WO2003074531A1 - Heterocyclic amide derivatives having glycogen phosphorylase inhibitory activity - Google Patents

Heterocyclic amide derivatives having glycogen phosphorylase inhibitory activity Download PDF

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Publication number
WO2003074531A1
WO2003074531A1 PCT/GB2003/000875 GB0300875W WO03074531A1 WO 2003074531 A1 WO2003074531 A1 WO 2003074531A1 GB 0300875 W GB0300875 W GB 0300875W WO 03074531 A1 WO03074531 A1 WO 03074531A1
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Prior art keywords
alkyl
thieno
inden
pyrrole
amino
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PCT/GB2003/000875
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French (fr)
Inventor
Paul Robert Owen Whittamore
Stuart Norman Lile Bennett
Iain Simpson
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication date
Priority to BR0308145-1A priority Critical patent/BR0308145A/en
Priority to MXPA04008611A priority patent/MXPA04008611A/en
Priority to EP03743418A priority patent/EP1483271B1/en
Priority to JP2003572999A priority patent/JP2005524669A/en
Priority to KR10-2004-7013865A priority patent/KR20040091101A/en
Priority to US10/506,746 priority patent/US7122567B2/en
Priority to DE60309849T priority patent/DE60309849T2/en
Priority to CA002477125A priority patent/CA2477125A1/en
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to IL16380203A priority patent/IL163802A0/en
Priority to SI200330609T priority patent/SI1483271T1/en
Priority to DK03743418T priority patent/DK1483271T3/en
Priority to AU2003209445A priority patent/AU2003209445A1/en
Priority to NZ534684A priority patent/NZ534684A/en
Publication of WO2003074531A1 publication Critical patent/WO2003074531A1/en
Priority to IS7433A priority patent/IS7433A/en
Priority to NO20044033A priority patent/NO20044033L/en
Priority to HK05103055A priority patent/HK1070365A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • 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

Definitions

  • the present invention relates to heterocyclic amide derivatives, pharmaceutically acceptable salts and in vivo hydrolysable esters thereof. These heterocyclic 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 heterocyclic 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).
  • heterocyclic 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.
  • Z is CH or nitrogen
  • R 6 and R 7 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl,
  • A is phenylene or heteroarylene; n is 0, 1 or 2; R 1 is independently selected from halo, nitro, cyano, hydroxy, carboxy, carbamoyl, N-C ⁇ - alkylcarbamoyl, N,N-(C 1 - alkyl) 2 carbamoyl, sulphamoyl, N-C 1 - 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 is 1 or 2; and when r is 1 the group
  • Y is - ⁇ R 2 R 3 or -OR 3 ;
  • R 2 and R 3 are independently selected from hydrogen, hydroxy, C ⁇ - alkoxy, C 1 - alkanoyl, carbamoyl, C 3 - cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), cyano(C ⁇ . )alkyl, heterocyclyl, aryl, C 1 - 4 alkyl [optionally substituted by 1 or 2 R groups], -COR 8 , -SO b R 8 (wherein b is 0, 1 or 2) and groups of the formulae B and B' :
  • R 8 is independently selected from hydrogen, hydroxy, C 1 . alkyl, C 2 . 4 alkenyl, C ⁇ - alkoxy, cyano(C 1 - 4 )alkyl, amino(C 1 - )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - 4 alkyl, hydroxy, hydroxy(C ⁇ - 4 )alkyl, dihydroxy(C ⁇ - 4 )alkyl, -CO 2 C 1 .
  • R 11 is independently selected from hydrogen, C ⁇ - 4 alkyl, and hydroxyC ⁇ - 4 alkyl; or a pharmaceutically acceptable salt or pro-drug thereof; with the proviso that the compound of formula (1) is not: i) 2,3-dichloro-5-(N- ⁇ l-[N-(l,l-dimethylethoxy)carbonylamino]indan-2- yl ⁇ carbamoyl)-4H-thieno[3,2-b]pyrrole; ii) 5-[N-(l-aminoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iii) 5-[N-(l-acet-unidoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iv) 2,3-dichloro-5- ⁇ N-[l-(methanesul
  • Z is C ⁇ or nitrogen
  • R 6 and R 7 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, ureido, C ⁇ - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C ⁇ .
  • R 1 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, N-Ci- 4 alkylsulphamoyl, N,N-(C ⁇ - 4 alkyl) 2 sulphamoyl, sulfino, sulfo, C ⁇ - alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, C 1 . 4 alkoxy, C ⁇ - 4 alkanoyl, Ci- alkanoyloxy, N-(C ⁇ - 4 alkyl)amino,
  • N,N-(C ⁇ - 4 alkyl) 2 amino, hydroxyC 1 - 4 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, C ⁇ - 4 alkoxy and R 1 is of the formula A' or A" :
  • Y is - ⁇ R 2 R 3 or -OR 3 ;
  • R 2 and R 3 are independently selected from hydrogen, hydroxy, C ⁇ - alkyl (substituted by 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), C5- 7 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 ⁇ - 4 )alkyl, 4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranylgroup, 1 , 1-dioxotetrahydrothiopyranyl, fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, C ⁇ - alkyl [substituted by 1 or 2 R 8 groups
  • R is independently selected from hydrogen, hydroxy, C 1 . alkoxyC 1 - alkoxy, hydroxyC ⁇ - alkoxy, 2,2-dimethyl-l,3 ⁇ dioxolan-4-yl, heterocyclyl (optionally substituted on carbon or nitrogen by 1 or 2 groups selected from hydrogen, nitro, halo, cyano, hydroxy and C ⁇ - 4 alkyl), (heterocyclyl)C ⁇ - 4 alkyl (wherein the heterocyclyl is optionally substituted on carbon or nitrogen by 1 or 2 groups selected from hydrogen, nitro, halo, cyano, hydroxy and C ⁇ - 4 alkyl), aryl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and C ⁇ - alkyl), C ⁇ - 4 alkyl, C 2 - alkenyl, cyclo(C 3 - 8 )alkyl, C ⁇ - 4 alkoxy, cyano(C ⁇ - )alkyl,
  • 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), Cs- 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), C 2 - 4 alkenyl, cyano(C 1 - 4 )alkyl, 4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranylgroup, 1,1-dioxotetrahydrothiopyranyl, 2,2-dimethyl-l,3-dioxolan-4-yl, aryl (optionally substituted by 1 or 2 substituents selected from hydrogen, nitro, halo, hydroxy and C ⁇ - a-kyl) and C ⁇ - 4 alkyl substituted
  • R 13 is selected from hydroxy, C ⁇ - 4 alkoxy, heterocyclyl, C ⁇ - 4 alkanoyl, C 1 - 4 alkylS(O) d (wherein d is 0, 1 or 2)1, -N(OH)CHO, (R ⁇ )(R 12 )NCO-, (R ⁇ )(R 12 )NSO 2 -, - COCH 2 OR ⁇ and (R ⁇ )(R 12 )N-; ⁇ wherein R 11 and R 12 are independently selected from hydrogen, C 1 - alkyl, C ⁇ - 4 alkoxy, hydroxyC ⁇ - 4 alkyl, C 1 - 4 alkylS(O) e (wherein e 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, N-Ci-
  • a to the piperidinone ring may be heteroatoms. Therefore, for example, the definition of
  • 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.
  • 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, dimethylamme, 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, dimethylamme, 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. 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 al, 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.
  • esters for carboxy include C ⁇ _ 6 alkoxymethyl esters for example methoxymethyl, Ci-galkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 - 8 cycloalkoxycarbonyloxyC ⁇ - 6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-ealkoxycarbonyloxyethyl 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 acetoxyrnethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in-vivo hydrolysable ester forming groups for hydroxy include Ci-ioalkanoyl, for example acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, Ci-ioalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-(C ⁇ - 4 )alkylcarbamoyl and N-(di-(C 1 - 4 )alkylaminoethyl)-N- (C ⁇ -- t )alkylcarbamoyl (to give carbamates); di-(C 1 - 4 )alkylaminoacetyl and carboxyacetyl.
  • Ci-ioalkanoyl for example acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl
  • Ci-ioalkoxycarbonyl to
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, (Ci.
  • esters include, for example, R A C(O)O(C ⁇ - 6 )alkyl- CO-, wherein R A is for example, benzyloxy-(C ⁇ - 4 )alkyl, or phenyl).
  • Suitable substituents on a phenyl group in such esters include, for example, 4-(C 1 - 4 )piperazino-(C ⁇ - 4 )alkyl, piperazino-
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • 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
  • examples of “C ⁇ - 6 alkyl” include the examples of "C ⁇ - 4 alkyl”and additionally pentyl, 2,3-dimethylpro ⁇ yl, 3-methylbutyl and hexyl.
  • An analogous convention applies to other generic terms, for example "C 2 .
  • alkenyl includes vinyl, allyl and 1-propenyl and examples of "C 2 . 6 alkenyl” include the examples of "C . 4 alkenyl” and additionally 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3- methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • C - 4 alkynyl includes ethynyl, 1-propynyl and 2-propynyl and examples of “C - 6 alkynyl”include the examples of “C 2 - 4 alkynyl” and additionally 3-butynyl, 2-pentynyl and l-methylpent-2-ynyl.
  • hydroxyC 1 - 4 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 1 - 4 alkyl includes dihydroxyethyl, dihydroxypropyl, dihydroxyisopropyl and dihydroxybutyl.
  • dihydroxypropyl includes 1,2-dihydroxypropyl and 1,3- dihydroxypropyl.
  • halo refers to fluoro, chloro, bromo and iodo.
  • dihaloC ⁇ - 4 alkyl includes difluoromethyl and dichloromethyl.
  • trihaloC 1 - 4 alkyl 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-1 ,3-dioxan-4-yl; 2,2-dimethyl- 1 ,3-dioxan-5-yl; 1 ,3-dioxan-2-yl.
  • C ⁇ - 4 alkoxy examples include methoxy, ethoxy, propoxy and isopropoxy.
  • Examples of “C ⁇ - 6 alkoxy” include the examples of “C 1 - 4 alkoxy” and additionally butyloxy, t- butyloxy, pentoxy and l,2-(methyl) 2 propoxy.
  • Examples of “C ⁇ - 4 alkanoyl” include formyl, acetyl and propionyl.
  • Examples of “Ci- ⁇ alkanoyl” include the example of “C ⁇ - alkanoyl” and additionally butanoyl, pentanoyl, hexanoyl and l,2-(methyl) 2 propionyl.
  • Examples of “Ci- alkanoyloxy” are formyloxy, acetoxy and propionoxy.
  • C ⁇ - 6 alkanoyloxy examples include the examples of “C ⁇ - 4 alkanoyloxy” and additionally butanoyloxy, pentanoyloxy, hexanoyloxy and l,2-(methyl) 2 propionyloxy.
  • Examples of "N-(C ⁇ - 4 alkyl)amino” include methylamino and ethylamino.
  • Examples of "N-(C ⁇ - 6 alkyl)amino” include the examples of "N-(C ⁇ - 4 alkyl)amino” and additionally pentylamino, hexylamino and 3-methylbutylamino.
  • N,N-(C ⁇ - 4 alkyl) 2 amino examples include N-N-(methyl) 2 amino, N-N-(ethyl) 2 amino and N-ethyl-N-methylamino.
  • Examples of "N,N-(C 1 - 6 alkyl) 2 amino” include the example of “N,N-(C ⁇ - 4 -dkyl) 2 amino” and additionally N-methyl-N-pentylamino and N,N-(pentyl) 2 amino.
  • N-(C ⁇ - 4 alkyl)carbamoyl are methylcarbamoyl and ethylcarbamoyl.
  • Examples of are the examples of additionally pentylcarbamoyl, hexylcarbamoyl and l,2-(methyl) 2 propylcarbamoyl.
  • Examples of "N,N-(C 1 - 4 alkyl) 2 carbamoyl” are N,N-(methyl) 2 carbamoyl, N,N-(ethyl) 2 carbamoyl and N- methyl-N-ethylcarbamoyl.
  • N,N-(C 1 - 6 alkyl) 2 carbamoyl are the examples of “N,N-(C 1 - alkyl) 2 carbamoyl” and additionally N,N-(pentyl) 2 carbamoyl, N-methyl-N- pentylcarbamoyl and N-ethyl-N-hexylcarbamoyl.
  • N-(C ⁇ - 4 alkyl)sulphamoyr are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl.
  • N-(C ⁇ - 6 alkyl)sulphamoyl are the examples of “N-(C ⁇ -4alkyl)sulphamoy and additionally N-pentylsulphamoyl, N- hexylsulphamoyl and l,2-(methyl) 2 propylsulphamoyl.
  • N,N-(C 1 - 4 alkyl) 2 sulphamoyl are N,N-(methyl) 2 sulphamoyl, N,N-(ethyl) sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl.
  • Examples of "N,N-(C 1 - 6 alkyl) 2 sulphamoyl” are the examples of "N,N-(C 1 .
  • Examples of "cyano(C ⁇ - 4 )alkyl” are cyanomethyl, cyanoethyl and cyanopropyl.
  • Examples of “C 5 - 7 cycloalkyl” are cyclopentyl, cyclohexyl and cycloheptyl.
  • Examples of “C 3 - scycloalkyl” and “C 3 - 7 cycloalkyl” include “C 5 - 7 cycloalkyl", cyclopropyl, cyclobutyl and cyclooctyl.
  • Examples of "C 3 - 6 cycloalkyl” includelde cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aminoC ⁇ - 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.
  • C ⁇ - 4 alkoxyC ⁇ - alkoxy are methoxymethoxy, ethoxymethoxy, ethoxyethoxy and methoxyethoxy.
  • hydroxyC ⁇ - 4 alkoxy are hydroxyethoxy and hydroxypropoxy.
  • hydroxypropoxy are 1-hydroxypropoxy, 2-hydroxypropoxy and 3 -hydroxypropoxy.
  • C 3 . 6 cycloalkylS(O)b examples include cyclopropylthio, cyclopropylsulphinyl, cyclopropylsulphonyl, cyclobutylthio, cyclobutylsulphinyl, cyclobutylsulphonyl, cyclopentylthio, cyclopentylsulphinyl and cyclopentylsulphonyl.
  • Examples of "arylS(O) b (wherein b is 0,1 or 2)” examples include phenylthio, phenylsulphinyl and phenylsulfonyl.
  • 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.
  • C ⁇ - 6 alkoxycarbonyl examples include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.
  • C ⁇ - 6 alkoxycarbonylamino examples include methoxycarbonylamino, ethoxycarbonylamino, n- and t-butoxycarbonylamino.
  • Examples of "C ⁇ - 6 alkylsulphonyl-N-(C ⁇ - 6 alkyl)amino” include methylsulphonyl-N-methylamino, ethylsulphonyl-N-methylamino and propylsulphonyl-N-ethylamino. Examples of
  • C ⁇ - 6 alkylsulphonylamino include methylsulphonylamino, ethylsulphonylamino and propylsulphonylamino.
  • Examples of “C ⁇ - 6 alkanoylamino” include formamido, acetamido and propionylamino.
  • 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).
  • heterocyclyl examples and suitable values of the term "heterocyclyl” are morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, dioxolanyl, thiadiazolyl, piperazinyl, isothiazolidinyl, triazolyl, tetrazolyl, pyrrolidinyl, 2-oxazolidinonyl, 5-isoxazolonyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, 3-oxopyrazolin-5-yl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, pyrimid
  • a “heterocyclyl” is morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl,
  • 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 ⁇ . 4 alkyl, Ci- 4 alkoxy and C 1 - 4 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, methylsulfinyl 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 ⁇ - 4 alkyl, Ci- 4 alkoxy, C 1 - 4 alkylS(O) b (wherein b is 0, 1 or 2), N-(C 1 - 4 alkyl)amino and N,N-(C ⁇ -4alkyl) 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)Ci- 4 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 ⁇ - )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 ⁇ - 4 alkoxy, C 1 - 4 alkylS(O) b (wherein b is 0, 1 or 2), N-(C 1 - 4 alkyl)amino and N,N-(C 1 - alkyl) 2 amino.
  • 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 ⁇ - 4 alkyl, C ⁇ - 4 alkoxy, C 1 - alkylS(O) b (wherein b is 0, 1 or 2), N-(C 1 - 4 alkyl)amino and
  • 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, Y, R 1 , R 4 , R 5 , r 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.
  • 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).
  • Particular examples of in-vivo hydrolysable esters of compounds of the formula (1) are such esters of compounds of the formula (1) wherein Y comprises a group containing a carboxy group. Suitable esters are those hereinbefore described for carboxy groups.
  • R and R are independently selected from hydrogen, halo or C ⁇ . 6 alkyl.
  • R 6 and R 7 are independently selected from hydrogen, chloro, bromo or methyl.
  • R 6 and R 7 are independently selected from hydrogen or chloro.
  • R 6 and R 7 is chloro. h one embodiment, one of R 6 and R 7 is chloro and the other is hydrogen.
  • both R 6 and R 7 are chloro.
  • A is phenylene
  • A is heteroarylene.
  • A is selected from phenylene, pyridylene, pyrimidinylene, pyrrolylene, imidazolylene, triazolylene, tetrazolylene, oxazolylene, oxadiazolylene, thienylene and furylene.
  • A when A is heteroarylene, there is a nitrogen in a bridgehead position. In another embodiment, when A is heteroarylene, the heteroatoms are not in bridgehead positions. It will be appreciated that the preferred (more stable) bridgehead position is as shown below:
  • 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 ⁇ - 4 alkoxy.
  • R 1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -S(O) b C 1 - 4 alkyl (wherein b is 0, 1 or 2), C ⁇ - 4 alkyl and Ci- 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 C ⁇ - alkyl.
  • R 1 is selected from halo and C ⁇ - 4 alkoxy.
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH 2 -O-.
  • I-n one aspect of the invention r is 1 and when r is 1 the group
  • r is 2 and when r is 2 the group
  • r is 2 and when r is 2 the group
  • Y is -NR 2 R 3 .
  • Y is -OR 3 .
  • Suitable values for R 2 and R 3 as heterocyclyl are morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 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
  • R 2 and R 3 are tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl, 1 , 1 -dioxotetrahydrothiopyranyl.
  • R 2 and R 3 are independently selected from groups of the formulae B and B' as hereinbefore described.
  • R 2 and R 3 are independently selected from hydrogen, hydroxy, C 1 - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], C 3 - 7 cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), cyano(C ⁇ - 4 )alkyl, phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolin
  • R 8 is independently selected from hydrogen, hydroxy, C 1 _ 4 alkoxy, C ⁇ - 4 alkoxyC ⁇ - alkyl, - 4 alkoxyC ⁇ - 4 alkoxy, hydroxyC ⁇ - 4 alkoxy, C ⁇ - 4 alkyl, amino(C ⁇ - 4 )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - 4 alkyl, hydroxy(C ⁇ - 4 )alkyl, dihydroxy(C 1 - 4 )alkyl, -CO 2 C ⁇ - alkyl, aryl and aryl(C ⁇ - 4 )alkyl], C 2 - 4 alkenyl, C 3 - 7 cycloalkyl (optionally substituted by -C(O)OC ⁇ - 4 alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C 1 .
  • R 2 and R 3 are independently selected from hydrogen, C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R groups], C 3 - 7 cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), -COR 8 and -SO b R 8 (wherein b is 0, 1 or 2); R 8 is independently selected from hydrogen, hydroxy, C 1 .
  • R 2 and R 3 are independently selected from hydrogen, C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and -SO b R 8 (wherein b is 0, 1 or
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - alkoxy, C ⁇ - 4 alkoxyC ⁇ - 4 alkyl, - alkyl, amino(C 1 - 4 )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Ci- alkyl, hydroxy(C ⁇ - )alkyl, dihydroxy(C ⁇ - 4 )alkyl, -CO 2 C ⁇ - alkyl, phenyl and aryl(C ⁇ - 4 )alkyl], C 2 - 4 alkenyl, C 3 - 7 cycloalkyl (optionally substituted by -C(O)OC 1 - 4 alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ .
  • R 9 , R 9' , R 10 and R 10' are independently selected from hydrogen, C ⁇ . 4 alkyl (optionally substituted by 1 or 2 hydroxy groups), C 2 . 4 alkenyl, and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano).
  • one of R 9 and R 10 is hydrogen and the other is selected from heterocyclyl and heterocyclyl(C ⁇ - 4 alkyl).
  • R 9 or R 10 as heterocyclyl and heterocyclyl(d-
  • 4 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 piperazinyle
  • R 2 is selected from hydrogen, acetyl and C ⁇ - 4 alkyl.
  • Suitable values for NR 2 R 3 as a 4 to 7 membered ring are morpholino, 2,5- dioxomorpholino, piperidinyl, pyrrolidinyl, pyrazolyl, pyrrolyl, imidazolyl, piperazinyl and thiomorpholinyl.
  • R 3 is selected from hydrogen, 1,3- dihydroxyisopropyl, 1,2-dihydroxypropyl, cyanomethyl, trifluoromethylcarbonyl, carboxyacetyl, carboxymethyl, formyl, acetyl, carbamoylacetyl, carbamoylmethyl, methoxyacetyl, methoxypropanoyl, acetoxyacetyl, methanesulfonyl, chloromethylsulfonyl, trifluoromethylsulfonyl, morpholinomethylcarbonyl, furylcarbonyl, thienylcarbonyl, nitrofurylcarbonyl, N,N-dimethylcarbamoyl, 4-methylpiperazinocarbonyl, N-ethylcarbamoyl, N-allylcarbamoyl, N-dinitrophenylcarbamoyl, pyridinylcarbonyl, te
  • R 3 is selected from trifluoromethylcarbonyl, carboxyacetyl, formyl, acetyl, , methanesulfonyl, morpholinomethylcarbonyl, furylcarbonyl, thienylcarbonyl, nitrofurylcarbonyl, N,N-dimethylcarbamoyl, 4-methylpiperazinocarbonyl, N- ethylcarbamoyl, N-allylcarbamoyl, N-dinitrophenylcarbamoyl, pyridinylcarbonyl, tetrahydrofuran-2-on-5-ylcarbonyl, hydroxyphenylcarbonyl, acryloyl, 2-(tert- butoxycarbonyl)methylcarbonyl, aminoacetyl, 1-amino-l-carboxypropanoyl, chloroacetyl, hydroxyacetyl, carbamoylacetyl,
  • R 7 is halo or hydrogen;
  • 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 1 or 2;
  • Y is -NR 2 R 3 or -OR 3 ;
  • R 2 and R 3 are independently selected from hydrogen, C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], C 3 - cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-ox
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - alkoxy, C 1 - 4 alkoxyC 1 - 4 alkyl, C ⁇ - 4 alkoxyCi- 4 alkoxy, hydroxyC ⁇ - 4 alkoxy, C ⁇ - 4 alkyl, amino(C ⁇ - )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - alkyl, hydroxy(C ⁇ - )alkyl, dihydroxy(C 1 - 4 )alkyl, -CO 2 C ⁇ .
  • R 9 , R 9' , R 10 and R 10' are independently selected from hydrogen, C ⁇ . alkyl (optionally substituted by 1 or 2 R 13 ), C 3 - 7 cycloalkyl (optionally substituted by 1 or 2 hydroxy groups),
  • R 13 is selected from halo, trihalomethyl and C ⁇ - alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2,3-mchloro-5-(N- ⁇ l-[N-(l,l-dimethylethoxy)carbonyl--mino]indan-2- yl ⁇ carbamoyl)-4H-thieno[3,2-b]pyrrole; ii) 5-[N-(l-aminoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iii) 5-[N-(l-acetamidoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3 ,2-b]pyrrole iv) 2,3-dichloro-5- ⁇ N-[l-(methan
  • 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 1 or 2;
  • Y is -NR 2 R 3 or -OR 3 ;
  • R 2 and R 3 are independently selected from hydrogen, C 1 . 4 alkyl [optionally substituted by 1 or 2 R 8 groups], C 3 . cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-o
  • R 8 is independently selected from hydrogen, hydroxy, C 1 - alkoxy, C ⁇ - 4 alkoxyC ⁇ - 4 alkyl, C ⁇ - 4 alkoxyC ⁇ - 4 alkoxy, hydroxyCi- 4 alkoxy, C ⁇ - 4 alkyl, amino(C ⁇ - 4 )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - 4 alkyl, hydroxy(C 1 - 4 )alkyl, dihydroxy(C ⁇ - 4 )alkyl, -CO C ⁇ - 4 alkyl, aryl and aryl(C ⁇ - 4 )alkyl], C 2 - alkenyl, C - 7 cycloalkyl (optionally substituted by -C(O)OC ⁇ - 4 alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ - )alkyl, dihalo(C 1 - )alkyl, trihalo(C 1 -
  • R 9 , R 9' , R 10 and R 10' are independently selected from hydrogen, C 1 . alkyl (optionally substituted by 1 or 2 R 13 ), C 3 . 7 cycloalkyl (optionally substituted by 1 or 2 hydroxy groups),
  • R 13 is selected from halo, trihalomethyl and C 1 - 4 alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2-chloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl-6H-thieno[2,3-b]pyrrole;
  • Another preferred class of compound is of the formula (1) wherein: Z is C ⁇ ;
  • R 7 is hydrogen or chloro;
  • 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 1 or 2; Y is - ⁇ R 2 R 3 ;
  • R 2 and R 3 are independently selected from hydrogen, C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and -SO b R 8 (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, C 1 - alkoxy, C ⁇ - alkoxyC ⁇ - alkyl, C ⁇ - 4 alkoxyC ⁇ - 4 alkoxy, hydroxyC ⁇ - 4 alkoxy, C ⁇ . 4 alkyl, amino(C ⁇ - 4 )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - alkyl, hydroxy(C 1 - 4 )alkyl, dihydroxy(C 1 - )alkyl, -CO 2 C ⁇ - 4 alkyl, aryl and aryl(C ⁇ - 4 )alkyl], C 2 - 4 alkenyl, C 3 - 7 cycloalkyl (optionally substituted by
  • -C(O)OC ⁇ - 4 alkyl 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ - 4 )alkyl, dihalo(C ⁇ - 4 )alkyl, trihalo(C ⁇ - 4 )alkyl, hydroxy(C ⁇ . 4 )alkyl,
  • R 13 is selected from halo, trihalomethyl and C ⁇ - 4 alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2,3-dichloro-5-(N- ⁇ l-[N-(l,l-dimethylethoxy)carbonylamino]indan-2- yl ⁇ carbamoyl)-4H-thieno[3,2-b]pyrrole; ii) 5-[N-(l-aminoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iii) 5-[N-(l-acetamidoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iv) 2,3-dichloro-5- ⁇ N-[l-(methanesulphon
  • R 6 is hydrogen or halo;
  • R is hydrogen or halo
  • 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 1 or 2;
  • Y is -OR 3 ;
  • R 3 is selected from hydrogen, Ci- 4 alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and -SO R 8 (wherein b is 0, 1 or 2); wherein R 8 is independently selected from hydrogen, hydroxy, C ⁇ - alkoxy, C ⁇ - 4 alkoxyC ⁇ - 4 alkyl, C 1 - alkoxyC ⁇ - 4 alkoxy, hydroxyC 1 - alkoxy, C 1 - 4 alkyl, amino(C ⁇ - )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - alkyl, hydroxy(C ⁇ - 4 )alkyl, dihydroxy(C ⁇ - 4 )alkyl, -CO 2 C 1 - 4 alkyl, aryl and aryl(C ⁇ - 4 )alkyl], C 2 - alkenyl, C 3 - 7 cycloalkyl (optionally substituted by -C(O)OC ⁇ - 4 alkyl), 5- and 6-membered cyclic
  • a further preferred class of compound is of the formula (1) wherein; Z is C ⁇ ;
  • R 7 is hydrogen; 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 1 or 2; Y is -NR 2 R 3 ;
  • R 2 and R 3 are independently selected from hydrogen, C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and -SO b R 8 (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - 4 alkoxy, C ⁇ - 4 alkoxyC ⁇ - alkyl, C ⁇ - 4 alkoxyC ⁇ - 4 alkoxy, hydroxyC ⁇ - 4 alkoxy, C ⁇ - 4 alkyl, amino(C ⁇ - )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C 1 - alkyl, hydroxy(C ⁇ - 4 )alkyl, dihydroxy(C ⁇ - 4 )alkyl, -CO 2 C ⁇ - alkyl, aryl and aryl(C ⁇ - 4 )alkyl], C 2 - 4 alkenyl, C 3 - 7 cycloalkyl (optionally substituted by
  • -C(O)OC ⁇ - alkyl 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ - 4 )alkyl, dihalo(C ⁇ - )alkyl, trihalo(C 1 - 4 )alkyl, hydroxy(C ⁇ - 4 )alkyl, dihydroxy(C ⁇ - 4 )alkyl, cyano(C 1 - 4 )alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Ci- 4 )alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(C ⁇ - 4 )alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups),
  • Another preferred class of compound is of the formula (1) wherein: Z is CH;
  • R 6 is hydrogen or halo
  • R 7 is hydrogen or halo
  • 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 1 or 2;
  • Y is -OR 3 ;
  • R is selected from hydrogen, C 1 . 4 alkyl [optionally substituted by 1 or 2 R groups], -COR 8 and -SO b R 8 (wherein b is 0, 1 or 2); R 8 is independently selected from hydrogen, hydroxy, C ⁇ . 4 alkoxy, C ⁇ - 4 a ⁇ koxyC ⁇ - 4 alkyl,
  • R 7 is hydrogen; A is phenylene; n is O r is 1; Y is -NR 2 R 3 ;
  • R 2 is hydrogen or C ⁇ - 4 alkyl
  • R 3 is selected from C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and -SO b R 8 (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, C 1 - 4 alkoxy, C 1 - 4 alkoxyC 1 - 4 alkyl, C 1 - alkyl, amino(C ⁇ - 4 )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - alkyl, hydroxy(C ⁇ - 4 )alkyl, ch ⁇ ydroxy(C ⁇ - )alkyl, -CO 2 C ⁇ - 4 alkyl, phenyl and aryl(C ⁇ - )alkyl], C 2 - 4 alkenyl, C 3 - 7 cycloalkyl (optionally substituted by -C(O)OC 1 - 4 alkyl), 5- and 6- membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ - 4 )alkyl, trihalo(C ⁇ - 4 )alkyl, hydroxy(C 1 - 4 )alkyl, dihydroxy(C 1 - 4
  • a further preferred class of compound is of the formula (1) wherein;
  • R 6 is halo
  • R 7 is hydrogen; A is phenylene; n is O; r is 1;
  • Y is -NR 2 R 3 ;
  • R 2 is hydrogen or C ⁇ - 4 alkyl
  • R 3 is selected from C ⁇ - alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - 4 alkoxy, C 1 - 4 alkoxyC 1 - 4 alkyl, C ⁇ - 4 alkyl, amino(C ⁇ - 4 )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - 4 alkyl, hydroxy(C ⁇ - 4 )alkyl, dihydroxy(C 1 - 4 )alkyl, -CO 2 C ⁇ - alkyl, phenyl and aryl(C ⁇ - 4 )alkyl], C 2 - 4 alkenyl, C 3 - 7 cycloalkyl (optionally substituted by -C(O)OC ⁇ - 4 alkyl), 5- and 6- membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ - 4 )alkyl, trihalo(C ⁇ - )alkyl, hydroxy(C 1 - 4 )alkyl, dihydroxy(Ci- 4 )alkyl,
  • a preferred class of compound is of the formula (1) wherein;
  • R 7 is halo or hydrogen
  • 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; ris 1 or 2;
  • Y is - ⁇ R 2 R 3 or -OR 3 ;
  • R 2 and R 3 are independently selected from hydrogen, C 1 . 4 alkyl [optionally substituted by 1 or 2 R 8 groups], C 3 . 7 cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-
  • R is selected from halo, trihalomethyl and C ⁇ - 4 alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not:
  • Another preferred class of compounds is of formula (1) wherein: Z is nitrogen;
  • 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 1 or 2;
  • Y is -NR 2 R 3 or -OR 3 ;
  • R 2 and R 3 are independently selected from hydrogen, C 1 . 4 alkyl [optionally substituted by 1 or 2 R 8 groups], C 3 . 7 cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-
  • R 8 is independently selected from hydrogen, hydroxy, Ci.-ialkoxy, C ⁇ - 4 alkoxyC ⁇ - 4 alkyl, - 4 alkoxyC ⁇ - alkoxy, hydroxyC 1 - 4 alkoxy, C 1 - 4 alkyl, amino(C ⁇ - 4 )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - 4 alkyl, hydroxy(C 1 - 4 )alkyl, dihydroxy(C ⁇ - )alkyl, -CO 2 C ⁇ - 4 alkyl, aryl and aryl(C ⁇ - 4 )alkyl], C - 4 alkenyl, C 3 - 7 cycloalkyl (optionally substituted by -C(O)OC ⁇ - 4 alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C 1 - 4 )alkyl, dihalo(Ci- 4 )alkyl, trihalo(C
  • R 13 is selected from halo, trihalomethyl, and or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: ii) 2-chloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl-6H-thieno[2,3-b]pyrrole;
  • R 6 is chloro
  • R 7 is hydrogen or chloro
  • 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 1 or 2; Y is -NR 2 R 3 ;
  • R 2 and R 3 are independently selected from hydrogen, C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and -SO b R 8 (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - 4 alkoxy, C ⁇ - alkoxyC ⁇ -4alkyl, C ⁇ - 4 alkoxyC 1 - 4 alkoxy, hydroxyC ⁇ - 4 alkoxy, C ⁇ - 4 alkyl, amino(C 1 - 4 )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - 4 alkyl, hydroxy(C 1 - )alkyl, dihydroxy(C ⁇ - )alkyl, -CO 2 C ⁇ - 4 alkyl, aryl and aryl(C ⁇ - 4 )alkyl], C 2 - 4 alkenyl, C 3 - cycloalkyl (optionally substituted by -C(O)OCi- 4 alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ - 4 )alkyl, dihalo(C ⁇ - 4 )alkyl, trihalo(C 1
  • R 13 is selected from halo, trihalomethyl, and C 1 - 4 alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • Another preferred class of compound is of the formula (1) wherein:
  • R 6 is hydrogen or halo;
  • R 7 is hydrogen or halo
  • 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 1 or 2;
  • Y is -OR 3 ;
  • R 3 is selected from hydrogen, C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and -SO b R 8 (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - 4 alkoxy, C 1 - 4 alkoxyC 1 - 4 alkyl, C ⁇ - 4 alkoxyC ⁇ - alkoxy, hydroxyC 1 - 4 alkoxy, C ⁇ - 4 alkyl, amino(C 1 - 4 )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C 1 - 4 alkyl, hydroxy(C ⁇ .
