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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
  • C07D411/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
  • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to a group of benzoyl amino heterocyclyl compounds which may be useful in the treatment or prevention of a disease or medical condition mediated through glucokinase (GLK or GK), leading to a decreased glucose threshold for insulin secretion.
• GLK or GK glucokinase
• 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.
• the main plasma membrane glucose transporter is GLUT2.
• GLK glucose-6-phosphate
• GLK glucokinase
• 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 whole body glucose homeostasis and both are dysfunctional in diabetes [2].
• Maturity-Onset Diabetes of the 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 glucose stimulated insulin secretion.
• rare activating mutations of GLK reduce this threshold resulting in familial hyperinsulinism [6, 6a, 7].
• hepatic glucokinase activity is also decreased in type 2 diabetics [8].
• GLK global or liver selective overexpression of GLK prevents or reverses the development of the diabetic phenotype in both dietary and genetic models of the disease [9-12].
• 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].
• GLK regulatory protein GLK regulatory protein
• F6P fructose-6-phosphate
• FlP fructose- 1 -phosphate
• F6P fructose-6-phosphate
• FlP 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 FlP predominates in the post-prandial state.
• the pancreatic ⁇ -cell expresses GLK in the absence of GLKRP. Therefore, ⁇ -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 selectively in the liver.
• 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 of the hypothalamus, a region of the 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].
• Intracerebroventricular (icv) infusion of glucose analogues that are competitive inhibitors of glucokinase, stimulate food intake in lean rats [29, 30].
• icv infusion of glucose suppresses feeding [31].
• 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 of the same compounds acting in the liver and/or pancreas in normalising glucose homeostasis, for the treatment of Type 2 diabetes.
• 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 of the incretin peptides GIP (glucose-dependent insulinotropic polypeptide) and GLP-I (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, b-cell function and survival and body weight as a consequence of stimulating GIP and GLP-I secretion from these entero-endocrine cells.
• glucokinase activators In WO00/58293 and WO01/44216 (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 of the in vitro assay described hereinafter.
• Compounds of the present invention may activate GLK directly or may activate GLK by inhibiting the interaction of GLKRP with GLK.
• 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).
• WO03/000267 describes a group of benzoyl amino pyridyl carboxylic acids which are activators of the enzyme glucokinase (GLK).
• R 3 is a phenyl or 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 R 1 is an (substituted) alkyl ether and R 2 is (substituted) phenoxy.
• the compounds of the invention may have favourable metabolic profiles and/or toxicity profiles.
• the compounds of the invention may also have superior potency and/or advantageous physical properties (as described above) and/or favourable toxicity profiles and/or favourable metabolic profiles in comparison with other GLK activators known in the art, as well as those described in WO 03/015774.
• R 1 is selected from (l-4C)alkyl and (3-6C)cycloalkyl;
• HET-I is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position relative to the amide nitrogen to which the ring is attached and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 7 and/or on 1 or 2 available carbon atoms by a substituent independently selected from R 6 ;
• Ring A is selected from phenyl, HET-2 and HET-3; wherein when Ring A is phenyl it is
• R 2 is selected from -C(O)NR 4 R 5 , SOpR 4 , and -SO 2 NR 4 R 5 ;
• R 3 is selected from halo, methyl and trifluoromethyl;
• R 4 is selected from hydrogen, (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-5, -OR 5 , -SO 2 R 5 , (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 15 ) and -C(O)NR 5 R 5 ], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 15 ) and HET-5;
• HET-5 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 2 - 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 (l-4C)alkyl substituents; R 5 is hydrogen or (l-4C)alkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4 to 7 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 2 - group can optionally be replaced by a -C(O)
• R 4 and R 5 together with the nitrogen atom to which they are attached form a 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 2 - group can optionally be replaced by a -C(O)-; which ring is optionally substituted on an available carbon by 1 substituent selected from hydroxy, methyl and halo, or on an available nitrogen atom by methyl;
• R 6 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 and di( 1 -4C)alkylamino(l -4C)alkyl;
• R 7 is independently selected from (l-4C)alkyl, 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 and di(l- 4C)alkylamino(l-4C)alkyl;
• R 8 is selected from hydroxy, (l-4C)al
• R 9 is selected from (l-4C)alkyl, -C(O)(I -4C)alkyl, aminocarbonyl, (1- 4C)alkylaminocarbonyl, di(l-4C)alkylaminocarbonyl, (l-4C)alkoxy(l-4C)alkyl, hydroxy(l-
• HET-2 is a 5- or 6- membered heteroaryl ring, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N; which ring is substituted on an available carbon atom by a substituent selected from R 2 , and is optionally further substituted on 1 or 2 available carbon atoms by a substituent independently selected from R 3 and/or on an available nitrogen atom (provided it is not thereby quatemised) by a substituent selected from R 10 ;
• R 10 is selected from (l-4C)alkyl, (3-6C)cycloalkyl, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-
• HET-3 is a fused bicyclic ring system of formula -B-C; wherein B is a Ring is directly attached to the linking oxygen atom and Ring B is phenyl or is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S (provided there are no 0-0, S-S or 0-S bonds in the ring); wherein Ring B is optionally substituted on any nitrogen atom by a substituent selected from
• R 11 is independently selected from (l-4C)alkyl, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-
• R 12 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;
• HET-4 is a 5- or 6-membered, C-or N- linked unsubstituted heteroaryl ring containing 1, 2 or
• Ring C is a 5-7 membered heterocyclic ring fused to Ring B, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N (provided that there are no 0-0, S-O or
• R 13 is selected from (l-4C)alkyl, (3-6C)cycloalkyl, benzyl, (l-4C)alkylcarbonyl, (1- 4C)alkylsulphonyl, hydroxy(l-4C)alkyl and (l-4C)alkoxy(l-4C)alkyl;
• R 14 is selected from (l-4C)alkyl, (3-6C)cycloalkyl, (l-4C)alkoxy, hydroxy, fluoro and chloro;
• R 15 is independently selected from (l-4C)alkyl, hydroxy(l-4C)alkyl and hydroxy; n is 0 or 1 ; p is (independently at each occurrence) 0, 1 or 2; or a salt thereof.
• R 1 is selected from (l-4C)alkyl and (3-6C)cycloalkyl;
• HET-I is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position relative to the amide nitrogen to which the ring is attached and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 7 and/or on 1 or 2 available carbon atoms by a substituent independently selected from R 6 ;
• Ring A is phenyl, substituted by R 2 and optionally further substituted by a group selected from R 3 ;
• R 2 is selected from -C(O)NR 4 R 5 , SOpR 4 , and -SO 2 NR 4 R 5 ;
• R 3 is selected from halo, methyl and trifluoromethyl;
• R 4 is selected from hydrogen, (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-5, -OR 5 , -SO 2 R 5 , (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 15 ) and -C(O)NR 5 R 5 ], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 15 ) and HET-5;
• HET-5 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 2 - 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 (l-4C)alkyl substituents; R 5 is hydrogen or (l-4C)alkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4 to 7 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 2 - group can optionally be replaced by a -C(O)
• R 6 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 and di(l-4C)alkylamino(l-4C)alkyl;
• R 7 is independently selected from (l-4C)alkyl, 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 and di(l- 4C)alkylamino( 1 -4C)alkyl;
• R 15 is independently selected from (l-4C)alkyl, hydroxy(l-4C)alkyl and hydroxy; n is 0 or 1; p is (independently at each occurrence) 0, 1 or 2; or a salt thereof.
