WO2003074513A2 - Indole amide derivatives and their use as glycogen phosphorylase inhibitors - Google Patents

Indole amide derivatives and their use as glycogen phosphorylase inhibitors Download PDF

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WO2003074513A2
WO2003074513A2 PCT/GB2003/000893 GB0300893W WO03074513A2 WO 2003074513 A2 WO2003074513 A2 WO 2003074513A2 GB 0300893 W GB0300893 W GB 0300893W WO 03074513 A2 WO03074513 A2 WO 03074513A2
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oxo
chloro
carboxamide
indole
tetrahydroquinolin
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PCT/GB2003/000893
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French (fr)
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WO2003074513A3 (en
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Alan Martin Birch
Andrew David Morley
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to AU2003216991A priority Critical patent/AU2003216991A1/en
Priority to JP2003572981A priority patent/JP2005525364A/en
Priority to EP03712313A priority patent/EP1485371A2/en
Priority to US10/506,748 priority patent/US7169927B2/en
Publication of WO2003074513A2 publication Critical patent/WO2003074513A2/en
Publication of WO2003074513A3 publication Critical patent/WO2003074513A3/en

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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P3/08—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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • 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
    • 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

Definitions

  • the present invention relates to heterocychc amide derivatives, pharmaceutically acceptable salts and in vivo hydrolysable esters thereof.
  • These heterocychc amides possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity and thus are potentially useful in methods of treatment of a warm-blooded animal such as man.
  • the invention also relates to processes for the manufacture of said heterocychc amide derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit glycogen phosphorylase activity in a warm-blooded animal such as man.
  • the liver is the major organ regulating glycaemia in the post-absorptive state. Additionally, although having a smaller role in the contribution to post-prandial blood glucose levels, the response of the liver to exogenous sources of plasma glucose is key to an ability to maintain euglycaemia.
  • An increased hepatic glucose output (HGO) is considered to play an important role in maintaining the elevated fasting plasma glucose (FPG) levels seen in type 2 diabetics; particularly those with a FPG >140mg/dl (7.8mM).
  • Liver glycogen phosphorylase a activity is elevated in diabetic animal models including the db/db mouse and the fa/fa rat (Aiston S et al (2000). Diabetalogia 43, 589-597). Inhibition of hepatic glycogen phosphorylase with chloroindole inhibitors (CP91149 and CP320626) has been shown to reduce both glucagon stimulated glycogenolysis and glucose output in hepatocytes (Hoover et al (1998) J Med Chem 41, 2934-8; Martin et al (1998) PNAS 95, 1776-81). Additionally, plasma glucose concentration is reduced, in a dose related manner, db/db and ob/ob mice following treatment with these compounds.
  • Bay K 3401 Studies in conscious dogs with glucagon challenge in the absence and presence of another glycogen phosphorylase inhibitor, Bay K 3401, also show the potential utility of such agents where there is elevated circulating levels of glucagon, as in both Type 1 and Type 2 diabetes. In the presence of Bay R 3401, hepatic glucose output and arterial plasma glucose following a glucagon challenge were reduced significantly (Shiota et al, (1997), Am J Physiol, 273: E868).
  • heterocychc amides of the present invention possess glycogen phosphorylase inhibitory activity and accordingly are expected to be of use in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia and obesity, particularly type 2 diabetes.
  • A is phenylene or heteroarylene
  • m is 0, 1 or 2
  • n is 0, 1 or 2
  • R 1 is independently selected from halo, nitro, cyano, hydroxy, carboxy, carbamoyl, N-C 1 . 4 alkylcarbamoyl, NN ⁇ Cwalkyl ⁇ carbamoyl, sulphamoyl, N-C- ⁇ alkylsulphamoyl,
  • the two R 1 groups, together with the carbon atoms of A to which they are attached, may form a 4 to 7 membered ring, optionally containing 1 or 2 heteroatoms independently selected from O, S and ⁇ , and optionally being substituted by one or two methyl groups;
  • R 4 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, C ⁇ - 4 alkyl, C 2 - 4 alkenyl,
  • R is hydrogen, hydroxy or carboxy
  • R 3 is selected from hydrogen, hydroxy, C ⁇ alkoxy, C ⁇ - 4 alkanoyl, carbamoyl, C 3 - cycloalkyl
  • R 8 is independently selected from hydroxy, C 1 - 4 alkoxyC 1 . 4 alkoxy, hydroxyC 1 - alkoxy, 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, aryl, heterocyclyl, C 3 . cycloalkyl, C ⁇ - 4 alkanoyl, ⁇ alkoxy, C ⁇ - 4 alkylS(O) b - (wherein b is 0, 1 or 2), C 3 .
  • R 9 and R 10 together with the nitrogen to which they are attached form a 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents independently selected from oxo, hydroxy, carboxy, halo, nitro, cyano, carbonyl, C ⁇ - 4 alkoxy and heterocyclyl; or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -O- group may be replaced by a methyl; R 13 is selected from hydroxy, halo, trihalomethyl and C ⁇ - 4 alkoxy;
  • R is independently selected from hydrogen, C ⁇ - alkyl and hydroxyC 1 - 4 alkyl; or a pharmaceutically acceptable salt or pro-drug thereof.
  • a compound of formula (1) wherein: is a single or double bond; A is phenylene or heteroarylene; m is 0, 1 or 2; n is 0, 1 or 2; wherein R 1 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, N-C 1 - 4 alkylcarbamoyl, N,N-(C ⁇ - alkyl) 2 carbamoyl, sulphamoyl, N-C 1 - 4 alkylsulphamoyl, N,N-(C ⁇ - 4 alkyl) 2 sulphamoyl, sulfino, sulfo, C 1 - 4 alkyl, C 2 - 4 alkenyl, C 2 - alkynyl, Ci- alkoxy, C ⁇ - alkanoyl, C ⁇ - alkanoyloxy, N-(Ci- 4 alkyl)amino,
  • R is hydrogen, hydroxy or carboxy;
  • R 3 is selected from hydrogen, hydroxy, Ci- 4 alkanoyl, carbamoyl, C 1 - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), C 5 - cycloalkyl (optionally substituted with 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), cyano(C 1 - 4 )alkyl, 4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, C- ⁇ alkyl [substituted by 1 or 2 R 8 groups (provided that when there are 2 R groups they are not substituents on the same carbon)] and groups of the formulae B and B' :
  • R 8 is independently selected from hydroxy, C ⁇ - alkoxyC ⁇ - 4 alkoxy, hydroxyC ⁇ - alkoxy, 2,2-dimethyl-l,3-dioxolan-4-yl, heterocyclyl, C 1 . 4 alkanoyl, C 1 . 4 alkoxy, C ⁇ - 4 alkanesulfinyl, C 1 - 4 alkanesulfonyl, - ⁇ (OH)CHO, -COCOOR 9 , (R 9 )(R 10 )NCO-, (R 9 )(R 10 )NSO 2 -, -COCH 2 OR ⁇ , (R 9 )(R 10 )N- and -COOR 9 ;
  • R 9 and R 10 are independently selected from hydrogen, hydroxy, C ⁇ - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), C 5 - 7 cycloalkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), cyanoCC ⁇ alkyl, 4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl g, 1,1-dioxotetrahydrothiopyranyl, 2,2-dimethyl-l,3-dioxolan-4-yl and Ci- 4 alkyl substituted by R 13 ;
  • R 13 is selected from hydroxy, Ci- 4 alkoxy, heterocyclyl, C ⁇ - alkanoyl, C 1 - 4 alkanesulfinyl, -N(OH)CHO, (R n )(R 12 )NCO-, (R ⁇ )(R 12 )NSO 2 -, -COCH 2 OR ⁇ , (R ⁇ )(R 12 )N- ;
  • R 11 and R 12 are independently selected from hydrogen, C ⁇ alkyl, C ⁇ - 4 alkoxy, hydroxyC 1 . alkyl, Ci- 4 alkylS(O)b (wherein b is 0, 1 or 2) ⁇ ); and
  • R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6- membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from oxo, hydroxy, carboxy, halo, nitro, nitroso, cyano, isocyano, amino,
  • R 3 , R 9 and R 10 (as defined hereinbefore or hereinafter) allows two hydroxy substituents on the alkyl or cycloalkyl group, or one hydroxy substituent and a second substituent linked by a heteroatom (for example alkoxy), then these two substituents are not substituents on the same carbon atom of the alkyl or cycloalkyl group.
  • the invention relates to compounds of formula (1) as hereinabove defined or to a pharmaceutically acceptable salt.
  • the invention relates to compounds of formula (1) as hereinabove defined or to a pro-drug thereof.
  • Suitable examples of pro-drugs of compounds of formula (1) are in-vivo hydrolysable esters of compounds of formula (1). Therefore in another aspect, the invention relates to compounds of formula (1) as hereinabove defined or to an in-vivo hydrolysable ester thereof.
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention includes in its definition any such optically active or racemic form which possesses glycogen phosphorylase inhibition activity.
  • 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.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • a compound of the formula (1) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which has glycogen phosphorylase inhibition activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
  • the formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein.
  • certain compounds of the formula (1) 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 have glycogen phosphorylase inhibition activity. It is also to be understood that certain compounds of the formula (1) may exhibit polymorphism, and that the invention encompasses all such forms which possess glycogen phosphorylase inhibition activity.
  • the present invention relates to the compounds of formula (1) as hereinbefore defined as well as to the salts thereof.
  • Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (1) and their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of the compounds of formula (1) as hereinbefore defined which are sufficiently basic to form such salts.
  • Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or phosphoric acid, or with trifluoroacetic, citric or maleic acid.
  • Suitable salts include hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates.
  • pharmaceutically acceptable salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation.
  • Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt such as a sodium or potassium salt
  • an alkaline earth metal salt such as a calcium or magnesium salt
  • an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • the compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the invention.
  • a prodrug may be used to alter or improve the physical and/or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains a suitable group or substituent which can be derivatised to form a prodrug.
  • pro-drugs include in- vivo hydrolysable esters of a compound of the invention or a pharmaceutically-acceptable salt thereof.
  • Various forms of prodrugs are known in the art, for examples see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p.
  • An in vivo hydrolysable ester of a compound of formula (1) containing carboxy or hydroxy group is, for example.
  • Suitable pharmaceutically acceptable esters for carboxy include -ealkoxymethyl esters for example methoxymethyl, Ci-ealkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 - 8 cycloalkoxycarbonyloxyC ⁇ -6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2 ⁇ onylmethyl; and C ⁇ - 6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
  • Suitable pharmaceutically-acceptable esters for hydroxy include 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-dimethylpropionyloxymethoxy.
  • a selection of in-vivo hydrolysable ester forming groups for hydroxy include -ioalkanoyl, for example acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, C ⁇ oalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-(C ⁇ - 4 )alkylcarbamoyl and N-(di-(C ⁇ - 4 )alkylaminoethyl)-N- (C ⁇ - 4 )alkylcarbamoyl (to give carbamates); di-(d- )alkylaminoacetyl and carboxyacetyl.
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, (C ⁇ pattern 4 )alkylaminomethyl and di-((C 1 - 4 )alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.
  • Other interesting in-vivo hyrolysable esters include, for example, CO-, wherein R A is for example, benzyloxy-(C 1 - )alkyl, or phenyl).
  • Suitable substituents on a phenyl group in such esters include, for example, 4-(C ⁇ - 4 )piperazino-(C 1 - 4 )alkyl, piperazino- (C ⁇ - )alkyl and morpholino-(C ⁇ -C 4 )alkyl.
  • alkyl includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched-chain alkyl groups such as t-butyl are specific for the branched chain version only.
  • C ⁇ - 4 alkyl includes methyl, ethyl, propyl, isopropyl and t-butyl.
  • An analogous convention applies to other generic terms, for example "C 2 . alkenyl” includes vinyl, allyl and 1-propenyl and "C 2 . alkynyl” includes ethynyl, 1-propynyl and 2-propynyl.
  • hydroxyC ⁇ - alkyl includes hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl and hydroxybutyl.
  • hydroxyethyl includes 1 -hydroxyethyl and 2- hydroxyethyl.
  • hydroxypropyl includes 1-hydroxypropyl, 2-hydroxypropyl and 3- hydroxypropyl and an analogous convention applies to terms such as hydroxybutyl.
  • dihydroxyC ⁇ - 4 alkyl includes dihydroxyethyl, dihydroxypropyl, dihydroxyisopropyl and dihydroxybutyl.
  • dihydroxypropyl includes 1,2-dihydroxypropyl and 1,3- dihydroxypropyl. An analogous convention applies to terms such as dihydroxyisopropyl and dihydroxybutyl.
  • halo refers to fluoro, chloro, bromo and iodo.
  • dihaloC ⁇ - 4 alkyl includes difluoromethyl and dichloromethyl. The term includes trifluoromethyl.
  • Examples of "5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof are: l,3-dioxolan-4-yl, 2-methyl-l,3-dioxolan-4-yl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2- dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl; l,3-dioxan-2-yl.
  • Examples of “C ⁇ - 4 alkoxy” include methoxy, ethoxy, propoxy and isopropoxy.
  • Examples of “Ci- ⁇ alkoxy” include the examples of “C 1 - 4 alkoxy” and additionally butyloxy, t- butyloxy, pentoxy and l,2-(methyl) 2 propoxy. Examples of include formyl, acetyl and propionyl.
  • Examples of “C ⁇ _ 6 alkanoyl” include the example of “C ⁇ - 4 alkanoyl” and additionally butanoyl, pentanoyl, hexanoyl and l,2-(methyl) 2 propionyl.
  • Examples of “C ⁇ - 4 alkanoyloxy” are formyloxy, acetoxy and propionoxy.
  • Examples of “C ⁇ - 6 alkanoyloxy” include the examples of “C ⁇ - 4 alkanoyloxy” and additionally butanoyloxy, pentanoyloxy, hexanoyloxy and l,2-(methyl) 2 propionyloxy.
  • Examples of "N-(C 1 . alkyl)amino” include methylamino and ethylamino.
  • Examples of “N,N-(Ci- 4 alkyl) 2 amino” include N-N- (methyl) 2 amino, N-N-(ethyl) 2 amino and N-ethyl-N-methylamino.
  • N-(C 1 - 4 alkyl)carbamoyl are methylcarbamoyl and ethylcarbamoyl.
  • Examples of "N,N-(C ⁇ - alkyl) 2 carbamoyl” are N,N-(methyl) 2 carbamoyl, N,N-(ethyl) 2 carbamoyl and N- methyl-N-ethylcarbamoyl.
  • N-(C 1 - 4 alkyl)sulphamoyl are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl.
  • Examples of "N,N-(C ⁇ - 4 alkyl) 2 sulphamoyl” are
  • C 1 - 4 alkoxyC ⁇ - alkoxy are methoxymethoxy, ethoxymethoxy, ethoxyethoxy and methoxyethoxy.
  • hydroxyC 1 - 4 alkoxy are hydroxyethoxy and hydroxypropoxy.
  • hydroxypropoxy are 1 -hydroxypropoxy, 2-hydroxypropoxy and 3 -hydroxypropoxy.
  • Examples of "cyano(C 1 . )alkyl” are cyanomethyl, cyanoethyl and cyanopropyl.
  • Examples of “C 5 - cycloalkyl” are cyclopentyl, cyclohexyl and cycloheptyl.
  • Examples of “C 3 - scycloalkyl” and “C 3 - cycloalkyl” include “C 5 - cycloalkyr', cyclopropyl, cyclobutyl and cyclooctyl.
  • Examples of "C 3 - 6 cycloalkyl” includelde cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aminoC 1 - 4 alkyl includes aminomethyl, aminoethyl, aminopropyl, aminoisopropyl and aminobutyl.
  • aminoethyl includes 1 -aminoethyl and 2- aminoethyl.
  • aminopropyl includes 1 -aminopropyl, 2-aminopropyl and 3- aminopropyl and an analogous convention applies to terms such as aminoethyl and aminobutyl.
  • sulfo means HOSO 2 - .
  • sulfino means HO 2 S- .
  • C ⁇ - alkylS(O) b (wherein b is 0,1 or 2)” include methylthio, ethylthio, propylthio, methanesulphinyl, ethanesulphinyl, propanesulphinyl, mesyl, ethanesulphonyl, propanesulphonyl and isopropanesulphonyl.
  • C 3 - 6 cycloalkylS(O) b examples include cyclopropylthio, cyclopropylsulphinyl, cyclopropylsulphonyl, cyclobutylthio, cyclobutylsulphinyl, cyclobutylsulphonyl, cyclopentylthio, cyclopentylsulphinyl and cyclopentylsulphonyl.
  • arylS(O) b examples include phenylthio, phenylsulphinyl and phenylsulfonyl.
  • benzylS(O) b examples include benzylthio, benzylsulfinyl and benzylsulfonyl.
  • heterocyclylS(O) b examples include pyridylthio, pyridylsulfinyl, pyridylsulfonyl, imidazolylthio, imidazolylsulfinyl, imidazolylsulfonyl, pyrimidinylthio, pyrimidinylsufinyl, pyrimidinylsulfonyl, piperidylthio, piperidylsulfinyl and piperidylsulfonyl.
  • Heterocyclyl is a saturated, partially saturated or unsaturated, optionally substituted monocyclic ring containing 5 to 7 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxide(s). Examples and suitable values of the term
  • heterocyclyl are morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, dioxolanyl, thiadiazolyl, piperazinyl, isothiazohdinyl, triazolyl, tetrazolyl, pyrrolidinyl, 2-oxazolidinonyl, 5-isoxazolonyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, 3-oxopyrazolin-5-yl, tetrahydropyranyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, pyrimidyl, pyrazinyl,
  • a "heterocyclyl” is morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazohdinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4- oxopydridyl, 2-oxopyrrohdyl, 4-oxothiazolidyl, furyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl
  • heterocyclyl is oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thizoyl, thiadiazolyl, pyridyl, imidazolyl, furyl, thienyl, morpholine, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, and piperazinyl.
  • Suitable optional substituents for "heterocyclyl” as a saturated or partially saturated ring are 1, 2 or 3 substituents independently selected from halo, cyano, hydroxy, C ⁇ - alkyl, - 4 alkoxy and C 1 - alkylS(O) b (wherein b is 0, 1 or 2).
  • Further suitable substituents for "heterocyclyl” as a saturated or partially saturated ring are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulf ⁇ nyl and methylsulfonyl.
  • Suitable optional susbtituents for "heterocyclyl" as an unsaturated ring are 1, 2 or 3 substituents independently selected from halo, cyano, nitro, amino, hydroxy, C ⁇ - alkyl, Ci- 4 alkoxy, C ⁇ - 4 alkylS(O)b (wherein b is 0, 1 or 2), N-(Ci alkyl)amino and N,N-(Ci- 4 alkyl) 2 amino.
  • heterocyclyl as an unsaturated ring
  • substituents independently selected from fluoro, chloro, cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl.
  • Examples of "(heterocyclyl)C 1 - alkyl” are morpholinomethyl, morpholinethyl, morpholinylmethyl, morpholinylethyl, piperidinomethyl, piperidinoethyl, piperidylmethyl, piperidylethyl, imidazolylmethyl, imidazolylethyl, oxazolylmethyl, oxazolylethyl, 1,3,4- oxadiazolylmethyl, 1,2,4-oxadiazolylmethyl, 1,2,4-oxadiazolylethyl, pyridylmethyl, pyridylethyl, furylmethyl, furylethyl, (thienyl)methyl, (thienyl)ethyl, pyrazinylmethyl, pyrazinylethyl, piperazinylmethyl and piperazinylethyl.
  • aryl are optionally substituted phenyl and naphthyl.
  • aryl(C 1 - )alkyl are benzyl, phenethyl, naphthylmethyl and naphthylethyl.
  • Suitable optional substituents for "aryl" groups are 1, 2 or 3 substituents independently selected from halo, cyano, nitro, amino, hydroxy, C ⁇ - alkyl, C ⁇ - alkoxy, C ⁇ - alkylS(O)b (wherein b is 0, 1 or 2), and N,N-(C 1 - 4 alkyl) 2 amino.
  • Further suitable optional susbtituents for "aryl” groups are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl.
  • Heteroarylene is a diradical of a heteroaryl group.
  • a heteroaryl group is an aryl, monocyclic ring containing 5 to 7 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen.
  • heteroarylene are oxazolylene, oxadiazolylene, pyridylene, pyrimidinylene, imidazolylene, triazolylene, tetrazolylene, pyrazinylene, pyridazinylene, pyrrolylene, thienylene and furylene.
  • Suitable optional substituents for heteroaryl groups are 1, 2 or 3 substituents independently selected from halo, cyano, nitro, amino, hydroxy, C 1 - alkyl, C ⁇ - 4 alkoxy, Ci- alkylS(O)b (wherein b is 0, 1 or 2), N-(C ⁇ - 4 alkyl)amino and N,N-(C ⁇ - 4 alkyl) 2 amino.
  • heteroaryl groups are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl.
  • compounds of formula (1) in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (1), in a further alternative embodiment are provided in-vivo hydrolysable esters of compounds of formula (1), and in a further alternative embodiment are provided pharmaceutically-acceptable salts of in-vivo hydrolysable esters of compounds of formula (1).
  • m is 1 or 2.
  • m is 1.
  • R 4 is selected from hydrogen, halo, cyano, hydroxy, fluoromethyl, difluoromethyl and trifluoromethyl.
  • R 4 is hydrogen or halo.
  • R 4 is selected from hydrogen, chloro or bromo.
  • R 4 is chloro
  • A is phenylene. In another aspect of the invention A is heteroarylene.
  • A is selected from phenylene, pyridylene, pyrimidinylene, pyrrolylene, imidazolylene, triazolylene, tetrazolylene, oxazolylene, oxadiazolylene, thienylene and furylene.
  • n is 0 or 1. In one aspect preferably n is 1.
  • n 0.
  • n 2
  • the two R 1 groups together with the carbon atoms of A to which they are attached, form a 4 to 7 membered ring, optionally containing 1 or 2 heteroatoms independently selected from O, S and N, conveniently such a ring is a 5 or 6 membered ring containing two O atoms (ie a cyclic acetal).
  • the two R 1 groups together form such a cyclic acetal, preferably it is not substituted.
  • the two R 1 groups together are the group -O-CH 2 -O-.
  • R 1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl and C ⁇ - alkoxy.
  • R 1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -S(O) b C 1 - alkyl (wherein b is 0, 1 or 2), C ⁇ - alkyl and - 4 alkoxy.
  • R 1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -S(O) b Me (wherein b is 0, 1 or 2), methyl and methoxy.
  • R 1 is Ci- alkyl
  • R 1 is selected from halo and d- 4 alkoxy. In another embodiment preferably R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH 2 -O-.
  • R 2 is hydrogen. In another aspect of the invention R 2 is carboxy.
  • R is hydroxy.
  • R 2 is hydrogen.
  • Suitable values for R as heterocyclyl are morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazohdinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-oxopyrrolidyl, 4-oxothiazolidyl, furyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, and 1,2,
  • R 3 tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl, 1 J -dioxotetrahydrothiopyranyl.
  • R 3 is selected from hydrogen, hydroxy, C ⁇ . alkoxy, C ⁇ - alkanoyl, carbamoyl, C 3 - cycloalkyl (optionally substituted with 1 or 2 hydroxy groups, cyano(C ⁇ - )alkyl, phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazohdinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, iso
  • R is selected from hydroxy, halo, trifluoromethyl and C ⁇ - alkoxy;
  • R 11 is selected from hydrogen, C 1 - 4 alkyl and hydroxyC ⁇ - 4 alkyl.
  • R 3 is selected from cyanoC ⁇ - alkyl and C 1 - 4 alkyl (optionally substituted by 1 or 2 of R 8 groups);
  • R 8 is independently selected from hydroxy, phenyl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, C ⁇ alkoxy, C 1 . 4 alkanoyl, Q.
  • R 9 and R 10 are independently selected from hydrogen, hydroxy, Ci- 4 alkyl optionally substituted with R 13 (wherein R 13 is Ci- 4 alkoxy or hydroxy); or
  • R 9 and R 10 together with the nitrogen to which they are attached form a 4- to 6-membered ring where the ring may be optionally substituted on carbon by 1 or 2 hydroxy groups or carboxy groups), or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -
  • O- group may be replaced by a methyl
  • R 3 is selected from cyanoC 1 - 4 alkyl and C 1 - alkyl
  • R 8 is independently selected from hydroxy, 2,2-dimethyl-l,3-dioxolan-4-yl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, C ⁇ - 4 alkoxy, C 1 .
  • R 9 and R 10 together with the nitrogen to which they are attached form a 4- to 6-membered ring selected from piperidine, 4-hydroxy piperidine, pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of 3,4-dihydroxypyrrolidine.
