WO2004058720A2

WO2004058720A2 - Compound libraries of 1,3,5-substitute indazole derivatives as compounds for targetting compounds capable of binding to the g-protein coupled receptor

Info

Publication number: WO2004058720A2
Application number: PCT/GB2003/005650
Authority: WO
Inventors: Graham Peter Jones; Christophe Parsy; Jacqueline Anne Macritchie
Original assignee: BIOFOCUS PLC
Current assignee: BIOFOCUS PLC
Priority date: 2002-12-24
Filing date: 2003-12-24
Publication date: 2004-07-15
Anticipated expiration: 2005-06-24
Also published as: AU2003295158A8; AU2003295158A1; WO2004058720A3

Abstract

The present invention provides a compound library that is targeted against a group of peptide liganded receptors, which can be characterised broadly as requiring an interaction with an amide or acid function interacting largely by hydrogen bonding. In addition the library picks up interactions for electron-rich aromatic rings and other interactions. The library comprises or consists of a set of structurally related compounds of general formulae (A), (B) and (C), as well as intermediates of structure (I).

Description

COMPOUND LIBRARIES

Introduction

Background

The present invention relates to compounds capable of binding to G-protein coupled receptors. In particular, a library of compounds is 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 ^ΛHits' 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 iversity' 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 modelling 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, prostaglandin 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 that will enhance the probability of finding a small molecule that 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 amine- 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 that 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 synt esise 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 a novel focused library 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.

International application WO 03/028720 discloses 3- aminoindazole derivatives or salts thereof for treatment of diseases caused by and/or associated with an altered protein kinase activity. The compound library of the present invention may include the compounds disclosed in WO 03/028720, but the compound library is not identical to the class of compounds claimed in WO 03/028720. where compounds per se are generally claimed by the present invention, any compounds specifically discloses in WO 03/028720 are hereby disclaimed per se.

Any other 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 06 is a library that is targeted against a group of peptide liganded receptors, which can be characterised broadly as requiring an interaction with an amide or acid function interacting largely by hydrogen bonding. In addition the library picks up interactions for electron-rich aromatic rings and other interactions. Receptors that fall into the broad scope for this library include receptors like bombesin, endothelin A, galanin, and the prolactin releasing peptide receptor GPRA amongst others.

The invention provides a compound^' library comprising or consisting of a set of structurally related compounds of the following general formulae A, B and C:

wherein the permitted substituents for Rl are derived from List 12 and from List 13; the permitted substituents for R2 are R9RION-# and R8S02NH-#, wherein the permitted substituents for R9R10N-# are as defined in List 14; the permitted substituents for R8S02NH-# are as defined in List 15 the permitted substituents for R3 are derived from List 12; the permitted substituents' for R5 are RllS0₂-#, R12NHC0-#,

R13CO-#,R140CO-#, and R15S0₂ NHCO-#, wherein the permitted substituents for Rll are derived from List 16; the permitted substituents for R12 are derived from List 17; the permitted substituents for R13 are derived from List 18; the permitted substituents for R14 are derived from List 19; the permitted substituents for R15 are derived ^'from

List 20; the permitted substituents for R6 is R16S0₂-#, wherein the permitted substituent for R16 is derived from List 21; the permitted substituent for R7 is R17CO-#, wherein the permitted substituent for R17 is derived from List 22; X can be hydrogen, methyl, methoxy, trifluoromethyl, nitro, chloro or fluoro; and # is the point of attachment

List 12 (Continued)

List 12 (Continued)

List 12 (Continued)

List 12 (Continued)

List 13

List 13 (Continued)

List 14

List 14 (Continued)

List 14 (Continued)

List 14 (Continued)

List 15

List 16

List 16 (Continued)

List 16 (Continued)

List 17

List 17 (Continued)

List 17 (Continued)

List 18

List 18 (Continued)

List 18 (Continued)

List 19

List 19 (Continued)

List 20

List 22

Structural Novelty of Library 6 The direct linked heterocycles

When the substructures below are drawn as an isolated ring system there are no known compounds and in particular there are no compounds where "net" is an aromatic heterocycle.

