AU2002334217B2 - Benzimidazoles and analogues and their use as protein kinases inhibitors - Google Patents

Description

WO 03/035065 PCT/GB02/04763 BENZIMIDAZOLES AND ANALOGUES AND THEIR USE AS PROTEIN KINASES INHIBITORS This invention is directed to benzimidazoles of formula their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of the protein kinases. Such protein kinases belong especially to the following group: EGFR, Fak, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, fit-1, IGF-lR, KDR, PDGFR, tie2, VEGFR, ITK and SYK.

Protein kinases are a family of enzymes that participate in the signalling events which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these kinases fall into several groups; those which preferentially catalyse the phosphorylation of hydroxy groups of serine and/or threonine residues and those which preferentially catalyse the phosphorylation of hydroxy groups of tyrosine residues [S.K.Hanks and T.Hunter, FASEB. 1995, 9, pages 576-596]. Such phosphorylations may greatly modify the function of the proteins; thus, protein kinases play an important role in regulating a wide variety of cell processes including, especially, metabolism, cell proliferation, cell differentiation or cell survival.

Among the various cellular functions in which the activity of a kinase protein is involved, certain processes represent attractive targets for treating certain diseases. As an example, mention may be made especially of angiogenesis and the control of the cell cycle, in which kinase proteins can play an essential role. These processes are essential for the growth of solid tunours and also for other diseases.

Angiogenesis or the formation of new blood vessels by sprouting from the preexisting vasculature is of central importance for embryonic development and organogenesis. Should the need arise, the vascular system has the potential to generate a network of new vessels so as to maintain the correct functioning of the tissues and organs. Angiogenesis is a complex multistage process which includes activation, migration, proliferation and survival of endothelial cells. In adults, angiogenesis is fairly limited, appearing mainly only in the processes of repair after an injury or of vascularization of the endometrium. (Merenmies et al., Cell Growth Differentiation, 8, 3-10, 1997). However, uncontrolled angiogenesis is found in certain pathologies such as retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration or cancer (solid tumours) (Folkman, Nature Med., 1, 27-31, 1995). The kinase proteins whose involvement it has been possible to demonstrate in the angiogenesis process include three members of the family of growth factor receptor tyrosine kinases: VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR, kinase insert domain receptor, or FLK-1), FGF-R (fibroblast growth factor receptor) and TEK (also known as Tie-2).

WO 03/035065 PCT/GB02/04763 -2- In conjunction with other systems, the Vascular Endothelial Growth Factor receptors (VEGFRs) transmit signals involved in the migration, proliferation and survival of endothelial cells. The family VEGFR includes VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR3 (Flt4). The receptor VEGF-R2, which is expressed only in the endothelial cells, binds to the angiogenic growth factor VEGF, and thus serves as a transduction signal mediator via the activation of its intracellular kinase domain. Thus, the direct inhibition of the kinase activity of VEGF-R2 makes it possible to reduce the phenomenon of angiogenesis in the presence of exogenous VEGF (Strawn et al., Cancer Research, 56, 3540-3545, 1996), this process being demonstrated especially with the aid of VEGF-R2 mutants (Millauer et al., Cancer Research, 56, 1615-1620, 1996). The VEGF-R2 receptor appears to have no other function in adults than that associated with the angiogenic activity of VEGF. Thus, a selective inhibitor of the kinase activity of VEGF-R2 should show only little toxicity.

In addition to this central role in the dynamic angiogenic process, recent results suggest that the expression of VEGF contributes towards the survival of tumoral cells after chemotherapy and radiotherapy, underlining the potential synergism of KDR inhibitors with other agents (Lee Heijn M. et al., (2000), Cancer Research, 60 5565-70). The KDR inhibitors thus especially constitute anti-angiogenic agents and such agents might be used as a first line treatment against tle emergence or regrowth of malignant tumours. The inhibition or regulation of VEGFR-2 (KDR) thus provides a powerful new mechanism of action for the treatment of a large number of solid tumours.

Extensive studies in the field of tumor angiogenesis in the past two decades have identified a number of therapeutic targets including kinases, proteases and integrins resulting in the discovery of many new anti-angiogenic agents, including KDR inhibitors some of which are currently under clinical evaluation (Jekunen, et al Cancer Treatment Rev. 1997, 23, pages 263-286.).

The present patent application thus relates particularly to novel inhibitors of the VEGFR-2 (KDR) receptor that may be used especially for anti-angiogenic treatment in oncology.

The protein kinases which preferentially catalyse the phosphorylation of hydroxy groups of serine and/or threonine residues include for example, protein kinase C isoforms [A.C.Newton, J. Biol. Chem., 1995, 270, pages 28495-28498] and a group of cyclin-dependent kinases such as cdk2 [J.Pines, Trends in Biochemical Sciences, 1995, 18, pages 195-197]. The protein kinases which preferentially catalyse the phosphorylation of hydroxy groups of serine and/or threonine residues include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [S.Iwashita and M.Kobayashi, WO 03/035065 PCT/GB02/04763 -3- Cellular Signalling, 1992, 4, pages 123-132], and cytosolic non-receptor kinases such as p561ck, p59fYn, ZAP-70 and csk kinases [C.Chan et. al., Ann. Rev. Immunol., 1994,12, pages 555-592].

Inappropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, for example by failure of the proper control mechanisms for the kinase, related for example to mutation, over-expression or inappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factors also participating in the transduction of signals upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect.

SYK (Spleen Tyrosine Kinase) is a 72-kDa cytoplasmic protein tyrosine kinase that is expressed in a variety of hematopoietic cells and is an essential element in several cascades that couple antigen receptors to cellular responses. Thus, SYK plays a pivotal role in signalling of the high affinity IgE receptor, FceR1, in mast cells and in receptor antigen signalling in T and B lymphocytes. The signal transduction pathways present in mast, T and B cells have common features. The ligand binding domain of the receptor lacks intrinsic tyrosine kinase activity. However, they interact with transducing subunits that contain immunoreceptor tyrosine based activation motifs (ITAMs) [M.Reth, Nature, 1989, 338, pages 383-384]. These motifs are present in both the P and y subunits of the FceRl, in the p-subunit of the T cell receptor (TCR) and in the IgGa and IgG P subunits of the B cell receptor (BCR). [N.S.van Oers and A.Weiss, Seminars in Immunology, 1995, 7, pages 227-236] Upon binding of antigen and multimerization, the ITAM residues are phosphorylated by protein tyrosine kinases of the Src family. SYK belongs to a unique class of tyrosine kinases that have two tandem Src homology 2 (SH2) domains and a C terminal catalytic domain. These SH2 domains bind with high affinity to ITAMs and this SH2 -mediated association of SYK with an activated receptor stimulates SYK kinase activity and localises SYK to the plasma membrane.