  • R 3 is selected from hydroxypropyl, 2-butanol, 3-hydroxy-2-hydroxymethyl-propyl, 2,3-dihydroxypropyl, l,3-dihydroxyprop-2-yl, (2,2- dimethyl-l,3-dioxolan-4-yl)methyl, (2,2-dimethyl-l,3-dioxan-4-yl)methyl, (2,2-dimethyl- l,3-dioxan-5-yl)methyl, (2-oxo-l,3-dioxan-5-yl)methyl, cyanomethyl, butanoyl, methoxyethyl, (3-hydroxypiperidino)carbonylmethyl, 1,2,4-oxadiazolylmethyl, (5-oxo)- 1,2,4- oxadiazolylmethyl, (5-methyl)- 1 ,2,4-oxadiazolylmethyl, (2-amino)- 1 ,3 ,4-oxadia
  • R 3 is selected from hydrogen, hydroxyethyl, l,3-dihydroxyprop-2-yl, 2,3-dihydroxypropyl, 2,2-dimethyl-l,3-dioxan-5-ylmethyl, methylthioethyl, methanesulfinylethyl, methanesulfonylethyl, N- methanesulfonamidocarbonylethyl, amino(N-hydroxy)iminomethyl, methoxycarbonylmethyl, carboxymethyl, acetylaminoethyl, trifluoroacetylaminoethyl, hydroxymethylcarbonylmethyl, N-(pyrid-4-yl)carbamoylmethyl, N-(pyrid-2-yl)carbamoylmethyl, N-(3-methyl-pyrid-2- yl)carbamoylmethyl, N-(6-methyl- ⁇ yrid-2-
  • R is selected from hydrogen, hydroxyethyl, hydroxypropyl, 2-butanol, 3-hydroxy-2-hydroxymethyl-propyl, 2,3-dihydroxypropyl, carbamoylmethyl, (dimethylcarbamoyl)methyl, (methylcarbamoyl)methyl,
  • one of R 9 and R 10 is hydrogen and the other is selected from heterocyclyl and heterocyclyl(C ⁇ - alkyl).
  • R 9 or R 10 as heterocyclyl and heterocyclyl(C ⁇ - alkyl) is selected from oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thiazoyl, thiadiazolyl, pyridyl, imidazolyl, furyl, thienyl, morpholine, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, piperazinyl.
  • morpholinomethyl morpholinethyl, morpholinylmethyl, morpholinylethyl, piperidinomethyl, piperidinoethyl, piperidylmethyl, piperidylethyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl, 1 , 1 -dioxotetrahydrothiopyranyl, imidazolylmethyl, imidazolylethyl, oxazolylmethyl, oxazolylethyl, 1,3,4-oxadiazolylmethyl, 1,2,4-oxadiazolylmethyl, 1,2,4-oxadiazolylethyl, pyridylmethyl, pyridylethyl, furylmethyl, furylethyl, (thienyl)methyl, (thienyl)ethyl, pyrazinylmethyl, pyrazinylethyl, piperazinylmethyl and
  • a preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0, 1 or 2; R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
  • R is hydrogen; R 3 is selected from cyanoC ⁇ alkyl, and C ⁇ - 4 alkyl (optionally substituted by 1 or 2 R 8 groups);
  • R 8 is independently selected from hydroxy, C 3 . cycloalkyl, phenyl, 2,2-dimethyl-l,3- dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Ci- 4 alkoxy, C ⁇ - 4 alkanoyl, C 1 - 4 alkylS(O)b- (wherein b is 0, 1 or 2), C 3 - 6 cycloalkylS(O)b- (wherein b is 0, 1 or 2), ary
  • R 9 and R 10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(Ci- alkyl), C ⁇ - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups) and Ci- alkyl substituted by C ⁇ alkoxy, and wherein R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -O- group may be replaced by a methyl;
  • R 11 is selected from hydrogen, C ⁇ - 4 alkyl and hydroxyC 1 - 4 alkyl; m is 1 or 2; and RR 44 iiss hhyyddrrooggeenn o or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • Another preferred class of compounds is of formula (1) wherein: is a single bond; A is phenylene; n is 0, 1 or 2; R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
  • R 2 is hydrogen; R 3 is selected from C ⁇ - 4 alkyl (optionally substituted by 1 or 2 R 8 groups);
  • R 8 is independently selected from hydroxy, phenyl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, C ⁇ - 4 alkoxy, C !
  • R 9 and R 10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C 1 . 4 alkyl), C- ⁇ alkyl (optionally substituted by 1 or 2 hydroxy groups) and Ci- alkyl substituted by Q ⁇ alkoxy, and wherein R 9 and R 10 together with the nitrogen to which they are attached form a 4- to 6-membered ring selected from piperidine, 4-hydroxy piperidine, pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of 3,4- dihydroxypyrrolidine; m is 1 or 2; and R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • Another preferred class of compound is of the formula (1) wherein: is a single bond; A is phenylene; n is 0;
  • R is hydrogen
  • R 3 is selected from C ⁇ - 4 alkyl (optionally substituted by 1 or 2 R 8 groups);
  • R 8 is independently selected from hydroxy, C 1 - 4 alkylS(O) b - (wherein b is 0, 1 or 2), -NHC(O)R 9 and -C(O)N(R 9 )(R 10 );
  • R 9 and R 10 are independently selected from hydrogen, C ⁇ - 4 alkyl, heterocyclyl and heterocycly C ⁇ alkyl); m is 1 or 2; and
  • R 4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a further preferred class of compound is of the formula (1) wherein; is a single bond;
  • A is phenylene; n is 0, 1 or 2;
  • R 1 is independently selected from halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy and, (when n is 2) methylenedioxy;
  • R 2 is hydrogen
  • R is selected from C ⁇ alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon); m is 1 or 2; R 4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0, 1 or 2;
  • R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
  • R 2 is hydrogen;
  • R is selected from groups of the formulae B and B ' :
  • R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a further preferred class of compound is of the formula (1) wherein; is a single bond;
  • R 2 is hydrogen
  • R 3 is hydroxypropyl, dihydroxypropyl or dihydroxybutyl; m is 1 or 2;
  • R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0;
  • R 2 is hydrogen
  • R is hydroxypropyl, dihydroxypropyl or dihydroxybutyl; m is 1; R 4 is chloro; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0
  • R 2 is hydrogen
  • R 3 is heterocyclylcarbamoylmethyl; m is 1 or 2;
  • R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • Another class of compounds is of the formula (1) wherein is a double bond; A is phenylene; n is 0, 1 or 2;
  • R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
  • R is carboxy
  • R is selected from cyanoC ⁇ - 4 alkyl, and C 1 - 4 alkyl (optionally substituted by 1 or 2 R groups);
  • R 8 is independently selected from hydroxy, C 3 - cycloalkyl, phenyl, 2,2-dimethyl-l,3- dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, C 1 - 4 alkoxy, C ⁇ - alkanoyl, Ci- alkylS(O) b - (wherein
  • R 9 and R 10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C 1 - alkyl), C ⁇ - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups) and Q- alkyl substituted by C 1 - 4 alkoxy and wherein R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -O- group may be replaced by a methyl; R 11 is selected from hydrogen, Ci- 4 alkyl and hydroxyC 1 - alkyl; m is 1 or 2; and R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof
  • a further class of compound is of formula (1) wherein: is a single bond
  • A is heteroarylene; n is 0, 1 or 2;
  • R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
  • R 2 is hydrogen
  • R is selected from cyanoC 1 - 4 alkyl, and C ⁇ alkyl (optionally substituted by 1 or 2 R groups)
  • R 8 is independently selected from hydroxy, C 3 - 7 cycloalkyl, phenyl, 2,2-dimethyl-l,3- dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Ci- 4 alkoxy, C ⁇ - 4 alkanoyl, C 1 - 4 alkylS(O) b - (wherein b is 0, 1 or 2), C 3 -6cycloalkylS(O)b- (wherein b is 0, 1 or 2),
  • R 9 and R 10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C 1 . 4 alkyl), C 1 . 4 alkyl (optionally substituted by 1 or 2 hydroxy groups) and Q- 4 alkyl substituted by C ⁇ .
  • R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -O- group may be replaced by a methyl; R 11 is selected from hydrogen, Q- alkyl, hydroxyC ⁇ alkyl; m is 1 or 2; R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a further class of compound is of formula (1) wherein: is a single bond; A is heteroarylene; n is 0, 1 or 2;
  • R 1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO 2 Me and, (when n is 2) methylenedioxy;
  • R 2 is hydrogen;
  • R is selected from cyanoC ⁇ - alkyl, and C 1 - 4 alkyl (optionally substituted by 1 or 2 R groups)
  • R 8 is independently selected from hydroxy, phenyl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Ci- alkoxy, C ⁇ - 4 alkanoyl, Q- 4 alkylS(O) b - (wherein b is 0, 1 or 2), C 3 - 6 cycloalkylS(O) b - (wherein b is 0, 1 or 2), arylS(O) b -
  • R 9 and R 10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C 1 - 4 alkyl), Ci. 4 alkyl (optionally substituted by 1 or 2 hydroxy groups) and Ci- 4 alkyl substituted by C ⁇ _ 4 alkoxy and wherein R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy or the ring may be optionally substituted on two adjacent carbons by -O-CH 2 -O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH 2 -O- group may be replaced by a methyl; m is 1 or 2; and R 4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a further class of compound is of formula (1) wherein: is a single bond; A is heteroarylene; n is 0, 1 or 2;
  • R 1 is independently selected from halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy and, (when n is 2) methylenedioxy;
  • R 2 is hydrogen;
  • R is selected from cyanoC 1 - 4 alkyl, and C ⁇ alkyl [optionally substituted by 1 or 2 R groups]; wherein R 8 is independently selected from -C(O)N(R 9 )(R 10 ), and -COOR 9 , R 9 and R 10 are independently selected from hydrogen, C ⁇ - 4 alkyl, heterocyclyl and heterocyclyl(C 1 - 4 alkyl); m is 1 or 2; and R 4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a further class of compound is of formula (1) wherein: is a single bond
  • A is heteroarylene; n is 0, 1 or 2; R 1 is independently selected from halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy and, (when n is 2) methylenedioxy;
  • R 2 is hydrogen
  • R 3 is selected from C 1 - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups); m is 1 or 2; R 4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 1 or 2; R 1 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl and
  • R 1 is of the formula A' or A":
  • R is selected from C 1 - alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), cyanoCi- 4 alkyl, and C- ⁇ alkyl [substituted by 1 or 2 R 8 groups (provided that when there are 2 R 8 groups they are not substituents on the same carbon)];
  • ⁇ R 8 is independently selected from hydroxy, heterocyclyl, C ⁇ - 4 alkanoyl, Ci- 4 alkoxy, C ⁇ alkanesulfinyl, C ⁇ - 4 alkanesulfonyl, -COCOOR 9 , (R 9 )(R 10 )NCO-, -COCH 2 OR ⁇ , (R 9 )(R 10 )N-, -COOR 9 and 2,2-dimethyl-l,3-dioxolan-4-yl; [R 9 and R 10 are independently selected from hydrogen, hydroxy, C ⁇ - alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon) and C ⁇ - 4 alkyl substituted by C ⁇ - 4 alkoxy and wherein R 9 and R 10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy
  • R 11 is selected from hydrogen, C ⁇ - 4 alkyl, C ⁇ _ alkoxy and hydroxyC ⁇ - 4 alkyl] ⁇ ; m is 1 or 2;
  • R 4 is hydrogen or halo.
  • a further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 1 or 2; R 1 is independently selected from hydrogen, halo, nitro, hydroxy, C 1 - 4 alkyl and R 1 is of the formula A' or A":
  • R 3 is selected from C 1 - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon); m is 1 or 2;
  • R 4 is hydrogen or halo.
  • preferred compounds of the invention are any one of:
  • Another aspect of the present invention provides a process for preparing a compound of formula (1) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof which process (wherein A, R 1 , R 2 , R 3 , R 4 , m, n and — are, unless otherwise specified, as defined in formula (1)) comprises of: a) reacting an acid of the formula (2):
  • Acids of formula (2) and amines of formula (3) may be coupled together in the presence of a suitable coupling reagent.
  • Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for example carbonyldiimidazole, l-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride (EDCI) and dicyclohexyl-carbodiimide (DCCI), optionally in the presence of a catalyst such as 1- hydroxybenzotriazole, dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, di-isopropylethylamine, pyridine, or such as 2,6-lutidine or 2,6-di-tert-butylpyridine.
  • Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and di
  • Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters.
  • the reaction of these types of compounds with amines is well known in the art, for example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above.
  • the reaction may conveniently be performed at a temperature in the range of -40 to 40°C.
  • R 3 of formula (1) contains an ester group
  • the conversion of a compound of the formula (1) into another compound of the formula (1) may involve hydrolysis of the ester group for example, acid or base hydrolysis, for example using lithium hydroxide.
  • the reaction of this type is well known in the art.
  • R 3 of formula (1) contains -COOH group
  • the conversion of a compound of the formula (1) into another compound of the formula (1) may involve reduction of this group using reducing agents such as lithium borohydride, sodium borohydride etc.
  • the conversion may also involve the coupling of this -COOH group with ammonia or a substituted amine in the presence of a base for example triethylamine, di-isopropylethylamine, pyridine, or 2,6-di- -.*iy ⁇ -pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine.
  • a base for example triethylamine, di-isopropylethylamine, pyridine, or 2,6-di- -.*iy ⁇ -pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine.
  • Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide.
  • Substituted amides wherein R 3 is CH 2 C(O)N(R 9 )(R 10 ) may be prepared from the corresponding acids by a coupling reaction using the appropriate amine in the presence of a coupling reagent, for example EDCI.
  • the acid may first be converted to a mixed anhydride, by reaction with, for example, ethyl chloroformate, which is reacted with an appropriate amine to produce the substituted amide.
  • CH 2 C(O)NHSO 2 R 9 may be prepared similarly, for instance by coupling the compounds wherein R 3 is CH 2 CO 2 H with the appropriate substituted sulphonamide in the presence of a coupling reagent, for example EDCI.
  • a coupling reagent for example EDCI.
  • Compounds of formula (1) wherein R 3 is 2-hydroxymethyl may be prepared by reduction of the mixed anhydrides described above with, for example, lithium borohydride.
  • Compounds of formula (1) wherein R 3 is an oxadiazol-5-ylmethyl group may be prepared by reaction of the mixed anhydrides described above with an appropriately substituted hydroxyamidine, for example N'-hydroxyethanimidamide, in the presence of a base such as N- methylmorpholine.
  • Compounds of formula (1) wherein R 3 is a tetrazol-5-ylmethyl group may be prepared by reaction of the corresponding compounds where R 3 is a cyanomethyl group with an azide, for example sodium azide, in the presence of an amine salt, for instance triethylamine hydrochloride.
  • (methylsulphinyl)ethyl group may be prepared by reaction of the corresponding compounds where R 3 is 2-methylthioethyl with an oxidising agent, for example oxone.
  • Compounds of formula (1) wherein R 3 is a dihydroxyalkyl group, for example 2,3- dihydroxypropyl or 2-(hydroxymethyl)-3-hydroxypropyl may be prepared by acid hydrolysis of the corresponding compounds of formula (1) wherein R 3 is a protected dihydroxyalkyl group for example (2,2-dimethyl-l,3-dioxan-5-yl)methyl, (2,2-dimethyl-l,3-dioxolan-4- yl)methyl or (2-oxo-l,3-dioxan-5-yl)methyl.
  • the acids of formula (2) are commercially available or they are know compounds or they are prepared by processes known in the art.
  • R 3 -L where L is a suitable leaving group (for example chloro, bromo or iodo) in the presence of a base such as sodium hydride in a suitable solvent.
  • a suitable leaving group for example chloro, bromo or iodo
  • Compounds of the formula (4) wherein A is phenylene and is a double bond may be prepared by the reductive cyclisation of a compound of formula (5), using for example tin (II) chloride in hydrochloric acid, followed by removal of the Boc protecting group, using for example trifluoroacetic acid.
  • Compounds of formula (5) may be prepared by reaction of compounds of formula (6) by reaction with a compound of formula (7) in the presence of a base, for example tetramethylguanidine.
  • Compounds of formula (6) are commercially available or described in the literature.
  • Steps 1 and 2 may be carried out by the process described in Tetrahedron 1998, 54(23), 6311- 6318.
  • Step 3 may be carried out by the method described in Synthesis 1992 (5) ,487.
  • Step 4 Assymetric hydrogenation reactions of olefins as shown in Step 4 are well known (see for example, JACS 1993, 115, 10125-10138) and lead to homochiral final products.
  • Step 5 may alternatively be carried out by hydrolysing the ester and activating the resulting acid with a carbodiimide such as EDCI or DCCI, or by preparing an acid chloride, or activated ester such as an N -hydroxysuccinimide ester.
  • Suitable bases are organic base such as taethylamine or di-isopropylethylamine (DIPEA) or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • Step 6 is a leaving group, for example CI, Br, I , OMesyl.
  • Step 7 alternative solvents such as dichloromethane or other acids such as trifluoroacetic acid can be used.
  • Steps 1, 2, 3 and 4 are described in JOC 1983, 48, 3401-3408.
  • R 1 and R 4 may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention.
  • Such reactions may convert one compound of the formula (1) into another compound of the formula (1).
  • Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents.
  • the reagents and reaction conditions for such procedures are well known in the chemical art.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkanesulphinyl or alkanesulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • the activity of the compounds is determined by measuring the inhibitory effect of the compounds in the direction of glycogen synthesis, the conversion of glucose- 1 -phosphate into glycogen with the release of inorganic phosphate, as described in EP 0 846 464 A2.
  • the reactions were in 96well microplate format in a volume of lOO ⁇ l.
  • the change in optical density due to inorganic phosphate formation was measured at 620nM in a Labsystems iEMS Reader MF by the general method of (Nordlie R.C and Arion W.J, Methods of Enzymology, 1966, 619-625).
  • the reaction is in 50mM HEPES (N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid);4-(2-Hydroxyethyl)piperazine-l-ethanesulfonic acid), 2.5mM MgCl 2 , 2.25mM ethylene glycol-bis(b-aminoethyl ether) N,N,N',N'-tetraacetic acid, lOOmM KC1, 2mM D-(+)-glucose pH7.2, containing 0.5mM dithiothreitol, the assay buffer solution, with O.lmg type Dl glycogen, 0.15ug glycogen phosphorylase a (GP ⁇ ) from rabbit muscle and 0.5mM glucose-1-phosphate.
  • HEPES N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid);4-(2-Hy
  • GP is pre-incubated in the assay buffer solution with the type in glycogen at 2.5 mg ml "1 for 30 minutes. 40 ⁇ l of the enzyme solution is added to 25 ⁇ l assay buffer solution and the reaction started with the addition of 25 ⁇ l 2mM glucose- 1-phosphate.
  • Compounds to be tested are prepared in lO ⁇ l 10% DMSO in assay buffer solution, with final concentration of 1% DMSO in the assay.
  • the non-inhibited activity of GP ⁇ is measured in the presence of lO ⁇ l 10% DMSO in assay buffer solution and maximum inhibition measured in the presence of 30 ⁇ M CP320626 (Hoover et al (1998) J Med Chem 41, 2934-8; Martin et al (1998) P ⁇ AS 95, 1776-81).
  • the reaction is stopped after 30min with the addition of 50 ⁇ l acidic ammonium molybdate solution, 12ug ml "1 in 3.48% H 2 SO 4 with 1% sodium lauryl sulphate and lOug ml "1 ascorbic acid. After 30 minutes at room temperature the absorbency at 620nm is measured.
  • the assay is performed at a test concentration of inhibitor of lO ⁇ M or lOO ⁇ M. Compounds demonstrating significant inhibition at one or both of these concentrations may be further evaluated using a range of test concentrations of inhibitor to determine an IC 50 , a concentration predicted to inhibit the enzyme reaction by 50%. Activity is calculated as follows :-
  • % inhibition (1 - (compound OD620 - fully inhibited OD620)/ (non-inhibited rate OD620 - fully inhibited OD620)) * 100.
  • OD620 optical density at 620nM.
  • Typical IC 5 0 values for compounds of the invention when tested in the above assay are in the range lOO ⁇ M to InM.
  • the activity of the compounds is alternatively determined by measuring the inhibitory effect of the compounds on glycogen degradation, the production of glucose- 1 -phosphate from glycogen is monitored by the multienzyme coupled assay, as described in EP 0 846464 A2, general method of Pesce et al ( Pesce, M A, Bodourian, S H, Harris, R C, and Nicholson, J F (1977) Clinical Chemistry 23, 1171 - 1717).
  • the reactions were in 384well microplate format in a volume of 50 ⁇ l.
  • the change in fluorescence due to the conversion of the co-factor NAD to NADH is measured at 340nM excitation, 465nm emission in a Tecan Ultra Multifunctional Microplate Reader.
  • the reaction is in 50mM HEPES, 3.5mM KH 2 PO 4 , 2.5mM MgCl 2 , 2.5mM ethylene glycol-bis -aminoethyl ether) N,N,N',N'-tetraacetic acid, lOOmM KCl, 8mM D-(+)-glucose pH7.2, containing 0.5mM dithiothreitol, the assay buffer solution.
  • Human recombinant liver glycogen phosphorylase a (hrl GP ⁇ ) 20nM is pre-incubated in assay buffer solution with 6.25mM NAD, 1.25mg type Dl glycogen at 1.25 mg ml "1 the reagent buffer, for 30 minutes.
  • the coupling enzymes phosphoglucomutase and glucose-6-phosphate dehydrogenase ( Sigma) are prepared in reagent buffer, final concentration 0.25Units per well. 20 ⁇ l of the hrl GPa solution is added to lO ⁇ l compound solution and the reaction started with the addition of 20ul coupling enzyme solution. Compounds to be tested are prepared in lO ⁇ l 5% DMSO in assay buffer solution, with final concentration of 1% DMSO in the assay. The non-inhibited activity of GP ⁇ is measured in the presence of lO ⁇ l 5% DMSO in assay buffer solution and maximum inhibition measured in the presence of 5mgs ml "1 N- ethylmaleimide. After 6 hours at 30°C Relative Fluoresence Units (RFUs) are measured at 340nM excitation, 465nm emission .
  • REUs Relative Fluoresence Units
  • the assay is performed at a test concentration of inhibitor of lO ⁇ M or lOO ⁇ M. Compounds demonstrating significant inhibition at one or both of these concentrations may be further evaluated using a range of test concentrations of inhibitor to determine an IC 5 o, a concentration predicted to inhibit the enzyme reaction by 50%. Activity is calculated as follows :-
  • % inhibition (1 - (compound RFUs - fully inhibited RFUs)/ (non-inhibited rate RFUs - fully inhibited RFUs)) * 100.
  • Typical IC 50 values for compounds of the invention when tested in the above assay are in the range lOO ⁇ M to InM.
  • Example 14 was found to have an IC 5 o of 4.6 ⁇ m.
  • Rat hepatocytes were isolated by the collagenase perfusion technique, general method of
  • a pharmaceutical composition which comprises a compound of the formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • 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).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • 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 r 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.
  • 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 rj-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions 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.
  • the pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more 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.
  • 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.
  • Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in
  • the compound of formula (1) will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose.
  • a unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
  • Preferably a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • glycogen phosphorylase activity described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances and/or treatments. 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.
  • simultaneous treatment may be in a single tablet or in separate tablets.
  • n ellitus chemotherapy may include the following main categories of treatment:
  • Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide) and prandial glucose regulators (for example repaglinide, nateglinide);
  • sulphonylureas for example glibenclamide, glipizide
  • prandial glucose regulators for example repaglinide, nateglinide
  • Insulin sensitising agents including PPARg agonists (for example pioglitazone and rosiglitazone);
  • Anti-obesity agents for example sibutramine and orlistat
  • Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (statins, eg pravastatin); PPAR ⁇ agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stanols, 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 VHa inhibitors); antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin; and 11) Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone).
  • a compound of the formula (1) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use in a method of treatment of a warm-blooded animal such as man by therapy.
  • a compound of the formula (1) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity in a warm-blooded animal such as man.
  • a method of producing a glycogen phosphorylase inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (1).
  • a method of treating type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity which comprises administering to said animal an effective amount of a compound of formula ( 1 ) .
  • a method of treating type 2 diabetes in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (1).
  • a dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
  • the compounds of formula (1) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C and under an atmosphere of an inert gas such as argon;
  • KP-SILTM silica 60 ⁇ , particle size 32-63mM, supplied by Biotage, a division of Dyax Corp.
