-sulfoaniline triethylamine (1: 1) 2-Fluoroaniline (40 g, 0.36 mol) was added dropwise to a stirred solution of concentrated sulfuric acid (60 ml ) and the mixture was stirred at 190 ° C for 15 h. The reaction mixture was then cooled to room temperature and poured slowly onto a stirred ice water solution. After stirring for 15 minutes the mixture was filtered to yield a solid, 2-fluoro-4-sulfoaniline (41 g). RM ?: 7.05 (t, 1H), 7.20-7.30 (m, 2H), 8.1 (broad s, 3H); MS: 190 (M-H). The 2-fluoro-4-sulfoaniline (41 g) was dissolved in acetic anhydride (70 ml) and stirred in an ice bath. Triethylamine (22 g, 0.22 mol) was added very slowly with vigorous stirring (and concomitant release of heat). The reaction mixture was allowed to stir for 14 h, at which point a solid formed; this was filtered to yield the title compound (39 g, 0.12 mol). MS: 232. Method J 1- (t-Butoxycarbonyl) -4- (4-amino-3-methylbenzene) sulfonyl-piperazinide Method D was followed except that N-acyl-2-methyl-4-chlorosulfonylaniline (Method K) it was used in place of? -acyl-2-chloro-4-chlorosulfonylaniline, l- (t-butyloxycarbonyl) piperazine was used in place of 4-methoxyaniline and 4-dimethylaminopyridine was not used to produce the title compound. Method K N-Acyl-2-methyl-4-chlorosulfonylaniline Salt of N-acyl-2-methyl-sulfoaniline triethylamine (1: 1) (Method L) (35 g, 0.11 mol) was added in portions, for 30 minutes, to P0C13 (50 ml) at 0 ° C. The reaction mixture was stirred at room temperature for 15 h and then poured slowly onto a stirred ice water solution. After stirring for 15 minutes the mixture was filtered to give the title compound as a solid (25 g, 0.10 mol). MS: 246. Method L? -acetyl-2-methyl-4-sulfoaniline triethylamine salt (1: 1) 2-methyl-4-sulfoaniline (30 g, 0.16 mol) was dissolved in acetic anhydride- (50 ml) and It stirred in an ice bath. Triethylamine (23 ml, 0.18 mol) was added very slowly with vigorous stirring (and concomitant release of heat). The reaction mixture was allowed to stir for 14 h, at which point a solid formed; this was filtered to yield the title compound (35 g, 0.11 mol). NMR: 1.15 (t, 9H), 2.05 (s, 3H), 2.45-2.50 (m, 1H), 3.1 (q, 6H), 7.25-7.40 (m, 2H), 7.85 '(t, 1H), 9.7 (s broad, 1H), MS: 228. Method M RN- (2-Chloro-4-chlorosulfonylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide RN- (2-chlorophenyl) - 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (Method?) (13.8 g, 52 mmol) in portions to a cooled solution (0 ° C) of chlorosulfonic acid (25 ml) for 15 minutes and then the mixture was heated to 85 ° C. after 4.5 h the reaction mixture was cooled in an ice bath and then poured very slowly over a stirred mixture of ice-water. After stirring for 15 minutes, the mixture was extracted with EtOAc (2 x 100 ml) and the combined organic layer was washed with brine, dried and concentrated to yield a brown oil. This oil was purified by flash column chromatography using 10: 1, iso-hexane: EtOAc to afford the title compound as a pale yellow solid (11 g, 30 mmol). RM ?: 1.6 (s, 3H), 7.55 (dd, 1H), 7.6 (d, 1H), 7.95 (d, 1H), 9.7 (broad s, 1H); MS: 364. Method N R-N- (2-Chlorophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide Acetyl chloride (11.7 ml) was added dropwise, 164 mmol) was added to a stirred solution of R-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (10 g, 63 mmol) in toluene (100 ml) cooled in an ice bath. The mixture was then heated to 80 ° C and the suspension dissolved to produce a clear solution. After 2 h the reaction mixture was cooled and then concentrated to yield a slightly brown oil. This oil was then redissolved in DCM (140 ml) and DMF (4 drops) was added followed by oxalyl chloride (6 ml, 69 mmol). The solution was vigorously bubbled and the reaction mixture was allowed to stir. After 15 h, this reaction mixture was slowly added to a stirred solution of 2-chloroaniline (8.7 g, 68 mmol) and pyridine (5.5 mL, 68 mmol) in DCM (150 mL). After stirring for 15 h at room temperature, the resulting mixture was concentrated and the residue was dissolved in methanol (500 ml). A solution of lithium hydroxide monohydrate (7.8 g, 0.19 mol) in water (120 ml) was then added and the mixture was stirred for 4 h. The mixture was then concentrated and the residue acidified to pH 2 (by the addition of concentrated hydrochloric acid). EtOAc (150 ml) was added and the mixture was washed with water (2 x 100 ml) and brine, dried and evaporated to dryness. The residue was purified by flash column chromatography using 6: 1, iso-hexane: EtOAc to yield the title compound as a white solid (13.8 g, 52 mmol). NMR: 1.6 (s, 3H), 7.1-7.25 (m, 1H), 7.3-7.4 (m, 1H), 7.55 (dd, 1H), 7.8 (s, 1H), 8.0 (dd, 1H), 9.7 ( s broad, 1H); MS: 266. Method O RN- [2-Clbro-4- (4-fluorosulfonylanilinesulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide A solution of RN- (2-chloro-4-) chlorosulifonylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Method M) (3.46 g, 9.45 mmol) in DCM (200 ml) was added to a stirred solution of 4-fluorosulfonylaniline (1.99 g, 11.3 g). mmoles) and pyridine (1.52 ml, 18.2 mmol) in DCM (50 ml). The resulting mixture was stirred at room temperature overnight, evaporated to dryness and the residue was