WO2004058755A2 - Compound libraries of imidazo[1,5-a]pyridin-3-yl derivatives and related heterobicycles for targetting compounds capable of binding to g-protein coupled receptors - Google Patents

Compound libraries of imidazo[1,5-a]pyridin-3-yl derivatives and related heterobicycles for targetting compounds capable of binding to g-protein coupled receptors Download PDF

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WO2004058755A2
WO2004058755A2 PCT/GB2003/005652 GB0305652W WO2004058755A2 WO 2004058755 A2 WO2004058755 A2 WO 2004058755A2 GB 0305652 W GB0305652 W GB 0305652W WO 2004058755 A2 WO2004058755 A2 WO 2004058755A2
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list
continued
library
compounds
compound
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WO2004058755A3 (en
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Terence Ward
Roger Crossley
Jacqueline Anne Macritchie
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Biofocus Plc
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Publication of WO2004058755A2 publication Critical patent/WO2004058755A2/en
Publication of WO2004058755A3 publication Critical patent/WO2004058755A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4747—Quinolines; Isoquinolines spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/08—Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support

Definitions

  • the present invention relates to compounds capable of binding to G-protein coupled receptors.
  • libraries of compounds are provided for use in screening programmes against GPCR targets as well as the individual compounds for use in hit to lead and lead optimisation projects and similar stages in the drug discovery process.
  • the method also provides methods for making compounds and libraries .
  • Screening libraries are commonly collections of compounds from several sources. As a result, they typically contain compounds synthesised as a part of previous projects in the history of a company. With regard to drug discovery, these collections will be drug-like but are likely to be limited in scope and will be directed to certain areas of a particular project. It has been the common practice of many pharmaceutical companies in recent times to augment the collections by purchasing either single compounds from vendors or by contracting the synthesis of combinatorial libraries of compounds. The singly purchased compounds may have been selected to fill in areas of compound space poorly represented in the compound collections . Combinatorial libraries are typically synthesised around well-performing chemistries with some design based on producing 'diversity' in compound space.
  • a complementary approach, and one that is increasingly preferred, is to screen focused libraries against the target of choice. Focused libraries are becoming of increasing importance in their ability to generate hits capable of rapid expansion in many areas including GPCRs . Such libraries are slightly more expensive to prepare but have attributes of reliability, reproducibility and provide a considerably higher hit rate: typically 10-100 fold and above compared with random screening. They are, however, very difficult to design and their efficiency relates directly to the amount of effort that, has gone into the design. Using focused libraries, it is usually possible to get a number of hits in the low micromolar and below range. As there is a defined set of compounds there is the potential to observe indications of SAR in a chemical series and progress the chemistry efficiently.
  • GPCRs G-protein-coupled receptors
  • the rhodopsin receptor is somewhat unusual in its interactions with its ligand and is not used as a drug target. Nevertheless, the overall three dimensional arrangement can be deduced from the X-ray and is in accordance with previous work based upon bacteriorhodopsin receptor which is not G-protein- coupled.
  • GPCRs are most often characterised by sequence homology as being comprised of several sub-families. Most attention currently is directed towards Family A receptors as being the most tractable class historically and also the one with the most potential targets .
  • Family A comprises about 300 receptors that are potential drug targets, approximately half of which have known ligands and the rest, the so-called orphan receptors.
  • the group of druggable receptors is composed, essentially of two types: those whose natural ligand interacts wholly within the transmembrane domain, such as the aminergic, nucleotide-like, prostaglandih receptors, etc. and those peptide liganded receptors, which have a large part of their interactions in the extracellular region and which may insert a peptide loop or tail into the transmembrane region to effect signal transduction. Examples of this class are angiotensin, cholecystokinin and opioid receptors .
  • the focused library provided herein is designed to interact with a range of the family A receptors.
  • Each library is a defined set of compounds which will enhance the probability of finding a small molecule which will interact with one or more type of GPCR receptor.
  • focused libraries can be provided having compounds which will interact with aminergic GPCRs, and peptidic GPCRs requiring an obligatory positive charge in ligands, or other types or groups of GPCRs.
  • Focused libraries according to this invention can provide hit rates of 1-13% or more for the requisite predicted GPCRs from both a ine- and peptide-liganded classes and with agonists and antagonists .
  • library means a group of compounds which are structurally related by virtue of a core chemical structure (or “scaffold”) but which differ from each other by virtue of permutation of specific substituent groups attached to the scaffold.
  • such a library will consist of or comprise a number of compounds, e.g. as many as about 100, 1000,2000, 3000 or indeed 10,000 compounds.
  • the number of compounds should be sufficient to provide an adequate diversity of related compounds without being so large as to be unduly complex/expensive to produce.
  • the substituent may appear in the compound exactly as shown- (i.e. simply covalently bonded to the scaffold) or may be a derivative of the shown chemical formula of the substituent by virtue of use of a reactive group to couple the substituent to the scaffold.
  • the total number of permutations created by the permitted substituents may be a very large number, far greater in magnitude than the actual number of compounds in an actual library.
  • the number of possible compounds for any "virtual" library may well greatly exceed the number of synthesised compounds making up an embodiment of the "real" library.
  • the invention is intended to encompass libraries having all, and a number, which is less than all, of the permitted substitutions represented by compounds therein.
  • the present invention provides novel focused libraries of compounds .