• R 1 is selected from (l-4C)alkyl and (3-6C)cycloalkyl;
• HET-I is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position relative to the amide nitrogen to which the ring is attached and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 7 and/or on 1 or 2 available carbon atoms by a substituent independently selected from R 6 ;
• Ring A is HET-2;
• HET-2 is a 5- or 6- membered heteroaryl ring, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N; which ring is substituted on an available carbon atom by a substituent selected from R 2 , and is optionally further substituted on 1 or 2 available carbon atoms by a substituent independently selected from R 3 and/or on an available nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 10 ;
• R 2 is selected from -C(O)NR 4 R 5 , SOpR 4 , and -SO 2 NR 4 R 5 ;
• R 3 is selected from halo, methyl and trifluoromethyl
• R 4 is selected from hydrogen, (l-4C)alkyl [optionally substituted by 1 or 2 substituents independently selected from HET-5, -OR 5 , -SO 2 R 5 , (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 15 ) and -C(O)NR 5 R 5 ], (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 15 ) and HET-5
• HET-5 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 2 - 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
• R 4 and R 5 together with the nitrogen atom to which they are attached form a 4 to 7 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 2 - 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 atom by 1 or 2 substituents independently selected from R 8 and/or on an available nitrogen atom by a substituent selected from R 9 ; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 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 2 - group can optionally be replaced by
• R 7 is independently selected from (l-4C)alkyl, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-4C)alkyl,
• R is selected from hydroxy, (l-4C)alkoxy, (l-4C)alkyl, aminocarbonyl, (1-
• R 9 is selected from (l-4C)alkyl, -C(O)(I -4C)alkyl, aminocarbonyl, (1-
• R 10 is selected from (l-4C)alkyl, (3 ⁇ 6C)cycloalkyl, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-
• R 15 is independently selected from (l-4C)alkyl, hydroxy(l-4C)alkyl and hydroxy; n is O or 1; p is (independently at each occurrence) 0, 1 or 2; or a salt thereof.
• R 1 is selected from (l-4C)alkyl and (3-6C)cycloalkyl;
• HET-I is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position relative to the amide nitrogen to which the ring is attached and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 7 and/or on 1 or 2 available carbon atoms by a substituent independently selected from R 6 ;
• R 6 is independently selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-
• R 7 is independently selected from (l-4C)alkyl, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-4C)alkyl,
• Ring A is HET-3; HET-3 is a fused bicyclic ring system of formula -B-C; wherein B is a ring directly attached to the linking oxygen atom and Ring B is phenyl or is a
• R 11 is independently selected from (l-4C)alkyl, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-
• R 12 is independently selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-
• HET-4 is a 5- or 6-membered, C-or N- linked unsubstituted heteroaryl ring containing 1, 2 or
• Ring C is a 5-7 membered heterocyclic ring fused to Ring B, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N (provided that there are no 0-0, S-O or
• R 13 is selected from (l-4C)alkyl, (3-6C)cycloalkyl, benzyl, (l-4C)alkylcarbonyl, (1-
• R 14 is selected from (l-4C)alkyl, (3-6C)cycloalkyl, (l-4C)alkoxy, hydroxy, fluoro and chloro; n is O or 1; p is (independently at each occurrence) 0, 1 or 2; or a salt thereof.
• Reference hereinafter to a compound of formula (I) should be understood to apply equally to compounds of formula (II), (III) or (IV), even where not explicitly stated.
• heterocyclyl group HET-I encompass heteroaryl rings which may be substituted on nitrogen, such substitution may not result in charged quaternary nitrogen atoms, removal of aromaticity of the ring or unstable structures. It will be appreciated that the definition of HET-I is not intended to include any O- O, O-S or S-S bonds. It will be appreciated that the definition of HET-I is not intended to include unstable structures.
• any single carbon atom in HET-I may only be substituted by one group R 6 in order to maintain aromaticity of the ring.
• Up to two different carbon atoms in a HET-I ring may be substituted by an R 6 group, each of which may be the same or different, provided the structure thereby formed is stable and aromatic.
• R 8 can be present on any or all available carbon atoms in the heterocyclic ring formed by NR 4 R 5 ; each carbon atom can be substituted with 1 or 2 R 8 groups which may be the same or different, provided the structure thereby formed is stable (so, for example, it is not intended to cover gem-dihydroxy substitution).
• Compounds of Formula (I) may form salts which are within the ambit of the invention.
• Pharmaceutically acceptable salts are preferred although other salts may be useful in, for example, isolating or purifying compounds.
• the invention relates to compounds of formula (I) as hereinabove defined or to a pharmaceutically acceptable salt.
• 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 hydroly sable 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.
• 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 ⁇ -butyl are specific for the branched chain version only. For example, "(l-4C)alkyl” includes methyl, ethyl, propyl, isopropyl and ⁇ -butyl. An analogous convention applies to other generic terms.
• HET-I containing a nitrogen in the 2-position
• HET-I encompasses but is not limited to the heterocycles shown in the following structures:
• HET-I 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.
• HET-2 examples include thienyl, furyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl.
• Further suitable examples of HET-2 include aromatic heterocycles where a ring nitrogen or sulfur atom has been oxidised but aromaticity has been preserved, for example a pyridine N-oxide.
• Further suitable examples of HET-2 include thiazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl.
• Suitable examples for a 4-7 membered ring formed by R 4 and R 5 together with the ' nitrogen to which they are attached include morpholino, thiomorpholino (and versions thereof wherein the sulfur is oxidised to an SO or S(O) 2 group), piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, 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 for a 6-10 membered bicyclic heterocyclic ring formed by R 4 and R 5 together with the nitrogen to which they are attached, as hereinbefore defined, 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 and wherein R represents the optional substituents on carbon or nitrogen defined hereinbefore):
• such a ring system is a [2,2,1] system such as (7-azabicyclo[2.2.1]hept-7-yl).
• such a ring system is a [2.1.1] system such as
• Suitable values for the bicyclic system HET-3 formed by ring B fused to Ring C include those where Ring C is pyridyl, pyrazinyl, pyrimidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, homothiomorpholinyl, oxathianyl, homooxathianyl, furyl, thienyl, pyrrolyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, isothiazolyl, pyranyl, 1 ,A- dioxolanyl, dihydrothienyl, dihydrofuryl and oxathiazepinyl. Further suitable values include those wherein Ring C is oxathiaze
• Ring C have been oxidised to a carbonyl group
• sulfur atoms in Ring C have been oxidised to an S(O) or S(O) 2 group.
• Ring B as a 5- or 6-membered heterocyclyl ring are furyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
• Further suitable vaues for Ring B are thiazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
• Still further suitable values for Ring B are thiazolyl and pyridyl.
• Ring B is phenyl.