In SYK deficient mice, mast cell degranulation is inhibited, suggesting that this is an important target for the development of mast cell stabilising agents [P.S.Costello, Oncogene, 1996, 13, pages 2595- 2605]. Similar studies have demonstrated a critical role for SYK in BCR and TCR signalling [A.M.Cheng, Nature, 1995, 378, pages 303-306, (1995) and D.H.Chu et al., Immunological Reviews, 1998, 165, pages 167-180]. SYK also appears to be involved in eosinophil survival in response to and GM-CSF [S.Yousefi et al., J. Exp. Med., 1996, 183, pages 1407-1414]. Despite the key role of SYK in mast cell, BCR and T cell signalling, little is known about the mechanism by which SYK transmits downstream effectors. Two adaptor proteins, BLNK (B cell Linker protein, SLP-65) and SLP-76 have been shown to be substrates of SYK in B cells and mast cells respectively and have been postulated to interface SYK with downstream effectors [M.Ishiai et al., Immunity, 1999, 10, pages 117- 00

O

C 125 and L.R.Hendricks-Taylor et al., J.Biol. Chem, 1997, 272, pages 1363-1367].

SIn addition SYK appears to play an important role in the CD40 signalling pathway, which plays an important role in B cell proliferation [M.Faris et al., J.Exp. Med., 1994, 179, pages 1923-1931].

SYK is further involved in the activation of platelets stimulated via the lowaffinity IgG receptor (Fc gamma-RIIA) or stimulated by collagen [F.Yanaga et al., Biochem. 1995, 311, (Pt. 2) pages 471-478].

ITK, is a T cell specific tyrosine kinase of the Tec family that is required for 0 normal Th2 function. Asthma is a disease characterised by increased Th2 c 10 cytokine production including IL-4. An inhibitor of ITK should therefore have an impact on disease progression in asthma through inhibition of Th2 cytokine production.

We have now found a novel group of benzimidazoles, which have valuable pharmaceutical properties, in particular, the ability to inhibit protein kinases, more particularly, the ability to inhibit the protein kinase SYK, the protein kinase KDR, the protein kinase tie2 or the protein kinase ITK.

Thus, in one aspect, the present invention is directed to compounds of general formula (Ix)

R

3 R2H- R W (Ix) wherein X, Y, Z and W are carbon atoms;

A

5 represents H or alkyl;

R

1 is a pyrazolyl moiety R'in which

R

7 is hydrogen or alkyl,

R

8 is selected from the group consisting of hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 14

-C(=O)R

4 -C(=O)NYly 2 -C(=O)0R 4

N(R

6

)C(=O)R

4

-N(R

6 )C(=O)NY1 y 2

-N(R

6

)C(=O)OR

4

-N(R

6 )S0 2

R

4

-N(R

6

)SO

2 NYly 2

-NY

1 y 2

-OR

4

-OC(=O)R

4

-OC(=O)NY

1 y 2 -S(O)nR 4 and

-S(O)

2 NYly 2 and

R

9 is selected from the group consisting of hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 4

-C(=O)R

4 -C(=O)NYly 2 -C(=O)0R 4

N(R

6

)C(=O)R

4

-N(R

6 )C(=O)NY1 y 2

-N(R

6 )G(=O)0R 4

-N(R

6 )S0 2

R

4

-N(R

6

)SO

2 NYiy 2

-NY

1 y 2

-OR

4

-OC(=O)R

4 -OC(=O)NYly 2 -S(O)nR 4 and -S(O) 2 NY1 y 2 or

R

8 and R 9 together with the carbon atoms to which they are attached form a 5 to 8 membered carbocyclic ring optionally substituted by one or more carbocyclic ring substituents; (ii) a phenyl ring optionally substituted by one or more aryl group substituents; (iii) a 5 or 6 membered heteroaromatic ring in which one or more of the ring members is/are nitrogen, oxygen or sulfur and which is optionally substituted by one or more groups selected from haloalkyl, hydroxy, halo, cyano, nitro, R 4 -C(=O)NYly 2

-N(R

6

)C(=O)R

4

-N(R

6 )C(=O)NYly 2

-N(R

6 )S0 2

R

4

-NY

1 y 2 and -OR 5 or (iv) a 5 or 6 membered heterocyclic ring unsubstituted or substituted by alkyl or oxo, and comprising a heteroatom-containing group selected from 0, S, SO 2 and NY 5 ,where y 5 is hydrogen, R 4

-C(=O)R

4 -C(0)NY1 y 2 -C(0O)0R 4 or -S0 2

R

4

R

2 and R 3 are attached to X, Y, Z, or W but they are not attached to the same atom simultaneously:

R

2 and R 3 are independently H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 24

-C(=O)R

4 -C(=O)NYly 2 -C(=O)0R 4

-NY

1 y 2

-N(R

6

)C(=O)R

4 00 8N(R 6 )C(=O)NY1 y 2

-N(R

6 )C(=O)0R 4

-N(R

6 )S0 2

R

4

-N(R

6

)SO

2 NYI y 2

-OR

4

-OCF

2 H, -OCF 3

-OC(=O)R

4 -OC(0)NYly 2

S(~R

4 SOnNY 1 y 2 or S(O) nOR 4 provided that R 2 and R 3 are not both H simultaneously; or

R

2 represents carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 4

C(=O)R

4 -C(=O)NYlY 2 -C(=O)0R 4

-NY

1 y 2

-N(R

6

)C(=O)R

4 c-IN(R 6 )C(=O)NYly 2

-N(R

6 )C(=O)0R 4

-N(R

6 )S0 2

R

4

-N(R

6

)SO

2 NYly 2

-OR

4

-OCF

2 H, 0OCF 3 0OC(0)R 4 0OC(0)NYly 2 ,-S(O)nR 4 -S(O)nNYly 2 or -S(O) nOR 4 and R 3 represents alkyl, haloalkyl, halogen and OR 6

R

4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with one or more substituents selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl, -C(=O)Ny 3 y 4 -C(=O)0R 6

-N(R

6 )C(0)NYly 2

-NY

1 y 2

-OR

5 or alkyl substituted by -Ny 3 y 4

R

14 is alkyl with more than one carbon atoms, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with one or more substituents selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl, -C(=O)Ny 3 y 4 -C(=O)0R 6

-N(R

6 )C(0)NYly 2

-NY

1 y 2

-OR

5 or alkyl substituted by -Ny 3 y 4

R

24 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, each optionally substituted with one or more substituents selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl, -C(=O)Ny 3

Y

4 C(=O)0R 6

-N(R

6 )C(=O)NY1 y 2

-NY

1 y 2

-OR

5 or alkyl substituted by -Ny 3 y 4

R

5 is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;

R

6 is alkyl, alkenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; n is zero or an integer 1 or 2;