  • C 1 - 4 alkylS(O) c (C 1 - 4 )alkyl (wherein c is 0, 1 or 2), -CH 2 CH(NR R 10 )CO(NR 9' R 10' ), -CH 2 OR 9 , (R 9 )(R 10 )N-, -COOR 9 , -CH 2 COOR 9 , -C(O)N(R 9 )(R 10 ), -CH 2 CH(CO 2 R 9 )OH, -
  • R 13 is selected from halo, trihalomethyl, and C 1 . 4 alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a further preferred class of compound is of the formula (1) wherein; Z is nitrogen;
  • R 6 is halo
  • R 7 is hydrogen
  • 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 1 or 2; Y is -NR 2 R 3 ;
  • R 2 and R 3 are independently selected from hydrogen, C ⁇ - alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and -SO b R 8 (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - alkoxy, C 1 - 4 alkoxyC ⁇ - alkyl, C ⁇ . 4 alkoxyC ⁇ - 4 alkoxy, hydroxyC - t alkoxy, C ⁇ - alkyl, amino(C 1 - )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - alkyl, hydroxy(C ⁇ - 4 )alkyl, dihydroxy(C ⁇ - 4 )alkyl, -CO 2 Ci- 4 alkyl, aryl and aryl(C ⁇ - )alkyl], C 2 - alkenyl, C 3 - 7 cycloalkyl (optionally substituted by -C(O)OC ⁇ - 4 alky ⁇ ), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C 1 - 4 )alkyl, dihalo(C 1 - )alkyl, trihalo(C ⁇ - )
  • R 13 is selected from halo, trihalomethyl, and C ⁇ - 4 alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • Another preferred class of compound is of the formula (1) wherein:
  • R 6 is hydrogen or halo
  • R 7 is hydrogen or halo
  • 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 1 or 2;
  • Y is -OR 3 ;
  • R 3 is selected from hydrogen, C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups],
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - alkoxy, C 1 - alkoxyC ⁇ - 4 alkyl,
  • -C(O)OC ⁇ - alkyl 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ - 4 )alkyl, dihalo(C ⁇ - 4 )alkyl, trihalo(C 1 - 4 )alkyl, hydroxy(C ⁇ - 4 )alkyl, dihydroxy(C ⁇ - )alkyl, cyano(C 1 - )alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(C ⁇ - 4 )alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(C ⁇ - 4 )alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl
  • a further preferred class of compound is of the formula (1) wherein; Z is nitrogen;
  • R 6 is halo
  • R 7 is hydrogen; A is phenylene; n is O; r is 1;
  • Y is -NR 2 R 3 ;
  • R 2 is hydrogen or C ⁇ - 4 alkyl;
  • R 3 is selected from C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and - SO b R 8 (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - 4 alkoxy, C 1 - 4 alkoxyC 1 - 4 alkyl, C ⁇ - alkyl, amino(C 1 - )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - alkyl, hydroxy(C 1 - 4 )alkyl, dihydroxy(C 1 - 4 )alkyl, -CO 2 Ci- 4 alkyl, phenyl and aryl(C ⁇ - )alkyl], C 2 - 4 alkenyl, C 3 - 7 cycloalkyl (optionally substituted by -C(O)OC 1 - 4 alkyl), 5- and 6- membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ .
  • a further preferred class of compound is of the formula (1) wherein; Z is nitrogen;
  • A is phenylene; n is O r is 1; Y is -NR 2 R 3 ;
  • R 2 is hydrogen or C ⁇ - 4 alkyl
  • R 3 is selected from C 1 - alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and - SO b R 8 (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ . 4 alkoxy, C ⁇ - 4 alkoxyC ⁇ - 4 alkyl, C ⁇ - 4 alkyl, amino(C ⁇ - )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - 4 alkyl, hydroxy(C ⁇ - 4 )alkyl, dihydroxy(C ⁇ - )alkyl, -CO 2 C 1 - 4 alkyl, phenyl and aryl(C ⁇ - 4 )alkyl], C 2 - 4 alkenyl, C 3 - 7 cycloalkyl (optionally substituted by -C(O)OC 1 - 4 alkyl), 5- and 6- membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ .
  • R 9 , R 9' , R 10 and R 10 are independently selected from hydrogen, C ⁇ - alkyl (optionally substituted by 1 or 2 hydroxy groups), C 2 - alkenyl, and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • R 6 is hydrogen or halo;
  • R is hydrogen or halo;
  • 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;
  • Y is -NR 2 R 3 or OR 3 ;
  • R 2 is hydrogen or C ⁇ - 4 alkyl;
  • R 3 is selected from C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], -COR 8 and -SO b R 8 (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - 4 alkoxy, C ⁇ - 4 alkoxyC ⁇ - 4 alkyl, Ci- alkyl, amino(C 1 - 4 )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - 4 alkyl, hydroxy(C ⁇ - )alkyl, dihydroxy(C ⁇ - 4 )alkyl, -CO 2 C ⁇ - alkyl, phenyl and aryl(C ⁇ - )alkyl], C 2 - alkenyl, C 3 - 7 cycloalkyl (optionally substituted by -C(O)OC ⁇ - 4 alkyl), 5- and 6- membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C ⁇ - 4 )alkyl, trihalo(C ⁇ - )alkyl, hydroxy(C 1 - )alkyl, dihydroxy(C 1 - 4 )alkyl, cyano(Ci- 4
  • R 9 , R 9' , R 10 and R 10' are independently selected from hydrogen, C ⁇ - 4 alkyl (optionally substituted by 1 or 2 hydroxy groups), C 2 - 4 alkenyl, and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a further preferred class of compound is of the formula (1) wherein;
  • R 7 is halo or hydrogen
  • 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 is 1 or 2;
  • Y is -NR 2 R 3 or -OR 3 ;
  • R 2 and R 3 are independently selected from hydrogen, C ⁇ - 4 alkyl [optionally substituted by 1 or 2 R 8 groups], C 3 - cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 1,3,4-triazolyl, tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopydridyl, 2-ox
  • R 8 is independently selected from hydrogen, hydroxy, C ⁇ - 4 alkoxy, C ⁇ - 4 alkoxyC ⁇ - 4 alkyl, C ⁇ - alkoxyC ⁇ - 4 alkoxy, hydroxyC 1 . 4 alkoxy, C ⁇ - 4 alkyl, amino(C ⁇ - )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C ⁇ - alkyl, hydroxy(C ⁇ - 4 )alkyl, dihydroxy(C 1 - )alkyl, -CO 2 C ⁇ .
  • R 13 is selected from halo, trihalomethyl, and C ⁇ - 4 alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • a preferred class of compound is of the formula (1) wherein;
  • R 6 is halo or hydrogen
  • R 7 is halo or hydrogen
  • A is phenylene; n is 1 or 2; R 1 is independently selected from hydrogen, halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, C ⁇ - 4 alkoxy and and R 1 is of the formula A' or A" : -CH 2 CH(OH)(CH 2 ) u CO 2 H (A') herein x is 0 or 1, p 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; r is 1 or 2; Y is -NR 2 R 3 or -OR 3 ;
  • R and R 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), Cs- 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 ⁇ - 4 )alkyl, fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, C ⁇ - 4 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)], -COR and -SO b R (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(C ⁇ - 4 )alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(C ⁇ - 4 )alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, morpholino, pyridyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and C ⁇ - 4 alky
  • R 9 and R 10 are independently selected from hydrogen, 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), C 2 - 4 alkenyl, cyano(C ⁇ - 4 )alkyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano) and C 1 - 4 alkyl substituted by R 13 ;
  • R 13 is selected from C 1 - 4 alkoxy, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(C ⁇ - 4 )alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Ci- 4 )alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and C ⁇ . 4 alkyl), pyrazinyl, pipe
  • 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, N-C ⁇ - 4 alkylamino, N,N-(C ⁇ - 4 ) 2 alkylamino, carbonyl, sulfo, C ⁇ - alkoxy, heterocyclyl, C ⁇ - 4 alkanoyl, and Ci- 4 alkylS(O) f (C ⁇ - 4 )alkyl (wherein f is 0, 1 or 2)] ⁇ ; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2,3-dichloro-5-(N- ⁇ l-[N-(l,l-dimethylethoxy)carbonylamino]indan-2-
  • Another preferred class of compounds is of formula (1) wherein: Z is C ⁇ ;
  • R 6 is chloro
  • R 7 is hydrogen
  • A is phenylene; n is 1 or 2;
  • R 1 is independently selected from hydrogen, halo, nitro, hydroxy, C 1 . alkyl, C 1 . 4 alkoxy and and R 1 is of the formula A' or A' ' :
  • Y is -NR 2 R 3 or -OR 3 ;
  • R 2 and R 3 are independently selected from hydrogen, 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 . 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 ⁇ - 4 )alkyl, fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, C ⁇ - 4 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)], -COR 8 and -SO b R 8 (wherein b is 0, 1 or 2);
  • R 8 is independently selected from hydrogen, hydroxy, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(C ⁇ - 4 )alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(C ⁇ - )alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and C 1 .
  • R 9 and R 10 are independently selected from hydrogen, 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), C - 4 alkenyl, cyano(C 1 - 4 )alkyl, phenyl (optionally substituted by 1 or 2 groups selected
  • R 13 is selected from C ⁇ - 4 alkoxy, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(C ⁇ - 4 )alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(C ⁇ - 4 )alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by
  • 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, N-C ⁇ -
  • preferred compounds of the invention are any one of: 2,3-dichloro-N-[(lR,2R)-l-(formylamino)-2,3-dihydro-lH-inden-2-yl]-4H-thieno[3,2- b]pyrrole-5-carboxamide;
  • 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, Y, R 1 , R 4 , R 5 , r and n 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 2,6-di- Z£yZ-pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine.
  • Suitable solvents include dimethylacetamide, dichloromethane,
  • 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.
  • a compound of the formula (2) wherein X is nitrogen may be formed by reacting the compound of the formula (4) with (Cl 3 CCO) 2 O and Cl 3 CCO 2 H in the presence of magnesium chloride using Cl 3 CCO 2 H as solvent, to form a compound of the formula (5):
  • the compound of formula (4) may be prepared from a compound of formula (6) and (7) using conditions known for the Curtius rearrangement (Tetrahedron 1999, 55, 6167):
  • P' is an amino protecting group such as butoxycarbonyl.
  • a carboxy group is introduced into the compound of the formula (10) or (11) by reacting an alkyl lithium reagent such as n-butyl lithium, in an inert organic solvent such as
  • aldehyde precursor of a compound of the formula (12) or (13) can be prepared using standard techniques known in the art. For example, many compounds of the formula
  • R 6 and R 7 are both chloro a compound of the formula (14) or (15) may be chlorinated with a chlorinating agent such as chlorine in the presence of aluminium chloride or iron (HI) chloride, in an inert organic chlorinated solvent such as dichloromethane or 1,2- dichloroethane, followed by treatment with an aqueous base, such as, aqueous sodium hydroxide.
  • a chlorinating agent such as chlorine in the presence of aluminium chloride or iron (HI) chloride
  • an inert organic chlorinated solvent such as dichloromethane or 1,2- dichloroethane
  • an aqueous base such as, aqueous sodium hydroxide
  • the conversion of compounds of formula (10) into compounds of formula (16) may be carried out by directed ortho lithiation reactions (J. Org. Chem, 2001, volume 66, 3662-3670), for example with n-butyl lithium and (CHO)N(alkyl) 2 .
  • the protecting group P' in compounds of formula (10) must be suitable directing group for this reaction and may be for example - CO tBu.
  • Compounds of formula (3) where Y is OR 3 are commercially available or they are known compounds or they are prepared by processes known in the art. When Y is NR R , the amines of formula (3) may be prepared according to Scheme 3:
  • R 1 and/or R 2 may be introduced by acylation, (for example reacting with acetoxyacetic acid and l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride -ED AC), alkylation, reductive alkylation, sulphonation or related processes, followed by O-deprotection when appropriate.
  • acylation for example reacting with acetoxyacetic acid and l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride -ED AC
  • alkylation for example reacting with acetoxyacetic acid and l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride -ED AC
  • alkylation for example reacting with acetoxyacetic acid and l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochlor
  • R 1 and/or R 2 may be obtained by modification of functionality in groups previously thus introduced, by reduction, oxidation, hydrolysis (for example the conversion of an acetoxy group to a hydroxy group), nucleophilic displacement, amidation, or a related process, or a combination of these processes, followed by O-deprotection when appropriate. It will be appreciated that such modifications may include modifications which convert one compound of the formula (1) into another compound of the formula (1).
  • Amines of formula (3) may alternatively be obtained by applying the processes described for the preparation of compounds of formula (3 a) to compounds of formula (20) in which W is NH 2 or a nitrogen atom with one or two suitable protecting groups.
  • Steps 2, 3, 4, 5, 6, 7 and 8 are performed using standard techniques known in the art.
  • bromopyrindinone isomers (21a, 21b and 21c) could be any bromopyrindinone isomers (21a, 21b and 21c).
  • (21a) (21b) (21c) be converted to the corresponding heterocylic version of (3) by the means described in Scheme 4.
  • the bromopyridinones can be prepared from the corresponding pyrindinone by standard techniques known in the art.
  • the pyrindinones (22a, 22b, 22c) are known in the literature or they are prepared by processes known in the 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 alkylsulphinyl or alkylsulphonyl.
  • 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 dimethylaminopropylarnine, 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.
  • 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 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 846464 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 HI 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-
  • GP ⁇ is pre-incubated in the assay buffer solution with the type UI 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) PNAS 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 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 5 o, a concentration predicted to inhibit the enzyme reaction by 50%.
  • OD620 optical density at 620nM.
  • Typical IC 5 o 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 0 846 464 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 , 2.5mM MgCl 2 ,
  • 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 " N- ethylmaleimide. After 6 hours at 30°C Relative Fluoresence Units (RFUs) are measured at 340nM excitation, 465nm emission .
  • REUs Relative Fluoresence Units
  • Typical IC 50 values for compounds of the invention when tested in the above assay are in the range lOO ⁇ M to InM.
  • Example 10 was found to have an IC 5 o of 4.5 ⁇ m.
  • the inhibitory activity of compounds was further tested in rat primary hepatocytes. Rat hepatocytes were isolated by the collagenase perfusion technique, general method of Seglen (P.O. Seglen, Methods Cell Biology (1976) 13 29-83).
  • DMEM Dulbeco's Modified Eagle's Medium
  • NEAA non essential amino acids
  • Glutamine penicillin /streptomycin ((100units/100ug)/ml)
  • 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 CaCl 2 and 1% gelatin.
  • 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 p-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.
  • 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
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions 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.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to disp
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the 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 include the following main categories of treatment: 1) Insulin and insulin analogues;
  • Insulin secretagogues including sulphonylureas (for example glibencla ide, glipizide) and prandial glucose regulators (for example repaglinide, nateglinide);
  • sulphonylureas for example glibencla ide, glipizide
  • prandial glucose regulators for example repaglinide, nateglinide
  • Insulin sensitising agents including PPARg agonists (for example pioglitazone and rosiglitazone); 4) Agents that suppress hepatic glucose output (for example metformin).
  • 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); 9) Antihypertensive agents such as, ⁇ blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg.
  • Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor NHa 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).
  • non-steroidal anti-inflammatory drugs eg. aspirin
  • 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, for use as a medicament.
  • a compound of the formula (1) 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.
  • 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 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.
  • 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 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 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).
  • 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.
  • 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;
  • ⁇ MR 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
  • reduced pressures are given as absolute pressures in Pascals (Pa); elevated pressures are given as gauge pressures in bars;
  • DIPEA di-isopropylethylamine EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride;
  • Example 3 N-((lS.2S -l- ⁇ r(3(R -3-(tert-Butoxycarbonylamino)-3- carbamoylpropanoyll- ⁇ minol-2.3-dihvdro-lH-inden-2-yl)-2.3-dichloro-4H-thienor3,2- blpyrrole-5-carboxamide
  • Example 4 2.3-Dichloro-N-. QR,2R -l-( ⁇ r(4R)-2.2-dimethyl-5-oxo-l,3-dioxolan-4- yllacetyl
  • Example 5 2.3-Dichloro-N- ⁇ (lR.2R)-l-r(3-methoxypropanoyl)amino1-2,3-dihvdro-lH- inden-2-yl
  • Example 6 N-l(lR.2RVl-[(2-Acetoxyacetyl)aminol-2,3-dihvdro-lH-inden-2-yl
  • Example 7 N-((lR.2RVl-r(2-Carbamoylacetyl aminol-2.3-dihvdro-lH-inden-2-yl ⁇ -2.3- dichloro-4H-thienor3.2-blpyrrol-5-carboxamide
  • Example 10 2,3-Dichloro-N- ⁇ (lS S)-l-r(3-tMenylcarbonyl aminol-2,3-dihvdro-lH-inden-2- yl ⁇ -4H-thieno ⁇ 3 ,2-b1pyrrole-5 -carboxamide
  • Example 11 2,3-Dichloro-N-(QS,2S)-l- j r(5-nitrofuran-2-yl carbonyllaminol-2.3-dihydro- lH-inden-2-yl)-4H-thieno[3,2-blpyrrole-5-c- ⁇ rboxamide
  • Example 15 N-r(lS.2S)-l-(Acetylamino)-2,3-dihvdro-lH-inden-2-yll-2.3-dichloro-4H- thieno ⁇ 3.2-blpyrrole-5-carboxamide
  • Example 16 N-r(lS.2S)-l-r(2-Carboxyacetyl)aminol-2,3-dihvdro-lH-inden-2-yll-2 - dichloro-4H-thienor3.2-blpyrrole-5-carboxamide
  • Example l7 2 -Dichloro-N-((lS S)-1 r(dimethylamino)carbonyl1aminol-2,3- dihvdro-lH-inden-2-yl)-4H r -thienor3,2-blpyrrole-5-carboxamide
  • Example 23 N- ⁇ (lR,2R) -r((3R)-3-Amino-3-carbamoylpropanoyl)amino1-2,3-dihvdro- lH-inden-2-vU-2,3-dichIoro-4H-thienor3,2-blpyrrole-5-earboxamide
  • Example 24 iV-(lR,2R)-l-r((3R)-3-Carboxy-3-hvdroxypropanoyl)amino1-2,3-dihvdro- lH-inden-2-vU-2 -dichloro-4H-thienor3,2-b1pyrrole-5 arboxamide
  • Example 27 2.3-D.chloro-iV- ⁇ (lS.2S)-l-rmethyl(morpholin-4-ylacetyl)aminol-2,3- dihydro-ljH r -inden-2-vU-4H-thienor3,2-blpyrrole-5-carboxamide
  • Acetyl chloride (17 ⁇ L, 0.24 mmol) was added to a solution of N- ⁇ (lR,2R)-l-[(2- ar-iino-2-oxoethyl)amino]-2,3-dihydro-lH-inden-2-yl ⁇ -2,3-dichloro-4H-thieno[3,2-b]pyrrole- 5-carboxamide (Example 28, 100 mg, 0.24 mmol) in T ⁇ F (10 mL). The reaction was stirred at ambient temperature for 1 h.
  • Example 35 2-Chloro-N-r(lR.2R)-l-(formylamino)-2.3-dihvdro-lg-inden-2-vn-6H- thienor2,3-b1pyrrole-5-carboxamide
  • Example 36 2-Chloro-N (lR.2R)-1 (methoxyacetyl)amino1-2,3-dihvdro-lH-inden-2- yl ⁇ -6H r -thienor2.,3-b1Pyrrole-5-carboxamide
  • Example 37 V-r(lR,2R)-l-(Acetylamino)-2,3-dihvdro-lH-inden-2-vn-2-chloro-6H- thienor2,3-b1pyrrole-5-carboxamide
  • Example 38 2-Chloro-iV- ⁇ (lR-2R)-l-r(3-methoxypropanoyl)amino1-2 -dihvdro-liH r - inden-2-yll-6H r -thienor2,3-b1pyrrole-5-carboxamide
  • Example 39 iV- ⁇ (lR,2R)-l-r(2-Acetoxyacetyl)amino1-2,3-dihydro-lH;-inden-2-vU-2- chloro-6H-thienor2,3-blpyrrole-5-carboxamide
  • Example 40 iV-((lS,25)-l-ir(2(S)-2-(tgrt-ButoxycarbonvIamino)-2- carbamoylacetyl1amino>-2,3-dihydro-lH-inden-2-yl)-2-chloro-6i-r-thienor2,3-b1pyrrole-
  • Example 41 N (15,2S)-l-r(2-(fe/ ⁇ -Butoxycarbonylamino)acetylamino1-2-3-dihvdro-lH- inden-2-vU-2-chloro-6H-thienor2,3-b1pyrrole-5-carboxamide
  • Example 42 N- ⁇ (1R,2R)-1- r2-Carbamoylacetyl)amino1-2,3-d ⁇ hydro-lH-inden-2-yl>-2-chloro-6H- thienor2,3 ⁇ blpyrrole-5-carboxamide
  • Example 48 N-((lR-2R)-l- rBis(2-hvdroxyethyl)an ⁇ ino1acetyl)amino)-2.3-dihvdro-lH- inden-2-yl)-2-chIoro-6H-thienor2.,3-blpyrrole-5-carboxamide
  • Example 49 2-Chloro-iV-((lR,2R)-l-( ⁇ rethyl(2-hvdroxyethvI)amino1acetvI)amino)-2,3- dihvdro-lH r -inden-2-yl)-6H-thienor2,3-b1pyrroIe-5-carboxamide
  • Example 50 2-Chloro-N-((lR,2R)-l-(ir(2,3- dihydroxypropyl)(methyl)amino1acetyl)amino)-2,3-dihvdro-lH r -inden-2-yl)-6ij r - thienor2,3-b1pyrrole-5-carboxamide
  • Example 51 N-((lR,2R)-l-( ⁇ rBis(2-hydroxypropyl)an ⁇ inolacety amino)-2,3-dihydro-lH- inden-2-yl)-2-chIoro-6H-thienor2-3-blpyrrole-5-carboxamide
  • Example 52 iV-l(lR-2R)-l-r(2-Amino-2-oxoethyl)aminol-2,3-dihvdro-lH-inden-2-yl>-2- chloro-6H-thienor2 -blpyrrole-5-carboxamide
  • Example 54 iV- ⁇ (lR-2R)-l-(Carboxymethylamino)-2,3-dihydro-lH-inden-2-yl)-2- chloro-6H-thieno(3,2,blpyrrole-5-carboxa ⁇ nide
  • Example 60 iV- ⁇ (lR,2R)-l-r((35)-3-Amino-3-carboxypropanoyl)a ⁇ ninol-2,3-dihvdro- lH-inden-2-yl>-2.,3-dichloro-4H r -thieno(3,2.,b1pyrrole-5-carboxamide
  • N-[(lR,2R)-l-Amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide (Method 8, 350 mg, 0.73 mmol) was added to a solution of N- ⁇ -/j>b ⁇ -t-Boc-E-aspartic acid alpha-t- butyl ester (232 mg, 0.80 mmol), 1-hydroxybenzotriazole monohydrate (123 mg, 0.80 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.80 mmol), 4-methylmorpholine (0.18 mL, 1.6 mmol) in N,N- dimethylformamide (20 mL). The mixture was stirred at ambient temperature for 16 hours.