treated with 1M aqueous hydrochloric acid (50 ml). The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated. The residue was purified by column chromatography using 30% EtOAc in DCM to afford the title compound as a foam (4.56 g, 9.05 mmol). RM ?: 1.6 (s, 3H), 7.45 (d, 2H), 7.9 (dd, 1H), 8.0 (d, 1H), 8.05 (d, 2H), 8.3 (d, 1H); MS: 504. Method P Chloride of S-3, 3, 3-Trifluoro-2-hydroxy-2-methylpropanoyl Oxalyl chloride (1.07 ml, 12 mmol) was added dropwise to a stirred suspension of acid (R) - ( +) -2-hydroxy-2-methyl-3, 3, 3-trifluoropropanoic. (Method Q) (1.95 g, 12 mmol) in DCM (42 ml) and DMF (0.8 ml). The mixture was stirred at room temperature for 2-15h to produce a solution of the title compound which was used in subsequent reactions without further purification. Method (R) - (+) - 2-Hydroxy-2-methyl-3, 3, 3-trifluoropropanoic acid The R / S-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid was resolved in accordance to the solution method described in European Patent Application No. EP 524781 (described for the preparation of (S) - (-) acid except that (1S, 2R) -norephedrine was used in place of (IR, 2S) -norephedrine or (S) - (-) - 1-phenylethylamine to produce the title compound, [a] D20 + 18.1 ° (c, 8.8 in MeOH); NMR analysis of acid in the presence of (R) - (+) -l-phenylethylamine gave an enantiomeric purity of> 98% NMR (CDC13): 1.27 (s, 3H) for the (R) -enantiomer, 1.21 (s, 3H) for the (S) -enantiomer, Method R 2-Chlorine -4- [4- (2-hydroxyethylthio) anilinosulfonyl] aniline A solution of 4-acetamidothiophenol (8.35 g, 50.0 mmol), ethylene carbonate (5.5 g, 62.5 mmol) and sodium ethoxide (4.1 g, 60.0 mmol) in methanol (250 ml) was heated to reflux overnight and then cooled to room temperature and evaporated to dryness. The residue was dissolved in diethyl ether (500 ml), washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (120 ml) and 2M aqueous sodium hydroxide (60 ml) was added, the mixture was heated to reflux overnight and then cooled to room temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralized to pH 7 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to dryness. The residue was dissolved in DCM (100 ml) and added to a solution of 4-acetamido-3-chlorobenzenesulfonyl chloride (5.5 g, 20.5 mmol), 4-dimethylaminopyridine (50 mg, 0.4 mmol) and pyridine (5.0 ml, 60 mmol) in DCM (100 ml). The mixture was stirred at room temperature overnight, the solution was evaporated to dryness, the residue was dissolved in diethyl ether (450 ml) ,. it was washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (100 ml) and 2M aqueous sodium hydroxide (25 ml) was added. The mixture was refluxed overnight and then cooled to room temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralized to pH 7 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to dryness. The residue was purified by column chromatography using 25% EtOAc in DCM to yield the title compound (630 mg, 1.8 mmol). NMR: 2.9 (t, 2H), 3.5 (m, 2H), 4.8 (t, IH), 6.2 (s, 2H), 6.75 (d, 1H), 7.0 (d, 2H), 7.2 (d, 2H) , 7.3 (dd, 1H), 7.45 (d, 1H); MS: 357. Method S 2-Chloro-4- [4- (2-ethoxyethylthio) anilinosulfonyl] aniline A solution of 4-acetamidothiophenol (8.35 g, 50.0 mmol), ethylene carbonate (5.5 g, 62.5 mmol) and ethoxide Sodium (4.1 g, 60.0 mmol) in ethanol (250 ml) was heated to reflux overnight and then cooled to room temperature - and evaporated to dryness. The residue was dissolved in diethyl ether (500 ml), washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in methanol (120 ml) and 2M aqueous sodium hydroxide (60 ml) was added. The mixture was heated to reflux overnight and then cooled to room temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralized to pH 7 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to dryness. The residue was dissolved in DCM (100 ml) and added to a solution of 4-acetamido-3-chlorobenzenesulfonyl chloride (5.5 g, 20.5 mmol), 4-dimethylaminopyridine (50 mg, 0.4 mmol) and pyridine (5.0 ml, 60 mmol) in DCM (100 ml). The mixture was stirred at room temperature overnight, the solution was evaporated to dryness, the residue was dissolved in diethyl ether (450 ml), washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (100 ml) and 2M aqueous sodium hydroxide (25 ml) was added. The mixture was refluxed overnight and then cooled to room temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralized to pH 7 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to dryness. The residue was purified by column chromatography using 10% EtOAc in DCM to yield the title compound (1.53 g, 3.96 mmol). NMR: 1.0 (t, 3H), 3.0 (t, 2H), 3.3-3.5 (m, 4H), 6.2 (s, 2H), 6.75 (d, 1H), 7.0 (t, 2H), 7.2 (d, 2H), 7.3 (dd, 1H), 7.45 (d, 1H); MS: 385. Method T. 2-Chloro-4- [4- (methoxycarbonyl) anilinosulfonyl] aniline A solution of N-acyl l -2-chloro-4-chlorosulfonylaniline (13.4 g, 50.0 mmol), methyl 4-aminobenzoate (7.55 g, 50.0 mmol), 4-dimethylaminopyridine (100 mg, 0.8 mmol) and pyridine (5.0 mL, 60 mmol) in DCM (350 mL) was stirred at room temperature for 4 h. The solution was evaporated to dryness, the residue was dissolved in EtOAc (1.0 L), washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (600 ml) and 2M aqueous sodium