Y

1 and y 2 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or alkyl optionally substituted by one or more groups selected from cyano, aryl, heteroaryl, hydroxy, -C(=O)0R 6 -C(=O)Ny 3 y 4 -Ny 3 y 4 and -OR 5 or the group -NY 1 y 2 may form a cyclic amine; 00 S y 3 and Y 4 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY 3

Y

4 may form a cyclic amine; where all the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals are optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, 1 cyano, alkyl, alkoxy, acylamino (NH-COalk), -C(=0)OR 6

-C(=O)R

6 hydroxyalkyl, t' carboxyalkyl, S(O)n-alkyl, S(O)n-NH2, S(O)n-NH(alk), S(O)n-N(alk)2, CF 3 O OCF 3

NO

2 arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C(=0)-NY 3

Y

4 and

NY

3

Y

4 radicals, the latter radicals containing alkyl, aryl and heteroaryl being themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, free, salified or esterified carboxyl radicals and acylamino radicals NH-C(O)R 5 or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of said compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate; In the present specification, the term "compounds of the invention", and equivalent expressions, are meant to embrace compounds of general formula (Ix) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.

As used above for compounds of formula and throughout the description of the invention hereinafter, the following terms unless otherwise indicated, shall be understood to have the following meanings:- "Patient" includes both human and other mammals.

"Acid bioisostere" means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21,p283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application Of 00 0 Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995, pages 34-38 cl "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteres").

Examples of suitable acid bioisosteres include: -C(=O)-NHOH, -C(=O)-CH 2 0H,

-C(=O)-CH

2 SH, sulfo, phosphono, alkylsulfonylcarbamoyl, c tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, cN-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4- N oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 0 10 3-hydoxy-l-methylpyrazolyl.

"Acyl" denotes a radical in which R represents a radical chosen from a hydrogen atom, linear or branched alkyl radicals containing not more than 6 carbon atoms; optionally substituted amino; aryl, heteroaryl, cycloalkyl or heterocycloalkyl radicals, for example phenyl or pyrrolidinyl 9 00 c-i This page is intentionally left blank.

;1 c-I WO 03/035065 PCT/GB02/04763 radicals: the term "acyl" thus especially denotes, for example, formyl radicals and acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, benzoyl and pyrrolidinylcarbonyl radicals.

"Acylamino" denotes -C(=O)-NH 2 -C(O)-NH(alk) and -C(O)-N(alk)(alk) radicals: in these radicals, NH(alk) and N(alk)(alk) have the meanings given hereinafter defined.

"Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain and containing one or more double bonds. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms 2 to 4 carbon atoms) in the chain. "Branched," as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain, which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl, decenyl, and 3,7-dimethyl-octa-2,6-dienyl.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as described herein. Exemplary alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy, and also the linear or branched positional isomers thereof.

"Alkoxycarbonyl" means an alkyl-O-CO- group in which the alkyl group is as described herein.

Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.

"Alkyl" means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched chain having about 1 to about 15 carbon atoms in the chain, optionally substituted by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. "Lower alkyl" as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be a straight or branched chain having 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl and dodecyl, and also the linear or branched positional isomers thereof. Exemplary alkyl groups substituted by one or more halogen atoms include trifluoromethyl, difluoromethyl, trifluoroethyl and difluoroethyl.

WO 03/035065 PCT/GB02/04763 -11- "Alkylene" means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein. Exemplary alkylene radicals include methylene, ethylene and trimethylene.

"Alkylenedioxy" means an -O-alkylene-O- group in which alkylene is as defined above. Exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.

"Alkylsulfinyl" means an alkyl-SO- group in which the alkyl group is as previously described.

Preferred alkylsulfinyl groups are those in which the alkyl group is C -4alkyl.

"Alkylsulfonyl" means an alkyl-S0 2 group in which the alkyl group is as previously described.

Preferred alkylsulfonyl groups are those in which the alkyl group is C 1 -4alkyl.

"Alkylsulfonylcarbamoyl" means an alkyl-S0 2 group in which the alkyl group is as previously described. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is

C

1

I

4 alkyl.

"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio, isohexylthio and heptylthio, and also the linear or branched positional isomers thereof. Preferred alkylthio groups have not more than 4 carbon atoms.

"Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which group may be a straight or branched chain having about 2 to about 15 carbon atoms in the chain.

Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms 2 to 4 carbon atoms) in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.

"Aroyl" means an aryl-CO- group in which the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.

"Aroylamino" is an aroyl-NH- group wherein aroyl is as previously defined.

WO 03/035065 PCT/GB02/04763 -12- "Ary]" as a group or part of a group denotes: an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which a monocyclic aromatic carbocyclic moiety and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Except where otherwise defined, aryl groups may be substituted with one or more aryl group substituents, which may be the same or different, where "aryl group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or an acid bioisostere), cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl,

-C(=O)NYLY

2 -NYl-C(=O)alkyl, -NY 1

SO

2 alkyl, -NY 1

Y

2

-SO

2 NYlY 2 or alkyl, alkenyl or alkynyl each optionally substituted with aryl, cycloalkyl, heteroaryl, hydroxy, -C(=0)OR 6

-C(=O)NY

1 y 2

-NY

1 y 2 or -OR 5 "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C 1 -4alkyl moiety. Exemplary aylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.

"Arylalkyloxy" means an arylalkyl-O- group in which the arylalkyl group is as previously described.

Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.

"Arylalkyloxycarbonyl" means an arylalkyl-O-CO- group in which the arylalkyl group is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.

"Arylalkylthio" means an arylalkyl-S- group in which the arylalkyl group is as previously described.

An exemplary arylalkylthio group is benzylthio.

"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Exemplary aryloxy groups include phenoxy and naphthoxy, each optionally substituted.

"Aryloxycarbonyl" means an aryl-O-C(=O)- group in which the aryl group is as previously described.

Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

"Arylsulfinyl" means an aryl-SO- group in which the aryl group is as previously described.

WO 03/035065 PCT/GB02/04763 -13- "Arylsulfonyl" means an aryl-S02- group in which the aryl group is as previously described.

"Arylsulfonylcarbamoyl" means an aryl-S0 2 group in which the aryl group is as previously described.

"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.

"Carbocyclic" means a saturated ring system comprising carbon atoms.

"Carbocyclic group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or an acid bioisostere), cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl, -C(=O)NY 1

Y

2

-NY

1 -C(=O)alkyl, -NY 1 SO2alkyl, -NY 1

Y

2

-SO

2

NY

1

Y

2 or alkyl, alkenyl or alkynyl each optionally substituted with aryl, cycloalkyl, heteroaryl, hydroxy, -C(=0)OR 6

-C(=O)NY

1

Y

2

-NY'Y

2 or -OR "Cyclic amine" means a 3 to 8 membered monocyclic cycloalkyl ring system wherein one of the ring carbon atoms is replaced by nitrogen and which may also contain a further heteroatom-containing group selected from 0, S, SO 2 or NY 6 (where Y 6 is hydrogen, alkyl, aryl, arylalkyl, -C(=O)R 5 -C(=0)OR 5

-C(=O)NY

1

Y

2 or -S02R 5 and (ii) may be fused to additional aryl phenyl), heteroaryl pyridyl), heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system.

Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline, tetrahydroquinoline and the like groups.

"Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.

"Cycloalkyl" means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms, optionally substituted by oxo. Exemplary monocyclic cycloalkyl rings include C3-8cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

WO 03/035065 PCT/GB02/04763 -14- "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

"Halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred are fluoro, bromo and chloro.

"Haloalkyl1" means an alkyl group having about 1 to about 6 carbon atoms in the chain and substituted by one or more halo atoms. Exemplary haloalkyl groups include trifluoromethyl.

"Heteroaroyl" means a heteroaryl-C(=O)- group in which the heteroaryl group is as described herein.

Exemplary heteroaryl groups include pyridylcarbonyl.

"Heteroaroylamino" means a heteroaroyl-NH- group in which the heteroaryl moiety is as previously described.

"Heteroaryl" as a group or part of a group denotes: an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur (examples of such groups include benzoimidazolyl, benzothiazolyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above except where otherwise defined); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which a monocyclic heteroaromatic moiety and a cycloalkyl, cycloalkenyl or heterocycloalkyl group are fused together to form a cyclic structure (examples of such groups include tetrahydro-indazolc, tetrahydro-pyrazolopyridine, 5-oxo-1,4,5,6,7,8,9,9a-octahydro-1,2,4,5a-tetrazacyclopenta[a]naphthyl, optionally substituted by one or more "aryl group substituents" as defined above, except where otherwise defined). Optional substituents include one or more "aryl group substituents" as defined above, except where otherwise defined. When R1 is heteroaryl this may particularly represent pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, phenyl, pyridinyl, oxodihydropyridinyl, pyrimidinyl, indolyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetahydropyridinopyrazolyl, or oxodihydropyridinopyrazolyl.

WO 03/035065 PCT/GB02/04763 "Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a Cl_ 4 alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.

"Heteroarylalkyloxy" means an heteroarylalkyl-O- group in which the heteroarylalkyl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.

"Heteroaryloxy" means an heteroaryl-O- group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy.

"Heteroarylsulfonylcarbamoyl" means a heteroaryl-S02-NH-C(=0)- group in which the heteroaryl group is as previously described.

"Heterocycloalkyl" means: a cycloalkyl group of about 3 to 10 ring members which contains one or more heteroatoms or heteroatom-containing groups selected from O, S and NY 6 and may be optionally substituted by oxo (examples of such groups include hexahydropyran, pyrrolidinyl, piperidinyl, tetrahydropyranyl and octahydro-pyrido[1,2-c]pyrimidin-1-one); (ii) a partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl) ring, each optionally substituted by one or more "aryl group substituents," and a heterocycloalkyl group are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).

"Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.

"Hydroxyalkyl" means an alkyl group substituted by one or hydroxy groups.

"NH(alk)" and "N(alk)(alk)" denote an amino radical substituted, respectively, with one or two alkyl radicals, such alkyl radicals being linear or branched and chosen from alkyl radicals as defined above, preferably containing not more than 4 carbon atoms.

"Prodrug" means a compound which is convertible in vivo by metabolic means by hydrolysis) to a compound of formula including N-oxides thereof. For example an ester of a compound of formula (Ix) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively, an ester of a compound of formula (Ix) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.

WO 03/035065 PCT/GB02/04763 -16- Suitable esters of compounds of formula (Ix) containing a hydroxy group are, for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-1-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

Suitable esters of compounds of formula (Ix) containing a carboxy group are, for example, those described by F.J.Leinweber, Drug Metab. Res., 1987, 18, page 379.

An especially useful class of esters of compounds of formula (Ix) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 pages 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin- -yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.

Where the compound of the invention of formula (Ix) contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, NN'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.

Some of the compounds of the present invention of formula (Ix) are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.

WO 03/035065 PCT/GB02/04763 -17- Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

As well as being useful in themselves as active compounds, salts of compounds of the invention of compounds of formula (Ix) are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.

It will be appreciated that compounds of the present invention of formula (Ix) may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (Ix) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates. Additionally, tautomers of the compounds of formula (Ix) are possible, and the present invention is intended to include all tautomeric forms of the compounds.

WO 031035065 PCT/GB02/04763 -18- One subject of the present invention is thus the compounds of formula

A

inwhiich: X represents C-F? and W, Y and Z, which may be identical or different, represenL CH or CR 3 R' represents aryl or heteroaryl chosen from pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahlydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl, and oxodihydropyridinopyrazolyl radicals, all these radicals being optionally substituted with one or more radicals X1, X 2 or X 3 chosen from H, halogen, haloalkyl, OH, R 4

NO

2 CN, S(O).R 4 ORW, INY 1

Y

2

COW

4 -C(=O)NY 1y 2 _C(0)0R 4

-N(R

6 4 -N(R)S0 2

R

4

-N(R

6

)C(=O)NY'Y

2

-N(R

6 )C(=O)0R 4 -S(O)nOR 4 -S(O)~n'JY 1

Y

2

-OC(='O)I\Y'Y

2

-OS(O),R

4

-OC(=O)R

4 and optionally substituted thienyl, W? and are such that: either W2 and W, which may be identical or different, represent H, RW, halogen, haloalkyl, OH, NOQ, CN, OR4, CORI, S(O)"R 4 2 -C(=O)0R 4

-N-Y

1 Y, -N(R 5

)C(=O)R

4

-N(R

6 )S0 2

R

4 -N(R 6 )C(=O)Ny 1 y 2

-N(R

6 )C(=O)0R 4

OR

4 "Ny 1 y 2

-OC("'O)NY'Y

2 and -OC( =O)R 4 or W] represents H, le, halogen, haloalkyl, OH, NO,, CN, OR 4

COR

4

S(O),,R

4 -C(=O)NYlY 2 -C(=O)0R 4 O)OH, -NY'Y 2 -N(R )C(=O)R 4 -N(R 6 )S0,R 4

-N(R

6 )C(=O)Ny 1 y 2

-N(R

6 )C(=DOR, -S(O)DOR 4 -S(O)nNY'Y 2

-OC(=O)NYY

2 and -OC( O)R 4 and R 2 represents alkyl, haloalkyl, halogen and OR or W 2 and W 3 together form a 5- to 6-membered carbon-based ring containing one or more hetero atoms, which may be identical or different, chosen from 0, N and S, RW represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl and arylalkyl, all these radicals being optionally substituted with one or more radicals chosen from aryl (optionally substituted), halogen, alkyl, hydroxyalkyl, OH, OW 5 y 4

NY

2 alk-NY 2

Y

4 and C('-O)0R 6 RW represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl,, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl.