• HET-3 may suitably be selected from the structures below (which may optionally be substituted as hereinbefore defined):
• suitable values for HET-3 are ring systems where Ring C is a 7- membered ring, for example:
• HET-3 includes the following formulae A to F, wherein each R 12a is independently hydrogen or is R 12 as hereinbefore defined, each R 13a is independently hydrogen or is R 13 as hereinbefore defined, each R 14a is independently hydrogen or is R 14 as hereinbefore defined:
• HET-3 Further suitable values for HET-3 include formulae G to P as follows:
• Ring C as 1,3-dioxolyl are intended to refer to structures such as the following (illustrated with Ring B is phenyl):
• Ring C as 1,4-dioxolanyl are intended to refer to structures such as the following (illustrated with Ring B is phenyl):
• suitable values for the bicyclic system formed by Ring C fused to Ring B as phenyl include the following (wherein each R 13a is hydrogen or is selected from R 13 as hereinbefore defined, R 14a is hydrogen or is selected from R 14 as hereinbefore defined and each R 12a is hydrogen or is R 12 as hereinbefore defined):
• the bicyclic system formed by Ring C fused to Ring B as phenyl is selected from formulae AA to MM (wherein R 12a is hydrogen or is selected from R 12 as hereinbefore defined, R 13a is hydrogen or is selected from R 13 as hereinbefore defined and each R 14a is hydrogen or R 14 as hereinbefore defined):
• the bicyclic system formed by Ring C fused to Ring B as phenyl is selected from:
• R 13a is hydrogen or is methyl and R 12a is hydrogen or is R 12 as hereinbefore defined, for example R 12a is hydrogen or fluoro, or for example R 12a is hydrogen.
• the bicyclic system formed by Ring C fused to Ring B as phenyl is selected from
• R 14a are hydrogen
• R 13a is hydrogen or is methyl
• R l2a is hydrogen or is R 12 as hereinbefore defined, for example R 12a is hydrogen or fluoro, or for example R 12a is hydrogen.
• the bicyclic system formed by Ring C fused to Ring B as phenyl is of formula EE.
• the bicyclic system formed by Ring C fused to Ring B as phenyl is of formula FF.
• the bicyclic system formed by Ring C fused to Ring B as phenyl is of formula GG.
• the bicyclic system formed by Ring C fused to Ring B as phenyl is of formula HH.
• the bicyclic system formed by Ring C fused to Ring B as phenyl is of formula (Z):
• Ring C is an optionally substituted 5-7 membered heterocyclic ring fused to the benzene ring, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N (provided that there are no 0-0, S-O or S-S bonds within the ring), wherein any ring carbon or sulfur atom may optionally be oxidised, provided that where Ring C contains two ring heteroatoms they are not both oxygen (such that for example, Ring C is not dioxolyl or dioxolanyl).
• HET-4 examples include thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl.
• HET-5 can be a saturated, or partially or fully unsaturated ring.
• HET-5 examples include azetidinyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, morpholino, morpholinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrrolidinyl, pyrrolidonyl, 2,5-dioxopyrrolidinyl, 1,1- dioxotetrahydrothienyl, 2-oxoimidazolidinyl, 2,4-dioxoimidazolidinyl, 2-oxo-l,3,4-(4- triazolinyl), 2-oxazolidin
• HET-5 may be linked by any appropriate available C or N atom, therefore for example, for HET-5 as "imidazolyl” includes 1- , 2-, 4- and 5- imidazolyl.
• 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 hydroxy(l-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-me
• 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 interaction.
• the synthesis of optically active forms 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.
• certain compounds may exist in tautomeric forms and that the invention also relates to any and all tautomeric forms of the compounds of the invention which activate GLK.
• the compound of formula (I) has the (S)-configuration at the pyrrolidone ring and is thereby a compound of formula (IA):
• the compound of formula (I) has the (Reconfiguration at the pyrrolidone ring and is thereby a compound of formula (IB):
• compounds of formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which activate GLK.
• compounds of formula (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.
• R 1 is (l-4C)alkyl
• R 1 is methyl or ethyl
• R 1 is (3-6C)acycloalkyl, such as cyclobutyl (4) R 1 is methyl, ethyl or cyclobutyl
• HET-I is a 5-membered heteroaryl ring
• HET-I is a 6-membered heteroaryl ring
• HET-I is substituted with 1 or 2 substituents independently selected from R 6
• HET-I is substituted with 1 substituent selected from R 6 (9) HET-I is substituted with 1 substituent selected from R 7
• HET-I is unsubstituted (11)
• HET-I is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, and triazolyl
• HET-I is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl
• HET-I is pyrazolyl, optionally substituted with a methyl group on an available carbon
• HET-I is pyrazinyl, optionally substituted with a methyl group on an available carbon atom
• HET-I is thiazolyl, optionally substituted with a methyl group on an available carbon atom
• HET-I is pyrazinyl, pyrazolyl or thiazolyl, optionally substituted with a methyl group on an available carbon atom
• R 6 is selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl and di(l-4C)alkylamino(l- 4C)alkyl (18) R 6 is selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl, aminomethyl, N-methylaminomethyl, dimethylaminomethyl
• R 6 is selected from (l-4C)alkyl, halo, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-4C)alkyl, (1-
• R 6 is selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl and methoxymethyl
• R 6 is selected from methyl, ethyl, chloro and fluoro
• R 7 is selected from (l-4C)alkyl, hydroxy(l-4C)alkyl and di(l-4C)alkylamino(l-4C)alkyl (24) R 7 is selected from methyl, ethyl, hydroxymethyl, methoxymethyl, aminomethyl, N-methylaminomethyl, dimethylaminomethyl
• R 7 is selected from (l-4C)alkyl, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-4C)alkyl, (1- 4C)alkylS(O)p(l-4C)alkyl, amino(l-4C)alkyl, (l-4C)alkylamino(l-4C)alkyl, and di(l- 4C)alkylamino(l-4C)alkyl (26) R 7 is selected from methyl, ethyl, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl (27) R 7 is selected from methyl, ethyl, hydroxymethyl and methoxymethyl (28) R 7 is selected from methyl and ethyl
• R 7 is methyl
• Ring A is phenyl (31) Ring A is HET-2 (32) Ring A is HET-3
• R 3 is chloro or fluoro
• R 3 is fluoro
• R 2 is -C(O)NR 4 R 5 (37) R 2 is -SO 2 NR 4 R 5
• R 2 is SOpR 4
• R 2 is -C(O)NR 4 R 5 or SO P R 4
• R 4 is selected from hydrogen, optionally substituted (l-4C)alkyl and optionally substituted (3-6C)cycloalkyl (41)
• R 4 is (l-4C)alkyl, such as methyl
• R 5 is (l-4C)alkyl, such as methyl
• R 4 and R 5 together with the nitrogen atom to which they are attached form a ring selected from morpholino, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl (50) R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidinyl ring (5I) R 4 and R 5 together with the nitrogen atom to which they are attached form an unsubstituted ring
• R 4 and R 5 together with the nitrogen atom to which they are attached form a ring mono- substituted either with a substituent R 8 or with a substituent R 9 (53) R 4 and R 5 together with the nitrogen atom to which they are attached form a 6-10 membered bicyclic saturated or partially unsaturated ring
• R 8 is selected from hydroxy, (l-4C)alkoxy, (l-4C)alkyl
• R 8 is selected from hydroxy, methoxy and methyl