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO- ⁇ 6 ) as solvent unless otherwise indicated, other solvents (where indicated in the text) include deuterated chloroform
  • Example 2 N-ri-CCarboxymethvD- -oxo-l ⁇ -tetrahvdroquinolin-S-yll-S- chloroindole-2-carboxamide;
  • Example 11 5-chloro-N-( 1 - ⁇ 2- [(5-methyl- 1 ,3 ,4-thiadiazol-2-yl)amino] -2-oxoethyl ⁇ -2-oxo- l,2,3,4-tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 12 5-chloro-N-(l- ⁇ 2-[(5-ethyl-l,3,4-thiadiazol-2-yl)aminol-2-oxoethyll-2-oxo- l,2,3,4-tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 13 5-chloro-N-(l- ⁇ 2-r(4-cvano-lH-pyrazol-3-yl)amino]-2-oxoethyl
  • Example 14 5-chloro-N-(l- ⁇ 2-[(4-methyl-l,3-thiazol-2-yl)aminol-2-oxoethyl ⁇ -2-oxo- 1,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide
  • Example 16 5-chloro-N-( 1- ⁇ 2-[(3-hvdroxypyridin-2-yl)aminol -2-oxoethyl ) -2-oxo- 1 ,2,3 ,4- tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 17 5-chloro-N-(2-oxo- 1 - ⁇ 2-oxo-2-[(pyridin-2-ylmethyl)amino1ethyl 1-1.2.3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 19 5 -chloro-N-( 1 - ⁇ 2- r 1 -methyl- lH-pyrazol-5-yl)amino] -2-oxoethyl I -2-oxo- 1 ,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide
  • Example 20 5-chloro-N-(l- ⁇ 2-[(l,3-dimethyl-lH-pyrazol-5-yl aminol-2-oxoethyll-2-oxo- l,2,3,4-tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 21 5-chloro-N-(2-oxo-l- ⁇ 2-oxo-2-[(pyrazin-2-ylmethyl)aminolethyl
  • Example 22 5-chloro-N-(l- ⁇ 2-[f6-fluoropyridin-3-yl)aminol-2-oxoethyl ⁇ -2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 25 5-chloro-N-( 1 - ⁇ 2- [( 1 -ethyl- lH-pyrazol-5-yl)amino] -2-oxoethyl ⁇ -2-oxo- l,2,3,4-tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 26 5-chloro-N-(2-oxo- 1- ⁇ 2-oxo-2- [(5-oxo-4,5-dihydro- lH-pyrazol-3- vDaminol ethyl 1-1,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide
  • Example 27 5-chloro-N-( 1 - ⁇ 2- ⁇ ( 4-hvdroxypyrimidin-2-yl)amino1 -2-oxoethyl ⁇ -2-oxo- l,2,3,4-tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 28 5-chloro-N-(l- ⁇ 2-r(3-methylpyridin-2-yl)aminol-2-oxoethv ⁇ -2-oxo-l,2,3.4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 29 5-chloro-N-(l- ⁇ 2-[(6-chloropyridazin-3-yl)amino]-2-oxoethyl]-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 30 5-chloro-N-( 1- ⁇ 2- ( lH-imidazol-2-ylmethyl)amino1 -2-oxoethyl I -2-oxo-
  • Example 32 5-chloro-N- ( 2-oxo- 1 - [2-oxo-2-(2H-tetrazol-5-ylamino)ethyl1- 1 ,2,3 ,4- tetrahvdroquinolin-3-yl
  • Example 34 5-chloro-N-(l- ⁇ 2-[(5-fluoropyridin-2-yl)amino1-2-oxoethyl ⁇ -2-oxo-l,2,3,4- tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
  • Example 35 N-( 1 - ⁇ 2-[(6-bromopyridin-3-yl)amino1-2-oxoethyl I -2-oxo- 1 ,2,3 ,4- tetrahvdroquinolin-3-yl)-5-chloro-lH-indole-2-carboxamide
  • Triethylamine (0.168 mL, 1.21 mmol) then ethyl chloroformate (0.115 mL, 1.21 mmol) were added to N-[l-(carboxymethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5- chloroindole-2-carboxamide (Example 2, 437 mg, 1.10 mmol) in anhydrous THF (10 mL) at 0 °C followed by stirring for 1 h.
  • LiBHt 2.0 M in THF, 0.69 mL, 1.37 mmol
  • Example 38 5-Chloro-N-(l-r3-hvdroxy-2-(hvdroxymethvI)propyl1-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indoIe-2-carboxamide
  • Example 37 The procedure of Example 37 was followed using 3-amino-l-[(2,2-dimethyl-l,3- dioxolan-4-yl)methyl]-3,4-dihydroquinolin-2(lH)-one (Method 5) as amine and 5-Chloro- l ⁇ -indole-2-carboxylic acid as the acid component, to give the title compound as a white solid which was used without purification and subjected to acid catalysed hydrolysis according to the method used for Example 38 gave the title compound (90%) as a white solid.
  • Dess-Martin Periodinane 120 mg, 0.28 mmol was added to a stirring solution of N- [l-(3- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-hydroxypropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl] -5 -chloro- lH-indole-2-carboxamide (Method 6, 74 mg, 0.14 mmol) in DCM and the reaction was stirred for 2 hours. The reaction was quenched by addition of sat. aqueous
  • Example 42 5-Chloro-N-(l- ⁇ 2-[(methylsulfonyl)amino1ethyl ⁇ -2-oxo-1.2.3.4- tetrahvdroquinolin-3-yl)-lH-indoIe-2-carboxamide
  • Triethylamine (80 ⁇ L, 0.6 mmol) was added to a stirred suspension of N-[l-(2- aminoethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5-chloro-lH-indole-2-carboxamide_ trifluoroacetate (Method 9, 150 mg, 0.3 mmol) and methanesulfonyl chloride (25 ⁇ L, 0.33 mmol) in anhydrous DCM (5 mL) at 0 °C. The reaction was stirred at 0°C for 30 rnins, then warmed and stirred at ambient temperature for 30 rnins.
  • reaction was stirred for 90 rnins at ambient temperature, diluted with EtOAc (5 mL), washed with 1 ⁇ ⁇ aO ⁇ (3 mL), 1 N HCl (3 mL), saturated aqueous NaHCO 3 solution (5 mL) and dried (MgSO ).
  • Triethylamine (184 ⁇ L, 1.32 mmol), HOBt (89 mg, 0.66 mmol), 3-amino-6-fluoro-3,4- dihydro-2(lH)-quinolinone monohydrochloride (CAS Reg. No: 82420-54-0) (143 mg, 0.66 mmol), and ED AC (127 mg, 0.66 mmol) were added to a solution of 5-chloroindole-2- carboxylic acid (129 mg, 0.66 mmol) in anhydrous DMF (3.5 mL). The reaction was stirred at ambient temperature for approximately 16 h, and then poured into water (50 mL). This was stirred vigorously for about 10 mins. and filtered. The collected precipitate was washed with water and dried in vacuum at 40°C, to give the title compound (200 mg, 85%) as an amorphous solid.
  • Example 48 5-ChIoro-N-[6-(methyIoxy)-2-oxo-1.2.3,4-tetrahydroquinoIin-3-yn-lH- indole-2-carboxamide
  • reaction was quenched by addition of IM aqueous ⁇ C1 (5 mL) and the volatiles were removed by evaporation. The residue was dissolved in DCM (250 mL) and washed with sat. aqueous Na ⁇ CO 3 (100 mL) and the organic layer was dried (MgSO 4 ), filtered and evaporated to yield the title compound (5.89 g, 100%) as yellow paste which was used in the next reaction 0 without further purification.
  • N-Hydroxysuccinimide (496 mg, 4.31 mmol) and EDCI (1.04g, 5.38 mmol) were added to a suspension of N-[l-(carboxymethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5- chloroindole-2-carboxamide (Example 2, 1.71 g, 4.31 mmol)) in DCM (50 mL) and stirred for 18 hours. The suspension was evaporated and the residue partitioned between EtOAc:THF (4:1)(200 mL) and H 2 O. The organic was dried ( ⁇ a 2 SO 4 ), filtered and evaporated.
  • DIPEA (0.27 mL, 1.55 mmol) and then EDCI (370 mg, 1.94 mmol) were added to a solution of 3-amino-l- ⁇ [(4R)-2,*2-dimethyl-l,3-dioxolan-4-yl]methyl ⁇ -3,4-dihydroquinolin-2(lH)-one (Method 8, 428 mg, 1.55 mmol) in DCM (10 mL).
  • the title compound was prepared in an analogous method to Method 1 using (3- bromopropoxy)(tert-butyl)dimethylsilane as elecrophile.

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Abstract

Heterocyclic amides of formula (1) wherein: is a single or double bond; A is phenylene or heteroarylene; m is 0, 1 or 2;n is 0, 1 or 2;R1 is selected from for example halo, nitro, cyano, hydroxy, carboxy; R2 is hydrogen, hydroxy or carboxy;R3 is selected from for example hydrogen, hydroxy, aryl, heterocyclyl and C 1-4 alkyl(optionally substituted by 1 or 2 R8 groups);R4 is independently selected from for example hydrogen, halo, nitro, cyano, hydroxy, C 1-4 alkyl, and C 1-4 alkanoyl; R8 is selected from for example hydroxy, -COCOOR9, -C(O)N(R9)(R10), -NHC(O)R9 , (R9)(R10)N- and -COOR9;R9 and R10 are selected from for example hydrogen, hydroxy, C 1-4 alkyl (optionally substituted by 1 or 2 R13 );R13 is selected from hydroxy, halo, trihalomethyl and C 1-4 alkoxy;or a pharmaceutically acceptable salt or pro-drug thereof; possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity. Processes for the manufacture of said heterocyclic amide derivatives and pharmaceutical compositions containing them are described.

Description

CHEMICAL COMPOUNDS
The present invention relates to heterocychc amide derivatives, pharmaceutically acceptable salts and in vivo hydrolysable esters thereof. These heterocychc amides possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity and thus are potentially useful in methods of treatment of a warm-blooded animal such as man. The invention also relates to processes for the manufacture of said heterocychc amide derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit glycogen phosphorylase activity in a warm-blooded animal such as man.
The liver is the major organ regulating glycaemia in the post-absorptive state. Additionally, although having a smaller role in the contribution to post-prandial blood glucose levels, the response of the liver to exogenous sources of plasma glucose is key to an ability to maintain euglycaemia. An increased hepatic glucose output (HGO) is considered to play an important role in maintaining the elevated fasting plasma glucose (FPG) levels seen in type 2 diabetics; particularly those with a FPG >140mg/dl (7.8mM). (Weyer et al, (1999), J Clin Invest 104: 787-794; Clore & Blackgard (1994), Diabetes 43: 256-262; De Fronzo, R. A., et al, (1992) Diabetes Care 15; 318 - 355; Reaven, G.M. (1995) Diabetologia 38; 3-13). Since current oral, anti-diabetic therapies fail to bring FPG levels to within the normal, non-diabetic range and since raised FPG (and glycHbAlc) levels are risk factors for both macro- (Charles, M.A. et al (1996) Lancet 348, 1657-1658; Coutinho, M. et al (1999) Diabetes Care 22; 233-240; Shaw, J.E. et al (2000) Diabetes Care 23, 34-39) and micro-vascular disease (DCCT Research Group (1993) New. Eng. J. Med. 329; 977-986); the reduction and normalisation of elevated FPG levels remains a treatment goal in type 2 DM. It has been estimated that, after an overnight fast, 74% of HGO was derived from glycogenolysis with the remainder derived from gluconeogenic precursors (Hellerstein et al (1997) Am J Physiol, 272: E163). Glycogen phosphorylase is a key enzyme in the generation by glycogenolysis of glucose- 1 -phosphate, and hence glucose in liver and also in other tissues such as muscle and neuronal tissue.
Liver glycogen phosphorylase a activity is elevated in diabetic animal models including the db/db mouse and the fa/fa rat (Aiston S et al (2000). Diabetalogia 43, 589-597). Inhibition of hepatic glycogen phosphorylase with chloroindole inhibitors (CP91149 and CP320626) has been shown to reduce both glucagon stimulated glycogenolysis and glucose output in hepatocytes (Hoover et al (1998) J Med Chem 41, 2934-8; Martin et al (1998) PNAS 95, 1776-81). Additionally, plasma glucose concentration is reduced, in a dose related manner, db/db and ob/ob mice following treatment with these compounds.
Studies in conscious dogs with glucagon challenge in the absence and presence of another glycogen phosphorylase inhibitor, Bay K 3401, also show the potential utility of such agents where there is elevated circulating levels of glucagon, as in both Type 1 and Type 2 diabetes. In the presence of Bay R 3401, hepatic glucose output and arterial plasma glucose following a glucagon challenge were reduced significantly (Shiota et al, (1997), Am J Physiol, 273: E868).
The heterocychc amides of the present invention possess glycogen phosphorylase inhibitory activity and accordingly are expected to be of use in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia and obesity, particularly type 2 diabetes.
According to one aspect of the present invention there is provided a compound of formula (1):
Figure imgf000003_0001
wherein: is a single or double bond; A is phenylene or heteroarylene; m is 0, 1 or 2; n is 0, 1 or 2; R1 is independently selected from halo, nitro, cyano, hydroxy, carboxy, carbamoyl, N-C1.4alkylcarbamoyl, NN^Cwalkyl^carbamoyl, sulphamoyl, N-C-^alkylsulphamoyl,
N,N-(C1- alkyl)2sulphamoyl, -S(O) Cι- alkyl (wherein b is 0,1, or 2), Ci- alkyl, C2-4alkenyl,
C2- alkynyl, Cι- alkoxy, Cι-4alkanoyl, Ci-4alkanoyloxy, hydroxyCi-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl and trifluoromethoxy; or, when n is 2, the two R1 groups, together with the carbon atoms of A to which they are attached, may form a 4 to 7 membered ring, optionally containing 1 or 2 heteroatoms independently selected from O, S and Ν, and optionally being substituted by one or two methyl groups;
R4 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, Cι-4alkyl, C2-4alkenyl,
C2- alkynyl, C^alkoxy and Cι-4alkanoyl;
R is hydrogen, hydroxy or carboxy;
R3 is selected from hydrogen, hydroxy, C^alkoxy, Cι-4alkanoyl, carbamoyl, C3- cycloalkyl
(optionally substituted with 1 or 2 hydroxy groups), cyano(Cι-4)alkyl, aryl, heterocyclyl, Cι- alkyl (optionally substituted by 1 or 2 R8 groups), and groups of the formulae B and B':
Figure imgf000004_0001
(B) (B') wherein y is 0 or 1, t is 0, 1, 2 or 3 and u is 1 or 2; provided that the hydroxy group is not a substituent on the ring carbon adjacent to the ring oxygen;
R8 is independently selected from hydroxy, C1-4alkoxyC1.4alkoxy, hydroxyC1- alkoxy, 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, aryl, heterocyclyl, C3. cycloalkyl, Cι-4alkanoyl, ^alkoxy, Cι-4alkylS(O)b- (wherein b is 0, 1 or 2), C3.6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O)b- (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2), benzylS(O) - (wherein b is 0, 1 or 2), -Ν(OH)CHO, -C(=N-OH)NH2, -C(=N-OH)NHCι-4alkyl, -C(=N-OH)N(C1-4alkyl)2, -C(=N-OH)NHC3-6cycloalkyl, -C(=N-OH)N(C3-6cycloalkyl)2, -COCOOR9, -C(O)N(R9)(R10), -NHC(O)R9 , -C(O)NHSO2(C1-4alkyl), -NHSO2R9, (R9)(R10)NSO2-, -COCH2ORπ, (R9)(R10)N- and -COOR9; R9 and R10 are independently selected from hydrogen, hydroxy, Cι-4alkyl (optionally substituted by 1 or 2 R13 ), C3-7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups ), cyano(Cι- )alkyl, trihalo(Cι. )alkyl, aryl, heterocyclyl and heterocycly ^alkyl); or
R9 and R10 together with the nitrogen to which they are attached form a 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents independently selected from oxo, hydroxy, carboxy, halo, nitro, cyano, carbonyl, Cι-4alkoxy and heterocyclyl; or the ring may be optionally substituted on two adjacent carbons by -O-CH2-O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH2-O- group may be replaced by a methyl; R13 is selected from hydroxy, halo, trihalomethyl and Cι-4alkoxy;
R is independently selected from hydrogen, Cι- alkyl and hydroxyC1-4alkyl; or a pharmaceutically acceptable salt or pro-drug thereof.
In another aspect of the present invention there is provided a compound of formula (1): wherein: is a single or double bond; A is phenylene or heteroarylene; m is 0, 1 or 2; n is 0, 1 or 2; wherein R1 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, N-C1-4alkylcarbamoyl, N,N-(Cι- alkyl)2carbamoyl, sulphamoyl, N-C1-4alkylsulphamoyl, N,N-(Cι-4alkyl)2sulphamoyl, sulfino, sulfo, C1-4alkyl, C2-4alkenyl, C2- alkynyl, Ci- alkoxy, Cι- alkanoyl, Cι- alkanoyloxy, N-(Ci-4alkyl)amino, N,N-(Cι-4alkyl) amino, hydroxyCι-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, ^alkoxy and R1 is of the formula A' or A":
Figure imgf000005_0001
(A') -CH2CH(OH)(CH2)uCO2H (A") wherein x is 0 or 1, r is 0, 1, 2 or 3 and s is 1 or 2; provided that the hydroxy group is not a substituent on the ring carbon adjacent to the ring oxygen; wherein R4 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, N-Cι-4alkylcarbamoyl,
Figure imgf000006_0001
sulphamoyl, N-Cι-4alkylsulphamoyl, N,N-(C1-4alkyl) sulphamoyl, sulfino, sulfo, C1-4alkyl, C2-4alkenyl,
C2-4alkynyl, C^alkoxy, Cι-4alkanoyl, Cι-4alkanoyloxy, N-(Cι- alkyl)amino, N,N-(C .
4alkyl)2amino, hydroxyC1- alkyl, fluoromethyl, difluoromethyl, trifluoromethyl and trifluoromethoxy;
R is hydrogen, hydroxy or carboxy; R3 is selected from hydrogen, hydroxy, Ci-4alkanoyl, carbamoyl, C1-4alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), C5- cycloalkyl (optionally substituted with 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), cyano(C1-4)alkyl, 4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, C-^alkyl [substituted by 1 or 2 R8 groups (provided that when there are 2 R groups they are not substituents on the same carbon)] and groups of the formulae B and B' :
Figure imgf000006_0002
-CH2CH(OH)(CH2)uCO2H (B') wherein y is 0 or 1, t is 0, 1, 2 or 3 and u is 1 or 2; provided that the hydroxy group is not a substituent on the ring carbon adjacent to the ring oxygen);
{wherein R8 is independently selected from hydroxy, Cι- alkoxyCι-4alkoxy, hydroxyCι- alkoxy, 2,2-dimethyl-l,3-dioxolan-4-yl, heterocyclyl, C1.4alkanoyl, C1.4alkoxy, Cι-4alkanesulfinyl, C1-4alkanesulfonyl, -Ν(OH)CHO, -COCOOR9, (R9)(R10)NCO-, (R9)(R10)NSO2-, -COCH2ORπ, (R9)(R10)N- and -COOR9;
[wherein R9 and R10 are independently selected from hydrogen, hydroxy, Cι-4alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), C5-7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), cyanoCC^alkyl, 4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl g, 1,1-dioxotetrahydrothiopyranyl, 2,2-dimethyl-l,3-dioxolan-4-yl and Ci-4alkyl substituted by R13;
(wherein R13 is selected from hydroxy, Ci-4alkoxy, heterocyclyl, Cι- alkanoyl, C1-4alkanesulfinyl,
Figure imgf000007_0001
-N(OH)CHO, (Rn)(R12)NCO-, (Rπ)(R12)NSO2-, -COCH2ORπ, (Rπ)(R12)N- ;
{wherein R11 and R12 are independently selected from hydrogen, C^alkyl, Cι-4alkoxy, hydroxyC1. alkyl, Ci-4alkylS(O)b (wherein b is 0, 1 or 2)}); and
R9 and R10 can together with the nitrogen to which they are attached form 4- to 6- membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from oxo, hydroxy, carboxy, halo, nitro, nitroso, cyano, isocyano, amino,
N-C1- alkylamino, N,N-(Cι-4)2alkylamino, carbonyl, sulfo, C1-4alkoxy, heterocyclyl, Cι- alkanoyl, C1-4alkanesulfinyl, Cι-4alkanesulfonyl, -Ν(OH)CHO, (Rπ)(R12)NCO-, (Rn)(R12)NSO2-, -COCH2ORπ, (Rn)(R12)N-; wherein R11 and R12 are as defined above] } ; provided that when R1 is of the formula A' or A" then R3 does not contain a group of the formula B or B' and when R3 is of the formula B or B' then R1 does not contain a group of the formula A' or A"; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
It is to be understood that when A is heteroarylene, the bridgehead atoms joining ring A to the piperidinone ring may be heteroatoms. Therefore, for example, the definition of
Figure imgf000007_0002
when A is heteroarylene encompasses the structures
Figure imgf000007_0003
It is to be understood that, where optional substitution on alkyl or cycloalkyl groups in
R3, R9 and R10 (as defined hereinbefore or hereinafter) allows two hydroxy substituents on the alkyl or cycloalkyl group, or one hydroxy substituent and a second substituent linked by a heteroatom (for example alkoxy), then these two substituents are not substituents on the same carbon atom of the alkyl or cycloalkyl group.
In another aspect, the invention relates to compounds of formula (1) as hereinabove defined or to a pharmaceutically acceptable salt.
In another aspect, the invention relates to compounds of formula (1) as hereinabove defined or to a pro-drug thereof. Suitable examples of pro-drugs of compounds of formula (1) are in-vivo hydrolysable esters of compounds of formula (1). Therefore in another aspect, the invention relates to compounds of formula (1) as hereinabove defined or to an in-vivo hydrolysable ester thereof.
It is to be understood that, insofar as certain of the compounds of formula (1) defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses glycogen phosphorylase inhibition activity. 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. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
Within the present invention it is to be understood that a compound of the formula (1) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which has glycogen phosphorylase inhibition activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein. It is also to be understood that certain compounds of the formula (1) 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 have glycogen phosphorylase inhibition activity. It is also to be understood that certain compounds of the formula (1) may exhibit polymorphism, and that the invention encompasses all such forms which possess glycogen phosphorylase inhibition activity.
The present invention relates to the compounds of formula (1) as hereinbefore defined as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (1) and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of the compounds of formula (1) as hereinbefore defined which are sufficiently basic to form such salts. Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or phosphoric acid, or with trifluoroacetic, citric or maleic acid. Suitable salts include hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates. In addition where the compounds of formula (1) are sufficiently acidic, pharmaceutically acceptable salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation. Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
The compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the invention. A prodrug may be used to alter or improve the physical and/or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains a suitable group or substituent which can be derivatised to form a prodrug. Examples of pro-drugs include in- vivo hydrolysable esters of a compound of the invention or a pharmaceutically-acceptable salt thereof. Various forms of prodrugs are known in the art, for examples see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al, Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et α/., Chem Pharm Bull, 32, 692 (1984).
An in vivo hydrolysable ester of a compound of formula (1) containing carboxy or hydroxy group is, for example. A pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include -ealkoxymethyl esters for example methoxymethyl, Ci-ealkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxycarbonyloxyCι-6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2~onylmethyl; and Cι-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
Suitable pharmaceutically-acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-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. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include -ioalkanoyl, for example acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, Cπoalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-(Cι-4)alkylcarbamoyl and N-(di-(Cι-4)alkylaminoethyl)-N- (Cι-4)alkylcarbamoyl (to give carbamates); di-(d- )alkylaminoacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, (Cι„ 4)alkylaminomethyl and di-((C1-4)alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring. Other interesting in-vivo hyrolysable esters include, for example,
Figure imgf000010_0001
CO-, wherein RA is for example, benzyloxy-(C1- )alkyl, or phenyl). Suitable substituents on a phenyl group in such esters include, for example, 4-(Cι-4)piperazino-(C1-4)alkyl, piperazino- (Cι- )alkyl and morpholino-(Cι-C4)alkyl. In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched-chain alkyl groups such as t-butyl are specific for the branched chain version only. For example, "Cι-4alkyl" includes methyl, ethyl, propyl, isopropyl and t-butyl. An analogous convention applies to other generic terms, for example "C2. alkenyl" includes vinyl, allyl and 1-propenyl and "C2. alkynyl" includes ethynyl, 1-propynyl and 2-propynyl.