WO 03/035065 PCT/GB02/04763 -19- Y' and Y 2 are such that: either Y and Y 2 which may be identical or different, represent H and optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or Y' and Y 2 form, together with the nitrogen atom to which they are attached, a cyclic amino radical,

Y

3 and Y 4 are such that: either Y 3 and Y 4 which may be identical or different, represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl or Y 3 and Y 4 form, together with the nitrogen atom to which they are attached, an optionally substituted cyclic amino radical,

A

5 represents H or alkyl, R' is chosen from the values of R, all the alkyl (or alk, which represents alkyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals furthermore being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH-COalk), -C(=O)OR 6 acyl -C(=O)R 6 hydroxyalkyl, carboxyalkyl, S(O),-alk, S(O)n-NH 2 S(O)n-NH(alk), S(O)n-N(alk) 2 CF3, OCF 3 NO2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C(=O)-NY 3

Y

4 and NY 3

Y

4 radicals, the latter radicals containing alkyl, aryl and heteroaryl being themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, free, salified or esterified carboxyl radicals and acylamino radicals NH-C(O)R', the phenyl radicals furthermore being optionally substituted with a dioxole radical, n represents an integer from 0 to 2, it being understood that when R' represents an indazolyl radical to give the compounds of formula below:

W

X N N N H H WO 03/035065 PCT/GB02/04763 with X representing H, R 2 or R 3 as defined above, then W necessarily represents H or unsubstituted alkyl, the said compounds of formula being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral bases.

One subject of the present invention is thus the compoundss of formula as defined above corresponding to the formula (Ia): ,.Za N Ya, r R, XII R a N-- Wa N

A

5 (Ia) in which: Xa represents C-R a and Wa, Ya and Za, which may be identical or different, represent CH or CR 3 a; Rla represents aryl or heteroaryl chosen from pyrazolyl, triazolyl and indazolyl radicals, all these radicals being optionally substituted with one or more radicals X'a, X 2 a or X 3 a chosen from H, halogen, OH, Ra, OR 4 a, NY aa, S(O)Ra, -C(O)NY'aY'a, -C(=O)OR 4 a, -N(R 6 a)C(=O)R 4 a,

-N(R

6 a)SOR 4 a, -N(R 6 a)C(=O)NY'aY 2 a, -N(R 6 a)C(=O)OR 4 a, -OC(=O)NY'aY 2 a, -OC(=O)R 4 a, -OS(O)nR 4 a and thienyl optionally substituted with an alkyl radical, R-a and R 3 a are such that: either Ra and R3a, which may be identical or different, represent H, R 4 a, halogen, OH, OR 4 a, C(=O)NY'aY 2 a, -C(=O)OR 4 a and and Ra represents alkyl, halogen and OR 6 a, or R'a represents H, R 4 a, halogen, OH, OR 4 a, C(=O)NY'aY 2 a, -C(=O)OR 4 a and and R 3 a represents alkyl, halogen and ORSa, or Ra and R 3 a together form an -O-CH 2 or -O-CH 2 -CHz-O- ring, Ra represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl and arylalkyl, all these radicals being optionally substituted with one or more radicals chosen from aryl (optionally substituted), halogen, alkyl, hydroxyalkyl, OH, ORSa, C(=O)NY 3 aY 4 a,

NY

3 aY 4 a, alk-NY 3 aY 4 a and C(=O)OR6a, Ra represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl, all these radicals being optionally substituted, Y'a and Y 2 a are such that: either Y'a and Y 2 a, which may be identical or different, represent H, alkyl, alkoxyalkyl, aryloxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkyl, aryl and heteroaryl, all these radicals being optionally substituted, or Y'a and Y 2 a form, together with the nitrogen atom to which they are attached, an optionally substituted cyclic amino radical, WO 03/035065 PCT/GB02/04763 -21-

Y

3 a and Y 4 a are such that: either Y 3 a and Y 4 a, which may be identical or different, represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y 3 a and Y 4 a form, together with the nitrogen atom to which they are attached, a cyclic amino radical,

A

5 represents H- or alkyl, all the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals furthermore being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH-C(O)R6a),

-C(=O)OR

6 a, acyl -C(=O)R6a, hydroxyalkyl, carboxyalkyl, S(O)n-alk, S(O)n-NH 2 S(O),-NI-(alk), S(O),-N(alk) 2 CF3, OCF 3

NO

2 arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C(=O)-NY 3 aY a and NY 3 aY 4 a radicals, the latter radicals containing alkyl, aryl and heteroaryl themselves being optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, alkoxy radicals, free, salified or esterified carboxyl radicals and acylamino radicals NH-C(O)Ra, the phenyl radicals furthermore being optionally substituted with a dioxole radical,

R

6 a is chosen from the values of R 5 a, n represents an integer from 0 to 2, the said compounds of formula (Ia) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral bases.

One subject of the present invention is thus the compounds of formula

N

II

R

1 w -N

A

WO 031035065 PCT/GB02/04763 -22in which: X represents C-R 2 and W, Y and Z, which may be identical or different, represent CH or CR 3 R' represents atyl or heteroaryl chosen from pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl,, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl, and oxodihydro-pyridinopyrazolyl radicals, all these radicals optionally being substituted with one or more radicals X' or X' chosen from H, halogen, haloalkyl, OH, R 4 NO,, CN, S(O),R 4 OW, NY'Y 2

COW

4

-C(=O)NY

1 Y, -C(=O)0R 4

N(R

6

)C(=OD)R

4

-N(R

6 )S0 2 -N(R 6

)C(=O)NY'Y

2

-N(R

6 )C(=O)0R 4

-S(O)

11 0R 4

-S(O)

1 ,NY'Y,

OC(=O)NY

1

Y

2

-OS(O),,R

4

-OC(=O)R

4 and optionally substituted thienyl, W. and W. are such that: either W. and W, which may be identical or different, represent H, R 4 halogen, haloalkyl, OH, NO 2 CN, ORW, COW 4

S(O),R

4 2

-C(=O)OR

4

-NY'Y

2 N(R 6

)C(=O)R

4 -N(R6)S02R4, -N(R6)C(=O)NY 1Y2, -N(R6)C(=O)0R4, -S(O)nOR4, -S(O)nN Y 1 Y2, -OC(=CO)NY 1 y 2 and -OC(0C)R 4 or R represents H, W 4 halogen, haloalkyl, OH, NO 2 CN, OR 4 CORW, S(O)nR 4

-C(=O)NY

1

Y

2 -C(=O)0R 4

-NY'Y

2

-N(R

6

)C(=O)R

4 -N(R )0 2

)C@=O)NY'Y

2

O)OR

4

_S(O)'OR

4 -S(O)'Ny'Y 2

-OC(=O)NY'Y

2 and -OC(0)R 4 and R 3 represents alkyl, haloalkyl, halogen and OR 6 or R 2 and R.