• R 9 is selected from (l-4C)alkyl and -C(O)(I -4C)alkyl (57)
• R 2 is azetidinylcarbonyl
• HET-2 is a 5-membered heteroaryl ring
• HET-2 is a 6-membere heteroaryl ring
• HET-2 is selected from pyrazinyl and pyridyl
• HET-2 is substituted with a substituent selected from R 3 (62) HET-2 has one nitrogen substituent selected from R 10
• R 10 is (l-4C)alkyl
• R 10 is (3-6C)cycloalkyl
• R 10 is hydroxy(l-4C)alkyl or (l-4C)alkoxy(l-4C)alkyl
• R 10 is -C(O)(l-4C)alkyl
• R 10 is benzyl
• R 10 is (l-4C)alkylsulfonyl
• Ring B is 5- or 6-membered heteroaryl ring
• Ring B is phenyl or a 6-membered heteroaryl ring
• Ring B is a 5-membered heteroaryl ring
• Ring B is a 6-membered heteroaryl ring
• Ring C is a 5-membered ring
• Ring C is a 6-membered ring
• Ring C is a 7-membered ring (80) Ring C is unsubstituted
• Ring C is substituted on an available nitrogen atom by R 13
• Ring C is substituted on each available nitrogen atom by a substituent R 13 , wherein each R 13 is independently selected from (l-4C)alkyl and benzyl (83) Ring C is substituted on an available carbon atom by R 14
• Ring C is substituted on more than one available carbon atom by substituents independently selected from R 14
• Ring C is substituted on one or more available carbon atom by methyl, and/or twice on one carbon atom by methyl (86)
• Ring B is heteroaryl and Ring C is phenyl
• Ring B is heteroaryl and Ring C is heterocyclyl
• HET-3 is a 5,6 fused bicyclic system
• HET-3 is a 5,5 fused bicyclic system
• HET-3 is a 6,6 fused bicyclic system (91) HET-3 is a 5 ,7 fused bicyclic system
• HET-3 is a 6,7 fused bicyclic system
• HET-3 is selected from structures A to F as hereinbefore defined, particularly wherein R 13 and R 14 are both methyl and R 12 is chloro or fluoro
• HET-3 is selected from structures G to P as hereinbefore defined (95) Ring C is substituted by two R 14 and both are either methyl or fluoro
• Ring C is gem di-substituted by R 14 and both are either methyl or fluoro
• R 12 is chloro (100) R 12 is hydrogen or fluoro
• HET-3 is selected from structures AA to MM as hereinbefore defined
• HET-3 is selected from structures EE, FF, GG and HH
• HET-3 is selected from structures EE, FF and GG
• R 1 is selected from (l-4C)alkyl and (3-6C)cycloalkyl
• HET-I is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position relative to the amide nitrogen to which the ring is attached and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 7 and/or on 1 or 2 available carbon atoms by a substituent independently selected from R 6 ;
• Ring A is selected from phenyl, HET-2 and HET-3; wherein when Ring A is phenyl it is substituted by R 2 and optionally further substituted by a group selected from R 3 ;
• R 2 is selected from -C(O)NR 4 R 5 , SOpR 4 , and -SO 2 NR 4 R 5 ;
• R 3 is selected from halo, methyl and trifluoromethyl;
• R 4 is selected from hydrogen and (l-4C)alkyl [optionally substituted by a substituent selected from -OR 5 and -C(O)NR 5 R 5 ];
• R 5 is hydrogen or (l-4C)alkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4 to 7 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 2 - 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;
• R 6 is (l-4C)alkyl;
• R 7 is (l-4C)alkyl
• HET-2 is a 5- or 6- membered heteroaryl ring, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N; which ring is substituted on an available carbon atom by a substituent selected from R 2 , and is optionally further substituted on 1 or 2 available carbon atoms by a substituent independently selected from R 3 and/or on an available nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 10 ;
• R 10 is (l-4C)alkyl
• HET-3 is a fused bicyclic ring system of formula -B-C; wherein B is a Ring is directly attached to the linking oxygen atom and Ring B is phenyl or is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S (provided there are no 0-0, S-S or 0-S bonds in the ring); wherein Ring B is optionally substituted on any nitrogen atom by a substituent selected from R 11 and/or on any available carbon atom by 1 or 2 substituents independently selected from
• R n is (l-4C)alkyl
• R 12 is independently selected from (l-4C)alkyl and halo
• Ring C is a 5-7 membered heterocyclic ring fused to Ring B, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N (provided that there are no 0-0, S-O or
• R 13 is (l-4C)alkyl
• R 14 is selected from (l-4C)alkyl, fluoro and chloro; n is 0 or 1; p is (independently at each occurrence) 0, 1 or 2.
• R 1 is selected from (l-4C)alkyl and (3-6C)cycloalkyl;
• HET-I is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position relative to the amide nitrogen to which the ring is attached and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 7 and/or on 1 or 2 available carbon atoms by a substituent independently selected from R 6 ; Ring A is phenyl, substituted by R 2 and optionally further substituted by a group selected
• R 2 is selected from -C(O)NR 4 R 5 , SOpR 4 and -SO 2 NR 4 R 5 ;
• R 3 is halo
• R 4 is selected from hydrogen and (l-4C)alkyl [optionally substituted by a substituent selected from -OR 5 and -C(O)NR 5 R 5 ] ;
• R 5 is hydrogen or (l-4C)alkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4 to 7 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 2 - 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;
• R 6 is (l-4C)alkyl
• R 7 is (l-4C)alkyl; n is 0 or 1 ; p is (independently at each occurrence) 0, 1 or 2.
• R 1 is selected from (l-4C)alkyl and (3-6C)cycloalkyl;
• HET-I is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position relative to the amide nitrogen to which the ring is attached and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 7 and/or on 1 or 2 available carbon atoms by a substituent independently selected from R 6 ;
• Ring A is HET-3;
• HET-3 is a fused bicyclic ring system selected from formulae A to P as hereinbefore defined;
• R 12 is independently selected from (l-4C)alkyl and halo
• R 13 is (l-4C)alkyl
• R 14 is selected from (l-4C)alkyl, fluoro and chloro;
• R 6 is (l-4C)alkyl
• R 7 is (l-4C)alkyl
• n is 0 or 1
• p is (independently at each occurrence) 0, 1 or 2.
• R 1 is selected from (l-4C)alkyl and (3-6C)cycloalkyl;
• HET-I is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position relative to the amide nitrogen to which the ring is attached and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 7 and/or on 1 or 2 available carbon atoms by a substituent independently selected from R 6 ; Ring A is HET-3;
• HET-3 is a fused bicyclic ring system selected from formulae AA to MM as hereinbefore defined;
• R 12 is independently selected from (l-4C)alkyl and halo
• R 13 is (l-4C)alkyl
• R 14 is selected from (l-4C)alkyl, fiuoro and chloro
• R 6 is (l-4C)alkyl
• R 7 is (l-4C)alkyl; n is 0 or 1; p is (independently at each occurrence) 0, 1 or 2.
• R 1 is selected from (l-4C)alkyl and (3-6C)cycloalkyl;
• HET-I is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position relative to the amide nitrogen to which the ring is attached and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R 7 and/or on 1 or 2 available carbon atoms by a substituent independently selected from R 6 ;
• Ring A is HET-3;
• HET-3 is a fused bicyclic ring system selected from formulae EE, FF, GG and HH as hereinbefore defined;
• R 12 is independently selected from (l-4C)alkyl and halo
• R 13 is (l-4C)alkyl
• R 14 is selected from (l-4C)alkyl, fiuoro and chloro; R 6 is (l-4C)alkyl;
• R 7 is (l-4C)alkyl; n is 0 or 1; p is (independently at each occurrence) 0, 1 or 2.
