WO2005080359A1

WO2005080359A1 - Benzamide derivatives and their use as glucokinae activating agents

Info

Publication number: WO2005080359A1
Application number: PCT/GB2005/000545
Authority: WO
Inventors: Craig Johnstone; Darren Mckerrecher; Kurt Gordon Pike
Original assignee: Astrazeneca Ab; Astrazeneca Uk Limited
Priority date: 2004-02-18
Filing date: 2005-02-15
Publication date: 2005-09-01
Also published as: US20110034432A1; KR20070007103A; HK1096092A1; RU2006130684A; EP1718624B1; JP2007523142A; TW200602028A; ES2322709T3; IL177216A0; AR047678A1; ATE426597T1; UY28756A1; AU2005214132A1; NO20063452L; AU2005214132B2; BRPI0507746A; AU2005214132B9; RU2392275C2; CA2554310A1; US20080280872A1

Abstract

Compounds of Formula (I): wherein: R1 is methoxymethyl; R2 is selected from -C(O)NR4R5, -SO2NR4R5, -S(O)pR4 and HET-2; HET-1 is a 5- or 6-membered, optionally substituted C-linked heteroaryl ring; HET-2 is a 4-, 5- or 6-membered, C- or N-linked optionally substituted heterocyclyl ring; R3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano; R4 is selected from for example hydrogen, optionally substituted (1-4C)alkyl and HET-2; R5 is hydrogen or (1-4C)alkyl; or R4 and R5 together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3; HET-3 is for example an optionally substituted N-linked, 4, 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring; p is (independently at each occurrence) 0, 1 or 2; mis 0 or1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof, are described. Their use as GLK activators, pharmaceutical compositions containing them, and processes for their preparation are also described.

Description

BENZAMIDE DERIVATIVES AND THEIR USE AS GLUCOKINASE ACTIVATING AGEN

The present invention relates to a group of benzoyl amino heterocyclyl compounds which are useful in the treatment or prevention of a disease or medical condition mediated 5 through glucokinase (GLK or GK), leading to a decreased glucose threshold for insulin secretion. In addition the compounds are predicted to lower blood glucose by increasing hepatic glucose uptake. Such compounds may have utility in the treatment of Type 2 diabetes and obesity. The invention also relates to pharmaceutical compositions comprising said compounds and to methods of treatment of diseases mediated by GLK using said compounds.

10 In the pancreatic β-cell and liver parenchymal cells the main plasma membrane glucose transporter is GLUT2. Under physiological glucose concentrations the rate at which GLUT2 transports glucose across the membrane is not rate limiting to the overall rate of glucose uptake in these cells. The rate of glucose uptake is limited by the rate of phosphorylation of glucose to glucose-6-phosphate (G-6-P) which is catalysed by glucokinase

15 (GLK) [ 1 ] . GLK has a high (6- 1 OmM) Km for glucose and is not inhibited by physiological concentrations of G-6-P [1]. GLK expression is limited to a few tissues and cell types, most notably pancreatic β-cells and liver cells (hepatocytes) [1]. In these cells GLK activity is rate limiting for glucose utilisation and therefore regulates the extent of glucose induced insulin secretion and hepatic glycogen synthesis. These processes are critical in the maintenance of

20 whole body glucose homeostasis and both are dysfunctional in diabetes [2]. In one sub-type of diabetes, Maturity-Onset Diabetes of he Young Type 2 (MODY-2), the diabetes is caused by GLK loss of function mutations [3, 4]. Hyperglycaemia in MODY-2 patients results from defective glucose utilisation in both the pancreas and liver [5], Defective glucose utilisation in the pancreas of MODY-2 patients results in a raised threshold for

25 glucose stimulated insulin secretion. Conversely, rare activating mutations of GLK reduce this threshold resulting in familial hyperinsulinism [6, 6a, 7]. In addition to the reduced GLK activity observed in MODY-2 diabetics, hepatic glucokinase activity is also decreased in Type 2 diabetics [8]. Importantly, global or liver selective overexpression of GLK prevents or reverses the development ofthe diabetic phenotype in both dietary and genetic models ofthe

30 disease [9-12]. Moreover, acute treatment of Type 2 diabetics with fructose improves glucose tolerance through stimulation of hepatic glucose utilisation [13]. This effect is believed to be mediated through a fructose induced increase in cytosolic GLK activity in the hepatocyte by the mechanism described below [13]. Hepatic GLK activity is inhibited through association with GLK regulatory protein (GLKRP). The GLK/GLKRP complex is stabilised by fractose-6-phosphate (F6P) binding to the GLKRP and destabilised by displacement of this sugar phosphate by fructose- 1 -phosphate (F1P). F1P is generated by fructokinase mediated phosphorylation of dietary fructose. Consequently, GLK GLKRP complex integrity and hepatic GLK activity is regulated in a nutritionally dependent manner as F6P is dominant in the post-absorptive state whereas F1P predominates in the post-prandial state. In contrast to the hepatocyte, the pancreatic β-cell expresses GLK in the absence of GLKRP. Therefore, β-cell GLK activity is regulated extensively by the availability of its substrate, glucose. Small molecules may activate GLK either directly or through destabilising the GLK GLKRP complex. The former class of compounds are predicted to stimulate glucose utilisation in both the liver and the pancreas whereas the latter are predicted to act exclusively in the liver. However, compounds with either profile are predicted to be of therapeutic benefit in treating Type 2 diabetes as this disease is characterised by defective glucose utilisation in both tissues. GLK, GLKRP and the K_ATP channel are expressed in neurones ofthe hypothalamus, a region ofthe brain that is important in the regulation of energy balance and the control of food intake [14-18]. These neurones have been shown to express orectic and anorectic neuropeptides [15, 19, 20] and have been assumed to be the glucose-sensing neurones within the hypothalamus that are either inhibited or excited by changes in ambient glucose concentrations [17, 19, 21, 22]. The ability of these neurones to sense changes in glucose levels is defective in a variety of genetic and experimentally induced models of obesity [23- 28], Intracerebro ventricular (icv) infusion of glucose analogues, that are competitive inhibitors of glucokinase, stimulate food intake in lean rats [29, 30]. In contrast, icv infusion of glucose suppresses feeding [31]. Thus, small molecule activators of GLK may decrease food intake and weight gain through central effects on GLK. Therefore, GLK activators may be of therapeutic use in treating eating disorders, including obesity, in addition to diabetes. The hypothalamic effects will be additive or synergistic to the effects ofthe same compounds acting in the liver and/or pancreas in normalising glucose homeostasis, for the treatment of Type 2 diabetes. Thus the GLK GLKRP system can be described as a potential "Diabesity" target (of benefit in both Diabetes and Obesity). GLK is also expressed in specific entero-endocrine cells where it is believed to control the glucose sensitive secretion ofthe incretin peptides GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (Glucagon-Like Peptide- 1) from gut K-cells and L-cells respectively (32, 33, 34). Therefore, small molecule activators of GLK may have additional beneficial effects on insulin secretion, β-cell function and survival and body weight as a consequence of stimulating GIP and GLP-1 secretion from these entero-endocrine cells. hi WO00/58293 and WOO 1/44216 (Roche), a series of benzylcarbamoyl compounds are described as glucokinase activators. The mechanism by which such compounds activate GLK is assessed by measuring the direct effect of such compounds in an assay in which GLK activity is linked to NADH production, which in turn is measured optically - see details ofthe in vitro assay described hereinafter. Compounds ofthe present invention may activate GLK directly or may activate GLK by inliibiting the interaction of GLKRP with GLK. Further GLK activators have been described in WO03/095438 (substituted phenylacetamides, Roche), WO03/055482 (carboxamide and sulphonamide derivatives, Novo Nordisk), WO2004/002481 (arylcarbonyl derivatives, Novo Nordisk), and in WO03/080585 (amino-substituted benzoylaminoheterocycles, Banyu). Our International application Number: WO03/000267 describes a group of benzoyl amino pyridyl carboxylic acids which are activators ofthe enzyme glucokinase (GLK). Our International application Number: WO03/015774 describes compounds ofthe Formula (A):

(A) wherein R³ is a substituted heterocycle other than a carboxylic acid substituted pyridyl. International application WO2004/076420 (Banyu) describes compounds which are generally a subset of those described in WO03/015774, wherein for example R¹ is an (substituted) alkyl ether and R is (substituted) phenoxy. We have surprisingly found a small group of compounds, generally a selected subgroup of those described in WO 03/015774, which have generally superior potency for the GLK enzyme, and more advantageous physical properties, including, for example, one or more of higher aqueous solubility, higher permeability, and/or lower plasma protein binding. Consequently, such compounds having a balance of these properties would be expected to display higher plasma free drug levels and superior in vivo efficacy after oral dosing as determined, for example, by activity in Oral Glucose Tolerance Tests (OGTTs). Therefore this group of compounds would be expected to provide superior oral exposure at a lower dose and thereby be particularly suitable for use in the treatment or prevention of a disease or medical condition mediated through GLK. Thus, according to the first aspect ofthe invention there is provided a compound of Formula (I):

(I) wherein:

R¹ is methoxymethyl;

R² is selected from -C(O)NR⁴R⁵, -SO₂NR⁴R⁵, -S(O)_pR⁴ and HET-2; HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from

R⁶;

HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- , and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to a S(O) or S(O)₂ group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁷; R³ is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano;

R⁴ is selected from hydrogen, (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and HET-2;

R⁵ is hydrogen or (l-4C)alkyl; or R⁴ and R together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3;

R⁶ is independently selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-

4C)alkyl, (l-4C)alkylS(O)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)alkylamino(l-4C)alkyl, di(l-4C)alkylamino(l-4C)alkyl and HET-4;

R⁷ is selected from -OR⁵, (l-4C)alkyl, -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkoxy(l- 4C)alkyl, hydroxy(l-4C)alkyl and-S(O)pR⁵;

HET-3 is an N-linked, 4, 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁸; or

HET-3 is an N-linked, 7 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further heteroatom (in addition to the linking N atom) independently selected from O, S and N, wherein a -CH₂- group can optionally be replaced by a -C(O)- group and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁸; or

HET-3 is an 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom (in addition to the linking N atom) wherein a -CH₂- group can optionally be replaced by a -C(O)-; which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from hydroxy and R³;

R⁸ is selected from -OR⁵, (l-4C)alkyl, -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkylamino, di(l-4C)alkylamino, HET-3 (wherein said ring is unsubstituted), (l-4C)alkoxy(l-4C)alkyl, hydroxy(l-4C)alkyl and -S(O)pR⁵; HET-4 is a 5- or 6-membered, C-or N- linked unsubstituted heteroaryl ring containing 1, 2 or

3 ring heteroatoms independently selected from O, N and S; p is (independently at each occurrence) 0, 1 or 2; m is 0 or 1 ; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention there is provided a compound of formula (I), or a salt, pro-drug or solvate thereof as hereinbefore defined, with the proviso that compounds exemplified in WO2004/076420, which would otherwise fall within the scope of this invention, are excluded. In another aspect ofthe invention, there is provided a compound ofthe formula (I) as hereinbefore defined, wherein

R¹ is methoxymethyl;

R² is selected from -C(O)-HET-3 and -SO₂-HET-3;

HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from

R⁶;

HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, wherem a -CH₂- group can optionally be replaced by a -C(O)- , and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to a S(O) or S(O)₂ group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁷;

R³ is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano; R⁴ is selected from hydrogen, (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and HET-2;

R⁵ is hydrogen or (l-4C)alkyl; or R⁴ and R together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3; R⁶ is independently selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-

4C)alkyl, (l-4C)alkylS(0)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)alkylamino(l-4C)alkyl, di(l-4C)alkylamino(l-4C)alkyl and HET-4;

R⁷ is selected from -OR⁵, (l-4C)alkyl, -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkoxy(l- 4C)alkyl, hydroxy(l-4C)alkyl and -S(O)pR⁵;

HET-3 is an N-linked, 4, 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R ; or

HET-3 is an 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom (in addition to the linking N atom) wherein a -CH - group can optionally be replaced by a -C(O)-; which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from hydroxy and R³;

R⁸ is selected from -OR⁵, (l-4C)alkyl, -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkylamino, di(l-4C)alkylamino, HET-3 (wherein said ring is unsubstituted), (l-4C)alkoxy(l-4C)alkyl, hydroxy(l-4C)alkyl and-S(O)pR⁵; HET-4 is a 5- or 6-membered, C-or N- linked unsubstituted heteroaryl ring containing 1, 2 or

3 ring heteroatoms independently selected from O, N and S; p is (independently at each occurrence) 0, 1 or 2; m is O or 1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof; In a further aspect ofthe invention there is provided a compound ofthe formula (I), as hereinbefore defined or a salt, pro-drug or solvate thereof, wherein: HET-3 is an N-linked, 4 to 6 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH - group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R . In another aspect ofthe invention, there is provided a compounds ofthe formula (I) as hereinbefore defined, wherem R¹ is methoxymethyl; R² is selected from -C(O)NR⁴¹R⁵¹, -SO₂NR⁴¹R⁵¹ and -S(O)_pR⁴¹;

HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R⁶;

HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- , and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to a S(O) or S(O)₂ group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁷;

R³ is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano;

R⁴¹ is selected from (l-4C)alkyl [substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and HET-2; R⁵¹ is hydrogen or (l-4C)alkyl;

R⁴ is selected from (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and HET-2; R⁵ is hydrogen or (l-4C)alkyl; or R⁴ and R together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3;

4C)alkyl, (l-4C)alkylS(O)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)allcylamino(l-4C)alkyl, di(l-4C)alkylamino(l-4C)alkyl and HET-4;

R⁷ is selected from -OR⁵, (l-4C)alkyl, -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkoxy(l-

4C)alkyl, hydroxy(l-4C)alkyl and -S(O)pR⁵;

HET-3 is an N-linked, 4, 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH - group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁸; or

HET-3 is an N-linked, 7 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further heteroatom (in addition to the linking N atom) independently selected from O, S and N, wherein a -CH₂- group can optionally be replaced by a -C(O)- group and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁸; or HET-3 is an 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom (in addition to the linking N atom) wherein a

-CH₂- group can optionally be replaced by a -C(O)-; which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from hydroxy and R³;

R⁸ is selected from -OR⁵, (l-4C)alkyl, -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkylamino, di(l-4C)alkylamino, HET-3 (wherein said ring is unsubstituted), (l-4C)alkoxy(l-4C)alkyl, hydroxy(l-4C)alkyl and-S(O)pR⁵;

HET-4 is a 5- or 6-membered, C-or N- linked unsubstituted heteroaryl ring containing 1, 2 or

3 ring heteroatoms independently selected from O, N and S; p is (independently at each occurrence) 0, 1 or 2; m is O or l; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof.

In a further aspect ofthe invention there is provided a compound ofthe formula (I) as hereinbefore defined, or a salt, pro-drug or solvate thereof, wherein: R⁴ is selected from hydrogen, (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵], and HET-2;

HET-3 as an 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom (in addition to the linking N atom) wherein a -CH₂- group can optionally be replaced by a -C(O)-, is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from R³. In another aspect ofthe invention, there is provided a compounds ofthe formula (I) as hereinbefore defined, wherein R¹ is methoxymethyl; R² is HET-2;

HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- , and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to a S(O) or S(O)₂ group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R ;

R⁴ is selected from hydrogen, (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and HET-2; R⁵ is hydrogen or (l-4C)alkyl; or R⁴ and R together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3;

4C)alkyl, (l-4C)alkylS(O)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)alkylamino(l-4C)alkyl, di(l -4C)alkylamino(l-4C)alkyl and HET-4;

4C)alkyl, hydroxy(l-4C)alkyl and -S(O)pR⁵;

R⁸ is selected from -OR⁵, (l-4C)alkyl, -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkylamino, di(l-4C)allcylamino, HET-3 (wherein said ring is unsubstituted), (l-4C)alkoxy(l-4C)alkyl, hydroxy(l-4C)alkyl and -S(O)pR⁵;

3 ring heteroatoms independently selected from O, N and S; p is (independently at each occurrence) 0, 1 or 2; m is O or l; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof;

It will be understood that when R⁴ is -C(O)NR⁵R⁵, each R⁵ is independently selected from hydrogen and (l-4C)alkyl, and therefore this definition of R⁴ includes (but is not limited to) -CONH₂, -CONHMe, -CONMe₂ and -CONMeEt. It will be understood that where a compound ofthe formula (I) contains more than one HET-2 ring, they may be the same or different. It will be understood that where a compound ofthe formula (I) contains more than one group R⁴, they may be the same or different. It will be understood that where a compound ofthe formula (I) contains more than one group R⁵, they may be the same or different. It will be understood that where a compound ofthe formula (I) contains more than one group R , they may be the same or different. A similar convention applies for all other groups and substituents on a compound of formula (I) as hereinbefore defined. Compounds of Formula (I) may form salts which are within the ambit ofthe invention. Pharmaceutically acceptable salts are preferred although other salts may be useful in, for example, isolating or purifying compounds. In another aspect, the invention relates to compounds of formula (I) as hereinabove defined or to a pharmaceutically acceptable salt. In another aspect, the invention relates to compounds of formula (I) as hereinabove defined or to a pro-drug thereof. Suitable examples of pro-drugs of compounds of formula (I) are in- vivo hydrolysable esters of compounds of formula (I). Therefore in another aspect, the invention relates to compounds of formula (I) as hereinabove defined or to an in- vivo hydrolysable ester thereof. In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched-chain alkyl groups such as t-butyl are specific for the branched chain version only. For example,

"(l-4C)alkyl" includes methyl, ethyl, propyl, isopropyl and t-butyl. An analogous convention applies to other generic terms. For the avoidance of doubt, reference to the group HET-1 containing a nitrogen in the 2-position, is intended to refer to the 2-position relative to the amide nitrogen atom to which the group is attached. For example, the following structures are encompassed (but not limited to):

Suitable examples of HET-1 as a 5- or 6-membered, C-linked heteroaryl ring as hereinbefore defined, include thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl. It will be understood that HET-2 can be a saturated, or partially or fully unsaturated ring. Suitable examples of HET-2 include azetidinyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, morpholino, morpholinyl, piperidinyl, piperazinyl, morpholinyl, thiomojrpholinyl, pyrrolyl, pyrrolidinyl, pyrrolidonyl, 2,5-dioxopyrrolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxoimidazolidinyl, 2,4-dioxoimidazolidinyl, 2-oxo-l,3,4-(4- triazolinyl), 2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyranyl, and 4-pyridonyl. It will be understood that HET-2 may be linked by any appropriate available C or N atom, therefore for example, for HET-2 as "imidazolyl" includes 1- , 2-, 4- and 5- imidazolyl. Suitable examples of HET-3 as a 4-6 membered saturated or partially unsaturated heterocyclic ring are morpholino, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl. Suitable examples of HET-3 as a 7-membered saturated or partially unsaturated heterocyclic ring are homopiperazinyl, homo-morpholino, homo-thiomorpholino (and versions thereof wherein the sulfur is oxidised to an SO or S(O)₂ group) and homo- piperidinyl. Suitable examples of HET-3 as an 6-10 membered bicyclic heterocyclic ring are bicyclic saturated or partially unsaturated heterocyclyl ring such as those illustrated by the structures shown below (wherein the dotted line indicates the point of attachment to the rest of the molecule):

[2,2,2] [4,1 ,0] [4,2,0]

[3,2,0]

[2,1 ,1] [3,1 ,0] [1 ,1 ,1] In particular HET-3 is a [2,2,1] system such as

(7-azabicyclo[2.2.1]hept-7-yl). Suitable examples of HET-4 are furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl and triazolyl. It will be appreciated that, where definitions of heterocylyl groups HET-1 to HET-4 encompass heteroaryl rings which may be substituted on nitrogen, such substitution may not result in charged quaternary nitrogen atoms. It will be appreciated that the definitions of HET- 1 to HET-4 are not intended to include any O-O, O-S or S-S bonds. It will be appreciated that the definitions of HET-1 to HET-4 are not intended to include unstable structures. Examples of (l-4C)alkyl include methyl, ethyl, propyl, isopropyl, butyl and tert-butyl; examples of (3-6C)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; examples of halo include fluoro, chloro, bromo and iodo; examples of hydrox (1-4C) alkyl include hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1 -hydroxyisopropyl and 4-hydroxybutyl; examples of (l-4C)alkoxy(l-4C)alkyl include methoxymethyl, ethoxymethyl, tert-butoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, methoxypropyl, 2-mefhoxypropyl and methoxybutyl; examples of (l-4C)alkylS(O)p(l- 4C)alkyl include methylsulfmylmethyl, ethylsulfinylmethyl, ethylsulfinylethyl, methylsulfinylpropyl, methylsulfmylbutyl, methylsulfonylmethyl, ethylsulfonylmethyl, ethylsulfonylefhyl, methylsulfonylpropyl, methylsulfonylbutyl, methylthiomethyl, ethylthiomethyl, ethylthioethyl, methylthiopropyl, and methylthiobutyl; examples of aminofl- 4C)alkyl include aminomethyl, aminoethyl, 2-aminopropyl, 3-aminopropyl, 1-aminoisopropyl and 4-aminobutyl; examples of (l-4C)alkylamino(l-4C)aIkyl include (N- methyl)aminomethyl, (N-ethyl)aminomethyl, l-((N-methyl)amino)ethyl, 2-((N- methyl)amino)ethyl, (N-ethyl)aminoethyl, (N-methyl)aminopropyl, and 4-((N- methyl)amino)butyl; examples of di(l-4C)alkylamino(l-4C)alkyl include dimethylaminomethyl, ιnethyl(ethyl)aminomethyl, methyl(ethyl)aminoethyl, (N,N- diethyl)aminoethyl, (N,N-dimethyl)aminopropyl and (N,N-dimethyl)aininobutyl; examples of (l-4C)alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino and tert-butylamino; examples of di(l-4C)alkyIamino include dimethylamino, methyl(ethyl)amino, diethylamino, dipropylamino, di-isopropylamino and dibutylamino; examples of — C(O)(l-4C)alkyl include methylcarbonyl, ethylcarbonyl, propylcarbonyl and tert-butyl carbonyl. It is to be understood that, insofar as certain ofthe compounds of Formula (I) defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of stimulating GLK directly or inhibiting the GLK GLKRP mteraction. The synthesis of optically active fonns may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. It is also to be understood that certain compounds may exist in tautomeric forms and that the invention also relates to any and all tautomeric forms ofthe compounds ofthe invention which activate GLK. In one embodiment ofthe invention are provided compounds of fonnula (I), in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (I), in a further alternative embodiment are provided in-vivo hydrolysable esters of compounds of formula (I), and in a further alternative embodiment are provided pharmaceutically-acceptable salts of in-vivo hydrolysable esters of compounds of formula (I). Preferred values of each variable group are as follows. Such values maybe used where appropriate with any ofthe values, definitions, claims, aspects or embodiments defined hereinbefore or hereinafter. In particular, each may be used as an individual limitation on the broadest definition of formula (I). Further, each ofthe following values may be used in combination with one or more ofthe other following values to limit the broadest defintion of formula (I).