3 together form a 5- to 6-membered carbon-based ring containing one or more hetero atoms, which may be identical or different, chosen from 0, N and S, W. represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, hetero-arylalkyl and arylalkyl, all these radicals being optionally substituted with one or more radicals chosen from aryl, OH, OR 5

C(=O)NY

3 Y4, NY 3 Y' and CQ=O)0R 6 W. represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloallalkyl.

RP6 represents H and Cl-C4 alkyl, n represents an integer from 0 to 2 Y' and Y 2 are such that: either Y' and Y 2 which may be identical or different, represent H, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, all these radicals being optionally substituted with one or more radicals chosen from hydroxyl, -C(Q=O)-NYY 4 6 and Ny 3

Y

4 or Y' and Y 2 form, together with the nitrogen atom to which they are attached, a cyclic amino radical,

Y

3 and Y 4 are such that: either Y 3 and Y 4 which may be identical or different, represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl or Y 3 and Y4 form, together with the nitrogen atom to which they are attached, a cyclic amino radical,

A

5 represents H or alkyl, WO 03/035065 PCT/GB02/04763 -23it being understood that when R' represents an indazolyl radical to give the compounds of formula below:

W

N

N

H

H

(F)

with X representing H, R 2 or R 3 as defined above, then W necessarily represents H or unsubstituted alkyl, the said compounds of formula being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral bases.

It is obvious that, according to the ring represented by R' and its number of members, R' can comprise one, two or three substituents represented by X 2 and X 3 One subject of the present invention is thus the compounds of formula as defined above corresponding to the formula (Ia): ,Za N Ya R II rI- R~a XWa N A A 5 (Ia) in which: Xa represents C-Ra and Wa, Ya and Za, which may be identical or different, represent CH or CR 3 a; R'a represents aryl or heteroaryl chosen from pyrazolyl, triazolyl or indazolyl radicals, all these radicals being optionally substituted with one or more radicals X'a, X2a or X 3 a chosen from H, halogen, OH, R 4 a, OR 4 a, NY'aY2a, S(O)nR 4 a, -C(=O)NY'aY 2 a, -C(=O)ORa, -N(R 6 a)C(=O)Ra,

-N(R

6 a)SO 2

R

4 a, -N(R 6 a)C(=O)NYaY 2 a, -N(R 6 a)C(=O)OR 4 a, -OC(=O)NY'aY 2 a and -OC(O)R 4 a,

-OS(O),R

4 a and thienyl optionally substituted with an alkyl radical, Ra and Ra are such that: either Ra and R 3 a, which may be identical or different, represent H, R 4 a, halogen, OH, OR 4 a, C(=O)NY'aY 2 a, -C(=O)OR 4 a, and R 3 a represents alkyl, halogen and OR 6 a, WO 03/035065 PCT/GB02/04763 -24or R t a represents H, R 4 a, halogen, OH, OR 4 a, C(=O)NYlaY 2 a, -C(=O)OR 4 a, and R 3 a represents alkyl, halogen and OR 6 or R 2 a and Ra together form an -O-CH 2 -O or -O-CH 2

-CH

2 ring, R4a represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all these radicals being optionally substituted with one or more radicals chosen from aryl, OH, OR a,

C(=O)NY

3 a 4 a, NY 3 ay 4 a and C(=O)OR 6 a, represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl,

R

6 a represents H and C1-C4 alkyl, n represents an integer from 0 to 2, Y'a and Y 2 a are such that: either Y'a and Y'a, which may be identical or different, represent H, alkyl, cycloalkyl, aryl and heteroaryl, all these radicals being optionally substituted with one or more radicals chosen from hydroxyl, -C(=0)-NY 3

Y

4 -C(=0)OR 6 and NY 3

Y

4 or Y'a and Ya form, together with the nitrogen atom to which they are attached, a cyclic amino radical, Ya and Y 4 a are such that: either Y3a and Y 4 a, which may be identical or different, represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or y3a and Y 4 a form, together with the nitrogen atom to which they are attached, a cyclic amino radical,

A

5 represents H or alkyl, the said compounds of formula (la) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral bases.

One subject of the present invention is thus the compounds of formula as defined above corresponding to the formula (IA):

A

1 AA

A

3

N

A

4

A

5

(IA)

in which A represents a saturated heterocyclic radical which is either a 5- or 6-membered monocyclic radical or a bicyclic radical that is not more than 10-membered, these members being such that at least two of them represent a nitrogen atom and the others, which may be identical or different, represent a carbon member or a hetero atom member chosen from O, N WO 03/035065 PCT/GB02/04763 and S, this heterocycle A being optionally substituted with one or more radicals XA', XA 2 or

XA

3 chosen from the values indicated hereinabove for the radicals X X 2 or X 3 A, A 2

A

3 and A 4 which may be identical or different, are chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, aryl, heteroaryl and aryloxy radicals, a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical

NA

6

A

7 such that either A 6 and A 7 which may be identical or different, are chosen from a hydrogen atom and optionally substituted alkyl, alkoxyalkyl, phenoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl radicals, or A 6 and A 7 form, together with the nitrogen atom to which they are attached, an optionally substituted 5- or 6-membered cyclic radical, it being understood that two consecutive radicals among Ai, A2, A 3 and A 4 can form, with the benzimidazole radical to which they are attached, a 5- to 6-membered carbon-based ring containing one or more hetero atoms, which may be identical or different, chosen from O, N and S, As represents a hydrogen atom or an alkyl radical, R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl, all the alkyl, alkenyl, aryl, heteroaryl, aryloxy, cycloalkyl and heterocycloalkyl radicals present in the above radicals being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NH-COR 6

-C(=O)OR

6 b, acyl -C(=O)R 6 b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S(O)n-alk, S(O)n-NFI, S(O)n-NH(alk), S(O)n-N(alk) 2

CF

3 OCF3, NO2, CN, phenyl, itself optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C(=O)-NH2, -C(=O)-NH(alk) and C(=O)-N(alk)2 radicals, all the above alkyl, alkenyl, alkoxy and alkylthio radicals being linear or branched and containing not more than 4 carbon atoms, all the phenyl radicals of the above radicals furthermore being optionally substituted with a dioxole radical, n represents an integer from 0 to 2, the said compounds of formula (IA) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (LA).