• N-(5-methylpyrazin-2-yl)benzamide 3-[6-(Azetidine- 1 -carbonyl)pyridin-3-yl]oxy-5-[(3R)- 1 -ethyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5- methylpyrazin-2-yl)benzamide;
• a pro-drug is a bioprecursor or pharmaceutically acceptable compound being degradable in the body to produce a compound of the invention (such as an ester or amide of a compound of the invention, particularly an in- vivo hydroly sable ester).
• a compound of the invention such as an ester or amide of a compound of the invention, particularly an in- vivo hydroly sable ester.
• Various forms of prodrugs are known in the art.
• pro-drags are as follows.
• An in- vivo hydrolysable ester of a compound of the invention containing a carboxy or a hydroxy group is, for example, a pharmaceutically- acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
• Suitable pharmaceutically-acceptable esters for carboxy include
• C 1 to Cgalkoxymethyl esters for example methoxymethyl
• C 1 to C ealkanoyloxymethyl esters for example pivaloyloxymethyl
• phthalidyl esters C 3 to CgcycloalkoxycarbonyloxyC] to C 6 alkyl esters for example
• An in- vivo hydrolysable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
• inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
• ⁇ -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.
• compounds of Formula (I) may form pharmaceutically acceptable salts.
• a suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the 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.
• a suitable pharmaceutically acceptable salt of a compound of the invention 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, morpholine or tris-(2-hydroxyethyl)amine.
• 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
• a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxye
• a further feature of the invention is a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula (I) as defined above, or a pharmaceutically-acceptable salt thereof, together with a pharmaceutically-acceptable diluent or carrier.
• a compound of Formula (I), or a pharmaceutically-acceptable salt thereof as defined above for use as a medicament for treatment of a disease mediated through GLK, in particular type 2 diabetes.
• a compound of Formula (I) or a pharmaceutically-acceptable salt thereof in the preparation of a medicament for treatment of a disease mediated through GLK, in particular type 2 diabetes.
• the compound is suitably formulated as a pharmaceutical composition for use in this way.
• a method of treating GLK mediated diseases, especially diabetes by administering an effective amount of a compound of Formula (I) or a pharmaceutically-acceptable salt thereof, to a mammal in need of such treatment.
• a compound of Formula (I), or a pharmaceutically-acceptable salt thereof for treatment of a disease mediated through GLK.
• Specific diseases which may be treated by a compound or composition of the 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.
• the GLK/GLKRP system can be described as a potential "Diabesity" target (of benefit in both Diabetes and Obesity).
• a compound of Formula (I) or a pharmaceutically-acceptable salt thereof in the preparation of a medicament for use in the combined treatment or prevention, particularly treatment, of diabetes and obesity.
• a method for the combined treatment of obesity and diabetes by administering an effective amount of a compound of Formula (I) or a pharmaceutically-acceptable salt thereof, to a mammal in need of such treatment.
• a compound of Formula (I) or a pharmaceutically-acceptable salt thereof as defined above for use as a medicament for treatment or prevention, particularly treatment of obesity.
• a method for the treatment of obesity by administering an effective amount of a compound of Formula (I) or a pharmaceutically-acceptable salt thereof, to a mammal in need of such treatment.
• compositions of the invention may be particularly suitable for use as pharmaceuticals because of advantageous physical and/or pharmacokinetic properties, and/or favourable toxicity profile.
• the compositions of the invention may be 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 preferred.
• compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
• 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 rj-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
• Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the 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.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• 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-pyrrolidone, gum tragacanth 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
• the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, antioxidants (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 of the 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-occurring 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 of the 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.
• 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 of the 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 arranged to dispense a metered quantity of active ingredient.
• Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to disp
• 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.
• 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 of the total composition.
• Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
• the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
• 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.
• lower doses will be administered when a parenteral route is employed.
• a dose in the range for example, 0.5 mg to 30 mg per kg body weight will generally be used.
• a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
• Oral administration is however preferred.
• 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 of the simultaneous, sequential or separate administration of the individual components of the treatment. Simultaneous treatment may be in a single tablet or in separate tablets.
• chemotherapy may include the following main categories of treatment: 1) Insulin and insulin analogues;
• Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide), prandial glucose regulators (for example repaglinide, nateglinide);
• Agents that improve incretin action for example dipeptidyl peptidase IV inhibitors, and GLP-I agonists);
• Insulin sensitising agents including PPARgamma agonists (for example pioglitazone and rosiglitazone), and agents with combined PPARalpha and gamma activity;
• 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 absorption of glucose from the intestine for example acarbose
• Agents designed to treat the complications of prolonged hyperglycaemia for example aldose reductase inhibitors
• Anti-obesity agents for example sibutramine and orlistat
• Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (eg statins); PP ARa agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stands, synthetic inhibitors); bile acid absorption inhibitors (IBATi) and nicotinic acid and analogues (niacin and slow release formulations);
• Antihypertensive agents such as, ⁇ blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine); Angiotensin receptor antagonists (eg candesartan), ⁇ antagonists and diuretic agents (eg. furosemide, benzthiazide);
• ⁇ blockers eg atenolol, inderal
• ACE inhibitors eg lisinopril
• Calcium antagonists eg. nifedipine
• Angiotensin receptor antagonists eg candesartan
• ⁇ antagonists and diuretic agents eg. furosemide, benzthiazide
• Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor Vila inhibitors); antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin; 13) Agents which antagonise the actions of glucagon; and
• Anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone).
• non-steroidal anti-inflammatory drugs eg. aspirin
• steroidal anti-inflammatory agents eg. cortisone
• a compound of the 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 may be protected and deprotected using conventional methods.
• 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 York, 1991.
• Processes for the synthesis of compounds of Formula (I) are provided as a further feature of the invention.
• a process for the preparation of a compound of Formula (I) which comprises a process a) to g) (wherein the variables are as defined hereinbefore for compounds of Formula (I) unless otherwise defined): (a) reaction of an acid of Formula (V) or activated derivative thereof with a compound of Formula (VI);
• Y 1 and Y 2 are 0-4 atom linkers, wherein each linker atom is independently selected from C, N, S or O (wherein any C or S can be optionally oxidised and any atom can be optionally substituted provided it is not quaternised and there are no S-S or 0-0 bonds), X 6 can be any nucleophilic species and X 7 a leaving group or vice versa; process (f) could also be accomplished using the intermediate ester Formula (XVII), followed by ester hydrolysis and amide formation by procedures described elsewhere and well known to those skilled in the art;
• Suitable leaving groups X 1 to X 5 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-toluenesulfonyloxy; or a group (such as a hydroxy group) that may be converted into a leaving group (such as an oxytriphenylphosphonium group) in situ.
• Suitable values for R 1 containing a protected hydroxy group are any suitable protected hydroxy group known in the art, for example simple ethers such as a methyl ether, tert-butyl ether or silylethers such as -OSi[(l-4C)alkyl]3 (wherein each (l-4C)alkyl group is independently selected from methyl, ethyl, propyl, isopropyl, and tertbutyl).