  • Most of the compounds defined by the permitted substitutions on the scaffolds are also novel compounds per se and the invention is intended to encompass each individual novel compound.
  • Any known compound having a structural formula identical to any one of the compounds covered by the formulae of scaffolds and permitted substitutions described herein is hereby explicitly disclaimed per se.
  • Library 4 has been designed to take advantage of a common recognition feature of G-protein coupled receptors, namely the 'benzhydryl' or 'rabbit ears' arrangement of aromatic rings. At the same time this library utilises several themes common in GPCRs selecting for subsets which recognise basic and 'acidic' ligands. Examples of drugs which interact with receptors of this type are sertindole, devazepide and brompheniramine, however there are many more.
  • this library has a wide focus in its ability to pick up the recognition features provided by TM3 aspartates for basic groups and also by interactions, typically with histidines in TM6 in basic environments for acidic groups and in other environments for more neutral carboxylate bioisosteres .
  • a final feature of the design extends this recognition site for a subset of compounds to recruit antagonist recognition sites around TM7.
  • the invention provides a library comprising or consisting of a set of structurally related compounds of general formula A:
  • Rl is a hydrogen, alkyl, alkoxy or halogen
  • R2 is an optionally substituted aryl or heteroaryl group
  • R4 is an optionally substituted alkyl, acyl or sulphonyl group; where R3 does not form part of a ring it may be hydrogen or an optionally substituted alkyl;
  • Y can be nitrogen or carbon.
  • R2MgZ Grignard reagents
  • the cyano pyridine (0.1 mol) was dissolved in dry toluene (300 ml) and cooled to 0-5°C.
  • the Grignard reagent (0.11 mol) was added dropwise over 30 minutes to give a thick creamy precipitate.
  • the reaction was stirred for a further 30 minutes at 0-5°C then iso butanol (120 ml) was added dropwise keeping the temperature below 0-5°C to give a clear brown solution.
  • the reaction was cooled to 0-5°C and sodium borohydride (0.14 mol) added portionwise and the whole stirred at RT overnight.
  • the reaction was quenched with methanol/water and concentrated in vacuo to remove the toluene .
  • the mixture was extracted with DCM and the organics dried over magnesium sulfate before concentrating in vacuo.
  • Purification was carried out by flash column chromatography on silica eluted with ethyl acetate and ethyl acetate/3% TEA mixtures.
  • An alternative purification involved dissolving the residue in diethyl ether and extraction into dilute HC1.
  • the acidic solution was washed three times with diethyl ether and then basified with IN sodium hydroxide and the product extracted with diethyl ether.
  • the organics were dried over magnesium sulfate and concentrated in vacuo to yield the benzhydryl amine.
  • the BOC protected amino acid (2, 15 mmol) was dissolved in dry DCM (25 ml) and CDI (15 mmol) added. The reaction was stirred for 30 minutes and then a solution of the benzhydryl amine (1, 15 mmol) in DCM (5 ml) was added. The whole was stirred overnight. The solution was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield the desired amide. The amide was used without further purification.
  • the BOC protected amine (8.86 mmol) was dissolved in 4N methanolic HC1 (15 ml) and stirred overnight at RT. The solvent was removed in vacuo and the solid residue triturated with diethyl ether. The solid was removed by filtration and dried to give the amine hydrochloride . The compounds were stored as the HC1 salt and then converted to the free base by aqueous sodium hydroxide for further reaction.
  • reaction mixture was dissolved in DMSO ( ⁇ 1.5ml). This solution was loaded onto a 10mm xtera MS C 18 column at room temperature and eluted with the following gradient
  • Mass Spectra APCI, M+l and possibly acetonitrile adducts present and coincident with the major uv peak
  • the substituted amino imidazopyridine solution (0.175 m in THF 0.5 ml) and the triethylamine solution (0.175 m in THF 0.5 ml) were mixed together and then the solution of acetyl chloride (0.175 m in THF 0.5 ml) or methane sulphonyl chloride (0.175 m in THF 0.5 ml) added.
  • the reaction mixture was shaken at room temperature overnight . Water 2ml was added and the mixture extracted with ethyl acetate (2 x 1 ml) and the extract concentrated in vacuo. The residue was purified by reverse phase HPLC.

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Abstract

The present invention provides a library designed to take advantage of a common recognition feature of G-protein coupled receptors, namely the ‘benzhydryl’ or ‘rabbit ears’ arrangement of aromatic rings. In addition the library utilises several themes common in GPCRs selecting for subsets which recognise basic and ‘acidic’ ligands. The library comprises or consists of a set of structurally related compounds of general formulae (A)or (B). The present invention also provides intermediates (formula (3)).

Description

COMPOUND LIBRARIES
Introduction
Background
The present invention relates to compounds capable of binding to G-protein coupled receptors. In particular, libraries of compounds are provided for use in screening programmes against GPCR targets as well as the individual compounds for use in hit to lead and lead optimisation projects and similar stages in the drug discovery process.
The method also provides methods for making compounds and libraries .
As part of the process of discovering drugs or agrochemicals it is customary to screen libraries of compounds against biological targets to discover "Hits' which are then further developed into 'Leads' and subsequently drugs or agrochemicals by using the techniques of medicinal chemistry. Accordingly the success or not of a drug or agrochemical discovery project is critically dependent on the quality of the hit and this in turn is dictated by the quality of the screening library.