For the acid below there are no known compounds that are permitted in the library

The direct linked aryls

There are 16 known compounds which have the general substructure shown, however, they are not permitted to appear in the library. The known compounds have one of four aryl groups (unsubstituted phenyl; 4-C1; 4-F; 2,4-diN02). All of the compounds of the library 6 have a more complex pattern based on a substituted amine in the 4 position.

There is one known compound which has unsubstituted phenyl as the aryl group. Compounds in the library that have a substituted aryl group are not known.

The benzyl case - nitrogen linked

There are no sulphonamides or ureas known but there is one carbamate, which is shown below.

There are 12 known amides based on the substructure below.

However in all but one case they possess an unsubstituted benzyl moiety. Only one substance with a substituted benzyl is known, which is shown below.

For the benzyl case - carbon linked

There are no sulphonamides and only one hydroxamate known which is shown below.

Methods of Synthesising Compounds of Formula A

Substituted l-H-indazole-3-carboxylic acids (1) were reacted with benzyl halides (List 1) and halo-heterocycles (List 2) to give compounds of formula A (R2 = OH) .

The indazole-3-carboxylic acids of formula A can be converted to acyl sulphonamides of Formula A (R2 = NHS0₂R8) by reacting with a sulphonyl isocyanate (List 4) as shown below.

The indazole-3-carboxylic acids of formula A (R2 = OH) were converted to their acid chlorides and reacted with amines and hydroxylamines (List 3) to give a series of amides and hydroxamides of formula A, (R2 = NR9R10)

Methods of Synthesising of Compounds of General Formula B

l-H-Indazole-3-ylamine was reacted with a series of benzyl halides (List 1) to give benzyl 3-amino-indazoles of Formula B, (R4 = H, R5 = H)

These were then reacted with sulphonyl chlorides (List 5) , isocyanates (List 6) , chloroformates (List 8 ] , sulphonyl isocyanates (List 9) and acid chlorides (List 7) to give sulphonamides (a) , ureas (b) , carbamates (c) , acyl sulphonamides (d) and amides (e)

Methods of Synthesising of Compounds of general Formula C

l-H-Indazole-3-ylamine (f) was reacted with l-fluoro-4- nitrobenzene to give the nitro phenyl indazoles (g) . These were reacted with sulponyl chlorides (List 10) to give the sulphonamides (h) , the nitro was reduced to give the amine (i) and this was reacted with acid chlorides (List 11) to give the amides of Formula C (R7 = S0₂R16 and R6 = COR17) .

Other methods for the synthesis of the intermediates will be apparent to the chemist skilled in the art, as will be the methods for preparing starting materials. The isolated novel compounds were confirmed by IH N.M.R and/or other appropriate methods .

n or R3-Halogen)

List 1 (Continued)

List 1 (Continued)

List 1 (Continued)

List 1 (Continued)

List 2 (R1 -Halogen)

List 2 (Continued)

List 3 (HNR9R10)

List 3 (Continued)

List 3 (Continued)

List 3 (Continued)

List 4 (R8S0₂NCO)

List5(R11S0₂CI)

List 5 (Continued)

List 5 (Continued)

List6(R12NC0)

List 6 (Continued)

List 6 (Continued)

List 7 (R13COCI)

List 7 (Continued)

List 7 (Continued)

List8(R140COCI)

List 8 (Continued)

List9(R15S0₂NCO)

List 10 (R16S0₂CI)

List 11 (R17COCI)

Detailed Methods of Preparation: Library 6

The compounds of formulae (B) and (C) may be obtained by applying synthetic procedures, some of which are illustrated in the scheme 1, 2 and 3. The synthesis provided for in these schemes is applicable for producing compounds of formulae (B) and (C) below, having a variety of different R3, R4, R5, R6, R7 and X groups .