hydroxide (137 ml) was added. The mixture was refluxed for 4 h and then cooled to room temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was acidified to pH 1 by the addition of concentrated aqueous hydrochloric acid. The solution was evaporated to dryness, the residue was dissolved in methanol (200 ml), the solution was cooled to -35 ° C and treated with thionyl chloride (18.0 ml). The mixture was stirred at room temperature overnight and evaporated to dryness. The residue was dissolved in carbonate solution, saturated sodium acid, the aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to dryness to yield the title compound (13.6 g, 40.0 mmol ); MS: 339. Method U 2-Chloro-4- [1- (t-butoxycarbonyl) piperazin-4-ylsulfonyl] aniline A solution of N-acyl-2-chloro-4-chlorosulfonylaniline (10.0 g, 37.3 mmol), - (t-butoxycarbonyl) piperazine (7.0 g, 37.6 mmol) and triethylamine (7.77 mL, 56.4 mmol) in DCM (150 mL) was stirred at room temperature for 4 h. The solution was evaporated to dryness, the residue was dissolved in EtOAc (150 ml), washed with 0.7 M aqueous citric acid, saturated aqueous sodium acid carbonate solution and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (100 ml) and 2M aqueous sodium hydroxide (87.5 ml) was added. The mixture was refluxed overnight and then cooled to room temperature and evaporated to dryness. Water (75 ml) was added to the residue and the mixture was filtered, the solid was washed with water, dried and crystallized from EtOAc to yield the title compound as a solid (11.4 g, 30.3 mmol); M.pt. 243-244 ° C. NMR: 1.35 (s, 9H), 2.8 (m, 4H), 3.4 (m, 4H), 6.35 (s, 2H), 6.9 (d, 1H), 7.35 (dd, 1H), 7.5 (d, 1H); MS: 374. Method V 2- (4-Aminophenyl) -1,3-dioxolane To a mixture of 4-nitrobenzaldehyde (7.55 g, 50 mmol) and ethylene glycol (4.65 g, 75.0 mmol) in toluene (125 ml) was added 4-Toluenesulfonic acid (100 mg, 0.5 mmol) and the mixture was heated under reflux using a Dean-Stark water separator for 2 h. The solution was evaporated to dryness, the residue was dissolved in EtOAc (125 ml), washed with saturated sodium hydrogen carbonate solution, dried and evaporated to dryness. The residue was dissolved in ethanol (200 ml) and hydrogenated over 10% Pd / C for 4 h at room temperature. The catalyst was removed by filtration, the ethanol was evaporated to yield the title compound which was used without further purification. Method W 4- (2-Hydroxyethylamino) aniline A mixture of ethanolamine (2.29 g, 37.5 mmol) and 1-fluoro-4-nitrobenzene (3.53 g, 25.0 mmol) in dimethylsulfoxide (25 ml) was treated with potassium carbonate (6.9 g, 50 mmol) and heated at 90 ° C overnight. The mixture was cooled and poured into water (250 ml), the precipitated solid was filtered, dried, and dissolved in ethanol (50 ml) and hydrogenated over 10% Pd / C for 4h at room temperature. The catalyst was removed by filtration, the ethanol was evaporated and the residue was purified by column chromatography using EtOAc to yield the title compound (740 mg, .5.0 mmol). NMR: 2.95 (t, 2H), 3.5 (t, 2H), 4.1 (s, 2H), 4.4 (s, 1H), 4.55 (t, 1H), 6.4 (m, 4H); MS: 153 (M + H) +. Method X 4- (N-2-Tetrahydropyranyloxyethyl-t-butoxycarbonylamino) aniline To a mixture of N-t-butoxycarbonylethanolamine (7.7 ml, 50 mmol) and 3,4-dihydropyran (5.7 ml, 62.5 mmol) in DCM (125 ml 4-Toluenesulfonic acid (100 mg, 0.5 mmol) was added and the mixture was stirred at room temperature for 3 h. The solution was washed with saturated sodium hydrogen carbonate solution, dried and evaporated to dryness. The residue was filtered through a short pad of basic alumina with 10% EtOAc in hexane, the solvent was evaporated to dryness. The residue was dissolved in dimethylacetamide (5 ml) and added to a suspension of sodium hydride (400 mg of 50% dispersion in mineral oil, 10 mmol) in dimethylacetamide (5 ml). The mixture was heated at 50 ° C for 1 h, cooled to room temperature and added to a solution of 1-fluoro-4-nitrobenzene (1.06 g, 7.5 mmol) in dimethylacetamide (5 ml) and heated to 50 ° C. for 4h. The cooled mixture was poured into water (150 ml), the aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated. The residue was dissolved in ethanol (50 ml) and hydrogenated over 10% Pd / C for 4 h at room temperature. The catalyst was removed by filtration, the ethanol was evaporated and the residue was purified by column chromatography using 30% EtOAc in hexane to yield the title compound (640 mg, 1.9 mmol). NMR: 1.2-1.6 (m, 15H), 3.4-3.8 (m, 6H), 6.6 (d, 2H), 7.0 (d, 2H); MS: 337 (M + H) +. Method Y RN- (2-Chloro-4-chlorosulfonylphenyl) -3,3,3-trifluoro-2-hydroxy-2-ethylpropanamide R- N- (2-chlorophenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide (Method Z) (4.71 g, 17.6 mmol) was added portionwise to a cooled (ice bath) and stirred solution of chlorosulfonic acid (9 ml). The resulting mixture was heated at 85 ° C for 270 minutes. The reaction mixture was then cooled to room temperature and poured onto an ice / water suspension. The resulting aqueous mixture was extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated to yield an oil. Purification by column chromatography afforded the title compound as a solid (4.03 g, 11.0 mmol). RM? (CDC13): 1.80 (s, 3H), 