Technological advances have enabled screening on a very large scale and the screening of hundreds of thousands of compounds at the start of a discovery program is routine. This, however, does entail a significant cost. The hits obtained from such screening efforts are not all of the best quality and often take a large amount of subsequent time and effort in order to get a good lead. It has been estimated that only about 25% of projects actually get to the lead optimisation stage and part of the reason for this is the intractability of hits from high throughput screening.
Screening libraries are commonly collections of compounds from several sources. As a result, they typically contain compounds synthesised as a part of previous projects in the history of a company. With regard to drug discovery, these collections will be drug-like but are likely to be limited in scope and will be directed to certain areas of a particular project. It has been the common practice of many pharmaceutical companies in recent times to augment the collections by purchasing either single compounds from vendors or by contracting the synthesis of combinatorial libraries of compounds. The singly purchased compounds may have been selected to fill in areas of compound space poorly represented in the compound collections . Combinatorial libraries are typically synthesised around well-performing chemistries with some design based on producing 'diversity' in compound space.
A complementary approach, and one that is increasingly preferred, is to screen focused libraries against the target of choice. Focused libraries are becoming of increasing importance in their ability to generate hits capable of rapid expansion in many areas including GPCRs . Such libraries are slightly more expensive to prepare but have attributes of reliability, reproducibility and provide a considerably higher hit rate: typically 10-100 fold and above compared with random screening. They are, however, very difficult to design and their efficiency relates directly to the amount of effort that, has gone into the design. Using focused libraries, it is usually possible to get a number of hits in the low micromolar and below range. As there is a defined set of compounds there is the potential to observe indications of SAR in a chemical series and progress the chemistry efficiently.
G-protein-coupled receptors (GPCRs) are very important in the regulation of numerous body processes and a significant proportion of all drugs work by interaction with these receptors. There are several hundred known, many of which are orphans - those receptors that have no established ligands . They fall into a class of 7-transmembrane receptors and there is only one X-ray structure known, that of the bovine rhodopsin receptor, and this is at a resolution of 2.8 Angstroms and is thus not suitable for accurate modeling work. In addition, the rhodopsin receptor is somewhat unusual in its interactions with its ligand and is not used as a drug target. Nevertheless, the overall three dimensional arrangement can be deduced from the X-ray and is in accordance with previous work based upon bacteriorhodopsin receptor which is not G-protein- coupled.
GPCRs are most often characterised by sequence homology as being comprised of several sub-families. Most attention currently is directed towards Family A receptors as being the most tractable class historically and also the one with the most potential targets .
Family A comprises about 300 receptors that are potential drug targets, approximately half of which have known ligands and the rest, the so-called orphan receptors. The group of druggable receptors is composed, essentially of two types: those whose natural ligand interacts wholly within the transmembrane domain, such as the aminergic, nucleotide-like, prostaglandih receptors, etc. and those peptide liganded receptors, which have a large part of their interactions in the extracellular region and which may insert a peptide loop or tail into the transmembrane region to effect signal transduction. Examples of this class are angiotensin, cholecystokinin and opioid receptors . Irrespective of the mode of action of the natural ligand or the GPCR family, the vast majority of drug molecules interact in the all-helical domain of the transmembrane region with exceptions being those mimics of glutamate at the metabotropic glutamate receptor and some peptide therapeutics administered parenterally. In looking for lead molecules for an unexplored or orphan GPCR it therefore makes sense to concentrate on interactions in the transmembrane domain.
The focused library provided herein is designed to interact with a range of the family A receptors. Each library is a defined set of compounds which will enhance the probability of finding a small molecule which will interact with one or more type of GPCR receptor.
For example, focused libraries can be provided having compounds which will interact with aminergic GPCRs, and peptidic GPCRs requiring an obligatory positive charge in ligands, or other types or groups of GPCRs.
Focused libraries according to this invention can provide hit rates of 1-13% or more for the requisite predicted GPCRs from both a ine- and peptide-liganded classes and with agonists and antagonists . Summary of Invention
We provide herein a "focused" library of compounds which will provide "leads" for ligands which bind to Family A G-Protein coupled receptors .
In the context of the present invention, "library" means a group of compounds which are structurally related by virtue of a core chemical structure (or "scaffold") but which differ from each other by virtue of permutation of specific substituent groups attached to the scaffold.
Generally speaking such a library will consist of or comprise a number of compounds, e.g. as many as about 100, 1000,2000, 3000 or indeed 10,000 compounds. The number of compounds should be sufficient to provide an adequate diversity of related compounds without being so large as to be unduly complex/expensive to produce.
In the context of the present invention the terms "permitted substituents" and analogous terms are used to refer to defined chemical groups which may be attached to a "scaffold" to provide permutations of the chemical structure of related compounds .
Where the chemical formulae of permitted substituents are shown in this description and claims, the substituent may appear in the compound exactly as shown- (i.e. simply covalently bonded to the scaffold) or may be a derivative of the shown chemical formula of the substituent by virtue of use of a reactive group to couple the substituent to the scaffold.
It will be appreciated that the total number of permutations created by the permitted substituents may be a very large number, far greater in magnitude than the actual number of compounds in an actual library. In other words, the number of possible compounds for any "virtual" library may well greatly exceed the number of synthesised compounds making up an embodiment of the "real" library. The invention is intended to encompass libraries having all, and a number, which is less than all, of the permitted substitutions represented by compounds therein.