• Examples of such trialkylsilyl groups are trimethylsilyl, triethylsilyl, triisopropylsilyl and tert- butyldimethylsilyl.
• Suitable values for hydroxy protecting groups are given hereinafter.
• Compounds of Formulae (V) to (XIV) are commercially available, or are known in the art, or may be made by processes known in the art, for example as shown in the accompanying Examples, or as described below. 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-0 or alkyl-O bond may be formed by nucleophilic substitution or metal catalysed processes, optionally in the presence of a suitable base.
• Compounds of Formula (XV) may be made by processes such as those shown in processes a) to d) and/or by those processes mentioned above for compounds of formulae (V) to (XIV).
• XVI may be made by reaction of suitable precursors with compounds of formula (VII) or derivatives thereof, for example, by nucleophilic displacement of a leaving group X 1 in a compound of formula (VII).
• Compounds of formula (VII) are generally commercially available or maybe made by simple functional group interconversions from commercially available compounds, or by literature methods. Examples of approaches to the pyrrolidone group are outlined in Schemes 1 and 2 below and are further illustrated in the accompanying examples.
• Step (i) proceeds according to the Mitsunobu reaction as is well known in the literature, more specifically, step (i) involves the reaction of a compound of Formula (VlII) with 3- hydroxyoxolan-2-one in the presence of triphenyl phosphine and DIAD, in a suitable solvent, for example anhydrous THF, and at a suitable temperature, for example 0 to 25°C, more suitably 20 to 25 0 C;
• a suitable solvent for example anhydrous THF
• a suitable temperature for example 0 to 25°C, more suitably 20 to 25 0 C;
• Step (ii) involves the reaction of a compound of Formula (XVIII) with a suitable alcohol, for example ethanol, in the presence of a suitable base, for example potassium carbonate, and at a suitable temperature, for example 0 to 25°C, more suitably 20 to 25 0 C;
• a suitable alcohol for example ethanol
• a suitable base for example potassium carbonate
• Step (iii) involves the reaction of a compound fo Formula (XIX) with methanesulfonyl chloride in the presenc of a suitable base, for example triethylamine, in a suitable solvent, for example DCM, and at a suitable temperature, for example 0 to 25 0 C, more suitably 20 to 25 0 C; and
• a suitable base for example triethylamine
• a suitable solvent for example DCM
• Steps (iv) and (v) involve the reaction of a compound of Formula (XX) with a suitable metal iodide, such as sodium iodide, and a (l-4C)alkylamine or (3-6C)cycloalkylamine, in a suitable solvent, for example acetonitrile, and at a suitable temperature with heating in a microwave, for example 100 to 130 0 C, more suitably 115 to 125°C.
• a suitable metal iodide such as sodium iodide
• a (l-4C)alkylamine or (3-6C)cycloalkylamine for example acetonitrile
• R 1 is selected from (l-4C)alkyl and (3-6C)cycloalkyl.
• Suitable reaction conditions for steps (i) and (ii) of Scheme 2 are as follows:
• Step (i) involves the reaction of 2,4-dibromobutanoyl chloride with a (l-4C)alkylamine or (3-6C)cycloalkylamine in a suitable solvent, such as water and DCM, and at a suitable temperature, for example 0 to 50 0 C, more suitably 10 to 3O 0 C; and
• a suitable solvent such as water and DCM
• Step (ii) involves the reaction of a compound of Formula (XXIII) with a suitable base, for example sodium hydride, in a suitable solvent, for example THF, and at a suitable temperature, for example 0 to 30 0 C, more suitably 10 to 15°C.
• a suitable base for example sodium hydride
• THF a suitable solvent
• a suitable temperature for example 0 to 30 0 C, more suitably 10 to 15°C.
• substituents R 3 , R 6 and/or R 7 may be introduced into the molecule at any convenient point in the synthetic sequence or may be present in the starting materials.
• a precursor to one of these substituents may be present in the molecule during the process steps a) to e) above, and then be transformed into the desired substituent as a final step to form the compound of formula (I); followed where necessary by i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a salt thereof.
• an appropriate coupling reaction such as a carbodiimide coupling reaction performed with EDAC (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in the presence of dimethylaminopyridine (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 a reagent known for such reactions such as l-chloro-N,N,2-trimethyl-prop-l -en- 1 -amine in the presence of a suitable solvent such as DCM.
• EDAC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
• DMAP dimethylaminopyridine
• DCM dichloromethane
• DMF dimethylformamide
• the acid chloride can then be reacted with a compound of Formula (VI) in the presence of a base, such as triethylamine or pyridine, in a suitable solvent such as chloroform or DCM at a temperature between O 0 C and 8O 0 C.
• a base such as triethylamine or pyridine
• a suitable solvent such as chloroform or DCM
• Process b) - compounds of Formula (VII) and (VIII) 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 0 C, optionally using microwave heating or metal catalysis such as palladium(H)acetate, palladium on carbon, copper(II)acetate or copper(I)iodide; alternatively, compounds of Formula (VII) and (VIII) can be reacted together in a suitable solvent, such as THF or DCM, with a suitable phosphine such as triphenylphosphine, and an azodicarboxylate such as diethylazodicarboxylate; process b) could also be carried out using a precursor to the ester of formula (IX) such as an aryl-nitrile or trifluoromethyl derivative, followed by conversion to a carboxylic acid
• Process d) - reaction of a compound of Formula (XIII) with a compound of Formula (XIV) 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 fert-butoxide at a temperature between 0 and 200 0 C, optionally using microwave heating or metal catalysis, such as palladium(II)acetate, palladium on carbon, copper(II)acetate or copper(I)iodide;
• Process e) - coupling reactions of amino groups with carboxylic or sulfonic acids or acid derivatives to form an amide are well known in the art and are described above for Process a).
• Process f) - cyclisations of a compound of formula (XVI) to a compound of formula (I) are well known in the art; for example, i) a coupling reaction of amino groups with carboxylic acids using coupling reagents or acid chlorides (see process a) to form amide bonds; ii) a coupling reaction of an amino group with a sulphonyl chloride in the presence of a suitable base, such as pyridine or triethylamine, in a suitable solvent such as DCM, toluene or pyridine at a temperature between O 0 C and 8O 0 C, to form a sulphonamide group; iii) reaction with 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 0 C, optionally using microwave heating or metal catalysis such as palladium(II)a
• compounds of the Formula (XVI) may be made from compounds of Formula (XVII), wherein each R group is independently a simple substituent (such as halo or cyano) or hydrogen, by processes well known to those skilled in the art such as functional group interconversions (for example hydrolysis, hydrogenation, hydrogenolysis, oxidation or reduction), and/or further functionalisation by standard reactions (such as amide or sulphonamide or metal-catalysed coupling, or nucleophilic displacement or electrophilic substitution reactions); compounds of formula (XVII) may be made from commercially available materials by processes such as those described herein in processes a) to e).
• each R group is independently a simple substituent (such as halo or cyano) or hydrogen
• Ring C from a pre-cursor and form the phenoxy link in a one-pot reaction, so that it is unclear whether process c) or process e) is actually the final step.
• Rearrangement of Ring C may also occur in some circumstances, for example it may occur in the following circumstances:
• 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. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
• a carboxy protecting group may be 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).