  • Example 2 N- ⁇ (lR,2R)-l-r(2-Carboxyacetyl)amino1-2,3-dihydro-lH r -inden-2-yl>-2- chloro-6H-thieno(3,2,b1pyrrole-5-carboxamide
  • Example 63 iV- ⁇ (lR,2R)-l-r((3S)-3-Amino-3-carboxypropanovDamino1-2-3-dihvdro-lH- inden-2-yl>-2-chIoro-6H-thieno(3,2,b1pyrrole-5-carboxamide
  • Example 64 2 ⁇ 3-Dichloro-iV- ⁇ (lR,2R)-l-r(methylsulfonyl)aminol-2,3-dihvdro-lH-inden- 2-yl>-4H-thienor3,2-b1pyrrole-5-carboxamide
  • Method 4 5-Carboxy-2,3-dichloro-4H-thieno[3,2-b] ⁇ yrrole
  • Method 4a 5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole
  • Acetoxyacetic acid 34 mg, 0.3 mmol
  • DMTMM 81 mg, 0.3 mmol
  • N-(lR,2R)-l-[(tert-butoxycarbonylmethyl)amino]-2,3-dihydro-lH-inden-2- yl ⁇ -2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide Example 29, 140 mg, 0.3 mmol
  • T ⁇ F 10 mL

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Abstract

Heterocyclic amides of formula (1) wherein: Z is CH or nitrogen; R4 and R5 together are either -S-C(R6)=C(R7)- or -C(R7)=C(R6)-S- ; R6 and R7 are selected from for example hydrogen, halo, C1-4alkyl, and C1-4alkanoyl; A is phenylene or heteroarylene; n is 0, 1 or 2; R1 is selected from for example halo, nitro, cyano, hydroxy, carboxy; r is 1 or 2; Y is -NR2R3 or -OR3; R2 and R3 are selected from for example hydrogen, hydroxy, aryl, heterocyclyl and C1-4alkyl (optionally substituted by 1 or 2 R8 groups); R4 is selected from for example hydrogen, halo, nitro, cyano, hydroxy, C1-4alkyl, and C1-4alkanoyl; 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, C1-4alkyl (optionally substituted by 1 or 2 R13 ); R13 is selected from hydroxy, halo, trihalomethyl and C1-4alkoxy; 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

HETEROCYCLIC AMIDE DERIVATIVES HAVING GLYCOGEN PHOSPHORYLASE INHIBITORY ACTIVITY
The present invention relates to heterocyclic amide derivatives, pharmaceutically acceptable salts and in vivo hydrolysable esters thereof. These heterocyclic 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 heterocyclic 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 heterocyclic 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:
Z is CH or nitrogen;
R4 and R5 together are either -S-C(R6)=C(R7)- or -C(R7)=C(R6)-S- ; R6 and R7 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl,
Cι-4alkyl, C -4alkenyl, C2-4alkynyl, Cι-4alkoxy and Cι-4alkanoyl;
A is phenylene or heteroarylene; n is 0, 1 or 2; R1 is independently selected from halo, nitro, cyano, hydroxy, carboxy, carbamoyl, N-Cι- alkylcarbamoyl, N,N-(C1- alkyl)2carbamoyl, sulphamoyl, N-C1- alkylsulphamoyl,
N,N-(C1-4alkyl)2sulphamoyl, -S(O)bC1- alkyl (wherein b is 0,l,or 2), Cι- alkyl, C - alkenyl,
C2-4alkynyl, Cι- alkoxy, Ci-4alkanoyl, Cι- alkanoyloxy, hydroxyC1-4alkyl, 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; r is 1 or 2; and when r is 1 the group
Figure imgf000004_0001
is a substituent on carbon (2) and when r is 2 (hereby forming a six membered ring) the same group is a substituent on carbon (2) or on carbon (3); Y is -ΝR2R3 or -OR3;
R2 and R3 are independently selected from hydrogen, hydroxy, Cι- alkoxy, C1- alkanoyl, carbamoyl, C3- cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), cyano(Cι. )alkyl, heterocyclyl, aryl, C1-4alkyl [optionally substituted by 1 or 2 R groups], -COR8, -SObR8 (wherein b is 0, 1 or 2) and groups of the formulae B and B' :
Figure imgf000004_0002
(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; or wherein NR2R3 may form a 4 to 7 membered saturated, partially saturated or unsaturated ring, optionally containing 1, 2 or 3 additional heteroatoms independently selected from N, O and S, wherein any -CH2- may optionally be replaced by -C(=O)-, and any N or S atom may optionally be oxidised to form an N-oxide or SO or SO2 group respectively, and wherein the ring is optionally substituted by 1 or 2 substituents independently selected from halo, cyano,
Cι- alkyl, hydroxy, C1- alkoxy and Cι- alkylS(O)b- (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, C1. alkyl, C2.4alkenyl, Cι- alkoxy, cyano(C1-4)alkyl, amino(C1- )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy, hydroxy(Cι-4)alkyl, dihydroxy(Cι-4)alkyl, -CO2C1.4alkyl, aryl and aryl(Cι-4)alkyl], halo(C1-4)alkyl, dihalo(Cι-4)alkyl, trihalo(C1- )alkyl, hydroxy(Cι- )alkyl, dihydroxy(Cι-4)alkyl, Cι- alkoxyC1-4alkoxy, C1- alkoxyC1.4alkyl, hydroxyC1- alkoxy,
5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, aryl, heterocyclyl, (heterocyclyι)Cι-4alkyl, C3- cycloalkyl (optionally substituted with 1 or 2 hydroxy groups, C1-4alkyl or -C(O)OCι- alkyl), Cι-4alkanoyl, Cι- alkylS(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), - 4alkylS(O)c(Cι-4)alkyl (wherein c is 0, 1 or 2), -N(OH)CHO, -C(=N-OH)NH2, -C(=N- OH)NHCι-4alkyl, -C(=N-OH)N(Cι-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-, -COCH^R1 \ (R9)(R10)N- and -COOR9, -CH2OR9, -CH2COOR9, -CH2OCOR9, -CH2CH(CO2R9)OH, -CH2C(O)NR9R10, -(CH2)WCH(NR9R10)CO2R9' (wherein w is 1, 2 or 3), and -(CH2)WCH(NR9R10)CO(NR9'R10') (wherein w is 1, 2 or 3) ; R9 , R9 , R10 and R10 are independently selected from hydrogen, hydroxy, Cι- alkyl
(optionally substituted by 1 or 2 R13), C -4alkenyl, C3- cycloalkyl (optionally substituted by 1 or 2 hydroxy groups), cyano(C1-4)alkyl, trihaloalkyl, aryl, heterocyclyl, heterocycryl(Ci-4alkyl), and -C(=O)O(Cι-4)alkyl; or
R9 and R10 together with the nitrogen to which they are attached, and/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- alkoxy 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 halo, trihalomethyl, and Cι- alkoxy;
R11 is independently selected from hydrogen, Cι-4alkyl, and hydroxyCι-4alkyl; or a pharmaceutically acceptable salt or pro-drug thereof; with the proviso that the compound of formula (1) is not: i) 2,3-dichloro-5-(N-{ l-[N-(l,l-dimethylethoxy)carbonylamino]indan-2- yl}carbamoyl)-4H-thieno[3,2-b]pyrrole; ii) 5-[N-(l-aminoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iii) 5-[N-(l-acet-unidoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iv) 2,3-dichloro-5-{N-[l-(methanesulphonamido)indan-2-yl]carbamoyl}-4H- thieno[3 ,2-b]pyrrole v) 2,3-dichloro-5- { N- [ 1 -(methylamino)indan-2-yl] carbamoyl } -4H-thieno [3 ,2- b]pyrrole; vi) 2,3-dichloro-5-{N-[l-(methylacetamido)indan-2-yl]carbamoyl}-4H-thieno[3,2- bjpyrrole; vii) 2,3-dichloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole; viii) 2-chloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl-6H-thieno[2,3-b]pyrrole; ix) 2,3-dichloro-5-[N-(6-fluoro-l-hydroxyindan-2-yl)carbamoyl-4H-thieno[3,2- bjpyrrole x) 2,3-dichloro-5-[N-(l-methoxyindan-2-yl)carbamoyl-4H-thieno[3,2-b]pyrrole; xi) 2,3-dichloro-5-[Ν-(l-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)carbamoyl]-4H- thieno[3,2-b]pyrrole.
According to another aspect of the present invention there is provided a compound of formula (1):
Figure imgf000006_0001
wherein: Z is CΗ or nitrogen;
R4 and R5 together are either -S-C(R6)=C(R7)- or -C(R7)=C(R6)-S- ; R6 and R7 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, ureido, Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, Cι.6alkoxy, Cι-6alkanoyl, Ci-6alkanoyloxy,
Figure imgf000006_0002
N,N-(C1-6alkyl)2amino, Ci-6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C^ealkoxycarbonyl, Cι-6alkoxycarbonylamino, N-(Cι-6alkyl)sulphamoyl, N,N-(Cι-6alkyl)2sulphamoyl, Cι-6alkylsulphonylamino and C1-6alkylsulphonyl-N-(C1-6alkyl)amino; A is phenylene or heteroarylene; n is 0, 1 or 2;
R1 is independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
Figure imgf000007_0001
sulphamoyl, N-Ci-4alkylsulphamoyl, N,N-(Cι-4alkyl)2sulphamoyl, sulfino, sulfo, Cι- alkyl, C2-4alkenyl, C2-4alkynyl, C1.4alkoxy, Cι-4alkanoyl, Ci- alkanoyloxy, N-(Cι-4alkyl)amino,
N,N-(Cι-4alkyl)2amino, hydroxyC1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Cι-4alkoxy and R1 is of the formula A' or A" :
Figure imgf000007_0002
-CH2CH(OH)(CH2)uCO2H (A') wherein x is 0 or 1, p 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; r is 1 or 2; and when r is 1 the group
Figure imgf000007_0003
is a substituent on carbon (2) and when r is 2 (hereby forming a six membered ring) the same group is a substituent on carbon (2) or on carbon (3); Y is -ΝR2R3 or -OR3;
R2 and R3 are independently selected from hydrogen, hydroxy, Cι- alkyl (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 with 1 or 2 hydroxy groups provided that when there are 2 hydroxy groups they are not substituents on the same carbon), cyano(Cι- 4)alkyl, 4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranylgroup, 1 , 1-dioxotetrahydrothiopyranyl, fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, Cι- alkyl [substituted by 1 or 2 R8 groups
(provided that when there are 2 R8 groups they are not substituents on the same carbon)],
-COR8, -SObR8 (wherein b is 0, 1 or 2) and groups of the formulae B and B':
~(CH2)t
Figure imgf000008_0001
-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 R is independently selected from hydrogen, hydroxy, C1. alkoxyC1- alkoxy, hydroxyCι- alkoxy, 2,2-dimethyl-l,3~dioxolan-4-yl, heterocyclyl (optionally substituted on carbon or nitrogen by 1 or 2 groups selected from hydrogen, nitro, halo, cyano, hydroxy and Cι-4alkyl), (heterocyclyl)Cι-4alkyl (wherein the heterocyclyl is optionally substituted on carbon or nitrogen by 1 or 2 groups selected from hydrogen, nitro, halo, cyano, hydroxy and Cι-4alkyl), aryl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι- alkyl), Cι-4alkyl, C2- alkenyl, cyclo(C3-8)alkyl, Cι-4alkoxy, cyano(Cι- )alkyl, amino(Cι- )alkyl (optionally substituted on nitrogen by 1 or 2 groups selected from hydrogen, Cι- alkyl, hydroxy, hydroxy(Cι- )alkyl, dihydroxy(Cι- )alkyl, aryl and aryl(Cι- )alkyl), Ci- 4-dkylS(O)c(C1-4)alkyl (wherein c is 0, 1 or 2), -N(OH)CHO, -CH2CH(CO2R9)N(R9R10), - CH2OR9, (R9)(R10)N-, -COOR9 and -CH2COOR9 , -CH2CONR9R10, - (CH2)UCH(NR9R10)CO2R9 (wherein u is 1, 2 or 3);
[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), Cs- 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), C2-4alkenyl, cyano(C1-4)alkyl, 4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranylgroup, 1,1-dioxotetrahydrothiopyranyl, 2,2-dimethyl-l,3-dioxolan-4-yl, aryl (optionally substituted by 1 or 2 substituents selected from hydrogen, nitro, halo, hydroxy and Cι- a-kyl) and Cι-4alkyl substituted by R13 ;
(wherein R13 is selected from hydroxy, Cι-4alkoxy, heterocyclyl, Cι-4alkanoyl, C1-4alkylS(O)d (wherein d is 0, 1 or 2)1, -N(OH)CHO, (Rπ)(R12)NCO-, (Rπ)(R12)NSO2-, - COCH2ORπand (Rπ)(R12)N-; {wherein R11 and R12 are independently selected from hydrogen, C1- alkyl, Cι-4alkoxy, hydroxyCι-4alkyl, C1-4alkylS(O)e (wherein e 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-Ci-
4alkylamino, N,N-(C1- ) alkylamino, carbonyl, sulfo, Cι-4alkoxy, heterocyclyl, Cι-4alkanoyl,
Cι-4alkylS(O)f(C1-4)alkyl (wherein f is 0, 1 or 2), -Ν(OH)CHO, (Rn)(R12)NCO-,
(Rπ)(R12)NSO2-, -COCH2ORn, (Rπ)(R12)N-; wherein R11 and R12 are as defined above] } ; provided that when R1 is of the formula A' or A' ' then R2 and R3 do not contain a group of the formula B or B' and when R2 or R3 is of the formula B or B' then R1 does not contain a group of the formula A' or A' ' such that a compound of formula (1) can contain only one of A' , A" ,
B andB'; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2,3-dichloro-5-(N-{l-[N-(l,l-dimethylethoxy)carbonylamino]indan-2- yl}carbamoyl)-4H-thieno[3,2-b]pyrrole; ii) 5-[N-(l-aminoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iii) 5-[N-(l-acetamidoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole iv) 2,3-dichloro-5-{N-[l-(methanesulphonamido)indan-2-yl]carbamoyl}-4H- thieno[3,2-b]pyrrole v) 2,3 -dichloro-5 - { N-[ 1 -(methylamino)indan-2-yl] carbamoyl } -4H-thieno [3 ,2- b]pyrrole; vi) 2,3-dichloro-5-{N-[l-(methylacetamido)indan-2-yl]carbamoyl}-4H- thieno[3,2-b]pyrrole; vii) 2,3-dichloro-5 - [N-( 1 -hydroxyindan-2-yl)carbamoyl] -4H-thieno [3 ,2-b]pyrrole; viii) 2-chloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl-6H-thieno[2,3-b]pyrrole; ix) 2,3-dichloro-5-[N-(6-fluoro-l-hydroxyindan-2-yl)carbamoyl-4H-thieno[3,2- b]pyrrole x) 2,3-dichloro-5-[N-(l-methoxyindan-2-yl)carbamoyl-4H-thieno[3,2-b]pyrrole; xi) 2,3-dichloro-5-[Ν-(l-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)carbamoyl]-4H- thieno[3,2-b]pyrrole. 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
Y
Figure imgf000010_0001
when A is heteroarylene encompasses the structures:
Figure imgf000010_0002
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, dimethylamme, 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 al, 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 Cι_6alkoxymethyl esters for example methoxymethyl, Ci-galkanoyloxymethyl 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 Ci-ealkoxycarbonyloxyethyl 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 -acyloxyalkyl ethers include acetoxyrnethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include Ci-ioalkanoyl, for example acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, Ci-ioalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-(Cι-4)alkylcarbamoyl and N-(di-(C1-4)alkylaminoethyl)-N- (Cι--t)alkylcarbamoyl (to give carbamates); di-(C1-4)alkylaminoacetyl and carboxyacetyl.
Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, (Ci.
4)alkylaminomethyl and di-((Cι-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, RAC(O)O(Cι-6)alkyl- CO-, wherein RA is for example, benzyloxy-(Cι-4)alkyl, or phenyl). Suitable substituents on a phenyl group in such esters include, for example, 4-(C1-4)piperazino-(Cι-4)alkyl, piperazino-
(Cι-4)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 and examples of "Cι-6alkyl" include the examples of "Cι-4alkyl"and additionally pentyl, 2,3-dimethylproρyl, 3-methylbutyl and hexyl. An analogous convention applies to other generic terms, for example "C2.4alkenyl" includes vinyl, allyl and 1-propenyl and examples of "C2.6alkenyl" include the examples of "C .4alkenyl" and additionally 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3- methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Examples of "C -4alkynyl" includes ethynyl, 1-propynyl and 2-propynyl and examples of "C -6alkynyl"include the examples of "C2-4alkynyl" and additionally 3-butynyl, 2-pentynyl and l-methylpent-2-ynyl.
The term "hydroxyC1-4alkyl" 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 "dihydroxyC1-4alkyl" 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 "trihaloC1-4alkyl" 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-1 ,3-dioxan-4-yl; 2,2-dimethyl- 1 ,3-dioxan-5-yl; 1 ,3-dioxan-2-yl.
Examples of "Cι-4alkoxy" include methoxy, ethoxy, propoxy and isopropoxy.
Examples of "Cι-6alkoxy" include the examples of "C1-4alkoxy" and additionally butyloxy, t- butyloxy, pentoxy and l,2-(methyl)2propoxy. Examples of "Cι-4alkanoyl" include formyl, acetyl and propionyl. Examples of "Ci-βalkanoyl" include the example of "Cι- alkanoyl" and additionally butanoyl, pentanoyl, hexanoyl and l,2-(methyl)2propionyl. Examples of "Ci- alkanoyloxy" 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-(Cι-4alkyl)amino" include methylamino and ethylamino. Examples of "N-(Cι-6alkyl)amino" include the examples of "N-(Cι-4alkyl)amino" and additionally pentylamino, hexylamino and 3-methylbutylamino. Examples of "N,N-(Cι-4alkyl)2amino" include N-N-(methyl)2amino, N-N-(ethyl)2amino and N-ethyl-N-methylamino. Examples of "N,N-(C1-6alkyl)2amino" include the example of "N,N-(Cι-4-dkyl)2amino" and additionally N-methyl-N-pentylamino and N,N-(pentyl)2amino. Examples of "N-(Cι-4alkyl)carbamoyl" are methylcarbamoyl and ethylcarbamoyl. Examples of
Figure imgf000014_0001
are the examples of
Figure imgf000014_0002
additionally pentylcarbamoyl, hexylcarbamoyl and l,2-(methyl)2propylcarbamoyl. Examples of "N,N-(C1-4alkyl)2carbamoyl" are N,N-(methyl)2carbamoyl, N,N-(ethyl)2carbamoyl and N- methyl-N-ethylcarbamoyl. Examples of "N,N-(C1-6alkyl)2carbamoyl" are the examples of "N,N-(C1- alkyl)2carbamoyl" and additionally N,N-(pentyl)2carbamoyl, N-methyl-N- pentylcarbamoyl and N-ethyl-N-hexylcarbamoyl. Examples of "N-(Cι-4alkyl)sulphamoyr are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of "N-(Cι-6alkyl)sulphamoyl" are the examples of "N-(Cι-4alkyl)sulphamoy and additionally N-pentylsulphamoyl, N- hexylsulphamoyl and l,2-(methyl)2propylsulphamoyl. Examples of
"N,N-(C1-4alkyl)2sulphamoyl" are N,N-(methyl)2sulphamoyl, N,N-(ethyl) sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of "N,N-(C1-6alkyl)2sulphamoyl" are the examples of "N,N-(C1.4alkyl)2sulphamoyl" and additionally N,N-(pentyl)2sulphamoyl, N- methyl-N-pentylsulphamoyl and N-ethyl-N-hexylsulphamoyl.
Examples of "cyano(Cι-4)alkyl" are cyanomethyl, cyanoethyl and cyanopropyl. Examples of "C5-7cycloalkyl" are cyclopentyl, cyclohexyl and cycloheptyl. Examples of "C3- scycloalkyl" and "C3-7cycloalkyl" include "C5-7cycloalkyl", cyclopropyl, cyclobutyl and cyclooctyl. Examples of "C3-6cycloalkyl" inclulde cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "aminoCι-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.
Examples of "Cι-4alkoxyCι- alkoxy" are methoxymethoxy, ethoxymethoxy, ethoxyethoxy and methoxyethoxy. Examples of "hydroxyCι-4alkoxy" are hydroxyethoxy and hydroxypropoxy. Examples of "hydroxypropoxy" are 1-hydroxypropoxy, 2-hydroxypropoxy and 3 -hydroxypropoxy.
Examples of "Ci-4alkylS(O)b (wherein b is 0,1 or 2)", "C1-4alkylS(O)c (wherein c is 0 to 2)", "C1-4alkylS(O)d (wherein d is 0 to 2)", "C1-4alkylS(O)e (wherein e is 0 to 2)", and "Cι-4alkylS(O)f (wherein f is 0 to 2)" independently 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.
Examples of "Cι-6alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "Cι-6alkoxycarbonylamino" include methoxycarbonylamino, ethoxycarbonylamino, n- and t-butoxycarbonylamino. Examples of "Cι-6alkylsulphonyl-N-(Cι-6alkyl)amino" include methylsulphonyl-N-methylamino, ethylsulphonyl-N-methylamino and propylsulphonyl-N-ethylamino. Examples of
"Cι-6alkylsulphonylamino" include methylsulphonylamino, ethylsulphonylamino and propylsulphonylamino. Examples of "Cι-6alkanoylamino" include formamido, acetamido and propionylamino.
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, isothiazolidinyl, 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- oxopyrrolidyl, 4-oxothiazolidyl, furyl, thienyl, oxazolyl, and oxadiazolyl.
Suitably a "heterocyclyl" is morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 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.
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.4alkyl, Ci- 4alkoxy and C1-4alkylS(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, methylsulfinyl 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-4alkyl, Ci- 4alkoxy, C1-4alkylS(O)b (wherein b is 0, 1 or 2), N-(C1-4alkyl)amino and N,N-(Cι-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)Ci-4alkyl" 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(Cι- )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-4alkoxy, C1-4alkylS(O)b (wherein b is 0, 1 or 2), N-(C1-4alkyl)amino and N,N-(C1- alkyl)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, Cι-4alkyl, Cι-4alkoxy, C1- alkylS(O)b (wherein b is 0, 1 or 2), N-(C1-4alkyl)amino and
N,N-(C1-4alkyl)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, Y, R1, R4, R5, r 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). Particular examples of in-vivo hydrolysable esters of compounds of the formula (1) are such esters of compounds of the formula (1) wherein Y comprises a group containing a carboxy group. Suitable esters are those hereinbefore described for carboxy groups.
In one aspect of the present mvention there is provided a compound of formula (1) as depicted above wherein z is CH. In another aspect of the invention Z is nitrogen.
In one aspect of the present invention there is provided a compound of formula (1) as depicted above wherein R4 and R5 are together -S-C(R6)=C(R7)-.
In another aspect of the invention R4 and R5 are together -C(R7)=C(R6)-S-.
In a further aspect of the invention, R and R are independently selected from hydrogen, halo or Cι.6alkyl.
Preferably R6 and R7 are independently selected from hydrogen, chloro, bromo or methyl.
Particularly R6 and R7 are independently selected from hydrogen or chloro.
More particularly one of R6 and R7 is chloro. h one embodiment, one of R6 and R7 is chloro and the other is hydrogen.
In another embodiment, both R6 and R7 are 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 embodiment, when A is heteroarylene, there is a nitrogen in a bridgehead position. In another embodiment, when A is heteroarylene, the heteroatoms are not in bridgehead positions. It will be appreciated that the preferred (more stable) bridgehead position is as shown below:
Y
Figure imgf000019_0001
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-4alkoxy. In a further aspect R1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -S(O)bC1-4alkyl (wherein b is 0, 1 or 2), Cι-4alkyl and Ci- 4alkoxy.
I-n 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 Cι- alkyl.
Preferably R1 is selected from halo and Cι-4alkoxy.
In another embodiment preferably R1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH2-O-. I-n one aspect of the invention r is 1 and when r is 1 the group
Figure imgf000020_0001
is a substituent on carbon (2) such that an example of when r is 1 is:
Figure imgf000020_0002
In another aspect of the invention r is 2 and when r is 2 the group
Figure imgf000020_0003
is a substituent on carbon (2) such that an example of when r is 2 is:
Figure imgf000020_0004
In another aspect of the invention r is 2 and when r is 2 the group
Figure imgf000020_0005
is a substituent on carbon (3) such that an example of when r is 2 is:
Figure imgf000020_0006
In one aspect of the invention Y is -NR2R3. hi another aspect of the invention Y is -OR3.
Suitable values for R2 and R3 as heterocyclyl are morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 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 R2 and R3 as heterocyclyl are pyridyl, pyrimidinyl and imidazolyl.
Further suitable values for R2 and R3 as heterocyclyl are tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl, 1 , 1 -dioxotetrahydrothiopyranyl.
In one aspect of the invention, R2 and R3 are independently selected from groups of the formulae B and B' as hereinbefore described.
In one aspect of the invention R2 and R3 are independently selected from hydrogen, hydroxy, C1-4alkyl [optionally substituted by 1 or 2 R8 groups], C3-7cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), cyano(Cι-4)alkyl, phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 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, -COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, C1_4alkoxy, Cι-4alkoxyCι- alkyl, - 4alkoxyCι-4alkoxy, hydroxyCι-4alkoxy, Cι-4alkyl, amino(Cι-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy(Cι-4)alkyl, dihydroxy(C1-4)alkyl, -CO2Cι- alkyl, aryl and aryl(Cι-4)alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C1. )alkyl, dihalo(Cι- )alkyl, trihalo(C1- )alkyl, hydroxy(C1-4)alkyl, dihydroxy(Cι-4)alkyl, cyano(Cι- )alkyl, heterocyclyl, heterocyclylCι-4alkyl, aryl, Ci-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), Cι-4alkylS(O)c(Ci-4)alkyl (wherein c is 0, 1 or 2), - CH2CH(NR9R10)CO(NR9,R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -
CH2OCOR9;
R9 , R9' , R10 and R10' are independently selected from hydrogen, Cι- alkyl (optionally substituted by 1 or 2 R13), C3-7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups), -C(=O)OtBu, C2-4alkenyl, cyano(Cι-4)alkyl and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or
R9 and R10 together with the nitrogen to which they are attached, and/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 and Cι-4alkoxy; or the ring may be optionally substituted on two adjacent carbons by -O-CH -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 halo, trihalomethyl and Cι.4alkoxy.
In a further aspect of the invention R2 and R3 are independently selected from hydrogen, Cι-4alkyl [optionally substituted by 1 or 2 R groups], C3-7cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), -COR8 and -SObR8 (wherein b is 0, 1 or 2); R8 is independently selected from hydrogen, hydroxy, C1.4alkoxy, Cι-4alkoxyC1-4alkyl, Ci- alkoxyCι- alkoxy, hydroxyC1-4alkoxy, Cι-4alkyl, amino(Cι-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C1-4alkyl, hydroxy(C1-4)alkyl, dihydroxy(C1-4)alkyl, -CO Cι-4alkyl, aryl and aryl(Cι-4)alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OCi-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C1-4)alkyl, dihalo(Ci-4)alkyl, trihalo(Cι-4)alkyl, hydroxy(C1-4)alkyl, dihydroxy(Cι- )alkyl, cyano(Cι- )alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and C1.4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, 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), Cι-4alkylS(O)c(Cι-4)alkyl (wherein c is 0, 1 or 2), -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9,
(R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -
CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and
-CH2OCOR9; R9 , R9' , R10 and R10' are independently selected from hydrogen, Cι- alkyl (optionally substituted by 1 or 2 R13), -C(=O)OtBu, C2- alkenyl, cyano(Cι-4)alkyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or
R9 and R10 together with the nitrogen to which they are attached, and/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 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; R13 is selected from halo, trihalomethyl and Cι-4alkoxy.
In another aspect of the invention R2 and R3 are independently selected from hydrogen, Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and -SObR8 (wherein b is 0, 1 or
2);
R8 is independently selected from hydrogen, hydroxy, Cι- alkoxy, Cι-4alkoxyCι-4alkyl, - alkyl, amino(C1-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Ci- alkyl, hydroxy(Cι- )alkyl, dihydroxy(Cι-4)alkyl, -CO2Cι- alkyl, phenyl and aryl(Cι-4)alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OC1-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι. )alkyl, trihalo(Cι-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι- )alkyl, cyano(Cι-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Ci- 4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, 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 -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -
CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9;
R9 , R9' , R10 and R10' are independently selected from hydrogen, Cι.4alkyl (optionally substituted by 1 or 2 hydroxy groups), C2.4alkenyl, and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano).
In one aspect, one of R9 and R10 is hydrogen and the other is selected from heterocyclyl and heterocyclyl(Cι-4alkyl). Conveniently R9 or R10 as heterocyclyl and heterocyclyl(d-
4alkyl) 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-4alkyl, Cι-4alkoxy and Ci- 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- alkyl)amino and N,N-(C1- alkyl)2amino, and/or wherein any heterocyclic 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).
In another aspect of the invention R2 is selected from hydrogen, acetyl and Cι-4alkyl. In a further aspect of the invention, Y is ΝR2R3 and NR2R3 forms a 4 to 7 membered saturated, partially saturated or unsaturated ring, optionally containing 1, 2 or 3 additional heteroatoms independently selected from N, O and S, wherein any -CH2- may optionally be replaced by -C(=O)-, and any N or S atom may optionally be oxidised to form an N-oxide or SO or SO2 group respectively, and wherein the ring is optionally substituted by 1 or 2 substituents independently selected from halo, cyano, Cι-4alkyl, hydroxy, Cι- alkoxy and Cι- alkylS(O)b- (wherein b is 0, 1 or 2). Suitable values for NR2R3 as a 4 to 7 membered ring are morpholino, 2,5- dioxomorpholino, piperidinyl, pyrrolidinyl, pyrazolyl, pyrrolyl, imidazolyl, piperazinyl and thiomorpholinyl.