The term "hydroxyCι- alkyl" includes hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl and hydroxybutyl. The term "hydroxyethyl" includes 1 -hydroxyethyl and 2- hydroxyethyl. The term "hydroxypropyl" includes 1-hydroxypropyl, 2-hydroxypropyl and 3- hydroxypropyl and an analogous convention applies to terms such as hydroxybutyl. The term "dihydroxyCι-4alkyl" includes dihydroxyethyl, dihydroxypropyl, dihydroxyisopropyl and dihydroxybutyl. The term "dihydroxypropyl" includes 1,2-dihydroxypropyl and 1,3- dihydroxypropyl. An analogous convention applies to terms such as dihydroxyisopropyl and dihydroxybutyl.
The term "halo" refers to fluoro, chloro, bromo and iodo. The term "dihaloCι-4alkyl" includes difluoromethyl and dichloromethyl. The term
Figure imgf000011_0001
includes trifluoromethyl.
Examples of "5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof are: l,3-dioxolan-4-yl, 2-methyl-l,3-dioxolan-4-yl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2- dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl; l,3-dioxan-2-yl.
Examples of "Cι-4alkoxy" include methoxy, ethoxy, propoxy and isopropoxy. Examples of "Ci-όalkoxy" include the examples of "C1-4alkoxy" and additionally butyloxy, t- butyloxy, pentoxy and l,2-(methyl)2propoxy. Examples of
Figure imgf000011_0002
include formyl, acetyl and propionyl. Examples of "Cι_6alkanoyl" include the example of "Cι-4alkanoyl" and additionally butanoyl, pentanoyl, hexanoyl and l,2-(methyl)2propionyl. Examples of "Cχ-4alkanoyloxy" are formyloxy, acetoxy and propionoxy. Examples of "Cι-6alkanoyloxy" include the examples of "Cι-4alkanoyloxy" and additionally butanoyloxy, pentanoyloxy, hexanoyloxy and l,2-(methyl)2propionyloxy. Examples of "N-(C1. alkyl)amino" include methylamino and ethylamino. Examples of "N,N-(Ci-4alkyl)2amino" include N-N- (methyl)2amino, N-N-(ethyl)2amino and N-ethyl-N-methylamino. Examples of "N-(C1-4alkyl)carbamoyl" are methylcarbamoyl and ethylcarbamoyl. Examples of "N,N-(Cι- alkyl)2carbamoyl" are N,N-(methyl)2carbamoyl, N,N-(ethyl)2carbamoyl and N- methyl-N-ethylcarbamoyl. Examples of "N-(C1-4alkyl)sulphamoyl" are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of "N,N-(Cι-4alkyl)2sulphamoyl" are
N,N-(methyl)2sulphamoyl, N,N-(ethyl)2sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of "C1-4alkoxyCι- alkoxy" are methoxymethoxy, ethoxymethoxy, ethoxyethoxy and methoxyethoxy. Examples of "hydroxyC1-4alkoxy" are hydroxyethoxy and hydroxypropoxy. Examples of "hydroxypropoxy" are 1 -hydroxypropoxy, 2-hydroxypropoxy and 3 -hydroxypropoxy.
Examples of "cyano(C1. )alkyl" are cyanomethyl, cyanoethyl and cyanopropyl. Examples of "C5- cycloalkyl" are cyclopentyl, cyclohexyl and cycloheptyl. Examples of "C3- scycloalkyl" and "C3- cycloalkyl" include "C5- cycloalkyr', cyclopropyl, cyclobutyl and cyclooctyl. Examples of "C3-6cycloalkyl" inclulde cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "aminoC1-4alkyl" includes aminomethyl, aminoethyl, aminopropyl, aminoisopropyl and aminobutyl. The term "aminoethyl" includes 1 -aminoethyl and 2- aminoethyl. The term "aminopropyl" includes 1 -aminopropyl, 2-aminopropyl and 3- aminopropyl and an analogous convention applies to terms such as aminoethyl and aminobutyl.
The term "sulfo" means HOSO2- . The term "sulfino" means HO2S- . Examples of "Cι- alkylS(O)b (wherein b is 0,1 or 2)" include methylthio, ethylthio, propylthio, methanesulphinyl, ethanesulphinyl, propanesulphinyl, mesyl, ethanesulphonyl, propanesulphonyl and isopropanesulphonyl.
Examples of "C3-6cycloalkylS(O)b (wherein b is 0,1 or 2)" include cyclopropylthio, cyclopropylsulphinyl, cyclopropylsulphonyl, cyclobutylthio, cyclobutylsulphinyl, cyclobutylsulphonyl, cyclopentylthio, cyclopentylsulphinyl and cyclopentylsulphonyl.
Examples of "arylS(O)b (wherein b is 0,1 or 2)" include phenylthio, phenylsulphinyl and phenylsulfonyl. Examples of "benzylS(O)b (wherein b is 0,1 or 2)" inculde benzylthio, benzylsulfinyl and benzylsulfonyl. Examples of "heterocyclylS(O)b (wherein b is 0,1 or 2)" include pyridylthio, pyridylsulfinyl, pyridylsulfonyl, imidazolylthio, imidazolylsulfinyl, imidazolylsulfonyl, pyrimidinylthio, pyrimidinylsufinyl, pyrimidinylsulfonyl, piperidylthio, piperidylsulfinyl and piperidylsulfonyl.
Where optional substituents are chosen from "0, 1, 2 or 3" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups. An analogous convention applies to substituents chose from "0, 1 or 2" groups and "1 or 2" groups.
"Heterocyclyl" is a saturated, partially saturated or unsaturated, optionally substituted monocyclic ring containing 5 to 7 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxide(s). Examples and suitable values of the term
"heterocyclyl" are morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, dioxolanyl, thiadiazolyl, piperazinyl, isothiazohdinyl, triazolyl, tetrazolyl, pyrrolidinyl, 2-oxazolidinonyl, 5-isoxazolonyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, 3-oxopyrazolin-5-yl, tetrahydropyranyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2- oxopyirolidyl, 4-oxothiazolidyl, furyl, thienyl, oxazolyl, and oxadiazolyl.
Suitably a "heterocyclyl" is morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazohdinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4- oxopydridyl, 2-oxopyrrohdyl, 4-oxothiazolidyl, furyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl.
Conveniently "heterocyclyl" is oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thizoyl, thiadiazolyl, pyridyl, imidazolyl, furyl, thienyl, morpholine, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, and piperazinyl. Suitable optional substituents for "heterocyclyl" as a saturated or partially saturated ring are 1, 2 or 3 substituents independently selected from halo, cyano, hydroxy, Cι- alkyl, - 4alkoxy and C1- alkylS(O)b (wherein b is 0, 1 or 2). Further suitable substituents for "heterocyclyl" as a saturated or partially saturated ring are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfϊnyl and methylsulfonyl.
Suitable optional susbtituents for "heterocyclyl" as an unsaturated ring are 1, 2 or 3 substituents independently selected from halo, cyano, nitro, amino, hydroxy, Cι- alkyl, Ci- 4alkoxy, Cι-4alkylS(O)b (wherein b is 0, 1 or 2), N-(Ci alkyl)amino and N,N-(Ci-4alkyl)2amino. Further suitable optional susbtituents for "heterocyclyl" as an unsaturated ring are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl. Examples of "(heterocyclyl)C1- alkyl" are morpholinomethyl, morpholinethyl, morpholinylmethyl, morpholinylethyl, piperidinomethyl, piperidinoethyl, piperidylmethyl, piperidylethyl, imidazolylmethyl, imidazolylethyl, oxazolylmethyl, oxazolylethyl, 1,3,4- oxadiazolylmethyl, 1,2,4-oxadiazolylmethyl, 1,2,4-oxadiazolylethyl, pyridylmethyl, pyridylethyl, furylmethyl, furylethyl, (thienyl)methyl, (thienyl)ethyl, pyrazinylmethyl, pyrazinylethyl, piperazinylmethyl and piperazinylethyl.
Examples of "aryl" are optionally substituted phenyl and naphthyl. Examples of "aryl(C1- )alkyl" are benzyl, phenethyl, naphthylmethyl and naphthylethyl.
Suitable optional substituents for "aryl" groups are 1, 2 or 3 substituents independently selected from halo, cyano, nitro, amino, hydroxy, Cι- alkyl, Cι- alkoxy, Cι- alkylS(O)b (wherein b is 0, 1 or 2),
Figure imgf000014_0001
and N,N-(C1-4alkyl)2amino. Further suitable optional susbtituents for "aryl" groups are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl. "Heteroarylene" is a diradical of a heteroaryl group. A heteroaryl group is an aryl, monocyclic ring containing 5 to 7 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen. Examples of heteroarylene are oxazolylene, oxadiazolylene, pyridylene, pyrimidinylene, imidazolylene, triazolylene, tetrazolylene, pyrazinylene, pyridazinylene, pyrrolylene, thienylene and furylene. Suitable optional substituents for heteroaryl groups, unless otherwise defined, are 1, 2 or 3 substituents independently selected from halo, cyano, nitro, amino, hydroxy, C1- alkyl, Cι-4alkoxy, Ci- alkylS(O)b (wherein b is 0, 1 or 2), N-(Cι-4alkyl)amino and N,N-(Cι-4alkyl)2amino. Further suitable optional susbtituents for "heteroaryl" groups are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl.
Preferred values of A, R1, R2, R3, R4, m and n are as follows. Such values may be used where appropriate with any of the definitions, claims, aspects or embodiments defined hereinbefore or hereinafter.
In one embodiment of the invention are provided compounds of formula (1), in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (1), in a further alternative embodiment are provided in-vivo hydrolysable esters of compounds of formula (1), and in a further alternative embodiment are provided pharmaceutically-acceptable salts of in-vivo hydrolysable esters of compounds of formula (1).
In one aspect of the present invention m is 1 or 2.
In another aspect of the invention m is 1.
In one aspect of the present invention R4 is selected from hydrogen, halo, cyano, hydroxy, fluoromethyl, difluoromethyl and trifluoromethyl.
In another aspect of the invention R4 is hydrogen or halo.
Preferably R4 is selected from hydrogen, chloro or bromo.
More preferably R4 is chloro.
In one aspect of the invention A is phenylene. In another aspect of the invention A is heteroarylene.
Preferably A is selected from phenylene, pyridylene, pyrimidinylene, pyrrolylene, imidazolylene, triazolylene, tetrazolylene, oxazolylene, oxadiazolylene, thienylene and furylene.
In one aspect of the invention n is 0 or 1. In one aspect preferably n is 1.
In another aspect, preferably n is 0.
When n is 2, and the two R1 groups, together with the carbon atoms of A to which they are attached, form a 4 to 7 membered ring, optionally containing 1 or 2 heteroatoms independently selected from O, S and N, conveniently such a ring is a 5 or 6 membered ring containing two O atoms (ie a cyclic acetal). When the two R1 groups together form such a cyclic acetal, preferably it is not substituted. Most preferably the two R1 groups together are the group -O-CH2-O-.
In another aspect of the present invention R1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl and Cι- alkoxy. In a further aspect R1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -S(O)bC1- alkyl (wherein b is 0, 1 or 2), Cι- alkyl and - 4alkoxy. In a further aspect R1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -S(O)bMe (wherein b is 0, 1 or 2), methyl and methoxy.
In a further aspect, R1 is Ci- alkyl.
Preferably R1 is selected from halo and d-4alkoxy. In another embodiment preferably R1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH2-O-.
In one aspect of the invention is a single bond.
In another aspect of the invention is a double bond.
In one aspect of the invention R2 is hydrogen. In another aspect of the invention R2 is carboxy.
In another aspect of the invention R is hydroxy. Preferably R2 is hydrogen.
Suitable values for R as heterocyclyl are morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazohdinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-oxopyrrolidyl, 4-oxothiazolidyl, furyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl, tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl, 1 , 1 -dioxotetrahydrothiopyranyl. More suitable values for R3 as heterocyclyl are pyridyl, pyrimidinyl and imidazolyl.
Further suitable values for R3 as heterocyclyl are tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl, 1 J -dioxotetrahydrothiopyranyl.
In one aspect of the invention R3 is selected from hydrogen, hydroxy, Cχ. alkoxy, Cι- alkanoyl, carbamoyl, C3- cycloalkyl (optionally substituted with 1 or 2 hydroxy groups, cyano(Cι- )alkyl, phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazohdinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4- oxopydridyl, 2-oxopyrrolidyl, 4-oxothiazolidyl, furyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl, 1,1- dioxotetrahydrothiopyranyl and Cι-4alkyl (optionally substituted by 1 or 2 R8 groups); R9 and R10 are independently selected from hydrogen, hydroxy, Ci-4alkyl (optionally substituted by 1 or 2 R13 groups), C3- cycloalkyl (optionally substituted by 1 or 2 hydroxy groups), cyano(C1-4)alkyl, trihalo
Figure imgf000017_0001
aryl, heterocyclyl and heterocyclyl(C1-4alkyl); or R9 and R10 together with the nitrogen to which they are attached form a 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from oxo, hydroxy, carboxy, halo, nitro, cyano, carbonyl and C^alkoxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH2-O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH2-O- group may be replaced by a methyl; R is independently selected from hydroxy, C1- alkoxyC1- alkoxy, hydroxyC1-4alkoxy,
5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, aryl, heterocyclyl, C3. cycloalkyl, C1.4alkanoyl, Cι-4alkoxy, Cι-4alkylS(O)b- (wherein b is 0, 1 or 2), C3.6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O)b- (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2), benzylS(O)b- (wherein b is 0, 1 or 2), -N(OH)CHO, -C(=N-OH)NH2, -C(=N-OH)NHCι-4alkyl, -C(=N-OH)N(C1-4alkyl)2, -C(=N- OH)NHC3-6cycloalkyl, -C(=N-OH)N(C3-6cycloalkyl)2, -COCOOR9, -C(O)N(R9)(R10), -NHC(O)R9 , -C^NHSO^C^alkyl), -NHSO2R9, (R9)(R10)NSO2-, -COCH2ORπ, (R9)(R10)N- and -COOR9 ;
R is selected from hydroxy, halo, trifluoromethyl and Cι- alkoxy; R11 is selected from hydrogen, C1-4alkyl and hydroxyCι-4alkyl.
In a further aspect of the invention R3 is selected from cyanoCι- alkyl and C1-4alkyl (optionally substituted by 1 or 2 of R8 groups);
R8 is independently selected from hydroxy, phenyl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, C^alkoxy, C1.4alkanoyl, Q. 4alkylS(O)b- (wherein b is 0, 1 or 2), -C(O)N(R9)(R10), -COOR9 , -C(O)NHSO2Me, -C(=N- OH)NH2 , -C(=N-OH)NHC1-4alkyl, -C(=N-OH)N(Cι-4alkyl)2 and-NHSO2R9; R9 and R10 are independently selected from hydrogen, hydroxy, Ci-4alkyl optionally substituted with R13 (wherein R13 is Ci-4alkoxy or hydroxy); or
R9 and R10 together with the nitrogen to which they are attached form a 4- to 6-membered ring where the ring may be optionally substituted on carbon by 1 or 2 hydroxy groups or carboxy groups), or the ring may be optionally substituted on two adjacent carbons by -O-CH2-O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH2-
O- group may be replaced by a methyl.
In a further aspect of the invention R3 is selected from cyanoC1-4alkyl and C1- alkyl
(optionally substituted by 1 or 2 R8 groups); wherein R8 is independently selected from hydroxy, 2,2-dimethyl-l,3-dioxolan-4-yl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, Cι-4alkoxy, C1.4alkanoyl, Cι-4alkylS(O)b- (wherein b is 0, 1 or 2), -C(O)N(R9)(R10), -COOR9 , -C(O)NHSO2Me, -C(=N-OH)NH2; wherein R9 and R10 are independently selected from hydrogen, hydroxy, Cι-4alkyl optionally substituted with R13 (wherein R13 is C^alkoxy or hydroxy); or
R9 and R10 together with the nitrogen to which they are attached form a 4- to 6-membered ring selected from piperidine, 4-hydroxy piperidine, pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of 3,4-dihydroxypyrrolidine.
In yet a further aspect of the inventions R3 is selected from hydroxypropyl, 2-butanol, 3-hydroxy-2-hydroxymethyl-propyl, 2,3-dihydroxypropyl, l,3-dihydroxyprop-2-yl, (2,2- dimethyl-l,3-dioxolan-4-yl)methyl, (2,2-dimethyl-l,3-dioxan-4-yl)methyl, (2,2-dimethyl- l,3-dioxan-5-yl)methyl, (2-oxo-l,3-dioxan-5-yl)methyl, cyanomethyl, butanoyl, methoxyethyl, (3-hydroxypiperidino)carbonylmethyl, 1,2,4-oxadiazolylmethyl, (5-oxo)- 1,2,4- oxadiazolylmethyl, (5-methyl)- 1 ,2,4-oxadiazolylmethyl, (2-amino)- 1 ,3 ,4-oxadiazolylmethyl, tetrazolylmethyl, (3,4-dihydroxypyrrolidinyl)carbonylmethyl, [(3,4- dihydroxypyrrolidinyl)carbonylmethyl]dimethylacetal, methylthioethyl, methanesulfinylethyl, methanesulfonylethyl, N-methanesulfonamidocarbonylmethyl, N- methanesulfonamidocarbonylethyl, N-(l,3-dihydroxyprop-2-yl)carbamoylmethyl, 2-
(dimethylamino)ethyl, 2-hydroxy-3-(dimethylamino)propyl, amino(N-hydroxy)iminomethyl, methoxycarbonylmethyl, hydroxymethylcarbonylmethyl, carboxymethyl, carbamoylmethyl, (dimethylcarbamoyl)methyl, (methylcarbamoyl)methyl, (methylcarbamoyl)ethyl, (hydroxycarbamoyl)methyl, (hydroxyethylcarbamoyl)methyl, and (methoxyethylcarbamoyl)methyl, acetylaminoethyl, trifluoroacetylaminoethyl, N-(pyrid-4- yl)carbamoylmethyl, N-(pyrid-2-yl)carbamoylmethyl, N-(3-methyl-pyrid-2- yl)carbamoylmethyl, N-(6-methyl-pyrid-2-yl)carbamoylmethyl, N-(3-hydroxy-pyrid-2- yl)carbamoylmethyl, N-(6-fluoro-pyrid-2-yl)carbamoylmethyl, N-(6-bromo-pyrid-2- yl)carbamoylmethyl, N-(6-fluoro-ρyrid-3-yl)carbamoylmethyl, N-(6-chloro-pyrid-3- yl)carbamoylmethyl, N-(N-methyl-imidazol-3-yl)carbamoylmethyl, N-(imidazol-2- ylmethyl)carbamoylmethyl, N-(tetrazol-5-ylmethyl)carbamoylmethyl, N-(4-methyl-thiazol-2- yl)carbamoylmethyl, N-(l,3,4-thiadiazol-2-yl)carbamoylmethyl, N-(5-methyl-l,3,4- thiadiazol-2-yl)carbamoylmethyl, N-(5-ethyl- 1 ,3 ,4-thiadiazol-2-yl)carbamoylmethyl, N-(4- cyano-pyridazin-3-yl)carbamoylmethyl, N-(6-chloro-ρyridazin-3-yl)carbamoylmethyl, N-(2,4- dimethyl-2H-pyridazin-3-yl)carbamoylmethyl, N-(2-ethyl-2H-pyridazin-3- yI)carbamoylmethyl, N-(pyrazin-2-ylmethyl)carbamoylmethyl, N-(pyrimidin-4- yl)carbamoylmethyl, N-(2-hydroxy-pyrimidin-4-yl)carbamoylmethyl, N-(4-hydroxy- pyrimidin-2-yl)carbamoylmethyl, N-(N-methylpyrazol-3-yl)carbamoylmethyl, N-(5- ethylpyrazol-3-yl)carbamoylmethyl and N-(5-oxo-2H-pyrazol-3-yl)carbamoylmethyl .
In yet a further aspect of the inventions R3 is selected from hydrogen, hydroxyethyl, l,3-dihydroxyprop-2-yl, 2,3-dihydroxypropyl, 2,2-dimethyl-l,3-dioxan-5-ylmethyl, methylthioethyl, methanesulfinylethyl, methanesulfonylethyl, N- methanesulfonamidocarbonylethyl, amino(N-hydroxy)iminomethyl, methoxycarbonylmethyl, carboxymethyl, acetylaminoethyl, trifluoroacetylaminoethyl, hydroxymethylcarbonylmethyl, N-(pyrid-4-yl)carbamoylmethyl, N-(pyrid-2-yl)carbamoylmethyl, N-(3-methyl-pyrid-2- yl)carbamoylmethyl, N-(6-methyl-ρyrid-2-yl)carbanιoylmethyl, N-(3-hydroxy-pyrid-2- yl)carbamoylmethyl, N-(6-fluoro-pyrid-2-yl)carbamoylmethyl, N-(6-bromo-pyrid-2- yl)carbamoylmethyl, N-(6-fluoro-pyrid-3-yl)carbamoylmethyl, N-(6-chloro-pyrid-3- yl)carbamoylmethyl, N-(N-methyl-imidazol-3-yl)carbamoylmethyl, N-(imidazol-2- ylmethyl)carbamoylmethyl, N-(tetrazol-5-ylmethyl)carbamoylmethyl, N-(4-methyl-thiazol-2- yl)carbamoylmethyl, N-(l,3,4-thiadiazol-2-yl)carbamoylmethyl, N-(5-methyl-l,3,4- thiadiazol-2-yl)carbamoylmethyl, N-(5-ethyl- 1 ,3 ,4-thiadiazol-2-yl)carbamoylmethyl, N-(4- cyano-pyridazin-3-yl)carbamoylmethyl, N-(6-chloro-pyridazin-3-yl)carbamoylmethyl, N-(2,4- dimethyl-2H-pyridazin-3-yl)carbamoylmethyl, N-(2-ethyl-2H-pyridazin-3- yl)carbamoylmethyl, N-(pyrazin-2-ylmethyl)carbamoylmethyl, N-(pyrimidin-4- yl)carbamoylmethyl, N-(2-hydroxy-pyrimidin-4-yl)carbamoylmethyl, N-(4-hydroxy- pyrimidin-2-yl)carbamoylmethyl, N-(N-methylpyrazol-3-yl)carbamoylmethyl, N-(5- ethylpyrazol-3-yl)carbamoylmethyl and N-(5-oxo-2H-pyrazol-3-yl)carbamoylmethyl . In yet a further aspect of the invention R is selected from hydrogen, hydroxyethyl, hydroxypropyl, 2-butanol, 3-hydroxy-2-hydroxymethyl-propyl, 2,3-dihydroxypropyl, carbamoylmethyl, (dimethylcarbamoyl)methyl, (methylcarbamoyl)methyl,
(methylcarbamoyl)ethyl, (hydroxycarbamoyl)methyl, (hydroxyethylcarbamoyl)methyl, (methoxyethylcarbamoyl)methyl, amino(N-hydroxy)iminomethyl, methanesulfinylethyl, and methanesulfonylethyl.
In one aspect, one of R9 and R10 is hydrogen and the other is selected from heterocyclyl and heterocyclyl(Cι- alkyl). Conveniently R9 or R10 as heterocyclyl and heterocyclyl(Cι- alkyl) is selected from oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thiazoyl, thiadiazolyl, pyridyl, imidazolyl, furyl, thienyl, morpholine, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, piperazinyl. morpholinomethyl, morpholinethyl, morpholinylmethyl, morpholinylethyl, piperidinomethyl, piperidinoethyl, piperidylmethyl, piperidylethyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl, 1 , 1 -dioxotetrahydrothiopyranyl, imidazolylmethyl, imidazolylethyl, oxazolylmethyl, oxazolylethyl, 1,3,4-oxadiazolylmethyl, 1,2,4-oxadiazolylmethyl, 1,2,4-oxadiazolylethyl, pyridylmethyl, pyridylethyl, furylmethyl, furylethyl, (thienyl)methyl, (thienyl)ethyl, pyrazinylmethyl, pyrazinylethyl, piperazinylmethyl and piperazinylethyl; wherein the heterocylic ring is optional substituted on any available atom by 1, 2 or 3 substituents independently selected from halo, cyano, hydroxy, Cι- alkyl, Cι- alkoxy and Cι- alkylS(O)b (wherein b is 0, 1 or 2), and additionally when the heterocyclyl ring is a heteroaryl ring, further suitable optional substituents are selected from nitro, amino, N-(C1-4alkyl)amino and N,N-(C1- alkyl)2amino, and/or wherein any heterocychc ring is optionally oxidised such that a -CH2- group is replaced by a -C(O)-and/or a ring sulphur atom is oxidised to form the S-oxide(s).
A preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0, 1 or 2; R1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO2Me and, (when n is 2) methylenedioxy;
R is hydrogen; R3 is selected from cyanoC^alkyl, and Cι-4alkyl (optionally substituted by 1 or 2 R8 groups);
R8is independently selected from hydroxy, C3. cycloalkyl, phenyl, 2,2-dimethyl-l,3- dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Ci-4alkoxy, Cι-4alkanoyl, C1-4alkylS(O)b- (wherein b is 0, 1 or 2), C3-6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O)b- (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2), - C(O)N(R9)(R10), -COOR9 , -C(O)NHSO2Me, -C(=N-OH)NH2 , -C(=N-OH)NHCι-4alkyl, -C(=N-OH)N(Ci-4alkyl)2 , -C(=N-OH)NHC3-6cycloalkyl, -C(=N-OH)N(C3-6cycloalkyl)2, -N(OH)CHO, -COCOOR9, -NHC(O)R9, (R9)(R10)NSO2-, -COCH2ORπ and-NHSO2R9;
R9 and R10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(Ci- alkyl), Cι-4alkyl (optionally substituted by 1 or 2 hydroxy groups) and Ci- alkyl substituted by C^alkoxy, and wherein R9 and R10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH2-O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH2-O- group may be replaced by a methyl;
R11 is selected from hydrogen, Cι-4alkyl and hydroxyC1-4alkyl; m is 1 or 2; and RR44 iiss hhyyddrrooggeenn o or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
Another preferred class of compounds is of formula (1) wherein: is a single bond; A is phenylene; n is 0, 1 or 2; R1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO2Me and, (when n is 2) methylenedioxy;
R2 is hydrogen; R3 is selected from Cι-4alkyl (optionally substituted by 1 or 2 R8 groups);
R8 is independently selected from hydroxy, phenyl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Cι-4alkoxy, C!-4alkanoyl, Q- alkylS(O)b- (wherein b is 0, 1 or 2), arylS(O)b- (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2), -C(O)N(R9)(R10), -COOR9 , -C(O)NHSO2Me, -C(=N-OH)NH2 , -C(=N-OH)NHCι-4alkyl, -C(=N-OH)N(C!-4alkyl)2 and -NHSO2R9;
R9 and R10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C1.4alkyl), C-^alkyl (optionally substituted by 1 or 2 hydroxy groups) and Ci- alkyl substituted by Q^alkoxy, and wherein R9 and R10 together with the nitrogen to which they are attached form a 4- to 6-membered ring selected from piperidine, 4-hydroxy piperidine, pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of 3,4- dihydroxypyrrolidine; m is 1 or 2; and R4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
Another preferred class of compound is of the formula (1) wherein: is a single bond; A is phenylene; n is 0;
R is hydrogen;
R3 is selected from Cι-4alkyl (optionally substituted by 1 or 2 R8 groups); R8 is independently selected from hydroxy, C1-4alkylS(O)b- (wherein b is 0, 1 or 2), -NHC(O)R9 and -C(O)N(R9)(R10);
R9 and R10 are independently selected from hydrogen, Cι-4alkyl, heterocyclyl and heterocycly C^alkyl); m is 1 or 2; and
R4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further preferred class of compound is of the formula (1) wherein; is a single bond;
A is phenylene; n is 0, 1 or 2;
R1 is independently selected from halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy and, (when n is 2) methylenedioxy;
R2 is hydrogen;
R is selected from C^alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon); m is 1 or 2; R4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0, 1 or 2;
R1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO2Me and, (when n is 2) methylenedioxy; R2 is hydrogen;
R is selected from groups of the formulae B and B ' :
Figure imgf000023_0001
(B) (B') wherein y is 0 or 1, t is 0, 1, 2 or 3 and u is 1 or 2; provided that the hydroxy group is not a substituent on the ring carbon adjacent to the ring oxygen; m is 1 or 2; and
R4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further preferred class of compound is of the formula (1) wherein; is a single bond;
A is phenylene; n is 0
R2 is hydrogen;
R3 is hydroxypropyl, dihydroxypropyl or dihydroxybutyl; m is 1 or 2;
R4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0;
R2 is hydrogen;
>_ι
R is hydroxypropyl, dihydroxypropyl or dihydroxybutyl; m is 1; R4 is chloro; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 0
R2 is hydrogen;
R3 is heterocyclylcarbamoylmethyl; m is 1 or 2;
R4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
Another class of compounds is of the formula (1) wherein is a double bond; A is phenylene; n is 0, 1 or 2;
R1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO2Me and, (when n is 2) methylenedioxy;
R is carboxy;
R is selected from cyanoCι-4alkyl, and C1-4alkyl (optionally substituted by 1 or 2 R groups); R8 is independently selected from hydroxy, C3- cycloalkyl, phenyl, 2,2-dimethyl-l,3- dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, C1-4alkoxy, Cι- alkanoyl, Ci- alkylS(O)b- (wherein b is 0, 1 or 2), C3.6cycloalkylS(O) - (wherein b is 0, 1 or 2), arylS(O)b- (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2), - C(O)N(R9)(R10), -COOR9 , -C(O)NHSO2Me, -C(=N-OH)NH2 , -C(=N-OH)Ϊ HCι-4alkyl, -C(=N-OH)N(C1.4alkyl)2 ,-N(OH)CHO, -COCOOR9, -NHC(O)R9, (R9)(R10)NSO2-, -COCH2ORπ and -NHSO2R9;
R9 and R10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C1- alkyl), Cι-4alkyl (optionally substituted by 1 or 2 hydroxy groups) and Q- alkyl substituted by C1-4alkoxy and wherein R9 and R10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH2-O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH2-O- group may be replaced by a methyl; R11 is selected from hydrogen, Ci-4alkyl and hydroxyC1- alkyl; m is 1 or 2; and R4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further class of compound is of formula (1) wherein: is a single bond;
A is heteroarylene; n is 0, 1 or 2;
R1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO2Me and, (when n is 2) methylenedioxy;
R2 is hydrogen;
R is selected from cyanoC1-4alkyl, and C^alkyl (optionally substituted by 1 or 2 R groups)
R8is independently selected from hydroxy, C3-7cycloalkyl, phenyl, 2,2-dimethyl-l,3- dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Ci-4alkoxy, Cι-4alkanoyl, C1-4alkylS(O)b- (wherein b is 0, 1 or 2), C3-6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O)b- (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2), - C(O)N(R9)(R10), -COOR9 , -C(O)NHSO2Me, -C(=N-OH)NH2 , -C(=N-OH)NHCι-4alkyl, -C(=N-OH)N(Cι-4alkyl)2 ,-N(OH)CHO, -COCOOR9, -NHC(O)R9, (R9)(R10)NSO2-, -COCH2ORn and -NHSO2R9;
R9 and R10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C1.4alkyl), C1.4alkyl (optionally substituted by 1 or 2 hydroxy groups) and Q- 4alkyl substituted by Cι.4alkoxy and wherein R9 and R10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH2-O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH2-O- group may be replaced by a methyl; R11 is selected from hydrogen, Q- alkyl, hydroxyC^alkyl; m is 1 or 2; R4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further class of compound is of formula (1) wherein: is a single bond; A is heteroarylene; n is 0, 1 or 2;
R1 is independently selected from halo, cyano, nitro, hydroxy, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -SMe, -SOMe, -SO2Me and, (when n is 2) methylenedioxy; R2 is hydrogen;
R is selected from cyanoCι- alkyl, and C1-4alkyl (optionally substituted by 1 or 2 R groups)
R8 is independently selected from hydroxy, phenyl, 2,2-dimethyl-l,3-dioxolan-4-yl; 2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Ci- alkoxy, Cι-4alkanoyl, Q- 4alkylS(O)b- (wherein b is 0, 1 or 2), C3-6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O)b- (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2), -C(O)N(R9)(R10), -COOR9 , -C(O)NHSO2Me, -C(=N-OH)NH2 , -C(=N-OH)NHCι-4alkyl, -C(=N- OH)N(Cι-4alkyl)2 and -NHSO2R9;
R9 and R10 are independently selected from hydrogen, hydroxy, phenyl, heterocyclyl, heterocyclyl(C1-4alkyl), Ci.4alkyl (optionally substituted by 1 or 2 hydroxy groups) and Ci- 4alkyl substituted by Cι_4alkoxy and wherein R9 and R10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy or the ring may be optionally substituted on two adjacent carbons by -O-CH2-O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH2-O- group may be replaced by a methyl; m is 1 or 2; and R4 is hydrogen or halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further class of compound is of formula (1) wherein: is a single bond; A is heteroarylene; n is 0, 1 or 2;
R1 is independently selected from halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy and, (when n is 2) methylenedioxy; R2 is hydrogen;
R is selected from cyanoC1-4alkyl, and C^alkyl [optionally substituted by 1 or 2 R groups]; wherein R8 is independently selected from -C(O)N(R9)(R10), and -COOR9 , R9 and R10 are independently selected from hydrogen, Cι-4alkyl, heterocyclyl and heterocyclyl(C1-4alkyl); m is 1 or 2; and R4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further class of compound is of formula (1) wherein: is a single bond;
A is heteroarylene; n is 0, 1 or 2; R1 is independently selected from halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy and, (when n is 2) methylenedioxy;
R2 is hydrogen;
R3 is selected from C1-4alkyl (optionally substituted by 1 or 2 hydroxy groups); m is 1 or 2; R4 is halo; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 1 or 2; R1 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl and
R1 is of the formula A' or A":
~(CH2)r
Figure imgf000029_0001
-CH2CH(OH)(CH2)uCO2H (A") wherein x is 0 or 1, r is 0, 1, 2 or 3 and s is 1 or 2; provided that the hydroxy group is not a substituent on the ring carbon adjacent to the ring oxygen; R2 is hydrogen;
R is selected from C1- alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), cyanoCi- 4alkyl, and C-^alkyl [substituted by 1 or 2 R8 groups (provided that when there are 2 R8 groups they are not substituents on the same carbon)];
{R8 is independently selected from hydroxy, heterocyclyl, Cι-4alkanoyl, Ci-4alkoxy, C^alkanesulfinyl, Cι-4alkanesulfonyl, -COCOOR9, (R9)(R10)NCO-, -COCH2ORπ, (R9)(R10)N-, -COOR9 and 2,2-dimethyl-l,3-dioxolan-4-yl; [R9 and R10 are independently selected from hydrogen, hydroxy, Cι- alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon) and Cι-4alkyl substituted by Cι-4alkoxy and wherein R9 and R10 can together with the nitrogen to which they are attached form 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from hydroxy or carboxy;
R11 is selected from hydrogen, Cι-4alkyl, Cι_ alkoxy and hydroxyCι-4alkyl]}; m is 1 or 2;
R4 is hydrogen or halo.
A further preferred class of compound is of the formula (1) wherein; is a single bond; A is phenylene; n is 1 or 2; R1 is independently selected from hydrogen, halo, nitro, hydroxy, C1-4alkyl and R1 is of the formula A' or A":
~(CH2)r
Figure imgf000030_0001
-CH2CH(OH)(CH2)uCO2H (A") wherein x is 0 or 1, r is 0, 1, 2 or 3 and s is 1 or 2; provided that the hydroxy group is not a substituent on the ring carbon adjacent to the ring oxygen; R2 is hydrogen;
R3 is selected from C1-4alkyl (optionally substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon); m is 1 or 2;
R4 is hydrogen or halo.
In another aspect of the invention, preferred compounds of the invention are any one of:
5-chloro-N-[l-(methoxycarbonylmethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide; N-[l-(carboxymethyl)-2-oxo-l,2,3,4-te1xahydroquinolin-3-yl]-5-chloroindole-2-carboxarnide; 5-chloro-N-(2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5 -chloro-N- [ { 2-oxo- 1 - [2-oxo-2-(pyridin-2-ylamino)ethyl] - 1 ,2,3 ,4-tetrahydroquinolin-3 -yl } - lH-indole-2-carboxamide;
5-chloro-N- { 1 - [2-(methylthio)ethyl] -2-oxo- 1,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole-2- carboxamide;
5-chloro-N- { 1 - [2-(methylsulphinyl)ethyl] -2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole- 2-carboxamide;
5-chloro-N-{ l-[2-(methylsulphonyl)ethyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}-lH-indole- 2-carboxamide; 5 -chloro-N- { 2-oxo- 1 - [2-oxo-2-( 1 ,3 ,4-thiadiazol-2-ylamino)ethyl] - 1 ,2,3 ,4-tetrahydroquinolin- 3-yl}-lH-indole-2-carboxamide;
5-chloro-N-( 1 - { 2-[(6-methylpyridin-2-yl)amino]-2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; 5-chloro-N- { 2-oxo- 1 -[2-oxo-2-(pyridin-3-ylamino)ethyI]- 1 ,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(5-methyl-l,3,4-thiadiazol-2-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; 5-chloro-N-(l- { 2- [(5-ethyl- 1 ,3 ,4-thiadiazol-2-yl)amino]-2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-( 1- { 2-[(4-cyano- lH-pyrazol-3-yl)amino] -2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(4-methyl-l,3-thiazol-2-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)- lH-indole-2-carboxamide;
5-chloro-N-(l - { 2-[(6-chloropyridin-3-yl)amino]-2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l - { 2-[(3-hydroxypyridin-2-yl)amino] -2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; 5-chloro-N-(2-oxo- 1 - { 2-oxo-2-[(pyridin-2-ylmethyl)amino] ethyl } - 1 ,2,3 ,4-tetrahydroquinolin-
3-yl)-lH-indole-2-carboxamide;
5-chloro-N-{2-oxo-l-[2-oxo-2-(pyridin-4-ylamino)ethyl]-l,2,3,4-tetrahydroquinolin-3-yl}- lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(l-methyl-lH-pyrazol-5-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(l,3-dimethyl-lH-pyrazol-5-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(2-oxo-l - { 2-oxo-2- [(pyrazin-2-ylmethyl)amino]ethyl } - 1 ,2,3 ,4-tetrahydroquinolin-
3-yl)-lH-indole-2-carboxamide; 5-chloro-N-(l-{2-[(6-fluoropyridin-3-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(2-hydroxypyrimidin-4-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-{2-oxo-l-[2-oxo-2-(pyrimidin-4-ylamino)ethyl]-l,2,3,4-tetrahydroquinolin-3-yl}- lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(l-ethyl-lH-pyrazol-5-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; 5-chloro-N-(2-oxo- 1 - { 2-oxo-2-[(5-oxo-4,5-dihydro- lH-pyrazol-3-yl)amino]ethyl } -1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5 -chloro-N-( 1 - { 2- [(4-hydroxypyrimidin-2-yl)amino] -2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; 5-chloro-N-(l-{2-[(3-methylpyridin-2-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(6-chloropyridazin-3-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(lH-imidazol-2-ylmethyl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(l-methyl-lH-pyrazol-3-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-{2-oxo-l-[2-oxo-2-(2H-tetrazol-5-ylamino)ethyl]-l,2,3,4-tetrahydroquinolin-3- yl } - lH-indole-2-carboxamide ; 5-chloro-N-( 1 - { 2-[(3-ethyl- lH-pyrazol-5-yl)amino]-2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5 -chloro-N-( 1 - { 2- [(5-fluoropyridin-2-yl)amino] -2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
N-(l-{2-[(6-bromopyridin-3-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)-5- chloro- lH-indole-2-carboxamide;
5 -chloro-N- [ 1 -(2-hydroxyethyl)-2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3 -yl] - lH-indole-2- carboxamide;
5-chloro-N- { 1 -[(2,2-dimethyl- 1 ,3-dioxan-5-yl)methyl] -2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3- yl } - lH-indole-2-carboxamide; 5-chloro-N- { 1 - [3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo- 1 ,2,3 ,4-tetrahydiOquinolin-3-yl } - lH-indole-2-carboxamide;
5-chloro-N-[l-(2,3-dihydroxypropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide;
5-chloro-N-[l-(3-hydroxy-2-oxopropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide;
5-chloro-N-{l-[(2R)-2,3-dihydroxypropyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}-lH-indole-
2-carboxamide; 5-chloro-N-(l-{2-[(methylsulfonyl)amino]ethyl}-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)-lH- indole-2-carboxamide;
N-{ l-[2-(acetylamino)ethyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}-5-chloro-lH-indole-2- carboxamide; 5-chloro-N-(2-oxo- 1 - { 2- [(trifluoroacetyl)amino]ethyl } - 1 ,2,3 ,4-tetrahydroquinolin-3-yl)- 1H- indole-2-carboxamide;
5-chloro-N-[l-(3-hydroxypropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide;
N-{ l-[(2Z)-2-aιrήno-2-(hydroxyimino)ethyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}-5-chloro- lH-indole-2-carboxamide;
5-chloro-N-(6-fluoro-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)-lH- indole-2-carboxamide; and
5-chloro-N-[6-(methyloxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2-carboxamide; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
In another aspect of the invention, further preferred compounds of the invention are any one of:
5-chloro-N- [ 1 -(2-hydroxyethyl)-2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl]- lH-indole-2- carboxamide;
5-chloro-N-{ l-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}- lH-indole-2-carboxamide;
5-chloro-N-[l-(2,3-dihydroxypropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide; and
5-chloro-N-{ l-[(2R)-2,3-dihydroxypropyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}-lH-indole-
2-carboxamide; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
In another aspect of the invention, further preferred compounds of the invention are any one of:
5-chloro-N-[l-(2,3-dihydroxypropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide; and
5-chloro-N- { 1 - [(2R)-2,3-dihydroxypropyl] -2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl } -lH-indole-
2-carboxamide; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. Another aspect of the present invention provides a process for preparing a compound of formula (1) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof which process (wherein A, R1, R2, R3, R4, m, n and — are, unless otherwise specified, as defined in formula (1)) comprises of: a) reacting an acid of the formula (2):
Figure imgf000034_0001
(2) or an activated derivative thereof; with an amine of formula (3):
Figure imgf000034_0002
(3) and thereafter if necessary: i) converting a compound of the formula (1) into another compound of the formula (1); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester. Specific reaction conditions for the above reaction are as follows.
Process a) Acids of formula (2) and amines of formula (3) may be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for example carbonyldiimidazole, l-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride (EDCI) and dicyclohexyl-carbodiimide (DCCI), optionally in the presence of a catalyst such as 1- hydroxybenzotriazole, dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, di-isopropylethylamine, pyridine, or
Figure imgf000034_0003
such as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of -40 to 40°C.
Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters. The reaction of these types of compounds with amines is well known in the art, for example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above. The reaction may conveniently be performed at a temperature in the range of -40 to 40°C.
Where R3 of formula (1) contains an ester group, the conversion of a compound of the formula (1) into another compound of the formula (1) may involve hydrolysis of the ester group for example, acid or base hydrolysis, for example using lithium hydroxide. The reaction of this type is well known in the art. Where R3 of formula (1) contains -COOH group, the conversion of a compound of the formula (1) into another compound of the formula (1) may involve reduction of this group using reducing agents such as lithium borohydride, sodium borohydride etc. The conversion may also involve the coupling of this -COOH group with ammonia or a substituted amine in the presence of a base for example triethylamine, di-isopropylethylamine, pyridine, or 2,6-di- -.*iyϋ-pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide.
Substituted amides wherein R3 is CH2C(O)N(R9)(R10) may be prepared from the corresponding acids by a coupling reaction using the appropriate amine in the presence of a coupling reagent, for example EDCI. Alternatively, the acid may first be converted to a mixed anhydride, by reaction with, for example, ethyl chloroformate, which is reacted with an appropriate amine to produce the substituted amide. Substituted sulphonamides wherein R3 is
CH2C(O)NHSO2R9 may be prepared similarly, for instance by coupling the compounds wherein R3 is CH2CO2H with the appropriate substituted sulphonamide in the presence of a coupling reagent, for example EDCI.
Compounds of formula (1) wherein R3 is 2-hydroxymethyl may be prepared by reduction of the mixed anhydrides described above with, for example, lithium borohydride. Compounds of formula (1) wherein R3 is an oxadiazol-5-ylmethyl group may be prepared by reaction of the mixed anhydrides described above with an appropriately substituted hydroxyamidine, for example N'-hydroxyethanimidamide, in the presence of a base such as N- methylmorpholine. Compounds of formula (1) wherein R3 is a tetrazol-5-ylmethyl group may be prepared by reaction of the corresponding compounds where R3 is a cyanomethyl group with an azide, for example sodium azide, in the presence of an amine salt, for instance triethylamine hydrochloride. Compounds of formula (1) wherein R3 is 2-amino-2-(hydroxyimino)ethyl may be prepared by reaction of compounds wherein R3 is cyanomethyl with hydroxylamine hydrochloride in the presence of a base, for example sodium methoxide.
Compounds of formula (1) wherein R3 is a 2-(methylsulphonyl)ethyl or 2-
(methylsulphinyl)ethyl group may be prepared by reaction of the corresponding compounds where R3 is 2-methylthioethyl with an oxidising agent, for example oxone. Compounds of formula (1) wherein R3 is a dihydroxyalkyl group, for example 2,3- dihydroxypropyl or 2-(hydroxymethyl)-3-hydroxypropyl may be prepared by acid hydrolysis of the corresponding compounds of formula (1) wherein R3 is a protected dihydroxyalkyl group for example (2,2-dimethyl-l,3-dioxan-5-yl)methyl, (2,2-dimethyl-l,3-dioxolan-4- yl)methyl or (2-oxo-l,3-dioxan-5-yl)methyl. The acids of formula (2) are commercially available or they are know compounds or they are prepared by processes known in the art.
Compounds of formula (3) may be prepared by reacting an amine of formula (4)
Figure imgf000036_0001
with R3-L where L is a suitable leaving group (for example chloro, bromo or iodo) in the presence of a base such as sodium hydride in a suitable solvent.
Compounds of the formula (4) wherein A is phenylene and is a single bond may be made from 3-amino-3,4-dihydroquinolin-2-(lH)-one hydrochloride (J. Med. Chem.,
28, 1985, 1511-16). Compounds of the formula (4) wherein A is phenylene and is a double bond may be prepared by the reductive cyclisation of a compound of formula (5), using for example tin (II) chloride in hydrochloric acid, followed by removal of the Boc protecting group, using for example trifluoroacetic acid. Compounds of formula (5) may be prepared by reaction of compounds of formula (6) by reaction with a compound of formula (7) in the presence of a base, for example tetramethylguanidine. Compounds of formula (6) are commercially available or described in the literature.
Figure imgf000037_0001
(5) (6) (7)
Compounds of the formula (4) wherein A is heterocyclylene can be prepared from cyclisation of suitably functionalised heterocycles. For example, when A is pyridine,
Figure imgf000037_0002
(4a) (4b) compounds of formula (4a) and (4b)may be prepared from an appropriately substituted nitro- methyl pyridine or amino-pyridine according to the Schemes 2 and 3:-
Figure imgf000038_0001
Scheme 2
Steps 1 and 2 may be carried out by the process described in Tetrahedron 1998, 54(23), 6311- 6318. Step 3 may be carried out by the method described in Synthesis 1992 (5) ,487.
Assymetric hydrogenation reactions of olefins as shown in Step 4 are well known (see for example, JACS 1993, 115, 10125-10138) and lead to homochiral final products. Step 5 may alternatively be carried out by hydrolysing the ester and activating the resulting acid with a carbodiimide such as EDCI or DCCI, or by preparing an acid chloride, or activated ester such as an N -hydroxysuccinimide ester. Suitable bases are organic base such as taethylamine or di-isopropylethylamine (DIPEA) or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
In Step 6 X is a leaving group, for example CI, Br, I , OMesyl. In Step 7 alternative solvents such as dichloromethane or other acids such as trifluoroacetic acid can be used.
Figure imgf000039_0001
Figure imgf000039_0002
Scheme 3
Steps 1, 2, 3 and 4 are described in JOC 1983, 48, 3401-3408.
The processes described above and shown in Schemes 2 and 3 may also be applied to other isomeric pyridines or six membered heterocycles containing more than one nitrogen.
Compounds of the formula (4) wherein A is a heterocyclene and there is a bridgehead nitrogen, for example a compound of formula (4c),
Figure imgf000040_0001
(4c) may be prepared by cyclisation of a compound of the formula (8):
Figure imgf000040_0002
(8) wherein P is an amino protecting group such as triphenylmethyl. This transformation is induced by heating compounds of the formula (8) to reflux in a solvent, for example, ethanol. Compounds of the formula (8) may be prepared from a compound of the formula (9) by hydrogenation using a catalyst such as Pd/C at ambient temperature.
(9)
Compounds of the formula (9) may be prepared from compounds of the formula (10) and (11):
Figure imgf000040_0004
(10) (11) using conditions known for the Mitsunobu reaction (Bull. Chem. Soc. Jpn., 1967, 40, 2380). Compounds of the formulae (10) and (11) are commercially available.
Compounds of the formula (4) wherein A is heteroarylene and there is a bridgehead heteroatom, for example, compounds of the formula (4d) may be made by analogous chemistry to that shown for making compounds of the formula (4c).