• 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 acyloxy lower alkyl groups, (e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (e.g. 1-methoxycarbonyloxy ethyl,
• aryl lower alkyl groups e.g. ⁇ -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
• (2-6C)alkenyl groups e.g. allyl and vinylethyl.
• hydroxy protecting groups include methyl, t-butyl, 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, rj-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, rj-nitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (e.g.
• amino protecting groups include formyl, aralkyl groups (e.g. benzyl and substituted benzyl, e.g. D . -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.
• aryl lower alkoxycarbonyl groups e.g. benzyloxycarbonyl, p_-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p_-nitrobenzyloxycarbonyl
• trialkylsilyl e.g. trimethylsilyl and t-butyldimethylsily
• Methods appropriate for removal of hydroxy and amino protecting groups include, for example, hydrogenation, nucleophilic displacement, acid-, base, metal- or enzymically-catalysed hydrolysis, catalytic hydrogenolysis or photolytically for groups such as o-nitrobenzyloxycarbonyl, or with fluoride ions for silyl groups.
• methylether protecting groups for hydroxy groups may be removed by trimethylsilyliodide.
• a tert-butyl ether protecting group for a hydroxy group may be removed by hydrolysis, for example by use of hydrochloric acid in methanol.
• 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-phenylvinyl).
• 4-alkoxybenzyl e.g. 4-methoxybenzyl
• 2,4- di(alkoxy)benzyl e.g. 2,4-di(methoxy)benzyl
• alk-1-enyl e.g. allyl, but-1-enyl and substituted vinyl e.g. 2-phenylvinyl
• 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 of the 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.
• alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid.
• Example 8 S-M-tAzetidine-l-carbonyQphenoxyl-S-rDSVl-methyl- ⁇ -oxo-pyrrolidin-S- ylloxy-N-(5-methylpyrazin-2-vDbenzamide
• Example 11 3-f(5-methyl-6.,6-dioxo-2-oxa-6- ⁇ 6 -thia-5-azabicvclor5.4.01undeca-8,10 ⁇ 2- trien-10-yl)oxyl-5-(l-methyl-2-oxo-pyrrolidin-3-vL)oxy-N-(5-methylpyrazin-2- yDbenzamide
• Example 12 S-f ⁇ -fAzetidine-l-carbonvOpyridin-S-ylloxy-S-fOSVl-methyl-l-oxo- pyrrolidin-3-ylloxy-N-pyrazin-2-yl-benzamide
• Example 13 3-f6-(Azetidine-l-carbonyl ' )pyridin-3-ylloxy-5-[(3S)-l-methyl-2-oxo- pyrroIidin-3-ylloxy-N-pyridin-2-yl-benzamide
• Example 14 3-f(ll-Chloro-5-methyl-6-oxo-2-oxa-5-azabicvclof5.4.01undeca-8.10.12- trien-10-yl)oxyl-5-f(3S)-l-methyl-2-oxo-pyrrolidin-3-ylloxy-N-(5-methylpyrazin-2- vDbenzamide
• Example 20 3-[6-(Azetidine-l-carbonyr)pyridin-3-yll oxy-5-r(3RVl-cvclobutyl-2-oxo- pyrro ⁇ din-3-ylloxy-N-(5-methylpyrazin-2-yl)benzamide
• Example 22 -f6-(Azetidine-l-carbonyl)pyridin-3-ylloxy-5-[(3R)-l-ethyl-2-oxo- pyrrolidin-3-yl
• Example 25 3-f(2,2-Dioxo-6-oxa-2- ⁇ 6 -thiabicvclof5.4.01undeca-7,9,ll-trien-9-vnoxyl-5- [(3S " )-l-methyl-2-oxo-pyrrolidin-3-ylloxy-N-(lH-pyrazol-3-yl)benzamide
• Example 27 3-[(6,6-dioxo-2-oxa-6- ⁇ 6 -thia-5-azabicvclo[5.4.01undeca-8 ⁇ 0.12-trien-10- v ⁇ oxyl-5-[(3S)-l-methyl-2-oxo-pyrrolidin-3-ylloxy-N-(5-methylpyrazin-2-v ⁇ benzamide
• N 9 N- Dimethylacetamide was removed by evaporation under reduced pressure.
• the residue was partitioned between ethyl acetate (30 mL) and water (50 mL).
• the organic phase was separated and the aqueous layer was acidified with hydrochloric acid (IN, 5 mL) and extracted with ethyl acetate (2 x 50 mL).
• the combined organic extracts were washed with brine, dried (MgSO 4 ) and concentrated under reduced pressure.
• the residue was purified by flash chromatography on silica eluting with 0-5% methanol in DCM to afford the product (120 mg, 40%).
• Example 32 N.N-DimethvI-5-r3-rf3S)-l-methyl-2-oxo-pyrrolidin-3-ylloxy-5-r(4-methyl- l,3-thiazol-2-vDcarbamoyl]phenoxylpyrazine-2-earboxamide
• the DMA was evaporated under reduced pressure and the residue was dissolved in water (200 mL), washed with ethyl acetate (3x50 mL), acidified with 2N hydrochloric acid and extracted with ethyl acetate (3 ⁇ 100 mL): The organic layer washed with water (2x20 mL) and brine (20 mL), dried (MgSO 4 ) and the solvent removed under reduced pressure to afford the product (6.18 g, 76%).
• 2,4-Dibromobutanoyl chloride (CAS no. 82820-87-9) (16.9 g, 64 mmol) in DCM (20 mL) was added dropwise to a solution of methylamine (20 mL) in water (30 mL) and DCM (30 mL) at 10-15°C, then warmed to 3O 0 C and stirred for 30 minutes. The organic layer was separated and the aqueous layer re-extracted with DCM (2x10 mL), the combined organic layers were washed with brine (20 mL), dried (MgSO 4 ) and evaporated to afford the product (16.3 g, 98%).
• the residue was purified by flash chromatography on silica eluting with 0-100% ethyl acetate in hexane to give the racemic product (8.7 g).
• the desired product was separated from its enantiomer by chiral HPLC using Merck 50mm 20 ⁇ m Chiralpak AS - No ASVOOSC JGOOl and ASVOOOSC BD004 columns in series, eluting with 30% ethylacetate in isohexane at a flow rate of 60 mL / min, using 9 separate injections of 70 mL of a 14 mg/ml solution of the racemate in ethanol (32 mL) and isohexane (38 mL) to afford the product (3.6 g, 41%) which eluted before its enantiomer.
• Methyl 3-hydroxy-5-phenylmethoxy-benzoate (CAS no. 54915-31-0) (10.3 g, 40 mmol) and 3-bromo-l-methyl-pyrrolidin-2-one (Intermediate 4) (8.54 g, 48 mmol) were dissolved in DMF and treated with potassium carbonate (12.1 g, 88 mmol) and stirred at room temperature for 16 hours and then at 50 0 C for 3 hours.
• the DMF was evaporated under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and water (30 mL). The organic layer was separated, washed with brine (30 mL), dried (MgSO 4 ) and evaporated under reduced pressure.
• the residue was purified by flash chromatography on silica eluting with 0- 100% ethyl acetate in hexane to give the racemic product (8.7 g).