Synthetic examples

The synthesis of compound of formula (B) with X = R3 = R4 = R5

= H was carried out according to Lessel et al,

(Arch. Pharm. (Weinheim Ger. ) ;GE; 328; 5; 1995; 397-402) . The same procedure was applied when X = CH₃ and OCH₃. The synthesis of compound of formula (B) with X = N0₂ was carried out according to Parnell. ( . Chem. Soc. , 1959, 2363-2365) The same procedure was applied when X = CI or CF₃. Example 1

(3) a) NaH, DMF; b) Pyridine, DMAP. Scheme 1

Preparation of 1- (4-Bromomethyl-benzyl) -3-ethyl-l ,3-dihydro- benzoimidazol-2-one (1)

Sodium hydride (60% in mineral oil, 1.52g, 0.038mol) was dissolved in DMF (10 cm³) and cooled at 0°C. l-Ethyl-2- benzimidazolinone (5.1g, 0.031mol) was added to the solution portionwise. After 30 minutes, a solution of bis-benzyl bromide (16.6g, 0.063mol) in DMF (90cm³) was added dropwise. During the addition the temperature was maintained at 0°C then the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (1000cm³) and stirred for 30 minutes. The solid was filtered, dried and purified by flash column chromatography (10% ethyl acetate/petroleum ether 40-60°) on silica gel to give the titled compound (5.9g, 55%) as a pink solid. ^λE NMR (CDCl₃-400MHz) : 1.4 (3H) , 4.0 (2H) , 4.4 (2H), 5.1 (2H) , 6.9-7.1 (4H) , 7.2-7.4 (4H)

Preparation of 1- [4- (3-Amino-indol-l-ylmethyl) -benzyl] -3-ethyl- 1 ,3-dihydro-benzoimidazol-2-one (2)

Sodium hydride (60% in mineral oil, 0.88g, 0.022mol) was dissolved in DMF (10 cm³) and cooled at 0°C. lH-Indazol-3- ylamine (2.44g, 0.018mol) was added to the stirring solution portionwise. After 30 minutes, a solution of 1- (4-Bromomethyl- benzyl) -3-ethyl-l, 3-dihydro-benzoimidazol-2-one (1) (6.329g, O.Olδmol) in DMF (40cm³) was added dropwise. During the addition the temperature was maintained at 0°C then the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (500cm³) and stirred for 30 minutes. Ethyl acetate (150cm³) was added, the layers separated and the aqueous phase was extracted with ethyl acetate (2x150cm³) . The organic layers were combined, washed with brine (150cm³) , dried over magnesium sulphate, filtered and concentrated in vacuo . Purification by flash column chromatography (30% EtOAc/Petroleum Ether 40-60°) on silica gel gave the titled compound (2.522g, 35%) as a pale yellow solid, mp: 152-153°C Preparation of 4-Cyano-N-{l- [4- (3-ethyl-2-oxo-2,3-dihydro- benzoimidazol-1-ylmethyl) -benzyl] -lH-indol-3-yl}- benzenesulfonamide (3)

4- (dimethylamine) pyridine (5mg, 0.04mmol) was added to 1.25 cm³ of a solution of 1- [4- (3-Amino-indol-l-ylmethyl) -benzyl] -3- ethyl-1, 3-dihydro-benzoimidazol-2-one (2) (1.589g, 0.004mol) in pyridine (50cm³) followed by addition of 0.34 cm³ of a solution of 4-cyanobenzenesulfonylchloride (0.725g, 0.0036mol) in DCM

(10cm³) The reaction mixture was shaken overnight, concentrated in vacuo and diluted with ethyl acetate (3 cm ) and water (2cm³) . The layers were separated and the organic layer was concentrated in vacuo . The solid was purified by preparative HPLC to give the title compound (33.9mg, 60%). mp: 227-229°C ^■