3.46 (s, 1H), 8.00 (dd, 1H), 8.10 (d, 1H), 8.77 (d, 1H), 9.44 (s, 1H); MS: 364. Method Z RN- (2-chlorophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide 2-chloroaniline (3.2 ml) and 2,6-di-t-butylpyridine (7.4 ml) to a solution of S-3,3,3, -trifluoro-2-hydroxy-2-methylpropanoyl chloride [produced in itself by the reaction of R-3, 3, 3, -trifluoro-2-hydroxy acid -2-methylpropanoic acid (4.74 g, 30 mmol) with 2M oxalyl chloride (16.5 ml, 33 mmol) in DCM (50 ml)] in DCM. The resulting solution was stirred for 20 h at room temperature. The reaction mixture was then washed with water, brine, dried, evaporated and purified by column chromatography to yield the title compound as a solid (4.76 g, 17.8 mmol). NMR: 1.60 (s, 3H), 7.25 (t, 1H), 7.38 (t; 1H), 7.55 (d, 1H), 7.80 (s, 1H), 8.00 (d, 1H), 9.70 (s, 1H); MS: 266. Method To 2-chloro-4- [(4-sulfamoyl-anilino) sulfonyl] aniline A solution of 4-acetamido-3-chlorobenzenesulfonyl chloride (2.68 g, 10.0 mmol), sulfanilamide (2.06 g, 12.0 mmol) ), dimethylaminopyridine (1.22 g, 10.0 mmol) and pyridine (2.40 mL, 10.0 mmol) in EtOAc (150 mL) was stirred at room temperature for 3 days. The solution was washed with 1.0 M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (100 ml) and 2 M aqueous sodium hydroxide (22.1 ml) was added. The mixture was refluxed for 4 hours and then cooled to room temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralized to pH 7.0 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc, the EtOAc 'extracts were washed with brine, dried and evaporated to give, as a solid, the title compound (2.34 g, 6.5 mmol). P.f. 197 ° -198 °; NMR: 6.3 (s, 2H), 6.8 (d, 1H), 7.2 (s, 2H), 7.25 (d, 2H), 7.4 (dd, 2H), 7.55 (d, 1H), 7.65 (d, 2H); MS: 360. Method Bl 2-chloro-5- (2-chloroanilino-sulfonyl) aniline A solution of 3-nitro-4-chlorobenzenesulfonyl chloride (768 mg, 3.0 mmol), 2-chloroaniline (383 mg, 3.0 mmol) , 4-dimethylaminopyridine (10 mg, 0.08 mmol) and pyridine (0.30 ml, 3.6 mmol) in DCM (35 ml) was stirred at room temperature overnight. The solution was evaporated to dryness, the residue was dissolved in EtOAc and washed with 1.0 M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in EtOAc (30 ml) and acidified over 10% Pd / C for 4 h at room temperature. The catalyst was removed by filtration and the EtOAc was evaporated to dryness. The residue was purified by column chromatography on basic alumina using 5% methanol in EtOAc to give, as a solid, the title compound (140 mg, 0.44 mmol). MS: 315. Method Cl Chloride of R-3, 3, 3-trifluoro-2-hydroxy-2-methylpropanoyl. Oxalyl chloride (1.07 ml, 12 mmol) was added dropwise to a stirred suspension of (S) - ( -) - 2-hydroxy-2-methyl-3, 3, 3-trifluoropropanoic (Method DI) (1.95 g, 12 mmol) in DCM (42 ml) and DMF (0.8 ml). The mixture was stirred at room temperature for 2-15 h to produce a solution of the title compound which was used in the subsequent reactions without further purification. Method DI acid (S) - (-) -2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid R / S-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid was resolved according to to the resolution method described in European Patent Application No. EP 524781 to produce the title compound, [α] D20-18.6 ° (c, 8.8 in MeOH). Method Chloride of R / S-3, 3, 3-trifluoro-2-hydroxy-2-methylpronanoyl. Oxalyl chloride (1.07 mL, 12 mmol) was added dropwise to a stirred suspension of R / S-2-hydroxy acid. -2-methyl-3, 3, 3-trifluoropropanoic (1.95 g, 12 mmol) in DCM (42 ml) and DMF (0.8 ml). The mixture was stirred at room temperature for 2-15 h to produce a solution of the title compound which was used in the subsequent reactions without further purification. EXAMPLE 273 The following illustrates the representative pharmaceutical dosage forms containing the compound of the formula I, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof (hereinafter compound X), for therapeutic or prophylactic use in humans: ( a) Tablet I mg / tablet Compound X 100 Lactose Ph. Eur 182.75 Croscarmellose sodium 12.0 Corn starch paste (5% ' of paste w / v) 2.25 Magnesium stearate 3.0 (b) Tablet II mg / tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyvinylpyrrolidone (5% pulp w / v) 2.25 Magnesium stearate 3.0 (c) Tablet III. mg / tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Corn starch paste (5% paste w / v) 0.75 Magnesium stearate 1.0 (d) Capsule mg / capsule Compound X 10 Lactose Ph.Eur 488.5 Stearate magnesium 1.5 (e) Injection I (50 mg / ml) Compound X 5.0% w / v 1M sodium hydroxide solution 15.0% v / v 0.1 M hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w / v Water for 100% injection (f) Injection II (10 mg / ml) Compound X 1.0% w / v Sodium phosphate BP 3.6% w / v 0.1M sodium hydroxide solution 15.0% v / v Water for 100% injection % (g) Injection III (1 mg / ml, regulated at pH6) Compound X t 1.0% w / v Sodium phosphate BP 2.26% w / v Citric acid 0.38% w / v Polyethylene glycol 400 3.5% w / v Water for 100% injection Note: The above formulations can be obtained by conventional procedures well known in the pharmaceutical art. Tablets (a) - (c) can be enteric coated by conventional means, for example to provide a cellulose acetate phthalate coating.