It will be appreciated that some specific combinations of permitted substituents may be more or less difficult to synthesise and/or use in a focused library of the invention. This does not detract from the generality of applicability of the invention as described herein. It is to be expected that real libraries will be synthesised from a selected group of permutations/combinations of permitted substituents, taking into consideration factors affecting the intended purpose of the library and its cost and complexity of synthesis.
Even if theoretically permitted, it is currently considered unlikely that any compound would be prepared for inclusion in a focused library if it had either or both of the following properties
(1) molecular weight >700
(2) log p <-3 or >9 (an index of lipophilicity as calculated using commercially available "Chemenlighten 2.8" and "Biobyte" software for the log p calculation) .
The present invention provides novel focused libraries of compounds . Most of the compounds defined by the permitted substitutions on the scaffolds are also novel compounds per se and the invention is intended to encompass each individual novel compound. Any known compound having a structural formula identical to any one of the compounds covered by the formulae of scaffolds and permitted substitutions described herein is hereby explicitly disclaimed per se.
DESCRIPTION OF THE INVENTION
Library 4 has been designed to take advantage of a common recognition feature of G-protein coupled receptors, namely the 'benzhydryl' or 'rabbit ears' arrangement of aromatic rings. At the same time this library utilises several themes common in GPCRs selecting for subsets which recognise basic and 'acidic' ligands. Examples of drugs which interact with receptors of this type are sertindole, devazepide and brompheniramine, however there are many more.
There appear to be around three separate recognition sites for the 'rabbit ears' moiety in GPCRs and the molecular interactions are presumed to be a feature of aromatic-aromatic interactions in an all-helical receptor environment. In addition to utilizing this recognition function this library has a wide focus in its ability to pick up the recognition features provided by TM3 aspartates for basic groups and also by interactions, typically with histidines in TM6 in basic environments for acidic groups and in other environments for more neutral carboxylate bioisosteres . A final feature of the design extends this recognition site for a subset of compounds to recruit antagonist recognition sites around TM7.
The invention provides a library comprising or consisting of a set of structurally related compounds of general formula A:
Figure imgf000010_0001
A
wherein X is a carbon chain (CH2)n, and n = 2 or 3 , or alternatively X-N-R3 form part of a 5 or 6 member saturated ring;
Rl is a hydrogen, alkyl, alkoxy or halogen;
R2 is an optionally substituted aryl or heteroaryl group;
R4 is an optionally substituted alkyl, acyl or sulphonyl group; where R3 does not form part of a ring it may be hydrogen or an optionally substituted alkyl;
and Y can be nitrogen or carbon.
Structural Novelty of Compounds of Library 4
Compounds of the following general formulae are unknown
Figure imgf000011_0001
wherein Y = CH, or N, and n = 1 or 2 ;
Figure imgf000011_0002
wherein X as defined in formula A is (CH2)n (n=2 or 3); and
Figure imgf000011_0003
Methods for Synthesising Scaffolds of Library 4
Compounds of formula 4 can be made according to Scheme 1 .COOH X
Figure imgf000012_0001
Figure imgf000012_0002
(5) Scheme 1 (6)
Nitriles ( 1) selected from List 1 are reacted with Grignard reagents (R2MgZ) , selected from List 2 wherein Z = chloro or bromo to give the amines (2) . These are then reacted with a range of t-butyloxycarbonyl protected amino acids selected from List 3 to give the amides (3) . Treatment with phosphorous oxychloride in pyridine gives the fused ring compounds (4) . The t-butyloxycarbonyl protecting group is then removed by treatment with acid to give the amines (5) .
The amines can either be alkylated with compounds selected from List 4, wherein # is a leaving group (especially halogen or sulphonate) , to give compounds where R4 = substituted alkyl or alkylated by reductive alkylation with compounds selected from List 5 to give compounds where R4 = substituted alkyl, or acylated with methane sulphonyl chloride or acetyl chloride to give compounds where R4 = #-S0Me or #-COMe, where # is the point of attachment .
Where R3 = H, amines (6) can then be further alkylated by reductive alkylation with aldehydes and ketones selected from List 6 to give compounds (6) where R3 = substituted alkyl.
The permitted substituents at positions Rl, R2 , R3 and R4 for compounds of Library 4 are shown below.