WO 03/035065 PCT/GB02/04763 -26- A subject of the present invention is thus the compounds of formula as defined above, corresponding to the formula (IAa): A a A|aAa

A

2 a N Aa

A

3 a

N

A

4 a Asa

(A

(IAa) in which Aa represents a pyrazolyl, triazolyl or indazolyl radical, this heterocycle Aa being optionally substituted with one or more radicals XA', XA 2 or XA 3 chosen from the values indicated hereinabove for the radicals X 2 or X 3 Ala, A 2 a, A 3 a and A 4 a, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 aA 7 a such that either A"a and A 7 a, which may be identical or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl radicals, or A6a and A7a form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, morpholino or piperazinyl radical optionally substituted on the second nitrogen atom with an alkyl or phenyl radical, which are themselves optionally substituted, it being understood that two consecutive radicals from among Ala, A 2 a, A 3 a and A 4 a may form, with the benzimidazole radical to which they are attached, an optionally substituted 5- to 6membered carbon-based ring containing one or two oxygen atoms,

A

5 a represents a hydrogen atom or an alkyl radical, the phenyl and phenoxy radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salified or esterified carboxyl, and dioxole radicals, WO 03/035065 PCT/GB02/04763 -27all the alkyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 6 carbon atoms, the said compounds of formula (IAa) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAa).

The substituents X 2 and X 3 as defined above are in particular such that one represents a hydrogen atom and the other two, which may be identical or different, are chosen from halogen atoms and OH,

R

4 a, OR 4 a, CF 3

OCF

3

NO

2 CN, NY'aY 2 a, acylamino (NH-COR 6 S(O)n-alk, S(O)n-NH 2 S(O)n-NH(alk), S(O)n-N(alk)2, C(=O)-N(alk)2, -C(=O)OR 4a

-N(R

6 b)C(=O)R 4 a, -N(R'b)SO 2 R a, -N(R6b)C(=O)NY aY 2 a, -N(R 6 b)C(=O)OR 4 a, -OC(=O)NY'aY'a and thienyl radicals, the thienyl radical being optionally substituted with an alkyl radical,

R

4 a, Y'a, Y 2 a and R 6 b having the values defined above and alk representing a linear or branched alkyl radical including not more than 6 carbon atoms and optionally substituted as indicated above.

All the alkylthio radicals are such that the sulfur atom is optionally oxidized to sulfone or sulfoxide with one or two oxygen atoms.

Tables I, II and III described below give examples of compounds illustrating the present invention, with in particular substituents chosen from the values ofX', X 2 and X 3 as defined above.

WO 03/035065 PCT/GB02/04763 -28-

TABLEI

R

R'-N

N

:O

HN

X

N H

H

-N

HN

H

0 HN X N H

H

O N

HN

O

HN X N H

H

H

HN

X

VN

N H

H

H

No HN X

H

with X represents hydrogen, halogen or alkoxy as defined above.

WO 031035065 WO 03/35065PCT/GB02/04763 -29- TABLE II

N-R

H

N

NX H

H

H

N

H

H H N N H

HH

H

N

>~yN~N N H

H

H

N

H H

H

N'N

H

,jC:kcl 0 Ci

H

in which NR'R represents NY'Y 2 as defined above.

WO 03/035065 PCT/GB02/04763 TABLE III OH

NH

2 H 2

N

HN

xX x

NXNN

DO:I N'

N'

H N N H H H H

HO

x

N'

N N

H

H

NH

2 x

NN

N H

H

OH

0 x N

IN

WN

H

in which X represents hydrogen, alkynyl or NHCOCH 2 Ph which is optionally substituted.

The subject of the present invention is thus the compounds of formula as defined above in which the substituents of the said compounds of formula have the any of the values indicated as defined hereinabove and in which the aryl radicals represent the phenyl and naphthyl radicals; the heteroaryl radicals represent the furyl, thienyl, benzothienyl, thianthrenyl, pyridyl, pyrazolyl, benzimidazolyl, benzofuran, isobenzofuran and dihydrobenzofuran radicals; the cycloalkyl radicals represent a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical; the heterocycloalkyl radicals represent the hexahydropyran, piperidyl or morpholino radicals; the heterocycloalkylalkyl radicals represent the hexahydropyranylalkyl, piperidylalkyl and morpholinoalkyl radicals; the arylalkyl radicals represent the phenylalkyl, ethylenedioxyphenylalkyl and naphthylalkyl radicals; the heteroarylalkyl radicals represent the thienylalkyl, pyridylalkyl, furylalkyl, pyrazolylalkyl, benzothienylalkyl, dihydrobenzofuranylalkyl and benzimidazolylalkyl radicals; the aryloxy radicals represent the phenoxy and naphthyloxy radicals; the arylalkoxy radicals represent the phenylalkoxy and naphthylalkoxy WO 03/035065 PCT/GB02/04763 -31radicals; and the aryloxyalkyl radicals represent the phenoxyalkyl radical; all these radicals being optionally substituted as indicated hereinabove.

One subject of the present invention is, more particularly, the compounds of formula as defined above corresponding to the formula (IA):

A

1

A

2

N

A

3

N

A A

(IA)

in which A represents a saturated heterocyclic radical which is either a 5- or 6-membered monocyclic radical or a hicyclic radical that is not more than 10-membered, these members being such that at least two of them represent a nitrogen atom and the others, which may be identical or different, represent a carbon member or a hetero atom member chosen from O, N and S, this heterocycle A optionally being substituted with one or more radicals XA', XA 2 or XA 3 chosen from halogen atoms, alkyl, alkoxy or alkylthio radicals or thienyl radicals optionally substituted with an alkyl radical,

A

i

A

2

A

3 and A 4 which may be identical or different, are chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6

A

7 such that either A 6 and A 7 which may be identical or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and heteroarylalkyl radicals, or A 6 and A 7 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered cyclic radical, it being understood that two consecutive radicals among A 1

A

2

A

3 and A 4 can form, with the benzimidazole radical to which they are attached, a 5- to 6-membered carbon-based ring containing one or more hetero atoms, which may be identical or different, chosen from 0, N and S,

A

5 represents a hydrogen atom or an alkyl radical, all the phenyl, phenoxy, cycloalkyl and heteroarylalkyl radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salified or esterified carboxyl, and dioxole radicals, all the alkyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 6 carbon atoms, WO 03/035065 PCT/GB02/04763 -32the said compounds of formula (IA) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IA).