Claims

CLAIMS 1. A compound of the formula (I): ) characterized in that: Ring X is phenyl or a six-membered heteroaryl ring containing one or two ring nitrogens wherein the nitrogens are optionally oxidized to form the N-oxide; R1 and R2 are independently as defined in (a) or (b); R3 and R4 are as defined in (c) or (d); R5 is as defined in (e) or (f); YZ are as defined in (g) or (h) wherein: (a) R1 and R2 are each independently selected from hydrogen, C3_3 alkyl, pyridyl and phenyl which is unsubstituted or substituted by one or two substituents independently selected from C 1 -4 alkyl, C 1 alkoxy, C 2 alkenyloxy, hydroxy, halo and cyano, or R 1 and R 2 together with the nitrogen atom to which they are attached of morpholine, thiomorpholino, piperidinyl, pyrrolidinyl or imidazolyl; (b) R and R2 are each independently selected from phenyl substituted by one or more P (wherein P is as defined below), phenyl substituted by one or more groups selected from C? -4 alkyl, C alkoxy? 4, alkenyloxy, hydroxy, halo and cyano and further substituted by one or more groups selected from P, a heterocyclic group other than unsubstituted pyridyl which is optionally substituted on a carbon ring by one or more Q (wherein Q is as is defined later) and wherein if the heterocyclic group contains a portion -NH- that nitrogen may optionally be substituted by a group selected from D (where D is as defined below), naphthyl optionally substituted by one or more Q , C4-g alkyl, C3_g cycloalkyl optionally substituted with one or more Q, C2-e alkenyl, C2_6 alkynyl, C6_6 alkyl substituted by one or more V (wherein V is as defined below ), R6T- (where R6 and T s as defined below) and Ralkyl of C? -gT- (wherein R7 is as defined below), or R1 and R2 together with the nitrogen atom to which they are attached, form a heterocyclic group other than unsubstituted morpholino, unsubstituted thiomorpholino, unsubstituted piperidinyl, unsubstituted pyrrolidinyl or unsubstituted imidazolyl which are optionally substituted on a carbon ring by one or more Q (wherein Q is as defined below) and wherein if the heterocyclic group contains a portion -NH- that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined below); (c) R3 and R4 are independently Ck alkyl optionally substituted by 1 to 2k + 1 atoms selected from fluorine and chlorine wherein k is 1-3, with the proviso that R3 and R4 are not both methyl; or R and R together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl ring from 1 to 2m-2 fluorine atoms wherein m is 3-5; (d) R3 and R4 are both methyl; (e) R5 is hydrogen, C? -4 alkyl, C? _4 haloalkyl, C? _4 alkoxy, C? -4 haloalkoxy, cyano, nitro, C2_4 alkenyloxy or trifluoromethylthio; (f) R5 is halo, hydroxy, amino, C? -6 alkylamino, C? -g) 2amino alkyl, C? -g alkanoylamino, C? -g alkanoylamino (C? 6), thiol, C 1 -g alkylsulfonylamino, C 1 -C 6 alkylsulfonylamino (C 1 -g-alkyl), thiol, C 1 -g alkylsulfanyl, C 1 -C 6 alkylsulfinyl, C 1 -g alkylsulfonyl, sulphamoyl, N- (C6_6 alkyl) aminosulfonyl, N- (C6_6 alkyl) 2-amino-sulfonyl, carboxy, carbamoyl, N- (Cd-alkyl) carbamoyl, N- (C_-d-alkyl) 2-carbamoyl, C6-6 alkoxycarbonyl, formyl, C6_6 alkanoyl, C2_6 alkenyl, C2_6 alkynyl, C5_6alkyl, C5_6haloalkyl, C5_6alkoxy, C5_6haloalkoxy or C5_6alkenyloxy; (g) Y-Z is -NHC (O) -, -OCH2-, -SCH2-, -NHCH2-, trans-vinylene, and ethynylene; (h) Y-Z is -NHC (S) -; R6 is selected from C? _6 alkyl (optionally substituted with one or more R8), C3_6 cycloalkyl optionally substituted with one or more R8, a heterocyclic group optionally substituted on a carbon ring by one or more R8 and if the heterocyclic group contains a portion -NH- that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined below), phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8; R7 is a heterocyclic group optionally substituted on a carbon ring by one or more R and if the heterocyclic group contains an -NH- portion that nitrogen may be optionally substituted by a group selected from D (where D is as defined below), phenyl optionally substituted by one or more R, naphthyl optionally substituted by one or more R; R8 is trifluoromethyl, C? -6 alkyl, halo, hydroxy, trifluoromethoxy, cyano, C? _6 alkoxy, formyl, C? _g alkanoyl, C? _6 alkanoyloxy, amino, C? -6 alkylamino, (alkyl) of C? _6) 2amino, C? _6 