In yet a further aspect of the inventions R3 is selected from hydrogen, 1,3- dihydroxyisopropyl, 1,2-dihydroxypropyl, cyanomethyl, trifluoromethylcarbonyl, carboxyacetyl, carboxymethyl, formyl, acetyl, carbamoylacetyl, carbamoylmethyl, methoxyacetyl, methoxypropanoyl, acetoxyacetyl, methanesulfonyl, chloromethylsulfonyl, trifluoromethylsulfonyl, morpholinomethylcarbonyl, furylcarbonyl, thienylcarbonyl, nitrofurylcarbonyl, N,N-dimethylcarbamoyl, 4-methylpiperazinocarbonyl, N-ethylcarbamoyl, N-allylcarbamoyl, N-dinitrophenylcarbamoyl, pyridinylcarbonyl, tetrahydrofuran-2-on-5- ylcarbonyl, hydroxyphenylcarbonyl, acryloyl, 2-(tert-butoxycarbonyl)methylcarbonyl, aminoacetyl, 1-amino-l-carboxypropanoyl, chloroacetyl, hydroxyacetyl, carbamoylacetyl, carbamoylmethyl, methoxyacetyl, methoxypropanoyl, acetoxyacetyl, hydroxypiperidinoaminoacetyl, hydroxypyrrolidinylaminoacetyl, N-methyl-N- hydroxyethylaminoacetyl, N-benzyl-N-hydroxyethylaminoacetyl, N-(2,3-dihydroxypropyl)-N- methylaminoacetyl, N,N-bis(hydroxyethyl)aminoacetyl, N,N-bis(hydroxypropyl)aminoacetyl, (l-amino-l-carbonylamino)ethylcarbonyl, 1-hydroxy-l-carboxyethylcarbonyl, tert- butoxycarbonylmethyl, l,3-dihydroxyisoprop-2-ylcarbonyl, l-(tert-butoxycarbonylamino)-l- (carbamoyl)propanoyl, N-ethyl-N-(2-hydroxyethyl)aminoacetyl, thienylmethyl, tetrazolylmethyl, [2-(ethoxycarbonyl)cyclopropyl]methyl, N-(tert-butoxycarbonyl)aminoacetyl and N-(aminocarbonyl)-N-(tert-butoxycarbonyl)aminoacetyl.
In yet a further aspect of the inventions R3 is selected from trifluoromethylcarbonyl, carboxyacetyl, formyl, acetyl, , methanesulfonyl, morpholinomethylcarbonyl, furylcarbonyl, thienylcarbonyl, nitrofurylcarbonyl, N,N-dimethylcarbamoyl, 4-methylpiperazinocarbonyl, N- ethylcarbamoyl, N-allylcarbamoyl, N-dinitrophenylcarbamoyl, pyridinylcarbonyl, tetrahydrofuran-2-on-5-ylcarbonyl, hydroxyphenylcarbonyl, acryloyl, 2-(tert- butoxycarbonyl)methylcarbonyl, aminoacetyl, 1-amino-l-carboxypropanoyl, chloroacetyl, hydroxyacetyl, carbamoylacetyl, carbamoylmethyl, methoxyacetyl, methoxypropanoyl, acetoxyacetyl, N-methyl-N-hydroxyethylaminoacetyl, N-benzyl-N-hyciroxyethylaminoacetyl, N-(2,3-dihydroxypropyl)-N-methylaminoacetyl, N,N-bis(hydroxyethyl)aminoacetyl, N,N- bis(hydroxyproρyl)aminoacetyl, (l-amino-l-carbonylamino)ethylcarbonyl, 1-hydroxy-l- carboxyethylcarbonyl, tert-butoxycarbonylmethyl, l,3-dihydroxyisoprop-2-ylcarbonyl, l-(tert- butoxycarbonylamino)-l-(carbamoyl)propanoyl andN-ethyl-N-(2-hydroxyethyl)aminoacetyl. A preferred class of compound is of the formula (1) wherein; Z is CH;
R4 and R5 are together -S-C(R6)=C(R7)-; R6 is halo or hydrogen;
R7 is halo or hydrogen; 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 1 or 2;
Y is -NR2R3 or -OR3;
R2 and R3 are independently selected from hydrogen, Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], C3- cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 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, 1,2,4-oxadiazolyl, tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, -COR and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι- alkoxy, C1-4alkoxyC1-4alkyl, Cι-4alkoxyCi-4alkoxy, hydroxyCι-4alkoxy, Cι-4alkyl, amino(Cι- )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι- alkyl, hydroxy(Cι- )alkyl, dihydroxy(C1-4)alkyl, -CO2Cι.4alkyl, aryl and aryl(Cι- )alkyl], C2-4alkenyl, C3- cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, dihalo(Cι- )alkyl, trihalo(C1-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(C1- )alkyl, cyano(C1-4)alkyl, heterocyclyl, heterocycιylCι-4alkyl, aryl, Cι- alkylS(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), C1-4alkylS(O)c(C1-4)alkyl (wherein c is 0, 1 or 2), - CH2CH(NR R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 ,
-C(O)N(R9)(R10), -CH2CH(CO2R9)OH,
-CH2CONR9R10, -CH2CH(NR9R10)CO2R9: and -CH2OCOR9;
R9 , R9' , R10 and R10' are independently selected from hydrogen, Cι. alkyl (optionally substituted by 1 or 2 R13), C3-7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups),
-C(=O)OtBu, C . alkenyl, cyano(Cι- )alkyl and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or
R9 and R10 together with the nitrogen to which they are attached, and/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 and C1. 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;
R13 is selected from halo, trihalomethyl and Cι- alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2,3-mchloro-5-(N-{ l-[N-(l,l-dimethylethoxy)carbonyl--mino]indan-2- yl}carbamoyl)-4H-thieno[3,2-b]pyrrole; ii) 5-[N-(l-aminoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iii) 5-[N-(l-acetamidoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3 ,2-b]pyrrole iv) 2,3-dichloro-5-{N-[l-(methanesulphonamido)indan-2-yl]carbamoyl}-4H- thieno[3,2-b]pyrrole v) 2,3-dichloro-5-{N-[l-(methylamino)indan-2-yl]carbamoyl}-4H-thieno[3,2- b]pyrrole; vi) 2,3-dichloro-5-{N-[l-(methylacetamido)indan-2-yl]carbamoyl}-4H-thieno[3,2- bjpyrrole; vii) 2,3-dichloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole; viii) 2,3-dichloro-5 - [N-(6-fluoro- 1 -hydroxyindan-2-yl)carbamoyl-4H-thieno [3,2- b]pyrrole; ix) 2,3-dichloro-5-[N-(l-methoxyindan-2-yl)carbamoyl-4H-thieno[3,2-b]pyrrole x) 2,3-dichloro-5-[Ν-(l-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)carbamoyl]-4H- thieno[3 ,2-b]pyrrole. Another preferred class of compounds is of formula (1) wherein:
Z is CH;
R4 and R5 are together -C(R7)=C(R6)-S-;
R6 is chloro; R7 is hydrogen;
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 1 or 2;
Y is -NR2R3 or -OR3;
R2 and R3 are independently selected from hydrogen, C1.4alkyl [optionally substituted by 1 or 2 R8 groups], C3. cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 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, -COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, C1- alkoxy, Cι-4alkoxyCι-4alkyl, Cι-4alkoxyCι-4alkoxy, hydroxyCi-4alkoxy, Cι-4alkyl, amino(Cι-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy(C1-4)alkyl, dihydroxy(Cι-4)alkyl, -CO Cι-4alkyl, aryl and aryl(Cι-4)alkyl], C2- alkenyl, C -7cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι- )alkyl, dihalo(C1- )alkyl, trihalo(C1-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(C1-4)alkyl, cyano(C1-4)alkyl, heterocyclyl, heterocyclylCι-4alkyl, aryl, Cι- alkylS(O)b- (wherein b is 0, 1 or 2), C3.6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O) - (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), C1.4alkylS(O)c(Cι-4)alkyl (wherein c is 0, 1 or 2), - CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, ~CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9;
R9, R9', R10 and R10' are independently selected from hydrogen, C1. alkyl (optionally substituted by 1 or 2 R13), C3.7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups),
-C(=O)OlBu, C2. alkenyl, cyano(Cι- )alkyl and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or
R9 and R10 together with the nitrogen to which they are attached, and/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 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;
R13 is selected from halo, trihalomethyl and C1-4alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2-chloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl-6H-thieno[2,3-b]pyrrole;
Another preferred class of compound is of the formula (1) wherein: Z is CΗ;
R4 and R5 are together -S-C(R6)=C(R7)-; R6 is chloro;
R7 is hydrogen or chloro; 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 1 or 2; Y is -ΝR2R3;
R2 and R3 are independently selected from hydrogen, Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, C1- alkoxy, Cι- alkoxyCι- alkyl, Cι-4alkoxyCι-4alkoxy, hydroxyCι-4alkoxy, Cι.4alkyl, amino(Cι-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι- alkyl, hydroxy(C1-4)alkyl, dihydroxy(C1- )alkyl, -CO2Cι-4alkyl, aryl and aryl(Cι-4)alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by
-C(O)OCι-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, dihalo(Cι-4)alkyl, trihalo(Cι-4)alkyl, hydroxy(Cι.4)alkyl,
(ϋhydroxy(Cι--t)alkyl, cyano(Cι-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(C1-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι- )alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups),
1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and C1.4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, Cι- 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), benzylS(O)b- (wherein b is 0, 1 or 2),
Cι-4alkylS(O)c(Cι-4)alkyl (wherein c is 0, 1 or 2), -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -
CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and
-CH2OCOR9;
R9 , R9 , R10 and R10 are independently selected from hydrogen, Cι-4alkyl (optionally substituted by 1 or 2 R13), -C(=O)OlBu, C -4alkenyl, cyano(Cι-4)alkyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano);
R13 is selected from halo, trihalomethyl and Cι-4alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2,3-dichloro-5-(N-{l-[N-(l,l-dimethylethoxy)carbonylamino]indan-2- yl}carbamoyl)-4H-thieno[3,2-b]pyrrole; ii) 5-[N-(l-aminoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iii) 5-[N-(l-acetamidoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iv) 2,3-dichloro-5-{N-[l-(methanesulphonamido)indan-2-yl]carbamoyl}-4H- thieno [3 ,2-b]pyrrole v) 2,3-cnchloro-5-{N-[l-(methylamino)indan-2-yl]carbamoyl}-4H-thieno[3,2- b]pyrrole; vi) 2,3-dichloro-5-{N-[l-(methylacetamido)indan-2-yl]carbamoyl}-4H-thieno[3,2- b]pyrrole. Another preferred class of compound is of the formula (1) wherein:
Z is CH;
R4 and R5 are together -S-C(R6)=C(R7)-; R6 is hydrogen or halo;
R is hydrogen or halo;
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 1 or 2;
Y is -OR3;
R3 is selected from hydrogen, Ci-4alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and -SO R8 (wherein b is 0, 1 or 2); wherein R8 is independently selected from hydrogen, hydroxy, Cι- alkoxy, Cι-4alkoxyCι-4alkyl, C1- alkoxyCι-4alkoxy, hydroxyC1- alkoxy, C1-4alkyl, amino(Cι- )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι- alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι-4)alkyl, -CO2C1-4alkyl, aryl and aryl(Cι-4)alkyl], C2- alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, dihalo(C1-4)alkyl, trihalo(Ci-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(C1-4)alkyl, cyano(C1-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι- )alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι- alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, Ci-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), Cι- alkylS(O)c(C1-4)alkyl (wherein c is 0, 1 or 2), -CH2CH(NR9R10)CO(NR9,R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -
CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and
-CH2OCOR9;
R9, R9' R10 and R10' are independently selected from hydrogen, Cι-4alkyl (optionally substituted by 1 or 2 R13), -C(=O)OlBu, C2.4alkenyl, cyano(C1.4)alkyl and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); R13 is selected from halo, trihalomethyl and Cι.4alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2,3-dichloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole; ii) 2,3-dichloro-5-[N-(6-fluoro-l-hydroxyindan-2-yl)carbamoyl-4H-thieno[3,2- b]pyrrole; iii) 2,3-dichloro-5-[N-(l-methoxyindan-2-yl)carbamoyl-4H-thieno[3,2-b]pyrrole iv) 2,3-dichloro-5-[Ν-(l-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)carbamoyl]-4H- thieno[3,2-b]pyrrole.
A further preferred class of compound is of the formula (1) wherein; Z is CΗ;
R4 and R5 are together -C(R7)=C(R6)-S-; R6 is halo;
R7 is hydrogen; 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 1 or 2; Y is -NR2R3;
R2 and R3 are independently selected from hydrogen, Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι-4alkoxy, Cι-4alkoxyCι- alkyl, Cι-4alkoxyCι-4alkoxy, hydroxyCι-4alkoxy, Cι-4alkyl, amino(Cι- )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C1- alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι-4)alkyl, -CO2Cι- alkyl, aryl and aryl(Cι-4)alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by
-C(O)OCι- alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, dihalo(Cι- )alkyl, trihalo(C1-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι-4)alkyl, cyano(C1-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Ci-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups),
1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι- alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, 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), Cι-4alkylS(O)c(Cι-4)alkyl (wherein c is 0, 1 or 2), -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, - CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9;
R9, R9', R10 and R10' are independently selected from hydrogen, Cι-4alkyl (optionally substituted by 1 or 2 R13), -C(=O)OlBu, C2.4alkenyl, cyano(Cι-4)alkyl and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); R13 is selected from halo, trihalomethyl and Cι-4alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
Another preferred class of compound is of the formula (1) wherein: Z is CH;
R4 and R5 are together -C(R7)=C(R6)-S-;
R6 is hydrogen or halo;
R7 is hydrogen or halo;
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 1 or 2;
Y is -OR3;
R is selected from hydrogen, C1.4alkyl [optionally substituted by 1 or 2 R groups], -COR8 and -SObR8 (wherein b is 0, 1 or 2); R8 is independently selected from hydrogen, hydroxy, Cι.4alkoxy, Cι-4aιkoxyCι-4alkyl,
Cι- alkoxyCι- alkoxy, hydroxyCι- alkoxy, Cι-4alkyl, amino(Cι- )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C1-4alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι-4)alkyl, -CO2Cι- alkyl, aryl and aryl(Cι-4)alkyl], C -4alkenyl, C3- cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, dihalo(C1-4)alkyl, trihalo(C1-4)alkyl, hydroxy(C1-4)alkyl, dihydroxy(Cι-4)alkyl, cyano(C1-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι- )alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι-4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, 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),
Ci-4alkylS(O)c(Ci-4)alkyl (wherein c is 0, 1 or 2), -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, - CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9; R9 , R9 , R10 and R10' are independently selected from hydrogen, Cι- alkyl (optionally substituted by 1 or 2 R13), -C(=O)OtBu, C2.4alkenyl, cyano(Cι. )alkyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; provided that the compound of formula (1) is not: 2-chloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl-6H-thieno[2,3-b]pyrrole. A further preferred class of compound is of the formula (1) wherein;
Z is CH;
R4 and R5 are together -C(R7)=C(R6)-S-; R6 is halo;
R7 is hydrogen; A is phenylene; n is O r is 1; Y is -NR2R3;
R2 is hydrogen or Cι-4alkyl;
R3 is selected from Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, C1-4alkoxy, C1-4alkoxyC1-4alkyl, C1- alkyl, amino(Cι-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι- alkyl, hydroxy(Cι-4)alkyl, ch^ydroxy(Cι- )alkyl, -CO2Cι-4alkyl, phenyl and aryl(Cι- )alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OC1-4alkyl), 5- and 6- membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, trihalo(Cι-4)alkyl, hydroxy(C1-4)alkyl, dihydroxy(C1-4)alkyl, cyano(Cι-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι- alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, C1.4alkylS(O)b- (wherein b is 0, 1 or 2), C3.6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O) - (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2 -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, - CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9; R9, R9 , R10 and R10' are independently selected from hydrogen, Cι-4alkyl (optionally substituted by 1 or 2 hydroxy groups), C2-4alkenyl, and phenyl (optionally substituted by 1 or
2 groups selected from nitro, halo, hydroxy and cyano); or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. A further preferred class of compound is of the formula (1) wherein;
Z is CH;
R4 and R5 are together -S-C(R6)=C(R7)-;
R6 is halo;
R7 is hydrogen; A is phenylene; n is O; r is 1;
Y is -NR2R3;
R2 is hydrogen or Cι-4alkyl; R3 is selected from Cι- alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and
-SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι-4alkoxy, C1-4alkoxyC1-4alkyl, Cι-4alkyl, amino(Cι-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy(Cι-4)alkyl, dihydroxy(C1-4)alkyl, -CO2Cι- alkyl, phenyl and aryl(Cι- 4)alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6- membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, trihalo(Cι- )alkyl, hydroxy(C1-4)alkyl, dihydroxy(Ci-4)alkyl, cyano(Cι-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι-4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, 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 -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and-CH2OCOR9; R9 , R9' , R10 and R10' are independently selected from hydrogen, C1-4alkyl (optionally substituted by 1 or 2 hydroxy groups), C2-4alkenyl, and phenyl (optionally substituted by 1 or
2 groups selected from nitro, halo, hydroxy and cyano); or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; provided that the compound of formula (1) is not:
(i) 2,3-dichloro-5-(N-{l-[N-(l,l-dimethylethoxy)carbonylamino]indan-2- yl } carbamoyl)-4H-thieno [3 ,2-b]pyrrole;
(ii) 5-[N-(l---minoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole
(iii) 5-[N-(l-acetamidoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole (iv) 2,3-dichloro-5-{N-[l-(methanesulphonamido)indan-2-yl]carbamoyl}-4H- thieno [3 ,2-b]pyrrole
(v) 2,3-dichloro-5-{N-[l-(methylamino)indan-2-yl]carbamoyl}-4H-thieno[3,2- b]pyrrole;
(vi) 2,3-dichloro-5-{N-[l-(methylacetamido)indan-2-yl]carbamoyl}-4H-thieno[3,2- b]pyrrole;
A preferred class of compound is of the formula (1) wherein;
Z is nitrogen;
R4 and R5 are together -S-C(R6)=C(R7)-; R6 is halo or hydrogen;
R7 is halo or hydrogen;
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; ris 1 or 2;
Y is -ΝR2R3 or -OR3;
R2 and R3 are independently selected from hydrogen, C1.4alkyl [optionally substituted by 1 or 2 R8 groups], C3.7cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 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, -COR and -SObR8 (wherein b is 0, 1 or 2); R8 is independently selected from hydrogen, hydroxy, Cι- alkoxy, Cι-4alkoxyCι-4alkyl,
Cι- alkoxyCι- alkoxy, hydroxyC1- alkoxy, Cι-4alkyl, amino(Cι. )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy(Ci-4)alkyl, dihydroxy(C1-4)alkyl, -CO2C1-4alkyl, aryl and aryl(Cι-4)alkyl], C -4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OC1- alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C1.4)alkyl, dihalo(Cι- )alkyl, trihalo(Cι- )alkyl, hydroxy(Cι-4)alkyl, dihydroxy(C1-4)alkyl, cyano(Ci-4)alkyl, heterocyclyl, heterocyclylC1-4alkyl, aryl, 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), Cι- alkylS(O)c(C1-4)alkyl (wherein c is 0, 1 or 2), - CH2CH(NR9R10)CO(NR9 R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9;
R9 , R9' , R10 and R10' are independently selected from hydrogen, Cι- alkyl (optionally substituted by 1 or 2 R13), C3-7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups), -C(=O)OtBu, C2-4alkenyl, cyano(C1-4)alkyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or
R9 and R10 together with the nitrogen to which they are attached, and/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 and Cι- 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 selected from halo, trihalomethyl and Cι-4alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not:
(i) 2,3-dichloro-5-(N-{l-[N-(l,l-dimethylethoxy)carbonylamino]indan-2- yl}carbamoyl)-4H-thieno[3,2-b]pyrrole; (ii) 5-[N-(l-aminoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole (iii) 5-[N-(l-acetamidoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole
(iv) 2,3-dichloro-5-{N-[l-(methanesulphonamido)indan-2-yl]carbamoyl}-4H- thieno[3,2-b]pyrrole (v) 2,3-dichloro-5-{N-[l-(methylamino)indan-2-yl]carbamoyl}-4H-thieno[3,2- b]pyrrole;
(vi) 2,3 -dichloro-5 - { N- [ 1 -(methylacetamido)indan-2-yl]carbamoyl } -4H-thieno [3 ,2- b]pyrrole; (vii) 2,3-dichloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole; (viii) 2,3-dichloro-5-[N-(6-fluoro-l-hydroxyindan-2-yl)carbamoyl-4H-thieno[3,2- b]pyrrole;
(ix) 2,3-dichloro-5-[N-(l-methoxyindan-2-yl)carbamoyl-4H-thieno[3,2-b]pyrrole (x) 2,3-dichloro-5-[Ν-(l-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)carbamoyl]-4H- thieno[3 ,2-b]pyrrole.
Another preferred class of compounds is of formula (1) wherein: Z is nitrogen;
R4 and R5 are together -C(R7)=C(R6)-S-; R6 is chloro; R7 is hydrogen;
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 1 or 2;
Y is -NR2R3 or -OR3;
R2 and R3 are independently selected from hydrogen, C1.4alkyl [optionally substituted by 1 or 2 R8 groups], C3.7cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 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, o tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, -COR and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Ci.-ialkoxy, Cι-4alkoxyCι-4alkyl, -4alkoxyCι- alkoxy, hydroxyC1-4alkoxy, C1-4alkyl, amino(Cι-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy(C1-4)alkyl, dihydroxy(Cι- )alkyl, -CO2Cι-4alkyl, aryl and aryl(Cι-4)alkyl], C -4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C1-4)alkyl, dihalo(Ci-4)alkyl, trihalo(Cι-4)alkyl, hydroxy(C1-4)alkyl, dihydroxy(C1-4)alkyl, cyano(C1- )alkyl, heterocyclyl, heterocyclylC1-4alkyl, aryl,
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), C1-4alkylS(O)c(C1-4)alkyl (wherein c is 0, 1 or 2), - CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH,
-CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9;
R9 , R9 , R10 and R10 are independently selected from hydrogen, Cι-4alkyl (optionally substituted by 1 or 2 R13), C3-7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups), -C(=O)OlBu, C2.4alkenyl, cyano(Cι-4)alkyl and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or
R9 and R10 together with the nitrogen to which they are attached, and/or R9 and R 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 and C1-4alkoxy; 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;
R13 is selected from halo, trihalomethyl, and
Figure imgf000040_0001
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: ii) 2-chloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl-6H-thieno[2,3-b]pyrrole;
Another preferred class of compound is of the formula (1) wherein: Z is nitrogen; R4 and R5 are together -S-C(R6)=C(R7)-;
R6 is chloro;
R7 is hydrogen or chloro;
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 1 or 2; Y is -NR2R3;
R2 and R3 are independently selected from hydrogen, Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι-4alkoxy, Cι- alkoxyCι-4alkyl, Cι-4alkoxyC1-4alkoxy, hydroxyCι-4alkoxy, Cι-4alkyl, amino(C1-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy(C1- )alkyl, dihydroxy(Cι- )alkyl, -CO2Cχ-4alkyl, aryl and aryl(Cι-4)alkyl], C2-4alkenyl, C3- cycloalkyl (optionally substituted by -C(O)OCi-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, dihalo(Cι-4)alkyl, trihalo(C1-4)alkyl, hydroxy(Ci-4)alkyl, dihydroxy(Cι-4)alkyl, cyano(Cι- )alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι-4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, Cι-4alkylS(O)b- (wherein b is 0, 1 or 2), C3-6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O) - (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), Cι-4alkylS(O)c(Cι-4)alkyl (wherein c is 0, 1 or 2), -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, - CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9; R9 , R9' , R10 and R10' are independently selected from hydrogen, Cι-4alkyl (optionally substituted by 1 or 2 R13), -C(=O)OlBu, C2.4alkenyl, cyano(Cι-4)alkyl and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano);
R13 is selected from halo, trihalomethyl, and C1-4alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
Another preferred class of compound is of the formula (1) wherein:
Z is nitrogen ;
R4 and R5 are together -S-C(R6)=C(R7)-; R6 is hydrogen or halo;
R7 is hydrogen or halo;
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 1 or 2;
Y is -OR3;
R3 is selected from hydrogen, Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι-4alkoxy, C1-4alkoxyC1-4alkyl, Cι-4alkoxyCι- alkoxy, hydroxyC1-4alkoxy, Cι-4alkyl, amino(C1-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C1-4alkyl, hydroxy(Cι. )alkyl, dihydroxy(C1- )alkyl, -CO Cι-4alkyl, aryl and aryl(Cι-4)alkyl], C2-4alkenyl, C3- cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, dihalo(Cι-4)alkyl, trihalo(Cχ- )alkyl, hydroxy(Cι- )alkyl, dihydroxy(Cι-4)alkyl, cyano(Cι-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι- )alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι--t)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι-4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, Cι- alkylS(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),
C1-4alkylS(O)c(C1-4)alkyl (wherein c is 0, 1 or 2), -CH2CH(NR R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -
CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and
-CH2OCOR9;
R9 , R9' , R10 and R10 are independently selected from hydrogen, Cι-4alkyl (optionally substituted by 1 or 2 R13), -C(=O)OtBu, C2.4alkenyl, cyano(C1. )alkyl and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano);
R13 is selected from halo, trihalomethyl, and C1.4alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further preferred class of compound is of the formula (1) wherein; Z is nitrogen;
R4 and R5 are together -C(R7)=C(R6)-S-;
R6 is halo;
R7 is hydrogen;
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 1 or 2; Y is -NR2R3;
R2 and R3 are independently selected from hydrogen, Cι- alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι- alkoxy, C1-4alkoxyCι- alkyl, Cι.4alkoxyCι-4alkoxy, hydroxyC -talkoxy, Cι- alkyl, amino(C1- )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι- alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι-4)alkyl, -CO2Ci-4alkyl, aryl and aryl(Cι- )alkyl], C2- alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OCι-4alkyι), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C1-4)alkyl, dihalo(C1- )alkyl, trihalo(Cι- )alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι- )alkyl, cyano(C1- )alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Ci-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and -4-ukyl), pyrazinyl, piperazinyl, 4-methylpiperazino, Cι. alkylS(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),
C1.4alkylS(O)c(C1-4)alkyl (wherein c is 0, 1 or 2), -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9,
(R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -
CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and
-CH2OCOR9; R9 , R9 , R10 and R10 are independently selected from hydrogen, Cι- alkyl (optionally substituted by 1 or 2 R13), -C(=O)OlBu, C2-4alkenyl, cyano(C1-4)alkyl and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano);
R13 is selected from halo, trihalomethyl, and Cι-4alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
Another preferred class of compound is of the formula (1) wherein:
Z is nitrogen;
R4 and R5 are together -C(R7)=C(R6)-S-;
R6 is hydrogen or halo; R7 is hydrogen or halo;
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 1 or 2;
Y is -OR3; R3 is selected from hydrogen, Cι-4alkyl [optionally substituted by 1 or 2 R8 groups],
-COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι- alkoxy, C1- alkoxyCι-4alkyl,
Cι-4alkoxyC1-4alkoxy, hydroxyCι-4alkoxy, C1-4alkyl, amino(Cι-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy(Cι-4)alkyl, chhydroxy(Cι- )alkyl,
-CO2Cι-4alkyl, aryl and aryl(Cι-4)alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by
-C(O)OCι- alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, dihalo(Cι-4)alkyl, trihalo(C1-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι- )alkyl, cyano(C1- )alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι-4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, 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), benzylS(O)b- (wherein b is 0, 1 or 2), Cι-4alkylS(O)c(Cι-4)alkyl (wherein c is 0, 1 or 2), -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, - CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9;
R9, R9 , R10 and R10 are independently selected from hydrogen, C1. alkyl (optionally substituted by 1 or 2 R13), -C(=O)O'Bu, C2-4alkenyl, cyano(C1-4)alkyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); R13 is selected from halo, trihalomethyl, and C1-4alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof;
A further preferred class of compound is of the formula (1) wherein; Z is nitrogen;
R4 and R5 are together -C(R7)=C(R6)-S-;
R6 is halo;
R7 is hydrogen; A is phenylene; n is O; r is 1;
Y is -NR2R3; R2 is hydrogen or Cι-4alkyl;
R3 is selected from Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and - SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι-4alkoxy, C1-4alkoxyC1-4alkyl, Cι- alkyl, amino(C1- )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι- alkyl, hydroxy(C1-4)alkyl, dihydroxy(C1-4)alkyl, -CO2Ci-4alkyl, phenyl and aryl(Cι- )alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OC1-4alkyl), 5- and 6- membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι. )alkyl, trihalo(Cι-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(C1. )alkyl, cyano(Cι-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(C1-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(C1-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι- alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, C1.4alkylS(O)b- (wherein b is 0, 1 or 2), C3-6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O) - (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2 -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R )(R10), -CH2CH(CO2R9)OH, - CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9; R9, R9 , R10 and R10' are independently selected from hydrogen, Cι-4alkyl (optionally substituted by 1 or 2 hydroxy groups), C2-4alkenyl, and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further preferred class of compound is of the formula (1) wherein; Z is nitrogen;
R4 and R5 are together -S-C(R6)=C(R7)-; R6 is halo; R7 is hydrogen;
A is phenylene; n is O r is 1; Y is -NR2R3;
R2 is hydrogen or Cι-4alkyl;
R3 is selected from C1- alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and - SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι.4alkoxy, Cι-4alkoxyCι-4alkyl, Cι-4alkyl, amino(Cι- )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι- )alkyl, -CO2C1-4alkyl, phenyl and aryl(Cι- 4)alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OC1-4alkyl), 5- and 6- membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι.4)alkyl, trihalo(Cι- )alkyl, hydroxy(C1-4)alkyl, dihydroxy(Cι-4)alkyl, cyano(Cι-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι.4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι-4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, Cι-4alkylS(O)b- (wherein b is 0, 1 or 2), C3-6cycloalkylS(O)b- (wherein b is 0, 1 or 2), arylS(O) - (wherein b is 0, 1 or 2), heterocyclylS(O)b- (wherein b is 0, 1 or 2 -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and-CH2OCOR9;
R9, R9' , R10 and R10 are independently selected from hydrogen, Cι- alkyl (optionally substituted by 1 or 2 hydroxy groups), C2- alkenyl, and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
In a further preferred aspect of the invention is provided a compound of the formula (1A):
Figure imgf000048_0001
(1A) wherein Z is CH;
R4 and R5 are together -S-C(R6)=C(R7)- or -C(R7)=C(R6)-S-; R6 is hydrogen or halo;
R is hydrogen or halo; 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;
Y is -NR2R3 or OR3; R2 is hydrogen or Cι-4alkyl;
R3 is selected from Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι-4alkoxy, Cι-4alkoxyCι-4alkyl, Ci- alkyl, amino(C1-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy(Cι- )alkyl, dihydroxy(Cι-4)alkyl, -CO2Cι- alkyl, phenyl and aryl(Cι- )alkyl], C2- alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6- membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, trihalo(Cι- )alkyl, hydroxy(C1- )alkyl, dihydroxy(C1-4)alkyl, cyano(Ci-4)alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(C1-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, 1-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι-4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, 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 -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -
CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9;
R9, R9' , R10 and R10' are independently selected from hydrogen, Cι-4alkyl (optionally substituted by 1 or 2 hydroxy groups), C2-4alkenyl, and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A further preferred class of compound is of the formula (1) wherein;
Z is CH;
R4 and R5 are together -S-C(R6)=C(R7)- or -C(R7)=C(R6)-S-; R is halo or hydrogen;
R7 is halo or hydrogen;
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; r is 1 or 2;
Y is -NR2R3 or -OR3;
R2 and R3 are independently selected from hydrogen, Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], C3- cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 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, -COR8 and -SObR8 (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι-4alkoxy, Cι-4alkoxyCι-4alkyl, Cι- alkoxyCι-4alkoxy, hydroxyC1.4alkoxy, Cι-4alkyl, amino(Cι- )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι- alkyl, hydroxy(Cι-4)alkyl, dihydroxy(C1- )alkyl, -CO2Cι.4alkyl, aryl and aryl(Cι-4)alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(C1-4)alkyl, dihalo(C1-4)alkyl, trihalo(Cι-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι-4)alkyl, cyano(Cι-4)alkyl, heterocyclyl, heterocyclylCi-4alkyl, aryl,
Cι- alkylS(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), Cι-4alkylS(O)c(C1.4)alkyl (wherein c is 0, 1 or 2), - CH2CH(NR9R10)CO(NR9,R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 ,
-C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and-
CH2OCOR9;
R9, R9 , R10 and R10 are independently selected from hydrogen, Cι-4alkyl (optionally substituted by 1 or 2 R13), C3-7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups), -C(=O)OlBu, C2.4alkenyl, cyano(Ci-4)alkyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or
R9 and R10 together with the nitrogen to which they are attached, and/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 andCι-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;
R13 is selected from halo, trihalomethyl, and Cι-4alkoxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
A preferred class of compound is of the formula (1) wherein;
Z is CH;
R4 and R5 are together -S-C(R6)=C(R7)-;
R6 is halo or hydrogen; R7 is halo or hydrogen;
A is phenylene; n is 1 or 2; R1 is independently selected from hydrogen, halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-4alkoxy and and R1 is of the formula A' or A" :
Figure imgf000051_0001
-CH2CH(OH)(CH2)uCO2H (A') herein x is 0 or 1, p 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; r is 1 or 2; Y is -NR2R3 or -OR3;
R and R 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), Cs- 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(Cι-4)alkyl, fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, Cι-4alkyl [substituted by 1 or 2 R8 groups (provided that when there are 2 R groups they are not substituents on the same carbon)], -COR and -SObR (wherein b is 0, 1 or 2);
{wherein R8 is independently selected from hydrogen, hydroxy, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, morpholino, pyridyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι-4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, Cι-4alkyl, C2-4alkenyl, cyclo(C3-8)alkyl, Cι-4alkoxy, cyano(C1-4)alkyl, amino(Cι- )alkyl (optionally substituted on nitrogen by 1 or 2 groups selected from hydrogen, Cι-4alkyl, hydroxy, hydroxy(Cι-4)alkyl, dihydroxy(C1-4)alkyl, aryl and aryl(Cι-4)alkyl), C1-4alkylS(O)c(Cι- )alkyl (wherein c is 0, 1 or 2), -CH2CH(CO2R9)N(R9R10), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , - CH2CONR9R10, and -CH2CH2CH(NR9R10)CO2R9;
[wherein R9 and R10 are independently selected from hydrogen, 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), C2-4alkenyl, cyano(Cι-4)alkyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano) and C1-4alkyl substituted by R13;
(wherein R13 is selected from C1-4alkoxy, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Ci-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι.4alkyl), pyrazinyl, piperazinyl,
C1-4alkylS(O)d(C1-4)alkyl (wherein d 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-Cι- 4alkylamino, N,N-(Cι-4)2alkylamino, carbonyl, sulfo, Cι- alkoxy, heterocyclyl, Cι-4alkanoyl, and Ci-4alkylS(O)f(Cι-4)alkyl (wherein f is 0, 1 or 2)]}; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2,3-dichloro-5-(N-{ l-[N-(l,l-dimethylethoxy)carbonylamino]indan-2- yl}carbamoyl)-4H-thieno[3,2-b]pyrrole; ii) 5-[N-(l-aminoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iii) 5- [N-( 1 -acetamidoindan-2-yl)carbamoyl] -2,3 -dichloro-4H-thieno [3 ,2-b]pyrrole iv) 2,3-dichloro-5-{N-[l-(methanesulphonamido)indan-2-yl]carbamoyl}-4H- thieno [3 ,2-b]pyrrole v) 2,3-dichloro-5-{N-[l-(methylamino)indan-2-yl]carbamoyl}-4H-thieno[3,2- b]pyrrole; vi) 2,3-dichloro-5-{N-[l-(methylacetamido)indan-2-yl]carbamoyl}-4H-thieno[3,2- b]pyrrole; vii) 2,3-dichloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole; viii) 2,3-dichloro-5-[N-(6-fluoro-l-hydroxyindan-2-yl)carbamoyl-4H-thieno[3,2- b]pyrrole; ix) 2,3-dichloro-5-[N-(l-methoxyindan-2-yl)carbamoyl-4H-thieno[3,2-b]pyrrole x) 2,3-dichloro-5-[N-(l-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)carbamoyl]-4H- thieno[3 ,2-b]ρyrrole.