List 1
Figure imgf000014_0001
Figure imgf000014_0002
List 2
Figure imgf000014_0003
List 2 (Continued)
Figure imgf000015_0001
List 3
Figure imgf000015_0002
BOC
Figure imgf000015_0003
List 4
Figure imgf000016_0001
Figure imgf000016_0002
List 4 (Continued)
Figure imgf000017_0001
List 4 (Continued)
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0004
Figure imgf000018_0003
Figure imgf000019_0001
List 4 (Continued)
Figure imgf000020_0001
List 5
Figure imgf000020_0002
List 5 (Continued)
Figure imgf000021_0001
Figure imgf000021_0003
Figure imgf000021_0004
Figure imgf000021_0002
Figure imgf000021_0005
List 5 (Continued)
Figure imgf000022_0001
List 5 (Continued)
Figure imgf000023_0001
List 6
Figure imgf000023_0002
Figure imgf000023_0003
List 6 (Continued)
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000024_0003
Methods for Synthesisisng Compounds of Library 4
General method for the synthesis of benzhydryl amines (2)
The cyano pyridine (0.1 mol) was dissolved in dry toluene (300 ml) and cooled to 0-5°C. The Grignard reagent (0.11 mol) was added dropwise over 30 minutes to give a thick creamy precipitate. The reaction was stirred for a further 30 minutes at 0-5°C then iso butanol (120 ml) was added dropwise keeping the temperature below 0-5°C to give a clear brown solution. The reaction was cooled to 0-5°C and sodium borohydride (0.14 mol) added portionwise and the whole stirred at RT overnight. The reaction was quenched with methanol/water and concentrated in vacuo to remove the toluene . The mixture was extracted with DCM and the organics dried over magnesium sulfate before concentrating in vacuo. Purification was carried out by flash column chromatography on silica eluted with ethyl acetate and ethyl acetate/3% TEA mixtures. An alternative purification involved dissolving the residue in diethyl ether and extraction into dilute HC1. The acidic solution was washed three times with diethyl ether and then basified with IN sodium hydroxide and the product extracted with diethyl ether. The organics were dried over magnesium sulfate and concentrated in vacuo to yield the benzhydryl amine.
Examples of benzhydryl amines (2)
C- (4-Fluoro-phenyl) -C-pyridin-2-yl-methylamine Yellow δ.CDCl3 °il 2.1 (2H, bs, NH2) , 5.3 (1H, s.
Figure imgf000025_0001
CH) , 6.9-7.5 (7H, m, 7ArH) , 8.6 (1H, m, ArH)
C-Phenyl-C-pyrazin-2-yl-methylamine
Brown δ.CDCl3 oil 2.2 (2H, bs, NHa) , 5.3 (1H, m,
Figure imgf000025_0002
CH) , 7.2-7.4 (5H, m, 5ArH) , 8.4 (lH,.'m, ArH), 8.5 (1H, m, ArH), 8.6 (1H, s, ArH)
4-Chloro-2- (2-methoxy-benzyl) -pyridine Yellow δ.CDCl3 oil 2.1 (2H, bs, NH2) , 3.8 (3H, S,
Figure imgf000026_0001
OMe) , 5.5 (1H, s, CH) , 6.8-7.3
(6H, m, ArH) , 8.4 (1H, m, ArH)
C- (4 -Methyl -pyridin-2-yl) -C-phenyl-methylamine Brown δ.CDCl3 oil 2.1 (3H, bs, NH3.C1) , 2.3 (3H,
S, CH3) , 5.2 (1H, S, CH) , 6.9-
Figure imgf000026_0002
7.5 (7H, m, ArH) , 8.4 (1H, m, ArH)
General method for the synthesis of amides (3)
The BOC protected amino acid (2, 15 mmol) was dissolved in dry DCM (25 ml) and CDI (15 mmol) added. The reaction was stirred for 30 minutes and then a solution of the benzhydryl amine (1, 15 mmol) in DCM (5 ml) was added. The whole was stirred overnight. The solution was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield the desired amide. The amide was used without further purification.
Examples of amides (3)
4-{ [ (4-Fluoro-phenyl) -pyridin-2-yl-methyl] -carbamoyl}' piperidine-1-carboxylic acid tert-butyl ester cream solid δ.CDCl31.4 (9H, s, fcBu) , 1.7 (2H, bm, 2xCH) , 1.9 (2H, bm,
2xCH) , 2.4 (IH, bm, CH) , 2.8
Figure imgf000027_0001
(2H, bm/ 2xCH) , 4.1 (2H, bm,
2xCH) , 6.1 (IH, m, CHNH) , 6.9 (IH, m, ArH), 7.2-7.3 (3H, m,
ArH+NH) , 7.6-7.8 (2H, m, ArH),
8.6 (IH, m, ArH)
C=0 1693, 1637
{3- [ (Phenyl-pyridin-2-yl-methyl) -carbamoyl] -propyl}-carbamic acid tert-butyl ester
δ.CDCl31.4 (9H, m, fcBu) , 2.5 (2H, m, CH2) , 3.4 (2H, m, CH2) , 5.4 (IH, m, NHBOC), 6.1 (IH, d, CH) , 7.2-7.4 (7H, m, ArH&NH) ,
Figure imgf000027_0002
7.6-7.7 (2H, m, ArH), 8.6 (IH, m, ArH)
s, fcBu) , 2.1 (2H, m, 9 (IH, m, CH) , 3.3 (IH, 3.5-3.8 (3H, m, CH) ,
Figure imgf000028_0001