Example 2

Scheme 2 Preparation of Furan-2-carboxylic acid {1- [4- (3-ethyl-2-oxo- 2 ,3-dihydro-benzoimidazol-l-ylmethyl) -benzyl] -lH-indazol-3-yl}- amide (4)

4- (dimethylamine) pyridine (5mg, 0.04mmol) was added to 1.25 cm³ of a solution of 1- [4- (3-Amino-indol-l-ylmethyl) -benzyl] -3- ethyl-1, 3-dihydro-benzoimidazol-2-one (2) (1.589g, 0.004mol) in pyridine (50cm³) followed by addition of 0.34 cm³ of a solution of furan-2-carbonylchloride (0.469g, 0.0036mol) in DCM (10cm³). The reaction mixture was shaken overnight, concentrated in vacuo and diluted with ethyl acetate (3 cm³) and water (2cm³) . The layers were separated and the organic layer was concentrated in vacuo. The solid was dissolved in dimethylformamide (1cm³) and purified by preparative HPLC to give the titled compound (31.7mg, 64%). mp: 110-112°C

Example 3

a) THF, reflux Scheme 3

Preparation of N-{1- [4- (Benzo [1,3] dioxol-5-ylmethoxy) -benzyl] - 5-methyl-lH-indazol-3-yl} -4-cyano-benzamide (6) 1- [4- (Benzo [1, 3] dioxol-5-ylmethoxy) -benzyl] -5-methyl-lH- indazol-3-ylamine (5) (44 mg, O.lmmol) was dissolved in THF (1.5 cm³) and 4-isocyanatobenzonitrile (29mg, 0.2mmol) was added. The reaction mixture was stirred at 70 °C for 16h. The solid that precipitated out on cooling was filtered and the cake washed with ether to give the titled compound (37mg, 63%) . mp: 252-254°C Example 4

a)K₂C0_3; b) Pyridine, DMAP; c) Zn, H₂SO.,; d) Pyridine, DMAP

Scheme 4 Preparation of 1- (4-Nitro-phenyl) -lH-indazol-3-ylamine (7)

lH-Indazol-3-ylamine (1) (0.760g, 5.7mmol) was dissolved in dimethylformamide (20 cm³) followed by addition of potassium carbonate (0.789g, 5.7mmol) and l-fluoro-4-nitrobenzene (0.806g, 5.7mmol). The reaction mixture was stirred at 120°C for 16h. After cooling, the reaction mixture was poured into water (150cm3) and stirred for 30 minutes. The solid was filtered and the cake washed with water and dried to give the title compound (0.907g, 62%) as a red solid, mp: 203-205°C

Preparation of N- [1- (4-Nitro-phenyl) -lH-indazol-3-yl] -C-phenyl- methanesul onamide (8)

4- (dimethylamind) pyridine (44 mg, 0.36 mmol) was added to a stirred solution of 1- (4-Nitro-phenyl) -lH-indazol-3-ylamine (7)

(0.92 g, 3.62 mmol) in pyridine (9 cm3) . The resulting mixture was cooled to 0°C and a solution of phenylmethylsulfonyl chloride (0.83 g, 4.35 mmol) in DCM (4 cm3) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16h. The solvents were removed under reduced pressure and the resulting oil treated with a saturated solution of NaHC0₃ (15 cm3) . The supernatant was removed and the solid further washed with NaHC0₃ (2 x 15 cm3) followed by water (3 x 20cm3) . The sulfonamide was used in the subsequent reduction stage with no further purification.