Another preferred class of compounds is of formula (1) wherein: Z is CΗ;
R4 and R5 are together -C(R7)=C(R6)-S-;
R6 is chloro;
R7 is hydrogen;
A is phenylene; n is 1 or 2;
R1 is independently selected from hydrogen, halo, nitro, hydroxy, C1. alkyl, C1.4alkoxy and and R1 is of the formula A' or A' ' :
Figure imgf000053_0001
-CH2CH(OH)(CH2)uCO2H (A') wherein x is 0 or 1, p 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; r is 1 or 2;
Y is -NR2R3 or -OR3;
R2 and R3 are independently selected from hydrogen, 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. 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(Cι-4)alkyl, fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, Cι-4alkyl [substituted by 1 or 2 R8 groups (provided that when there are 2 R8 groups they are not substituents on the same carbon)], -COR8 and -SObR8 (wherein b is 0, 1 or 2);
{wherein R8 is independently selected from hydrogen, hydroxy, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι- )alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and C1.4alkyl), pyrazinyl, piperazinyl, Ci-4alkyl, C2-4alkenyl, cyclo(C3-8)alkyl, Cι- alkoxy, cyano(C1-4)alkyl, anιino(Cι-4)alkyl (optionally substituted on nitrogen by 1 or 2 groups selected from hydrogen,
Cι- alkyl, hydroxy, hydroxy(Cι-4)alkyl, dihydroxy(C1-4)alkyl, aryl and aryl(Cι-4)alkyl), Ci-
4alkylS(O)c(C1-4)alkyl (wherein c is 0, 1 or 2), -CH2CH(CO2R9)N(R9R10), -CH2OR9,
(R9)(R10)N-, -COOR9 and -CH2COOR9 , -CH2CONR9R10, - CH2CH2CH(NR9R10)CO2R9;
[wherein R9 and R10 are independently selected from hydrogen, 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), C -4alkenyl, cyano(C1-4)alkyl, phenyl (optionally substituted by 1 or 2 groups selected
1 from nitro, halo, hydroxy and cyano) and C1-4alkyl substituted by R ; (wherein R13 is selected from Cι-4alkoxy, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by
1 or 2 groups selected from nitro, halo, cyano, hydroxy and Cι. alkyl), pyrazinyl, piperazinyl,
C1-4alkylS(O)d(C1.4)alkyl (wherein d 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-Cι-
4alkylamino, N,N-(C1-4) alkylamino, carbonyl, sulfo, Cι-4alkoxy, heterocyclyl, Cι-4alkanoyl, and Cι-4alkylS(O)f(Cι-4)alkyl (wherein f is 0, 1 or 2)]}; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof; with the proviso that the compound of formula (1) is not: i) 2-chloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl-6H-thieno[2,3-b]pyrrole;
In another aspect of the invention, preferred compounds of the invention are any one of: 2,3-dichloro-N-[(lR,2R)-l-(formylamino)-2,3-dihydro-lH-inden-2-yl]-4H-thieno[3,2- b]pyrrole-5-carboxamide;
2,3-dichloro-N-(( 1R,2R)- 1- { [(methyloxy)acetyl] amino } -2,3-dihydro- lH-inden-2-yl)-4H- thieno[3,2-b]pyrrole-5-carboxamide; N-((lS,2S)-l-{[(3(R)-3-(tert-butoxyc-ιrbonylar no)-3-carbamoylpropanoyl]amino}-2,3- dihydro-lH-inden-2-yl)-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-[(lR,2R)-l-({[(4R)-2,2-dimethyl-5-oxo-l,3-dioxolan-4-yl]acetyl}amino)-2,3- dihydro-lH-inden-2-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lR,2R)-l-[(3-methoxyproρanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3 ,2-b]pyrrole-5-carboxamide;
N- { (1R,2R)- 1- [(2-acetoxyacetyl)amino] -2,3-dihydro- lH-inden-2-yl } -2,3-dichloro-4H- thieno[3 ,2-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[(2-carbamoylacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H- thieno[3,2-b]pyrrol-5-c-ιrboxamide; 2,3-dichloro-N-{(lR,2R)-l-[(trifluoroacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
2,3-mchloro-N-{(lS,2S)-l-[(furan-2-ylcarbonyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno [3 ,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lS,2S)-l-[(furan-3-ylcarbonyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
2,3-mchloro-N-{(lS,2S)-l-[(3-thienylcarbonyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-((lS,2S)-l-{[(5-nitrofuran-2-yl)carbonyl]amino}-2,3-dihydro-lH-inden-2-yl)-
4H-thieno[3,2-b]pyrrole-5-carboxamide; 2,3-dichloro-N-{ (lS,2S)-l-[(pyridin-3-ylcarbonyl)amino]-2,3-dihydro-lH-inden-2-yl }-4H- thieno[3,2-b]pyrrole-5-carboxamide;
N-[(lS,2S)-l-(acryloylamino)-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide;
2,3-mchloro-N-((lS,2S)-l-{[(3-hydroxyphenyl)c-ιrbonyl]amino}-2,3-dihydro-lH-inden-2-yl)- 4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-[(lS,2S)-l-(acetylamino)-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide; N-[(lS,2S)-l-[(2-carboxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H- thieno[3,2-b]pyrcole-5-carboxamide;
2,3-mchloro-N-((lS,2S)-l-{[(dimethylamino)carbonyl]amino}-2,3-dihydro-lH-inden-2-yl)-
4H-thieno[3,2-b]pyrrole-5-carboxamide; 2,3-dichloro-N-((lS,2S)- 1 - { [(4-methylpiperazin- 1 -yl)carbonyl] amino } -2,3-dihydro- lH-inden-
2-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-((lS,2S)-l-{[(ethylarnino)carbonyl]amino}-2,3-dihydro-lH-inden-2-yl)-4H- thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-((lS,2S)- 1 - { [(prop-2-en-l -ylamino)carbonyl] amino } -2,3-dihydro- lH-inden-2- yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-[(lS,2S)-l-({[(3,5-dinitrophenyl)amino]c-u-bonyl}amino)-2,3-dihydro-lH- inden-2-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-[(lS,2S)-l-(formylamino)-2,3-dihydro-lH-inden-2-yl]-4H-thieno[3,2- b]pyrrole-5-carboxamide; N-{(lR,2R)-l-[((3R)-3-amino-3-carbamoylpropanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3- dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-(lR,2R)-l-[((3R)-3-carboxy-3-hydroxypropanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3- dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lR,2R)-l-[(hydroxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
2,3-mchloro-N-{(lS,2S)-l-[(methylsulfonyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lS, 2S)-l-[methyl(morpholin-4-ylacetyl)amino]-2,3-dihydro-lH-inden-2- yl}-4H-thieno[3,2-b]pyrrole-5-c-ιrboxamide; N- { ( 1R,2R)- 1 -[(2-amino-2-oxoethyl)amino] -2,3-dihydro- lH-inden-2-yl } -2,3-dichloro-4H- thieno[3,2-b]pyrrole-5-carboxamide;
N-(lR,2R)-l-[(tert-butoxycarbonylmethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-
4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-[(lR,2R)-l-(carboxymethylamino)-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrtole-5-carboxamide;
N-(lR,2R)-l-[N-acetyl-N-(c-ιrboxymethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-
4H-thieno[3,2-b]ρyrtole-5-carboxamide; N-{(iR,2R)-l-[acetyl(2-amino-2-oxoethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-
4H-thieno [3 ,2-b]pyrrole-5 -carboxamide ;
N-{(lR,2R)-l-[N-(carboxymethyl)-N-(hydroxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3- dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide; 2-chloro-N-[(lR,2R)-l-({[(2S)-5-oxotetrahydrofuran-2-yl]carbonyl}amino)-2,3-dihydro-lH- inden-2-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;
2-chloro-N-[(lR,2R)-l-(formylamino)-2,3-dihydro-lH-inden-2-yl]-6H-thieno[2,3-b]pyrrole-5- carboxamide;
2-chloro-N-{(lR,2R)-l-[(methoxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-6H-thieno[2,3- b]pyrrole-5-carboxamide;
N-[(lR,2R)-l-(acetylamino)-2,3-dihydro-lH-inden-2-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5- carboxamide;
2-chloro-N-{(lR,2R)-l-[(3-methoxypropanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-6H- thieno[2,3-b]pyrrole-5-carboxamide; Ν-{(lR,2R)-l-[(2-acetoxyacettyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H-thieno[2,3- b]pyrrole-5-carboxamide;
N-((lS,2S)-l-{[(2(S)-2-(tert-butoxyc-ιrbonylamino)-2-carbamoylacetyl]amino}-2,3-dihydro- lH-inden-2-yl)-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;
N-{(lS,2S)-l-[(2-(tert-butoxycarbonylamino)acetylamino]-2,3-dihydro-lH-inden-2-yl}-2- chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[2-carbamoylacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno[2,3,b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[2-(tert-butoxycarbonyl)acetylamino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno [2,3 ,b]pyrrole-5 -carboxamide ; 2-chloro-N-((lR,2R)-l-{[3-hydroxy-2-(hydroxymethyl)propanoyl]amino}-2,3-dihydro-lH- inden-2-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[((3R)-3-amino-3-carbamoylpropanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-2- chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[(-ιminoacetyl)-urιino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H-thieno[2,3- b]pyrrole-5-carboxamide;
2-chloro-N-[(lR,2R)-l-({[(2-hydroxyethyl)(phenylmethyl)amino]acetyl} amino)-2,3-dihydro- lH-inden-2-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide; 2-chloro-N-{(lR,2R)-l-[(moφholin-4-ylacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-6H- thieno[2,3-b]pyrrole-5-carboxamide;
2-chloro-N-((lR,2R)-l-({[(2-hydroxyethyl)(methyl)-ιmino]acetyl}amino)-2,3-dihydro-lH- inden-2-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide; N-((lR,2R)-l-({[bis(2-hydroxyethyl)-ιmino]acetyl}anιino)-2,3-dihydro-lH-inden-2-yl)-2- chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;
2-chloro-N-((lR,2R)-l-({[ethyl(2-hydroxyethyl)amino]acetyl}amino)-2,3-dihydro-lH-inden-
2-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;
2-chloro-N-(( 1R,2R)- 1 -({ [(2,3-dihydroxypropyl)(methyl)amino] acetyl } amino)-2,3-dihydro- lH-inden-2-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;
N-((lR,2R)-l-({[bis(2-hydroxypropyl)amino]acetyl}amino)-2,3-dihydro-lH-inden-2-yl)-2- chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[(2-amino-2-oxoethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno[2,3-b]pyrrole-5-carboxamide; N-[(lR,2R)-l-[(tert-butoxycarbonylmethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno[2,3-b]pyrrole-5-carboxamide;
N- { ( 1R,2R)~ 1 -(carboxymethylamino)-2,3-dihydro- lH-inden-2-yl } -2-chloro-6H- thieno(3,2,b]pyrrole-5-carboxamide;
2-chloro-N-{(lR,2R)-l-[(hydroxyacetyl-unino]-2,3-dihydro-lH-inden-2-yl}-6H-thieno[2,3- b]pyrrole-5-carboxamide;
2,3-mchloro-N-{(lR,2R)-l-[(chloroacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H-thieno[3,2- b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[((3S)-3-aιmno-3-c-ιrboxyρropanoyl)anιino]-2,3-dihyclro-lH-inden-2-yl}-2,3- dichloro-4H-thieno(3,2,b]pyirole-5-carboxamide; N-{(lR,2R)-l-[(2-carboxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H- thieno(3,2,b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[(2-carboxyacetyl)-irnino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno(3,2,b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[((3S)-3-arnino-3-carboxyρropanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-2- chloro-6H-thieno(3 ,2,b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lR,2R)-l-[(methylsulfonyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-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:
2-chloro-N-{(lR,2R)-l-[(hydroxyacetylamino]-2,3-dihydro-lH-inden-2-yl}-6H-thieno[2,3- b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[(2-amino-2-oxoethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H- thieno[3,2-b]pynOle-5-carboxamide;
2,3-dichloro-N-{(lR,2R)-l-[(hydroxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide; 2,3-dichloro-N-[(lR,2R)-l-(formylamino)-2,3-dihydro-lH-inden-2-yl]-4H-thieno[3,2- b]pyrrole-5-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, Y, R1, R4, R5, r and n are, unless otherwise specified, as defined in formula (1)) comprises of: a) reacting an acid of the formula (2):
Figure imgf000059_0001
(2) or an activated derivative thereof; with an amine of formula (3):
Y
Figure imgf000059_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 2,6-di- Z£yZ-pyridines 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.
A compounds of formula (2) where Z is CH may be prepared according to Scheme 1:
Figure imgf000060_0001
Scheme 1
Compounds of formula (2a) are commercially available or they are known compounds or they are prepared by processes known in the art. A compound of the formula (2) wherein X is nitrogen, can be prepared from a compound of the formula (4):
Figure imgf000061_0001
(4) by firstly converting the oxo group to chlorine or bromine with a halogenating agent such as POCl3 or POBr3, in an inert organic solvent such as dichloromethane in a temperature range of ambient temperature to reflux (for example see Nucleic Acid Chem. 1991, 4, 24-6) , then displacing the chlorine or bromine group with cyanide using a cyanide salt such as potassium cyanide, in an inert organic solvent such as toluene, benzene or xylene, optionally in the presence of a catalyst such as 18-crown-6 (for example see J. Heterocycl. Chem 2000, 37(1), 119-126) and finally hydrolysing the cyano group to a carboxy group, with for example, an aqueous acid such as aqueous hydrogen chloride (for example see Chem. Pharm. Bull. 1986, 34(9), 3635-43).
Alternatively, a compound of the formula (2) wherein X is nitrogen may be formed by reacting the compound of the formula (4) with (Cl3CCO)2O and Cl3CCO2H in the presence of magnesium chloride using Cl3CCO2H as solvent, to form a compound of the formula (5):
Figure imgf000061_0002
(5) and then hydrolyising the compound of the formula (5), using, for example, aqueous sodium hydroxide, at a temperature range of ambient temperature to reflux (for example see J Heterocycl. Chem. 1980, 17(2), 381-2).
The compound of formula (4) may be prepared from a compound of formula (6) and (7) using conditions known for the Curtius rearrangement (Tetrahedron 1999, 55, 6167):
Figure imgf000061_0003
(6) (7) The compounds of the formula (8) and (9):
Figure imgf000062_0001
(8) (9) transform into compounds of the formula (6) and (7) respectively. This transformation either occurs spontaneously or may be induced with acid or base. Compounds of the formula (8) and (9) may be prepared by introducing a carboxy group into a compound of the formula (10) or (11):
Figure imgf000062_0002
(10) (11) wherein P' is an amino protecting group such as butoxycarbonyl. A carboxy group is introduced into the compound of the formula (10) or (11) by reacting an alkyl lithium reagent such as n-butyl lithium, in an inert organic solvent such as
THF, at low temperature, for example in the range -10°C to -78°C and then forming the compound of the formula (8) or (9) as appropriate by either a) reacting the resulting compound with carbon dioxide; or b) by reacting with DMF in the temperature range of -10°C to ambient temperature to form the corresponding aldehyde and oxidizing the aldehyde to carboxy with standard reagents to give the compound of the formula (8) or (9).
Compounds of the formula (10) and (11) may be prepared from a compound of the formula (12) and (13):
Figure imgf000062_0003
(12) (12) using conditions known for the Curtius reaction. Compounds of the formula (12) and (13) may be prepared by oxidizing the corresponding aldehyde using standard oxidizing reagents such as potassium manganate or sodium periodate.
The aldehyde precursor of a compound of the formula (12) or (13) can be prepared using standard techniques known in the art. For example, many compounds of the formula
(12) or (13) may be prepared by introducing the appropriate R and R into a compound of the formula (14) or (15) as appropriate:
Figure imgf000063_0001
(14) (15) For example, when R6 and R7 are both chloro a compound of the formula (14) or (15) may be chlorinated with a chlorinating agent such as chlorine in the presence of aluminium chloride or iron (HI) chloride, in an inert organic chlorinated solvent such as dichloromethane or 1,2- dichloroethane, followed by treatment with an aqueous base, such as, aqueous sodium hydroxide. The mono chlorinated compound can be formed in the same way. Compounds of formula (2b) may also be prepared as illustrated in Scheme 2:
Figure imgf000063_0002
Scheme 2
The conversion of compounds of formula (10) into compounds of formula (16) may be carried out by directed ortho lithiation reactions (J. Org. Chem, 2001, volume 66, 3662-3670), for example with n-butyl lithium and (CHO)N(alkyl)2. The protecting group P' in compounds of formula (10) must be suitable directing group for this reaction and may be for example - CO tBu. Reaction of compounds of formula (16) with LCH2CO2R where L is a leaving group, and replacement of the protecting group P' with an alternative P' ' (for example - COalkyl) according to standard processes, gives a compound of formula (17). This may be cyclised using a base, for example potassium carbonate or sodium methoxide. Compounds of formula (3) where Y is OR3 are commercially available or they are known compounds or they are prepared by processes known in the art. When Y is NR R , the amines of formula (3) may be prepared according to Scheme 3:
Figure imgf000064_0001
NaN3 / dimethylacetamide
Figure imgf000064_0002
Scheme 3
Compounds of formula (3 a) are commercially available or they are known compounds or they are prepared by processes known in the art. For example, starting from primary amines of formula (4), in which R is H or a suitable protecting group, one or both of R1 and/or R2 may be introduced by acylation, (for example reacting with acetoxyacetic acid and l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride -ED AC), alkylation, reductive alkylation, sulphonation or related processes, followed by O-deprotection when appropriate. Alternatively, one or both of R1 and/or R2 may be obtained by modification of functionality in groups previously thus introduced, by reduction, oxidation, hydrolysis (for example the conversion of an acetoxy group to a hydroxy group), nucleophilic displacement, amidation, or a related process, or a combination of these processes, followed by O-deprotection when appropriate. It will be appreciated that such modifications may include modifications which convert one compound of the formula (1) into another compound of the formula (1).
Figure imgf000064_0003
Amines of formula (3) may alternatively be obtained by applying the processes described for the preparation of compounds of formula (3 a) to compounds of formula (20) in which W is NH2 or a nitrogen atom with one or two suitable protecting groups.
Figure imgf000065_0001
Compounds of the formula (3) where r = 1 and wherein A is heteroarylene can be prepared from suitably functionalised cycloalkyl fused heterocycles. For example, when A is pyridine,
Figure imgf000065_0002
(3b) (3c) compounds of formula (3b) and (3c) may be prepared from the corresponding pyrindinone regioisomer according to Scheme 4 :-
Figure imgf000065_0003
Fmoc-CI, NaHCOg
Step 3 aq. dioxane
Figure imgf000065_0004
Scheme 4 Step 1 is performed on a compound known in the literature (Jpn. Kokai Tokkyo Koho,
1995, 14. JP 07070136). Steps 2, 3, 4, 5, 6, 7 and 8 are performed using standard techniques known in the art.
It will be appreciated that the bromopyrindinone isomers (21a, 21b and 21c) could
Figure imgf000066_0001
(21a) (21b) (21c) be converted to the corresponding heterocylic version of (3) by the means described in Scheme 4. The bromopyridinones can be prepared from the corresponding pyrindinone by standard techniques known in the art. The pyrindinones (22a, 22b, 22c) are known in the literature or they are prepared by processes known in the art.
Figure imgf000066_0002
The process described above and shown in Scheme 4 may also be applied to other six membered heterocycles containing more than one nitrogen.
It will be appreciated that, in a similar manner, compounds of the formula (3) wherein A is heteroarylene containing a bridgehead nitrogen can be prepared from the appropriate suitably functionalised cycloalkyl fused heterocycles .
It will be appreciated that the processes described above for formation and modification of Y as NRXR2 may be applied similarly whether to make the compound of formula (3) before coupling to the acid of formula (2) or whether to the product of such a coupling. It will be appreciated that certain of the various ring substituents in the compounds of the present invention, for example R1 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 alkylsulphinyl or alkylsulphonyl.
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 dimethylaminopropylarnine, 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 846464 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 HI glycogen, 0.15ug glycogen phosphorylase a (GPα) from rabbit muscle and 0.5mM glucose- 1 -phosphate. GPα is pre-incubated in the assay buffer solution with the type UI 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) PNAS 95, 1776-81). The reaction is stopped after 30min with the addition of 50μl acidic ammonium molybdate solution, 12ug ml"1 in 3.48% H2SO 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 IC5o, 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 IC5o 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 0 846 464 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 KH2PO , 2.5mM MgCl2,
2.5mM ethylene glycol-bis(b-aminoethyl ether) N,N,N',N'-tetraacetic acid, lOOmM KC1, 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 in 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" 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 10 was found to have an IC5o of 4.5μm. The inhibitory activity of compounds was further tested in rat primary hepatocytes. 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%O2/5%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 p-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 p-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present. The pharmaceutical compositions 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 mellitus chemotherapy may include the following main categories of treatment: 1) Insulin and insulin analogues;
2) Insulin secretagogues including sulphonylureas (for example glibencla ide, 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 NHa 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 rnmHg) 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 Narian, 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-SJL™ silica, 60μ, particle size 32-63mM, supplied by Biotage, a division of Dyax Corp.,
1500 Avon Street Extended, Charlottesville, NA 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, ΝMR 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;
(vii) 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) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where indicated ionisation was effected by electron impact (El), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported and unless otherwise stated the value quoted is (M-H)";
(xi) 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)carbodiimide hydrochloride;
Et2O diethyl ether; THF tetrahydrofuran;
DMF N, N-dimethylformamide;
HATU 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluroniumhexafluorophosphate ED AC l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride TFA Trifluoroacetic acid
DMTMM 4-(4,6-Dimethoxy- 1 ,3 ,5-triazin-2-yl)-4-methylmorpholinium chloride DMA Ν, Ν-dimethylacetamide
Example 1: 2,3-Dichloro-N-r(lR,2R)-l-(formylamino)-2,3-dihvdro-lH-inden-2-yll-4H- thienor3,2-b1pyrrole-5-carboxamlde
Figure imgf000078_0001
N-[(lR,2R)-l-Amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide trifluoroacetic acid salt (Method 8, 240 mg, 0.5 mmol), formic acid
(50 μL, 1.4 mmol), DIPEA (174 μL, 1.0 mmol) and ΗOBT (67 mg, 0.5 mmol) were dissolved in DCM (5 ml), stirred for 5 mins, EDCI (120 mg, 0.625 mmol) added and the reaction stirred for lhr. Formic acid (50 μL, 1.4 mmol) and EDCI (240 mg, 1.25 mmol) were added, the reaction stirred for 2 hours and the volatiles removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with water (2 x 10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure. The residue was purified by column chromatography (2:1 EtOAc :Ηexane) to afford the title compound (175mg, 89%) as a white foam.