Figure imgf000041_0001
It will be appreciated that certain of the various ring substituents in the compounds of the present invention, for example R1 and R4, may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions may convert one compound of the formula (1) into another compound of the formula (1). Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkanesulphinyl or alkanesulphonyl.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
Certain intermediates in the preparation of a compound of the formula (1) are novel and form another aspect of the invention. As stated hereinbefore the compounds defined in the present invention possesses glycogen phosphorylase inhibitory activity. This property may be assessed, for example, using the procedure set out below.
Assay
The activity of the compounds is determined by measuring the inhibitory effect of the compounds in the direction of glycogen synthesis, the conversion of glucose- 1 -phosphate into glycogen with the release of inorganic phosphate, as described in EP 0 846 464 A2. The reactions were in 96well microplate format in a volume of lOOμl. The change in optical density due to inorganic phosphate formation was measured at 620nM in a Labsystems iEMS Reader MF by the general method of (Nordlie R.C and Arion W.J, Methods of Enzymology, 1966, 619-625). The reaction is in 50mM HEPES (N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid);4-(2-Hydroxyethyl)piperazine-l-ethanesulfonic acid), 2.5mM MgCl2, 2.25mM ethylene glycol-bis(b-aminoethyl ether) N,N,N',N'-tetraacetic acid, lOOmM KC1, 2mM D-(+)-glucose pH7.2, containing 0.5mM dithiothreitol, the assay buffer solution, with O.lmg type Dl glycogen, 0.15ug glycogen phosphorylase a (GPα) from rabbit muscle and 0.5mM glucose-1-phosphate. GP is pre-incubated in the assay buffer solution with the type in glycogen at 2.5 mg ml"1 for 30 minutes. 40μl of the enzyme solution is added to 25μl assay buffer solution and the reaction started with the addition of 25μl 2mM glucose- 1-phosphate. Compounds to be tested are prepared in lOμl 10% DMSO in assay buffer solution, with final concentration of 1% DMSO in the assay. The non-inhibited activity of GPα is measured in the presence of lOμl 10% DMSO in assay buffer solution and maximum inhibition measured in the presence of 30μM CP320626 (Hoover et al (1998) J Med Chem 41, 2934-8; Martin et al (1998) PΝAS 95, 1776-81). The reaction is stopped after 30min with the addition of 50μl acidic ammonium molybdate solution, 12ug ml"1 in 3.48% H2SO4 with 1% sodium lauryl sulphate and lOug ml"1 ascorbic acid. After 30 minutes at room temperature the absorbency at 620nm is measured.
The assay is performed at a test concentration of inhibitor of lOμM or lOOμM. Compounds demonstrating significant inhibition at one or both of these concentrations may be further evaluated using a range of test concentrations of inhibitor to determine an IC50, a concentration predicted to inhibit the enzyme reaction by 50%. Activity is calculated as follows :-
% inhibition = (1 - (compound OD620 - fully inhibited OD620)/ (non-inhibited rate OD620 - fully inhibited OD620)) * 100.
OD620 = optical density at 620nM. Typical IC50 values for compounds of the invention when tested in the above assay are in the range lOOμM to InM.
The activity of the compounds is alternatively determined by measuring the inhibitory effect of the compounds on glycogen degradation, the production of glucose- 1 -phosphate from glycogen is monitored by the multienzyme coupled assay, as described in EP 0 846464 A2, general method of Pesce et al ( Pesce, M A, Bodourian, S H, Harris, R C, and Nicholson, J F (1977) Clinical Chemistry 23, 1171 - 1717). The reactions were in 384well microplate format in a volume of 50μl. The change in fluorescence due to the conversion of the co-factor NAD to NADH is measured at 340nM excitation, 465nm emission in a Tecan Ultra Multifunctional Microplate Reader. The reaction is in 50mM HEPES, 3.5mM KH2PO4, 2.5mM MgCl2, 2.5mM ethylene glycol-bis -aminoethyl ether) N,N,N',N'-tetraacetic acid, lOOmM KCl, 8mM D-(+)-glucose pH7.2, containing 0.5mM dithiothreitol, the assay buffer solution. Human recombinant liver glycogen phosphorylase a (hrl GPα) 20nM is pre-incubated in assay buffer solution with 6.25mM NAD, 1.25mg type Dl glycogen at 1.25 mg ml"1 the reagent buffer, for 30 minutes. The coupling enzymes, phosphoglucomutase and glucose-6-phosphate dehydrogenase ( Sigma) are prepared in reagent buffer, final concentration 0.25Units per well. 20μl of the hrl GPa solution is added to lOμl compound solution and the reaction started with the addition of 20ul coupling enzyme solution. Compounds to be tested are prepared in lOμl 5% DMSO in assay buffer solution, with final concentration of 1% DMSO in the assay. The non-inhibited activity of GPα is measured in the presence of lOμl 5% DMSO in assay buffer solution and maximum inhibition measured in the presence of 5mgs ml"1 N- ethylmaleimide. After 6 hours at 30°C Relative Fluoresence Units (RFUs) are measured at 340nM excitation, 465nm emission .
The assay is performed at a test concentration of inhibitor of lOμM or lOOμM. Compounds demonstrating significant inhibition at one or both of these concentrations may be further evaluated using a range of test concentrations of inhibitor to determine an IC5o, a concentration predicted to inhibit the enzyme reaction by 50%. Activity is calculated as follows :-
% inhibition = (1 - (compound RFUs - fully inhibited RFUs)/ (non-inhibited rate RFUs - fully inhibited RFUs)) * 100.
Typical IC50 values for compounds of the invention when tested in the above assay are in the range lOOμM to InM. For example, Example 14 was found to have an IC5o of 4.6μm.
Rat hepatocytes were isolated by the collagenase perfusion technique, general method of
Seglen (P.O. Seglen, Methods Cell Biology (1976) 13 29-83). Cells were cultured on Nunclon six well culture plates in DMEM (Dulbeco's Modified Eagle's Medium) with high level of glucose containing 10% foetal calf serum, NEAA (non essential amino acids), Glutamine, penicillin /streptomycin ((100units/100ug)/ml) for 4 to 6 hours. The hepatocytes were then cultured in the DMEM solution without foetal calf serum and with lOnM insulin and lOnM dexamethasone. Experiments were initiated after 18-20 hours culture by washing the cells and adding Krebs-Henseleit bicarbonate buffer containing 2.5mM CaCl2 and 1% gelatin. The test compound was added and 5 minutes later the cells were challenged with 25nM glucagon. The Krebs-Henseleit solution was removed after 60 min incubation at 37°C , 95%O /5%CO2 and the glucose concentration of the Krebs-Henseleit solution measured.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
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).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl r 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.
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 monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl rj-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions 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. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more 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.
For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in
Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The compound of formula (1) will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
The inhibition of glycogen phosphorylase activity described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances and/or treatments. 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. For example in the treatment of diabetes n ellitus chemotherapy may include the following main categories of treatment:
1) Insulin and insulin analogues;
2) Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide) and prandial glucose regulators (for example repaglinide, nateglinide);
3) Insulin sensitising agents including PPARg agonists (for example pioglitazone and rosiglitazone);
4) Agents that suppress hepatic glucose output (for example metformin).
5) Agents designed to reduce the absorption of glucose from the intestine (for example acarbose); 6) Agents designed to treat the complications of prolonged hyperglycaemia;
7) Anti-obesity agents (for example sibutramine and orlistat);
8) Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (statins, eg pravastatin); PPARα agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stanols, synthetic inhibitors); bile acid absorption inhibitors (IBATi) and nicotinic acid and analogues (niacin and slow release formulations);
9) Antihypertensive agents such as, β blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine); Angiotensin receptor antagonists (eg candesartan), antagonists and diuretic agents (eg. furosemide, benzthiazide);
10)Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor VHa inhibitors); antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin; and 11) Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone).
According to a further aspect of the present invention there is provided a compound of the formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use in a method of treatment of a warm-blooded animal such as man by therapy.
According to an additional aspect of the invention there is provided a compound of the formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use as a medicament. According to an additional aspect of the invention there is provided a compound of the formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use as a medicament in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity in a warm-blooded animal such as man. According to this another aspect of the invention there is provided the use of a compound of the formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity in a warm-blooded animal such as man.
According to this another aspect of the invention there is provided the use of a compound of the formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of type 2 diabetes in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided a method of producing a glycogen phosphorylase inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (1).
According to this further feature of this aspect of the invention there is provided a method of treating type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula ( 1 ) .
According to this further feature of this aspect of the invention there is provided a method of treating type 2 diabetes in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (1). As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. A unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
In addition to their use in therapeutic medicine, the compounds of formula (1) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
In the above other pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply. Examples
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C and under an atmosphere of an inert gas such as argon;
(ii) organic solutions were dried over anhydrous magnesium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of up to 60°C; (iii) chromatography means flash chromatography on silica gel; thin layer chromatography
(TLC) was carried out on silica gel plates; where a Bond Elut column is referred to, this means a column containing 10 g or 20 g or 50 g of silica of 40 micron particle size, the silica being contained in a 60 ml disposable syringe and supported by a porous disc, obtained from
Varian, Harbor City, California, USA under the name "Mega Bond Elut SI"; "Mega Bond Elut" is a trademark; where a Biotage cartridge is referred to this means a cartridge containing
KP-SIL™ silica, 60μ, particle size 32-63mM, supplied by Biotage, a division of Dyax Corp.,
1500 Avon Street Extended, Charlottesville, VA 22902, USA;
(iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only; (v) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
(vi) where given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO-δ6) as solvent unless otherwise indicated, other solvents (where indicated in the text) include deuterated chloroform
CDC13;
(vϋ) chemical symbols have their usual meanings; SI units and symbols are used;
(viii) reduced pressures are given as absolute pressures in Pascals (Pa); elevated pressures are given as gauge pressures in bars; (ix) solvent ratios are given in volume : volume (v/v) terms;
(x) The following abbreviations are used: SM starting material;
EtOAc ethyl acetate;
MeOH methanol;
EtOH ethanol;
DCM dichloromethane;
HOBT 1 -hydroxybenzotriazole;
DIPEA di-isopropylethylamine ;
EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride;
Et2O diethyl ether;
THF tetrahydrofuran;
DMF N, N-dimethylformamide;
HATU O-(7-Azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluroniumhexafluorophosphate
DMAP 4-dimethylaminopyridine
TBAF tetrabutylammonium fluoride
TFA trifluoroacetic acid
Certain intermediates described hereinafter within the scope of the invention may also possess useful activity, and . are provided as a further feature of the invention.
Example 1: 5-Chloro-N-ri- methoxvcarbonvlmethvl)-2-oxo-l,2,3,4- tetrahvdroquinolin-3-vl] - lH-indole-2-carboxamide
Figure imgf000052_0001
5-Chloro-lH-indole-2-carboxylic acid (493 mg, 2.52 mmol), ΗOBT (340 mg, 2.52 mmol), DCM (100 mL) and finally EDCI (483 mg, 2.52 mmol) were added to methyl 2-(3- amino-2-oxo-3,4-dihydroquinolin-l(2H)-yl)acetate (Method 1; 590 mg, 2.52 mmol) and the reaction was stirred for 18 h. The reaction was then diluted with water (50 mL) and stirred vigorously for 30 min. The resultant precipitate was filtered and washed with Et2O (2 x 20 mL). After filtration the resultant solid was then triturated with refluxing Et2O (25 mL) and after cooling the title compound (608 mg, 59%) was collected again by filtration as a white solid.
1H NMR3.11 (dd, 1H), 3.25 (app. t, 1H), 3.69 (s, 3H), 4.67 (d, 1H), 4.83 (m, 2H), 7.09 (m,
2H), 7.23 (m, 2H), 7.32 (m, 2H), 7.47 (d, 1H), 7.76 (s, 1H), 8.92 (d, 1H), 11.83 (s, 1H); MS
5 m/z MNa+434, 436.
Example 2: N-ri-CCarboxymethvD- -oxo-l^^^-tetrahvdroquinolin-S-yll-S- chloroindole-2-carboxamide;
Figure imgf000053_0001
10 LiOH (91.5 g, 2.18 mmol) in H2O (2 mL) was added to a stirring solution of 5-chloro-
N- [ 1 -(methoxycarbonylmethyl)-2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl]- lH-indole-2- carboxamide (Example 1; 557 mg, 1.09 mmol) in TΗF (11 mL) and the reaction was stirred for 3 h. The reaction was quenched by addition of 1M aqueous ΗC1 (40 mL) and EtOAc (60 mL) and the organic layer was dried (MgSO4), filtered and evaporated. The resultant white
15 foam was triturated with hot Et2O (20 mL) cooled, filtered, dried and collected by filtration to afford the title compound (500 mg, 92%) as a white solid.
1H ΝMR3.08 (dd, 1Η), 3.25 (app. t, 1Η), 4.53 (d, 1Η), 4.77 (m, 2Η), 7.06 (m, 2H), 7.24 (m, 4H), 7.45 (d, 1H), 7.74 (s, 1H), 8.90 (d, 1H), 11.83 (s, 1H); MS m z M_tf 398, 400.
20 Example 3: 5-Chloro-N-(2-oxo-l,2,3,4-tetrahvdroquinolin-3-yl)-lJH-indole-2- carboxamide
Figure imgf000053_0002
5-Chloroindole-2-carboxylic acid (196mg, lmmol) was dissolved in DMF (5 mL) containing 3-amino-3,4-dihydroquinolin-2(lH)-one hydrochloride (J. Med. Chem. 28, 1985, 25 1511-16; 162mg, lmmol), EDCI (192 mg, 1 mmol) and ΗOBT (135 mg, 1 mmol). The mixture was stirred at ambient temperature for approximately 18 h before being partitioned between water and EtOAc. The organics were washed with water, saturated aqueous
NaHCO3, saturated brine and dried over MgSO ; then filtered and evaporated to afford the title compound (212 mg, 66%) as an amorphous white solid.
1H NMR 3.13 (m, 2H), 4.77 ( , 1H), 6.92 (d, 1H), 6.96 (t, 1H), 7.21 (m, 4H), 7.47 (d, 1H),
5 7.76 (d, 1H), 8.80 (d, 1H), 10.38 (s, 1H), 11.84 (s, 1H); MS m/z MH" 340, 342.
Example 4: 5-Chloro-N-r{2-oxo-l-r2-oxo-2-(pyridin-2-vIamino)ethvn-l,2.,3,4- tetrahydroquinolin-3-yl}-lH-indole-2-carboxamide
Figure imgf000054_0001
10 N-(l-{2-[(2,5-Dioxopyrrolidin-l-yl)oxy]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-5-methyl-lH-indole-2-carboxamide (Method 2; 188 mg, 0.38 mmol) and 2-aminopyridine (108 mg, 1.14 mmol) were dissolved in l-methyl-2-ρyrrolidinone (0.4 mL) and heated to 150°C for 3 hours. On cooling the mixture was poured into Η O (10 mL) and the resultant solid filtered off and dried under reduced pressure. The residue was purified
15 by column chromatography (DCM to DCM:THF (4: 1)) to give a yellow solid. The solid was triturated with refluxing Et2O (25 mL), filtered, washed with Et2O (25 mL) then hexane (25 mL) to afford the title compound as an off white solid.
1HΝMR 3.11 (dd, 1H), 3.28 (app. t, 1H), 4.73 (d, 1H), 4.87 (m, 1H), 5.00 (d, 1H), 7.11 (m, 3H), 7.27 (m, 4H), 7.46 (d, 1H), 7.63-7.71 (m, 2H), 8.00 (d, 1H), 8.34 (d, 1H), 8.91 (d, 1H),
20 10.81 (br. s, 1H), 11.85 (br. s, 1H); MS m/z (M-H)" 472, 474.
25 Example 5: 5-Chloro-N-ll-r2-(methylthio)ethvn-2-oxo-l,2,3.4-tetrahvdroquinolin-3- yl}- lHr-indole-2-carboxamide
Figure imgf000055_0001
Sodium thiomethoxide (280 mg, 4.00 mmol) and KI (10 mg, 0.06 mmol) were added to a soluton of 5-chloro-N-[l-(2-chloroethyl)-2-oxo-l ,2,3,4-tetrahydroquinolin-3-yl]-lH- indole-2-carboxamide (Method 3; 1.07 g, 2.67 mmol) in DMF (10 mL) under an inert atmosphere and heated at 80 °C for 2 hours. On cooling the mixture was diluted with EtOAc (100 mL), washed with water (20 mL), dried (Νa2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:TΗF (2:23)) to give a white solid. The solid was triturated with refluxing Et2O (20 mL) and the solid filtered, washed with Et O (10 mL) then hexane (10 mL) to afford the title compound (410 mg, 37%) as an off white solid.
1H NMR 2.13 (s, 3H), 2.70 (t, 2H), 3.06 (dd, IH), 3.18 (app. t,lH), 4.15 (m, 2H), 4.77 (m, IH), 7.08 (t, IH), 7.23 (m, 3H), 7.33 (m, 2H), 7.46 (d, IH), 7.75 (d, IH), 8.92 (dd, IH), 11.88 (br. s, IH); MS m/z (M-H)" 412, 414
Example 6: 5-Chloro-N-{l-r2-(methylsulphinyl)ethyl1-2-oxo-l,2,3.4- tetrahydroquinoIin-3-yl)-lH-mdole-2-carboxamide nd
Example 7; 5-ChIoro-N-{l-r2-(methylsulphonyl)ethyl]-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl}-lH-indoIe-2-carboxamide
Figure imgf000055_0002
Oxone (701 mg, 1.14 mmol) in H2O (12 mL) was added to 5-chloro-N-{l-[2- (methylthio)ethyl] -2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole-2-carboxamide (Example 5; 355 mg, 0.86 mmol) in MeOH (12 mL) and stirred for 18 hours. The mixture was diluted with EtOAc (100 mL) washed with saturated NaHCO3 (20 mL), dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to
DCM:THF (3:2) then DCM:MeOH (4:1)) to give 2 yellow solids. Each solid was triturated with refluxing Et2O (25 mL) and the solids filtered, washed with Et2O (25 mL) then hexane
(25 mL) to afford 5-chloro-N-{ l-[2-(methylsulphinyl)ethyl]-2-oxo-l,2,3,4-tetrahydroquinolin-
3-yl}-lH-indole-2-carboxamide (125 mg, 34%) and 5-chloro-N-{ l-[2-
(methylsulphonyl)ethyl] -2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole-2-carboxamide (95 mg, 25%) as white solids. 5-Chloro-N-{ l-[2-(methylsulphinyl)ethyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}-lH-indole-
2-carboxamide: 1H ΝMR 2.63 (s, 3Η), 3.08 (m, 4H), 4.32 (m, 2H), 4.77 (m, IH), 7.10 (t, IH), 7.28 (m, 5H),
7.46 (d, IH), 7.75 (s, IH), 8.86 (dd, IH), 11.85 (br. s, IH); MS m z (M-H)" 428, 430.
5-Chloro-N- { 1 -[2-(methylsulphonyl)ethyl]-2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole- 2-carboxamide:
1H ΝMR 3.08 (m, 5Η), 3.47 (m, 2H), 4.36 (t, 2H), 4.77 (m, IH), 7.10 (t, IH), 7.24 (m, 3H),
7.35 (m, 2H), 7.46 (d, IH), 7.75 (s, IH), 8.86 (dd, IH), 11.85 (br. s, IH); MS m/z (M+Νa)+
468, 470.
Example 8: 5-Chloro-N-{2-oxo-l-r2-oxo-2-(l,3,4-thiadiazol-2-ylamino)ethyl1-l,2,3,4- tetrahydroquinolin-3-yl>-lH-indole-2-carboxamide
Figure imgf000056_0001
N-[l-(Carboxymethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5-chloroindole-2- carboxamide (Example 2; 250 mg, 0.629 mmol), HOBT (85 mg, 0.629 mmol) and amine (1.89 mmol) were mixed together and dissolved in DMF ( 3 mL). EDCI (363 mg, 1.89 mmol) was added in one portion and the sides of the tubes rinsed down with DMF (2 mL). After stirring overnight at room temperature the reaction was poured into water (25 mL) and the title compound filtered off as a solid. Analysis was by lcms using the following conditions:- Phenomenex Synergi Column 50x 2.0 mm 4u. Acetonitrile (B) / Water (A) eluent Flow rate 1.2 mis min-1 Gradient:- 1.0% B to 95% B over 4.5mins Wavelength 254 n.m.
Figure imgf000057_0001
Examples 9-22
The following examples were synthesized by an analogous method to Example 8:
Example 9; 5-chloro-N-(l-{2-r(6-methylpyridin-2-yl)aminol-2-oxoethyll-2-oxo- 2.3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
Example 10; 5-chloro-N-{ 2-oxo-l-[2-oxo-2-(pyridin-3-ylamino)ethyl]-l ,2,3,4- tetrahvdroquinolin-3-yl } - lH-indole-2-carboxamide
Example 11 : 5-chloro-N-( 1 - { 2- [(5-methyl- 1 ,3 ,4-thiadiazol-2-yl)amino] -2-oxoethyl } -2-oxo- l,2,3,4-tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide Example 12; 5-chloro-N-(l-{2-[(5-ethyl-l,3,4-thiadiazol-2-yl)aminol-2-oxoethyll-2-oxo- l,2,3,4-tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
Example 13: 5-chloro-N-(l-{2-r(4-cvano-lH-pyrazol-3-yl)amino]-2-oxoethyl|-2-oxo- l,2,3,4-tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
Example 14: 5-chloro-N-(l-{2-[(4-methyl-l,3-thiazol-2-yl)aminol-2-oxoethyl}-2-oxo- 1,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide
Example 15: 5-chloro-N-(l-{2-[(6-chloropyridin-3-yl)amino1-2-oxoethyl|-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
Example 16: 5-chloro-N-( 1- { 2-[(3-hvdroxypyridin-2-yl)aminol -2-oxoethyl ) -2-oxo- 1 ,2,3 ,4- tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide Example 17: 5-chloro-N-(2-oxo- 1 - { 2-oxo-2-[(pyridin-2-ylmethyl)amino1ethyl 1-1.2.3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
Example 18 : 5-chloro-N- { 2-oxo- 1 - [2-oxo-2-(pyridin-4-ylamino)ethyl] - 1 ,2,3 ,4- tetrahydroquinolin-3-yl|-lH-indole-2-carboxamide
Example 19: 5 -chloro-N-( 1 - { 2- r 1 -methyl- lH-pyrazol-5-yl)amino] -2-oxoethyl I -2-oxo- 1 ,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide Example 20: 5-chloro-N-(l-{2-[(l,3-dimethyl-lH-pyrazol-5-yl aminol-2-oxoethyll-2-oxo- l,2,3,4-tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
Example 21: 5-chloro-N-(2-oxo-l-{2-oxo-2-[(pyrazin-2-ylmethyl)aminolethyl|-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide Example 22: 5-chloro-N-(l-{2-[f6-fluoropyridin-3-yl)aminol-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000059_0001
Examples 23-35
The following examples were synthesized by an analogous method to Example 8 with additional purification by reverse phase prep HPLC using the following conditions: Column = Phenomenex Luna lOu C18. Flow rate = 25mIJmin Run time = 9 mins Eluent H2O (0.1% formic acid): CH3CN (0.1% formic acid) (Gradient (95:5) to (0:100)).