Preparation of N- [1- (4-Amino-phenyl) -lH-indazol-3-yl] -C-phenyl- methanesulfonamide (9)

A mixture of the crude N- [1- (4-Nitro-phenyl) -lH-indazol-3-yl] - C-phenyl-methanesulfonamide (1.4 g, 3.43 mmol) and powdered zinc (2.2 g, 34.3 mmol) in absolute ethanol (35 cm3) was heated at reflux. A 50% H₂S0 solution (1.4 cm3) was added dropwise. The reaction mixture was maintained at reflux for 90 minutes, cooled and filtered. The zinc filter cake was washed with ethanol and the combined filtrates were concentrated in vacuo . The residue was partitioned between DCM (200 cm3) and a saturated solution of NaHC0₃ (100 cm3) . The layers were separated and the aqueous layer further extracted with DCM (1 x 100 cm3) . The combined organic extracts were dried over magnesium sulphate (MgS0) , filtered and concentrated in va cuo to afford the crude amine which was purified by flash column chromatography using gradient elution [starting solvent: DCM; final solvent: DCM-MeOH (9:1)] on silica gel to give the titled compound (0.55g, 40% over 2 steps). ^Η NMR (DMS0-d₆, 400MHz) , δ 4.9(2H), 5.5(2H), 6.9(2H), 7.3(1H), 7.5(5H), 7.6(3H), 7.8(1H), ^' 8.0(1H), 10.6(1H)^'.

Preparation of N- [4- (3-Phenylmethanesulfonylamino-indazol-l- yl) -phenyl] -isobutyramide (10)

An ice-cooled solution of isobutyryl chloride (0.038 g, 0.36 mmol) in dichloromethane (1 cm³) was added to an ice-cooled solution of N- [1- (4-Amino-phenyl) -lH-indazol-3-yl] -C-phenyl- methanesulfonamide (9) (38 mg, 0.1 mmol) in dry pyridine (1 cm³). A solution of 4- (dimethylamino) pyridine (1.2 mg, 0.01 mmol) in dry DCM (0.3 cm³) was then added, and the resulting mixture shaken at room temperature for 16h. The solvents were concentrated in vacuo . DMF (0.175 cm³) was added and the mixture shaken for a further 20 minutes. The mixture was partitioned between EtOAc (3 cm³) and water (2 cm³) and the organic layer concentrated to afford the crude product that was purified by preparative HPLC to give the title compound (18.0mg, 40%). mp : 156-158°C Example 5

Preparation of 1- (4-benzyloxy benzyl) -lH-indazole-3-carboxylic acid.

IH Indazole-3-carboxylic acid (1.2g, 0.0075M) was .dis-solved in 25ml dimethyl formamide under nitrogen. Sodium hydride (0.6g of 40% in oil, 0.015M) was added portionwise. Stirred at room temperature for 30 minutes, a solution of 4-benzyloxy-benzyl chloride (1.74g, 0.0075M) in dimethyl formamide (10ml) was added dropwise and the mixture was stirred at room temperature overnight.

The mixture was treated with water (125ml) and acidified (pH 1) with 2N hydrochloric acid. The resulting solid was filtered and washed with water giving 2.6g of 1- (4-benzyloxy benzyl) -1H- indazole-3-carboxylic acid.

δ_H(400 MHz; CDC1₃)

5 (s) 2H; 5.6 (s) 2H; 6.83 (d) 2H; 7.19 (d) 2H; 7.22-7.94 (m) 8H; 8.22 (d) IH Preparation of 1- (4-benzyloxybenzyl) -lH-indazole-3-carboxylic acid(4-trifluoromethyl-1-phenyl) amide

1- (4-benzyloxy benzyl) -lH-inadazole-3-carboxylic acid (0.716g; 0.002M) was stirred in thionyl chloride (5ml) at 50°C for 30 minutes to give a clear solution. This was evaporated and the residue was treated with dry tetrahydrofuran (50ml) and evaporated twice to remove traces of thionyl chloride. The resulting yellow oil was made up to 20ml with tetrahydrofuran. 2ml of the acid chloride solution was added to a solution of 4- trifluoromethylaniline in 0.5ml of dry pyridine at room temperature and the resulting solution was gently shaken overnight. The reaction mixture was evaporated and the residue was treated with ethyl acetate (2ml) and washed with water. The ethyl acetate was evaporated to give 81mg of l-(4- benzyloxybenzyl) -lH-indazole-3-carboxylic acid (4- trifluoromethyl-1-phenyl) amide.