1HΝMR 2.86 (dd, IH), 3.23 (dd, IH), 4.6 (m, IH), 5.53 (m, IH), 7.12 (m, 2H), 7.25 (m, IH), 8.2 (s, IH), 8.55 (d, IH), 8.63 (d, IH), 12.36 (s, IH); MS m/z 394. Example 2 2 -Dichloro-iV-((lR-2R)-l-{r(methyloxy)acetvnaminol-2.3-dihvdro-lH- inden-2-yl)-4H-thienor3,2-b1pyrrole-5-carboxanιide
Figure imgf000079_0001
DIPEA (180 μL, 1.05 mmol), HOBT (68 mg, 0.5 mmol), methoxyacetic acid (0.5 mmol, 38 μL) and ED AC (120 mg, 0.63 mmol) were added to a suspension of N-[(1R,2R)-1- amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]ρyrrole-5-carboxamide (Method 8, 240 mg, 0.5 mmol) in anhydrous DCM (7 mL). The reaction was stirred at ambient temperature for approximately 16 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with water (2 x 10 mL), brine (10 mL) and dried (MgSO ). The volatiles were removed by evaporation under reduced pressure and the residue was purified by flash column chromatography on SiO2 (1:1 EtOAc:isohexane); the solvent removed by evaporation under reduced presssure and dried to give the title compound (44 mg, 20%) as a white solid. 1H ΝMR 2.88 (dd, 1Η), 3.26 (dd, 1Η), 3.87 (dd, 2Η), 4.73 (m IH), 5.51 (t, IH), 7.17 (m, 5H), 8.26 (d, IH), 8.59 (d, IH), 12.36 (s, IH); MS m/z 439.
The following examples were made by the process similar to Example 2 using N- [(lR,2R)-l-amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5- carboxamide (Method 8) and the appropriate commercially available carboxylic acid: Example 3: N-((lS.2S -l-{r(3(R -3-(tert-Butoxycarbonylamino)-3- carbamoylpropanoyll-ιminol-2.3-dihvdro-lH-inden-2-yl)-2.3-dichloro-4H-thienor3,2- blpyrrole-5-carboxamide
Example 4; 2.3-Dichloro-N-. QR,2R -l-({ r(4R)-2.2-dimethyl-5-oxo-l,3-dioxolan-4- yllacetyl|aπnnoV2.3-mhydro-lH-inden-2-yll-4H-tMenor3,2-blpyrrole-5-carboxamide Example 5; 2.3-Dichloro-N-{ (lR.2R)-l-r(3-methoxypropanoyl)amino1-2,3-dihvdro-lH- inden-2-yl|-4H-thienor3,2-blpyrrole-5-carboxarnide
Example 6: N-l(lR.2RVl-[(2-Acetoxyacetyl)aminol-2,3-dihvdro-lH-inden-2-yl|-2,3- dichloro-4H-thienor3,2-blpyrtole-5-c-u'box--mide Example 7: N-((lR.2RVl-r(2-Carbamoylacetyl aminol-2.3-dihvdro-lH-inden-2-yl}-2.3- dichloro-4H-thienor3.2-blpyrrol-5-carboxamide
Example 55; 2.3-Dichloro-N-( (lR.2R)-l-r(trifluoroacetyl)aminol-23-dihvdro-lH-inden-2- yl|-4H-thienor3.2-blpyrrole-5-carboxamide
Figure imgf000080_0001
Figure imgf000080_0002
The following examples were made by the process of Example 2 using N-[(1S,2S)-1- amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide
(Method 9) and the appropriate commercially available carboxylic acid.
Example 8; 2.3-Dichloro-N-{ (lS.2S)-l-r(furan-2-ylcarbonyl aminol-2,3-dihvdro-lH-inden-2- .yl)-4H-thienor3,2-blpyrrole-5-carboxamide
Example 9; 2.3-Dichloro-N- 1 (lS.2S)-l-r(furan-3-ylcarbonyl)aminol-2.3-dihvdro-lH-inden-2- yl ) -4H-thieno f3 ,2-blpyrrole-5 -carboxamide
Example 10; 2,3-Dichloro-N-{(lS S)-l-r(3-tMenylcarbonyl aminol-2,3-dihvdro-lH-inden-2- yl } -4H-thieno \3 ,2-b1pyrrole-5 -carboxamide Example 11; 2,3-Dichloro-N-(QS,2S)-l- j r(5-nitrofuran-2-yl carbonyllaminol-2.3-dihydro- lH-inden-2-yl)-4H-thieno[3,2-blpyrrole-5-c-ιrboxamide
Example 12; 2,3-Dichloro-N- 1 (lS,2S -l-r(pyridin-3-ylcarbonyl)aminol-2.3-dihvdro-lH- inden-2-yl|-4H-thienor3,2-blpyrrole-5-carboxamide
Example 13: N-r(lS,2S)-l-(Acryloylamino)-2.3-dihvdro-lH-inden-2-yll-2.3-dichloro-4H- thienor3,2-blpyrrole-5-carboxamide
Example 14: 2,3-Dichloro-N-((lS,2S)-l-{ r(3-hvdroxyphenyl)carbonyllamino f-2,3-dihydro- lH-inden-2-yl)-4H-thienor3,2-blpyrrole-5-carboxamide
Example 15: N-r(lS.2S)-l-(Acetylamino)-2,3-dihvdro-lH-inden-2-yll-2.3-dichloro-4H- thieno \3.2-blpyrrole-5-carboxamide Example 16: N-r(lS.2S)-l-r(2-Carboxyacetyl)aminol-2,3-dihvdro-lH-inden-2-yll-2 - dichloro-4H-thienor3.2-blpyrrole-5-carboxamide
Figure imgf000082_0001
Figure imgf000082_0002
Example l7: 2 -Dichloro-N-((lS S)-1 r(dimethylamino)carbonyl1aminol-2,3- dihvdro-lH-inden-2-yl)-4Hr-thienor3,2-blpyrrole-5-carboxamide
Figure imgf000083_0001
To a solution of N-[(lS,2S)-l-amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H- thieno[3,2-b]pyrrole-5-carboxamide (Method 9, 240 mg, 0.5 mmol) and Et3Ν (101 mg, 1.0 mmol) in DCM (4 mL) was added a solution of dimethylcarbamoyl chloride (54 mg, 0.5 mmol) in DCM (1 mL). The reaction was stirred at ambient temperature for 2 hours, washed with saturated NaΗCO3 (1 mL), water (1 mL), brine (1 rnL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (50 mg, 23%) as a foam.
1H NMR 2.81 (s, 6H), 2.83 (m, IH), 3.25 (m, IH), 4.61 (m, IH), 5.33 (m, IH), 7.16 (m, 5H), 8.6 (d, IH), 12.37 (s, IH); MS m z 437.
Example 18; 2,3-DichIoro-iV-((lS,2S)-l-{r(4-methylpiperazin-l-yl)carbonyl1amino}-2,3- dihydro-lH nden-2-yl)-4Hr-thienor3<2-b1pyrrole-5-carboxamide
Figure imgf000083_0002
To a solution of N-[(lS,2S)-l-amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H- thieno[3,2-b]pyrrole-5-carboxarnide (Method 9, 240 mg, 0.5 mmol) andEt3Ν (101 mg, 1.0 mmol) in DCM (4 mL) was added a solution of 4-methyl-l -piperazine carbonyl chloride (100 mg, 0.5 mmol) in DCM (1 mL). The reaction was stirred at ambient temperature for 2 hours, washed with saturated NaΗCO3 (1 mL), water (1 mL), brine (1 mL) and dried (MgSO ). The volatiles were removed by evaporation under reduced pressure to give the title compound (110 mg, 45%) as a foam. MS m/z (M-H)" 491.
The following examples were made by the method below using N-[(lS,2S)-l-amino-
2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carbox-unide trifluoroacetic acid salt (Method 9) and the appropriate commercially available isocyanate: N-[(lS,2S)-l-amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5- carboxamide trifluoroacetic acid salt (0.5 mmol) andEt3Ν (1.0 mmol) were dissolved in dry TΗF (5 mL), the appropriate isocyanate (1.0 mmol) was added and the reaction stirred at ambient temperature for 20 hours. EtOAc (15 mL) was added and the mixture washed with water (2 x 5 mL) brine (5 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound as a foam. Example 19: 2,3-Dichloro-N-((lS,25)-l-{r(ethylamino)carbonvnamino|-2,3-dihydro-lH- inden-2-yl)-4H-thienor3,2-blpyrrole-5-carboxamide
Example 20: 2-3-Dichloro-N-((lS,25)-1 r(prop-2-en-l-ylamino)carbonyllamino>-2,3- dihvdro-lH-inden-2-yl)-4H-thienor3,2-blpyrrole-5-carboxamide
Example 21: 2,3-Dichloro-N-r(lS,25) -({r(3,5-dinitrophenyl)amino1carbonyl>amino)-
2 -dihvdro-lH-inden-2-yl1-4H-thienor3,2-blpyrrole-5-carboxamide
Figure imgf000084_0001
Figure imgf000084_0002
Example 22: 2,3-DichIoro-iV-r(lS,2S)-l-(formylamlno)-2,3-dihvdro-lH-inden-2-vn-4H- _thienoF3,2-b1pyrrole-5-carboxamide
Figure imgf000085_0001
N-[(lS,2S)-l-Amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide trifluoroacetic acid salt (Method 9, 240 mg, 0.5mmol), formic acid (50 μL, 1.4 mmol), DIPEA (174 μL, 1.0 mmol) and ΗOBT (67 mg, 0.5 mmol) were dissolved in DCM (5 ml), stirred for 5 mins, EDCI (120 mg, 0.625 mmol) added and the reaction stirred for lhr. Formic acid (50 μL, 1.4 mmol) and EDCI (240 mg, 1.25 mmol) were added, the reaction stirred for 2 hours and the volatiles removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with water (2 x 10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure. The residue was purified by column chromatography (2:1 EtOAc:Ηexane) to afford the title compound (180mg, 97%) as a white foam.
1H ΝMR 2.86 (dd, IH), 3.23 (dd, IH), 4.6 (m, IH), 5.53 (m, IH), 7.12 (m, 2H), 7.25 (m, IH), 8.2 (s, IH), 8.55 (d, IH), 8.63 (d, IH), 12.36 (s, IH); MS m/z 394.
Example 23: N-{(lR,2R) -r((3R)-3-Amino-3-carbamoylpropanoyl)amino1-2,3-dihvdro- lH-inden-2-vU-2,3-dichIoro-4H-thienor3,2-blpyrrole-5-earboxamide
Figure imgf000085_0002
N-((1S,2S)- 1 - { [(3 (R)-3-(tert-Butoxycarbonylamino)-3-carbamoylpropanoyl] amino } - 2,3-dihydro- lH-inden-2-yl)-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 3; 290 mg, 0.5 mmol) was dissolved in TFA (3 mL) and the reaction stirred at ambient temperature for 1 hour. The volatiles were evaporated under reduced pressure and the crude material was azeotroped with chloroform (3 x 5 mL) to afford a gum. The gum was triturated with ether (5 mL), the solid collected by filtration, washed with ether (2 x 5 mL) and dried to give the trifluoroacetate salt of the title compound (270 mg, 91%) as a yellow solid.
1H NMR 1.24 (m, IH), 2.72 (m, IH), 2.90 (dd, IH), 3.26 (dd, IH), 4.04 (m, IH), 4.61 (m,
IH), 5.50 (t, IH), 7.12 (s, IH), 7.24 (m, 4H), 7.55 (s, IH), 7.74 (s, IH), 8.06 (br, 3H), 8.66 (d,
IH), 8.72 (d, IH), 12.36 (s, IH); MS m/z 502 (M+Na)+.
Example 24: iV-(lR,2R)-l-r((3R)-3-Carboxy-3-hvdroxypropanoyl)amino1-2,3-dihvdro- lH-inden-2-vU-2 -dichloro-4H-thienor3,2-b1pyrrole-5 arboxamide
Figure imgf000086_0001
2,3-Dichloro-N-[(lR,2R)-l-({[(4R)-2,2-dimethyl-5-oxo-l,3-dioxolan-4- yl]acetyl}armno)-2,3-dihyαι-o-lH-inden-2-yl]-4H-thieno[3,2-b]pyrrole-5-carboxarnide (Example 4; 200 mg, 0.4 mmole) was dissolved in TΗF (2 mL) and water (2 mL) and ΝaOΗ (100 mg) were added and the suspension stirred at ambient temperature for 48 hours. 2N ΗC1 was added until pΗ 1 and the aqueous phase was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with water (10 mL), brine (10 mL) and dried (MgSO ). The solvent was evaporated under reduced pressure and the reisdue was triturated with Et2O, filtered and dried to give the title compound (133 mg, 69%) as a brown solid.
1H ΝMR 2.45 (obs m, 2Η), 2.87 (dd, IH), 3.26 (obs dd, IH), 4.39 (m, IH), 4.57 (m, IH), 5.52 (t, IH), 7.18 (m, 5H), 8.43 (d, IH), 6.63 (d, IH), 12.39 (s, IH); MS m/z 483. Example 25: 2,3-Dichloro-iV-((lR,2R)-l-r(hvdroxyacetyl)aιnino1-2.3-dihvdro-lH;-inden- 2'yl}-4iHr-thienor3.,2-b1pyrrole-5-carboxamide
Figure imgf000087_0001
N-{(lR,2R)-l-[(2-Acetoxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H- thieno[3,2-b]pyrrole-5-carboxamide (Example 6; 632 mg, 1.36 mmol) was dissolved in TΗF (10 mL), MeOΗ (10 mL) and K CO3 (100 mg) were then added and the suspension stirred at ambient temperature for 16 hours. Water (50 mL) was added and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with water (2 x 50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed by evaporation under reduced pressure, the crude product was triturated (EtOAc sohexane, 1:10), filtered, washed with isohexane (5 mL) and dried to give the title compound (428 mg, 74%) as a white solid. 1H ΝMR 2.86 (dd, 1Η), 3.25 (obs dd, 1Η), 3.89 (m, 2Η), 4.72 (m, IH), 5.39 (t, IH), 5.51 (t, IH), 7.17 (m, 5H), 8.13 (d, IH), 8.59 (d, IH), 12.35 (s, IH); MS m/z 424.
Example 26: 2,3-Dichloro-N-((15,2S)-l-r(methylsulfonyl)amino1-2,3-dihvdro-lH-inden- 2-yl}-4H-thienor3,2-b1pyrroIe-5-carboxamide
Figure imgf000087_0002
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]ρyrrole (Method 4, 236 mg, 1.0 mmol), N- [(lS,2S)-2-amino-2,3-dihydro-lH-inden-l-yl]methanesulfonamide (226 mg, l.O mol), DIPEA (174 μL, 1.0 mmol) and ΗOBT (135 mg, 1.0 mmol) were dissolved in DCM (10 mL) and stirred for approximately 5 mins. EDCI (240 mg, 1.25 mmol) was added and the reaction stirred for 20 hours. The volatiles were removed by evaporation, EtOAc (25mL) added, the mixture washed with water (2 x 10 mL) and brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (430mg,
97%) as a foam.
1H NMR 2.83 (m, IH), 2.99 (s, 3H), 3.23 (m, IH), 4.57 (m, IH), 4.95 (m, IH), 7.13 (s, IH), 7.21-7.34 (m, 4H), 7.87 (d, IH), 8.66 (d, IH), 12.41 (s, IH); MS m/z (M-H)" 442.
Example 27: 2.3-D.chloro-iV-{(lS.2S)-l-rmethyl(morpholin-4-ylacetyl)aminol-2,3- dihydro-ljHr-inden-2-vU-4H-thienor3,2-blpyrrole-5-carboxamide
Figure imgf000088_0001
2,3-Dichloro-N-{(lR,2R)-l-[(chloroacetyl)(methyl)amino]-2,3-dihydro-lH-inden-2- yl}-4H-thieno[3,2-b]pyrτole-5-carboxamide (Method 10, 100 mg, 0.22 mol) and morpholine (100 mg, 12.6 mmol) were dissolved in DCM, stirred at ambient temperature for 20hours and the volatiles removed by evaporation under reduced pressure. EtOAc (10 L) was added and the mixture washed with water (2 x 5 mL), brine (5 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (60 mg, 54%) as a buff coloured powder.
1H ΝMR 2.36 (m, 4Η), 2.74 (d, 3H), 2.9-3.55 (m, IH), 4.8 (m, IH), 5.96 (dd, IH), 7.0 (m, IH), 7.09 (d, IH), 7.26 (m, 3H), 8.62 (dd, IH); MS m/z 507.
Example 28: N-{(lR-2R)-l-r(2-Amino-2-oxoethyl)aminol-2.3-dihvdro-lH-inden-2-yl}- 2,3-dichloro-4H-thienor3,2-b1pyrrole-5-carboxamide
Figure imgf000088_0002
Prepared in a similar manner to Example 29 using N-{(lR,2R)-l-amino-2,3-dihydro- lH-inden-2-yl}-2,3-dichloro-4H- thieno[3,2-b]pyrrol-5-yl-2-carboxarιiide (Method 8) and bromoacetamide.
1H ΝMR 2.69 (s, 1Η), 2.8 (dd, 1Η), 3.16 (m, 2Η), 3.24 (m, IH), 4.21 (m, IH), 4.44 (m, IH), 7.03 (s, IH), 7.12 (s, IH), 7.23 (m, 3H), 7.28 (s, IH), 7.37 (s, IH), 8.49 (d, IH), 12.36 (s, IH);
MS m/z (M-H)" 422.
Example 29: N-(lR R)-1 (tert-Butoxycarbonylmethyl)amino1-2,3-dihydro-lH-inden- 2-yl>-2,3-dichloro-4jg-thienor3,2-b1pyrrole-5-carboxamide
Figure imgf000089_0001
DIPEA (520 μL, 3.0 mmol) and t-butyl bromoacetate (150 μL, 1.0 mmol) were added to a solution of N-{(lR,2R)-l-amino-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H- thieno[3,2-b]pyrrol-5-yl-2-carboxamide (Method 8, 479 mg, 1.0 mmol) in CΗ3CΝ (15 mL). The resulting suspension was stirred at 60°C for approximately 2 h. Upon cooling the volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (20 mL), washed with water (2 x 20 mL), brine (20 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc:isohexane 1:1) to afford the title compound (100 mg, 21%) as a white solid. 1H NMR 1.49 (s, 9H), 1.87 (brs, IH), 2.75 (dd, IH), 3.62 (d, 2H), 3.65 (dd, IH), 4.15 (d, IH), 4.40 (m, IH), 6.82 (s, IH), 7.10 (d, IH), 7.25 (s, 2H), 7.40 (d, IH), 9.80 (s, IH); MS m/z 480. Example 30: iV-r(lR.2R)-l-(CarboxymethylaminoV2.3-dihvdro-lH-inden-2-yll-2,3-
.dichloro-4H-thienor3,2-b1pyrrole-5-carboxamide
Figure imgf000090_0001
N-(lR,2R)-l-[(tert-Butoxycarbonylmethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3- dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 29; 100 mg, 0.21 mmol) dissolved in DCM (10 mL). TFA (1 mL) added and the reaction stirred at ambient temperature for 6 hours. Evaporation under reduced pressure, co-evaporation with CΗC13 (2 x 10 mL) and drying gave the title compound (85mg, 36%) as a white powder.
1H ΝMR 2.71 (dd, IH), 3.16 (dd, IH), 3.29 (m, 2H), 4.25 (m, IH), 4.39 (m, IH), 6.97 (m, 2H), 7.08 (m, 3H), 7.24 (m, 2H), 7.48 (d, IH), 8.63 (d, IH), 11.62 (s, IH); MS m/z (M-H)" 422.
Example 31: N-(lR,2R)-l-rN-Acetyl-N-(carboxymethyl)amino1-2,3-dihydro-lH-inden-2- yU-2,3-dichloro-4H-thienor3,2-b1pyrrole-5-carboxamide
Figure imgf000090_0002
TFA (1 mL) was added to a solution of 1,1-dimethylethyl [acetyl((lR,2R)-2-{[(2,3- dichloro-4H-thieno [3 ,2-b ]pyrrol-5 -yl)carbonyl] amino } -2,3 -dihydro- lH-inden- 1 - yl)amino] acetate (Method 18, 40 mg, 0.08 mmol) in DCM (5 mL) and the reaction was stirred at ambient temperature for 1 h. The volatiles were removed by evaporation under reduced pressure to afford the title compound (35 mg, 94%) as a white solid.
1H NMR 2.49 (s, 3Η), 2.97 (dd, IH), 3.20 (dd, IH), 3.90 (m, 2H), 4.70 (m, IH), 5.50 (d, IH), 7.25 (m, 5H), 8.60 (d, IH), 12.43, (s, IH); MS m/z 466, 349. Example 32: N-i R.2R) Acetyl(2-amino-2-oxoethyl)aminol-2,3-dihvdro-lH-inden-2- yl}-2 -dichIoro-4-r-r-thienor3,2-b1pyrrole-5-carboxamide
Figure imgf000091_0001
Acetyl chloride (17 μL, 0.24 mmol) was added to a solution of N-{(lR,2R)-l-[(2- ar-iino-2-oxoethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H-thieno[3,2-b]pyrrole- 5-carboxamide (Example 28, 100 mg, 0.24 mmol) in TΗF (10 mL). The reaction was stirred at ambient temperature for 1 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (50 mL), washed with water (2 x 10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc sohexane 1:2) to afford the title compound (50 mg, 45%) as a white solid.
1H ΝMR 2.49 (s, 3Η), 2.98 (dd, IH), 3.20 (dd, IH), 3.29 (brs, 2H), 4.0 (m, 2H), 4.65 (m, IH), 5.70 (d, IH), 7.25 (m, 5H), 8.30 (d, IH), 12.10, (s, IH); MS m/z 487.
Example 33: JV-((lR,2R)-l-riV-(Carboxymethyl)-iV-(hvdroxyacetyl)amino1-2-3-dihvdro- lH-inden-2-yl>-2,3-dichloro-4H-thienor3,2-b1pyrrole-5-carboxamide
Figure imgf000091_0002
Potassium carbonate (20 mg) and MeOH (1 mL) were added to a solution of [[(acetyloxy)acetyl]((lR,2R)-2-{[(2,3-chchloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}- 2,3-dihydro- lH-inden-l-yl)amino] acetic acid (Method 19, 120 mg, 0.23 mmol) in TΗF (5 mL) and the reaction was stirred at ambient temperature for 24 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in water and acidified to pΗ 2.0 and then extracted into EtOAc (3 x 10 mL). The volatiles were removed by evaporation under reduced pressure to afford the title compound (110 mg, 100%) as a white solid. 1H NMR 3.07 (dd, IH), 3.18 (dd, IH), 3.92 (d, IH), 4.35 (d, IH), 4.82 (m, 3H), 5.96 (d, IH), 7.25 (m, 5H), 8.67 (d, IH), 12.40 (s, IH); MS m/z 482.
Example 34: 2-Chloro-N QR,2R) -({r(2S)-5-oxotetrahvdrofuran-2- yllcarbonyl)amino)-2,3-dihvdro-lH-inden-2-vIl-6H-thienor2,3-b1pyrrole-5-carboxamide
Figure imgf000092_0001
DIPEA (180 μL, 1.05 mmol), HOBT (68 mg, 0.5 mmol), (2S)-5-oxotetrahydrofuran~2- carboxylic acid (CAS Reg. No: [21461-84-7], 0.5 mmol, 65 mg) and EDAC (120 mg, 0.63 mmol) were added to a suspension of N-[(lR,2R)-l-amino-2,3-dihydro-lH-inden-2-yl]-2- chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 21, 223 mg, 0.5 mmol) in anhydrous DCM (7 mL). The reaction was stirred at ambient temperature for approximately 16 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (5 mL), washed with water (2 x 5 mL), brine (10 mL) and dried (MgSO ). The volatiles were removed by evaporation under reduced pressure and the residue triturated (EtOAc:hexane, 1 : 10), collected by filtration, washed with hexane (2 x 5 mL) and dried to give the title compound (112 mg, 56%) as a brown solid.
1H ΝMR 2.15 (m, 1Η), 2.43 (m, 3Η), 2.91 (dd, IH), 3.25 (dd, IH), 4.70 (m, IH), 4.92 (m, IH), 5.46 (t, IH), 7.03 (s, IH), 7.13 (m, IH), 7.18 (s, IH), 7.25 (m, 3H), 8.55 (d, IH), 8.75 (s, IH), 11.85 (s, IH); MS m/z 444, 446
The following examples were made by a similar process to Example 34 using N- [(lR,2R)-l-amino-2,3-dihydro-lH-inden-2-yl]-2-chloro-6H-thieno[2,3-b]ρyrrole-5- carboxamide (Method 21) and the appropriate commercially available carboxylic acid: Example 35: 2-Chloro-N-r(lR.2R)-l-(formylamino)-2.3-dihvdro-lg-inden-2-vn-6H- thienor2,3-b1pyrrole-5-carboxamide
Example 36: 2-Chloro-N (lR.2R)-1 (methoxyacetyl)amino1-2,3-dihvdro-lH-inden-2- yl}-6Hr-thienor2.,3-b1Pyrrole-5-carboxamide Example 37: V-r(lR,2R)-l-(Acetylamino)-2,3-dihvdro-lH-inden-2-vn-2-chloro-6H- thienor2,3-b1pyrrole-5-carboxamide
Example 38: 2-Chloro-iV-{(lR-2R)-l-r(3-methoxypropanoyl)amino1-2 -dihvdro-liHr- inden-2-yll-6Hr-thienor2,3-b1pyrrole-5-carboxamide
Example 39: iV-{(lR,2R)-l-r(2-Acetoxyacetyl)amino1-2,3-dihydro-lH;-inden-2-vU-2- chloro-6H-thienor2,3-blpyrrole-5-carboxamide
Example 40: iV-((lS,25)-l-ir(2(S)-2-(tgrt-ButoxycarbonvIamino)-2- carbamoylacetyl1amino>-2,3-dihydro-lH-inden-2-yl)-2-chloro-6i-r-thienor2,3-b1pyrrole-
5-carboxamide
Example 41: N (15,2S)-l-r(2-(fe/^-Butoxycarbonylamino)acetylamino1-2-3-dihvdro-lH- inden-2-vU-2-chloro-6H-thienor2,3-b1pyrrole-5-carboxamide Example 42: N-{(1R,2R)-1- r2-Carbamoylacetyl)amino1-2,3-dιhydro-lH-inden-2-yl>-2-chloro-6H- thienor2,3ιblpyrrole-5-carboxamide
Example 56: N-{(lR,2R)-l-r2-(fert'-ButoxycarbonvI)acetylanunol-2,3-dihvdro-lHr-inden-
2-yl}-2-chloro-6iHr-thienor2,3<b1pyrrole-5-carboxanιide Example 57: 2-Chloro-iV-((lR-2R)-l-{r3-hvdroxy-2-(hvdroχymethyl)propanoynamino>-
2,3-dihydro-lH-inden-2-yl)-6-g-thienor2.,3-b1pyrrole-5-carboxamide
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0003
Example 43: N-|(lR,2R)-l-r((3R)-3-Amino-3-carbamoylpropanoyl)anιinol-2,3-dihvdro- lH-inden-2-yl}-2-chloro-6H-thienor2,3-blpyrrole-5-carboxamide
Figure imgf000095_0001
N-(( 1S,2S)- 1 - { [(2(S)-2-(tert-Butoxyc-ιrbonylarrιino)-2-carbamoylacetyl] amino } -2,3- dihydro- lH-mden-2-yl)-2-chloro-6H-thieno[2,3-b]pyreole-5-carboxamide (Example 40, 251 mg, 0.46 mmol) was dissolved in trifluoroacetic acid (4 mL) and stirred at ambient temperature for 24 hours. The volatiles were evaporated under reduced pressure and the crude material was azeotroped with chloroform (3 x 5 mL) to afford a gum. The gum was triturated with ether (5 mL), the solid collected by filtration, washed with ether (2 5 mL) and dried to give the trifluoroacetate salt of the title compound (239 mg, 93%) as a brown solid. 1H ΝMR 2.75 (m, 2Η), 2.90 (dd, IH), 3.23 (dd, IH), 4.04 (m, IH), 4.59 (m, IH), 5.50 (t, IH), 7.00 (s, IH), 7.19 (m, 5H), 7.54 (s, IH), 7.74 (s, IH), 8.05 (br s, 3H), 8.56 (d, IH), 8.70 (d, IH), 11.83 (s, IH); MS m/z 468, 469.
Example 44: N (lR,2R)-1 (Aminoacetyl)aminol-2-3-dihvdro-lH-inden-2-yl>-2-chloro- 6iff-thienor2,3-blpyrrole-5-carboxamide
Figure imgf000095_0002
N-{(lS,2S)-l-[(2-(tert-Butoxycarbonylarmno)acetylamino]-2,3-dihydro-lH-inden-2- yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 41; 366 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (0.5 mL) was added and the reaction stirred at ambient temperature for 7 hours. The volatiles were evaporated under reduced pressure and the crude solid was azeotroped with chloroform (3 x 5 mL), triturated with ether (5 mL), collected by filtration, washed with ether (2 5 mL) and dried to give the trifluoroacetate salt of the title compound (200 mg, 53%) as a brown solid.
1H ΝMR 2.90 (dd, 1Η), 3.21 (m, 1Η), 3.65 (m, 2Η), 4.59 (m, IH), 5.51 (t, IH), 6.99 (s, IH),
7.19 (m, 5H), 8.08 (br, 3H), 8.58 (d, IH), 8.84 (d, IH); MS m/z 389, 391.