(1) R¹ is methoxymethyl and the configuration is preferably (S), that is:

2) R² is -C(O)NR⁴R⁵ 3) R² is -S0₂NR⁴R⁵ 4) R² is -S(0)_pR⁴ 5) R² is HET-2 6) m is 1 and R² is in the para position relative to the ether linkage 7) m is 1 and n is 0 or 1 8) m is 1 and n is 0

(9) m is 1, n is 0 and R² is in the para position relative to the ether linkage

(10) m is 1, n is 1, R is in the para position relative to the ether linkage, R is in the ortho position relative to the ether linkage (11) m is 1 , n is 1, R is in the para position relative to the ether linkage, R is in the meta position relative to the ether linkage

(12) n is 0

(13) n is i (14) n is 2

(15) n is 2 and both R³ are halo

(16) n is 2 and each R³ is independently halo or methoxy

(17) m is 1 , n is 2 and R² is in the para position relative to the ether linkage

(18) m is 1 , n is 2, R² is in the para position relative to the ether linkage and each R³ is in an ortho position relative to the ether linkage

(19) m is 1, n is 2, both R³ are halo, R² is in the para position relative to the ether linkage and each R³ is in an ortho position relative to the ether linkage

(20) R³ is fluoromethyl or difluoromethyl

(21) R is halo or trifluoromethyl (22) R³ is halo

(23) R³ is chloro or fluoro

(24) R³ is fluoro

(25) R³ is methoxy

(26) n is 2 and both R³ are fluoro, (27) n is 2, both R³ are fluoro and are in the 3- and 5-positions (meta-positions) relative to the ether linkage

(28) m is 1 , n is 2, R² is in the para position relative to the ether linkage, both R³ are fluoro and are in the 3- and 5-positions relative to the ether linkage

(29) p is 0 (30) p is l

(31) p is 2

(32) HET-1 is a 5-membered heteroaryl ring

(33) HET-1 is a 6-membered heteroaryl ring

(34) HET-1 is substituted with 1 or 2 substituents independently selected from R⁶ (35) HET-1 is substituted with 1 substituent selected from R⁶

(36) HET-1 is unsubstituted (37) HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, and triazolyl

(38) HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl

(39) HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl

(40) HET-1 is selected from thiazolyl, pyrazolyl and oxazolyl

(41) HET-1 is selected from thiadiazolyl and oxadiazolyl

(42) HET-1 is selected from 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl (43) HET-1 is selected from 1,2,4-oxadiazolyl and 1,2,4-oxadiazolyl

(44) HET-1 is pyrazolyl

(45) HET-1 is pyridyl or pyrazinyl

(46) HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyridyl;

(47) R⁶ is selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, di(l-4C)alkylamino(l- 4C)alkyl and HET-4

(48) R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl, aminomef yl, N-methylaminomethyl, dimethylaminomethyl

(49) R⁶ is selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-4C)alkyl, (1- 4C)alkylS(0)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)alkylamino(l-4C)alkyl, and di(l- 4C)alkylamino(l-4C)alkyl

(50) R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N- methylaminomethyl, and dimethylaminomethyl

(51) R⁶is selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl and methoxymethyl (52) R⁶ is selected from methyl, ethyl, bromo, chloro and fluoro

(53) R⁶ is methyl

(54) R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N- methylaminomethyl, dimethylaminomethyl, hydroxymethyl and methoxymethyl

(55) R⁶ is selected from methyl, ethyl, aminomethyl, N-methylaminomethyl, dimethylaminomethyl, hydroxymethyl and methoxymethyl

(56) R⁶ is selected from methyl, ethyl, isopropyl and methoxymethyl

(57) when 2 substituents R^δ are present, both are selected from methyl, ethyl, bromo, chloro and fluoro; preferably both are methyl (58) R⁶is selected from (l-4C)alkylS(O)p(l-4C)alkyl, (l-4C)alkylamino(l-4C)alkyl, di(l-4C)alkylamino(l-4C)alkyl and HET-4

(59) R⁶ is HET-4

(60) HET-4 is selected from furyl, pyrrolyl and thienyl (61) HET-4 is furyl

(62) R⁴ is hydrogen

(63) R⁴ is (l-4C)alkyl [substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵] (64) R⁴ is (l-4C)alkyl [substituted by 1 substituent selected from HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl and -C(O)NR⁵R⁵] (65) R⁴ is (l-4C)alkyl

(66) R⁴ is (l-4C)alkyl substituted by -OR⁵

(67) R⁴ is (l-4C)alkyl substituted by HET-2 (68) R⁴ is (3-6C)cycloalkyl, particularly cyclopropyl

(69) R⁴ is (3-6C)cycloalkyl substituted by a group selected from R⁷

(70) R⁴ is (3-6C)cycloalkyl substituted by a group selected from -OR⁵ and (l-4C)alkyl

(71) R⁴ is HET-2

(72) R⁴ is selected from hydrogen, (l-4C)alkyl, and (l-4C)alkyl substituted with -OR⁵ (73) HET-2 is unsubstituted

(74) HET-2 is substituted with 1 or 2 substituents independently selected from (l-4C)alkyl, hydroxy and (1-4C) alkoxy

(75) HET-2 is a fully saturated ring system

(76) HET-2 is a fully unsaturated ring system (77) HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidinyl, piperazinyl, 3- oxopiperazinyl, thiomorpholinyl, pyrrolidinyl, pyrrolidonyl, 2,5-dioxopyrrolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tefrahyc ofϊiranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4- dioxoimidazolidinyl, pyranyl and 4-pyridonyl (78) HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, tetrahydrofuranyl, and tetrahydropyranyl (79) HET-2 is selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pynolyl, 1,2,4-triazolyl and 1,2, 3 -triazolyl

(80) HET-2 is selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinyl, 3- oxopiperazinyl, pyrrolidinyl, pyrrolidonyl, 2-oxazolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxotetrahydrothienyl, and 2-oxoimidazolidinyl

(81) HET-2 is selected from morpholino, furyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinyl, 3-oxopiperazinyl, pyrrolidinyl, 2-pyrrolidonyl, 2-oxazolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxotetrahydrothienyl, and 2-oxoimidazolidinyl

(82) HET-2 is selected from morpholino, furyl, imidazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinyl, 3-oxopiperazinyl, pynolidinyl, 2-pynolidonyl, tetrahydropyranyl, 1,1- dioxotetrahydrothienyl, and 2-oxoimidazolidinyl

(83) R⁵ is hydrogen (84) R⁵ is (l-4)alkyl, preferably methyl

(85) R⁵ is hydrogen or methyl

(86) R⁷ is selected from -OR⁵, (l-4C)alkyl, -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkoxy(l- 4C)alkyl, and hydroxy(l-4C)alkyl

(87) R⁷ is selected from -OR⁵, (l-4C)alkyl, -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, and hydroxy(l- 4C)alkyl

(88) R⁷ is selected from hydroxy, methoxy, -COMe, -CONH₂, -CONHMe, -CONMe₂, and hydroxymethyl

(89) R⁷ is selected from (l-4C)alkyl, hydroxy and (l-4C)alkoxy

(90) R is selected from methyl, ethyl, methoxy and hydroxy (91) R⁷ is methyl

(92) R⁸ is selected from methyl, hydroxy, methoxy, -COMe, -CONH₂, -CONHMe, -CONMe₂, hydroxymethyl, hydroxyethyl, -NHMe and -NMe₂(93) R⁸ is selected from morpholino, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl

(94) R⁸ is selected from methyl, -COMe, -CONH₂, hydroxyethyl and hydroxy (95) R⁸ is methyl

(96) HET-3 is a fully saturated ring

(97) HET-3 is selected from morpholino, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl (98) R⁴ and R⁵ together with the nitrogen to which they are attached form a ring as defined by HET-3

(99) HET-3 is selected from pyrrolidinyl and azetidinyl

(100) HET-3 is azetidinyl (101) HET-3 is a 4, 5 or 6-membered saturated or partially unsaturated heterocyclic ring as hereinbefore defined

(102) HET-3 is a 7-membered saturated or partially unsaturated heterocyclic ring as hereinbefore defined

(103) HET-3 is an 6 to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring as hereinbefore defined

(104) HET-3 is 7-azabicyclo[2.2.1]hept-7-yl

(105) HET-3 is selected from morpholino, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl and 7-azabicyclo[2.2.1]hept-7-yl

(106) HET-3 is selected from piperidinyl, pynolidinyl, azetidinyl and 7-azabicyclo[2.2.1]hept- 7-yl

According to a further feature ofthe invention there is provided the following prefened groups of compounds ofthe invention: In a further aspect ofthe invention there is provided a compound of Formula (I) wherein:

R¹ is methoxymethyl;

R² is selected from -C(O)NR⁴R⁵, -SO₂NR⁴R⁵, -S(O)_pR⁴ and HET-2;

HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1, 2 or 3 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R⁶;

HET-2 is a 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- , and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to an S(O) or S(0)₂ group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁷; R³ is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano;

R⁴ is selected from hydrogen, (l-4C)alkyl, [optionally substituted by -OR⁵] and HET-2;

R⁵ is hydrogen or (l-4C)alkyl; or R⁴ and R together with the nitrogen atom to which they are attached may form a 4-6 membered heterocyclyl ring system as defined by HET-3;

4C)alkyl, (l-4C)alkylS(O)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)alkylamino(l-4C)alkyl, di(l-4C)alkylamino(l-4C)alkyl and HET-4; R⁷ is selected from -OR⁵ and (l-4C)alkyl;

HET-3 is an N-linked, 4 to 6 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁸;

R⁸ is selected from -OR⁵ and (l-4C)alkyl;

3 ring heteroatoms independently selected from O, N and S; p is (independently at each occurrence) 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention there is provided a compound of Formula (I) wherein:

R¹ is methoxymethyl;

R² is selected from -C(O)NR⁴R⁵, -SO₂NR⁴R⁵, -S(O)_pR⁴ and HET-2;

HET-2 is a 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- , and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to an S(O) or S(0)₂ group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁷;

R³ is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano; R⁴ is selected from hydrogen, (l-4C)alkyl, [optionally substituted by -OR⁵] and HET-2;

R⁵ is hydrogen or (l-4C)alkyl; or R⁴ and R together with the nitrogen atom to which they are attached may fonn a heterocyclyl ring system as defined by HET-3;

R⁶ is independently selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l- 4C)alkyl, (l-4C)alkylS(O)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)alkylamino(l-4C)alkyl, di(l-4C)alkylamino(l-4C)alkyl and HET-4;

R⁷ is selected from -OR⁵ and (l-4C)alkyl;

HET-3 is an N-linked, 4 to 6 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or

S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁸; or

HET-3 is an N-linked, 7 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further heteroatom (in addition to the linking N atom) independently selected from O, S and N, wherein a -CH₂- group can optionally be replaced by a -C(O)- group and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁸; or HET-3 is an 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom (in addition to the linking N atom) wherein a -CH₂- group can optionally be replaced by a -C(O)-; which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from R ;

R⁸ is selected from -OR⁵ and (l-4C)alkyl;

HET-4 is a 5- or 6-membered, C-or N- linked unsubstituted heteroaryl ring containing 1, 2 or 3 ring heteroatoms independently selected from O, N and S; p is (independently at each occuπence) 0, 1 or 2; is 0 or 1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein:

R¹ is methoxymethyl;

R² is selected from -C(O)NR⁴R⁵, -SO₂NR⁴R⁵, -S(O)_pR⁴ and HET-2; HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and

S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from

R⁶; HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, wherein a -CH - group can optionally be replaced by a -C(O)- , and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to an S(O) or S(O) group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁷; R³ is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano;

R⁴ is selected from (l-4C)alkyl [substituted by 1 or 2 substituents independently selected from HET-2, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵]; R⁵ is hydrogen or (1 -4C)alkyl; or R⁴ and R together with the nitrogen atom to which they are attached may form a 4-6 membered heterocyclyl ring system as defined by HET-3; R⁶ is independently selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l- 4C)alkyl, (l-4C)alkylS(O)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)allcylamino(l-4C)alkyl, di(l-4C)alkylamino(l-4C)alkyl and HET-4;

R⁷ is selected from -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkoxy(l-4C)alkyl, hydroxy(l- 4C)alkyl and -S(0)pR⁵;

HET-3 is an N-linked, 4 to 6 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or S(O)₂ group; wliich ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R ;

R⁸ is selected from -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkylamino, di(l-4C)alkylamino,

HET-3 (wherem said ring is unsubstituted), (l-4C)alkoxy(l-4C)alkyl, hydroxy(l-4C)alkyl and

-S(O)pR⁵; HET-4 is a 5- or 6-membered, C-or N- linked unsubstituted heteroaryl ring containing 1, 2 or 3 ring heteroatoms independently selected from O, N and S; p is (independently at each occ xence) 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein: R¹ is methoxymethyl; R² is selected from -C(0)NR⁴R⁵, -SO₂NR⁴R⁵, -S(O)_pR⁴ and HET-2;

HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quatemised, with 1 or 2 substituents independently selected from R⁶;

HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- , and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to an S(O) or S(O)₂ group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁷; R³ is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano; R⁴ is selected from (l-4C)alkyl [substituted by 1 or 2 substituents independently selected from HET-2, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(0)NR⁵R⁵];

R⁶ is independently selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l- 4C)alkyl, (l-4C)alkylS(0)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)alkylamino(l-4C)alkyl, di(l-4C)alkylamino(l-4C)alkyl and HET-4; R⁷ is selected from -C(0)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkoxy(l-4C)alkyl, hydroxy(l- 4C)alkyl and -S(O)pR⁵;

HET-3 is an N-linked, 4 to 6 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or S(0)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁸; or

HET-3 is an N-linked, 7 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further heteroatom (in addition to the linking N atom) independently selected from O, S and N, wherein a -CH₂- group can optionally be replaced by a -C(O)- group and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or S(O) group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R ; or

HET-3 is an 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom (in addition to the linking N atom), wherein a -CH₂- group can optionally be replaced by a -C(O)-; which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from R³; R⁸ is selected from -C(O)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkylamino, di(l-4C)alkylamino,

HET-3 (wherein said ring is unsubstituted), (l-4C)alkoxy(l-4C)alkyl, hydroxy(l-4C)alkyl and

-S(O)pR⁵;

HET-4 is a 5- or 6-membered, C-or N- linked unsubstituted heteroaryl ring containing 1, 2 or 3 ring heteroatoms independently selected from O, N and S; p is (independently at each occurrence) 0, 1 or 2; m is 0 or 1 ; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof. hi a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1 ; HET-1 is a 5- or 6-membered heteroaryl ring;

R² is -CONR⁴R⁵ or-S0₂NR⁴R⁵;

R³ is halo or trifluoromethyl;

R⁴ is (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from

HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵];

R⁵is hydrogen or methyl;

HET-2 is a 5- or 6- membered heterocyclyl ring as hereinbefore defined, containing 1 or 2 heteroatoms independently selected from O, N and S; and

R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect of he invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵;

R³ is halo or trifluoromethyl; R⁴ is (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from

HET-2, -OR⁵, -S0₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from

R⁷) and -C(O)NR⁵R⁵];

R⁵is hydrogen or methyl; R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;

R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherem

R¹ is methoxymethyl; m is 1 and n is 0 or 1; HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl;

R² is -CONR⁴R⁵ or-SO₂NR⁴R⁵;

R³ is halo or trifluoromethyl;

R⁴ is (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -S0₂R⁵, (3-6C)cycloalkyl and -C(O)NR⁵R⁵];

R⁵is hydrogen or methyl;

R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;

HET-2 is selected from azetidinyl, morpholino, moφholinyl, piperidinyl, piperazinyl, 3- oxopiperazinyl, thiomorpholinyl, pyrrolidinyl, pyπolidonyl, 2,5-dioxopyrrolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4- dioxoimidazolidinyl, pyranyl and 4-pyridonyl; and

R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (1) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1;

HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵;

HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl and -C(O)NR⁵R⁵];

R⁵is hydrogen or methyl;

R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidinyl, piperazinyl, 3- oxopiperazinyl, thiomorpholinyl, pyrrolidinyl, pyrrolidonyl, 2,5-dioxopyrrolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofurai yl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4- dioxoimidazolidinyl, pyranyl and 4-pyridonyl; and R⁷ is selected from -OR⁵ and (1 -4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1 ;

HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl;

R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵;

HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl and -C(O)NR⁵R⁵];

R⁵is hydrogen or methyl;

R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; HET-2 is selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, 1,2,4-triazolyl and 1,2,3 -triazolyl; and

R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R is methoxymethyl; m is 1 and n is 0 or 1;

HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵;

R is halo or trifluoromethyl;

R⁴ is (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl and -C(O)NR⁵R⁵];

R⁵is hydrogen or methyl;

HET-2 is selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl,

1,2,4-triazolyl and 1,2,3-triazolyl; and

R¹ is methoxymethyl; m is 1 and n is 0 or 1;

HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl and oxadiazolyl; R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵;

R³ is halo or trifluoromethyl;

R⁴ is selected from hydrogen, (l-4C)alkyl [optionally substituted by -OR⁵], (3-6C)cycloalkyl

(optionally substituted with 1 group selected from R⁷) and HET-2;

R⁵is hydrogen or methyl; R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; HET-2 is selected from morpholino, furyl, imidazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinyl, 3-oxopiperazinyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydropyranyl, 1,1- dioxotetrahydrothienyl, and 2-oxoimidazolidinyl; and

R¹ is methoxymethyl; m is 1 and n is 0 or 1; HET-1 is selected from pyridyl and pyridazinyl;

R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵;

R³ is halo or trifluoromethyl;

R⁴ is selected from hydrogen, (l-4C)alkyl, [optionally substituted by -OR⁵], (3-6C)cycloalkyl

(optionally substituted with 1 group selected from R ) and HET-2; R⁵is hydrogen or methyl;

R is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;

HET-2 is selected from morpholino, furyl, imidazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinyl, 3-oxopiperazinyl, pynolidinyl, 2-pyrrolidonyl, tetrahydropyranyl, 1,1- dioxotetrahydrothienyl, and 2-oxoimidazolidinyl; and

R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein R¹ is methoxymethyl; m is 1 and n is 0 or 1 ;

HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl and oxadiazolyl;

R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵; R³ is halo or trifluoromethyl;

R⁴ is selected from (l-4C)alkyl, [optionally substituted by -OR⁵], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and HET-2;

HET-2 is selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, 2-pyπolidonyl,

2,5-dioxopyrrolidinyl, 2-oxotefrahydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 2- oxoimidazolidinyl, and 2,4-dioxoimidazolidinyl; and

R⁷ is (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein R¹ is methoxymethyl; m is 1 and n is 0 or 1 ;

R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵; R³ is halo or trifluoromethyl;

R⁵is hydrogen or methyl;

HET-2 is piperidinyl or piperazinyl; and

R⁷ is (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 ;

HET-1 is selected from thiazolyl, thiadiazolyl and pyrazolyl;

R² is -CONR⁴R⁵; R⁴ is piperidinyl, optionally substituted with methyl;

R⁵is hydrogen or methyl;

R⁶ is methyl; or a salt, pro-drug or solvate thereof. fri a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein R¹ is methoxymethyl; m is 1 and n is 0 or 1; HET-1 is selected from pyridyl and pyridazinyl; R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵;

R is halo or trifluoromethyl;

R⁴ is selected from (l-4C)alkyl, [optionally substituted by -OR⁵] and HET-2;

HET-2 is selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, 2-pynolidonyl,

2,5-dioxopyπolidinyl, 2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxoimidazolidinyl, and 2,4-dioxoimidazolidinyl; and R⁷ is (l-4C)alkyl; or a salt, pro-drug or solvate thereof.

In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein R¹ is methoxymethyl; m is 1 and n is 0 or 1 ;

HET-1 is selected from pyridyl and pyridazinyl;

R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵;

R³ is halo or trifluoromethyl; R⁴ is selected from (l-4C)alkyl, [optionally substituted by -OR⁵] and HET-2;

R⁵is hydrogen or methyl;

HET-2 is piperidinyl or piperazinyl; and R⁷ is (l-4C)alkyl; or a salt, pro-drug or solvate thereof. hi a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein R¹ is methoxymethyl; m is 1 and n is 0 or 1 ;

R³ is halo or trifluoromethyl;

R⁴ and R⁵ together with the nitrogen to which they are attached form a morpholino, piperidinyl, piperazinyl, pyrrolidinyl or azetidinyl ring, which ring is optionally substituted on a carbon or nitrogen atom by R ; R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; and

R⁸ is selected from hydroxy, (l-4C)alkoxy and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1;

R³ is halo or trifluoromethyl;

R⁸ is pyrrolidine or piperidine; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1 ; HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl and oxadiazolyl;

R² is -CONR⁴R⁵ or -SO₂NR⁴R⁵;

R is halo or trifluoromethyl; R⁴ and R⁵ together with the nitrogen to whichi they are attached form a morpholino, piperidinyl, piperazinyl, pynolidinyl or azetidinyl ring, which ring is optionally substituted on a carbon or nitrogen atom by (l-4C)alkyl; and

R^δ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; or a salt, pro-drug or solvate thereof. hi a further aspect ofthe mvention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1 ; HET- 1 is selected from pyridyl and pyridazirryl;

R² is -CONR⁴R⁵ or-SO₂NR⁴R⁵;

R³ is halo or trifluoromethyl;

R⁴ and R⁵ together with the nitrogen to whichi they are attached form a morpholino, piperidinyl, piperazinyl, pynolidmyl or azetidinyl ring, which ring is optionally substituted on a carbon or nitrogen atom by (l-4C)alkyl; and

R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylammomethyl, and dimethylaminomethyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0;

HET-1 is selected from thiazolyl, thiadiazolyl and pyrazolyl;

R² is -CONR⁴R⁵; R⁴ and R⁵ together with the nitrogen to whichi they are attached form a piperidinyl, or piperazinyl ring, which ring is optionally substituted on a carbon or nitrogen atom by (1-

4C)alkyl or by a pyrrolidinyl ring; R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0;

HET-1 is selected from thiazolyl, thiadiazolyl and pyrazolyl;

R² is -CONR⁴R⁵; R⁴ and R⁵ together with the nitrogen to which they are attached form an azetidinyl ring which ring is optionally substituted on a carbon atom by hydroxy;

R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, aminomethyl, Kf- methylaminomethyl, and dimethylaminomethyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0;

HET-1 is selected from thiazolyl, thiadiazolyl and pyrazolyl; R² is -CONR⁴R⁵;

R⁴ and R⁵ together with the nitrogen to which they are attached form a 7-membered ring HET-

3 which ring is optionally substituted on a carbon or nitrogen atom by methyl;

R is selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, aminomethyl, N- methylaminomethyl, and dimethylaminomethyl; or a salt, pro-drug or solvate thereof. hi a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0; HET-1 is selected from thiazolyl, thiadiazolyl and pyrazolyl;

R² is -CONR⁴R⁵;

R⁴ and R⁵ together with the nitrogen to which they are attached form a 6-10 membered bicyclic heterocyclic ring HET-3; R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, aminomethyl, N- methylaminomethyl, and dimethylaminomethyl; or a salt, pro-drug or solvate thereof. hi a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; is 1 and n is 0 or 1;

HET-1 is a 5- or 6-membered heteroaryl ring;

R² is -S(O)pR⁴; p is 1 or 2;

R³ is halo or trifluoromethyl;

HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from

R⁷) and -C(O)NR⁵R⁵]; R⁵is hydrogen or methyl;

R¹ is methoxymethyl; m is 1 and n is 0 or 1 ;

HET-1 is a 5- or 6-membered heteroaryl ring; R² is -S(O)pR⁴; p is 1 or 2;

R³ is halo or trifluoromethyl;

R⁵is hydrogen or methyl;

R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; HET-2 is a 5- or 6- membered heterocyclyl ring as hereinbefore defined, containing 1 or 2 heteroatoms independently selected from O, N and S; and

R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. h a further aspect ofthe invention is provided a compound ofthe fonnula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1 ;

R² is -S(O)pR⁴; p is 1 or 2;

R is halo or trifluoromethyl;

R⁵is hydrogen or methyl;

HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidinyl, piperazinyl, 3- oxopiperazinyl, thiomorpholinyl, pynolidinyl, pyrrolidonyl, 2,5-dioxopyrrolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4- dioxoimidazolidinyl, pyranyl and 4-pyridonyl; and

R² is -S(O)pR⁴; p is 1 or 2; R³ is halo or trifluoromethyl;

(optionally substituted with 1 group selected from R⁷) and HET-2;

HET-2 is selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pynolyl,

1,2,4-triazolyl and 1,2,3-triazolyl; and R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1;

HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R² is -S(O)pR⁴; p is 1 or 2;

HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl and -C(O)NR⁵R⁵];

R⁵is hydrogen or methyl;

R is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidinyl, piperazinyl, 3- oxopiperazinyl, thiomorpholinyl, pyrrolidinyl, pyrrolidonyl, 2,5-dioxopyrrolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4- dioxoimidazolidinyl, pyranyl and 4-pyridonyl; and R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherem R¹ is methoxymethyl; m is 1 and n is 0 or 1;

HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R² is -S(O)pR⁴; p is 1 or 2;

R is halo or trifluoromethyl;

R⁴ is selected from hydrogen, (l-4C)alkyl, [optionally substituted by -OR⁵], (3-6C)cycloa,lkyl

(optionally substituted with 1 group selected from R⁷) and HET-2;

R¹ is methoxymethyl; m is 1 and n is 0 or 1 ;

R² is -S(O)pR⁴; p is 1 or 2; R is halo or trifluoromethyl;

R⁴ is (l-4C)alkyl;

R is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R² is -S(O)pR⁴; p is 1 or 2;

R⁴ is (l-4C)alkyl; R⁶ is methyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe fonnula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0;

HET-1 is selected from thiazolyl, thiadiazolyl and pyrazolyl;

R² is -S(O)pR⁴; p is 1 or 2;

R⁴ is (3-6C)cycloalkyl; R⁶ is methyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1;

HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R² is -S(O)pR⁴; p is 1 or 2;

R³ is halo or trifluoromethyl; R⁴ is (l-4C)alkyl;

R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1;

HET-1 is a 5- or 6-membered heteroaryl ring; R² is HET-2;

R is halo or tnfluoromethyl;

R⁵ is hydrogen or (l-4C)alkyl;

R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. hi a further aspect ofthe invention is provided a compound ofthe fonnula (I) as hereinbefore defined wherein R¹ is methoxymethyl; m is 1 and n is 0 or 1;

R² is HET-2; R is halo or trifluoromethyl;

R⁵ is hydrogen or methyl;

HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidinyl, piperazinyl, 3- oxopiperazinyl, thiomorpholinyl, pyrrolidinyl, pyrrolidonyl, 2,5-dioxopyrrolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4- dioxoimidazolidinyl, pyranyl and 4-pyridonyl; and

R¹ is methoxymethyl; m is 1 and n is 0 or 1;

HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl; R² is HET-2;

R³ is halo or trifluoromethyl;

R⁵ is hydrogen or methyl; HET-2 is selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pynolyl,

1,2,4-triazolyl and 1,2,3-triazolyl; and

R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a fiirther aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1; HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R² is HET-2;

R³ is halo or trifluoromethyl;

R⁵ is hydrogen or methyl;

HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidinyl, piperazinyl, 3- oxopiperazinyl, thiomorpholinyl, pyrrolidinyl, pynolidonyl, 2,5-dioxopynolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4- dioxoimidazolidinyl, pyranyl and 4-pyridonyl; and

R¹ is methoxymethyl; m is 1 and n is O or 1; HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R² is HET-2;

R³ is halo or trifluoromethyl;

R⁵ is hydrogen or methyl;

HET-2 is selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, 1,2,4-triazolyl and 1,2,3-triazolyl; and

R⁷ is selected from -OR⁵ and (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a fiirther aspect ofthe invention is provided a compound ofthe formula (1) as hereinbefore defined wherein

R² is HET-2;

R³ is halo or trifluoromethyl;

HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidinyl, piperazinyl, 3- oxopiperazinyl, thiomorpholinyl, pyrrolidinyl, pyπolidonyl, 2,5-dioxopynolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4- dioxoimidazolidinyl, pyranyl and 4-pyridonyl; and

R⁷ is (l-4C)alkyl; or a salt, pro-drug or solvate thereof. h a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein R¹ is methoxymethyl; m is 1 and n is 0 or 1;

R² is HET-2; R³ is halo or trifluoromethyl;

HET-2 is selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pynolyl, 1,2,4-triazolyl and 1,2,3-triazolyl; and

R⁷ is (l-4C)alkyl; or a salt, pro-drug or solvate thereof. fri a further aspect ofthe invention is provided a compound ofthe fonnula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1 ; HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R² is HET-2;

R is halo or trifluoromethyl;

R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl; HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidinyl, piperazinyl, 3- oxopiperazinyl, thiomorpholinyl, pynolidinyl, pyrrolidonyl, 2,5-dioxopyrrolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4- dioxoimidazolidinyl, pyranyl and 4-pyridonyl; and R⁷ is (l-4C)alkyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 1 and n is 0 or 1;

HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R² is HET-2;

R³ is halo or trifluoromethyl;

1,2,4-triazolyl and 1,2,3-triazolyl; and

R¹ is methoxymethyl; m is 0 or 1 and n is 0, 1 or 2;

HET-1 is selected from thiazolyl, pyrazolyl, N-methylpyrazol-3-yl, N-ethylpyrazol-3yl, 5- methylpyrazol-3-yl, 4-methylthiazol-2-yl, 5-methylthiazol-2-yl, 5-methyl-l,3,4-thiadiazol-2- yl, 4-methyl-l,3,5-thiadiazol-2-yl, 4-hydroxymethylthiazol-2-yl, 4-methoxymethylthiazol-2-yl and 5-bromopyridin-2-yl;

R³ is selected from chloro, fluoro and trifluoromethyl;

R² is selected from azetidinylcarbonyl, methoxyethylaminocarbonyl, imidazolylmethylaminocarbonyl, N-methylpiperidin-4-ylaminocarbonyl, N-methylpiperazin-

4-ylcarbonyl, dimethylaminocarbonyl, morpholinocarbonyl, pynolidinylcarbonyl, 7- azabicyclo[2.2.1]hept-7-ylcarbonyl, dimethylaminosulfonyl, moφholinosulfonyl, isopropylaminosulfonyl, aminosulfonyl, N-methylpiperazin-4-ylsulfonyl, methoxyethylaminosulfonyl, cyano, ethylsulfonyl, methylsulfonyl, methylthio, methylsulfmyl, isopropylthio and isopropylsulfonyl; or a salt, pro-drug or solvate thereof. In a further aspect ofthe invention is provided a compound ofthe formula (I) as hereinbefore defined wherein

R¹ is methoxymethyl; m is 0 or 1 and n is 0, 1 or 2;

HET-1 is selected from thiazolyl, pyrazolyl, N-methylpyrazol-3-yl, N-ethylpyrazol-3yl, 5- methylpyrazol-3-yl, 4-methylthiazol-2-yl, 5-methylthiazol-2-yl, 5-methyl-l,3,4-thiadiazol-2- yl, 4-methyl-l,3,5-thiadiazol-2-yl, 4-hydroxymethylthiazol-2-yl, 4-methoxyιnethylthiazol-2-yl and 5-bromopyridin-2-yl;

R³ is selected from chloro, fluoro, methoxy and trifluoromethyl;

4-ylcarbonyl, dimethylaminocarbonyl, morpholinocarbonyl, pyrrolidinylcarbonyl, 7- azabicyclo[2.2. l]hept-7-ylcarbonyl, dimethylaminosulfonyl, moφholinosulfonyl, isopropylaminosulfonyl, aminosulfonyl, N-methylpiperazin-4-ylsulfonyl, methoxyethylaminosulfonyl, cyano, ethylsulfonyl, methylsulfonyl, methylthio, methylsulfmyl, isopropylthio and isopropylsulfonyl; or a salt, pro-drug or solvate thereof. Further prefened compounds ofthe invention are each ofthe Examples, each of which provides a further independent aspect ofthe invention, hi further aspects, the present invention also comprises any two or more compounds ofthe Examples. In one aspect, particular compounds ofthe invention comprise any one or more of: 3-(4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-

N- 1 ,3-thiazol-2-ylbenzamide;

3-(4-{[(lH-imidazol-2-ylmethyl)amino]carbonyl}phenoxy)-5-[(lS)-2-methoxy-(l- methylethyl)oxy] -N- 1 ,3 -thiazol-2-ylbenzamide;

3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-l,3-thiazol- 2-ylbenzamide;

3-[(l S)-2-methoxy-(l -methylethyl)oxy]-5- {4-[(4-methylpiperazin-l -yl)carbonyl]phenoxy} -N-

1 ,3-thiazol-2-ylbenzamide;

3-(3-{[(2-methoxyethyl)amino]carbonyl}phenoxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-

N- 1 ,3 -thiazol-2-ylbenzamide; 3-(3-{[(lH-imidazol-2-ylmethyl)amino]carbonyl}phenoxy)-5-[(lS)-2-methoxy-(l- methylethyl)oxy]-N- 1 ,3-thiazol-2-ylbenzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-{4-[(4-methylpiperazin-l-yl)carbonyl]phenoxy}-N-

(1 -methyl- 1 H-pyrazol-3 -yl)benzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[4-(moφholin-4- ylcarbonyl)phenoxy]benzamide;

3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-

1 H-pyrazol-3 -yDbenzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[4-(pyrrolidin-l- ylcarbonyl)phenoxy]benzamide; 3-[4-(7-azabicyclo[2.2.1]heρt-7-ylcarbonyl)ρhenoxy]-5-[(lS)-2-methoxy-(l- methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide;

3-{2-chloro-4-[(dimethylamino)sulfonyl]phenoxy}-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-

N-(l-methyl-lH-pyrazol-3-yl)benzamide;

3-[(2-chloro-4-{[(l-methylethyl)amino]sulfonyl}phenyl)oxy]-5-[(lS)-2-methoxy-(l- methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide;

3-{[2-chloro-4-({[2-(methyloxy)ethyl]amino}sulfonyl)phenyl]oxy}-5-[(lS)-2-methoxy-(l- methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide; 3-( {2-chloro-4-[(4-methylpiρerazin-l -yl)sulfonyl]phenyl} oxy)-5-[(l S)-2-methoxy-(l - methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide;

3- {4-[(dimethylamino)sulfonyl]phenoxy} -5-[(l S)-2-methoxy-(l -methylethyl)oxy]-N-(l - methyl-lH-pyrazol-3-yl)benzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-({4-[(4-methylpiperazin-l-yl)sulfonyl]phenyl}oxy)-

N-( 1 -methyl- 1 H-pyrazol-3 -yl)benzamide;

3- {4-[((l -methylethyl)amino)sulfonyl]phenoxy} -5-[(l S)-2-methoxy-(l-methylethyl)oxy]-N-

(l-methyl-lH-pyrazol-3-yl)benzamide;

3-(4-{[(2-methoxyethyl)amino]sulfonyl}phenoxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N- (1 -methyl-lH-pyrazol-3-yl)benzamide;

3-(4-cyanophenoxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3- yl)benzamide;

3 - { [4-(aminocarbonyl)phenyl] oxy} -5-[( 1 S)-2-methoxy-( 1 -methylethyl)oxy]-N-(l -methyl- 1 H- pyrazol-3-yl)benzamide; 3-[4-(ethylsulfonyl)phenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-l,3-thiazol-2- ylbenzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-{[3-

(methylthio)phenyl]oxy}benzamide;

3-({4-[(l-methylethyl)thio]phenyl}oxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl- lH-pyrazol-3-yl)benzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[3-

(methylsulfonyl)phenoxy]benzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[3-

(methylsulfmyl)phenoxy]benzamide; 3-({4-[(l-methylethyl)sulfonyl]phenyl}oxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l- methyl-lH-pyrazol-3-yl)benzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[4-

(methylsulfonyl)phenoxy]benzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-N-l,3-thiazol-2- ylbenzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-N-(4-methyl-l,3- thiazol-2-yl)benzamide; 3 - [( 1 S )-2-methoxy-( 1 -methylethyl)oxy] -5 - [4-(methylsulfonyl)phenoxy] -N-(5 -methyl- 1,3- thiazol-2-yl)benzamide;

3 - [( 1 )-2-methoxy-( 1 -methylethyl)oxy] -5 - [4-(methylsulfonyl)phenoxy] -N-(5 -methyl- 1,3,4- thiadiazol-2-yl)benzamide; 3 - [( 1 S )-2-methoxy-( 1 -methylethyl)oxy] -5- [4-(methylsulfonyl)phenoxy] -N-(3 -methyl- 1 ,2,4- thiadiazol-5-yl)benzamide;

N-(l-ethyl-lH-pyrazol-3-yl)-3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-[4-

(methylsulfonyl)phenoxy]benzamide;

3-(3,5-difluorophenoxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3- yl)benzamide;

N-(5-bromopyridin-2-yl)-3-(3,5-difluorophenoxy)-5-[(lS)-2-methoxy-(l- methylethyl)oxy]benzamide;

3-(3,5-difluorophenoxy)-N-[4-(hydroxymethyl)-l,3-thiazol-2-yl]-5-[(lS)-2-methoxy-(l- methylethyl)oxy]benzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(5-methyl-lH-pyrazol-3-yl)-5-[4-

(methylsulfonyl)phenoxy]benzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-[4-(methoxymethyl)-l,3-thiazol-2-yl]-5-[4-

(methylsulfonyl)phenoxy]benzamide;

3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(3-methyl- l,2,4-thiadiazol-5-yl)benzamide ;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-(4-{[(l-methylpiperidin-4- yl)amino]carbonyl}phenoxy)-N-(3-methyl-l,2,4-thiadiazol-5-yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)-2-chlorophenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l- methyl- lH-pyrazol-3-yl)benzamide; 3-[4-(azetidin-l-ylcarbonyl)-2-fluorophenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l- methyl-lH-pyrazol-3-yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)-2-(trifluoromethyl)phenoxy]-5-[(lS)-2-methoxy-(l- methylethyl)oxy] -N-(l -methyl- 1 H-pyrazol-3 -yl)benzamide; and

3-{4-[(dimethylamino)carbonyl]phenoxy}-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l- methyl- 1 H-pyrazol-3 -yDbenzamide; and/or is selected from

3 - {4-[ (dimethylamino)carbonyl]phenoxy } - 5 - [(1 S)-2-methoxy- 1 -methylethoxy]-N- 1 H- pyrazo 1-3 -ylb enzamide; 3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-lH-pyrazol-3- ylbenzamide;

3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-lH-pyrazol-3- ylbenzamide; 3-[2-fluoro-4-(methylsulfonyl)phenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-lH-pyrazol-

3-ylbenzamide;

3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-(l-methyl-lH- pyrazol-3-yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)-2-fluorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-(5- methyl-lH-pyrazol-3-yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)-2-fluorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-lH- pyrazol-3-ylbenzamide;

3-{4-[(dimethylamino)carbonyl]phenoxy}-5-[(lS)-2-methoxy-l-methylethoxy]-N-(3-methyl-

1 ,2,4-thiadiazol-5-yl)benzamide; 2-nιethoxy-4-(3 -[( 1 S)-2 -methoxy- 1 -methylethoxy] -5- { [( 1 -methyl- 1 H-pyrazol-3 - yl)amino]carbonyl}phenoxy)-N-methylbenzamide;

2-methoxy-4-(3-[(lS)-2-methoxy-l-methylethoxy]-5-{[(l-methyl-lH-pyrazol-3- yl)amino]carbonyl}phenoxy)-N,N-dimethylbenzamide;

3-fluoro-4-{3-[(lS)-2-methoxy-l-methylethoxy]-5-[(lH-pyrazol-3- ylamino)carbonyl]phenoxy} -N,N-dimethylbenzamide;

3- {4-[(dimethylamino)carbonyl]phenoxy}-5-[(lS)-2-methoxy-l-methylethoxy]-N-(5-methyl- lH-pyrazol-3-yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)-2-chlorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-(5- methyl-lH-pyrazol-3-yl)benzamide; 3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-(5-methyl-lH- pyrazol-3-yl)benzamide; and

3-[(lS)-2-methoxy-l-methylethoxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[4-(l,2,4-oxadiazol-3- yl)phenoxy]benzamide; or a salt, pro-drug or solvate thereof. In another aspect, particular compounds ofthe invention comprise any one or more of:

3-(4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-

N- 1 ,3 -thiazol-2-ylbenzamide; 3-(4-{[(lH-imidazol-2-ylmethyl)amino]carbonyl}phenoxy)-5-[(lS)-2-methoxy-(l- methylethyl)oxy]-N-l,3-thiazol-2-ylbenzamide;

3-(3 - { [(2-methoxyethyl)amino] carbonyl}phenoxy)-5-[( 1 S)-2-methoxy-( 1 -methylethyl)oxy] -

N- 1 ,3 -thiazol-2-ylbenzamide; 3-(3-{[(lH-imidazol-2-ylmethyl)amino]carbonyl}phenoxy)-5-[(lS)-2-methoxy-(l- methylethyl)oxy] -N- 1 ,3 -thiazol-2-ylbenzamide;

3-{[2-chloro-4-({[2-(methyloxy)ethyl]amino}sulfonyl)phenyl]oxy}-5-[(lS)-2-methoxy-(l- methylethyl)oxy] -N-(l -methyl- 1 H-pyrazol-3 -yl)benzamide;

3-(4-{[(2-methoxyethyl)amino]sulfonyl}phenoxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N- (1 -methyl- 1 H-pyrazol-3 -yl)benzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-(4-{[(l-methylpiperidin-4- yl)amino]carbonyl}phenoxy)-N-(3-methyl-l,2,4-thiadiazol-5-yl)benzamide; or a salt, pro-drug or solvate thereof. In another aspect, particular compounds ofthe invention comprise any one or more of: 3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-l,3-thiazol-

2-ylbenzamide;

1 ,3 -thiazol-2-ylbenzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-{4-[(4-methylpiperazin-l-yl)carbonyl]phenoxy}-N- (1 -methyl- lH-pyrazol-3-yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl- lH-pyrazol-3 -yl)benzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[4-(pyιτolidin-l- ylcarbonyl)phenoxy]benzamide;

3-[4-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-(l- methylethyl)oxy] -N-(l -methyl- 1 H-pyrazol-3 -yl)benzamide;

3-( {2-chloro-4-[(4-methylpiperazin- 1 -yl)sulfonyl]phenyl} oxy)-5-[(l S)-2-methoxy-(l - methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide;

3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-({4-[(4-methylpiperazin-l-yl)sulfonyl]phenyl}oxy)-

N-(l-methyl-lH-pyrazol-3-yl)benzamide; 3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(3-methyl-

1 ,2,4-thiadiazol-5-yl)benzamide;

3-[4-(azetidin- 1 -ylcarbonyl)-2-chlorophenoxy]-5-[(l S)-2-methoxy-(l -methylethyl)oxy]-N-(l - methyl- 1 H-pyrazol-3 -yl)benzamide; 3-[4-(azetidin- 1 -ylcarbonyl)-2-fluorophenoxy] -5-[( 1 S)-2-methoxy-( 1 -methylethyl)oxy] -N-( 1 - methyl- lH-pyrazol-3 -yl)benzamide;

3-[4-(azetidin- 1 -ylcarbonyl)-2-(trifluoromethyl)phenoxy]-5 -[(1 S)-2-methoxy-(l - methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide;

3 - [4-(azetidin- 1 -ylcarbonyl)phenoxy] -5 - [( 1 S)-2-me fhoxy- 1 -methylethoxy] -N- 1 H-pyrazol-3 - ylbenzamide;

3-[4-(azetidin-l-ylcarbonyl)-2-chlorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-(5- methyl- lH-pyrazol-3 -yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)-2-fluorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-(5- methyl- lH-pyrazol-3 -yl)benzamide; 3-[4-(azetidin- 1 -ylcarbonyl)-2-fluorophenoxy]-5-[(l S)-2-methoxy- 1 -methylethoxy] -N-1 H- pyrazol-3-ylbenz amide;

3 - [4-(azetidin- 1 -ylcarbonyl)phenoxy] -5 - [( 1 S)-2-methoxy- 1 -methylethoxy] -N-(5-methyl- 1 H- pyrazol-3-yl)benz amide; or a salt, pro-drug or solvate thereof. In another aspect, particular compounds ofthe invention comprise any one or more of:

3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-l,3-thiazol-

2-ylbenzamide;

3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl- lH-pyrazol-3-yl)benzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[4-(pyrrolidin-l- ylcarbonyl)phenoxy]benz amide;

3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(3-methyl-

1 ,2,4-thiadiazol-5-yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)-2-chlorophenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l- methyl-lH-pyrazol-3-yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)-2-fluorophenoxy]-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l- methyl-lH-pyrazol-3-yl)benzamide; 3 - [4-(azetidin- 1 -ylcarbonyl)-2-(trifluoromethyl)phenoxy] -5 - [( 1 S)-2-methoxy-( 1 - methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)phenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-lH-pyrazol-3- ylbenzamide; 3-[4-(azetidin-l-ylcarbonyl)-2-chlorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-(5- methyl-lH-pyrazol-3-yl)benzamide;

3-[4-(azetidin-l-ylcarbonyl)-2-fluorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-(5- methyl-lH-ρyrazol-3-yl)benzamide;

3-[4-(azetidin- 1 -ylcarbonyl)phenoxy]-5-[(l S)-2-methoxy- 1 -methylethoxy] -N-(5 -methyl- 1H- pyrazol-3 -yl)benzamide; or a salt, pro-drug or solvate thereof. In another aspect, particular compounds ofthe invention comprise any one or more of: 2-methoxy-4-(3-[(lS)-2-methoxy-l-methylethoxy]-5-{[(l-methyl-lH-pyrazol-3- yl)amino] carbonyl} phenoxy)-N-methylbenzamide;

2-methoxy-4-(3-[(lS)-2-methoxy-l-methylethoxy]-5-{[(l-methyl-lH-pyrazol-3- yl)amino]carbonyl}phenoxy)-N,N-dimethylbenzamide; or a salt, pro-drug or solvate thereof. In another aspect, particular compounds ofthe invention comprises

3-[(lS)-2-methoxy-l-methylethoxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[4-(l,2,4-oxadiazol-3- yl)phenoxy]benzamide; or a salt, pro-drug or solvate thereof. In another aspect, particular compounds ofthe invention comprise any one or more of: 3-{2-chloro-4-[(dimethylamino)sulfonyl]phenoxy}-5-[(lS)-2-methoxy-(l-metlιylethyl)oxy]-

N-(l -methyl- 1 H-pyrazol-3 -yl)benzamide;

3-[(2-chloro-4-{[(l-methylethyl)amino]sulfonyl}phenyl)oxy]-5-[(lS)-2-methoxy-(l- methylethyl)oxy] -N-(l -methyl- 1 H-pyrazol-3 -yl)benzamide;

3-{4-[(dimethylamino)sulfonyl]phenoxy}-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l- methyl- 1 H-pyrazol-3 -yl)benzamide;

3-{4-[((l-methylethyl)amino)sulfonyl]phenoxy}-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-

(l-methyl-lH-pyrazol-3-yl)benzamide; 3-(4-cyanophenoxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3- yl)benzamide; 3-{[4-(aminocarbonyl)phenyl]oxy}-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH- pyrazol-3-yl)benzamide; 3 - [4-(ethylsulfonyl)phenoxy] -5 - [ ( 1 S)-2-methoxy-( 1 -methylethyl)oxy] -N- 1 ,3 - thiazol-2- ylbenzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-{[3- (methylthio)phenyl] oxy} benzamide; 3-( {4-[(l -methylethyl)thio]phenyl} oxy)-5-[(l S)-2-methoxy-(l -methylethyl)oxy]-N-(l -methyl- 1 H-pyrazol-3 -yl)benzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[3- (methylsulfonyl)phenoxy]benzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[3- (methylsulfinyl)phenoxy]benzamide; 3-({4-[(l-methylethyl)sulfonyl]phenyl}oxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l- methyl- 1 H-pyrazol-3 -yDbenzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-[4- (methylsulfonyl)phenoxy]benzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-N-l,3-thiazol-2- ylbenzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-N-(4-methyl-l,3- thiazol-2-yl)benzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-N-(5-methyl-l,3- thiazol-2-yl)benzamide; 3-[(l S)-2-methoxy-(l-methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-N-(5-methyl-l ,3,4- thiadiazol-2-yl)benzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-N-(3-methyl-l,2,4- thiadiazol-5-yl)benzamide; N-(l-ethyl-lH-pyrazol-3-yl)-3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-[4- (methylsulfonyl)phenoxy]benzamide; 3-(3,5-difluorophenoxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3- , yl)benzamide; N-(5-bromopyridin-2-yl)-3-(3,5-difluorophenoxy)-5-[(lS)-2-methoxy-(l- methylethyl)oxy]benzamide;

3-(3,5-difluorophenoxy)-N-[4-(hydroxymethyl)-l,3rthiazol-2-yl]-5-[(lS)-2-methoxy-(l- methylethyl)oxy]benzamide; 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(5-methyl-lH-pyrazol-3-yl)-5-[4-

(methylsulfonyl)phenoxy]benzamide;

3-{4-[(dimethylamino)carbonyl]phenoxy}-5-[(lS)-2-methoxy-l-methylethoxy]-N-(3-methyl- 1 ,2,4-thiadiazol-5-yl)benzamide;

3- {4-[(dimethylamino)carbonyl]phenoxy} -5-[(l S)-2-methoxy-(l -methylethyl)oxy]-N-(l - methyl-lH-pyrazol-3-yl)benzamide;

3-{4-[(dimethylamino)carbonyl]phenoxy}-5-[(lS)-2-methoxy-l-methylethoxy]-N-lH- pyrazol-3-ylbenzamide; 3-fluoro-4-{3-[(lS)-2-methoxy-l-methylethoxy]-5-[(lH-pyrazol-3- ylamino)carbonyl]phenoxy}-N,N-dimethylbenzamide;

3 - {4- [(dimethylamino)carbonyl]phenoxy} -5 - [( 1 S)-2-methoxy- 1 -methylethoxy] -N-(5 -methyl-

1 H-pyrazol-3 -yl)benzamide;

3-[4-(Ethylsulfonyl)-2-fluorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-lH-pyrazol-3- ylbenzamide;

3 - [2-fluoro-4-(methylsulfonyl)phenoxy] -5 - [( 1 S)-2-methoxy- 1 -methylethoxy] -N- 1 H-pyrazol-

3-ylbenzamide;

3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]-N-(l-methyl-lH- pyrazol-3-yl)benzamide; or a salt, pro-drug or solvate thereof.

The compounds of the invention may be administered in the form of a pro-drug. A pro-drug is a bioprecursor or pharmaceutically acceptable compound being degradable in the body to produce a compound ofthe invention (such as an ester or amide of a compound ofthe invention, particularly an in-vivo hydrolysable ester). Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and-Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen; c) H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and f) N. Kakeya, et al, Chem Pharm Bull, 32, 692 (1984).