δ_H(400 MHz; CDC1₃)

5.03 (s) 2H; 5.58 (s) 2H; 6.9 (d) 2H; 7.14 (d) 2H; 7.25-δ7.53 (m) 8H; 7.64 (d) 2H; 7.89 (d) 2H; 8.4 (d) IH; 9.01 (s) IH

Claims

A compound library comprising or consisting of a set of structurally related compounds having core chemical structures (scaffolds) of general formulae A, B and C:

wherein the permitted substituents for Rl are derived from List 12 and from List 13; the permitted substituents for R2 are R9RION-# and R8S02NH-#, wherein the permitted substituents for R9R10N-# are as defined in List 14; the permitted substituents for R8S02NH-# are as defined in List 15 the permitted substituents for R3 are derived from List 12; the permitted substituents for R5 are RllS0₂-#, R12NHCO-#, R13CO-#,R140CO-#, and R15S0₂ NHCO-#, wherein the permitted substituents for Rll are derived from

List 16; the permitted substituents for R12 are derived from

List 17; the permitted substituents for R13 are derived from

List 18; the permitted substituents for R14 are derived from

List 19; the permitted substituents for R15 are derived from

List 20; the permitted substituents for R6 is R16S0₂-#, wherein the permitted substituent for R16 is derived from

List 21; the permitted substituents for R7 is R17CO-#, wherein the permitted substituent for R17 is derived from List 22;

X can be hydrogen, methyl, methoxy, trifluoromethyl, nitro, chloro or fluoro; and # is the point of attachment

List 12 (Continued)

List 12 (Continued)

List 12 (Continued)

List 12 (Continued)

List 13

List 13 (Continued)

List 14

List 14 (Continued)

List 14 (Continued)

List 14 (Continued)

List 15

List 16

List 16 (Continued)

List 16 (Continued)

List 17

List 17 (Continued)

List 17 (Continued)

List 18

List 18 (Continued)

List 18 (Continued)

List 19

List 19 (Continued)

List 20

List 22

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 wherein said compounds

10 have a core chemical structure and permitted substituents thereon, and wherein said library has about 100, 1000, 2000, 3000 or 10000 compounds represented therein.

A method for making a compound library according to claim

15. 1, which method comprises the step of synthesising compounds of formula A according to the following reaction scheme:

20 wherein Rl and X are as defined in claim 1;

R2=OH; and

#=a leaving group.

25 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 reaction scheme:

wherein Rl, R8 and X are as defined in claim 1.

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 reaction scheme:

wherein Rl, R9, R10 and X are as defined in claim 1.

7. A method for making a compound library according to claim 1, which method is according to claim 4, and wherein substituted l-H-indazole-3-carboxylic acids are reacted with benzyl halides (List 1) and halo-heterocycles (List 2) to give compounds of formula A (R2=OH) ; and Lists 1 and 2 are as defined in claim 1. A method for making a compound library according to claim 1, which method is according to claim 5, and wherein the indazole-3-carboxylic acids of formula A are reacted with sulphonyl isocyanates (List 4) in the presence of an Hunigs base to give acyl sulphonamides of formula A (R2=NHS0₂R8) ; and List 4 is as defined in Claim 1.

A method for making a compound library according to claim 1, which method is according to claim 6, and wherein the indazole-3-carboxylic acids of formula A are converted to their acid chlorides; reacted with amines and hydroxylamines (List 3) to give amides and hydroxamides of formula A (R2=NR9R190) ; and List 3 is as defined in claim 1.

10 A method for making a compound library according to claim 1, which method comprises the step of synthesising compounds of formula B according to the following reaction scheme:

wherein R3 and X are as defined in claim 1; and # is a leaving group.