Example 45 ; 2-Chloro-N-r(lR,2R)-l-({r(2-hvdroχyethyl)(phenylmethyl)aminolacetvU amino)-2,3-dihydro-lH-inden-2-yl)-6^r-thienor2,3-b1pyrrole-5-carboxamide
Figure imgf000096_0001
2-(Benzylamino)ethanol (160 mg, 1.06 mmol) was added to a solution of 2-chloro-N- {(lR,2R)-l-[(chloroacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-6H-thieno[2,3-b]pyrrole-5- carboxamide (Method 23; 216 mg, 0.53 mmol) and Et3Ν (500 μL, 3.60 mmol) in anhydrous TΗF (5 mL) and the reaction stirred for approximately 16 hours at room temperature then for a further 16 h at 50 °C. The volatiles were removed under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with Η2O (2 x 10 mL) and dried (MgSO4). The solvent was removed under reduced pressure, the residue triturated (EtOAc :isohexane, 1:5), collected by filtration, washed with isohexane (10 mL) and dried to give the title compound (100 mg, 36%) as a brown solid.
1H NMR 2.58 (t, 2H), 2.90 (dd, IH), 3.09 (dd, 2H), 3.18 (dd, IH), 3.50 (dd, 2H), 3.68 (dd, 2H), 4.55 (t, IH), 4.65 (m, IH), 5.46 (t, IH), 6.99 (s, IH), 7.04 (d, IH), 7.23 (m, 9H), 8.38 (d, IH), 8.53 (d, IH), 11.81 (s, IH); MS m/z 523, 525 The following examples were made by the process of Example 45 using 2-chloro-N-
{(lR,2R)-l-[(chloroacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-6H-thieno[2,3-b]ρyriOle-5- carboxamide and the appropriate commercially available amine:
Example 46: 2-Chloro-iV-((lR,2R)-l-r(morpholin-4-ylacetyl)amiιιo1-2-3-dihvdro-lH- indep-2-v -6Hr-thienor2,3-b1pyrrole-5-carboxamide
Example 47: 2-Chloro-N-((lR-2R) -({r(2-hvdroxyethyl)(methyl)aιmno1acetyllamlno)-
2,3-dihvdro-lH-inden-2-yl)-6H-thienor2,3-blpyrrole-5-carboxamide
Example 48: N-((lR-2R)-l- rBis(2-hvdroxyethyl)anιino1acetyl)amino)-2.3-dihvdro-lH- inden-2-yl)-2-chIoro-6H-thienor2.,3-blpyrrole-5-carboxamide Example 49: 2-Chloro-iV-((lR,2R)-l-({rethyl(2-hvdroxyethvI)amino1acetvI)amino)-2,3- dihvdro-lHr-inden-2-yl)-6H-thienor2,3-b1pyrroIe-5-carboxamide
Example 50: 2-Chloro-N-((lR,2R)-l-(ir(2,3- dihydroxypropyl)(methyl)amino1acetyl)amino)-2,3-dihvdro-lHr-inden-2-yl)-6ijr- thienor2,3-b1pyrrole-5-carboxamide Example 51: N-((lR,2R)-l-({rBis(2-hydroxypropyl)anιinolacety amino)-2,3-dihydro-lH- inden-2-yl)-2-chIoro-6H-thienor2-3-blpyrrole-5-carboxamide
Figure imgf000097_0001
Figure imgf000098_0001
Example 52: iV-l(lR-2R)-l-r(2-Amino-2-oxoethyl)aminol-2,3-dihvdro-lH-inden-2-yl>-2- chloro-6H-thienor2 -blpyrrole-5-carboxamide
Figure imgf000099_0001
N-{(lR,2R)-l-Amino-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H-thieno[2,3-b]pyrrol-5- yl)-2-carboxamide trifluoroacetic acid salt (Method 21, 225 mg, 0.5 mmol), DIPEA (216 μL, 1.5 mmol) and bromoacetamide (70 mg, 0.5 mmol) heated in a microwave at 180°C for 3 mins. EtOAc (30 mL) was added and the mixture washed with water (2 x 10 mL), brine (10 mL), dried (MgSO4) and evaporated. The residue was purified by column chromatography (EtOAc:MeOΗ 19:1) to afford the title compound (52 mg, 27%) as a white foam. 1H ΝMR 2.68 (s, IH), 2.79 (dd, IH), 3.24 (m, 3H), 4.21 (m, IH), 4.41 (m, IH), 7.02 (m, 2H), 7.14 (s, IH), 7.21 (m, 3H), 7.28 (m, IH), 7.36 (m, IH), 8.42 (d, IH), 11.83 (s, IH); MS m/z 389, 391.
Example 53 : N-\(1R ,2R)-1- Kfert-ButoxycarbonylmethyDaminol -2,3-dihydro- lH-inden- 2-yl}-2-chloro-6H-thienor2,3-b1pyrrole-5-carboxamide
Figure imgf000099_0002
DIPEA (350 μL, 2.0 mmol) and t-butyl bromoacetate (90 μL, 0.7 mmol) were added to a solution of N-{ (lR,2R)-l-amino-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H-thieno[2,3- b]ρyrrol-5-yl)-2-carboxamide (Method 21, 300 mg, 0.7 mmol) in CΗ3CΝ (10 mL). The resulting suspension was stirred at 60°C for approximately 2 h. Upon cooling the volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with water (2 x 10 mL), brine (10 mL) and dried (MgSO ). The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc:isohexane 1: 1) to afford the title compound (30 mg, 10%) as a white solid.
1H NMR 1.45 (s, 9H), 2.11 (br s, IH), 2.80 (dd, IH), 3.60 (m, 3H), 4.27 (d, IH), 4.46 (m, IH),
6.8 (d, 2H), 7.10 (d, IH), 7.30 (m, 4H), 11.35 (s, IH); MS m/z 446, 448.
Example 54: iV-{(lR-2R)-l-(Carboxymethylamino)-2,3-dihydro-lH-inden-2-yl)-2- chloro-6H-thieno(3,2,blpyrrole-5-carboxaιnide
Figure imgf000100_0001
N-[(lR,2R)-l-[(tert-Butoxycarbonylmethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno[2,3-b]pyrrole-5-carboxamide (Example 53, 100 mg, 0.22 mmol), dissolved in DCM
(5mL). TFA (1 mL) added and the reaction stirred at ambient temperature for 20 hours.
Evaporation under reduced pressure, co-evaporation with CΗC13 (2 x 10 mL) and drying gave the trifluoroacetic acid salt of the title compound (110 mg, 99%) as a grey powder.
1H ΝMR 3.1 (dd, IH), 3.52 (dd, IH), 4.2 (m, 2H), 4.9 (m, 2H), 7.05 (s, IH), 7.2 (s, IH), 7.4 (m, 3H), 7.7 (d, IH), 8.76 (d, IH), 9.73 (s, 2H), 12.02 (s, IH), 13.9 (s, IH); MS m/z (M-H)"
388, 390.
Example 58; 2-Chloro-iV-|(lR,2R)-l-r(hvdroxyacetylamino1-2,3-dihydro-lHr-inden-2- vU-6H-thienor2,3-bTpyrrole-5-carboxamide
Figure imgf000100_0002
N-{(lR,2R)-l-[(2-Acetoxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno[2,3-b]pyrcole-5-c-ιrboxarnide (Example 39; 393 mg, 0.92 mmol) was dissolved in TΗF
(5 mL), MeOΗ (5 mL) and K2CO3 (50 mg) were then added and the suspension stirred at ambient temperature for 4 hours. Water (10 mL) was added and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with water (50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed by evaporation under reduced pressure, the crude product was triturated (EtOAc sohexane, 1:5), filtered, washed with isohexane (5 mL) and dried to give the title compound (257 mg, 72%) as a white solid. 1H NMR 2.86 (dd, IH), 3.23 (dd, IH), 3.88 (dd, 2H), 4.70 (m, IH), 5.39 (t, IH), 5.50 (t, IH), 7.00 (s, IH), 7.18 (m, 5H), 8.10 (d, IH), 8.51 (d, IH), 11.81 (s, IH); MS m/z 391, 393.
Example 59: 2,3-DichIoro-iV-{(lR,2R)-l-r(chloroacetyl)aminol-2 -dihydro-lH-inden-2- yl}-4H-thienor3,2-b1pyrrole-5-carboxamide
Figure imgf000101_0001
N-[(lR,2R)-l-Amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide (Method 8, 602 mg, 1.6 mmol) was dissolved in dichloromethane (30 mL), to this was added triethylamine (0.25 mL, 1.8 mmol) and chloroacetyl chloride (0.14 mL, 1.8 mmol). The solution was stirred at ambient temperature for 16 hours, after which triethylamine (0.25ml, 1.8mmol) and chloroacetyl chloride (0.14ml, 1.8mmol) were added before stirring for 1 hour. To the resulting slurry, water (15 mL) was added before filtering to give the title product (532 mg, 73%) as a cream solid.
1HΝMR 2.88 (m, 1Η), 3.25 (m, 1Η), 4.11 (s, 2Η), 4.63 (m, IH), 5.47 (t, IH), 7.13 ( , 2H), 7.23 (m, 3H), 8.63 (d, IH), 8.73 (d, IH), 12.38 (s, IH); MS m/z 442.
Example 60: iV-{(lR,2R)-l-r((35)-3-Amino-3-carboxypropanoyl)aιninol-2,3-dihvdro- lH-inden-2-yl>-2.,3-dichloro-4Hr-thieno(3,2.,b1pyrrole-5-carboxamide
Figure imgf000101_0002
N-[(lR,2R)-l-Amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide (Method 8, 350 mg, 0.73 mmol) was added to a solution of N- α-/j>bα-t-Boc-E-aspartic acid alpha-t- butyl ester (232 mg, 0.80 mmol), 1-hydroxybenzotriazole monohydrate (123 mg, 0.80 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.80 mmol), 4-methylmorpholine (0.18 mL, 1.6 mmol) in N,N- dimethylformamide (20 mL). The mixture was stirred at ambient temperature for 16 hours.
The volatiles were removed by evaporation and the residue was dissolved in ethyl acetate (20 mL) and water (10 mL), the layers were separated before washing with 2 ΗC1 then saturated
ΝaHCO3. Evaporation afforded a white solid which was redissolved in dichloromethane (5 L) and trifluoroacetic acid (5 mL), the solution was allowed to stir at ambient temperature for 2 hours. The volatiles were removed by evaporation and the residue triturated with ether, collected by filtration, washed with ether (2 x 10 ml) and dried to give the title compound (210 mg, 48%) as a white solid. 1H NMR 2.85 (m, 2H), 3.25 (m, 2H), 3.94 (t, IH), 4.56 (m, IH), 5.45 (t, IH), 7.11 (s, IH), 7.23 (m, 4H), 8.64 (d, IH), 8.73 (d, IH); MS m/z 481.
The following examples were prepared in a similar manner to Example 60 using N- [(lR,2R)-l-amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5- carboxamide (Method 8) or N-{(lR,2R)-l-amino-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno[2,3-b]pyrrol-5-yl)-2-carboxamide (Method 21) as the amine component and the appropriately protected carboxylic acid as starting material, prior to deprotection.
Example 61: N-{(lR,2R)-l-r(2-Carboxyacetyl)amino1-2,3-dihydro-lH-inden-2-vU-2,3- dichIoro-4H-thieno(3,2,blpyrrole-5-carboxamide
Figure imgf000102_0001
1HΝMR 2.84 (m, 1Η), 3.25 (m, 3Η), 4.56 (m, IH), 5.47 (t, IH), 7.11 (s, IH), 7.20 (m, 4H), 8.59 (m, IH), 12.36 (s, IH); MS m/z 452. Example 2: N-{(lR,2R)-l-r(2-Carboxyacetyl)amino1-2,3-dihydro-lHr-inden-2-yl>-2- chloro-6H-thieno(3,2,b1pyrrole-5-carboxamide Example 63: iV-{(lR,2R)-l-r((3S)-3-Amino-3-carboxypropanovDamino1-2-3-dihvdro-lH- inden-2-yl>-2-chIoro-6H-thieno(3,2,b1pyrrole-5-carboxamide
Figure imgf000103_0001
Figure imgf000103_0003
Example 64: 2<3-Dichloro-iV-{(lR,2R)-l-r(methylsulfonyl)aminol-2,3-dihvdro-lH-inden- 2-yl>-4H-thienor3,2-b1pyrrole-5-carboxamide
Figure imgf000103_0002
N-[(lR,2R)-l-Amino-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide trifluoroacetate salt (Method 8, 223 mg, 0.5 mmol) was dissolved in TΗF (4 mL) and the solution cooled to 0 °C. Et3Ν (223 μL, 1.6 mmol) then methanesulfonyl chloride (43 μL, 0.55 mmol) were added and the reaction was stirred 0 °C for 5 mins.
Saturated aqueous NaΗCO3 (5 mL) was added, the phases separated and the aqueous phase extracted with EtOAc (3 x 10 mL). The combined organic fractions were washed with H2O (20 mL), dried (MgSO ) and the solvent removed under reduced pressure. The residue was subjected to purification by reverse phase preparative HPLC to afford the title compound (30 mg, 15%) as a white solid.
1H NMR 2.83 (dd, IH), 2.98 (s, 3H), 3.22 (dd, IH), 4.55 (m ,1H), 4.96 (t, IH), 7.01 (s, IH), 7.23 (m, 5H), 7.87 (d, IH), 8.57 (d, IH), 11.90 (s, IH); MS m/z 410, 412.
Method 1
3-Chloro-5-methoxycarbonyl-4H-thienor3.2-blpyrrole
Figure imgf000104_0001
Methanolic sodium methoxide solution (28%) (5 ml, 25.9 mmol) was diluted with
MeOH (5 ml) and was cooled to -25°C under nitrogen. A solution of 4-chloro-2- thiophenecarboxaldehyde (J Heterocyclic Chem, 1976, 13, 393; 1.1 g, 7.5 mmol) and methyl azidoacetate (3.0 g, 26.1 mmol) in MeOH (20 ml) was added dropwise, maintaining the temperature at -25 °C. On completion of addition the solution was allowed to warm to 5°C over a period of approximately 16 hours. The solution was added to saturated aqueous ammonium chloride (250 ml) and the mixture was extracted using DCM. The combined organic layers were concentrated at 0°C. The residue was taken up in xylene (30 ml) and this solution was added dropwise to xylene (120 ml) under reflux. The solution was heated under reflux for 30 minutes before being cooled and concentrated. The title compound was purified by a mixture of crystallisation (EtOAc/isohexane) and chromatography on a Bond Elut column eluting with a graduated solvent of 5-50% EtOAc in isohexane (640 mg, 40%). NMR (CDC13) 9.1 (IH, br), 7.1 (2H, s), 3.9 (3H, s); m z 214.3.
Method 2 and 2a The following compounds were made by the process of Method 1 using the appropriate starting materials
Method 2: 2,3-Dichloro-5-methoxycarbonyl-4H-thienor3,2-blpyrrole Method 2a: : 2-Chloro-5-methoxycarbonyl-6H-thienor2,3-blpyrrole
Figure imgf000105_0001
1 Aldehyde: D] E 2814798
2 Aldehyde: Gronowitz et al. Tetrahedron Nol.32 1976 p.1403
5 Method 3
5-Carboxy-3-chloro-4H-thienor3,2-blpyrrole
Figure imgf000105_0002
3-Chloro-5-methoxycarbonyl-4H-thieno[3,2-b]pyrrole (Method 1; 0.61 g, 2.83 mmol) was taken up in MeOΗ (10 ml) and was heated under reflux. Aqueous lithium hydroxide (2.0
10 M, 3.0 ml, 6.0 mmol) was added portionwise over 45 minutes. The mixture was heated under reflux for 30 minutes before being cooled and concentrated. Water (20 ml) was added and the solution was neutralised using aqueous hydrochloric acid (2.0 M, 3.0 ml). The solution was extracted using EtOAc, and the combined organic layers were concentrated to afford the title compound as a yellow solid (0.57 g, 100%). ΝMR: 12.4 (1Η, br), 7.4 (1Η, s), 7.0 (1Η, s); m/z
15 200.3.
Method 4 and 4a
The following compounds were made by the process of Method 3 using Methods 2 and 2a as starting materials. 20 Method 4: 5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]ρyrrole Method 4a: 5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole
Figure imgf000106_0003
Method 5
Cis - 1 - f( 1 , 1 -Dimethylethoxy)carbonylamino1 -2 hydroxyindan
Figure imgf000106_0001
Cw-l-Amino-2-hydroxyindan (12.0g, 80.5mmol) was dissolved in DCM (500 ml) and triethylamine (22.4 ml, lόlmmol). Di-tert-butyl dicarbonate (22.0g, lOOmmol) in DCM (50 ml) was added and the mixture stirred at room temperature for 20 hours then evaporated. EtOAc (200 ml) was added, the solution washed with water, dried over magnesium sulphate and evaporated. The crude product was purified by chromatography on silica with 4:1 iso- hexane:EtOAc as eluent to give the title compound (17.9 g, 90%) as a white solid. 1H NMR 1.42 (s, 9H), 2.78 (dd, IH), 3.00 (dd, IH), 4.40 (m, IH), 4.85 (m, IH), 4.95 (m, IH), 6.30 (d, IH), 7.10 (m, 4H).
Method 6
Trans-2- Amino- 1 -f( 1 ■ 1 -dimethylethoxy carbonylaminolindan
Figure imgf000106_0002
Cz-f-l-[(l,l-Dimethylethoxy)c-ιrbonyl-unino]-2-hydroxyindan (Method 5; 14.0g,
56.2mmol) was dissolved in DCM (200 ml) and triethylamine (11.8 ml, 84.3mmol).
Methanesulfonyl chloride (7.1g, 61.9rnmol) dissolved in DCM (20 ml) was added and the mixture stirred at room temperature for 3 hours. The mixture was evaporated and EtOAc (250 ml) added. After washing with water and drying over magnesium sulphate the organic solution was evaporated to yield Cw-l-[(l,l-dimethylethoxy)carbonylamino]-2- methanesulphonyloxyindan (9.7g, 98%) as a white solid.
1H NMR 1.45 (s, 9H), 3.15 (m, 2H), 3.18 (s, 3H), 5.20 (m, IH), 5.35 (m, IH), 7.15 (m, 4H),
7.45 (d, IH).
Cis- 1 - [( 1 , 1 -dimethylemoxy)carbonylamino] -2-methanesulphonyloxyindan ( 18.1 g,
55.3mmol) was dissolved in dry dimethyl acetamide (100 ml). Sodium azide (5.4g,
83.0mmol) was added and the mixture heated to 90°C for 6 hours. The reaction was cooled, diluted with ethyl acetate (150 ml), washed with water (6 x 200 ml) and dried over magnesium sulphate. 10% Palladium on activated carbon was added and the mixture stirred under a hydrogen atmosphere for 24 hours. Filtration through celite followed by evaporation gave the title compound (2.6g, 98%) as a white solid.
1H NMR: 1.45 (s, 9H), 2.50 (dd, IH), 3.05 (dd, IH), 3.30 (m, 3H), 4.55 (m, IH), 7.1 (m, 5H).
Method 7
23-Dichloro-5-(N-l(lR.2RVl-rN-( l-dimethylethoxy)carbonylamino1indan-2- yl}carbamoyl)-4H-thienor3,2-blpyrrole
Figure imgf000107_0001
2-aπuno-l-{N-[(l,l-dimethylethoxy)]carbonylamino}indan (Method 6; 2.5g, lO.Ommol), DIPEA (1.7 ml, lO.Ommol) and ΗOBT (1.35g, lO.Ommol) was stirred in DCM (75 ml) at room temperature for 2 minutes. EDCI (2.4g, 12.5mmol) was added and the mixture stirred at room temperature for 20 hours during which time the product precipitated. The reaction was filtered, washed with DCM (2 x 25 ml) and dried to give the title compound (3.7 g, 80%) as a pale green powder.
1H NMR 1.40 (s, 9H), 2.81 (dd, IH), 3.20 (dd, IH), 4.55 (m, IH), 5.15 (m, IH), 7.15 (m, 5H),
7.35 (d, IH), 8.55 (d, IH), 12.36 (broad s, IH); m/z 463.7/465.7.
Method 8
N-r(lR.2RVl-Arnino-2.3-dihvdro-lH-inden-2-yll-2.3-dichloro-4H-thienor3.2-blpyrrole-5- carboxamide
Figure imgf000108_0001
2,3 -Dichloro-5-(N- { 1 - [( 1 , 1 -dimethylethoxy)carbonylamino]indan-2-yl } carbamoyl)-
4H-thieno[3,2-b]ρyrrole (Method 7; 3.7g, 7.9mmol) was dissolved in DCM (75 ml). Trifluoroacetic acid (10 ml) was added and the mixture stirred at room temperature for 24 hours. The reaction was filtered and the isolated solid washed with DCM to give the trifluoroacetic acid salt of the title compound (3.1g, 82%) as a pale green powder. 1H ΝMR 3.05 (dd, 1Η), 3.42 (d, 1Η), 4.7 (m, 2Η), 7.20(d, IH), 7.35 (m, 3H), 7.55 (d, IH), 8.60 (broad s, 3H), 8.80 (d, IH), 12.5 (broad s, IH).
Method 9
N-r(lS.2S)-l-Amino-2.3-dihvdro-lH-inden-2-yll-2.3-dichloro-4H-thienor3,2-blpyrrole-5- carboxamide
Figure imgf000108_0002
The title compound was prepared in an analogous fashion to Method 8. 1H NMR 3.05 (dd, IH), 3.42 (d, IH), 4.7 (m, 2H), 7.20(d, IH), 7.35 (m, 3H), 7.55 (d, IH), 8.60 (broad s, 3H), 8.80 (d, IH), 12.5 (broad s, IH). Method 10
2 -Dichloro-N-{(lR.2R)-l-r(chloroacetviymethvnaminol-23-dihvdro-lH-inden-2-yl)-4H- thienor3,2-blpyrrole-5-carboxamide
Figure imgf000109_0001
2,3-Dichloro-N-[(lR,2R)-l-(methylamino)-2,3-dihydro-lH-inden-2-yl]-4H-thieno[3,2- b]pyrrole-5-carboxamide (Method 11; 300 mg, 0.79 mmol) and triethylamine (167 μL, 1.2 mmol) was dissolved in DCM (5 mL), chloroacetyl chloride (73 μL, 0.9 mmol) added and the reaction stirred at ambient temperature for 2 hours. The volatiles were removed by evaporation under reduced pressure and EtOAc (15 mL) added. The mixture was washed with water (10 mL), brine (10 ml), dried (MgSO4) and the volatiles were removed by evaporation under reduced pressure to give the title compound (310 mg, 86%) as a pale brown foam. 1H ΝMR 2.73 (d, 3Η), 2.98 (m, IH), 3.24 (m, IH), 4.45 (m, 2H), 4.82 (m, IH), 5.77 (dd, IH), 7.05 (m, 2H), 7.28 (m, 3H), 8.65 (m, IH); MS m/z 456.
Method 11
2.3-Dichloro-N-r(lR,2R)-l-(methylamino)-2.3-dihvdro-lH-inden-2-yll-4H-thienor3.2- bl pyrrole-5 -carboxamide
Figure imgf000109_0002
tert-Butyl ((lR,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]pyrtol-5-yl)carbonyl]amino}- 2,3-dihydro-lH-inden-l-yl)methylcarbamate (Method 12; 900 mg, 1.87 mmol) was dissolved in DCM (20 mL), TFA (2 mL) added and the reaction stirred at ambient temperature for 1 hour. The volatiles were removed by evaporation under reduced pressure and the residue purified by ion exchange chromatography (MeOΗ: Water 1:1 then MeOΗ:Water:ΝΗ-tOΗ 1:1:0.05) to afford, after evaporation, the title compound (300 mg, 32%) as an off white powder. 1H NMR 2.75 (s, 3H), 3.01 (dd, IH), 3.49 (dd, IH), 4.75 (m, IH), 4.86 (m, IH), 7.11 (d, IH),
7.35 (m, 3H), 7.58 (d, IH), 8.74 (d, IH), 9.04 (m, IH), 12.37 (s, IH); MS m/z 380.
Method 12 tert-Butyl (( 1R.2RV2- ( r(2 -dichloro-4H-thienor3.2-blρyrrol-5-vDcarbonyll amino I -2.3- dihydro- lH-inden- 1 - vDmethylcarbamate
Figure imgf000110_0001
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method 4, 472 mg, 2.0 mmol), tert- butyl [(lR,2R)-2-amino-2,3-dihydro-lH-inden-l-yl]methylcarbamate (Method 13; 524 mg, 2.0 mmol), DIPEA (348 μL, 2.0 mmol), ΗOBT (270 mg, 2.0 mmol) and EDCI (480 mg, 2.5 mmol) were dissolved in DCM (10 mL) and stirred at ambient temperature for 20 hours. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (50 mL), washed with water (3 x 25 mL), brine (25 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (900 mg, 93%) as a pale brown foam.
1H NMR 1.29 (m, 9Η), 2.66 (s, 3H), 2.9-3.25 (m, 2H), 4.8 (m, IH), 5.64 (m, IH), 6.23-7.34 (m, 4H), 8.65 (m, IH); MS m/z 480.
Method 13 tert-Butyl r(lR,2R)-2-amino-2,3-dihvdro-lH-inden-l-yllmethylcarbamate
Figure imgf000110_0002
(lR,2S)-l-[(tert-Butoxyc-ιrbonyl)(methyl)amino]-2,3-dihydro-lH-inden-2-yl methanesulfonate (Method 14; 3.0g, 8.8mmol) and sodium azide (2.3 g, 35.2 mmol) in dry DMA (30 mL) was heated to 90°C for 7 hours. The reaction was cooled and ethyl acetate (100 rnL) added. The mixture was washed with water (6 x 25 mL), brine (50 mL) and dried (MgSO4). 10% Palladium on carbon (400 mg) was added to the organic solution which was stirred under a hydrogen atmosphere for 4h, filtered through Celite and evaporated. The residue was purified by column chromatography (EtOAc and then DCM:MeOH 9:1) to afford the title compound (1.2 g, 55%) as a pale brown oil.
1H NMR 1.45 (m, 9H), 2.6 (s, 3H), 2.8 (m, IH), 3.3 (m, IH), 4.45 (m, IH), 5.55 (dd, IH),
7.26 (m, 4H); MS m/z 264.
Method 14
( 1R.2S)- 1 -r(tert-Butoxycarbonyl) ( methyPaminol -2,3-dihydro- lH-inden-2-yl methanesulfonate
Figure imgf000111_0001
tert-Butyl [(lR,2S)-2-hydroxy-2,3-dihydro-lH-inden-l-yl]methylcarbamate (Method
15; 3.0 g, 11.4 mmol) was dissolved in dry TΗF (40 mL) at 10°C. A solution of methane sulphonyl chloride (1.44 g, 12.55 mmol) in dry TΗF (10 mL) was added, the reaction allowed to warm to ambient temperature and stirred for 30 mins. The volatiles were removed by evaporation under reduced pressure and ethyl acetate (100 mL) added. The mixture was washed with water (2 x 50 mL), brine (50 mL) and the organic phase was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (EtOAc:Ηexane) to afford the title compound (3.1g, 80%)as a colourless syrup. 1H NMR 1.46 (s, 9H), 2.61 (s, 3H), 3.12 (m, IH), 3.18 (s, 3H), 3.32 (m, IH), 5.45 (m, IH), 5.68 (m, IH), 7.28 (m, 4H); MS m/z 342.
Method 15 tert-Butyl T( lR,2S)-2-hvdroxy-2,3-dihydro- lH-inden- 1 -yllmethylcarbamate
Figure imgf000111_0002
tert-Butyl methyl[(lR,2S)-2-(tetrahydro-2H-ρyran-2-yloxy)-2,3-dihydro-lH-inden-l- yl]carbamate (Method 16; 4.0 g, 11.5 mmol) was dissolved in methanol (50 mL), 4-toluene sulphonic acid added and the reaction stirred at ambient temperature for 2 hours. Saturated NaHCO3 (50 mL), water (100 mL) was added and ethyl acetate (100 mL) was added and the mixture stirred for 30 mins. The organic phase was separated, washed with water (50 mL), brine (50 mL) and dried (MgSO ). The volatiles were removed by evaporation under reduced pressure to give the title compound (3.0 g, 99%) as an oil. 1H NMR 1.45 (s, 9H), 2.6 (s, 3H), 2.75 (m, IH), 3.05 (m, IH), 4.5 (m, IH), 5.05 (m, IH), 5.34
(m, IH), 7.03-7.3 (m, 4H).
Method 16 tert-Butyl methvir(lR,2S)-2-(tetrahvdro-2H-pyran-2-yloxyV2.3-dihvdro-lH-inden-l- yllcarbamate
Figure imgf000112_0001
tert-Butyl [( lR,2S)-2-(tetrahydro-2H-pyran-2-yloxy)-2,3-dihydro- lH-inden- 1 - yljcarbamate (Method 17; 4.0 g, 12.0 mmol) was dissolved in dry DMA (25 mL) at 5°C. 60% Sodium hydride (575 mg, 14.4 mmol) was added, the reaction stirred at 5°C for 30 mins, allowed to warm to ambient temperature and stirred for a further 30 mins. Methyl iodide (896 μL, 14.4 mmol) was added and the reaction stirred at ambient temperature for 3 hours. The reaction was poured into water (100 mL) and extracted with ethyl acetate (2 x 50ml). The organic extracts were washed with water (6 x 25 mL), brine (50 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (4.1 g, 97%) as an oil.