alkanoylamino, C? -6 alkanoylamino (C? _6 N-alkyl), nitro, carboxy, carbamoyl, C? _6 / thiol alkoxycarbonyl, C? -6 alkylsulfanyl, C 1-6 alkylsulfinyl, C? -6 alkylsulfonyl, sulfamoyl, N- (Ci-β) aminosulfonyl, N- (C? _6) 2-amino sulfonyl, carbamoylalkyl C? -6, N- ( C? -6) carbamoylalkyl- of C? _6, N- (Ci-g alkyl) 2-carbamoylalkyl of C? _6, hydroxyalkyl of C? -6, C? -6 alkoxy of C? -6, phenylalkyl of C? _g or phenylalkoxy of C? _6; P is selected from C2-6 alkyl-M- substituted with one or more R9, C2_6-M-alkenyl optionally substituted with one or more R9, -C2-alkynyl-gM- optionally substituted with one or more R9 (with the condition that in the three previous groups R9 is not a substituent on the carbon atom attached to M), Rx ° -CH2-M-, Ru-M-, thiol, alkylsulfanyl of C? -6, alkylsulfinyl of C? _6 , Ci-g alkylsulfonyl, sulphamoyl, nitro, carboxy, C? -6 alkoxycarbonyl, amino, C? -g alkylamino, (C? -g) 2amino alkyl, carbamoyl, N- (C? _e alkyl) carbamoyl, N- (C? -6-alkyl) 2-carbamoyl, C? _6-alkanoylamino, C-6-alkanoylamino (N? -C6 alkyl), trifluoromethyl, trifluoromethoxy, formyl, C? -6 alkanoyl, C5-6, C2-6 alkenyl, C2-6 alkynyl, N- (C6-) alkylsulphonyl, hydroxymethyl, hydroxyacetyl, N- (C6-6) -amino-sulfonyl, C6-6-alkanoylaminosulfonyl, C6-C6 alkanoylaminsulfonyl (N-C6 alkyl), alkylsulfonylaminoca C6-6alkyl, C6-6 alkylsulfonylaminocarbonyl (N-C6-6alkyl), C5_6alkoxy, C6-6alkenyloxy, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8 and a heterocyclic group optionally substituted on a carbon ring by one or more R8 and if the heterocyclic group contains a -? H- portion that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined below); Q is selected from any of the values defined for P, C? -4 alkyl, C? -4 alkoxy, C2_4 alkenyloxy, hydroxy, halo, and cyano; V is selected from any of the values defined for Q, phenyl optionally substituted by one or more Q, naphthyl optionally substituted by one or more Q, a heterocyclic group optionally substituted on a carbon ring by one or more Q and if the heterocyclic group contains' a portion -? H- that nitrogen can be optionally substituted by a group selected from D (where D is as defined below) or C3-6 cycloalkyl optionally substituted with one or more Q; T is selected from -O-, -C (O) -, -? H-, -? (N-Ci-e alkyl) -, -C (0)? H-, -? HC (O) -, -C (O)? (N-C6-alkyl) -, - N (N-C6-6 alkyl) C (0) -, -S02-, -C (S) -, -C (S)? H-, - ? HC (S) -, -C (S)? (N-alkyl of C? _6) - and -? (N-C 1 alkyl -g) C (S) -; M is selected from -O-, -? (R12) -, -C (O) -, (R12) C (0) -, -C (0)? (R12) -, -StOX-, -OC (O) -, -C (0) 0-,? (R12) C (0) 0- , -OC (0)? (R12) -, -C (S)? (R12) -, -? (R12) C (S) -, S02? (R12) -, -? (R12) S02- and -? (R12) C (0)? (R12) -, -? (R12) C (S)? (R12) -, -S02? HC (O) -, -S02? (R12) C (0) -, -C (0)? HSO2-, -C (0)? (R12) S02- or M is a direct link; D is selected from C? -6 alkyl, C? 6 alkanoyl, C? -g alkylsulfonyl, C? -g alkoxycarbonyl, carbamoyl, N- (C? -6 alkyl) carbamoyl, N, N- (C ?_g alkyl) 2carbamoyl, benzoyl, (heterocyclic group) carbonyl, phenylsulfonyl, (heterocyclic group) sulfonyl, phenyl or a heterocyclic group attached to carbon, and wherein any C?-6 alkyl group may be optionally substituted by one or more R9, and wherein any phenyl or heterocyclic group can be optionally substituted on a carbon ring by one or more groups selected from R8 and if a heterocyclic group contains a -? H- portion that nitrogen can be optionally substituted by a selected group of E; E is selected from C? _6 alkyl, C? 6 alkanoyl, C? -6 alkylsulfonyl, C? _6 alkoxycarbonyl, carbamoyl, N- (C? -e) carbamoyl alkyl, N, N- (alkyl) of Cx-6) 2carbamoyl, C? -6alkanoyl alkoxy of C? -6, phenylalkyl of Ci-g, benzoyl, phenylalkanoyl of C? -6, phenylalkoxycarbonyl of C? -6 and phenylsulfonyl. R is selected from hydroxy, amino, C? -6 alkylamino, (C? _6) 2amino alkyl, carboxy, C? -6 alkoxy, carbamoyl, N- (C? _6 alkyl) carbamoyl, N- (alkyl) of C? _ 6) 2-carbamoyl, formyl, sulphamoyl, N-alkylaminosulfonyl of C? -6, N- (C? _6 alkyl) 2-amino sulfonyl, C? -6 alkylsulfonylamino, C? -6 alkanoylamino, a heterocyclic group optionally substituted on a carbon ring by one or more R8 and if the heterocyclic group contains a -? H-portion that nitrogen may be optionally substituted by a group selected from D (where D is as defined below), phenyl optionally