d, CHNH) , 6.9 (2H, m, ArH), 7.2-7.4 (3H, m, ArH), 7.6-7.7 (2H, m, ArH&NH), 8.5 (IH, m, ArH)
Cyclisation to give the bicyclic compounds (4)
a) For cyclic amino acids
POCl3 (8.5 mmol) was added dropwise to a cooled (ice/water) solution of the amide (7.2 mmol) and pyridine (44.5 mmol) in dry DCM (35 ml) . The mixture was stirred overnight at RT. The mixture was washed with water (2 x 10 ml) . The organics were dried over magnesium sulfate and concentrated in vacuo to yield the desired cyclised product. Purification was carried out by column chromatography on silica eluted with petrol: ethyl acetate
b) For open chain amino acids
The amide (2 mmol) was dissolved in dry DCM (10 ml) and pyridine (4 mmol) added. TFAA (2 mmol) was dissolved in dry DCM (2.5 ml) and added dropwise to the mixture at RT . The reaction was stirred for 1 h at RT. The mixture was washed with water (2 x 10 ml) . The organics were dried over magnesium sulfate and concentrated in vacuo to yield the desired cyclised product. Purification was carried out by column chromatography on silica eluted with petrol: ethyl acetate. Examples of" bicyclic compounds (4)
4- [1- (4-Fluoro-phenyl) -imidazo [1, 5-a] pyridin-3-yl] -piperidine -1-carboxylic acid tert-butyl ester
0
Figure imgf000029_0001
1 (2H, m, ArH) , 7.7-7.9 (4H, m,
ArH)
C=0 1682
{2- [1- (3-Methoxy-phenyl) -imidazo [1, 5-a] yridin-3-yl] -ethyl} -carbamic acid tert-butyl ester yellow gum
Figure imgf000029_0002
(IH, m, ArH) , 7.3 (IH, m,
ArH) , 7.4-7.5 (2H, m, ArH) ,
7.7-7.8 (2H, m, ArH)
{2- [7-Chloro-l- (3-methoxy-phenyl) -imidazo [1, 5-a] yridin-3-yl] -ethyl} -carbamic acid tert-butyl ester yellow solid .1- m, 3
Figure imgf000030_0001
4
(3H, m, ArH) , 7.8 (2H, m, ArH)
[2- (1-p-Tolyl -imidazo [1, 5-a] pyridin- 3 -yl) -ethyl] -carbamic acid tert-butyl ester
.2
m,
Figure imgf000030_0002
[3- (1-Phenyl-imidazo [1, 5-a]pyridin-3-yl) -propyl] -carbamic acid tert-butyl ester
Figure imgf000030_0003
(IH, m, ArH) , 7.4 (2H, m,
ArH), 7.7-7.9 (4H, m, ArH)
- (1-Thiophen-2-yl-imidazo [1, 5-a] pyridin-3-yl) -pyrrolidine-1-carboxyl acid tert-butyl ester m, 7- m, .1
Figure imgf000031_0001
ArH) , 7.4 (IH, m, ArH) 7.8- 7.9 (2H, m, ArH)
Removal of the tert-butyloxycarbonyl group to give the amines (5)
The BOC protected amine (8.86 mmol) was dissolved in 4N methanolic HC1 (15 ml) and stirred overnight at RT. The solvent was removed in vacuo and the solid residue triturated with diethyl ether. The solid was removed by filtration and dried to give the amine hydrochloride . The compounds were stored as the HC1 salt and then converted to the free base by aqueous sodium hydroxide for further reaction.
Examples of amines (5)
2- [1- (4-Fluoro-phenyl) -imidazo [1, 5-a] pyridin-3 -y] -ethylamine
.3
2
Figure imgf000031_0002
9 (2H, m, ArH)
Free base
3-Pyrrolidin-3-yl-l-thiophen-2-yl-imidazo [1, 5-a] pyridine
CH) , 2.5-2.6 2-3.3 (IH, m, H, m, CH) , 3.6- , 4.2-4.3 (IH,
Figure imgf000032_0001
m, CH) , 6.0-7.0 (water from DMSO) , 6.8 (IH, m, ArH) , 6.9 (IH, m, ArH), 7.1 (IH, m, ArH), 7.4 (IH, m, ArH), 7.5 (IH, m, ArH), 7.8 (IH, m, ArH), 8.3 (IH, m, ArH), 9.5-10.0 (2H, bd, NH.HC1) D20 shake - observe loss of NH
Alkylation of the amine ( 6) a) via displacement of a leaving group
The free amine (R3 = H) (0.2 mmol), alkylating agent (0.2 mmol) and Hunig's base (0.2 mmol) were heated in MIBK (2 ml) at 100°C for 5 hours. The reaction was cooled and water added. The mixture was extracted with ethyl acetate (2 x 1 ml) . The organics were dried over magnesium sulfate and concentrated in vacuo to yield the desired product. Purification was carried out by automated preparative HPLC. Automated Preparative HPLC
The reaction mixture was dissolved in DMSO (~1.5ml). This solution was loaded onto a 10mm xtera MS C18 column at room temperature and eluted with the following gradient
Eluant A 0.05% diethlamine in water
Eluant B 0.05% diethlyamine in acetonitrile
Figure imgf000033_0001
Sample collection was triggered by U.V. absorbance, (thresholds set appropriated for the specific plates) . The collected samples were analysed by LC-MS to ascertain the identity and purity of the constituents.