1H NMR 1.4-1.9 (m, 6Η), 1.5 (s, 9H), 2.7 (dd, 3H), 2.85-3.3 (m, 2H), 3.5 (m, IH), 3.7-4.0 (m, IH), 4.6-4.9 (m, 2H), 5.5-5.85 (m, IH), 7.2 (s, 4H).
Method 17 tert-Butvi rαR.2S)-2-(tetrahvdro-2H-pyran-2-yloxyV2.3-dihvdro-lH-inden-l-yllcarbamate
Figure imgf000113_0001
tert-Butyl [(lR,2S)-2-hydroxy-2,3-dihydro-lH-inden-l-yl]carbamate (Method 15, 7.0 g, 28.1 mmol) and 3,4-dihydro-2Η-pyran (4.7 g, 56.2 mmol) dissolved in DCM (50 mL). 4- Toluene sulphonic acid pyridinium salt (100 mg) was added and the reaction stirred for 4 hours at ambient temperature. The reaction was diluted with ethyl acetate (100 mL), washed with water (2 x 50 mL), brine (50 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (8.9 g, 95%) as an oil. 1HNMR 1.25-1.85 (m, 6H), 1.45 (s, 9H), 2.85-3.1 (m, 2H), 3.4 ( , IH), 3.8 (m, IH), 4.35-5.1 (m, 3H), 6.8 (dd, IH), 7.2(s, IH).
Method 18
Ll-Dimethylethvi racetyl((lR.2RV2-i r(2.3-dichloro-4H-thieno[3.2-b1pyrrol-5- vDcarbonvU amino ) -2,3-dihydro- lH-inden- l-yl)aminol acetate
Figure imgf000113_0002
Acetyl chloride (7 μL, 0.1 mmol) was added to a solution of N-(lR,2R)-l-[(tert- butoxycarbonylmethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide (Example 29, 50 mg, 0.1 mmol) in TΗF (5 mL). The reaction was stirred at ambient temperature for 1 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (5 mL), washed with water (2 5 mL), brine (10 mL) and dried (MgSO ). The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc:isohexane 1:1) to afford the title compound (168 mg, 76%) as a white solid.
1H ΝMR 1.40 (s, 9Η), 2.75 (dd, IH), 3.42 (m, 2H), 3.60 (dd, IH), 3.90 (s, 3H), 4.15 (d, IH), 4.45 (m, IH), 6.83 (d, IH), 7.20 (m, 4H), 7.70 (d, IH), 9.70 (s, IH); MS m/z 522. Method 19 rr(Acetyloxy)acetyll((lR.2R)-2-{r(23-dichloro-4H-thienor3.2-blpyrrol-5-vDcarbonvnamino}-
2.3-dihydro- lH-inden- 1 -yPaminol acetic acid
Figure imgf000114_0001
TFA (3 mL) was added to a solution of 1,1-dimethylethyl
[[(acetyloxy)acetyl]((lR,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]ρyrrol-5-yl)carbonyl]amino}- 2,3-dihydro-lH-inden-l-yl)amino]acetate (Method 20, 130 mg, 0.25 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 2 h. The volatiles were removed by evaporation under reduced pressure to afford the title compound (130 mg, 99%) as a white solid.
1H NMR 2.20 (s, 3Η), 2.78 (dd, IH), 3.32 (dd, IH), 3.97 (m, 2H), 4.35 (d, IH), 4.68 (m, 2H), 4.90 (d, IH), 6.42 (d, IH), 6.83 (s, IH), 7.25 (m, 4H), 11.14, (s, IH); MS m/z 524.
Method 20 l-Dimethylethvi rr(acetyloxy acetyll((lR,2R)-2-{ r(2.3-dichloro-4H-thienor3.2-blpyrrol-5- y carbonyll amino j -2,3-dihydro- lH-inden- 1 -vDamino] acetate
Figure imgf000114_0002
Acetoxyacetic acid (34 mg, 0.3 mmol) andDMTMM (81 mg, 0.3 mmol) were added to a solution of N-(lR,2R)-l-[(tert-butoxycarbonylmethyl)amino]-2,3-dihydro-lH-inden-2- yl}-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 29, 140 mg, 0.3 mmol) in TΗF (10 mL). The reaction was stirred at ambient temperature for 7 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with water (2 5 mL), brine (10 mL) and dried (MgSO ). The volatiles were removed by evaporation under reduced pressure to afford the title compound (145 mg, 83%) as a white solid.
1H NMR 1.45 (s, 9H), 2.10 (s, 3H), 2.75 (dd, IH), 3.50 (m, 3H), 3.90 (m, 2H), 4.15 (d, IH), 4.50 (m, IH), 6.83 (s, IH), 7.20 (m, 4H), 7.70 (d, IH), 9.70 (s, IH); MS m/z 580.
Method 21
N-r(lR,2RVl-Amino-2,3-dihvdro-lH-inden-2-yll-2-chloro-6H-thienor2,3-blpyrrole-5- carboxamide
Figure imgf000115_0001
tert-Butyl ((lR,2R)-2-{[(2-Chloro-6H-thieno[2,3-b]ρyrrol-5-yl)carbonyl]amino}-2,3- dihydro-lH-inden-l-yl)carbamate (Method 22, 10.6 g, 24.5 mmol) was suspended in DCM
(200 mL), TFA (20 mL) added and the reaction stirred at ambient temperature for 20 hours.
The volatiles were removed by evaporation under reduced pressure and the residue triturated with DCM (50 mL) then filtered and dried to give the title compound (10.9 g, 100 %) as the trifluoroacetic acid salt.
1H NMR 3.03 (dd, 1Η), 3.38 (dd, 1Η), 4.7 (m, 2Η), 7.06 (d, IH), 7.17 (s, IH), 7.35 (m, 3H),
7.55 (m, IH), 8.55 (s, 3H), 8.68 (d, IH), 11.9 (s, IH); MS m/z (M-NH3)+315, 317.
Method 22 tert-Butyl ((lR.2RV2-{r(2-chloro-6H-thienor2,3-blpyrrol-5-yl)carbonyllamino}-2,3-dihvdro- lH-inden- 1 - vDcarbamate
Figure imgf000115_0002
2-Chloro-5-carboxy-6H-thieno[3,2-b]pyrrole (Method 4a, 5.0 g, 25.0 mmol), trans-2- amino-l-[(l,l-dimethylethoxy)carbonylamino]indan (Method 6, 6.25 g, 25.0 mmol), DIPEA (4.35 mL, 25.0 mmol) and HOBT (3.4 g, 25.0 mmol) were dissolved in DCM (200 mL) and stirred for 5 mins. EDCI (6.0 g, 31.0 mmol) was added, the reaction stirred for 24 hours and evaporated under reduced pressure. EtOAc (150 mL) was added and the mixture filtered, washed with water (2 x 200 mL), brine (200 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (10.6g, 98%) as a brown solid.
1H NMR 1.38 (s, 9H), 2.81 (dd, IH), 3.17 (dd, IH), 4.56 (m, IH), 5.14 (m, IH), 7.01 (s, IH),
7.16 (m, 5H), 7.32 (d, IH), 8.47 (d, IH), 11.82 (s, IH).
Method 23
2-Chloro-N-{(lR,2R)-l-r(chloroacetyl)aminol-2,3-dihvdro-lH-inden-2-yll-6H-thienor2,3- blρyrrole-5-carboxamide
Figure imgf000116_0001
Et3Ν (3 mL, 21.6 mmol) was added to a suspension of N-[(lR,2R)-l-amino-2,3- dihydro-lH-inden-2-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 21, 3.11 g, 6.98 mmol) in anhydrous dichloromethane (55 mL) and stirred at ambient temperature for 5 miuntes. The suspension was cooled to -78 °C and chloroacetylchloride (611 μL, 7.68 mmol) was added and the reaction was warmed to 0 °C and stirred at this temperature for 3 hours. ΝaΗCO3 (50 mL) was added, the phases were separated and the aqueous phase was extracted with THF (2 x 50 mL). The combined organic fractions were washed with water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was triturated (THF sohexane, 1:5), collected by filtration, washed with hexane (20 mL) and dried to give the title compound (1.92 mg, 68%) as a brown solid.
1H NMR 2.88 (dd, IH), 3.24 (dd, IH), 4.11 (dd, 2H), 4.61 (m, IH), 5.46 (t, IH), 6.99 (s, IH), 7.20 (m ,5H), 8.55 (d, 2H), 8.73 (d, IH), 11.84 (s, IH); MS m/z 408, 410.

Claims

Claims
1. A compound of formula ( 1 ) :
Figure imgf000117_0001
wherein:
Z is CH or nitrogen;
R4 and R5 together are either -S-C(R6)=C(R7)- or -C(R7)=C(R6)-S- ;
R and R are independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl,
Cι-4alkyl, C2- alkenyl, C2- alkynyl, C1- alkoxy and Cι-4alkanoyl;
A is phenylene or heteroarylene; n is 0, 1 or 2;
R1 is independently selected from halo, nitro, cyano, hydroxy, carboxy, carbamoyl, N-Cι-4alkylcarbamoyl, N,N-(Cι-4alkyl)2carbamoyl, sulphamoyl, N-Cι- alkylsulphamoyl,
N,N-(Cι-4alkyl)2sulphamoyl, -S(O)bCι-4alkyl (wherein b is 0,1, or 2), Cι-4alkyl, C2-4alkenyl,
C2-4alkynyl, C1- alkoxy, Cι-4alkanoyl, Ci- alkanoyloxy, hydroxyCι- alkyl, 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; r is 1 or 2; and when r is 1 the group
Figure imgf000117_0002
is a substituent on carbon (2) and when r is 2 (hereby forming a six membered ring) the same group is a substituent on carbon (2) or on carbon (3); Y is -ΝR2R3 or -OR3; R2 and R3 are independently selected from hydrogen, hydroxy, Cι- alkoxy, Cι- alkanoyl, carbamoyl, C3-7cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), cyano(Cι- )alkyl, heterocyclyl, aryl, C1-4alkyl [optionally substituted by 1 or 2 R8 groups],
-COR8, -SObR8 (wherein b is 0, 1 or 2) and groups of the formulae B and B ' :
Figure imgf000118_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; or wherein NR2R3 may form a 4 to 7 membered saturated, partially saturated or unsaturated ring, optionally containing 1, 2 or 3 additional heteroatoms independently selected from N, O and S, wherein any -CH - may optionally be replaced by -C(=O)-, and any N or S atom may optionally be oxidised to form an N-oxide or SO or SO2 group respectively, and wherein the ring is optionally substituted by 1 or 2 substituents independently selected from halo, cyano, Cι- alkyl, hydroxy, Cι- alkoxy and C1- alkylS(O)b- (wherein b is 0, 1 or 2);
R8 is independently selected from hydrogen, hydroxy, Cι-4alkyl, C2- alkenyl, Cι-4alkoxy, cyano(Ci-4)alkyl, amino(C1- )alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Cι-4alkyl, hydroxy, hydroxy(Cι-4)alkyl, dihydroxy(Cι-4)alkyl, -CO2C1-4alkyl, aryl and aryl(Cι- )alkyl], halo(Cι-4)alkyl, dihalo(C1-4)alkyl, trihalo(C1-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(C1-4)alkyl, Cι-4alkoxyCι- alkoxy, C1.4alkoxyCι-4alkyl, hydroxyCι-4alkoxy, 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, aryl, heterocyclyl, (heterocyclyl)Cι-4alkyl, C3-7cycloalkyl (optionally substituted with 1 or 2 hydroxy groups, Cι-4alkyl or -C(O)OCι- alkyl), Cι- alkanoyl, C1- alkylS(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), Cι-4alkylS(O)c(Cι-4)alkyl (wherein c is 0, 1 or 2), -N(OH)CHO, -C(=N-OH)NH2, -C(=N-OH)NHCι-4alkyl, -C(=N-OH)N(Cι-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, -CH2OR9, -CH2COOR9, -CH2OCOR9, -CH2CH(CO2R9)OH, -CH2C(O)NR9R10,
-(CH2)WCH(NR9R10)CO2R9' (wherein w is 1, 2 or 3), and -(CH2)WCH(NR9R10)CO(NR9'R10')
(wherein w is 1, 2 or 3) ;
R9 , R9 , R10 and R10' are independently selected from hydrogen, hydroxy, Cι. alkyl (optionally substituted by 1 or 2 R13), C2.4alkenyl, C3.7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups), cyano(Cι.4)alkyl, trihaloalkyl, aryl, heterocyclyl, heterocyclyl(Cι- alkyl), and -C(=O)O(Cι-4)alkyl; or
R9 and R10 together with the nitrogen to which they are attached, and/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 halo, trihalomethyl, and Cι-4alkoxy; R11 is independently selected from hydrogen, Cι- alkyl, and hydroxyCι- alkyl; or a pharmaceutically acceptable salt or pro-drug thereof; with the proviso that the compound of formula (1) is not: i) 2,3-dichloro-5-(N-{l-[N-(l,l-dimethylethoxy)carbonylamino]indan-2- yl}carbamoyl)-4H-thieno[3,2-b]pyrrole; ii) 5-[N-(l-aminoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iii) 5-[N-(l-acetamidoindan-2-yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole iv) 2,3-dichloro-5-{N-[l-(methanesulphonamido)indan-2-yl]carbamoyl}-4H- thieno[3,2-b]pyrrole v) 2,3 -dichloro-5- { N- [ 1 -(methylamino)indan-2-yl] carbamoyl } -4H-thieno [3 ,2- bjpyrrole; vi) 2,3-dichloro-5-{N-[l-(methylacetamido)indan-2-yl]carbamoyl}-4H-thieno[3,2- bjpyrrole; vii) 2,3-dichloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole; viii) 2-chloro-5-[N-(l-hydroxyindan-2-yl)carbamoyl-6H-thieno[2,3-b]pyrrole; ix) 2,3-dichloro-5-[N-(6-fluoro-l-hydroxyindan-2-yl)carbamoyl-4H-thieno[3,2- bjpyrrole x) 2,3-dichloro-5-[N-(l-methoxyindan-2-yl)carbamoyl-4H-thieno[3,2-b]pyrrole; xi) 2,3-dichloro-5-[N-(l-hydroxy-l,2,3,4-tetrahydronaphth-2-yl)carbamoyl]-4H- thieno[3,2-b]pyrrole.
2. A compound of the formula (1) as claimed in claim 1, wherein: R2 and R3 are independently selected from hydrogen, hydroxy, Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], C3-7cycloalkyl (optionally substituted with 1 or 2 hydroxy groups), cyano(Cι-4)alkyl, phenyl, morpholino, morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, thiadiazolyl, piperazinyl, isothiazolidinyl, 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, -COR8 and -SObR8 (wherein b is 0, 1 or 2); R is independently selected from hydrogen, hydroxy, Cι-4alkoxy, Cι-4alkoxyCι-4alkyl, Cι- alkoxyCι- alkoxy, hydroxyC1- alkoxy, C1-4alkyl, amino(Cι-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from C1-4alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι- )alkyl, -CO2Cι-4alkyl, aryl and aryl(Cι-4)alkyl], C2-4alkenyl, C3-7cycloalkyl (optionally substituted by -C(O)OCι. alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, dihalo(C1- )alkyl, trihalo(Cι-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(C1-4)alkyl, cyano(Cι-4)alkyl, heterocyclyl, heterocyclylCι-4alkyl, aryl,
Cι- alkylS(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), C1. alkylS(O)c(Cι.4)alkyl (wherein c is 0, 1 or 2), - CΗ2CΗ(NR9R10)CO(NR9'R10'), -CΗ2OR9, (R9)(R10)N-, -COOR9, -CΗ2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9;
R9 , R9 , R10 and R10 are independently selected from hydrogen, Cι. alkyl (optionally substituted by 1 or 2 R13), C3-7cycloalkyl (optionally substituted by 1 or 2 hydroxy groups), -C(=O)OlBu, C2.4alkenyl, cyano(Ci-4)alkyl and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or
R9 and R10 together with the nitrogen to which they are attached, and/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 and Cι- 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;
R13 is selected from halo, trihalomethyl and Cι-4alkoxy; 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:
R2 and R3 are independently selected from hydrogen, Cι-4alkyl [optionally substituted by 1 or 2 R8 groups], -COR8 and -SObR8 (wherein b is 0, 1 or 2); R is independently selected from hydrogen, hydroxy, Cι.4alkoxy, C1.4alkoxyC1-4alkyl, - 4alkyl, amino(C1-4)alkyl [optionally substituted on nitrogen by 1 or 2 groups selected from Ci- alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι- )alkyl, -CO2Cι-4alkyl, phenyl and aryl(C1-4)alkyl], C -4alkenyl, C3- cycloalkyl (optionally substituted by -C(O)OCι-4alkyl), 5- and 6-membered cyclic acetals and mono- and di-methyl derivatives thereof, halo(Cι-4)alkyl, trihalo(C1-4)alkyl, hydroxy(Cι-4)alkyl, dihydroxy(Cι- )alkyl, cyano(Cι. )alkyl, furyl (optionally substituted on carbon by 1 or 2 nitro groups), thienyl (optionally substituted on carbon by 1 or 2 nitro groups), morpholino, furyl(Cι-4)alkyl (wherein furyl is optionally substituted on carbon by 1 or 2 nitro groups), thienyl(Cι-4)alkyl (wherein thienyl is optionally substituted on carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, pyridyl, tetrahydrofuryl, tetrahydropyranyl, l-oxo-tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, cyano, hydroxy and Ci. 4alkyl), pyrazinyl, piperazinyl, 4-methylpiperazino, C1. alkylS(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 -CH2CH(NR9R10)CO(NR9'R10'), -CH2OR9, (R9)(R10)N-, -COOR9, -CH2COOR9 , -C(O)N(R9)(R10), -CH2CH(CO2R9)OH, -CH2CONR9R10, -CH2CH(NR9R10)CO2R9' and -CH2OCOR9; R9 , R9' , R10 and R10 are independently selected from hydrogen, Cι- alkyl (optionally substituted by 1 or 2 hydroxy groups), C2.4alkenyl, and phenyl (optionally substituted by 1 or 2 groups selected from nitro, halo, hydroxy and cyano); or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
4. A compound as claimed in any preceding claim wherein Y is NR2R3, or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
5. A compound as claimed in any one of claims 1 to 3 wherein Y is OR , or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
6. A compound as claimed in any preceding claim wherein R4 and R5 together are 5 -S-C(R6)=C(R7)-, or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
7. A compound as claimed in any one of claims 1 to 5 wherein R4 and R5 together are -C(R7)=C(R6)-S- ; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
10 8. A compound as claimed in any preceding claim wherein A is phenylene, or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
9. A compound as claimed in any one of claims 1 to 7 wherein A is heteroarylene, or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
15
10. A compound as claimed in any preceding claim wherein Z is CH, or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
11. A compound of the formula (1) as claimed in any preceding claim, which is a
20 compound of formula (IB):
Figure imgf000122_0001
(IB) or a pharmaceutically acceptable salt or an in-vivo hydrolysable ester thereof.
25 12. A compound of the formula (1) as claimed in claim 1, which is any one of: 2,3-dichloro-N-[(lR,2R)-l-(formylamino)-2,3-dihydro-lH-inden-2-yl]-4H-thieno[3,2- b]pyrrole-5-carboxamide;
2,3-dichloro-N-((lR,2R)-l-{[(methyloxy)acetyl]amino}-2,3-dihydro-lH-inden-2-yl)-4H- thieno[3,2-b]pyrrole-5-carboxamide; N-((1S,2S)- 1 - { [(3 (R)-3-(tert-butoxycarbonylamino)-3-carbamoylpropanoyl] amino } -2,3- dihydro- lH-inden-2-yl)-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-[(lR,2R)-l-({[(4R)-2,2-dimethyl-5-oxo-l,3-dioxolan-4-yl]acetyl}amino)-2,3- dihydro-lH-inden-2-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide; 2,3-dichloro-N-{(lR,2R)-l-[(3-methoxyproρanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[(2-acetoxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H- thieno[3,2-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[(2-carbamoylacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H- thieno[3,2-b]pyrrol-5-carboxamide;
2,3-dichloro-N-{(lR,2R)-l-[(trifluoroacetyl)armno]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N- { ( 1S,2S)- 1 -[(furan-2-ylcarbonyl)amino]-2,3-dihydro- lH-inden-2-yl } -4H- thieno[3,2-b]pyrrole-5-carboxamide; 2,3-mchloro-N-{(lS,2S)-l-[(furan-3-ylcarbonyl)anιino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lS,2S)-l-[(3-thienylcarbonyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- tWeno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-(( 1S,2S)- 1 -{ [(5-nitrofuran-2-yl)carbonyl] amino } -2,3-dihydro- lH-inden-2-yl)- 4H-thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lS,2S)-l-[(pyridin-3-ylc-ιrbonyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
N-[(lS,2S)-l-(acryloylamino)-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide; 2,3-dichloro-N-((lS,2S)-l-{[(3-hydroxyphenyl)carbonyl]amino}-2,3-dihydro-lH-inden-2-yl)-
4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-[(lS,2S)-l-(acetylamino)-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrtθle-5-c-ιrboxamide;
N-[(lS,2S)-l-[(2-carboxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H- thieno[3,2-b]ρyrrole-5-carboxamide;
2,3-dichloro-N-((lS,2S)-l-{[(dimethylamino)carbonyl]-ιmino}-2,3-dihydro-lH-inden-2-yl)-
4H-thieno[3,2-b]pyrrole-5-carboxamide; 2,3-dichloro-N-((lS,2S)- 1- { [(4-methylpiperazin- 1 -yl)carbonyl] amino } -2,3-dihydro- lH-inden-
2-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-((lS,2S)-l-{[(ethylarnino)carbonyl]amino}-2,3-dihydro-lH-inden-2-yl)-4H- thieno[3,2-b]pyrrole-5-carboxamide; 2,3-dichloro-N-((lS,2S)- 1- { [(prop-2-en- 1 -ylamino)carbonyl] amino } -2,3-dihydro- lH-inden-2- yl)-4H-thieno[3,2-b]pyιτole-5-carboxamide;
2,3-dichloro-N-[(lS,2S)-l-({[(3,5-dinitrophenyl)anιino]carbonyl}amino)-2,3-dihydro-lH- inden-2-yl] -4H-thieno [3 ,2-b]pyrrole-5-carboxamide ;
2,3-dichloro-N-[(lS,2S)-l-(formylamino)-2,3-dihydro-lH-inden-2-yl]-4H-thieno[3,2- b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[((3R)-3-aπnno-3-carbamoylpropanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3- dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-(lR,2R)-l-[((3R)-3-carboxy-3-hydroxypropanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3- dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide; 2,3-dichloro-N-{(lR,2R)-l-[(hydroxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lS,2S)-l-[(methylsulfonyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lS, 2S)-l-[methyl(morpholin-4-ylacetyl)amino]-2,3-dihydro-lH-inden-2- yl }-4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[(2-amino-2-oxoethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H- thieno[3,2-b]pyrrole-5-carboxamide;
N-(lR,2R)-l-[(tert-butoxycarbonylmethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-
4H-thieno[3,2-b]pyrrole-5-carboxamide; N-[(lR,2R)-l-(carboxymethylamino)-2,3-dihydro-lH-inden-2-yl]-2,3-dichloro-4H-thieno[3,2- b]pyrrole-5-carboxamide;
N-(lR,2R)-l-[N-acetyl-N-(carboxymethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-
4H-thieno[3,2-b]pyrrole-5-carboxamide;
N- { (IR, 2R)- 1 -[acetyl(2-amino-2-oxoethyl)amino]-2,3-dihydro- lH-inden-2-yl } -2,3-dichloro- 4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[N-(carboxymethyl)-N-(hydroxyacetyl)arnino]-2,3-dihydro-lH-inden-2-yl}-2,3- dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide; 2-chloro-N-[(lR,2R)-l-({[(2S)-5-oxotetiahydrofuran-2-yl]carbonyl}amino)-2,3-dihydro-lH- inden-2-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide;
2-chloro-N-[(lR,2R)-l-(formylamino)-2,3-dihydro-lH-inden-2-yl]-6H-thieno[2,3-b]pyrrole-5- carboxamide; 2-chloro-N-{(lR,2R)-l-[(methoxyacetyl)-ιmino]-2,3-dihydro-lH-inden-2-yl}-6H-thieno[2,3- b]pyrrole-5-carboxamide;
N-[(lR,2R)-l-(acetylamino)-2,3-dihydro-lH-inden-2-yl]-2-chloro-6H-thieno[2,3-b]ρyrrole-5- carboxamide;
2-chloro-N-{(lR,2R)-l-[(3-methoxyprop- oyl)amino]-2,3-dihydro-lH-inden-2-yl}-6H- tmeno[2,3-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[(2-acetoxyacettyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H-thieno[2,3- b]pyrrole-5-carboxamide;
N-((lS,2S)-l-{[(2(S)-2-(tert-butoxycarbonylannno)-2-carbamoylacetyl]amino}-2,3-dihydro- lH-inden-2-yl)-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide; N-{(lS,2S)-l-[(2-(tert-butoxycarbonylamino)acetylamino]-2,3-dihydro-lH-inden-2-yl}-2- chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[2-carbamoylacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno[2,3,b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[2-(tert-butoxyc-ιrbonyl)acetylanιino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno[2,3,b]pyrrole-5-carboxamide;
2-chloro-N-(( 1R,2R)- 1 - { [3-hydroxy-2-(hydroxymethyl)propanoyl] amino } -2,3-dihydro- 1H- inden-2-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[((3R)-3-amino-3-carbamoylpropanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-2- chloro-6H-thieno[2,3-b]pyrrole-5-c-trboxamide; N-{(lR,2R)-l-[(anήnoacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H-thieno[2,3- b]pyrrole-5-carboxamide;
2-chloro-N-[( 1R,2R)- 1 -({ [(2-hydroxyethyl)(phenylmethyl)amino] acetyl } amino)-2,3-dihydro- lH-inden-2-yl)-6H-thieno[2,3-b]pyrrole-5-c-ιrboxamide;
2-chloro-N-{(lR,2R)-l-[(morpholin-4-ylacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-6H- thieno[2,3-b]pyrrole-5-carboxamide;
2-chloro-N-((lR,2R)-l-({[(2-hydroxyethyl)(methyl)amino]acetyl}amino)-2,3-dihydro-lH- inden-2-yl)-6H-thieno [2,3 -b] pyrrole-5-carboxamide ; N-((1R,2R)- 1 -({ [bis(2-hydroxyethyl)amino] acetyl } amino)-2,3-dihydro- lH-inden-2-yl)-2- chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;
2-chloro-N-((lR,2R)-l-({[ethyl(2-hydroxyethyl)annno]acetyl}amino)-2,3-dihydro-lH-inden-
2-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide; 2-chloro-N-((lR,2R)-l-({[(2,3-dihydroxypropyl)(methyl)amino]acetyl}amino)-2,3-dihydro- lH-inden-2-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide;
N-((lR,2R)-l-({[bis(2-hydroxypropyl)amino]acetyl}amino)-2,3-dihydro-lH-inden-2-yl)-2- chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[(2-amino-2-oxoethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno[2,3-b]pyrrole-5-carboxamide;
N-[(lR,2R)-l-[(tert-butoxycarbonylmethyl)amino]-2,3-dihydro-lH-inden-2-yl}-2-chloro-6H- thieno[2,3-b]pyrrole-5-carboxamide;
N- { (1R,2R)- 1 -(carboxymethylamino)-2,3-dihydro- lH-inden-2-yl } -2-chloro-6H- thieno(3,2,b]pyrrole-5-carboxamide; 2-chloro-N-{(lR,2R)-l-[(hydroxyacetylamino]-2,3-dihydro-lH-inden-2-yl}-6H-thieno[2,3- b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lR,2R)-l-[(chloroacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H-thieno[3,2- b]pyrrole-5-carboxamide;
N-{(lR,2R)-l-[((3S)-3-aπήno-3-carboxypropanoyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3- dichloro-4H-thieno(3 ,2,b]pyrcole-5-carboxamide;
N-{(lR,2R)-l-[(2-carboxyacetyl)amino]-2,3-dihydro-lH-inden-2-yl}-2,3-dichloro-4H- thieno(3,2,b]pyrrole-5-carboxamide;
N- { ( 1R,2R)- 1- [(2-carboxyacetyl)amino]-2,3-dihydro- lH-inden-2-yl } -2-chloro-6H- thieno(3,2,b]pyrrole-5-carboxamide; N- { ( 1R,2R)- 1 - [((3S)-3-amino-3-carboxypropanoyl)amino] -2,3-dihydro- lH-inden-2-yl } -2- chloro-6H-thieno(3,2,b]pyrrole-5-carboxamide;
2,3-dichloro-N-{(lR,2R)-l-[(methylsulfonyl)amino]-2,3-dihydro-lH-inden-2-yl}-4H- thieno[3,2-b]pyrrole-5-carboxamide; or a pharmaceutically acceptable salt or an in-vivo hydrolysable ester thereof.
13. 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 12 in association with a pharmaceutically-acceptable diluent or carrier.
14. 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 12, for use in a method of treatment of a warm-blooded animal such as man by therapy.
15. 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 12, for use as a medicament.
16. 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 12, 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.
17. 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 12, 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.
18. 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 12, in the manufacture of a medicament for use in the treatment of type 2 diabetes in a warm-blooded animal such as man.
19. 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 imgf000127_0001
(2) or an activated derivative thereof; with an amine of formula (3):
Figure imgf000128_0001
(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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US10/506,746 US7122567B2 (en) 2002-03-06 2003-03-04 Heterocyclic amide derivatives having glycogen phosphorylase inhibitory activity
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