The contents ofthe above cited documents are incoφorated herein by reference. Examples of pro-drugs are as follows. An in-vivo hydrolysable ester of a compound ofthe invention containing a carboxy or a hydroxy group is, for example, a pharmaceutically- acceptable ester which is hydro lysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include C_\ to C₆alkoxymethyl esters for example methoxymethyl, Ci to C ₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C₃ to CscycloalkoxycarbonyloxyCi to C₆alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl- l,3-dioxolen-2-onylmethyl; and C_1-6alkoxycarbonyloxyethyl esters. An in-vivo hydrolysable ester of a compound ofthe mvention containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result ofthe in-vivo hydrolysis ofthe ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. A suitable pharmaceutically-acceptable salt of a compound ofthe invention is, for example, an acid-addition salt of a compound ofthe invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a benzoxazinone derivative ofthe mvention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, moφholine or tris-(2-hydroxyethyl)amine. A further feature ofthe invention is a pharmaceutical composition comprising a compound of Formula (I) as defined above, or a salt, solvate or prodrug thereof, together with a pharmaceutically-acceptable diluent or carrier. According to another aspect ofthe invention there is provided a compound of Formula (I) as defined above for use as a medicament. Further according to the invention there is provided a compound of Formula (I) for use in the preparation of a medicament for treatment of a disease mediated tlirough GLK, in particular type 2 diabetes. The compound is suitably formulated as a phannaceutical composition for use in this way. According to another aspect of he present invention there is provided a method of treating GLK mediated diseases, especially diabetes, by administering an effective amount of a compound of Formula (I) or salt, solvate or pro-drug thereof, to a mammal in need of such treatment. Specific diseases which may be treated by a compound or composition ofthe invention include: blood glucose lowering in type 2 Diabetes Mellitus without a serious risk of hypoglycaemia (and potential to treat type 1), dyslipidemia, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance. As discussed above, thus the GLK/GLKRP system can be described as a potential "Diabesity" target (of benefit in both Diabetes and Obesity). Thus, according to another aspect ofthe invention there if provided the use of a compound of Formula (I) or salt, solvate or pro-drug thereof, in the preparation of a medicament for use in the combined treatment or prevention of diabetes and obesity. According to another aspect ofthe invention there if provided the use of a compound of Formula (I) or salt, solvate or pro-drug thereof, in the preparation of a medicament for use in the treatment or prevention of obesity. According to a further aspect ofthe invention there is provided a method for the combined treatment of obesity and diabetes by administering an effective amount of a compound of Formula (I) or salt, solvate or pro-drug thereof, to a mammal in need of such treatment. According to a further aspect ofthe invention there is provided a method for the treatment of obesity by administering an effective amount of a compound of Fonnula (1) or salt, solvate or pro-drug thereof, to a mammal in need of such treatment. The compositions ofthe invention maybe in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). Dosage forms suitable for oral use are prefened. The compositions ofthe invention maybe obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absoφtion ofthe active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pynolidone, gum fragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present. The pharmaceutical compositions ofthe invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occuπing gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products ofthe said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more ofthe appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently ananged to dispense a metered quantity of active ingredient. For further infonnation on formulation the reader is refened to Chapter 25.2 in Volume

5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight ofthe total composition. Dosage unit fonns will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is refened to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The size ofthe dose for therapeutic or prophylactic purposes of a compound ofthe Formula (I) will naturally vary according to the nature and severity ofthe conditions, the age and sex ofthe animal or patient and the route of administration, according to well known principles of medicine. In using a compound ofthe Formula (I) for therapeutic or prophylactic puφoses it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Oral administration is however prefened. The elevation of GLK activity described herein may be applied as a sole therapy or in combination with one or more other substances and/or treatments for the indication being treated. Such conjoint treatment may be achieved by way ofthe simultaneous, sequential or separate administration of the individual components of the treatment. Simultaneous treatment may be in a single tablet or in separate tablets. For example in the treatment of diabetes mellitus, chemotherapy may include the following main categories of treatment: 1) Insulin and insulin analogues; 2) Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide), prandial glucose regulators (for example repaglinide, nateglinide) ; 3) Agents that improve incretin action (for example dipeptidyl peptidase IV inhibitors, and GLP-1 agonists); 4) Insulin sensitising agents including PPARgamma agonists (for example pioglitazone and rosiglitazone), and agents with combined PPARalpha and gamma activity; 5) Agents that modulate hepatic glucose balance (for example metformin, fructose 1, 6 bisphosphatase inhibitors, glycogen phopsphorylase inhibitors, glycogen synthase kinase inhibitors); 6) Agents designed to reduce the absoφtion of glucose from the intestine (for example acarbose); 7) Agents that prevent the reabsoφtion of glucose by the kidney (SGLT inhibitors); 8) Agents designed to treat the complications of prolonged hyperglycaemia (for example aldose reductase inhibitors); 9) Anti-obesity agents (for example sibutramine and orlistat); 10) Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (eg statins); PPARα agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyrarnine); cholesterol absoφtion inhibitors (plant stanols, synthetic inhibitors); bile acid absoφtion inhibitors (IJBATi) and nicotinic acid and analogues (niacin and slow release formulations); 11) Antihypertensive agents such as, β bloc ers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine); Angiotensin receptor antagonists (eg candesartan), α antagonists and diuretic agents (eg. furosemide, benzthiazide); 12)Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor Vila inl ibitors); antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin; 13) Agents which antagonise the actions of glucagon; and 14) Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone).

According to another aspect ofthe present invention there is provided individual compounds produced as end products in the Examples set out below and salts, solvates and pro-drugs thereof. A compound ofthe invention, or a salt thereof, may be prepared by any process known to be applicable to the preparation of such compounds or structurally related compounds.

Functional groups maybe protected and deprotected using conventional methods. For examples of protecting groups such as amino and carboxylic acid protecting groups (as well as means of formation and eventual deprotection), see T.W. Greene and P.G.M. Wuts,

"Protective Groups in Organic Synthesis", Second Edition, John Wiley & Sons, New Υork,

1991. Processes for the synthesis of compounds of Formula (I) are provided as a further feature ofthe invention. Thus, according to a further aspect ofthe invention there is provided a process for the preparation of a compound of Fonnula (I), which comprises a process a) to d) (wherein the variables are as defined hereinbefore for compounds of Formula (I) unless otherwise defined): (a) reaction of an acid of Formula (ITT) or activated derivative thereof with a compound of Formula (IV),

(HI) (IV); or

(b) reaction of a compound of Formula (V) with a compound of Formula (VI),

(V) (VI) 1 1 wherein X is a leaving group and X is a hydroxyl group or X is a hydroxyl group and X² is a leaving group; process (b) could also be accomplished using the intermediate ester Formula (VII), wherein P¹ is a protecting group as hereinafter described, followed by ester hydrolysis and amide formation by procedures described elsewhere and well known to those skilled in the art;

(V) CVTJ) or

(c) reaction of a compound of Formula (VIII) with a compound of Formula (IX)

(vπo (IX) wherein X³ is a leaving group or an organometallic reagent and X⁴ is a hydroxyl group or X³ is a hydroxyl group and X⁴ is a leaving group or an organometallic reagent; process (c) could also be accomplished using the intermediate ester Formula (X), followed by ester hydrolysis and amide formation by procedures described elsewhere and well known to those skilled in the art; or

(VUJ) (X)

(d) reaction of a compound of Formula (XI) with a compound of Formula (XII),

(XI) (XI!); wherein X⁵ is a leaving group; and thereafter, if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a salt, pro-drug or solvate thereof. Suitable leaving groups X¹ to X⁵ for processes b) to d) are any leaving group known in the art for these types of reactions, for example halo, alkoxy, trifluoromethanesulfonyloxy, methanesulfonyloxy, or p-toulenesulfonyloxy; or a group (such as a hydroxy group) that may be converted into a leaving group (such as an oxytriphenylphosphonium group) in situ. Compounds of Formulae (HI) to (XII) are commercially available, or are known in the art, or may be made by processes known in the art as shown, for example, in the accompanying Examples. For further information on processes for making such compounds, we refer to our PCT publications WO 03/000267, WO 03/015774 and WO 03/000262 and references therein. In general it will be appreciated that any aryl-O or alkyl-O bond may be formed by nucleophilic substitution or metal catalysed processes, optionally in the presence of a suitable base. Examples of conversions of a compound of Formula (I) into another compound of

Formula (I), well known to those skilled in the art, include functional group interconversions such as hydrolysis, hydrogenation, hydrogenolysis, oxidation or reduction, and/or further functionalisation by standard reactions such as amide or metal-catalysed coupling, or nucleophilic displacement reactions; Specific reaction conditions for the above reactions are as follows, wherein when P¹ is a protecting group P¹ is preferably C_1-4alkyl, for example methyl or ethyl: Process a) — coupling reactions of amino groups with carboxylic acids to form an amide are well known in the art. For example, (i) using an appropriate coupling reaction, such as a carbodiimide coupling reaction performed with EDAC (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in the presence of dimethylammopyridine (DMAP) in a suitable solvent such as dichloromethane (DCM), chloroform or dimethylformamide (DMF) at room temperature; or (ii) reaction in which the carboxylic group is activated to an acid chloride by reaction with oxalyl chloride in the presence of a suitable solvent such as DCM. The acid chloride can then be reacted with a compound of Formula (IV) in the presence of a base, such as triethylamine or pyridine, in a suitable solvent such as chloroform or DCM at a temperature between 0°C and 80°C.

Process b) - compounds of Formula (V) and (VI) can be reacted together in a suitable solvent, such as DMF or tetrahydrofuran (THF), with a base such as sodium hydride or potassium tert-butoxide, at a temperature in the range 0 to 200°C, optionally using microwave heating or metal catalysis such as palladium(II)acetate, palladium on carbon, copper(IJ)acetate or copper(I)iodide; alternatively, compounds of Formula (V) and (VI) can be reacted together in a suitable solvent, such as THF or DCM, with a suitable phosphine such as triphenylphosphine, and azodicarboxylate such as diethylazodicarboxylate; process b) could also be carried out using a precursor to the ester of fonnula (VJJ) such as an aryl-nitrile or trifluoromethyl derivative, followed by conversion to a carboxylic acid and amide formation as previously described; Process c) - compounds of Formula (VET) and (IX) can be reacted together izri a suitable solvent, such as DMF or THF, with a base such as sodium hydride or potassium tert-butoxide, at a temperature in the range 0 to 200°C, optionally using microwave heating or metal catalysis such as palladium(II)acetate, palladium on carbon, copper(II)acetate= or copper(I)iodide; process c) could also be carried out using a precursor to the ester of formula (X) such as an aryl-nitrile or trifluoromethyl derivative, followed by conversi n to a carboxylic acid and amide formation as previously described;

Process d) - reaction of a compound of Formula (XI) with a compound of Formula (XU) can be performed in a polar solvent, such as DMF or a non-polar solvent such as THF with a strong base, such as sodium hydride or potassium tert-butoxide at a temperature between 0 and 200°C, optionally using microwave heating or metal catalysis, such as palladium(II)acetate, palladium on carbon, copper(IJ)acetate or copper(I)iodide. Certain intermediates of fonnula (IE), (VI), (VH), (IX) and/or (XI) are believed to be novel and comprise an independent aspect ofthe invention. Certain intermediates of formula (IJJ), (IX) and/or (XI) wherein R¹ is rrj ethoxymethyl are believed to be novel and comprise an independent aspect ofthe invention. During the preparation process, it may be advantageous to use a protecting group for a functional group within the molecule. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal ofthe protecting group in question, such methods being chosen so as to effect removal ofthe protecting group with minimum disturbance of groups elsewhere in the molecule. Specific examples of protecting groups are given below for the sake of convenience, in which "lower" signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Wliere specific examples of methods for the removal of protecting groups are given below these are simil arly not exhaustive. The use of protecting groups and methods of deprotection not sp> ecifically mentioned is of course within the scope ofthe invention. A carboxy protecting group maybe the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (e.g. isopropyl, t-butyl); lower alkoxy lower alkyl groups (e.g. methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphatic acylox;y lower alkyl groups, (e.g. acetoxymefhyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (e.g. 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (e.g. p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (e.g. trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (e.g. trimethylsilylethyl); and (2-6C)alkenyl groups (e.g. allyl and vinylethyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, metal- or enzymically-catalysed hydrolysis. Examples of hydroxy protecting groups include lower alkenyl groups (e.g. allyl); lower alkanoyl groups (e.g. acetyl); lower alkoxycarbonyl groups (e.g. t-butoxycarbonyl); lower alkenyloxycarbonyl groups (e.g. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g. benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (e.g. trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl); aryl lower alkyl groups (e.g. benzyl) groups; and triaryl lower alkyl groups (e.g. triphenylmethyl). Examples of amino protecting groups include formyl, aralkyl groups (e.g. benzyl and substituted benzyl, e.g. p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (e.g. t-butoxycarbonyl); lower alkenyloxycarbonyl (e.g. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (e.g. trimethylsilyl and t-butyldimethylsilyl); alkylidene (e.g. methylidene); benzylidene and substituted benzylidene groups. Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base, metal- or enzymically-catalysed hydrolysis, or photolytically for groups such as o-nitrobenzyloxycarbonyl, or with fluoride ions for silyl groups. Examples of protecting groups for amide groups include aralkoxymethyl (e.g. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (e.g. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (e.g. trimethylsilyl, t-butyldimethylsily, t- butyldiphenylsilyl); tri alkyl/arylsilyloxymethyl (e.g. t-butyldimethylsilyloxymethyl, t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (e.g. 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (e.g. 2,4-dimethoxyphenyl); 4-alkoxybenzyl (e.g. 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (e.g. 2,4-di(methoxy)benzyl); and alk-1-enyl (e.g. allyl, but-1-enyl and substituted vinyl e.g. 2- phenyl vinyl). Aralkoxymethyl, groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation. Alkoxymethyl, tri alkyl/arylsilyl and tri alkyl/silyloxymethyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid; or in the case ofthe silyl containing groups, fluoride ions. The alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with eerie ammonium nitrate. Finally alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid. The following examples are for illustration puφoses and are not intended to limit the scope of this application. Each exemplified compound represents a particular and independent aspect ofthe invention, hi the following non-limiting Examples, unless otherwise stated: (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration; (ii) operations were carried out at room temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon or nitrogen; (iii) yields are given for illustration only and are not necessarily the maximum attainable; (iv) the structures ofthe end-products ofthe Formula (I) were confirmed by nuclear (generally proton) magnetic resonance (NMR) with a field strength (for proton) of 300 or 400 MHz , and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet, quin, quintet; (v) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), high-perfoπnance liquid chromatography (HPLC), infra-red (IR) or NMR analysis; and (vi) Biotage cartridges refer to pre-packed silica cartridges (from 40g up to 400g), eluted using a biotage pump and fraction collector system; Biotage UK Ltd, Hertford, Herts, UK. Abbreviations DCM dichloromethane; DEAD diethylazodicarboxylate; DIAD diisopropylazodicarboxylate; DJREA NN-Diisopropylethylamine; DMSO dimethyl sulphoxide; DMA dimethylacetamide; DMF dimethylformamide; EDAC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

HATU O-(7-azabenzotriazol- 1 -yl)- 1 , 1 ,3 ,3-tetramethyluronium hexafluorophosphate;

HPLC high pressure liquid chromatography; HPMC Hydroxypropylmethylcellulose; LCMS liquid chromatography / mass spectroscopy; NMR nuclear magnetic resonance spectroscopy; RT room temperature; THF tetrahydrofuran.

All compound names were derived using ACD NAME computer package.

Example 1 : 3-(4-([(2-MethoxyethyI)amino1carbonyl}phenoxy)-5-(2-(lS -methoxy-(l- methylethyl)oxyVN-l,3-thiazol-2-ylbenzamide

To a suspension of 4-({3-{[(l)S)-2-methoxy-(l-methylethyl)oxy}-5-[(l,3-thiazol-2-ylamino) carbonyl] phenyl} oxy)benzoic acid (107 mg), HATU (122 mg) and 2-methoxyethylamine (3Σ mg) in DMF (2 L), was added DIPEA (0.11 mL) and the mixture stined at ambient temperature for 1 hour. Water (30 mL) was added and the mixture extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with brine, dried (MgSO₄), and evaporated to a residue which was chromatographed on silica with ethyl acetate as eluant to give the desired compound (63 mg). 1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 3.3 (s, 6H), 3.4-3.5 (m, 6H), 4.7-4.8 (m, IH), 6.85 (s, IH), 7.1 (d, 2H), 7.25 (m, 2H), 7.55 (d, 2H), 7.9 (d, 2H), 8.45 (s, IH); m/z 486 (M+H)⁺ h a similar manner to that described above, Examples la-lc were also prepared:- (s, (m, 2H),

2H), (d, 2H) 2.2 (s, 6H), (m, 2H),

The required acid for Example 1 was prepared as described below:

4-({3-([(l_ty)-2-Methoxy-(l-methylethyl oxy)-5-[(l,3-thiazol-2-ylamino)carbonyl] phenyl} oxy)benzoic acid

A solution of ethyl 4-({3-{[(1 )-2-methoxy-(l-methylethyl)oxy}-5-[(l,3-thiazol-2- ylamino)carbonyl] phenyl} oxy)benzoate (334 mg) in THF (10 mL) was added to a solution of lithium hydroxide monohydrate (82 mg) in water (5 mL). The mixture was stined at ambient temperature for 16 hours and the THF removed in vacuo. The aqueous layer was acidified with 1M hydrochloric acid (1.83 mL), and the solid precipitate filtered off, washed with water and dried in vacuo to give the desired compound (268 mg). 1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 3.25 (s, 3H), 3.5 (m, 2H), 4.7-4.8 (m, IH), 6.9 (t, IH), 7.1 (d, 2H), 7.25 (d, IH), 7.35 (s, IH), 7.55 (d, 2H), 7.95 (d, 2H), 12.75 (s, IH); m/z 429 (M+H)⁺

Ethyl 4-((3-( (:i»S^f)-2-methoxy-(l-methylethvnoxyl-5-[(L3-thiazol-2-ylamino carbonyll phenyl} oxyVbenzoate

A solution of 3-hydroxy-5-{[(15)-2-methoxy-(l-methylethyl)oxy}-N-l,3-thiazol-2- ylbenzamide (l.Og), 4-ethoxycarbonylphenylboronic acid (1.18 g), copper (fl) acetate (1.19g), triethylamine (2.25 mL) and freshly activated 4A molecular sieves (4 g) in DCM (50 mL) was stined at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through diatomaceous earth, washed with DCM (2 10 mL), the DCM removed in vacuo and the residual oil partitioned between ethyl acetate (75 mL) and 1M hydrochloric acid (30 mL). The ethyl acetate layer was separated, washed sequentially with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO ), and evaporated to a residue which was chromatographed on silica with 30% ethyl acetate in isohexane as eluant to give the desired compound (700 mg).

1H ΝMR δ (CDC1₃): 1.3 (d, 3H), 1.4 (t, 3H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 4.35 (q, 2H), 4.5-4.6 (m, IH), 6.85 (s, IH), 6.95 (d, IH), 7.0 (d, 2H), 7.15 (s, IH), 7.2 (d, IH), 7.35 (d, IH), 8.05 (d, 2H); m/z 457 (M+H)⁺

3-Hydroxy-5-([(l>S1-2-methoxy-(l-methylethyl oxy}-N-L3-thiazol-2-ylbenzamide

A solution of 3-{[(l)S)-2-methoxy-(l-methylethyl)oxy}-5-{[(2-methylphenyl)methyl]oxy}-N- l,3-thiazol-2-ylbenzamide (6.9 g) and thioanisole (10 mL) in trifluoroacetic acid (65 mL) was stined at ambient temperature for 16 hours. The trifluoroacetic acid was removed in vacuo and the residual oil partitioned between ethyl acetate (75 mL) and aqueous sodium hydrogen carbonate solution (200 mL). The aqueous layer was separated, extracted with ethyl acetate (2 x 75 mL), and the combined organic extracts washed with brine, dried (MgSO₄), and evaporated to a residue which was chromatographed on silica with 50% ethyl acetate in isohexane as eluant to give the desired compound (4.6 g).

1H ΝMR δ (CDC1₃): 1.3 (d, 3H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 4.5-4.6 (m, IH), 6.65 (s, IH), 6.95 (d, IH), 7.05 (s, IH), 7.1 (s, IH), 7.25 (d, IH); m/z 309 (M+H)⁺

3-(r(lS)-2-Methoxy-(l-methylethvnoχy}-5-(r(2-methv henvnmethylloxy}-N-1.3-thiazol-2- ylbenzamide

To a solution of 3-[(15 -2-methoxy-(l-methylethyl)oxy]-5- {[(2-methylphenyl)methyl]oxy} benzoic acid (9.55 g) in DCM (140 mL) was added oxalyl chloride (2.83 mL), followed by DMF (1 drop), and the mixture stined at ambient temperature for 16 hours. The DCM and excess oxalyl chloride were removed in vacuo, the residual oil dissolved in DCM (25 mL) and added to a solution of 2-aminothiazole (2.84g) and triethylamine (7.88 mL) in DCM (75 mL) at 0-5°C, and the mixture stined at ambient temperature for 4 hours. The DCM and excess triethylamine were removed in vacuo, the residual oil partitioned between ethyl acetate (100 mL) and 1M hydrochloric acid (100 mL). The ethyl acetate layer was separated, washed sequentially with 1M hydrochloric acid, aqueous sodium hydrogen carbonate solution, and brine, dried (MgSO₄), and evaporated to a residue which was chromatographed on alumina with ethyl acetate as eluant to give the desired compound (11.0 g). H ΝMR δ (CDCI₃): 1.3 (d, 3H), 2.35 (s,3H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 4.55-4.6 (m, IH), 5.0 (s,2H), 6.8 (s, IH), 6.95 (d, IH), 7.15 (s, IH), 7.25 (m, 5H), 7.4 (d, IH); m/z 413 (M+H)⁺ 3-[(lS)-2-Methoxy-(l-methylethyl)oxy]-5-{[(2-methylphenyl methyl]oxy}benzoic acid

A solution of methyl 3-[{(l,S)-2-methoxy-(l-methylethyl)oxy]-5-{[(2-methylphenyl) methyl] oxy}benzoate (10.65g) in THF (200 mL) and methanol (50 mL) was added to a solution of lithium hydroxide monohydrate (6.0g) in water (100 mL). The mixture was stined at ambient temperature for 16 hours and the THF and methanol removed in vacuo. The aqueous layer was acidified to pHl with hydrochloric acid, and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine, dried (MgSO₄), and evaporated to give the desired compound (9.55 g). m/z 329 (M-H)^"

Methyl 3- {(ljSV2-methoxy-(l-methylethyl)oxyj-5- (r(2-methylphenyl methyl1oxy} benzoate

A stined suspension of methyl 3-hydroxy-5-{[(2-methylphenyl)methyl]oxy}benzoate (15.3 g) and polymer-supported triphenyl phosphine (39.2 g) in dry DCM (900 mL) was cooled in an ice-bath and diisopropyl azodicarboxylate (11.88 mL) was added drop wise. The reaction mixture was stined at 0-5°C for 30 minutes and (R)-l-methoxy-propan-2-ol was added dropwise. The reaction mixture was stined at ambient temperature for 16 hours, filtered through diatomaceous earth and the DCM evaporated to a residue which was chromatographed on silica with 10%o ethyl acetate in isohexane as eluant to give the desired compound (10.7 g).