substituted by one or more R, naphthyl optionally substituted by one or more R8, C? -6 alkylsulfanyl, C? -6 alkylsulfinyl and C? -6 alkylsulfonyl, * R10 is carboxy, carbamoyl, N- (C? _6 alkyl) ) carbamoyl, N- (C6_6) alkylcarbamoyl, sulfamoyl, N- (C? -e) aminosulfonyl alkyl, N- (C? _ g alkyl) 2-aminosulfonyl, C? -g alkylsulfanyl, alkyl C 1-6 alsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, C 1-6 alkanoylamino, a heterocyclic group optionally substituted on a carbon ring by one or more R 8 and if the heterocyclic group contains a -? H - that nitrogen can optionally be replaced by a group selected from D (wherein D is as defined above), phenyl optionally substituted by one or more R or naphthyl optionally substituted by one or more R8; R is a heterocyclic group optionally substituted on a carbon ring by one or more R8 and if the heterocyclic group contains an -NH- portion that nitrogen may be optionally substituted by a group selected from D (where D is as defined above), phenyl optionally substituted by one or more R, C3_6 cycloalkyl optionally substituted by one or more R8, or naphthyl optionally substituted by one or more R8; R12 is hydrogen or C? _6 alkyl optionally substituted with R13 with the proviso that R13 is not a substituent on the carbon attached to the nitrogen atom of M; R13 is halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C? _g alkyl, C? -6 alkenyl, C? -6 alkynyl, C? -6 alkylamino, (C? ) 2-amino, C alca _g alkanoylamino, C? _g-alkanoylamino (C--6-N-alkyl), C?-6-alkylsulfonylamino, C_-6-alkylsulfonylamino (C 6 -alkyl), thiol, C alqu alkylsulfanyl; -6, C? -6 alkylsulfinyl, C? _6 alkylsulfonyl, sulfamoyl, N- (C? _6 alkyl) aminosulfonyl, N- (C? -g) 2-aminosulfonyl, carboxy, carbamoyl, N- (alkyl) of C? _g) carbamoyl, N- (C? _) alkylcarbamoyl, C? -6 alkoxycarbonyl, C? _6 alkanoyl or formyl; n is 0-2; with the proviso that where R1 and R2 are both as defined in (a), R3 and R4 are both as defined in (c), R5 is as defined in (e) and ring X is phenyl, YZ they must be -NHC (S) -; and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, and with the proviso that when R3 and R4 are both methyl, R5 is hydrogen, fluorine or chlorine, YZ is ethynylene, X is phenyl and one of R1 and R2 is hydrogen. and the other is pyrimidyl-NH-C (O) - or triazinyl-NH-C (O) - (wherein the triazine or pyrimidine is substituted by methyl, methoxy or dimethylamino) then the -S02NR1R2 portion can not be ortho to YZ; and with the proviso that the compound is not: 4- (3-hydroxy-3-methyl-1-butynyl) -N- (3-methyl-2-pyridinyl) -benzenesulfonamide, N-. { 4- [N, N-bis- (sec-butyl) aminosulfonyl] phenyl} -2-hydroxy-2-methyl-3, 3, 3-trifluoropropanamide, or N-. { 4 - [N, N-bis- (iso-butyl) aminosulfonyl] phenyl} -2-hydroxy-2-methyl-3,3,3-trifluoropropanamide.
2. A compound of the formula (I) according to claim 1, characterized in that R3 and R4 are independently Ck alkyl optionally substituted by l to 2k + l atoms selected from fluorine and chlorine wherein k is 1-3. '
3. A compound of the formula (I) according to claim 1 or 2, characterized in that one of R3 and R4 is methyl and the other is trifluoromethyl.
4. A compound of the formula (I) according to claim 1, 2 or 3, characterized in that R5 is selected from halogen, nitro, C? -4 alkyl, C? -4 alkoxy, C2-4 alkenyl , C2-4 alkynyl, hydroxy, hydrogen, amino, carboxy and sulfamoyl.
5. A compound of the formula (I) according to claim 1, 2, 3 or 4 characterized in that R5 is selected from fluorine and chlorine.
6. A compound of the formula (I) according to claim 1, 2, 3, 4 or 5, characterized in that X is phenyl.
7. A compound of the formula (I) according to claim 1, 2, 3, 4, 5 or 6, characterized in that Y-Z is -NHC (O) -.
8. A compound of the formula (I) according to claim 1, 2, 3, 4, 5, 6, or 7, characterized in that R1 and R2 are each independently selected from hydrogen, methyl, cyclopropyl, 4-hydroxycyclohexyl , 2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 4- (morpholin-sulfonyl) phenyl, pyrid-3-yl, 2-carbamoylthien-3-yl, 2-chloropyrid-3-yl, 5-chloropyrid-2- ilo, 5-methylpyrid-2-yl, pyrimid-2-yl, 4,6-dimethylpyrimid-2-yl or 5,6-dimethylpyrazin-2-yl; or R and R together with the nitrogen atom to which they bind, form 4-hydroxypiperidinyl or 1- (hydroxyacetyl) piperazin-4-yl.