The analytical conditions
1. Column: Waters xterra MS C18 100x4.6mm 5um packing (part No.186000486)
2. Temperature: ambient ~22°C
3. Eluant A: lOmM (NH4)HC03
Eluant B: Acetonitrile
4. Flow Rate during analysis: 2ml per min
5. Detection DAD window 210 - 400nm
6. Mass Spectra: APCI, M+l and possibly acetonitrile adducts present and coincident with the major uv peak
Figure imgf000033_0002
0.00 min - 95% A: 5% B 0.00 min - 70% A: 30% B
2ml/min 2ml/min
0.50 min - 95% A: 5% B 5.50 min - 5% A: 95% B
2ml/min 2ml/min
5.50 min - 5% A: 95% B 10.00 min - 5% A: 95% B
2ml/min 2ml/min
8.50 min - 5% A: 95% B 10.70 min - 70% A: 30% B
2ml/min 2ml/min
8.60 min - 95% A: 5% B 11.00 min - 70% A: 30% B
2ml/min 2ml/min
8.70 min - 95% A: 5% B
4ml/min
10.70 min - 95% A: 5% B
4ml/min
10.80 min - 95% A: 5% B
2ml/min
11.00 min - 95% A: 5% B
2ml/min
3-{l- [2- (4-Fluoro-phenoxy) -ethyl] -piperidin-4-yl} -1- (4-fluoro-phenyl) -imidazo [1, 5-a] pyridine
Purity Retention time 5.45 min 98% Method 1
Figure imgf000034_0001
3- (l-Allyl-piperidin-4-yl) -1-phenyl-imidazo [1, 5-a] pyridine
Purity Retention time 4.67 min 95% Method 1
Figure imgf000035_0001
l-{3- [4- (1-Phenyl-imidazo [1, 5-a] pyridin-3 -yl) -piperidin-1-yl] -propyl }-pyrrolidine-2 , 5-dione
Purity Retention time 4.71 min 91% Method 1
Figure imgf000035_0002
1- (2- {4- [1- (4-Chloro-phenyl) -imidazo [1, 5-a] pyridin-3-yl] -piperidin-1-yl}-ethyl) -pyrrolidine-2 , 5-dione
Purity Retention time 4.59 min 95% Method 1
Figure imgf000035_0003
h) via reductive amination
The free amine, aldehyde/ke one and sodium triacetoxyborohydride were mixed and shaken overnight at RT. The reaction was diluted with DCM, washed with 1M sodium bicarbonate solution and then water. The aqueous phase was back extracted with DCM. The organics were combined and concentrated. Purification was carried out by automated preparative HPLC.
(2-Methyl-3-phenyl-allyl) - [2- (l-thiophen-2-yl-imidazo [1, 5-a] pyridin-3-yl) -ethyl] -amine
tion time 5.35
d 1
Figure imgf000036_0001
3- [1- (2, 2-Diphenyl-ethyl) -pyrrolidin-3-yl] -1- (2-methoxy-phenyl) -imidazo [1, 5-a] pyridine tion time 6.04
d 1
Figure imgf000036_0002
3- [1- (l,2,3,4-Tetrahydro-naphthalen-2-yl) -pyrrolidin-3-yl] -1-m-tolyl-imidazo [1, 5-a] pyridine tion time 5.67
d 2
Figure imgf000037_0001
Acylation/sulfonylation of the amine (6)
The substituted amino imidazopyridine solution (0.175 m in THF 0.5 ml) and the triethylamine solution (0.175 m in THF 0.5 ml) were mixed together and then the solution of acetyl chloride (0.175 m in THF 0.5 ml) or methane sulphonyl chloride (0.175 m in THF 0.5 ml) added. The reaction mixture was shaken at room temperature overnight . Water 2ml was added and the mixture extracted with ethyl acetate (2 x 1 ml) and the extract concentrated in vacuo. The residue was purified by reverse phase HPLC.
1- {4- [1- (4-Fluoro-phenyl) -imidazo [1, 5-a] pyridin-3-yl] -piperidin-1-yl} -ethanone Purity Retention time 4.28 min 83% Method 1
Figure imgf000038_0001
l-{4- [1- (2-Methoxy-phenyl) -imidazo [1, 5-a] pyridin-3 -yl] -piperidin-1-yl } -ethanone
Purity Retention time .04 min 93% Method 1
Figure imgf000038_0002
1- {4- [1- (4 -Trifluoromethyl-phenyl) -imidazo [1, 5-a] pyridin-3 -yl -piperidin-1-yl} -ethanone
Purity Retention time 4.80 min 94% Method 1
Figure imgf000038_0003
1- [4- (l-Benzo [1,3] dioxol-5-yl-7-chloro-imidazo [1, 5-a] pyridin-3-yl) -piperidin-1-yl] -ethanone Purity Retention t me 4.55 min 95% Method 1
Figure imgf000039_0001
1- (4-Fluoro-phenyl) -3- (1-methanesulfonyl-piperidin-4-yl) -imidazo [1, 5-a] pyridine
Purity Retention time 4.68 min 91% Method 1
Figure imgf000039_0002
3- (l-Methanesulfonyl-piperidin-4-yl) -1- (2-methoxy-phenyl) -imidazo [1, 5-a] pyridine
Purity Retention time 4.42 min Method 1
Figure imgf000039_0003
3- (l-Methanesulfonyl-piperidin-4-yl) -1-m-tolyl -imidazo [1, 5-a] pyridine Purity Retention time 4.85 min 93% Method 1
Figure imgf000040_0001
-Chloro-3- (1-methanesulfonyl-piperidin-4-yl) -1- (2-methoxy-phenyl) -imidazo [1, 5-a] pyridine
Purity Retention time 4.90 min 96% Method 1
Figure imgf000040_0002

Claims

Claims
A compound library comprising or consisting of a set of structurally related compounds having a core chemical structure (scaffold) of general formula (A) :
Figure imgf000041_0001
A wherein the .permitted substituents for Rl are derived from List 1; the permitted substituents for R2 are derived from
List 2; the permitted substituents for R4 are derived from
Lists 4 and 5 ; the permitted substituents for R3 are hydrogen or a substituted alkyl derived from List 6;
Y can be either carbon or nitrogen;
X can be a carbon chain (CH2)n, derived from List 3, where n = 2 or 3 , or alternatively XNR3 may form part of a saturated ring derived from List 3, as shown below in formula B, where m = 2 or 3
Figure imgf000042_0001
List 1
Figure imgf000042_0002
List 2
Figure imgf000043_0001
List 2 (Continued)
Figure imgf000044_0001
List 3
Figure imgf000044_0002
List 4
Figure imgf000045_0001
Figure imgf000045_0002
List 4 (Continued)
Figure imgf000046_0001
Figure imgf000046_0003
Figure imgf000046_0002