1H NMR δ (CDC1₃): 1.3 (d, 3H), 2.4 (s,3H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 3.9 (s, 3H), 4.55-4.6 (m, IH), 5.0 (s,2H), 6.8 (s, IH), 7.25 (m, 5H), 7.4 (d, IH) Methyl 3-hydroxy-5- {[(2-methylphenyl methyl]oxy}benzoate

To a solution of methyl 3,5-dihydroxybenzoate (50 g, 0.30 mol) in DMF (500 mL) at 0°C was added sodium hydride (10.8 g, 0.27 mol) portionwise, maintaining the reaction temperature below 10°C. The reaction was allowed to waπn to 15°C, and was stined for 20 minutes. The mixture was cooled to 0°C and a solution of 2-methylbenzyl bromide (36 mL, 0.27 mol) in DMF (50 mL) was added over 30 minutes. The reaction was warmed to ambient temperature and concentrated in vacuo, the residual oil partitioned between ethyl acetate (500 mL) and water (250 mL), the ethyl acetate layer separated, washed sequentially with water and brine, dried (MgSO₄) and evaporated to a residue which was cliromatographed on silica eluting with a gradient of 0-100%> ethyl acetate in isohexane to give the desired compoixnd (21.9 g). 1H NMR δ (CDC1₃) 2.39 (s, 3H), 3.90 (s, 3H), 5.02 (s, 2H), 5.61 (s, IH), 6.69 (t, IH), 7.15- 7.42 (m, 6H)

Example 2: 3-(3-{[(2-Methoxyethyl)amino1carbonyl}phenoxy)-5-[(lS^r)-2-methoxy-(l- methylethyl)oxy1- V-l,3-thiazol-2-yIbenzamide

To a suspension of 3-({3-{[(15)-2-methoxy-(l-methylethyl)oxy}-5-[(l,3-thiazol-2- ylamino)carbonyl] phenyl} oxy)benzoic acid (107 mg), HATU (122 mg) and 2- methoxyethylamine (38 mg) in DMF (2 mL) was added DIPEA (0.11 mL) and the mixture stined at ambient temperature for 1 hour. Water (30 mL) was added and the mixture extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with brine, dried (MgSO ), and evaporated to a residue which was chromatographed on silica, with ethyl acetate as eluant, to give the desired compound (85 mg). 1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 3.25 (s, 3H), 3.3 (s, 3H), 3.4-3.5 (m, 6H), 4.7-4.8 (m, IH), 6.8 (s, lH),7.2-7.25 (m, 3H), 7.55 (m, 4H), 7.7 (d, IH) 8.55 (t, IH), 12.6 (s, IH); m/z 486 (M+H)⁺

The required acid for Example 2 was prepared as described below:

3-((3-([(l>S^r)-2-Methoxy-(l-methylethvnoxy}-5-[(1.3-thiazol-2-ylamino)carbonyll phenyl} oxy)benzoic acid

A solution of ethyl 3-({3-{[(l<S)-2-methoxy-(l-methylethyl)oxy}-5-[(l,3-thiazol-2-ylamino) carbonyl]phenyl}oxy)benzoate (319 mg) in THF (10 mL) was added to a solution of lithium hydroxide monohydrate (78 mg) in water (5 mL). The mixture was stined at ambient temperature for 16 hours and the THF removed in vacuo. The aqueous layer was acidified with IM hydrochloric acid (1.75 mL), the solid precipitate filtered off, washed with water and dried in vacuo to give the desired compound (283 mg). 1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 3.25 (s, 3H), 3.5 (m, 2H), 4.7-4.8 (m, IH), 6.85 (t, IH), 7.25 (m, 2H), 7.35 (dd, IH), 7.55 (m, 4H), 7.75 (d, IH); m/z 429 (M+H)⁺ Ethyl 3-((3-(r(lS -2-methoxy-(l-methylethvnoχy}-5-r(1.3-thiazol-2- ylamino carbonyl]phenyl}oχy)benzoate

A solution of 3 -hydroxy-5 - { [( 1 <S)-2-methoxy-(l -methylethyl)oxy} -N- 1 ,3-thiazol-2- ylbenzamide (1.0 g), 3-ethoxycarbonylphenylboronic acid (1.18 g), copper (II) acetate (1.19 g), triethylamine (2.25 mL) and freshly activated 4A molecular sieves (4g) in DCM (50 mL) was stined at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through diatomaceous earth, washed with DCM (2 x 10 mL), the DCM removed in vacuo, and the residual oil partitioned between ethyl acetate (75 mL) and IM hydrochloric acid (30 mL). The ethyl acetate layer was separated, washed sequentially with aqueous sodium hydrogen carbonate solution and brine, dried (MgS0 ), and evaporated to a residue which was chromatographed on silica (eluting with 30%o ethyl acetate in isohexane) to give the desired ester (680 mg). 1H ΝMR δ (CDC1₃): 1.3 (d, 3H), 1.4 (t, 3H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 4.35 (q, 2H), 4.5-4.6 (m, IH), 6.8 (t, IH), 6.95 (d, IH), 7.1 (d, IH), 7.2 (in, 2H), 7.3 (d, IH), 7.4 (t, IH), 7.7 (d, IH), 7.85 (d, IH), 11.6 (s, IH); m/z 457 (M+H)⁺

The synthesis of 3-hydroxy-5-{[(l<S)-2-methoxy-(l-methylethyl)oxy}-N-l,3-thiazol-2- ylbenzamide is described above in Example 1.

Example 3 : 3-r(lS)-2-Methoxy-(l-methylethyl)oxy1-5-{4-r(4-methylpiperazin-l- yl)carbonynphenoxy}-iV-(l-methyl-l_JH-pyrazol-3-yl)benzamide

To a suspension of 4-[(3-{[(l_S)-2-methoxy-(l-methylethyl)oxy}-5-{[(l-methyl-lH-pyrazol-3- yl)amino]carbonyl}phenyl)oxy]benzoic acid (212 mg), ΗATU (400 mg) andN- methylpiperazine (105 mg) in DMF (10 mL), was added DIPEA (0.35 mL) and the mixture stined at ambient temperature for 24 hours. Water (30 mL) was added and the mixture extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with brine, dried (MgSO₄), and evaporated to a residue which was chromatographed on silica eluting with a gradient of 0-50%> methanol in ethyl acetate to give the desired compound (130 mg). 1H NMR δ (CDC1₃): 1.32 (d, 3H), 2.35 (s, 3H), 2.43 (m, 4H), 3.41 (s, 3H), 3.54 (m, 2H), 3.6- 3.8 (m, 4H), 3.82 (s, 3H), 4.59 (m, IH), 6.78 (m, 2H), 7.05 (t, 3H), 7.22 (m, IH), 7.27 (m, IH), 7.42 (d, 2H), 8.30 (br s, IH); m/z 508 (M+H)⁺

In a similar manner to that described above, Examples 3a-3d were also prepared:-

The required acid for Example 3 was prepared as described below: 4-[(3-r(l»S^f)-2-Methoxy-(l-methylethyl oxyl)-5-irri-methyl-lH-ρyrazol-3- yl aminolcarbonyl}phenyl)oxy]benzoic acid

A solution of ethyl 4-[(3-[(l<S)-2-methoxy-(l-methylethyl)oxy])-5-{[(l-methyl-lH-pyrazol-3- yl)amino]carbonyl}phenyl)oxy]benzoate (5.45 g) in TΗF (200 mL) was added to a solution of lithium hydroxide monohydrate (2.52 g) in water (100 mL). The mixture was stined at ambient temperature for 48 hours and the TΗF removed in vacuo. The aqueous layer was acidified with IM hydrochloric acid (60 mL), and the solid precipitate filtered off, washed with water and dried in vacuo to give the desired acid (5 g). 1H NMR δ (d₆-DMSO): 1.22 (d, 3Η), 3.26 (s, 3H), 3.45 (m, 2H), 3.75 (s, 3H), 4.71 ( , IH), 6.51 (m, IH), 6.84 (m, IH), 7.08 (d, 2H), 7.24 (m, IH), 7.44 (s, IH), 7.57 (m, IH), 7.95 (d, 2H), 10.84 (hr s, IH), 12.80 (br s, IH); m/z 426 (M+H)⁺

Ethyl 4-[(3-r(lS)-2-methoxy-(l-methylethvnoxy]V5-([(l-methyl-lH-pyrazol-3- yl)amino1carbonyl}phenyl)oxy]benzoate

A solution of 3-hydroxy-5-[(15)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3- yl)benzamide (10.0 g), 4-ethoxycarbonylphenylboronic acid (9.4 g), copper (II) acetate (9 g), triethylamine (23 mL) and freshly activated 4A molecular sieves (36 g) in DCM (500 mL) was stined at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through celite, washed with DCM (2 x 50 mL), the DCM removed in vacuo and the residual oil partitioned between ethyl acetate (500 mL) and IM hydrochloric acid (200 mL). The ethyl acetate layer was separated, washed sequentially with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO₄), and evaporated to a residue which was chromatographed on silica eluting with a gradient of 50-100%> ethyl acetate in isohexane to give the desired compound (5.47 g). 1H NMR δ (CDCI₃): 1.3 (m, 3H), 1.41 (t, 3H), 3.39 (s, 3H), 3.49 (m, IH), 3.58 (m, IH), 3.78 (s, 3H), 4.38 (q, 2H), 4.58 (m, IH), 6.79 (m, 2H), 7.01-7.1 (m, 3H), 7.26 (m, 2H), 8.01 ( , 2H), 8.61 (br s, IH); m/z 454 (M+H)⁺

3-Hydroxy-5-[(lty)-2-methoxy-(l-methylethyl oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide

To a solution of 3-[(15)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5- [(phenylmethyl)oxy]benzamide (7.07 g) in TΗF (50 mL) and methanol (50 mL) was added 10% palladium on carbon (727 mg) as a slurry in TΗF (1 mL) and methanol (1 mL). The mixture was placed under vacuum and stined under an atmosphere of hydrogen for 70 hours. The mixture was filtered through diatomaceous earth, and the diatomaceous earth washed with methanol (2 x 100 mL), followed by evaporation in vacuo. The residues were dissolved in ethyl acetate (10 mL), treated with isohexane (40 mL), the solid filtered off and washed with isohexane (50 mL) to afford the desired compound (5.17 g) which was used without further purification.

1H ΝMR δ (d₆-DMSO): 1.22 (d, 3Η), 3.28 (s, 3H, obscured by water), 3.38-3.53 (m, 2H), 3.76 (s, 3H), 4.65 (m, IH), 6.44 (m, IH), 6.54 (m, IH), 6.93 (s, IH), 7.04 (s, IH), 7.57 (m, IH), 9.63 (br s, IH), 10.60 (s, IH); m/z 306 (M+H)⁺, 304 (M-HV

3-r(lS)-2-Methoxy-(l-methylethvnoxyl-N-(l-methyl-lH-pyrazol-3-yl)-5- [(phenylmethyl oxy]benzamide

A solution of 3-[(l»S)-2-methoxy-(l-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (8.73 g) in DCM (150 L) was cooled to 0°C. Oxalyl chloride (4.81 mL) and DMF (0.15 mL) were slowly added with stirring. The mixture was allowed to warm to ambient temperature and stined for 16 hours, following which the organics were removed in vacuo, and the residues azeotroped with toluene (75 mL). The crude material was dissolved in DCM (75 mL) and slowly added to a stined suspension of 1 -methyl- lH-pyrazol-3 -amine (3.35 g) and DIPEA (14.4 mL) in DCM (75 mL). The mixture was stined at ambient temperature for 18 hours, before the organics were evaporated in vacuo and the residue dissolved in ethyl acetate (150 mL). The organics were washed with IM aqueous hydrochloric acid (100 mL) and brine (50 mL), and dried (MgSO₄), before evaporation in vacuo to give crude material. This was chromatographed on a 200g Biotage Flash 75 SiO₂ column (eluting with 30 to 90%> ethyl acetate in isohexane), and evaporated in vacuo to afford the desired compound (7.07 g). 1H NMR δ (d₆-DMSO): 1.23 (d, 3Η), 3.28 (s, 3H, obscured by water), 3.40-3.52 (m, 2H), 3.77 (s, 3H), 4.70 (m, IH), 5.03 (s, 2H), 6.56 (m, IH), 6.71 (m, IH), 7.18 (s, IH), 7.24 (s, IH), 7.32-7.47 (br m, 5H), 7.58 (m, IH), 10.73 (s, IH); m/z 396 (M+H)⁺.

3 - r 1 iy)-2-Methoxy-( 1 -me thylethvDoxy] -5 - { [phenylmethyl] oxy} benzoic acid

A solution of methyl 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-{[phenylmethyl]oxy} benzoate (77.4 mmol) in a mixture of THF (232 mL) and methanol (232 mL) was treated with a solution of 2M sodium hydroxide (232 mmol), and the reaction mixture stined for 4 hours at ambient temperature. The resulting solution was diluted with water (250 mL) and most ofthe organic solvent removed in vacuo. The resulting suspension was washed with diethyl ether (3 x 200 mL) and the organic washings discarded. The resulting aqueous solution was acidified to pH4 with 2M hydrochloric acid solution and extracted with ethyl acetate (2 x 200 mL).

The extracts were combined, washed with brine, dried (MgSO₄), and evaporated to give the desired compound (99% yield).

1H NMR δ (d₆-DMSO): 1.20 (d, 3H), 3.46 (m, 2H), 4.64 (m, IH), 5.15 (s, 2H), 6.83 (app t,

IH), 7.06 (s, IH), 7.13 (s, IH), 7.30-7.49 (m, 5H), 12.67 (br s, IH)

Methyl 3-[(l>S^l)-2-methoxy-( 1 -methylethyl oxy1-5- {rphenylmethyl]oxy}benzoate

To a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7g of 3 mmol/g loading, 155 mmol) and (R)-(-)-l-methoxy-2-propanol (102 mmol). The stined solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stined for 20 minutes and filtered, washing the residue with THF (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification.

1H NMR δ (d₆-DMSO): 3.26 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.63 (m, IH), 5.14 (s, 2H), 6.85 (s, IH), 7.05 (s, IH), 7.11 (s, IH), 7.30-7.47 (m, 5H) The 1H NMR spectrum also contained signals consistent with a small amount of bis(l- me.hylethyl)hydrazine- 1 ,2-dicarboxylate.

Methyl 3-hvdroxy-5-{[phenylmethyl]oxy}benzoate

To a stined solution of methyl 3,5-dihydroxybenzoate (5.95 mol) in DMF (6 L) was added potassium carbonate (9 mol), and the suspension stined at ambient temperature under argon. To this was added benzyl bromide (8.42 mol) slowly over 1 hour, with a slight exotherm, and the reaction mixture stirred overnight at ambient temperature. The reaction was quenched cautiously with ammonium chloride solution (5 L) followed by water (35 L). The aqueous suspension was extracted with DCM (1 x 3 L and 2 x 5 L). The combined extracts were washed with water (10 L) and dried overnight (MgSO₄). The solution was evaporated in vacuo, and the crude product chromatographed in 3 batches (flash column, 3 x 2 kg silica, eluting with a gradient consisting of hexane containing 10%> DCM, to neat DCM, to DCM containing 50%o ethyl acetate) to eliminate starting material. The crude eluant was further chromatographed in 175 g batches (Amicon HPLC, 5 kg normal-phase silica, eluting with isohexane containing 20% v/v of ethyl acetate) to give the desired compound (21%> yield). ^!H NMR δ (d₆-DMSO): 3.8 (s, 3H), 5.1 (s, 2H), 6.65 (m, IH), 7.0 (m, IH), 7.05 (in, IH), 7.3- 7.5 (m, 5H), 9.85 (br s, IH) Example 4: General Procedure for Preparation of Halogenated Sulphonamides To a solution ofthe appropriate amine (1.8 mmol) in DCM (2 mL), was added the sulphonyl chloride (0.72 mmol) in DCM (2 mL), and the resulting mixture stined for 18 hours. The mixture was treated with IM aqueous hydrochloric acid (4 mL) and the organics separated. Evaporation in vacuo gave the crude fluorosulphonamide wliich was used without further purification. To a solution ofthe crude fluorosulphonamide (7.2 mmol) in acetonitrile (3 mL), was added 3-hydroxy-5-[(liS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide (0.36 mmol) and potassium carbonate (1 .8 mmol). The mixture was heated to 170°C in a 'Smith Creator Microwave' for 100 minutes, before being filtered and the resultant organics evaporated in vacuo. The residues were then chromatographed on a Redisep (12g, Si0 ) cartridge using an Isco Optix chromatography system, eluting with 30 to 100%. ethyl acetate in isohexane, and evaporated in vacuo to afford the desired compound. Examples 4a-4d were synthesised using the generic preparation described above:-

4c 553, 555 'H MR δ (d₆-DMSO): 1.23 (d, 3H), 2.96 (m, (M+-H)⁺ 2H), 3.09 (m, 2H), 3.14 (s, 3H), 3.28 (s, 3H, 551, 553 obscured by water), 3.48 (m, 2H), 3.76 (s, (M-H)^' 3H), 4.75 (m, IH), 6.53 (m, IH), 7.89 (m,

IH), 7.17-7.24 (m, 2H), 7.46 (m, IH), 7.57 (m, IH), 7.73 (dd, IH), 7.82 (m, IH), 7.96 (m, IH), 10.84 (s, IH) 4d^$ 578, 580 *H NMR δ (d₆-DMSO): 1.24 (d, 3H), 2.13 (s, (M+H)⁺ 3H), 2.35 (t, 4H), 2.94 (m, 4H), 3.28 (s, 3H, obscured by water), 3.42-3.53 (m, 2H), 3.75 (s, 3H), 4.76 (m, IH), 6.54 (m, IH), 6.93 (m,

IH), 7.21 (d, IH), 7.28 (s, IH), 7.49 (s, IH), 7.58 (m, IH), 7.69 (dd, IH), 7.90 (m, IH), 10.84 (s, IH) The requisite sulphonamide for this example was prepared using a 1:1 ratio of amine : sulphonyl chloride, and isolated by treatment with IM aqueous sodium hydroxide

The synthesis of 3-hydroxy-5-[(l»S)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol- 3-yl)benzamide is described in Example 3 above.

Example 5: General Procedure for Preparation of Sulphonamides

A solution ofthe requisite chlorosulphonamide from Example 4 above (0.12 mmol) in TΗF (5 mL) and methanol (5 mL) was treated with 10%o palladium on carbon (6 mg) and triethylamine (0.1 mL), The flask was put under vacuum, and stined under an atmosphere of hydrogen gas. The resulting mixture was stined at ambient temperature until starting material was consumed, before being filtered through diatomaceous earth and washed with methanol. Evaporation ofthe organics in vacuo, and azeotroping with diethyl ether (3 x 5 mL), followed by drying in vacuo, afforded the desired compound.

Examples 5a-5d were synthesised using the generic procedure described above:-

Example 6: 3-(4-Cyanophenoxy)-5-f(lS)-2-methoxy-(l-methyIethyl oxy1-N-(l-methyl- lH-pyrazoI-3-yllbenzamide

To a stined solution of 3-hydroxy-5-[(15')-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH- pyrazol-3-yl)benzamide (0.164 mmol) in DMF (1 mL) was added a IM solution of sodium hexamethyldisilazide in TΗF (0.164 mmol). The reaction was stined at room temperature for 10 minutes before adding 4-fluorobenzonitrile (0.164 mmol) The reaction was stined overnight at room temperature, then heated to 60°C and stined for a further 4 hours. The reaction was allowed to cool to room temperature, and treated with a further 0.2 equivalents of 4-fluorobenzoiiitrile and sodium hexamethyldisilazide, heated to 70°C and stined at this temperature for 3 hours. The reaction was cooled to room temperature, and treated with a further 0.2 equivalents of sodium hexamethyldisilazide, warmed to 70°C, and stined at this temperature overnight. The solvent was removed in vacuo and the residual oil partitioned between ethyl acetate and water. The water layer was separated and re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO₄), filtered and evaporated to a residue which was cliromatographed on silica, using 0-1% methanol in DCM as the eluent, to give the desired product (60% yield).

1H NMR δ (CDC1₃): 1.35 (d, 3H), 3.40 (s, 3H), 3.55 (m, 2H), 3.78 (s, 3H), 4.60 (m, IH), 6.80 (m, 2H), 7.10 (m, 3H), 7.30 (m, 2H), 7.62 (d, 2H), 8.55 (br s, IH); m/z 407 (M+H)⁺, 405 (M- H)-

The synthesis of 3-hydroxy-5-[(15)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol- 3-yl)benzamide is described in Example 3 above.

Example 7; 3-{f4-(AminocarbonyI)phenylloxy}-5-[(lS)-2-methoxy-(l-methylethyl)oxy1- N-(l-methyl-lH-pyrazol-3-yl)benzamide

A suspension of 3-(4-cyanophenoxy)-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl- lH-pyrazol-3-yl)benzamide (0.25 mmol), sodium azide (0.28 mmol) and zinc bromide (0.25 mmol) in water (2 mL) was heated to reflux and stined at this temperature overnight.

Isopropanol (2 mL) was added, and the reaction heated at reflux for a further 24 hours. The reaction was cooled to room temperature, evaporated to half volume in vacuo, and the residue partitioned between ethyl acetate and water. The water layer was separated and re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO₄), filtered and evaporated to a residue which was chromatographed on silica with 0-10%> methanol in DCM as eluent to yield crude material. This material was dissolved in ethyl acetate and washed twice with 2M sodium hydroxide. The organic layer was washed with brine, dried (MgSO₄), filtered and evaporated. This material was dissolved in DCM and purified using an 'Isolute-NH2' ion-exchange column eluting with 10% methanohDCM to yield the desired product.

1H NMR δ (CDC1₃): 1.30 (d, 3H), 3.40 (s, 3H), 3.50 (m, 2H), 3.75 (s, 3H), 4.60 (m, IH), 6.80 (m, 2H), 7.00 (d, 2H), 7.05 (s, IH), 7.25 (m, 2H), 7.80 (d, 2H), 8.75 (br s, IH); m/z 423 (M-H)-

The preparation of 3-(4-cyanophenoxy)-5-[(1 )-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl- lH-pyrazol-3-yl)benzamide was described in Example 6.

Example 8; 3-r4-(Ethylsulfonynphenoxy1-5-r(lS)-2-methoxy-(l-methylethvnoxy1-iV-l,3- thiazol-2-ylbenzamide

A solution of 3-hydroxy-5-[(liS)-2-methoxy-(l-methylethyl)oxy]-N-l,3-thiazol-2 -ylbenzamide (154 mg), 4-ethanesulphonylbenzeneboronic acid (203 mg), copper (TJ) acetate (183 mg), triethylamine (0.345 mL) and freshly activated 4A molecular sieves (1 g) in DCM (10 mL), was stined at ambient temperature and under ambient atmosphere for 3 days. The reaction mixture was filtered through diatomaceous earth, washed with DCM (10 mL), the DCM removed in vacuo and the residual oil dissolved in ethyl acetate (50 mL). The organic solution was washed with IM hydrochloric acid, saturated aqueous sodium hydrogen carbonate, brine, then dried (MgSO ) and evaporated in vacuo. The residue was chromatographed on alumina with 5% methanol in ethyl acetate as eluant. Further chromatography on silica with 50%o ethyl acetate in isohexane as eluant gave the desired compound (54 mg).

1HΝMR δ (CDCI3): 1.2-1.35 (m, 6Η), 3.15 (q, 2H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 4.5-4.6 ( , IH), 6.8 (s, IH), 6.95 (d, IH), 7.2 (d, 2H), 7.25 (d, 2H), 7.4 (s, IH), 7.85 (d, 2H). m/z 477 (M+H)⁺ The following compounds were also prepared in an analogous fashion from 3-h droxy-5- [(liS -2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide:

The syntheses of 3-hydroxy-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-l,3-thiazol-2- ylbenzamide and 3-hydroxy-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol- 3-yl)benzamide are described in Examples 1 and 3 respectively.

Example 9a: 3-rαS)-2-Methoxy-α-methylethvnoχy1-JV- -methyl-lH-pyrazoI-3-yl)-5-r3- (methylsulfonyDphenoxylbenzamide Example 9b: 3-l(lS^,)-2-Methoxy-(l-methylethvnoχyl-iV-(l-methyl-lH^r-pyrazol-3-ylV5-[3- (methylsulfinvDphenoxylbenzamide

To a solution of 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)-5-{[3- (methylthio)phenyl]oxy}benzamide (prepared as described in Example 8a above, 270 mg) in DCM (5 mL) was added /n-chloroperbenzoic acid (1.3 equivalents) and the reaction stined at room temperature for 1 hour. A further 1.4 equivalents of rø-chloroperbenzoic acid was added, and the reaction stined at room temperature for a further 30 minutes. The reaction was added to saturated aqueous sodium metabisulphite and stined for 20 minutes. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated to a white foam. The crude mixture was purified using a 20 g Redisep column eluting with 0-5% methanol in DCM to yield the desired sulphone (117 mg).

1H NMR δ (d₆-DMSO): 1.12 (d, 3H), 3.22 (s, 3H), 3.26 (s, 3H), 3.47 (m, 2H), 3.75 (s, 3H), 4.75 (m, IH), 6.54 (m, IH), 6.85 (m, IH), 7.23 (s, IH), 7.40 (m, IH), 7.45 (s, IH), 7.52 (m, IH), 7.57 (m, IH), 7.68 (m, 2H), 10.84 (br s, IH); m/z 460 (M+H)⁺ A further fraction yielded the desired sulphoxide (105 mg).