9. A compound of the formula (Ib): (Ib) wherein R1b and R2b are independently selected from: i) hydrogen; ii) C6-6 alkyl or C3_6 cycloalkyl optionally substituted with one or more C6_6 alkyl, C6_6 alkoxy, C2_6 alkenyloxy, hydroxy, halo, cyano, C6_6 alkylsulfanyl, C5_ alkylsulfinyl ? 6, C? -6 alkylsulfonyl, sulfamoyl, carboxy, C? -6 alkylcarbonyl, amino, C? _6 alkylamino, (C? _6 alkyl) 2-airaine, carbamoyl, N- (C? _g alkyl) carbamoyl , N- (C? 6 alkyl) 2-carbamoyl, C? -6-alkanoylamino, C? -6-alkanoylamino (Ci-β alkyl), Ci-g alkanoyl, C2-6 alkenyl, C2- alkynyl 6, N- (Ci-β) aminosulfonyl, hydroxymethyl, hydroxyacetyl or N- (Ci-6-alkyl) 2-aminosulfonyl; iii) a heterocyclic group selected from pyridyl, pyrimidyl, pyridacyl, or pyrazinyl, wherein the heterocyclic group is optionally substituted with one or more C? _6 alkyl, C? _6 alkoxy, C? -6 alkenyloxy, hydroxy, halo , cyano, C?-6 alkylsulfanyl, C?-6 alkylsulfinyl, C_6 alkylsulfonyl, sulfamoyl, carboxy, C? _6 alkoxycarbonyl, amino, C? _6 alkylamino, (Cx-gXamino alkyl, carbamoyl, N- (C? _6 alkyl) carbamoyl, N- (C? 6 alkyl) 2carbamoyl, C? -6 alkanoylamino, C? _g alkanoylamino (N-C? -g alkyl), trifluoromethyl, trifluoromethoxy, C? _g, C2-6 alkenyl, C2_6 alkynyl, N- (C6_6 alkyl) aminosulfinyl, hydroxymethyl, hydroxyacetyl or N- (C? -d) alminosulfinyl alkyl; or Rlb and R2b together with the nitrogen atom to which they are attached form piperidinyl or piperazinyl, wherein the piperidinyl and piperazinyl can be optionally substituted on a carbon ring by one or more groups selected from C? _6 alkyl, C? _6 alkoxy, C? -6 alkenyloxy, hydroxy, halo, cyano, C? -6 alkylsulfanyl, C? -6 alkylsulfinyl, Ci-g alkylsulfonyl, sulfamoyl, carboxy, alkoxycarbonyl of C? _g, amino, C? -6 alkylamino, (C? _6) 2amino alkyl, carbamoyl, N- (C? -6 alkyl) carbamoyl, N- (C6-alkyl) 2-carbamoyl, C? -6, C? _6 alkanoylamino (C? -d N-alkyl), C? -6 alkanoyl, C2-g alkenyl, C2-g alkynyl, N- (C? _6 alkyl) aminosulfinyl, hydroxymethyl, hydroxyacetyl or N- (Ci-g alkyl) aminosulfinyl; and the piperazinyl can be optionally substituted on the nitrogen in the ring by a group selected from C? _6 alkanoyl, C? -6 alkylsulfonyl, C? -6 alkoxycarbonyl, carbamoyl, N- (C? _ alkyl) carbamoyl and N, N- (C? _6 alkyl) carbamoyl; and wherein any C? _6 alkyl group can be optionally substituted by one or more selected hydroxy groups, amino, C alqu-6 alkyl alkylamino (C?-g) 2amino alkyl, carboxy, C?-6 alkoxy, carbamoyl, N- (C?-g) alkyl carbamoyl, N- (C alquilo alkyl? -6) 2-carbamoyl, sulphamoyl, N-alkylaminosulfinyl of C? -g, N- (C? E-alkyl) 2-aminosulfinyl, C? _6 alkylsulfonylamino, C? _6 alkanoylamino, C? _6 alkylsulfanyl, C? Alkylsulfinyl? _6 and C6_6 alkylsulfonyl, and a pharmaceutically acceptable salt or esters hydrolyzable in vivo thereof. '
10. A pharmaceutical composition characterized in that it comprises a compound of, the formula (I) or (Ib) according to claim 1 to 9, a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, in association with a pharmaceutically excipient or carrier. acceptable.
11. A compound of the formula (I) or (Ib) according to claim 1 to 9, and the pharmaceutically acceptable salts or esters hydrolysable in vivo thereof for use as a medicament.
The use of a compound of the formula (I) or (Ib) according to claim 1 to 9, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof in the manufacture of a medicament for use in the production of an elevation of PDH activity in a warm-blooded animal such as a human.
13. A process for preparing a compound of the formula (I) according to claim 1, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, which process is characterized in that it comprises: (a) deprotecting a compound protected from the formula (II) (II) wherein Pg is an alcohol protecting group; (b) for a compound of the formula (I) in which Y-Z is -NHC (O) -, coupling an aniline of the formula (III); (III) with an acid of the formula (IV) (IV) wherein G is a hydroxyl group; (c) coupling an aniline of the formula (III) with an activated acid derivative of the formula (IV) wherein G is an optionally protected hydroxyl group such as an ester or ether; (d) for a compound of the formula (I) in which Y-Z is ethynylene, by reacting an alkyne of the formula (V): with a base, followed by treatment with a ketone of the formula (VI): (VI); (e) for a compound of the formula (I) in which Y-Z is trans-vinylene, reducing a compound of the formula (I) in which Y-Z is ethynylene; (f) for a compound of the formula (I) in which Y-Z is trans-vinylene, by dehydration of a diol of the formula (VII): (Vile); (g) for a compound of the formula (I) in which Y-Z is trans-vinylene, by base catalyzed opening of an epoxide of the formula (VIII): (HIV); (h) for a compound of the formula (I) in which Y-Z is -NHCH2-, reducing a compound of the formula (I) in which Y'-Z is -NHC (O) -; (i) for a compound of the formula (I) in which Y-Z is -OCH2-, -SCH2- or -NHCH2- by reacting an ethylene oxide of the formula (IX) (IX) • with a compound of the formula (III) or a compound of the formula (X): (X) (X) where J is -OH, -NH2 or -SH; (j) by reacting a compound of the formula (XI): (XI) where K is an atom or leaving group, and in which Y-Z is OCH2, SCH2 or NHCH2 or -NHC (O) -. with an amine of the formula R1R2NH; (k) for a compound of the formula (I) in which Y-Z is -NHC (S) -, by reacting a compound of the formula (I) in which Y-Z is -NHC (O) - with a sulfur reagent; and subsequently if necessary: i) converting a compound of the formula (I) to another compound of the formula (I); ii) remove any protective groups; or iii) forming a pharmaceutically acceptable salt or a hydrolysable ester in vivo.