Example 23 : 5-chloro-N-( 1-12- [(2-hvdroxypyrimidin-4-yl)amino] -2-oxoethyl I -2-oxo-
1 ,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide
Example 24: 5-chloro-N- { 2-oxo- 1- [2-oxo-2-(pyrimidin-4-ylamino)ethyl1- 1 ,2,3 ,4- tetrahvdroquinolin-3 - yl ] - lH-indole-2-carboxamide
Example 25: 5-chloro-N-( 1 - { 2- [( 1 -ethyl- lH-pyrazol-5-yl)amino] -2-oxoethyl } -2-oxo- l,2,3,4-tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
Example 26: 5-chloro-N-(2-oxo- 1- { 2-oxo-2- [(5-oxo-4,5-dihydro- lH-pyrazol-3- vDaminol ethyl 1-1,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide
Example 27: 5-chloro-N-( 1 - { 2-\( 4-hvdroxypyrimidin-2-yl)amino1 -2-oxoethyl } -2-oxo- l,2,3,4-tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide Example 28: 5-chloro-N-(l-{2-r(3-methylpyridin-2-yl)aminol-2-oxoethvπ-2-oxo-l,2,3.4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide
Example 29: 5-chloro-N-(l-{2-[(6-chloropyridazin-3-yl)amino]-2-oxoethyl]-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide Example 30: 5-chloro-N-( 1- { 2- ( lH-imidazol-2-ylmethyl)amino1 -2-oxoethyl I -2-oxo-
1 ,2,3 ,4-tetrahydroquinolin-3-yl)- lH-indole-2-carboxamide
Example 31: 5-chloro-N-( 1 - { 2-r( 1 -methyl- lH-pyrazol-3-yl)amino1-2-oxoethyl I -2-oxo-
1 ,2,3 ,4-tetrahvdroquinolin-3-yl)- lH-indole-2-carboxamide
Example 32: 5-chloro-N- ( 2-oxo- 1 - [2-oxo-2-(2H-tetrazol-5-ylamino)ethyl1- 1 ,2,3 ,4- tetrahvdroquinolin-3-yl|-lH-indole-2-carboxamide
Example 33: 5-chloro-N-(l-{2-r(3-ethyl-lH-pyrazol-5-yl)amino]-2-oxoethyl]-2-oxo- l,2,3,4-tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
Example 34: 5-chloro-N-(l-{2-[(5-fluoropyridin-2-yl)amino1-2-oxoethyl}-2-oxo-l,2,3,4- tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide Example 35: N-( 1 - { 2-[(6-bromopyridin-3-yl)amino1-2-oxoethyl I -2-oxo- 1 ,2,3 ,4- tetrahvdroquinolin-3-yl)-5-chloro-lH-indole-2-carboxamide
Figure imgf000060_0001
Figure imgf000061_0002
Example 36: 5-Chloro-N-ri-(2-hvdroxyethyl)-2-oxo-l,2,3-<4-tetrahvdroquinolin-3-yl1- lH-indole-2-carboxamide
Figure imgf000061_0001
Triethylamine (0.168 mL, 1.21 mmol) then ethyl chloroformate (0.115 mL, 1.21 mmol) were added to N-[l-(carboxymethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5- chloroindole-2-carboxamide (Example 2, 437 mg, 1.10 mmol) in anhydrous THF (10 mL) at 0 °C followed by stirring for 1 h. LiBHt (2.0 M in THF, 0.69 mL, 1.37 mmol) was added slowly and the mixture stirred for a further 30 min. The reaction was carefully quenched with IM HCl (50 mL) and EtOAc (100 mL) and the organic layer was further washed with sat. aqueous ΝaHCO3 (30 mL), brine (30 mL), dried (MgSO4), filtered and evaporated. The residue was triturated with refluxing Et2O (10 mL) and after cooling the solid was filtered and dried to afford the title compound (325 mg, 77%) a white solid. 1H NMR 3.05 (dd, IH), 3.17 (t, IH), 3.61 (m, 2H), 3.93 (m, IH), 4.03 (m, IH), 4.77 (m, IH), 4.86 (t, IH), 7.05 (m, IH), 7.22 (m, 2H), 7.31 (m, 3H), 7.45 (d, IH), 7.75 (d, IH), 8.83 (d, IH), 11.85 (s, IH); MS m/z 384, 386
Example 37: 5-Chloro-N-{l-r(2.2-dimethyl-1.3-dioxan-5-yl)methvn-2-oxo-1.2.3.4- tetrahydroquinolin-3-yl>-lH-indole-2-carboxamide
Figure imgf000062_0001
Following a standard amide coupling procedure analogous to Example 1, using 3- a ino- 1 -[(2,2-dimethyl- 1 ,3-dioxan-5-yl)methyl] -3 ,4-dihydroquinolin-2( lH)-one (Method 4) as the amine and 5-chloroindole-2-carboxylic acid as the acid afforded the title compound (85%) as a white solid.
1H MR 1.34 (s, 3Η), 1.39 (s, 3H), 2.00 (m, IH), 3.08 (dd, IH), 3.20 (t, IH), 3.75 (m, 2H), 3.83 (m, 3H), 4.20 (dd, IH), 4.75 (quin, IH), 7.06 (t, IH), 7.24 (m, 2H), 7.30 (m, 3H), 7.45 (d, IH), 7.73 (s, IH), 8.82 (d, IH), 11.86 (s, IH); MS m/z 468, 470.
Example 38: 5-Chloro-N-(l-r3-hvdroxy-2-(hvdroxymethvI)propyl1-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indoIe-2-carboxamide
Figure imgf000062_0002
6M aqueous HCl (2.34 mL) was added to 5-chloro-N-{ l-[(2,2-dimethyl-l,3-dioxan-5- yl)methyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}-lH-indole-2-carboxamide (Example 37; 540 mg, 1.16 mmol) in TΗF (19 mL) and the reaction was stirred for 1 h. The reaction was quenched by addition of triethylamine (1.5 mL) and the reaction was diluted with water (20 mL) and EtOAc (40 mL). The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was triturated with hot Et2O (15 mL) and after cooling was filtered and dried to afford the title compound (421 mg, 85%) as white solid.
1H NMR 1.90 (m, IH), 3.13 (m, 2H), 3.39 (m, 3H), 3.51 (m, IH), 3.86 (dd, IH), 4.08 (dd, IH), 4.38 (t, IH), 4.50 (t, IH), 4.73 (quin, IH), 7.04 (t, IH), 7.18 (m, 2H), 7.29 (m, 3H), 7.43
(d, IH), 7.72 (s, IH), 8.80 (d, IH), 11.82 (s, IH); MS m/z 428, 430.
Example 39: 5-ChIoro-N-[l-(2,3-dihydroxypropyI)-2-oxo-l,2,3..4-tetrahydroquinolin-3- yl]-lHr-indole-2-carboxamide
Figure imgf000063_0001
The procedure of Example 37 was followed using 3-amino-l-[(2,2-dimethyl-l,3- dioxolan-4-yl)methyl]-3,4-dihydroquinolin-2(lH)-one (Method 5) as amine and 5-Chloro- lΗ-indole-2-carboxylic acid as the acid component, to give the title compound as a white solid which was used without purification and subjected to acid catalysed hydrolysis according to the method used for Example 38 gave the title compound (90%) as a white solid.
1H NMR 3.10 (m, 2H), 3.37 (m, 2H), 3.90 (m, 3H), 4.71 (m, 3H), 7.04 (t, IH), 7.23 (m, 5H),
7.46 (d, IH), 7.72 (s, IH), 8.81 (t, IH), 11.83 (s, IH); MS m/z 414
Example 40: 5-Chloro-N-ri-(3-hydroxy-2-oxopropyl)-2-oxo-l,2,3,4-tetrahydroquinolin- 3-yl1-lH-indole-2-carboxamide
Figure imgf000063_0002
Dess-Martin Periodinane (120 mg, 0.28 mmol) was added to a stirring solution of N- [l-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl] -5 -chloro- lH-indole-2-carboxamide (Method 6, 74 mg, 0.14 mmol) in DCM and the reaction was stirred for 2 hours. The reaction was quenched by addition of sat. aqueous
ΝaΗCO3 (20 mL) and EtOAc (40 mL) and the organic layer was separated and further washed with acidified (pH 0) sodium metabisulfite (10 mL) and the organic layer was dried (MgSO4), filtered and evaporated. Purification by column chromatography (1:19 MeOH:DCM) afforded the title compound (18 mg, 31%) as a white solid.
1H NMR 3.10 (dd, IH), 3.27 (m, IH), 4.27 (d, 2H), 4.83 (m, 2H), 5.09 (d, IH), 5.41 (t, IH), 6.90 (d, IH), 7.07 (t, IH), 7.27 (m, 4H), 7.47 (d, IH), 7.74 (s, IH), 8.89 (d, IH), 11.85 (s, IH); MS m/z 412, 414.
Example 41: 5-Chloro-N-U-r(2R)-2.3-dihvdroχypropyl1-2-oxo-1.2,3,4- tetrahydroquinolin-3-yI H-indole-2-carboxamide
Figure imgf000064_0001
6NHC1 was added dropwise to a solution of 5-chloro-N-(l-{[(4R)-2,2-dimethyl-l,3- dioxolan-4-yl]methyl } -2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl)- lH-indole-2-carboxamide (Method 7, 500 mg, 1.1 mmol) and the reaction was stirred at ambient temperature for 2 hours. Saturated ΝaΗCO3 solution was added cautiously until the reaction mixture was at pH 8, the mixture was extracted with EtOAc (2 x 20 mL), the combined organic phases dried (MgSO4) and the volatiles removed under reduced pressure to give the title compound (450 mg, 99%) as a yellow solid. 1H NMR 3.10 (m, IH), 3.25 (app. t, IH), 3.45 (m, 2H), 3.90 (m, 2H), 4.13 (m, IH), 4.70 (m, IH), 4.83 (m, IH), 4.95 (dd, IH), 7.43 (m, 8H), 8.92 (dd, IH), 11.92 (s, IH); MS m/z (M+Na) 436, 438. Example 42: 5-Chloro-N-(l-{2-[(methylsulfonyl)amino1ethyl}-2-oxo-1.2.3.4- tetrahvdroquinolin-3-yl)-lH-indoIe-2-carboxamide
Figure imgf000065_0001
Triethylamine (80 μL, 0.6 mmol) was added to a stirred suspension of N-[l-(2- aminoethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5-chloro-lH-indole-2-carboxamide_ trifluoroacetate (Method 9, 150 mg, 0.3 mmol) and methanesulfonyl chloride (25 μL, 0.33 mmol) in anhydrous DCM (5 mL) at 0 °C. The reaction was stirred at 0°C for 30 rnins, then warmed and stirred at ambient temperature for 30 rnins. The reaction was poured into water (10 mL) and the layers were separated. The organic phase was washed with 1 Ν ΗC1 (10 mL), brine (15 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give a pale yellow solid (100 mg). Purification by column chromatography (7:3 EtOAc :isohexane, then EtOAc) gave the title compound (34 mg, 22%) as a colourless solid. 1H ΝMR 2.93 (s, 3Η), 3.15 (m, 4H), 4.05 (m, 2H), 4.78 (m, IH), 7.28 (m, 8H), 7.75 (s, IH), 8.83 (d, IH); MS m/z (M+Νa) 483, 485.
Example 43 : N-f 1- [2-(Acetylamino)ethyl] -2-oxo- l,2,3,4-tetrahydroquinolin-3-yl|-5- chloro- lH-indole-2-carboxamide
Figure imgf000065_0002
HOBT (27 mg, 0.2 mmol), acetic acid (12.5 μL, 0.22 mmol), DIPEA (35 μl, 0.2 mmol) and then EDCI (48 mg, 0.25 mmol) were added to a solution of N-[l-(2-aminoethyl)-2- oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl]-5-chloro- lH-indole-2-carboxamide trifluoroacetate (Method 9, 100 mg, 0.2 mmol) in DCM (2 mL) and TΗF (0.5 mL). The reaction was stirred for 90 rnins at ambient temperature, diluted with EtOAc (5 mL), washed with 1 Ν ΝaOΗ (3 mL), 1 N HCl (3 mL), saturated aqueous NaHCO3 solution (5 mL) and dried (MgSO ).
Column chromatography (7:3 to 8:2 EtOAc:isohexane) gave the title compound (40 mg, 47%) as a tan solid.
1H NMR 1.23 (s, 3H), 3.15 (m, 2H), 4.30 (t, 2H), 4.75 (m, IH), 3.95 (m, 2H), 7.33 (m, 8H); MS m/z (M+Na) 447, 448.
Example 44: 5-Chloro-N-(2-oxo-l-{2-r(trifluoroacetyl)amino1ethvU-1.2.3.4- tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
Figure imgf000066_0001
Sodium borohydride (98 mg, 2.6 mmol) was added cautiously to a stirred suspension of cobalt chloride hexahydrate (124 mg, 0.52 mmol), trifluoroacetic anhydride (70 μL, 0.52 mmol) and 5-chloro-N-[l-(cyanomethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide (Method 11, 100 mg, 0.26 mmol) in MeOΗ (4 mL) and TΗF (2 mL) at 0°C. The reaction was allowed to warm to ambient temperature, stirred for five days and then filtered through a pad of Celite, washing through with 9: 1 MeOΗ:water (2 x 10 mL) and the filtrate evaporated under reduced pressure. The residue was taken up in EtOAc (20 mL), washed with saturated aqueous ΝaHCO3 solution (10 mL), 1 N HCl (10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed under reduced pressure. Column chromatography (1:1 EtOAc sohexane) gave the title compound (27 mg, 22%) as a pale yellow solid. 1H NMR 3.13 (m, 2H), 3.45 (br. m, 2H), 4.05 (m, 2H), 4.80 (m, IH), 7.38 (m, 8H), 8.80 (d, IH), 9.30 (s, IH); MS m/z (M+Na) 501, 503. Example 45: 5-Chloro-N-ri-(3-hvdroxypropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yll- lH-indole-2-carboxamide
Figure imgf000067_0001
A I solution of TB AF in THF (1 mL) was added dropwise to a solution of N-[l-(3-
{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5-chloro-lH- indole-2-carboxamide (Method 13, 400 mg, 0.78 mmol) in TΗF (5 mL). The reaction was stirred at ambient temperature for 24 h, partitioned between EtOAc (25 mL) and saturated aqueous ΝΗ4CI solution (20 mL), the layers separated and the organic phase dried (MgSO4). The volatiles were removed under reduced pressure to give an off-white solid which was washed with water, isohexane, diethyl ether and dried under vacuum to give the title compound (234 mg, 75%) as an off-white solid.
1HNMR 1.80 (m, 2H), 3.15 (m, 2H), 3.53 (m, 2H), 4.05 (m, IH), 4.58 (t, IH), 4.78 (m, IH), 7.30 (m, 7H), 7.79 (s, IH), 8.87 (d, IH), 11.90 (s, IH); MS m/z (M+Na) 420, 422.
Example 46: N-{l-r(2Z)-2-Amino-2-(hvdroxyimino)ethyll-2-oxo-l,2.,3,4- tetrahvdroquinolin-3-vU-5-chloro-lH-indole-2-carboxamide
Figure imgf000067_0002
A solution hydroxylamine hydrochloride (147 mg, 2.11 mmol) in MeOH (4 mL) was added to a solution of sodium methoxide in methanol (0.5 M, 4.2 mL, 2.1 mmol) that had been further diluted with methanol (4 mL). After stirring for 10 minutes, THF (4 mL) was added followed by portionwise addition of 5-chloro-N-[l-(cyanomethyl)-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl]-lH-indole-2-carboxamide (Method 11, 400 mg, 1.06 mmol). The reaction mixture was stirred at ambient temperature for 18 h, partitioned between EtOAc (80 mL) and diluted brine (80 mL), filtered and the layers of the filtrate separated. The organic phase was dried (Na2SO4) and the volatiles removed under reduced pressure to give the title material (191 mg, 44%) as a yellow solid.
1H NMR 3.20 (m, 2H), 4.35 (d, IH), 4.82 (d, IH), 4.90 (m, IH), 5.43 (br. s, 2H), 7.30 (m, 7H), 7.80 (s, IH), 8.92 (d, IH), 9.20 (s, IH), 11.93 (s, IH); MS m/z (M+Na) 434, 436.
Example 47: 5-Chloro-N-(6-fluoro-2-oxo-l.l2,3,4-tetrahvdroquinoIin-3-vI)-lH- indole-2- carboxamide
Figure imgf000068_0001
Triethylamine (184 μL, 1.32 mmol), HOBt (89 mg, 0.66 mmol), 3-amino-6-fluoro-3,4- dihydro-2(lH)-quinolinone monohydrochloride (CAS Reg. No: 82420-54-0) (143 mg, 0.66 mmol), and ED AC (127 mg, 0.66 mmol) were added to a solution of 5-chloroindole-2- carboxylic acid (129 mg, 0.66 mmol) in anhydrous DMF (3.5 mL). The reaction was stirred at ambient temperature for approximately 16 h, and then poured into water (50 mL). This was stirred vigorously for about 10 mins. and filtered. The collected precipitate was washed with water and dried in vacuum at 40°C, to give the title compound (200 mg, 85%) as an amorphous solid.
1H NMR 3.15 (m, 2Η), 4.76 (m, IH), 8.92 (m, IH), 7.06 (m, IH), 7.17 (m, IH), 7.20 (m, 2H), 7.46 (d, IH), 7.76 (s, IH), 8.80 (d, IH), 10.40 (s, IH), 11.86 (s, IH); MS m/z 358, 360.
The following examples were made, by the process of Example 47, using 3-amino- 3,4-dihydro-6-methoxy-2(lH)-quinolinone monohydrochloride (CAS Reg No: 35287-38-8) or 3-amino-3,4-dihydro-2(lH)-quinolinone (CAS Reg. No: 40615-17-6) and 5-chloroindole- 2-carboxylic acid, as appropriately. Example 48: 5-ChIoro-N-[6-(methyIoxy)-2-oxo-1.2.3,4-tetrahydroquinoIin-3-yn-lH- indole-2-carboxamide
Figure imgf000069_0001
1H NMR 3.06 (dd, IH), 3.14 (t, IH), 3.72 (s, 3H), 4.73 (m, IH), 4.78 (m, IH), 4.83 (s,lH), 5 4.87 (m, IH), 7.21 (m, 2H), 7.46 (d, IH), 7.74 (s, IH), 8.77 (d, IH), 10.21 (s, IH), 11.84 (s, IH); MS m/z 370, 372.
Method 1
Methyl 2- [3-amino-2-oxo-3 ,4-dihvdroquinolin- 1 (2H)-yl] acetate
Figure imgf000069_0002
Sodium hydride (60% in oil, 2.52 g, 63.0 mmol) was added to 3-amino-3,4- dihydroquinolin-2(lH)-one hydrochloride (J. Med. Chem. 28, 1985, 1511-16; 5.0 g, 25.2 mmol), in anhydrous DMF (100 mL) at 0 °C over a period of 5 min keeping the internal temperature at <10 °C. The reaction was stirred for a further 30 min before addition of methyl 5 bromoacetate (2.85 mL, 30.2 mmol), then stirred for a further 60 min. The reaction was quenched by addition of IM aqueous ΗC1 (5 mL) and the volatiles were removed by evaporation. The residue was dissolved in DCM (250 mL) and washed with sat. aqueous NaΗCO3 (100 mL) and the organic layer was dried (MgSO4), filtered and evaporated to yield the title compound (5.89 g, 100%) as yellow paste which was used in the next reaction 0 without further purification.
1H NMR 2.21 (br. s, 2H), 2.78 (d, IH), 2.97 (dd, IH), 3.47 (dd, IH), 3.67 (s, 3H), 4.55 (d, IH), 4.78 (d, IH), 6.96 (m, 2H), 7.23 (m, 2H); MS m/z MET1- 235.
Method 2 5 N-(l-{2-r(2,5-Dioxopyrrolidin-l-yl)oxyl-2-oxoethyl|-2-oxo-l,2,3,4-tetrahvαjOquinolin-3-yl)- 5-methyl- lH-indole-2-carboxamide
Figure imgf000070_0001
N-Hydroxysuccinimide (496 mg, 4.31 mmol) and EDCI (1.04g, 5.38 mmol) were added to a suspension of N-[l-(carboxymethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5- chloroindole-2-carboxamide (Example 2, 1.71 g, 4.31 mmol)) in DCM (50 mL) and stirred for 18 hours. The suspension was evaporated and the residue partitioned between EtOAc:THF (4:1)(200 mL) and H2O. The organic was dried (Νa2SO4), filtered and evaporated. The solid was triturated with refluxing Et2O (25 mL), filtered, washed with Et2O (25 mL) then hexane (25 mL) to afford the title compound (2.08g, 98%) as a pale brown powder. 1H NMR 2.83 (s, 4H), 3.12 (dd, IH), 3.27 (app. t, IH), 4.85 (m, IH), 5.15 (d, IH), 5.34 (d, IH), 7.12 (m, 2H), 7.22 (m, 2H), 7.35 (m, 2H), 7.46 (d, IH), 7.75 (d, IH), 8.96 (d, IH), 11.86 (s, IH); MS m/z (M-H)" 493, 495.
Method 3 5-Chloro-N-[l-(2-chloroethyl)-2-oxo-l,2,3,4-tetrahvdroquinolin-3-yl1-lH-indole-2- carboxamide
Figure imgf000070_0002
/?-Toluenesulphonyl chloride (285 mg, 1.49 mmol) was added to a solution of 5- chloro-N-[l-(2-hydroxyethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide (Example 36; 286 mg, 0.75 mmol) in pyridine (2 mL) under an inert atmosphere and stirred at ambient temperature for 18 hours. The mixture was diluted with TΗF (10 mL) and EtOAc (50 mL) and washed with IM ΗC1 aq. (20 mL), water (20 mL), brine (20 mL), dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography
(DCM to DCM:THF (9:1)) to afford the title compound (144 mg, 40%) as a yellow solid.
1H NMR3.11 (dd, IH), 3.24 (app. t, IH), 3.86 (t, 2H), 4.37 (m, 2H), 4.83 (m, IH), 7.14 (t,
IH), 7.33 (m, 5H), 7.51 (d, IH), 7.80 (d, IH), 8.92 (d, IH), 11.90 (br. s, IH); MS m/z 402,
5 404.
Method 4
3 -Amino- 1 - r(2,2-dimethyl- 1 ,3 -dioxan-5-yl)methyl] -3 ,4-dihydroquinolin-2( lHVone
Figure imgf000071_0001
0 Sodium hydride (60% in oil, 1.60 g, 39.80 mmol) was added to 3-amino-3,4- dihydroquinolin-2(lH)-one hydrochloride (3.59 g, 18.09 mmol), in anhydrous DMF (50 mL) at 0 °C over a period of 10 min. The reaction was stirred for a further 30 min before addition of (2,2-dimethyl-l,3-dioxan-5-yl)methyl methanesulfonate [CAS registary number 131372- 64-0] (4.05 g, 18.09 mmol) and the reaction has then heated to 60°C for a period of 16 h. The 5 reaction was then cooled and evaporated before addition of sat. aqueous NaΗCO3 (200 mL) and EtOAc (500 mL). The organic layer was then dried (MgSO4), filtered and evaporated and the residue was purified by column chromatography (MeOH:DCM, 3:37) to afford the title compound (3.00 g, 57%) as a colourless oil. 1HNMR 1.41 (s, 3H), 1.47 (s, 3H), 1.74 (s, 2H), 2.21 (m, IH), 2.82 (d, IH), 3.06 (dd, IH), 0 3.57 (dd, IH), 3.73 (m, 2H), 3.93 (m, 3H), 4.15 (m, IH), 7.02 (t, IH), 7.19 (m, 2H), 7.26 (m, IH); MS m/z 291
Method 5
3-Aιmno-l-[(2,2-dimethyl-l,3-dioxolan-4-yl)methyl1-3,4-dihvdroquinolin-2(lH)-one
Figure imgf000071_0002
Sodium hydride (60% in oil, 191 mg, 4.70 mmol) was added to 3-amino-3,4- dihydroquinolin-2(lH)-one hydrochloride (J. Med. Chem., 28, 1985; 1511-16, 450 mg, 2.27 mmol), in anhydrous DMF (6 mL) at 0 °C over a period of 5 min keeping the internal temperature at <10 °C. The reaction was stirred for a further 30 min before addition of [2,2- dimethyl- l,3-dioxolan-4-yl]methyl methanesulfonate (J. Med. Chem. 35, 1992, 1650-62; 528 mg, 2.50 mmol) and the reaction has then heated to 80°C for a period of 5 hours The reaction was then cooled and evaporated before addition of sat. aqueous NaΗCO3 (20 mL) and EtOAc
(50 mL). The organic layer was then dried (MgSO4), filtered and evaporated and the residue was purified by column chromatography (MeOH:DCM 1:19) to afford the title compound (330 mg, 53%) as colourless oil.
1H NMR 1.33 (s, 3H), 1.40 (s, 1.5H), 1.45 (s, 1.5H), 1.96 (br. s, 2H), 2.89 (m, IH), 3.07 (m,
IH), 3.60 (m, IH), 3.82 (m 1.5H), 4.08 (m, 1.5H), 4.33 (m, 2H), 7.04 (m, IH), 7.23 (m, 3H);
MS m/z 277.
Method 6
N- [ 1 -(3- { [tert-Butyl(dimethyl)silvHoxy } -2-hydroxypropyl)-2-oxo- 1 ,2,3 ,4-tetrahvdroquinolin- 3-vH-5-chloro-lH-indole-2-carboxamide
Figure imgf000072_0001
tert-Butylsilyldimethylsilyl trifluoromethane sulfonate (0.12 mL, 0.53 mmol), was added to a stirring suspention of 5-chloro-Ν-[l-(2,3-dihydroxypropyl)-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl]-lΗ-indole-2-carboxamide (Example 39, 200 mg, 0.48 mmol) in DCM (5 mL) at 0 °C under argon. The reaction was stirred for 1 hour then quenched by addition of sat. aqueous NaHCO3 (20 mL) and DCM (40 mL). The organic layer was then dried (MgSO ), filtered, evaporated and purified by column chromatography to afford the title compound (84 mg, 33%) as a colourless oil.