1H NMR δ (d₆-DMSO): 1.12 (d, 3H), 2.75 (s, 3H), 3.26 (s, 3H), 3.47 (m, 2H), 3.76 (s, 3H), 4.73 (m, IH), 6.53 (m, IH), 6.80 (m, IH), 7.19 (m, 2H), 7.33 (m, IH), 7.44 (m, 2H), 7.59 (m, 2H), 10.83 (br s, IH); m/z 444 (M+H)⁺

Example 10: 3-({4-r(l-Metnylethvι)sulfonvι] phenyl}oxyV5-r(lS)-2-methoxy-ri- metnylethyl)oxyI-N-(l-methV--lH-pyrazol-3-yl)benzamide

In a similar manner to that described above for Example 9, 3-({4-[(l-methylethyl)sulfonyl] phenyl}oxy)-5-[(l-S)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide was prepared from 3-({4-[(l-methylethyl)thio]phenyl}oxy)-5-[(l)S)-2-methoxy-(l- methylethyl)oxy] -N-( 1 -methyl- lH-pyrazol-3 -yl)benzamide. 1H ΝMR δ (d₆-DMSO): 1.32 ( , 9Η), 3.27 (m, IH), 3.41 (s, 3H), 3.50 (dd, IH), 3.58 (dd,

IH), 3.80 (s, 3H), 4.61 (m, IH), 6.82 (m, 2H), 7.09 (d, 2H), 7.17 (m, IH), 7.28 ( , IH), 7.33

(m, IH), 7.84 (d, 2H), 8.86 (br s, IH); m/z 488 (M+H)⁺

The synthesis of 3-( {4-[(l -methylethyl)thio]phenyl} oxy)-5-[(l_S)-2-methoxy-(l -methylethyl) oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide is described in Example 8b above. Example 11: General Procedure for Amide Synthesis - HATU Coupling

DIPEA (2.5 equivalents) was added to a suspension of 3-{(lιS)-2-methoxy-(l- methylethyl)oxy}-5-{[4-(methylsulfonyl)phenyl] oxy}benzoic acid (1 equivalent), HATU(1.25 equivalents) and amine (1.25 equivalents) in DMF (20 mL). The initial suspension dissolved into a dark orange solution. The resulting mixture was stined at ambient temperature for 2 hours. The DMF was removed in vacuo, and the residue azeotroped with toluene. Water was added and the mixture extracted with ethyl acetate. The extracts were combined and washed sequentially with IM hydrochloric acid, saturated sodium hydrogen carbonate solution and brine. The solution was dried (MgSO₄), filtered, and evaporated in vacuo to give the crude product which was chromatographed (50%> ethyl acetate in isohexane) to give desired compound (40-70% yield).

Examples lla-llg were prepared using an analogous method to that described above from the appropriate acid and amino heterocycle:

^Example llf may be crystallised by allowing isohexane to vapour diffuse into a solution of the compound in ethylacetate, in a closed system, with subsequent slow evaporation ofthe mixture at room temperature over 4 days, mp 109-11 2. ^$The required amino pyrazole for Example llg was prepared as follows:

Sodium hydride (60%> dispersion in mineral oil, 39 mg, 0.973 mmol), was added to 5-nitro- lH-pyrazole (100 mg, 0.885 mmol) in dry DMF (2 irαL) under an argon atmosphere. The solution was stined for 5 minutes, then ethyl iodide £0.85 mL, 1.062 mmol) added and the reaction warmed to 80°C for 3 hours. Saturated aqueous sodium hydrogen carbonate (30 mL) was added, and the mixture extracted with diethyl ethier (40 mL). The combined organic extracts were washed with brine, dried (MgSO ), and evaporated to a residue which was purified by chromatography on silica (eluting with isohexane containing ethyl acetate, 33 > v/v) to give the alkylated pyrazole (80 mg) which was used in the next step without further purification.

1H NMR δ (CDC1₃): 1.58 (t, 3H), 4.26 (q, 2H), 6.91 (d, IH), 7.48 (d, IH).

To a solution ofthe alkylated pyrazole (70 mg, 0.50 mmol) in THF (5 mL) under an inert atmosphere was added 10% palladium on carbon (15 mg). The flask was evacuated and refilled 3 times with hydrogen gas, and stined vigourously at room temperature for 3 hours. The reaction mixture was refilled with argon, and a further portion of 10%> palladium on carbon (50 mg) added, followed by refilling as above with a hydrogen atmosphere. The reaction was stined for 16 hours, filtered through diatomaceous earth, and evaporated to afford the title compound (56 mg) as a colourless oil which was used without further purification. 1H NMR δ (CDC1₃): 1.42 (t, 3H), 3.58 (br. s, 2H), 3.98 (q, 2H), 5.59 (d, IH), 7.16 (d, IH)

The required acids for Examples lla-llg were prepared as described below:

3-{(lS)-2-Methoxy-(l-methylethyl)oxy}-5-{[4-(methylsulfonyl phenyl]oxy}benzoic acid

A solution of methyl 3-[(15)-2-methoxy-(l-methylethyl)oxy]-5-{[4-(methylsulfonyl)phenyl] oxy}benzoate (60.9 mmol) in THF (400 mL) was treated with a solution of IM sodium hydroxide (125 mmol), and the reaction mixture stined for 13 hours at ambient temperature. Most ofthe organic solvent was removed in vacuo, and the remaining solution was diluted with water (150 mL). The resulting aqueous solution was acidified to pH4 with IM citric acid solution, and extracted with ethyl acetate (2 x 100 mL). The extracts were combined, washed with brine, dried (MgSO₄), and evaporated to give the desired compound (83% yield). 1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 3.2 (s, 3H), 3.26 (s, 3H), 3.44 (m, 2H), 4.63 (m, IH), 7.05 (s, IH), 7.11 (s, IH), 7.2 (d, 2H), 7.3 (s, IH), 7.9 (d, 2H); m z 479 (M-H)^" Methyl 3-r(lι-?)-2-methoxy-(l-methylethyl)oxy]-5- {[4-(methylsulfonyl)phenyl]oxy} benzoate

A suspension of methyl 3-hydroxy-5-[(l_S)-2-methoxy-(l-methylethyl)oxy]benzoate (154 mmol), boronic acid ( 1.1 equivalents), copper (TJ) acetate (1.1 equivalents), triethylamine (5 equivalents) and freshly activated 4A molecular sieves (200 g) in DCM (500 X) was stined at ambient temperature and under ambient atmosphere for 2 days. The reaction, mixture was filtered, the DCM removed in vacuo and the residual oil partitioned between ettiyl acetate and 1-2M hydrochloric acid. The ethyl acetate layer was separated, washed with aq_ueous sodium hydrogen carbonate and brine, dried (MgSO₄), and evaporated to a residue which was chromatographed on silica (with 20-60% ethyl acetate in isohexane as eluant) to give the desired ester (58%> yield).

1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 3.2 (s, 3H), 3.26 (s, 3H), 3.44 (m, 2H), 3.8 (s, 3H), 4.65 (m, IH), 7.05 (s, IH), 7.11 (s, IH), 7.2 (d, 2H), 7.3 (s, IH), 7.9 (d, 2H)

Methyl 3-Hydroxy-5-[(l₎S^f)-2-methoxy-(l-methylethyl)oxy]benzoate eO o^' r A OH

Methyl 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5- {[phenylmethyl]oxy}benzoafce (50. Og; 0.152 mmol) was dissolved in a mixture of THF:ethanol (600 mL) and the flask evacuated and purged with nitrogen (3 times). 10%> Palladium on carbon (5.0g) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stined at ambient temperature for 20 hours until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, and the filtrate concentrated in vacuo to give the desired compound (36.7g). 1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 3.25 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.55 (m, IH), 6.6 (s, IH), 6.9 (s, IH), 6.95 (s, tH), 9.8 (s, IH)

The synthesis of methyl 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-{[phenylmethyl]oxy} benzoate is described above in Example 1. Example 12: General Procedure for Amide Synthesis - Oxalyl Chloride Coupling

To a stined solution of 3-{(l»S)-2-methoxy-(l-methylethyl)oxy}-5-{3,5-difluorophenoxy} benzoic acid (0.285 mmol) in dry DCM (2 mL), was added, dropwise under argon, oxalyl chloride (2 equivalents) and DMF (1 drop). The resulting solution was stined at ambient temperature for 1-2 hrs. The solvent was removed in vacuo and the crude mixture taken up in pyridine (2 mL) and added to the appropriate amine (2.2 equivalents). The reaction mixture was stined at room temperature, or heated if necessary, and monitored by TLC and/or LCMS. The pyridine was removed in vacuo, and water and ethyl acetate added. The organic layer was washed sequentially with IM citric acid and brine solution and dried (MgSO₄), concentrated in vacuo, and the residue chromatographed on silica (eluting with 30-90% ethyl acetate in isohexane) to give the desired product (typically 35-40%) yield).

Examples 12a & 12b were prepared using the appropriate amine:

lh t s examp e, the ac d chlo de was ta en up in THF, followed by addition of pyridine the appropriate amine.

The synthesis of 3- {(l_Sj-2-methoxy-(l -methylethyl)oxy}-5- {3,5-difluorophenoxy}b enzoic acid is described below: 3-{(lS)-2-Methoxy-(l-methylethyl oxy}-5-{3,5-difluorophenoxy}benzoic acid

This was prepared from methyl 3-[(3,5-difluorophenyl)oxy]-5-[(lS)-2-methoxy-(l- methylethyl)oxy]benzoate using an analogous procedure to that described above for the synthesis of 3- {(1 S)-2-methoxy-(l-methylethyl)oxy} -5- {[4-(methylsulfonyl)phenyl]oxy} benzoic acid:

1H NMR δ (d₆-DMSO): 1.21 (d, 3H), 3.26 (s, 3H obscured by solvent peak), 3.46 (m, 2H), 4.67 (m, IH), 6.81 (d, 2H), 6.96 - 7.08 (m, 3H), 7.27 (s, IH), 13.13 (bs, IH); m/z 337 (M-H)^"

Methyl 3-[(3.5-difluorophenyl oxy]-5-[(15^f)-2-methoxy-(l-methylethyl oxy1benzoate

To a solution of methyl 3-[(3,5-difluorophenyl)oxy]-5-hydroxybenzoate (15.0 mmol), (R)-(-)- l-methoxy-2-propanol (18.75 mmol) and triphenylphosphine (18.0 mmol) in anhydrous THF (100 mL) at 0°C was added DIAD (18.0 mmol). The reaction was stined at ambient temperature overnight, concentrated in vacuo, and the residue triturated with a 1 : 1 mixture of ethyl acetateasohexane. The solid was removed by filtration and the filtrate concentrated in vacuo, chromatographed on silica (using a Biotage Flash 75 eluting with 10-15% ethyl acetate in isohexane) to give the title compound (75%> yield). 1H NMR δ (d₆-DMSO): 1.21 (d, 3H), 3.27 (s, 3H obscured by solvent peak), 3.46 (m, 2H), 3.82 (s, 3H), 4.69 (m, IH), 6.81 (dd, 2H), 7.01-7.07 (m, 2H), 7.10 (s, IH), 7.28 (s, IH)

Methyl 3-[(3.5-difluorophenyl)oxy]-5-hvdroxybenzoate

To a solution of methyl 3-[(3,5-difluorophenyl)oxy]-5-{[(4-methylphenyl)sulfonyOoxy} benzoate (16.3 mmol) in methanol (60 mL) was added a 20% solution of potassium hydroxide in methanol (13.75 g). The mixture was heated at 50°C for 1 hour then allowed to cool. Water (20 mL) was added and the mixture immediately acidified with IM hydrochloric acid. The methanol was removed in vacuo and the residue extracted with ethyl acetate. The organic phase was separated, washed with brine, dried (MgSO₄), and concentrated in vacuo to give the title compound (92% yield).

1H NMR δ (d₆-DMSO): 3.80 (s, 3H), 6.72 (m, IH), 6.79 (m, 2H), 6.98 - 7.05 (m, 2H), 7.19 (m, IH), 10.18 (bs, IH); m/z 279 (M-H)^"

Methyl 3-[(3,5-difluorophenyl)oxy1-5-{[(4-methylphenyl sulfonyl1oxy}benzoate

To a solution of methyl 3-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoate (30 mmol), copper (TJ) acetate (36 mmol), 3,5-difluorophenylboronic acid (42 mmol) and 4A molecular sieves (30 g) in DCM (300 mL) was added triethylamine (150 mmol). The reactiorx was allowed to stir for 40 hours then filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with IM citric acid solution, IM sodium hydrogen carbonate solution and brine, then dried (MgSO₄) and concentrated in vacuo. The residue was chroma-to graphed on silica (Biotage Flash 75) eluting with 10- 25% ethyl acetate in isohexane to give the title compound (55% yield).

^!H NMR δ (d₆-DMSO): 2.39 (s, 3H), 3.83 (s, 3H), 6.74 (dd, 2H), 6.93 (m, IH), 7.08 (m, IH), 7.44 (m, 3H), 7.50 (s, IH), 7.74 (d, 2H); m/z 452 (M+NH₄)⁺, 433 (M-H)^"

Methyl 3-hydroxy-5- {[(4-methylphenyl sulfonyl]oxy}benzoate

Methyl 3,5-dihydroxybenzoate (0.40 g) and 4-toluenesulphonylchloride (0.45 g) was stined vigorously in diethyl ether (20 mL) with saturated aqueous sodium hydrogen carbonate (20 mL) at ambient temperature for 62 hours. The aqueous layer was removed and the residue washed sequentially with saturated aqueous sodium hydrogen carbonate, brine, dried (MgSO₄), filtered, and concentrated in vacuo to yield a colourless oil. The crude product was dissolved in diethyl ether, washed with saturated aqueous potassium carbonate then with brine, dried (MgSO₄), filtered and concentrated in vacuo to give a colourless oil which crystallised on standing to give the title compound (0.51 g).

1H NMR δ (d₆-DMSO): 2.43 (s, 3H), 3.82 (s, 3H), 6.66 (m, IH), 6.97 (s, IH), 7.26 (s, IH), 7.47 (d, 2H), 7.75 (d, 2H); m/z 340 (M+NH₄)⁺

Example 13 : 3-f3.5-DifluorophenoxyVN-r4-(hvdroxymethvI)-1.3-thiazol-2-yll-5-r2-(lS)- methoxy-(l-methylethyl oxylbenzamide

To a solution of 3-(3,5-difluorophenoxy)-N-[4-chloromethyl-l,3-thiazol-2-yl]-5-[(l₁S)-2- methoxy-(l-methylethyl)oxy]benzamide (0.107 mmol) in THF (1 mL) was added 0.5M sodium hydroxide solution (1 mL). The reaction was stined at ambient temperature for 2 hours and the organics removed in vacuo. The residue was acidified with IM citric acid and partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO₄), and concentrated in vacuo. The residue was chromatographed on silica eluting with 80%> ethyl acetate in isohexane to give the title compound which was precipitated from a concentrated diethyl ether solution by the addition of isohexane to give a solid sample (35%> yield). 1H ΝMR δ (d₆-DMSO): 1.24 (d, 3H), 3.28 (s, 3H obscured by solvent peak), 3.48 (m, 2H), 4.49 (s, 2H), 4.75 (m, IH), 6.83 (d, 2H), 6.93 (s, IH), 6.98 (s, IH), 7.04 (m, IH), 7.32 (s, IH), 7.54 (s, IH); m/z 451 (M+H)⁺, 449 (M-H)^" 3-(3.5-DifluorophenoxyVN-r4-chloromethyl-1.3-thiazol-2-yl]-5-[(lS)-2-methoxy-(l- methylethyl oxy]benzamide

To a stined solution of 3-{(15)-2-methoxy-(l-methylethyl)oxy}-5-{3,5- difluorophenoxy}benzoic acid (3.06 mmol) in DCM (20 mL) was added 3 drops of DMF and oxalyl chloride (6.12 mmol; 2.0 equivalents) dropwise, and the resulting mixture stined at ambient temperature for 5 hours. The reaction mixture was concentrated in vacuo, azeotroped with toluene and dried overnight at reduced pressure. The residue was dissolved in DCM and 4-(chloromethyl)-l,3-thiazol-2-amine (3.36 mmol), triethylamine (3.36 mmol) and dimethylaminopyridine (0.31 mmol) added. The resulting mixture was stined for 16 hours at ambient temperature. The reaction mixture was washed sequentially with 2M hydrochloric acid and IM sodium hydrogencarbonate solution, dried (MgSO₄), and concentrated in vacuo. The residue was chromatographed (eluting with 15-20%o ethyl acetate in isohexane) to give the desired compound (33%> yield). 1H ΝMR δ (d₆-DMSO): 1.24 (d, 3H), 3.28 (s, 3H obscured by solvent pealc), 3.49 (m, 2H), 4.76 (m, 3H), 6.84 (dd, 2H), 6.94 (s, IH), 7.04 (m, IH), 7.32 (m, 2H), 7.55 (s, IH), 12.77 (bs, IH); m/z 469, 471 (M+H)⁺, 467, 469 (M-H)^"

The synthesis of 3-{(l)S)-2-methoxy-(l-methylethyl)oxy}-5-{3,5-difluorophenoxy}benzoic acid is described in Example 12 above.

The synthesis of 4-(chloromethyl)-l,3-thiazol-2-amine is described in the literature (J. Indian Chem. Soc. 1960, 37, 241). Reference Example 14: 3-r(lS)-2-Methoxy-tt-methylethyr)oxyl-5-.4- (methylsulfonvI)phenoxy1-N-lH-pyrazoI-3-ylbenzamide

Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl 3-({3-[(lS)-2-methoxy-(l- methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy]benzoyl}amino)-lH-pyrazole-l-carboxylate (180 mg, 0.330 mmol) in dry DCM (3 mL) and the reaction was stined under argon for 3 h. A further portion of trifluoroacetic acid (0.2 mL) was then added and the reaction was stined for 30 min, then evaporated in vacuo. The residue was taken up in ethyl acetate (30 mL) and saturated aqueous sodium hydrogencarbonate (15 mL) and the residue was evaporated, then dissolved in DCM and hexane and evaporated to produce the title compound (145 mg) as a colourless foam.

1H NMR δ (d₆-DMSO): 1.27 (d, 3Η), 3.22 (s, 3H), 3.31 (s, 3H), 3.60 (m, 2H, partially obscured by HOD), 4.78 (m, IH), 6.62 (s, IH), 6.93 (s, IH), 7.27 (d, 2H), 7.32 (s, IH), 7.53 (s, IH), 7.65 (s, IH), 7.96 (d, 2H), 10.86 (s, IH); m/z 444 (M-H)^"

tert-Butyl 3-({3-[(ltS)-2-methoxy-(l-methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy] benzoyl} amino)- lH-pyrazole- 1 -carboxylate

ΗATU (375 mg, 1.17 mmol) was added to 3-{(l_5)-2-methoxy-(l-methylethyl)oxy}-5-{[4- (methylsulfonyl) phenyl]oxy}benzoic acid (300 mg, 0.79 mmol) followed by addition of DMF (5 mL), DIPEA (0.35 mL) and tert-butyl 3 -amino- lH-pyrazole-1 -carboxylate (155 mg, 0.85 mmol). The reaction was stined under argon for 4 h, the solvent evaporated, and the residue dissolved in saturated aqueous sodium hydrogencarbonate (30 mL) and ethyl acetate (50 L). The organic layer was separated, washed with saturated aqueous ammonium chloride (30 mL), then dried (MgSO₄), filtered and evaporated. Purification by column chromatography, eluting with 1:1 ethyl acetate:hexanes, afforded the title compound (185 mg, 43%) as a colourless oil. 1H NMR δ (CDC1₃): 1.37 (d, 3H), 1.63 (s, 9H), 3.09 (s, 3H), 3.40 (s, 3H), 3.58 (m, 2H), 4.61 (m, IH), 6.85 (s, IH), 7.08 (m, 2H), 7.15 (d, 2H), 7.30 (s, IH), 7.92 (d, 2H), 8.01 (d, IH), 8.58 (br. s, IH); m/z 544 (M-H)^"

tert-Butyl 3-amino-lH-pyrazole-l-carboxylate

Η,N^' 'X . M^

lH-Pyrazol-3 -amine (428 mg, 5.15 mmol) was dissolved in DMF (5 mL) at 0°C and treated with sodium hydride (206 mg, 5.15 mmol) followed by stirring for a further 30 min. Wanned di-tert-butyl dicarbonate (1.12 g, 5.15 mmol) was then slowly added via syringe over 5 min and the reaction was allowed to warm to room temperature and stined for a further 2 h. The reaction was taken up in saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layer was separated then dried (MgSO₄), filtered and evaporated. Purification by column chromatography (eluting with 1:1 ethyl acetate:hexanes to neat ethyl acetate) afforded the title compound (117 mg) as a white solid. 1H NMR δ (CDC1₃): 1.62 (s, 9Η), 4.00 (br. s, 2H), 5.81 (d, IH), 7.82 (d, IH)

The synthesis of 3- {(1 S)-2-methoxy-(l -methylethyl)oxy} -5- {[4-(methylsulfonyl) phenyl]oxy}benzoic acid is described in Example 11 above.

Example 15: 3-f(lSl-2-Methoxy-(l-methylethvnoxyl-N-(5-methyl-lH-pyrazol-3-yl)-5-r4- (methylsulf onvDphenoxyl b enzamide

Trifluoroacetic acid (1.5 mL) was added to a solution of tert-butyl 3-({3-[(lS)-2-methoxy-(l- methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy]benzoyl}amino)-5-methyl-lH-pyrazole-l- carboxylate (500 mg, 0.330 mmol) in dry DCM (6 mL) and the reaction was stined under argon for 2 h. The solvent was removed in vacuo and the residue was taken up in ethyl acetate (30 mL) and saturated aqueous sodium hydrogencarbonate (15 mL). The organic layer was separated, dried (MgSO₄), filtered, evaporated, then re-evaporated with DCM / hexanes to produce the title compound (350 mg) as a colourless foam.

1H NMR δ (DMSO-d₆): 1.23 (d, 3H), 2.20 (s, 3H), 3.20 (s, 3H), 3.30 (s, 3H) (obscured by HOD), 3.50 (m, 2H) 4.78 (m, IH), 6.38 (s, IH), 6.90 (s, IH), 7.22 (d, 2H), 7.30 (s, IH), 7.45 (s, IH), 7.93 (d, 2H), 10.71 (br. s, IH), 12.08 (br. s, IH); m/z 458 L-Ε)^'

tert-Butyl 3-((3-[(15^f)-2-methoxy-(l-methylethynoxyl-5- 4- (methylsulfonvDphenoxy]benzoyl}amino)-5-methyl-lH-pyrazole-l-carboxylate

ΗATU (500 mg, 1.31 mmol) was added to 3-{(lS)-2-methoxy-(l-methylethyl)oxy}-5-{[4- (methylsulfonyl) phenyl] oxy} benzoic acid (400 mg, 1.05 mmol) followed by addition of DMF (6 mL), DTREA (0.47 mL) and tert-butyl 3-amino-5-methyl-lH-pyrazole-l-carboxylate (380 mg, 1.93 mmol). The reaction was stined under argon for 72 h, then dissolved in saturated aqueous sodium hydrogencarbonate (30 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated aqueous ammonium chloride (30 mL), then dried (MgSO ), filtered and evaporated. Purification by column chromatography eluting with 1 : 1 to 2: 1 ethyl acetate:hexanes afforded the title compound (500 mg, 85%) as a foam. 1H NMR δ (CDC ): 1.37 (d, 3Η), 1.62 (s, 9H), 2.54 (s, 3H), 3.08 (s, 3H), 3.40 (s, 3H), 3.58 (m, 2H), 4.60 (m, IH), 6.82 (m, 2H), 7.08 (m, IH), 7.15 (d, 2H), 7.30 (s, IH), 7.93 (d, 2H), 8.52 (brs, IH); m/z 558 (M-H)^"

tert-Butyl 3 -amino-5-methyl- lH-pyrazole- 1 -carboxylate

5-Methyl-lH-pyrazol-3-amine (800 mg, 8.25 mmol) was dissolved in DMF (10 mL) at 0 °C and treated with sodium hydride (336 mg, 8.25 mmol) followed by stirring for a further 30 min. Warmed di-tert-butyl dicarbonate (1.80 g, 8.25 mmol) was then slowly added via syringe over 5 min and the reaction was allowed to warm to room temperature and stined for a further 1 h. The reaction was taken up in saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layer was separated then dried (MgSO ), filtered and evaporated. Purification by column chromatography (eluting with 1:1 ethyl acetate:hexanes to 100% ethyl acetate) afforded the title compound (380 mg, 23%>) as a colourless oil. 1H NMR δ (CDC1₃): 1.62 (s, 9H), 2.43 (s, 3H), 3.87 (br. s, 2H), 5.60 (s, IH)

The synthesis of 3 - {( 1 S)-2-methoxy-( 1 -methylethyl)oxy} -5- { [4-(methylsulfonyl) phenyl] oxy} benzoic acid is described in Example 11 above.

Example 16: 3-f(lS)-2-methoxy-(l-methylethyl)oxy1-N-r4-

(methoxymethyl)-l,3-thiazol-2-yl1-5-f4-(methylsulfonyl)phenoxy1benzamide

To a stined solution of N-[4-(chloromethyl)-l,3-thiazol-2-yl]-3-[(lS)-2-methoxy-(l- methylethyl)oxy]-5-[4-(methylsulfonyl)phenoxy]benzamide (280mg; 0.55 mmol) in methanol (5 mL) was added sodium methoxide (1. Immol; 2.0 equiv; 25% weight in methanol) and the reaction mixture heated to 50°C and stined overnight. The reaction mixture was concentrated in vacuo and chromatographed (eluting with 50-70%> ethyl acetate: isohexane) to give the title compound (71mg; 26%).