• the desired product was separated from its enantiomer by chiral HPLC using Merck 50mm 20 ⁇ m Chiralpak AS - No ASVOOSC JGOOl and ASVOOOSC BD004 columns in series, eluting with 30% ethylacetate in isohexane at a flow rate of 60 mL / min, using 9 separate injections of 70 mL of a 14 mg/ml solution of the racemate in Ethanol (32 mL) and isohexane (38 mL) to afford the product (3.6 g, 41%) which eluted after its enantiomer.
• the combined aqueous extracts were acidified with 2N hydrochloric acid, extracted with a mixture of ethyl acetate and DCM (1:1, 3x20 mL), washed with brine, dried (MgSO 4 ), filtered and the solvent removed under reduced pressure.
• the residue from this was dissolved in THF (2 mL) and methanol (1 mL) and treated with 2M (trimethylsilyl)diazomethane (0.240 mL, 0.48 mmol) and stirred for 30 minutes.
• the solution was treated with acetic acid (1 drop), evaporated under reduced pressure.
• the reaction mixture was concentrated under reduced pressure then water (500 mL) and ethyl acetate (500 mL) were added. The organic layer was separated and the aqueous phase was re-extracted with ethyl acetate (5x15OmL). The combined organics were washed with citric acid (250 mL), saturated sodium bicarbonate solution (250 mL), brine (250 mL), dried (MgSO 4 ), filtered and evaporated under reduced pressure to give a solid which was recrystallised in ethyl acetate and dried under reduced pressure to give the product (18.2g, 47%).
• Methanesulfonyl chloride 13 ⁇ L, 0.16 mmol
• triethylamine 34 ⁇ L, 0.24 mmol
• ethyl 2-[3-[6-(azetidme-l-carbonyl)pyridin-3-yl]oxy-5-[(5- methylpyrazin-2-yl)carbamoyl]phenoxy]-4-hydroxy-butanoate (Intermediate 28) (65 mg, 0.12 mmol) in DCM (5 niL) at 0°C under nitrogen. The reaction was allowed to warm to RT and stirred for 2 hours.
• the aqueous fraction was acidified with 2N hydrochloric acid and extracted with ethyl acetate (3x100 mL), the combined organic layers were washed with water (2x20 mL) and brine (20 mL), dried (MgSO 4 ) and the solvent removed under reduced pressure. The residue was dissolved in THF (6 mL) and methanol (3 mL) and was treated dropwise with 2M
• Azetidine hydrochloride (6.14 g, 65.5 mmol) then triethylamine (24 mL, 187 mmol) were added and the mixture stirred at ambient temperature for 20 hours.
• the mixture was concentrated under reduced pressure and ethyl acetate (400 mL) added to the residue.
• the resulting mixture was washed with water (100 mL), filtered, washed with IM citric acid solution (50 mL), saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried (MgSO 4 ), filtered and the solvent removed under reduced pressure.
• the organic phase was separated, washed with water (10 mL) and brine (20 mL), dried (MgSO 4 ) and evaporated.
• the aqueous phase was acidified to pH 1 with 2N hydrochloric acid extracted with ethyl acetate (2 x 30 mL).
• the combined organic extracts were washed with water (2 x 20 mL), brine (20 mL), dried (MgSO 4 ) and evaporated.
• the residue was dissolved in THF (2 mL) and methanol (1 mL) and treated with 2M TMS- diazomethane (0.14 mL) stirred for 30 minutes.
• Enzymatic activity of recombinant human pancreatic GLK may be measured by incubating GLK, ATP and glucose.
• the rate of product formation may be determined by coupling the assay to a G-6-P dehydrogenase, NADP/NADPH system and measuring the linear increase with time of optical density at 340nm (Brocklehurst et al (Diabetes 2004, 53, 535-541 ).
• 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).
• GKHl and GKH4 were used to test the compounds of the invention.
• the GKHl assay is a manual, bench-top rate assay using 60 nmol/1 of recombinant human pancreatic GLK.
• the GLK activity rate is measured over a 5 minute window using a Multiskan Ascent spectrophotometer.
• the GKH4 assay is an automated end-point assay using 10 nmol/1 of recombinant human pancreatic GLK.
• the GLK activity is measured at 10 minutes after the initiation of the assay on a Perkin Elmer Envision spectrophotometer.
• GKHl and GKH4 do not contain GLKRP.
• Compounds of the invention generally have an activating activity for glucokinase with an EC 50 of less than about 20 ⁇ M, such as less than about 5 ⁇ M, such as less than about l ⁇ M, such as less than 50OnM, such as less than about 10OnM.
• Examples 1 to 32 activated glucokinase in the GKHl and/or GHK4 variants of the assay with EC 50 values as shown below. Table A
• Human GLK and GLKRP cDNA was obtained by PCR from human pancreatic and hepatic mRNA 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, Proc Natl Acad Sci 1991 Aug 15;88(16):7294-7 1991 and Bonthron, D.T. et al 1994 (later corrected in and Warner, J.P. et al, Mamm Genome. 1995 Aug;6(8):532-61995).
• GLK and GLKRP cDNA was cloned in E. coli using pBluescript II.
• 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 2,00Og. The cells were washed twice in ice-cold deionised water, resuspended in ImL 10% glycerol and stored in aliquots at -70 0 C. Ligation mixes were desalted using Millipore V seriesTM membranes (0.0025mm) pore size). 4OmL of cells were incubated with ImL of ligation mix or plasmid DNA on ice for 10 minutes in 0.2cm electroporation cuvettes, and then pulsed using a Gene PulserTM apparatus (BioRad) at
• 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.
• another suitable vector is pET21(+)DNA, Novagen, Cat number 697703.
• the 6-His tag was used to allow purification of the 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 of the FLAG tag for final purification on an M2 anti-FLAG immunoaff ⁇ nity column purchased from Sigma- Aldrich (cat no. A1205).
• Oral glucose tolerance tests may be performed 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 are fasted for 2 hours before use for experiments. A test compound or a vehicle is given orally 120 minutes before oral administration of a glucose solution at a dose of 2 g/kg body weight. Blood glucose levels are 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 of the blood glucose levels is generated and the area-under-the- curve (AUC) for 120 minutes calculated (the time of glucose administration being time zero). Percent reduction in glucose excursion is determined using the AUC in the vehicle-control group as zero percent reduction.
• Glucokinase activator efficacy in free feeding obese male Zucker fatty rats was assessed by measuring free feeding blood glucose levels in obese male Zucker fatty rats as follows. Rats were received from the AstraZeneca breeding unit at 9 weeks of age and allowed to acclimatise to a reverse light cycle (0900-2100 dark phase) for 3 weeks.
• vehicle group contains 10 animals and a single test group contains 8 animals; for each additional test group the control group size was increased by 2 animals.
• Animals were orally dosed, at a volume of 5ml/kg, at 0800 (ie Ih prior to entering the dark phase) with vehicle (1% w/v Pluronic F127) or the test compound (formulated in 1% Pluronic F127) at 3 mg/kg.
• Blood glucose was measured from a lO ⁇ l needle prick sample from the tail vein and determined using a Roche Accu-chek monitor. Measurements were taken at time zero (ie immediately prior to dosing), 0.5h, Ih, 2h, 3h, 4h, 6h, 8h, 12b. and 24h thereafter. Samples at the 12h and 24h time points were only taken if sufficient efficacy had been observed at the 8 hour time point.

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