11. A method for making a compound library according to claim 1, which method is according to claim 10, and wherein 1- H-indazole-3-ylamine is reacted with benzyl halides (List 1) to give benzyl 3-amino-indazoles of formula B (R4=H,

R5=H) ; the resultant benzyl 3-amino-indazoles of formula B are reacted with: sulphonyl chlorides (List 5) to give sulphonamides of formula B (R4=H, R5=S0₂R11) ; isocyanates (List 6) to give ureas of formula B (R4=H,

R5=ONHR12) ; chloroformates (List 8) to give carbamates of formula B (R4=H, R5=00R14); sulphonyl isocyanates (List 9) to give acyl sulphonamides of formula B (R4=H, R5=0NHS0₂R15) ; acid chlorides (List 7) to give amides of formula B (R4=H, R5=OR13) ; and X, Rll, R12, R14, R15 and R13, and Lists 1, 5, 6, 7,

8 and 9 are as defined in claim 1.

12. A method of making a compound library according to claim 1, which method comprises the step of synthesising compounds of formula C according to the following reaction scheme:

wherein X, R16 and R17 are as defined in claim 1.

13. A method of making a compound library according to claim 1, which method is according to claim 12, and wherein 1- ^' H-indazole-3-ylamine is reacted with l-fluoro-4- nitrobenzene; the resultant nitro phenyl indazoles are reacted with sulphonyl chlorides (List 10) to give sulphonamides of formula C (R7 = S0₂R16, R6=0) ; the nitro of the sulphonamides is reduced to give amines of formula C (R7=S0₂R16, R6=H) ; the resultant amine of formula C is reacted with acid chlorides (List 11) to give amides of formula C (R7 =

S0₂R16, R6=C0R17); and X, R16, and R17, and Lists 10 and 11 are as defined in claim 1.

14. A method for making a compound library according to claim 4, which method further comprises the step of introducing Rl by reacting the core chemical scaffold with any or all of the precursor groups in List 12 or List 13 where # is a leaving group; and Lists 12 and 13 are as defined in claim 1.

List 12 (Continued)

List 12 (Continued)

List 12 (Continued)

List 12 (Continued)

List 13

List 13 (Continued)

15. A method for making a compound library according to claim 6, which method further comprises the step of introducing R9NR10 by reacting the core chemical scaffold with any or all of the precursor groups in List 14 where # is a hydrogen:

List 14

List 14 (Continued)

ill

List 14 (Continued)

16. A method for making a compound library according to claim 6, which method further comprises the step of introducing R3 by reacting the core chemical scaffold with any or all of the precursor groups in List 12 where # is a leaving group especially halogen or sulphonate :

List 12 (Continued)

List 12 (Continued)

List 12 (Continued)

List 12 (Continued)

17. A method for making a compound library according to claim 12, which method further comprises the step of introducing R16S0₂ by reacting the core chemical scaffold with any or all of the precursor groups in List 21 where # is a leaving group:

18. A method for making a compound library according to claim 12, which method further comprises the step of introducing R17C0 by reacting the core chemical scaffold with any or all of the precursor groups in List 22 where # is a leaving group:

List 22

19. Intermediate compounds as defined in any of claims 4-18, for use in making a compound library according to any of claims 1 to 3.

20. A core chemical structure (scaffold) having the following structure wherein X is a hydrogen, methyl, methoxy, trifluoromethyl, nitro, chloro or fluoro.

21. A compound capable of binding to a G-protein coupled receptor, which compound is selected from compounds represented within a library according to claim 1 but not including compounds previously known in the art.

22. A method of making a compound library according to claim 21, which method is according to claims 4-18.

23. A compound library comprising or consisting of a set of structurally related compounds, substantially as herein described.

24. A compound capable of binding to a G-protein coupled receptor, substantially as herein described.