1H ΝMR δ (d₆-DMSO): 1.21 (d, 3H), 2.50 (2s, 6H, partially obscured by water pealc), 3.21 (s, 3H), 3.43-3.54 (m, 2H), 4.40 (s, 2H), 4.78 (m, IH), 6.98 (s, IH), 7.12 (s, IH), 7.25 (d, 2H),

7.37 (s, IH), 7.58 (s, IH), 7.95 (d, 2H), 12.69 (br s, IH); m/z 507 (M+H)⁺, 505 (M-H)^"

N- -^liloromethvD-LS-thiazol^-yll-S-rd^-Σ-methoxy-d-methylethvnoxyl-S-^- tøethylsulfonvDphenoxylbenzamide

To a stined solution of 3-{(lS)-2-methoxy-(l-methylethyl)oxy}-5-{[4-(methylsulfonyl) phenyl]oxy}benzoic acid (1.0 mmol) in DCM (10 mL) was added 1 drop of DMF and oxalyl chloride (2.0mmol; 2.0 equivalents) dropwise. The reaction mixture was stined at ambient temperature under argon for two hours, then concentrated in vacuo and azeotroped with DCM. The residue was dissolved in DCM and 4-(chloromethyl)-l,3-thiazol-2-amine (1.0 mmol) in DCM was added along with DIPEA (2.5 mmol) and dimethylaminopyridine (0.1 mmol). The resulting mixture was stined for 13 hours under argon at ambient temperature, then concentrated in vacuo and chromatographed (eluting with 50-60%> ethyl acetate in isohexane) to give the title compound (53%> yield).

1H NMR δ (d₆-DMSO): 1.3 (d, 3H), 3.2 (s, 3H), 3.25 (s, 3H) 3.45 (m, 2H), 4.75 (s, 2H), 4.8 (m, IH), 7.0 (s, IH), 7.25 (d, 2H), 7.3 (s, IH), 7.4 (s, IH), 7.6 (s, IH), 7.95 (d, 2H), 12.80 (br s, IH)

The synthesis of 3-{(lS)-2-methoxy-(l-methylethyl)oxy}-5-{[4-(methylsulfonyl) phenyl]oxy}benzoic acid is described in Example 11 above.

Example 17: 3-[4-(Azetidin-l-ylcarbonyl)phenoxy1-5-f(lS)-2-methoxy-(l- methylethyl)oxy1- V-(3-methyl-l,2,4-thiadiazol-5-yl)benzamide

To a suspension of 4-({3-{[(15)-2-methoxy-(l-methylethyl)oxy}-5-[(3-methyl-l,2,4- thiadiazol-2-ylamino)carbonyl] phenyl} oxy)benzoic acid (300 mg), HATU (336 mg) and azetidine hydrochloride (190 mg) in DMF (5 mL), was added DTPEA (0.68 mL) and the mixture stined at ambient temperature for 16 h. Water (75 mL) was added and the mixture extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were washed IM aqueous hydrochloric acid (25 mL), saturated aqueous sodium hydrogen carbonate solution (25 mL), brine, dried (MgSO₄), and evaporated to a residue which was cliromatographed on silica with ethyl acetate as eluant to give the desired compound (190 mg). 1H NMR δ (d₆-DMSO): 1.25 (d, 3H), 2.2-2.3 (m, 2H), 2.5 (m, 3H), 3.3 (s, 3H), 3.5 (m, 2H), 4.0 (m, 2H), 4.3 (m, 2H), 4.8 ( , IH), 6.95 (s, IH), 7.1 (d, 2H), 7.35 (s, IH), 7.55 (s, IH), 7.65 (d, 2H), 13.35 (s, IH); m/z 483 (M+H)⁺ fri a similar manner Examples 17a and 17b were also prepared:

4-({3--. r(lS)-2-Methoxy-(l-methylethvnoxy}-5-[(3-methyl-L2.4-thiadiazol-2- ylamino carbonyl]phenyl} oxy)benzoic acid

A solution of ethyl 4-({3-{[(l,S -2-methoxy-(l-methylethyl)oxy}-5-[(3-methyl-l,2,4- thiadiazol-2-ylamino)carbonyl] phenyl} oxy)benzoate (1.3g) in THF (40 mL) was added to a solution of lithium hydroxide monohydrate (310 mg) in water (20 mL). The mixture was stined at ambient temperature for 16 hours and the THF removed in vacuo. The aqueous layer was acidified with IM hydrochloric acid (6.9 mL), and the solid precipitate filtered off, washed with water and dried in vacuo to give the desired compound (1.12 g). 1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 2.45 (s, 3H), 3.25 (s, 3H), 3.5 (m, 2H), 4.7-4.8 (m, IH), 6.95 (s, IH), 7.1 (d, 2H), 7.35 (s, IH), 7.6 (s, IH), 7.95 (d, 2H); m/z 444 (M+H)⁺ Ethyl 4-({3-([(l^-2-methoxy-(l-methylethyl oxy}-5-[(3-methyl-L2.4-thiadiazol-2- ylamino)carbonyl] phenyl} oxy)benzoate

A solution of 3-hydroxy-5-{[(lS)-2-methoxy-(l-methylethyl)oxy}-N-(3-methyl-l,2,4- thiadiazol-2-yl)benzamide (3.23 g), 4-ethoxycarbonylphenylboronic acid (3.63 g), copper (TJ) acetate (3.63 g), triethylamine (6.9 mL) and freshly activated 4A molecular sieves (12.5g) in DCM (250 mL) was stined at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through diatomaceous earth, washed with DCM (2 x 50 mL), the DCM removed in vacuo and the residual oil partitioned between ethyl acetate (300 mL) and IM hydrochloric acid (200 L). The ethyl acetate layer was separated, washed sequentially with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO ), and evaporated to a residue which was chromatographed on silica with 40%> ethyl acetate in isohexane as eluant to give the desired compound (1.35 g).

1H ΝMR δ (CDC1₃): 1.3 (d, 3H), 1.4 (t, 3H), 2.45 (s, 3H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 4.35 (q, 2H), 4.5-4.6 (m, IH), 6.85 (s, IH), 7.0 (d, 2H), 7.1 (s, IH), 7.3 (d, IH), 8.05 (d, 2H), 10.5 (s, lH); m/z 472 (M+H)⁺

3-Hvdroxy-5- -!Tri»y)-2-methoxy-(l-methylethvnoxy}-N-(3-methyl-1.2.4-thiadiazol-2- ypbenzamide

A solution of 3-{[(lS)-2-methoxy-(l-methylethyl)oxy}-5-{phenylmethyloxy}-N-(3-methyl- l,2,4-thiadiazol-2-yl)benzamide (9.53 g) and thioanisole (13.9 mL) in trifluoroacetic acid (45 mL) was stirred at ambient temperature for 16 hours. The trifluoroacetic acid was removed in vacuo and the residual oil partitioned between ethyl acetate (100 mL) and aqueous sodium hydrogen carbonate solution (300 mL). The aqueous layer was separated, extracted with ethyl acetate (2 x 100 mL), and the combined organic extracts washed with brine, dried (MgSO ), and evaporated to a residue which was chromatographed on silica with 50%) ethyl acetate in isohexane as eluant to give the desired compound (4.5 g).

1H ΝMR δ (CDC1₃): 1.2 (d, 3H), 2.5 (s, 3H), 3.3 (s, 3H), 3.4-3.6 (m, 2H), 4.6-4.7 (m, IH), 6.6 (s, IH), 7.05 (s, IH), 7.1 (s, IH), 9.85 (s, IH), 13.2 (s, IH); m/z 324 (M+H)⁺ 3 - { \(l S >2-Methoxy-C 1 -methylethvnoxy} -5- {phenylmethyloxy} -N-(3-mefhyl- 1.2.4- thiadiazol-2-yl)benzamide

To a solution of 3-[(l₁S)-2-methoxy-(l-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (15.8 g) in DCM (260 mL) was added oxalyl chloride (5.24 mL), followed by DMF (1 drop), and the mixture stined at ambient temperature for 16 hours. The DCM and excess oxalyl chloride were removed in vacuo, the residual oil dissolved in DCM (50 L) and added to a solution of 5-amino-3-methyl- 1,2,4 thiadiazole (6.05 g) and triethylamine (14.6 mL) in DCM (150 mL) at 0-5°C, and the mixture stined at ambient temperature for 16 hours. The DCM and excess triethylamine were removed in vacuo, and the residual oil partitioned between ethyl acetate (250 mL) and IM hydrochloric acid (150 mL). The ethyl acetate layer was separated, washed sequentially with IM hydrochloric acid, aqueous sodium hydrogen carbonate solution, and brine, dried (MgSO₄), and evaporated to a residue which was chromatographed on alumina with ethyl acetate as eluant, then on silica with 30% ethyl acetate in isohexane as eluant to give the desired compound (9.6 g).

1HΝMR δ (CDCI₃): 1.3 (d, 3H), 2.45 (s,3H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 4.55-4.6 (m, IH), 5.05 (s,2H), 6.8 (s, IH), 7.1 (m, 2H), 7.25 (m, 5H), 10.7 (s, IH); m/z 414 (M+H)⁺

The synthesis of 3-[(lS)-2-methoxy-(l-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid is described in Example 3 above.

Example 18: 3-[4-(Azetidin-l-yIcarbonyl)-2-chlorophenoxy1-5-[(lS)-2-methoxy-(l- methyIethyl)oxy1-7V-(l-methyl-lH-pyrazol-3-yI)benzamide

To a suspension of 3-chloro-4-[(3-{[(l^)-2-methoxy-(l-methylethyl)oxy}-5-{[(l-methyl-lH- pyrazol-3-yl)amino]carbonyl}phenyl)oxy]benzoic acid (344 mg), HATU (366 mg) and azetidine hydrochloride (88 mg) in DMF (10 mL), was added DIPEA (0.50 mL) and the mixture stined at ambient temperature for 24 hours. Water (30 mL) was added and the mixture extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with brine, dried ( gSO₄), and evaporated to a residue which was cliromatographed on silica eluting with a gradient of 50-100%> ethyl acetate in hexane to give the desired compound (197 mg). 1H NMR δ (CDC1₃): 1.3 (d, 3H), 2.4 (m, 2H), 3.4 (s, 3H), 3.5 (m, 2H), 3.8 (s, 3H), 4.2-4.4 (m, 4H), 4.6 (m, IH), 6.7 (d, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (d, IH), 7.8 (d, IH), 8.60 (br s, IH); m/z 499 (M+H)⁺ hi a similar manner, Examples 18a-18e were also prepared:

The required acids for the preparation of Examples 18 & 18a-e were prepared as described below: 3-Chloro-4-[(3-r(lS)-2-methoxy-(l-methylethvnoxy1 -5-{r(l-methyl-lH-pyrazol-3- yl)amino]carbonyl}phenyl)oxy]benzoic acid

To a solution of methyl 3-chloro-4-(3-[(l<S)-2-methoxy-(l-methylethyl)oxy]-5-{[(l-methyl- lH-pyrazol-3-yl)amino]carbonyl}phenoxy)benzoate (2.23 g) in TΗF (58 mL) was added a IM solution of lithium hydroxide monohydrate in water (11.7 mL) . The mixture was stined at ambient temperature for 18 hours and the TΗF removed in vacuo. The aqueous layer was acidified with 2M hydrochloric acid (5.85 mL), and the solid precipitate filtered off, washed with water and dried in vacuo to give the desired acid (1.87g). 1HNMR δ (CDCI₃): 1.4 (d, 3Η), 3.4 (s, 3H), 3.6 (m, 2H), 3.8 (s, 3H), 4.7 (m, IH), 6.95 ( , IH), 7.05 (m, IH), 7.1 (d, IH), 7.3 (m, 2H), 7.6 (m, 2H), 8.1 (s, IH), 10.75 (br s, IH); m/z 460 (M+H)⁺

The acids required for the synthesis of Examples 18a-e were made using an analogous method:

The required esters for Example 18 & 18a-e were prepared as described below:

Methyl 3 -chloro-4-(3 -[ ( 1 -?)-2-methoxy-( 1 -methylethvDox v] -5 - ( F ( 1 -methyl- lH-pyrazol-3 - yl amino1carbonyl}phenoxy)benzoate

To a solution of 3-hydroxy-5-[(1 )-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol- 3-yl)benzamide (832 mg, 2.72 mmol) and methyl-3-chloro-4-fluorobenzoate (504 mg, 2.72 mmol) in acetonitrile (20 mL) was added potassium carbonate (364 mg, 2.72 mmol) and the stined mixture heated at 160°C in a 'Smith Creator Microwave' for 30 minutes. The mixture was allowed to return to ambient temperature and pressure, filtered and evaporated to a residue which was chromatographed on silica with 0 -50% ethyl acetate in hexane as eluant to give the desired compound (1.11 g). m/z 474 (M+Η)⁺ The esters required for the synthesis of Examples 18a-e were prepared using an analogous method:

The precursor for Example 18c was prepared at 150°C in DMF for 4 hours, using 1.2 equivalents ofthe fluoro-ester. The precursor for Examples 18d-e was prepared at 150°C in DMF for 2 hours.

The methyl 4-fluoro-2-methoxybenzoate used in the preparation ofthe precursor for Examples 18d-e was prepared from 4-fluoro-2-methoxybenzoic acid according to the procedure described in WO98/13332.

The synthesis of 3 -hydroxy-5 - [( 15)-2-methoxy-( 1 -methylethyl)oxy] -N-( 1 -methyl- 1 H-pyrazol- 3-yl)benzamide is described in Example 3. Example l9: 3-{4-f(Dimethylamino carbonyllphenoxy}-5-r(lS)-2-methoxy-l- methylethoxyl-N-lH-pyrazoI-3-ylbenzamide

To a suspension of 4-{3-[(lS)-2-methoxy-l-methylethoxy]-5-[(lH-pyrazol-3- ylamino)carbonyl]phenoxy}benzoic acid (280 mg, 0.55 mmol), HATU (260 mg, 0.685 mmol) and dimethylamine (0.345 mL of 2.0M solution in THF, 0.685 mmol) in DMF (1 mL) was added DIPEA (0.238 mL, 1.37 mmol) and reaction mixture stined for 16 hours at ambient temperature. Water was then added to reaction mixture and extracted into ethyl acetate (3x25 mL). Organic layer was washed with saturated sodium hydrogen carbonate and saturated brine solution and dried (MgSO₄). Filtrate was concentrated in vacuo and residue chromatographed (50-100% ethyl acetate in isohexane) to give a white solid (95 mg; 40%). 1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 2.95 (s, 6H), 3.3 (s, 3H), 3.5 (m, 2H), 4.75 (m, IH), 6.6 (s, IH), 6.8 (s, IH), 7.05 (d, 2H), 7.2 (s, IH), 7.4 (d, 2H), 7.45 (s, IH), 7.6 (s, IH), 10.8 (s, IH). m/z 439 (M+H)⁺

In a similar manner, Examples 19a-d were also prepared:

The required acid for the preparation of Examples 19 and 19a was prepared as described below: 4-{3-[(lιS)-2-Methoxy-l-methylethoxyl-5-[(lH-pyrazol-3-ylamino carbonyl]phenoxy}benzoic acid

To a solution of tert-butyl 3-({3-[4-(ethoxycarbonyl)phenoxy]-5-[(lS)-2-methoxy-l- methylethoxy]benzoyl} amino)- lH-pyrazole-1 -carboxylate (1.75 g, 3.25 mmol) in TΗF (16 mL) and water (8 mL) was added IM solution of sodium hydroxide (16 mL; 5.0equiv) and reaction mixture allowed to stir at room temperature for 16 hours. The TΗF was removed in vacuo and IM citric acid added until pΗ 3-4. Pale yellow precipitate was filtered off and washed with water to give a pale yellow solid which was dried in vacuo (1.18g, 71%>). ^!Η NMR δ (d₆-DMSO): 1.2 (d, 3H), 3.25 (s, 3H obscured by water pealc), 3.4-3.5 (m, 2H), 4.75 (m, IH), 6.55 (s, IH), 6.85 (s, IH), 7.1 (d, IH), 7.25 (s, IH), 7.45 (s, IH), 7.6 (d, IH), 7.95 (d, IH), 10.85 (s, IH); m/z 412 (M+H)⁺.

The acids required for the preparation of Examples 19b-d were prepared in a similar manner:

The ester required for the preparation of Examples 19 and 19a was prepared as follows: tert-Butyl 3-(i3-[4-(ethoxycarbonyl)phenoxy1-5-r(l>S)-2-methoxy-l- methylethoxy]benzoyl} amino^')- lH-pyrazole- 1 -carboxylate

tert-Butyl 3 -( {3-hydroxy-5- [(1 »S)-2-methoxy- 1 -methylethoxy]benzoyl} amino)- lH-pyrazole- 1 - carboxylate (391 mg, 1 mmol), ethyl-4-boronic acid benzoate (388 mg, 2.0 equiv), copper (TJ) acetate (363 mg, 2.0 equiv) and triethylamine (0.7 mL; 5.0 equiv) were suspended in dry DCM over freshly activated powdered 4 A molecular sieves (ca. 1 g) for 7 hours under an ambient atmosphere. Reaction mixture filtered through diatomaceous earth was washed with DCM (x3). Filtrate concentrated in vacuo, taken up in ethyl acetate and washed with IM hydrochloric acid, saturated sodium hydrogen carbonate, saturated brine and dried (MgSO₄). Filtered, filtrate concentrated in vacuo and chromatographed (0-50% ethyl acetate/isohexane) to give a brown oil (210 mg, 39%) ¹H NMR δ (CDCI3): 1.3 (d, 3H), 1.4 (t, 3H), 1.6 (s, 9H), 3.4 (s, 3H), 3.5 (m, 2H), 4.35 (q, 2H), 4.5 (m, IH), 6.8 (s, IH), 7.0 (d, 2H), 7.05 (s, 2H), 7.2 (s, IH), 8.0 (s, IH), 8.05 (d, 2H), 9.2 (s, br, IH); m/z 440 (M+H)⁺.

tert-Butyl 3-({3-hydroxy-5-[(liS -2-methoxy-l-methylethoxy]benzoyl}amino -lH-pyrazole-l- carboxylate

A solution of tert-butyl 3-({3-(benzyloxy)-5-[(l_5)-2-methoxy-l - methylethoxy]benzoyl} amino)- lH-pyrazole-1 -carboxylate (23 g, 47.8 mmol) in TΗF (140 mL) and ethanol (140 mL) was evacuated and purged with nitrogen (x3). 10% Palladium on carbon (2.3 g; 10% w/w) was added and reaction mixture was evacuated and finally purged with hydrogen gas. Reaction mixture was left to stir at ambient temperature under a hydrogen balloon for 16 hours. Pd/C was filtered tlirough diatomaceous earth and the filtrate concentrated in vacuo to give a white foam (18 g, 97%). 1H NMR δ (d₆-DMSO): 1.2 (d, 3Η), 1.55 (s, 9H), 3.25 (s, 3H obscured by water peak), 3.4-3.5

(m, 2H), 4.7 (m, IH), 6.5 (s, IH), 6.95 (d, IH), 7.0 (s, IH), 7.1 (s, IH), 8.2 (d, IH), 9.65 (s,

IH), 11.2 (s, br, IH); m/z 392 (M+H)⁺

tert-Butyl 3-({3-(berιzyloxy)-5-[(l)S)-2-methoxy-l-methylethoxy]beιιzoyl}amino)-lH- pyrazole-1 -carboxylate

To a suspension of 3-[(15)-2-methoxy-(l-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (20.7 g, 65.6 mmol), ΗATU (31.2 g, 82.0 mmol) and tert-butyl 3-amino-lH-pyrazole-l- carboxylate (15.0 g, 82.0 mmol) in DMF (30 mL) was added DIPEA (28.5 mL, 164 mmol) and reaction mixture stined for 16 hours at ambient temperature. Water (250 mL) was then added to reaction mixture and extracted into diethyl ether (3x150 mL). Organic layer was washed with saturated brine solution and dried (MgSO₄). Filtrate was concentrated in vacuo and residue crystallised on standing. Washed with isohexane to give yellow crystals (23.4 g;

73%). m/z 482 (M+H)⁺.

The preparation of 3-[(lιS)-2-methoxy-(l -methylethyl)oxy]-5- {[phenylmethyl]oxy}benzoic acid was described in Example 3.

The preparation of tert-butyl 3-amino-lH-pyrazole-l-carboxylate was described in Example 14.

The ester required for the preparation of Example 19b was prepared as follows:

Ethyl 3-fluoro-4-(3- (l»S -2-methoxy-l-methylethoxy1-5-[(lH-pyrazol-3- ylamino)carbonyl]phenoxy}benzoate

To a suspension of tert-butyl 3-({3-hydroxy-5-[(lxS)-2-methoxy-l- methylethoxy]benzoyl} amino)- lH-pyrazole-1 -carboxylate (587 mg, 1.5 mmol), caesium carbonate (488 mg, 1.5 mmol) in DMA (3 mL) was added ethyl 3,4-difLuorobenzoate (279 mg, 1.5 mmol). This mixture was heated at 110°C for 16 hours. The reaction mixture was filtered and concentrated in vacuo then the residue chromatographed on silica, eluting with 0- 70% ethyl acetate in hexane, to give the desired compound as a yellow oil (271 mg, 40%>) 1H NMR (CDC1₃): 1.3 (d, 3Η), 1.4 (t, 3H), 3.4 (s, 3H), 3.5 (m, 2H), 4.4 (q, 2H), 4.6 (m, IH), 6.75 (s, IH), 6.85 (s, IH), 7.1 (s, IH), 7.15 (s, IH), 7.3 (s, IH), 7.5 (d, IH), 7.8 (d, IH), 7.85 (d, IH), 9.4 (s, IH)

The preparation of tert-butyl 3-({3-hydroxy-5-[(l_S)-2-methoxy-l- methylethoxy]benzoyl}amino)-lH-pyrazole-l-carboxylate was described in Example 19.

The ester required for the preparation of Example 19c was prepared as follows: tert-Butyl 3-({3-[4-(ethoxycarbonvDphenoxy]-5-[(l_l$^r)-2-methoxy-l- methylethoxy]benzoyl}amino -5-methyl-lH-pyrazole-l-carboxylate

Freshly activated 4A molecular sieves (1.5 g) were added to a solution of tert-butyl 3-({3- hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoyl}amino)-5-methyl-lH-pyrazole-l- carboxylate (1.0 g, 2.47 mmol), (4-ethoxycarbonylphenyl)boronic acid (718 mg, 3.7 mmol), copper (TJ) acetate (672 mg, 3.7 mmol) and triethylamine (1.7 mL, 12.3 mmol) in DCM (40 mL). The mixture was stined at ambient temperature for 2 days then filtered through diatomaceous earth and the DCM removed in vacuo. The residual oil was partitioned between ethyl acetate (35 mL) and IN hydrochloric acid (35 mL), the ethyl acetate layer separated, washed with saturated aqueous sodium hydrogen carbonate solution (35 L), brine (35 mL), dried (MgSO₄) and evaporated to a residue which was chromatographed on silica, eluting with 40 - 60%) ethyl acetate in hexane, to give the desired compound as an orange oil (80mg, 6%). 1H NMR (CDC1₃): 1.3 (d, 3Η), 1.4 (t, 3H), 1.6 (s, 9H), 2.55 (s, 3H), 3.4 (s, 3H), 3.5 (m, 2H), 4.4 (q, 2H), 4.6 (m, IH), 6.8 (s, IH), 6.9 (s, IH), 7.05 (d, 2H), 7.2 (s, IH), 7.35 (s, IH), 8.05 (d, 2H), 9.4 (s, IH)

tert-Butyl 3 -( {3 -hydroxy- 5 - [(1 _S -2-mefhoxy- 1 -methylethoxy]benzoyl} amino)- 5 -methyl- 1H- pyrazole-1 -carboxylate was prepared in an analogous fashion to tert-butyl 3-({3-hydroxy-5- [(l_S)-2-methoxy-l-methylethoxy]benzoyl} amino)- lH-pyrazole-1 -carboxylate, described in Example 19, starting from 3-[(15)-2-methoxy-(l-methylethyl)oxy]-5- {[phenylmethyl]oxy}benzoic and tert-butyl 3-ammo-5-methyl-lH-pyrazole-l -carboxylate.

tert-Butyl 3-((3-hydroxy-5- (l-S^T)-2-methoxy-l-methylethoxy1benzoyl}amino -5-methyl-lH- pyrazole- 1 -carboxylate

1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 1.55(s, 9H), 3.2 -3.3 (s, 3H obscured by water peak), 3.2 -3.3 (s, 3H obscured by water peak), 3.4 - 3.5 (ro, 2H), 4.65 (m, IH), 6.45 (s, IH), 6.75 (s, IH), 6.95 (s, IH), 7.1 (s, IH), 9.65 (s, IH), 11.05 (brs, IH); m/z 406 (M+H)⁺.

tert-Butyl 3-((3-(berιzyloxy -5-[(lιS)-2-methoxy-l-methylethoxy1beι zoyl}amino)-5-rrιethyl- lH-pyrazole- 1 -carboxylate

1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 1.55 (s, 9H>, 3.25 (s, 3H obscured by water peak), 3.4-3.5 (m, 2H), 4.7 (m, IH), 5.15 (s, 2H), 6.7 (s, IH), 6.8 (s, IH), 7.2 (s, IH), 7.25 (s, IH), 7.3 - 7.5 (m, 5H), 11.15 (brs, IH); m/z 496 (M+H)⁺.