1H NMR 0.00 (m, 6H), 0.83 (2x s, 9H), 3.06 (m, 2H), 3.53 (m, 2H), 3.87 (m, 3H), 4.73 (m, 1.5H), 4.94 (d, 0.5H), 7.00 (t, IH), 7.20 (m, 5H), 7.42 (d, IH), 7.70 (s, IH), 8.75 (d, 0.5H), 8.78 (d, 0.5H), 11.80 (s, IH); MS m/z 528. Method 7
5-Chloro-N-(l-{[(4R)-2,2-dimethyl-l,3-dioxolan-4-yllmethyl)-2-oxo-l,2.3.4- tetrahvdroquinolin-3-yl)-lH-indole-2-carboxamide
Figure imgf000073_0001
ΗOBT (209 mg, 1.55 mmol), 5-chloroindole-2-carboxylic acid (303 mg, 1.55 mmol),
DIPEA (0.27 mL, 1.55 mmol) and then EDCI (370 mg, 1.94 mmol) were added to a solution of 3-amino-l-{[(4R)-2,*2-dimethyl-l,3-dioxolan-4-yl]methyl}-3,4-dihydroquinolin-2(lH)-one (Method 8, 428 mg, 1.55 mmol) in DCM (10 mL). The reaction was stirred for 18 h at ambient temperature, diluted with EtOAc (20 mL), washed with 1 Ν ΝaOΗ (15 mL), 0.1 Ν ΗC1 (15 mL), saturated aqueous ΝaΗCO3 solution (15 mL), dried (Na2SO4) and the volatiles removed under reduced pressure to give the title compound (684 mg, 97%) as a pale yellow solid.
1H NMR 1.27 (m, 6H), 3.06 (m, IH), 3.17 (app. t, IH), 3.71 (m, IH), 4.17 (m, 4H), 4.73 (m, IH), 7.38 (m, 8H), 8.80 (d, IH), 11.82 (s, IH); MS m/z 476/478 (M+Na)
Method 8
3-amino- 1 - { [(4R)-2,2-dimethyl- 1 ,3-dioxolan-4-yl]methyl } -3 ,4-dihydroquinolin-2( lHVone
Figure imgf000073_0002
Prepared according to Method 5 using [(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]methyl methanesulfonate (J. Org. Chem, 64, 1999 6782-6790) to give the title compound as a pale yellow oil.
1H NMR (CDC13) 1.42 (m, 6Η), 2.99 (m, 2H), 3.60 (m, IH), 3.83 (m, 1.5H), 4.11 (m, 1.5H), 4.38 (m, 2H), 7.03 (m, IH), 7.26 (d, 3H). Method 9
N-ri-(2-Aminoethyl)-2-oxo-1.2,3,4-tetrahydroquinolin-3-yl]-5-chloro-lH-indole-2- carboxamide trifluoroacetate
Figure imgf000074_0001
A solution of TFA:water (9:1, 4 mL) was added to tert-butyl {2-[3-{ [(5 -chloro- 1H- indol-2-yl)carbonyl] amino } -2-oxo-3 ,4-dihydroquinolin- 1 (2H)-yl]ethyl } carbamate (Method 10, 1 g, 2.1 mmol) and the solution stirred at ambient temperature for 1 hours The reaction mixture was then azeotroped with toluene (3 x 10 mL) to give the title compound (0.957 g, 93%) as a tan solid. 1H NMR 3.05 (m, 4Η), 3.91 (m, IH), 4.23 (m, IH), 4.78 (m, IH), 7.30 (m, 8H), 7.83 (br. s, 3H), 8.78 (d, IH), 11.80 (s, IH); MS m/z (M+Na) 405, 407.
Method 10 tert-butyl {2-[3-{ r(5-chloro- lH-indol-2-yl)carbonyl] amino 1-2-0X0-3 ,4-dihydroquinolin- 1 (2H)-yl1ethyl } carbamate
Figure imgf000074_0002
Prepared using an identical procedure as for Example 44 with sodium borohydride (1298 mg, 34.3 mmol), cobalt chloride hexahydrate (1632 mg, 6.86 mmol), tert- butyldicarbonate (1497 mg, 6.86 mmol) and 5-chloro-N-[l-(cyanomethyl)-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl]-lH-indole-2-carboxamide (Method 11, 1299 mg, 3.43 mmol) in MeOΗ (15 mL) and TΗF (10 mL). The reaction was stirred at ambient temperature for 1.5 h to give the title compound (1560 mg, 94%) as a pale tan solid. 1H NMR 1.47 (s, 6H), 3.13 (m, 4H), 3.93 (m, 2H), 4.78 (m, IH), 7.25 (m, 7H), 7.75 (s, IH),
8.85 (d, IH), 11.87 (s, IH); MS m/z (M+Na) 505, 507.
Method 11 5-Chloro-N- [ 1 -(cyanomethyl)-2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl]- lH-indole-2- carboxamide
Figure imgf000075_0001
ΗOBT (168 mg, 1.24 mmol), 5-chloroindole-2-carboxylic acid (243 mg, 1.24 mmol), DIPEA (0.22 mL, 1.24 mmol) and then EDCI (296 mg, 1.55 mmol) were added to a solution of (3-amino-2-oxo-3,4-dihydroquinolin-l(2H)-yl)acetonitrile (Method 12, 250 mg, 1.24 mmol) in DCM (10 mL). The reaction was stirred for 18 h at ambient temperature, diluted with EtOAc (15 mL), washed with 1 Ν ΝaOΗ (15 mL), 1 Ν ΗC1 (15 mL), saturated aqueous ΝaΗCO3 solution (15 mL), dried (MgSO4) and the volatiles removed under reduced pressure to give the title compound (366 mg, 78%) as a tan solid. 1H NMR 3.20 (m, 2H), 4.85 (m, IH), 5.11 (s, 2H), 7.30 (m, 7H), 7.74 (s, IH), 8.91 (d, IH), 11.84 (s, IH); MS m/z 377/379 (M-H)
Method 12
3-Amino-l-(2-cvanomethyl)-3,4-dihydroquinolin-2(lH)-one
Figure imgf000075_0002
Sodium hydride (60% in oil, 2.74g, 68.5 mmol) was added to 3-amino-3,4- dihydroquinolin-2(lH)-one hydrochloride (J. Med. Chem., 28, 1985; 1511-16, 6.47g, 32.6 mmol) in anhydrous DMF (70 mL) at 0 °C over a period of 5 min. After 1 hour the mixture was warmed to ambient temperature, stirred for 2 hours then cooled in an ice bath before bromoacetonitrile (2.28 mL, 32.68 mmol) was added. The mixture was again warmed to ambient temperature and stirred for 18 hours. The reaction was diluted with EtOAc (100 mL) and washed with sat. aqueous K2CO3 (20 mL). The aqueous was extracted with DCM:MeOΗ (19:1) (3 x 50 mL) and the combined organics dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:MeOH (9:1)) to afford the title compound (5.28g, 81%) as a brown oil.
1H NMR (CDCI3) 1.79 (br. s, 2H), 2.90 (app. t, IH), 3.11 (dd, IH), 3.65 (dd, IH), 4.68 (d,
5 IH), 5.03 (d, IH), 7.05 (d, IH), 7.13 (t, IH), 7.25 (d, IH), 7.35 (t, IH); MS m/z 202.
Method 13
N-ri-(3-{[tert-Butyl(dimethyl)silyl1oxy}propyl)-2-oxo-l,2,3,4-tetrahvdroquinolin-3-yl]-5- chloro- lH-indole-2-carboxamide
Figure imgf000076_0001
Prepared exactly as in Method 7 using ΗOBT (174 mg, 1.3 mmol), 5-chloroindole-2- carboxylic acid (252 mg, 1.3 mmol), DIPEA (0.22 mL, 1.3 mmol), EDCI (308 mg, 1.6 mmol) and 3-amino-l-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3,4-dihydroquinolin-2(lH)-one
(Method 14, 432 mg, 1.3 mmol) in DCM (10 mL). This gave the title compound (548 mg,
15 82%) as a pale yellow solid.
1H ΝMR 0.00 (2 x s, 6Η), 0.85 (s, 9H), 1.73 (m, 2H), 3.07 (m, 2H), 3.63 (m, 2H), 3.95 (br. t,
2H), 4.70 (m, IH), 7.12 (m, 6H), 7.40 (d, IH), 7.70 (s, IH), 8.78 (d, IH), 11.80 (s, IH); MS m/z 534/536 (M+Νa)
0 Method 14
3-Amino-l-(3-{rtert-butyl(dimethyl)silyl]oxy}propyl)-3,4-dihydroquinolin-2(lH)-one
Figure imgf000076_0002
The title compound was prepared in an analogous method to Method 1 using (3- bromopropoxy)(tert-butyl)dimethylsilane as elecrophile.
1H NMR 0.00 (s, 6H), 0.88 (s, 9H), 1.75 (s, 2H), 1.83 (m, 2H), 2.74 (d, IH), 3.00 (dd, IH),
3.48 (dd, IH), 3.66 (m, 2H), 3.98 (m, 2H), 6.96 (t, IH), 7.16 (m, 3H); MS m/z 335

Claims

Claims
1. A compound of formula (1):
Figure imgf000078_0001
wherein: is a single or double bond;
A is phenylene or heteroarylene; m is 0, 1 or 2; n is 0, 1 or 2;
R1 is independently selected from halo, nitro, cyano, hydroxy, carboxy, carbamoyl,
N-Cι-4alkylcarbamoyl, N,N-(Cι-4alkyl) carbamoyl, sulphamoyl, N-Cι-4alkylsulphamoyl,
N,N-(C1-4alkyl)2Sulphamoyl, -S(O)bC1- alkyl (wherein b is 0,l,or 2), C1- alkyl, C2-4alkenyl,
C2-4alkynyl, Cι- alkoxy, Cι-4alkanoyl, Cι- alkanoyloxy, hydroxyCι-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl and trifluoromethoxy; or, when n is 2, the two R1 groups, together with the carbon atoms of A to which they are attached, may form a 4 to 7 membered ring, optionally containing 1 or 2 heteroatoms independently selected from O, S and Ν, and optionally being substituted by one or two methyl groups; R4 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, Cι- alkyl, C2-4alkenyl,
C2-4alkynyl, Cι-4alkoxy and Ci- alkanoyl;
R2 is hydrogen, hydroxy or carboxy;
R3 is selected from hydrogen, hydroxy, Cι- alkoxy, Ci-4alkanoyl, carbamoyl, C3- cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), cyano(Ci-4)alkyl, aryl, heterocyclyl,
C^alkyl (optionally substituted by 1 or 2 R8 groups), and groups of the formulae B and B':
Figure imgf000079_0001
(B) (B') wherein y is 0 or 1, t is 0, 1, 2 or 3 and u is 1 or 2; provided that the hydroxy group is not a substituent on the ring carbon adjacent to the ring oxygen; R8 is independently selected from hydroxy, C1.4alkoxyCι-4alkoxy, hydroxyCι-4alkoxy, 5- and
6-membered cyclic acetals and mono- and di-methyl derivatives thereof, aryl, heterocyclyl, C3.
7cycloalkyl, Cι-4alkanoyl, Cι-4alkoxy, Cι-4alkylS(O) - (wherein b is 0, 1 or 2),
C3-6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O)b- (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2), benzylS(O)b- (wherein b is 0, 1 or 2), -N(OH)CHO, -C(=N-OH)NH2, -C(=N-OH)NHC1-4alkyl, -C(=N-OH)N(C1-4alkyl)2,
-C(=N-OH)NHC3-6cycloalkyl, -C(=N-OH)N(C3-6cycloalkyl)2, -COCOOR9, -C(O)N(R9)(R10),
-NHC(O)R9 , -C(O)NHSO2(C1.4alkyl), -NHSO2R9, (R9)(R10)NSO2-, -COCH2ORπ,
(R9)(R10)N- and -COOR9;
R9 and R10 are independently selected from hydrogen, hydroxy, Cι-4alkyl (optionally substituted by 1 or 2 R13 ), C3-7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups ), cyano(Cι.4)alkyl, trihalo(Cι- )alkyl, aryl, heterocyclyl and heterocyclyl(C1-4alkyl); or
R9 and R10 together with the nitrogen to which they are attached form a 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents independently selected from oxo, hydroxy, carboxy, halo, nitro, cyano, carbonyl, C-[-4alkoxy and heterocyclyl; or the ring may be optionally substituted on two adjacent carbons by -O-CH2-O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH2-O- group may be replaced by a methyl;
R is selected from hydroxy, halo, trihalomethyl and C1-4alkoxy;
R11 is independently selected from hydrogen, ^alkyl and hydroxyC1-4alkyl; or a pharmaceutically acceptable salt or pro-drug thereof.
2. A compound of the formula (1) as claimed in claim 1, wherein
R3 is selected from hydrogen, hydroxy, C1.4alkoxy, Ci-4alkanoyl, carbamoyl, C3- cycloalkyl
(optionally substituted with 1 or 2 hydroxy groups, cyano(C1-4)alkyl, phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazohdinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-oxopyrrolidyl, 4- oxothiazolidyl, furyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl, tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl and .
4alkyl (optionally substituted by 1 or 2 R8 groups);
R9 and R10 are independently selected from hydrogen, hydroxy, C^alkyl (optionally substituted by 1 or 2 R13 groups), C3- cycloalkyl (optionally substituted by 1 or 2 hydroxy groups), cyano(C!-4)alkyl, trihalo Ci-4alkyl, aryl, heterocyclyl and heterocyclyl(Cι.4alkyl); or
R9 and R10 together with the nitrogen to which they are attached form a 4- to 6-membered ring where the ring is optionally substituted on carbon by 1 or 2 substituents selected from oxo, hydroxy, carboxy, halo, nitro, cyano, carbonyl and Cι-4alkoxy, or the ring may be optionally substituted on two adjacent carbons by -O-CH2-O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH2-O- group may be replaced by a methyl;
R8 is independently selected from hydroxy, C^alkoxy ^alkoxy, hydroxyCι-4alkoxy, 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, aryl, heterocyclyl, C3.7cycloalkyl, C-ι- alkanoyl, Ci-4alkoxy, C1-4alkylS(O)b- (wherein b is 0, 1 or 2), C3-6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O)b- (wherein b is 0, 1 or 2), heterocyclylS(O) - (wherein b is 0, 1 or 2), benzylS(O)b- (wherein b is 0, 1 or 2), -N(OH)CHO, -C(=N-OH)NH2, -C(=N-OH)NHd-4alkyl, -C(=N-OH)N(C1-4alkyl)2, -C(=N- OH)NHC3.6cycloalkyl, -C(=N-OH)N(C3-6cycloalkyl)2, -COCOOR9, -C(O)N(R9)(R10), -NHC(O)R9 , -C(O)NHSO2(Cι-4alkyl), -NHSO2R9, (R9)(R10)NSO2-, -COCH2ORπ, (R9)(R10)N- and -COOR9 ;
R is selected from hydroxy, halo, trifluoromethyl and Cι- alkoxy; R11 is selected from hydrogen, Cι. alkyl and hydroxyC1-4alkyl; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
3. A compound of the formula (1) as claimed in claim 1 or claim 2 wherein: R3 is selected from cyanoCχ- alkyl and Cι- alkyl (optionally substituted by 1 or 2 of R8 groups); R8 is independently selected from hydroxy, phenyl, 2,2-dimethyl-l,3-dioxolan-4-yl;
2,2-dimethyl-l,3-dioxan-4-yl; 2,2-dimethyl-l,3-dioxan-5-yl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrothienyl, Cι-4alkoxy, Cι-4alkanoyl,
Figure imgf000081_0001
4alkylS(O)b- (wherein b is 0, 1 or 2), -C(O)N(R9)(R10), -COOR9 , -C(O)NHSO2Me, -C(=N- OH)NH2 , -C(=N-OH)NHCι-4alkyl, -C(=N-OH)N(Cι-4alkyl)2 and -NHSO2R9;
R9 and R10 are independently selected from hydrogen, hydroxy, Cι- alkyl optionally substituted with R13 (wherein R13 is Cι-4alkoxy or hydroxy); or
R9 and R10 together with the nitrogen to which they are attached form a 4- to 6-membered ring where the ring may be optionally substituted on carbon by 1 or 2 hydroxy groups or carboxy groups), or the ring may be optionally substituted on two adjacent carbons by -O-CH2-O- to form a cyclic acetal wherein one or both of the hydrogens of the -O-CH2- O- group may be replaced by a methyl; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
4. A compound of the formula (1) as claimed in any preceding claim, wherein:
R3 is selected from cyanoCι- alkyl and ^alkyl (optionally substituted by 1 or 2 R8 groups);
R8 is independently selected from hydroxy, 2,2-dimethyl-l,3-dioxolan-4-yl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, C^aU- oxy, Cι-4alkanoyl, Cι-4alkylS(O)b- (wherein b is 0, 1 or 2), -C(O)N(R9)(R10), -COOR9 , -C(O)NHSO2Me, -C(=N-OH)NH2;
R9 and R10 are independently selected from hydrogen, hydroxy, Cι.4alkyl optionally substituted with R13 (wherein R13 is Ci-4alkoxy or hydroxy); or
R9 and R10 together with the nitrogen to which they are attached form a 4- to 6-membered ring selected from piperidine, 4-hydroxy piperidine, pyrrolidine, 3,4-dihydroxypyrrolidine and the dimethylacetal of 3,4-dihydroxypyrrolidine; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
5. A compound of the formula (1) as claimed in any preceding claim, wherein: m is 1 and R4 is chlorine; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
6. A compound of the formula (1) as claimed in any preceding claim, wherein: A is phenylene; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
7. A compound of the formula (1) as claimed in any one of claims 1 to 5, wherein: A is heteroarylene; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
8. A compound of the formula (1) as claimed in any preceding claim, wherein: is a single bond; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
9. A compound of the formula (1) as claimed in claim 1, which is any one of: 5-chloro-N-[l-(methoxycarbonylmethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide; N-[l-(carboxymethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-5-chloroindole-2-carboxamide; 5-chloro-N-(2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-[ { 2-oxo- 1 - [2-oxo-2-(pyridin-2-ylamino)ethyl] - 1 ,2,3 ,4-tetrahydroquinolin-3 -yl } - lH-indole-2-carboxamide;
5-chloro-N- { 1- [2-(methylthio)ethyl]-2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole-2- carboxamide;
5-chloro-N-{l-[2-(methylsulphinyl)ethyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}-lH-indole- 2-carboxamide;
5-chloro-N- { 1 -[2-(methylsulphonyl)ethyl]-2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole- 2-carboxamide; 5-chloro-N- { 2-oxo- 1 - [2-oxo-2-( 1 ,3 ,4-thiadiazol-2-ylamino)ethyl] -1,2,3 ,4-tetrahydroquinolin-
3-yl } - lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(6-methylpyridin-2-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-{2-oxo-l-[2-oxo-2-(pyridin-3-ylamino)ethyl]-l,2,3,4-tetrahydroquinolin-3-yl}- lH-indole-2-carboxamide; 5 -chloro-N-( 1 - { 2-[(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)amino] -2-oxoethyl } -2-oxo- 1,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(5-ethyl-l,3,4-thiadiazol-2-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; 5-chloro-N-(l-{2-[(4-cyano-lH-ρyrazol-3-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinohn-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(4-methyl-l,3-thiazol-2-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l -{ 2- [(6-chloropyridin-3-yl)amino] -2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(3-hydroxypyridin-2-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(2-oxo- 1 - { 2-oxo-2-[(pyridin-2-ylmethyl)amino]ethyl } - 1 ,2,3 ,4-tetrahydroquinolin-
3-yl)-lH-indole-2-carboxamide; 5-chloro-N- { 2-oxo- 1 - [2-oxo-2-(pyridin-4-ylamino)ethyl] -1,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole-2-carboxamide;
5-chloro-N-(l - { 2-[(l -methyl- lH-pyrazol-5-yl)amino]-2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(l,3-dimethyl-lH-pyrazol-5-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)- lH-indole-2-carboxamide;
5-chloro-N-(2-oxo- 1 - { 2-oxo-2- [(pyrazin-2-ylmethyl)amino] ethyl } - 1 ,2,3 ,4-tetrahydroquinolin-
3-yl)- lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(6-fluoropyridin-3-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; 5-chloro-N-(l-{2-[(2-hyc oxypyrimidin-4-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-{2-oxo-l-[2-oxo-2-(pyriιmdin-4-ylamino)ethyl]-l,2,3,4-tetrahydroquinolin-3-yl}- lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(l-ethyl-lH-pyrazol-5-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)- lH-indole-2-carboxamide;
5-chloro-N-(2-oxo- 1 -{ 2-oxo-2-[(5-oxo-4,5-dihydro- lH-pyrazol-3-yl)amino]ethyl } - 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; 5-chloro-N-(l - { 2-[(4-hydroxypyrimidin-2-yl)amino]-2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-( 1 - { 2-[(3-methylpyridin-2-yl)amino] -2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; 5-chloro-N-(l-{2-[(6-chloropyridazin-3-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(lH-imidazol-2-ylmethyl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-( 1 - { 2- [( 1 -methyl- lH-pyrazol-3 -yl)amino] -2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
5-chloro-N-{2-oxo-l-[2-oxo-2-(2H-tetrazol-5-ylamino)ethyl]-l,2,3,4-tetrahydroquinolin-3- yl } - lH-indole-2-carboxamide;
5-chloro-N-(l-{2-[(3-ethyl-lH-pyrazol-5-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; 5-chloro-N-(l - { 2-[(5-fluoropyridin-2-yl)amino]-2-oxoethyl } -2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide;
N-(l-{2-[(6-bromopyridin-3-yl)amino]-2-oxoethyl}-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)-5- chloro- lH-indole-2-carboxamide ;
5-chloro-N-[l-(2-hydroxyethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide;
5-chloro-N-{ l-[(2,2-dimethyl-l,3-dioxan-5-yl)methyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl } - lH-indole-2-carboxamide ;
5-chloro-N- { 1 - [3 -hydroxy-2-(hydroxymethyl)propyl] -2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole-2-carboxamide; 5-chloro-N-[l-(2,3-dihydroxypropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide;
5-chloro-N-[ 1 -(3-hydroxy-2-oxopropyl)-2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-3-yl]- lH-indole-2- carboxamide;
5-chloro-N- { 1 -[(2R)-2,3-dihydroxyρropyl] -2-oxo-l ,2,3 ,4-tetrahydroquinolin-3-yl } - lH-indole- 2-carboxamide;
5-chloro-N-(l-{2-[(methylsulfonyl)amino]ethyl}-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)-lH- indole-2-carboxamide; N-{l-[2-(acetylamino)ethyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}-5-chloro-lH-indole-2- carboxamide;
5 -chloro-N-(2-oxo- 1 - { 2- [(trifluoroacetyl)amino] ethyl } - 1 ,2,3 ,4-tetrahydroquinolin-3-yl)- 1H- indole-2-carboxamide; 5-chloro-N-[l-(3-hydroxypropyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2- carboxamide;
N-{l-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl}-5-chloro- lH-indole-2-carboxamide;
5-chloro-N-(6-fluoro-2-oxo-l ,2,3,4-tetrahydroquinolin-3-yl)-lH- indole-2-carboxamide; and 5-chloro-N-[6-(methyloxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl]-lH-indole-2-carboxamide; or a pharmaceutically acceptable salt or an in-vivo hydrolysable ester thereof.
10. A pharmaceutical composition which comprises a compound of the formula (1), or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof, as claimed in any one of claims 1 to 9 in association with a pharmaceutically-acceptable diluent or carrier.
11. A compound of the formula (1), or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof, as claimed in any one of claims 1 to 9, for use in a method of treatment of a warm-blooded animal such as man by therapy.
12. A compound of the formula (1), or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof, as claimed in any one of claims 1 to 9, for use as a medicament.
13. A compound of the formula (1), or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof, as claimed in any one of claims 1 to 9, for use as a medicament in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity in a warm-blooded animal such as man.
14. The use of a compound of the formula (1), or a pharmaceutically acceptable salt or in- vivo hydrolysable ester thereof, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for use in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity in a warm-blooded animal such as man.
15. The use of a compound of the formula (1), or a pharmaceutically acceptable salt or in- vivo hydrolysable ester thereof, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for use in the treatment of type 2 diabetes in a warm-blooded animal such as man.
16. A process for the preparation of a compound of formula (1) as claimed in claim 1, which process comprises: reacting an acid of the formula (2):
Figure imgf000086_0001
(2) or an activated derivative thereof; with an amine of formula (3):
Figure imgf000086_0002
(3) and thereafter if necessary: i) converting a compound of the formula (1) into another compound of the formula (1); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.
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