Figure imgf000046_0004
List 4 (Continued)
Figure imgf000047_0001
Figure imgf000047_0002
Figure imgf000047_0004
Figure imgf000047_0003
Figure imgf000048_0001
List 4 (Continued)
Figure imgf000049_0001
List 5
Figure imgf000049_0002
Figure imgf000049_0003
Figure imgf000049_0004
Figure imgf000049_0005
List 5 (Continued)
Figure imgf000050_0001
Figure imgf000050_0003
Figure imgf000050_0004
Figure imgf000050_0002
Figure imgf000050_0005
List 5 (Continued)
Figure imgf000051_0001
List 5 (Continued)
Figure imgf000052_0001
List 6
Figure imgf000052_0002
Figure imgf000052_0003
List 6 (Continued)
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000053_0003
A library according to the claim 1 wherein said library has all or substantially all of the compounds represented therein.
A library according to claim 1 or 2 wherein said library has about 100, 1000, 2000, 3000, or 10000 of the compounds represented therein.
A method for making a compound library according to claims 1 to 3 , which method comprises the step of synthesising intermediate chemical structures according to the following scheme:
Figure imgf000054_0001
wherein Rl, R2, R3 , X and Y are as defined in claim 1.
A method for making a compound library according to claims 1 to 3 , which method comprises the step of synthesising intermediate chemical structures to the following scheme:
Figure imgf000054_0002
wherein Rl, R2 , R3 , X and Y are as defined in claim 1; and R4 is a substituted alkyl derived from List 5 by reductive alkylation.
List 5
Figure imgf000055_0001
List 5 (Continued)
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000056_0004
Figure imgf000056_0005
Figure imgf000056_0003
Figure imgf000056_0006
List 5 (Continued)
Figure imgf000057_0001
List 5 (Continued)
Figure imgf000058_0001
A method for making a compound library according to claim 1, which method comprises the step of synthesising compounds of formula A according to the following scheme:
Figure imgf000058_0002
wherein Rl, R2, X and Y are as defined in claim 1,-
where R3 does not form part of a ring it can be hydrogen or an optionally substituted alkyl;
R4 is a substituted alkyl derived by alkylation with compounds from List 4, wherein # is a leaving group . List 4
Figure imgf000059_0001
Figure imgf000059_0002
List 4 (Continued)
Figure imgf000060_0001
List 4 (Continued)
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0004
Figure imgf000061_0003
Figure imgf000062_0001
List 4 (Continued)
Figure imgf000063_0001
An intermediate chemical structure having the following structure for use in 'a method according to claims 5 to 6 for making a library according to claims 1 to 3.
Figure imgf000063_0002
An intermediate chemical structure having the following structure for use in a method according to claims 4 to 6 for making a library according to claims 1 to 3.
Figure imgf000064_0001
9. A compound capable of binding a G coupled
Receptor, which compound is selected from compounds represented within a library according to claim.
10. A method of making a compound according to claim 9, which method is according to the methods of claims 4 to 6
11. A compound library comprising or consisting of a set of structurally related compounds, substantially as herein described.
12. A compound capable of binding to a G-protein coupled receptor, substantially as herein described
PCT/GB2003/005652 2002-12-24 2003-12-24 Compound libraries of imidazo[1,5-a]pyridin-3-yl derivatives and related heterobicycles for targetting compounds capable of binding to g-protein coupled receptors WO2004058755A2 (en)

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DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 27 June 1988 (1988-06-27), XP002280231 Database accession no. BRN134243 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 28 April 1997 (1997-04-28), XP002280238 Database accession no. 645058 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 28 November 1988 (1988-11-28), XP002280232 Database accession no. 475308 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 28 November 1988 (1988-11-28), XP002280233 Database accession no. 475309 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 28 November 1988 (1988-11-28), XP002280234 Database accession no. 477795 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 28 November 1988 (1988-11-28), XP002280237 Database accession no. 514116 *

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WO2008022060A2 (en) * 2006-08-14 2008-02-21 Novartis Ag Imidazo-pyridine derivatives for modulating protein kinase activity
WO2008022060A3 (en) * 2006-08-14 2008-12-31 Novartis Ag Imidazo-pyridine derivatives for modulating protein kinase activity
WO2009038012A1 (en) * 2007-09-18 2009-03-26 Taisho Pharmaceutical Co., Ltd. Heterocyclic compound
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
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US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
US10933063B2 (en) * 2017-03-22 2021-03-02 Xibin Liao Bruton's tyrosine kinase inhibitors
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