The ester required for the preparation of Example 19d was prepared as follows:

Ethyl 3-chloro-4-(3-[ lιS)-2-methoxy-l-methylethoxy]-5-{[(5-methyl-lH-pyrazol-3- yl aminolcarbonyl}phenoxy)benzoate

Ethyl 3-chloro-4-fluorobenzoate (242 mg, 1.2 nrxnol) was added to a suspension of te -butyl 3 -( { 3 -hydroxy-5 -[( 1 »S)-2-mefhoxy- 1 -methylethoxy]benzoyl} amino)-5 -methyl- lH-pyrazole- 1 - carboxylate (405 mg, 1 mmol) and potassium caxbonate (1 mmol) in butyronitrile (5 rnL). This mixture was placed in a microwave and heated at 190°C for 2.5 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water then extracted with ethyl acetate (3 x 25 mL). Tlie organics were dried (MgSO ) and concentrated in vacuo. The crude mixture (420mg, 86%>) was used in the next step without further purification. The preparation of tert-butyl 3-({3-hydroxy-5-[(1 )-2-methoxy-l- methylethoxy]benzoyl}amino)-5-methyl-lH-pyrazole-l-carboxylate was described in Example 19c. The preparation of ethyl 3-chloro-4-fluorobenzoate is described in the literature (Journal of Fluorine Chemistry, 1991, 53(2), 301-305).

Example 20 : 3-[4-(Ethylsulfonyl -2-fluorophenoxyl-5-[(lιy)-2-methoxy-l-methylethoxy1- N-lH-pyrazol-3-ylbenzamide

A suspension of tert-butyl 3-({3-hydroxy-5-[(l_5 -2-methoxy-l- methylethoxy]benzoyl} amino)- lH-pyrazole-1 -carboxylate (391 mg, 1 mmol), cesium carbonate (325 mg, 1 mmol) and 3,4-difluorophenyl ethyl sulfone (206 mg, 1 mmol) in DMA (3 mL) was heated to 120°C for 4 hours. Water (20 mL) was added to the reaction mixture and then was extracted into ethyl acetate (3x30 mL) and washed with brine. Organic phase was dried (MgSO₄), concentrated in vacuo and residue chromatographed (50-100%) ethyl acetate/isohexane) to give a white solid (120 mg, 25%>). 1HΝMR δ (d₆-DMSO): 1.1 (t, 3Η), 1.2 (d, 3H), 3.25 (s, 3H), 3.3 (q, 2H), 3.5 (m, 2H), 4.75 (m, IH), 6.6 (s, IH), 6.95 (s, IH), 7.3 (s, IH), 7.35 (t, IH), 7.45 (s, IH), 7.6 (s, IH), 7.7 (d, IH), 7.95 (dd, IH), 10.8 (s, br IH). m/z 477 (M+H)⁺

The following examples were prepared in an analogous fashion.

The preparation of tert-butyl 3-({3-hydroxy-5-[(lS)-2-α ethoxy-l- methylethoxy]benzoyl}amino)-lH-pyrazole-l-carboxyLate used in the preparation of Examples 20 and 20a was described in Example 19.

The preparation of 3-hydroxy-5-[(lS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH- pyrazol-3-yl)benzamide used in the preparation of ExaMnple 20b was described in Example 3 The preparation of tert-butyl 3-({3-hydroxy-5-[(lS)-2-αιethoxy-l- methylethoxy]benzoyl} amino)-5 -methyl- IH-pyrazole-L -carboxylate used in the preparation of Example 20c was described in Example 19.

3,4-Difluorophenyl ethyl sulfone used in the preparation of Example 20 and 20b was prepared as described below.

3.4-Difluorophenyl ethyl sulfone

To a solution of 3,4-difluorophenyl ethyl sulfide (1.50 g) in DCM (50 mL) was added 75% m- chloroperbenzoic acid (2.97 g) and the mixture stined at ambient temperature for 16h. The mixture was washed successively with saturated potassium carbonate (20 mL) and brine (30 mL) then dried with magnesium sulphate, filtered and reduced in vacuo. The resultant clear oil was chromatographed on silica (eluting with 0-50%o ethyl acetate in ώo-hexane) and the faster running product isolated (0.90 g). The required 3,4-difluorophenyl ethyl sulfone was used without further characterisation.

3,4-DifTuorophenyl methyl sulfone used in the preparation of Example 20a was prepared in an analogous manner from 3,4-difluorophenyl methyl sulfide.

The l-(3,4-difluorobenzoyl)azetidine used in the preparation of Example 20c was prepared as described below.

1 -(3.4-Difluorobenzoyl azetidine

Oxalyl chloride (1.05 mL, 12.0 mmol) was added to a solution of 3,4-difluorobenzoic acid (1.58 g, 10 mmol) in DCM (50 mL) containing DMF (1 drop). The reaction was stined at ambient temperature for 16 h then evapourated to dryness. The residue was redissolved in DCM (25 mL) and azetidine hydrochloride (1.12 g, 12.0 mmol) added followed by triethylamine (4.18 mL, 30.0 mmol). The mixture was stined at ambient temperature for 2 h then concentrated in vacuo. The residue was partitioned between ethyl acetate and IN hydrochloric acid, the organic phase washed with a saturated aqueous solution of sodium bicarbonate followed by brine, dried (MgSO₄), and concentrated in vacuo. The title compound was crystallized from an ethyl acetate / hexane mixture to give a white crystalline solid (1.0 g, 51%). 1H NMR δ (CDCI₃): 2.4 (m, 2H), 4.3 (m, 4H), 7.2 (m, IH), 7.4 (m, IH), 7.5 (t, IH). Example 21 : 3-[4-(Azetidin-l-ylcarbonyI)-2-fluorophenoxyl-5-f(lS)-2-methoxy-l- methylethoxyl-N-lH-pyrazol-3-ylbenzamide

To a suspension of 3-[4-(azetidin-l-ylcarbonyl)-2-fluorophenoxy]-5-[(l)S)-2-methoxy-l- methylethoxy]benzoic acid (300 mg, 0.75 mmol), HATU (356 mg, 0.938 mmol) and tert- butyl 3-amino-lH-pyrazole-l-carboxylate (172 mg, 0.938 mmol) in DMF (2 mL) was added DIPEA (0.326 mL, 1.88 mmol) and reaction mixture stined for 16 hours at ambient temperature. Water was then added to reaction mixture and extracted into ethyl acetate (3x25 mL). Organic layer washed with saturated sodium hydrogen carbonate and saturated brine solution and dried (MgSO₄). Filtrate concentrated in vacuo to give an orange oil. This was dissolved in DCM (4 mL) and trifluoroacetic acid (0.445 mL, 8.0 equiv) was added. Reaction mixture stined at ambient temperature for 8 hours. Saturated sodium carbonate was added to the reaction mixture and the phases separated. Organic phase was dried (MgSO₄) and concentrated in vacuo to give a white foam (26 mg, 7%). 1H NMR δ (CDC1₃): 1.3 (d, 3Η), 2.4 (m, 2H), 3.4 (s, 3H), 3.55 ( , 2H), 4.2 (m, 2H), 4.35 (m, 2H), 4.6 (m, IH), 6.75 (s, IH), 6.8 (app s, IH), 7.05 (t, IH), 7.1 (s, IH), 7.3 (s, IH), 7.4 (d, IH), 7.5 (app d, IH), 7.5 (app s, IH), 9.6 (s, br, IH). m/z 469 (M+H)⁺, 467 (M-H)^"

3- 4-(Azetidm-l-ylcarbonyl -2-fluorophenoxy]-5-[(l^-2-methoxy-l-methylethoxy]benzoic acid

To a solution of methyl 3-[4-(azetidin-l-ylcarbonyl)-2-fluorophenoxy]-5-[(1 )-2-methoxy-l- methylethoxy]benzoate (400 mg, 1 mmol) in THF (6 mL) and water (1 mL) was added IM solution of sodium hydroxide (3 mL; 5.0equiv) and reaction mixture allowed to stir at room temperature for 3 hours. The THF was removed in vacuo and IM citric acid added until pH 3-4. Ethyl acetate was added and the phases separated. The organic phase was dried (MgSO₄) and concentrated in vacuo to give a clear oil (305 mg, 79%). 1H NMR δ (CDCI₃): 1.3 (d, 3H), 2.4 (m, 2H), 3.4 (s, 3H), 3.5 (m, 2H), 4.2-4.4 (m, 4H), 4.6 (m, IH), 6.8 (s, IH), 7.05 (t, IH), 7.25 (s, IH), 7.4 (s, IH), 7.45 (d, HT), 7.5 (d, IH); m/z 403 (M+H)⁺.

Methyl 3-[4-(azetidin-l-ylcarbonyl -2-fluorophenoxy]-5-[(l)S)-2-methoxy-l- ιnethylethoxy^"|benzoate

To a solution of methyl 3-hydroxy-5-[(l)S)-2-methoxy-(l-methylethyl)oxy]benzoate (480 mg, 2 mmol) in DMA (2 mL) were added potassium carbonate (552 mg, 4 mrnol), and a solution of 1- (3,4-difluorobenzoyl)azetidine (394 mg, 2 mmol) in DMA (2 mL). Re.action mixture was heated to 110°C and left to stir for 16 hours. Reaction mixture filtered and water (20 mL) added to reaction mixture. Extracted into ethyl acetate, washed with saturated sodium hydrogen carbonate solution and brine. Solution dried (MgS0 ) and concentrated in vacuo to an oil (400 mg, 48%>). Residue used without further purification or characterisation.

The preparation of methyl 3-hydroxy-5-[(l)S)-2-methoxy-(l-methylethyl)oxy]benzoate was described in Example 11. The preparation of l-(3,4-difluorobenzoyl)azetidine was described in Example 20c.

Example 22: 3-.4-(Azetidin-l-ylcarbonyl)phenoxyl-5-.(lS)-2-meth oxy-l-methylethoxyl-iV- (5-methyl-lH-pyrazol-3-yl)benzamide

A solution of 3-[4-(azetidin-l-ylcarbonyl)-2-chlorophenoxy]-5-[(lS)-2-methoxy-l-methylethoxy]- N-(5-methyl-lH-pyrazol-3-yl)benzamide (100 mg, 0.2 mmol) and triet-hyla ine (0.139 mL, 1 mmol) in THF (2.5 mL) and ethanol (2.5 mL) was evacuated and purged with nitrogen (x3). 10%> w/w Palladium on carbon (10 mg) was added, the reaction mixture evacuated and purged with hydrogen gas. The reaction mixture was left to stir at ambient temperature under hydrogen for 48 hours. The solid residues were removed by filtration through diatomaceous earth and the mixture partitioned between ethyl acetate and IM hydrochloric acid solution. The organic phase was dried (MgSO ) and the filtrate concentrated in vacuo. The residue was cliromatographed on silica, eluting with 0-70% methanol in ethyl acetate, to give the product (14 mg). 1H NMR δ (d₆-DMSO): 1.2 (d, 3H), 2.2 (s, 3H), 2.25 (m, 2H), 3.25 (s, 3H obscured by water pealc), 3.5 (m, 2H), 4.00 (m, 2H), 4.3 (m, 2H), 4.75 (m, IH), 6.35 (s, IH), 6.8 (s, IH), 7.05 (d, 2H), 7.2 (s, IH), 7.4 (s, IH), 7.65 (d, 2H), 10.7 (s, IH), 12.1 (s br, IH). m/z 465 (M+H)⁺, 463 (M-H)⁺

The preparation of 3-[4-(azetidin-l-ylcarbonyl)-2-chlorophenoxy]-5-[(l_S)-2-methoxy-l- methylethoxy]-N-(5-methyl-lH-pyrazol-3-yl)benzamide was described in Example 19d.

Example 23: 3-r(lS)-2-Methoxy-l-methylethoxyl-N-(l-methyl-lH-pyrazol-3-yl)-5-[4-(1.2.4- oxadiazol-3-yllphenoxylbenzamide

3-{4-[(Ηydroxyamino)(imino)methyl]phenoxy}-5-[(lιS)-2-methoxy-l-methylethoxy]-N-(l- methyl- lH-pyrazol-3-yl)benzamide was taken up in trimethyl orthoformate (3 mL) and 2 drops of BF₃.etherate added. The resulting solution was heated to 55°C in a CEM explorer microwave for 80 mins. The volatiles were removed under reduced pressure and the resulting oil chromatographed on silica, eluting with 0-100%> ethyl acetate in iso-hexane, to give the desired compound as a white foam (295 mg) 1H ΝMR δ(d₆-DMSO) δ 1.23 (d, 3Η), 3.40 - 3.58 (m, 2H), 3.75 (s, 3H), 4.71 m, IH), 6.54 (s, IH), 6.86 (s, IH), 7.18 - 7.28 (m, 3H), 7.44 (s, IH), 7.57 (s, IH), 8.06 (d, 2H), 9.65 (s, IH),

10.82 (s, IH); m/z 450 (M+H)⁺. 3 - {4-[(Hydroxyamino)(imino)methyl]phenoxy } -5 - [( 1 S)-2-methoxy- 1 -me thylefhox V| -N-( 1 - methyl- lH-pyrazol-3-yl)benzamide

Ηydroxylamine (50%> w/w solution, 1 mL) was added to a solution of 3-(4-cyaιιopb-tenoxy)-5- [(lιS)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3-yl)benzamide (30» 0 mg, 0.74 mmol) in ethanol (3 mL) and the reaction mixture allowed to stir at room temperature for 18 hours. The volatiles were removed in vacuo to give the desired compound as a colourless foam (325 mg). /z = 440 (M+Η)⁺

The preparation of 3-(4-cyanophenoxy)-5-[(l)S -2-methoxy-(l-methylethyl)oxy]-N- (1-methyl- lH-pyrazol-3-yl)benzamide was described in Example 6.

BIOLOGICAL

Tests:

The biological effects ofthe compounds of formula (1) may be tested in the following way:

(1) Enzymatic activity Enzymatic activity of recombinant human pancreatic GLK may be measured by incubating GLK, ATP and glucose. The rate of product (ie G-6-P) formation may b>e determined by coupling the assay to a G-6-P dehydrogenase, ΝADP/ΝADPH system and measuring the linear increase with time of optical density at 340nm (Matschinsky e^~t al 1993). Activation of GLK by compounds can be assessed using this assay in the presence or absence of GLKRP as described in Brocklehurst et al (Diabetes 2004, 53, 535-541).

Production of recombinant GLK and GLKRP Human GLK and GLKRP cDΝA was obtained by PCR from human pancreatic and hepatic mRΝA respectively, using established techniques described in Sambrook J, Fritsch EF & Maniatis T, 1989. PCR primers were designed according to the GLK and GLKRP cDNA sequences shown in Tanizawa et al 1991 and Bonthron, D.T. et al 1994 (later conected in Warner, J.P. 1995). Cloning in Bluescript II vectors GLK and GLKRP cDNA was cloned in E. coli using pBluescript TJ, (Short et al 1998) a recombinant cloning vector system similar to that employed by Yanisch-Penon C et al (1985), comprising a colEI-based replicon bearing a polylinker DNA fragment containing multiple unique restriction sites, flanked by bacteriophage T3 and T7 promoter sequences; a filamentous phage origin of replication and an ampicillin drug resistance marker gene.

Transformations E. Coli transformations were generally carried out by electroporation. 400 mL cultures of strains DH5a or BL21(DE3) were grown in L-broth to an OD 600 of 0.5 and harvested by centrifugation at 2,000g. The cells were washed twice in ice-cold deionised water, resuspended in lmL 10%> glycerol and stored in aliquots at -70°C. Ligation mixes were desalted using Millipore V series™ membranes (0.0025mm) pore size). 40mL of cells were incubated with lmL of ligation mix or plasmid DNA on ice for 10 minutes in 0.2cm electroporation cuvettes, and then pulsed using a Gene Pulser™ apparatus (BioRad) at 0.5kVcm^_1, 250mF. Transformants were selected on L-agar supplemented with tetracyline at lOmg/mL or ampicillin at lOOmg/mL.

Expression GLK was expressed from the vector pTB375NBSE in E.coli BL21 cells, producing a recombinant protein containing a 6-His tag immediately adjacent to the N-terminal methionine. Alternatively, another suitable vector is pET21(+)DNA, Novagen, Cat number

697703. The 6-His tag was used to allow purification ofthe recombinant protein on a column packed with nickel-nitrilotriacetic acid agarose purchased from Qiagen (cat no 30250). GLKRP was expressed from the vector pFLAG CTC (IBI Kodak) in E.coli BL21 cells, producing a recombinant protein containing a C-terminal FLAG tag. The protein was purified initially by DEAE Sepharose ion exchange followed by utilisation ofthe FLAG tag for final purification on an M2 anti-FLAG immunoaffinity column purchased from Sigma-Aldrich (cat no. A1205). (2) Oral Glucose Tolerance Test (OGTT) Oral glucose tolerance tests were done on conscious Zucker obese fa/fa rats (age 12-13 weeks or older) fed a high fat diet (45 %> kcal fat) for at least two weeks prior to experimentation. The animals were fasted for 2 hours before use for experiments. A test compound or a vehicle was given orally 120 minutes before oral adminisfration of a glucose solution at a dose of 2 g/kg body weight. Blood glucose levels were measured using a Accucheck glucometer from tail bled samples taken at different time points before and after administration of glucose (time course of 60 minutes). A time curve ofthe blood glucose levels was generated and the area-under-the-curve (AUC) for 120 minutes was calculated (the time of glucose administration being time zero). Percent inhibition was determined using the AUC in the vehicle-control group as zero percent inhibition.

Example lib Example III 07 Compounds ofthe invention generally have an activating activity for glucokinase with an EC₅₀ of less than about 500nM. For example, Example 1 lb has an EC₅₀ of 30nM. Example 1 lb and Example IJ107 in WO 03/015774 have broadly similar EC₅₀ values. However Example 1 lb has superior oral exposure and exhibits 29%> OGTT activity at 10 mg/kg but Example JJ107 in WO 03/015774 is not active at 10 mg/kg.

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Claims

Claims:

1. A compound of Formula (I) :

(I) wherein:

R¹ is methoxymethyl;

R² is selected from -C(O)NR⁴R⁵, -SO₂NR⁴R⁵, -S(O)_pR⁴ and HET-2; HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quatemised, with 1 or 2 substituents independently selected from

R⁶; HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, wherein a -CH₂- group can optionally be replaced by a -C(O)- , and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to an S(O) or S(O)₂ group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R ; R³ is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano;

R⁴ is selected from hydrogen, (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted 7 c c with 1 group selected from R ) and -C(O)NR R ], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and HET-2; R⁵ is hydrogen or (l-4C)alkyl; or R⁴ and R together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3; R⁶ is independently selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-

4C)alkyl, (l-4C)alkylS(O)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)aUcylamino(l-4C)alkyl, di(l-4C)alkylamino(l-4C)alkyl and HET-4;

R⁷ is selected from -OR⁵, (l-4C)alkyl, -C(0)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkoxy(l- 4C)alkyl, hydroxy(l-4C)alkyl and -S(O)pR⁵;

HET-3 is an N-linked, 4, 5 or 6- membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH - group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R⁸; or

HET-3 is an N-linked, 7 membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further heteroatom (in addition to the linking N atom) independently selected from O, S and N, wherein a -CH₂- group can optionally be replaced by a -C(O)- group and wherem a sulphur atom in the ring may optionally be oxidised to an S(O) or S(O)₂ group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R ; or

HET-3 is an 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom (in addition to the linking N atom), wherein a -CH - group can optionally be replaced by a -C(O)-; which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from hydroxy and R³;

R⁸ is selected from -OR⁵, (l-4C)alkyl, -C(0)(l-4C)alkyl, -C(O)NR⁴R⁵, (l-4C)alkylamino, di(l-4C)alkylamino, HET-3 (wherein said ring is unsubstituted), (l-4C)alkoxy(l-4C)alkyl, hydroxy(l-4C)alkyl and -S(O)pR⁵; HET-4 is a 5- or 6-membered, C-or N- linlced unsubstituted heteroaryl ring containing 1, 2 or

3 ring heteroatoms independently selected from O, N and S; p is (independently at each occunence) 0, 1 or 2; m is 0 or 1 ; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof.

2. A compound ofthe formula (I) as claimed in Claim 1 or a salt, pro-drug or solvate thereof with the proviso that compounds exemplified in WO2004/076420, which would otherwise fall within the scope of this invention, are excluded.

3. A compound ofthe formula (I) as claimed in Claim 1 or Claim 2 or a salt, pro-drug or solvate thereof wherein R¹ has the (S) configuration.

4. A compound ofthe formula (I) as claimed in Claim 1, Claim 2, or Claim 3 or a salt, pro-drug or solvate thereof, wherein HET-1 is a 5-membered ring.

5. A compound ofthe formula (I) as claimed in any one of Claims 1 to 4 or a salt, pro-drug or solvate thereof, wherein R² is selected from -C(O)NR⁴R⁵ and -SO₂NR⁴R⁵ and R⁴ and R together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3.

6. A compound ofthe formula (I) as claimed in any one of Claims 1 to 5, or a salt, pro-drug or solvate thereof, wherein HET-3 is a 4- to 6-membered ring.

7. A compound ofthe formula (I) as claimed in Claim 1, Claim 2 or Claim 3, or a salt, pro-drug or solvate thereof, wherein R² is selected from -C(O)NR⁴R⁵ and -SO₂NR⁴R⁵ and R⁴ is selected from (l-4C)allcyl [substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO₂R⁵, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and HET-2.

8. A compound ofthe formula (I) as claimed in Claim 1, Claim 2 or Claim 3, or a salt, pro-drug or solvate thereof, wherein R² is -SO₂R⁴ and R⁴ is selected from (l-4C)alkyl [substituted by 1 or 2 substituents independently selected from HET-2, -OR⁵, -SO₂R⁵, (3- 6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and -C(O)NR⁵R⁵], (3- 6C)cycloalkyl (optionally substituted with 1 group selected from R⁷) and HET-2.

9. A compound ofthe formula (I) as claimed in Claim 1, Claim 2 or Claim 3, or a salt, pro-drug or solvate thereof, wherein R² is HET-2.

10. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 9, or a salt, pro-drug or solvate thereof, together with a pharmaceutically acceptable diluent or carrier.

11. A compound according to any one of Claims 1 to 9 or a pharmaceutically-acceptable salt, solvate or pro-drug thereof for use as a medicament.

12. A compound according to any one of Claims 1 to 9 for use in the preparation of a medicament for treatment of a disease mediated through GLK..

13. A compound according to any one of Claims 1 to 9 for use in the preparation of a medicament for treatment of type 2 diabetes.

14. A method of treating GLK mediated diseases by administering an effective amount of a compound of Fonnula (I) as claimed in any one of Claims 1 to 9 or salt, solvate or pro-drag thereof, to a mammal in need of such treatment.

15. The method of Claim 14 wherein the GLK mediated disease is type 2 diabetes.

16. A process for the preparation of a compound of Formula (I) as claimed in any one of Claims 1 to 9, which comprises (wherein variables are as defined in Claim 1 unless otherwise stated):

(a) reaction of an acid of Formula (1TJ) or activated derivative thereof with a compound of Formula (IV),

COT) (IV); or

(b) reaction of a compound of Formula (V) with a compound of Formula (VI),

(V) (VI) 1 7 1 wherein X is a leaving group and X is a hydroxyl group or X is a hydroxyl group and X² is a leaving group; [or by reaction with the intermediate ester Formula (VTJ), wherein P¹ is a protectmg group followed by ester hydrolysis and amide formation];

(V) (vπ) or

(c) reaction of a compound of Formula (VIII) with a compound of Formula (IX)

wherein X³ is a leaving group or an organometallic reagent and X⁴ is a hydroxyl group or X³ is a hydroxyl group and X⁴ is a leaving group or an organometallic reagent; [or by reaction or (VIJJ) with the intermediate ester Formula (X), followed by ester hydrolysis and amide formation];

(VIU) (X) or

(d) reaction of a compound of Formula (XI) with a compound of Formula (XU),

^XVHET-I )

(XI) (XU); wherein X⁵ is a leaving group; and thereafter, if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a salt, pro-drag or solvate.

17. A compound as exemplified herein, or a salt, pro-drug or solvate thereof.