A subject of the present invention is also, more particularly, the compounds of formula as defined above, corresponding to the formula (IAb): Alb

A

2 b

N

Ab

A

3 b N A~b Asb

A

4 b A 5 b (IAb) in which Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or two radicals chosen from halogen atoms and OH, alkyl, alkynyl, -OR 6 b (including alkoxy), -COR'b, -O-COR 6 b, -OS(O),Rb, -O(CH 2 )n-CO-R 6 b, phenyl, phenylalkyl, CF 3

OCF

3

NO

2 CN, NYbY 2 b, -NH-C(=O)NY'bY 2 b, acylamino (NH-CO-R 6 S(O),-alk, S(O),-NY'bY 2 b, -C(=O)-NY'bY 2 b, -C(=O)ORb, -NH-S(O),R 6 b, -NH-C(=O)OR 6 b, -N(R 6 b)C(=O)NY'bY 2 b, -OC(=O)NY'bY 2 b and thienyl radicals, all these radicals being optionally substituted, with NY'bY 2 b such that either Y'b and Y 2 b, which may be identical or different, are chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y'b and Y 2 b form, together with the nitrogen atom to which they are attached, a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical, Alb, A~b, A 3 b and A 4 b, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, -ORb (including alkoxy), -CO-Rob, -O-COR"b, -OS(O)nR'b, -O(CH 2 )n-CO-R6b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy radicals and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 bA 7 b such that either A 6 b and Ab, which may be identical or different, are chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl radicals, all these radicals being optionally substituted, or A'b and A 7 b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or WO 03/035065 PCT/GB02/04763 -33piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom with an alkyl radical itself optionally substituted, it being understood that two consecutive radicals among Alb, A2b, A 3 b and A 4 b can form, with the benzimidazole radical to which they are attached, an optionally substituted radical or an optionally substituted radical,

A

5 b represents a hydrogen atom, all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NI-I-COR 6

-C(=O)OR

6 b, acyl -C(=O)R 6 b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S(O)n-alk, S(O)n-NH 2 S(O)n-NH(alk), S(O)n-N(alk)2, CF 3

OCF

3 NO2, CN, phenyl, itself optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C(-O)-NH(alk) and C(=O)-N(alk)2 radicals, with n representing an integer from 0 to 2, and R 6 b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihydroquinolone, -NH-phenyl, phenylalkyl and cycloalkylalkyl, all these radicals being optionally substituted with a morpholino, piperidyl or phenyl radical itself optionally substituted with one or more radicals chosen from halogen atoms and the cyano, CF 3

OCF

3 alkyl, phenyl-S(O)n-alk-phenyl, alkoxy, NI-, NI-alk, N(alk)2, SO 2

NH

2 SO2Nalk or SO 2 N(alk) 2 radical, all the alkyl, alkenyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 10 carbon atoms, all the phenyl radicals of the above radicals furthermore being optionally substituted with a dioxole radical, the said compounds of formula (IAb) being in any possible racemic, enantiomeric or diastereomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAb).

One subject of the present invention is thus in particular the compounds of formula as defined above corresponding to the formula (IAb) in which Ab represents a pyrazolyl or indazolyl radical WO 03/035065 PCT/GB02/04763 -34optionally substituted with one or two radicals chosen from halogen atoms and OH, alkyl, alkynyl, alkoxy, phenyl, phenylalkyl, CF 3

OCF

3

NO

9 CN, NY bY 2 b, -NH-C(=O)NY'bY 2 b, acylamino

(NH-CO-R

6 S(O),-alk, S(O),-NY bY 2 b, -C(=O)-NY'bY 2 b, -NH-C(=O)R'b,

-NH-S(O),R

6 b, -NH-C(=O)OR'b, -N(R'b)C(=O)NY'bY b, -OC(=O)NY'bY 2 b and thienyl radicals which are optionally substituted, with NY'bY 2 b such that either Y'b and Y 2 b, which may be identical or different, are chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y'b and Y 2 b form, together with the nitrogen atom to which they are attached, a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical, Alb, A 2 b, A 3 b and A 4 b, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy radicals and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 bA 7 b such that either

A

6 b and A 7 b, which may be identical or different, are chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl radicals, all these radicals being optionally substituted, or A'b and A 7 b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom with an alkyl radical itself optionally substituted, it being understood that two consecutive radicals among Alb, Ab, A 3 b and A 4 b can form, with the benzimnidazole radical to which they are attached, an optionally substituted radical or an optionally substituted radical,

A

5 b represents a hydrogen atom, all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NH-COR6b), -C(=O)ORb, acyl -C(=O)R 6 b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S(O)n-alk, S(O).-NH 2 S(O).-NH(alk), S(O)n-N(alk) 2

CF

3

OCF

3

NO

2 WO 03/035065 PCT/GB02/04763 CN, phenyl, itself optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C(=O)-NH 2 -C(=O)-NH(alk) and radicals, with n representing an integer from 0 to 2, and Rib representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl, all the alkyl, alkenyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 10 carbon atoms, all the phenyl radicals of the above radicals furthermore being optionally substituted with a dioxole radical, the said compounds of formula (IAb) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAb).

A subject of the present invention is thus in particular the compounds of formula as defined above corresponding to the formula (IAb) in which Ab represents a pyrazolyl radical substituted with one or two radicals such that one is chosen from hydrogen, halogen atoms and alkyl, alkynyl, -COR 5 b, phenyl, phenylalkyl, CF 3

NO

2 CN, NY'bY 2 b, -NH-C(=O)NY'bY 2 b, NH-CO-R 6 b, S(O)n-alk, S(O)-NY'bY 2 b, -C(=O)-NY'bY 2 b, -C(=O)OR 6 b, -NH-C(=O)R 6 b, -NH-S(O)nRb, -NH-C(=O)OR"b, -N(R'b)C(=O)NY'bY 2 b and thienyl radicals, all these radicals being optionally substituted, and the other is chosen from OH, -OR 6 b, -O-COR 6 b, -OS(O),R 6 b, -O(CH 2

),-CO-R

6 b and -OC(=O)NY'bY 2 b radicals, all these radicals being optionally substituted, with NY'bY 2 b such that Ylb and Y 2 b, which may be identical or different, are chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y'b and Y 2 b form, together with the nitrogen atom to which they are attached, a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical, Alb, A 2 b, A 3 b and A 4 b, which may be identical or different, are such that two of them represent hydrogen and the other two, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, -OR 6 b (including alkoxy), -CO-R6b, -O-CORb, -OS(O)nR 6 b, -O(CH 2 6 b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy radicals and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NAbA 7 b such that either A b and A'b, which may be identical or different, are chosen from hydrogen and alkyl, alkoxyalkyl, WO 03/035065 PCT/GB02/04763 -36phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl radicals, all these radicals being optionally substituted, or A 6 b and A'b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom with an alkyl radical itself optionally substituted, Asb represents a hydrogen atom, all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NH-COR'b), acyl -C(=O)R 6 b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S(O),n-alk, S(O)n-NH2, S(O)n-NH(alk), S(O)n-N(alk) 2

CF

3 OCF3, NO 2 CN, phenyl, itself optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C(=O)-NH 2 -C(=O)-NH(alk) and C(=O)-N(alk) 2 radicals, with n representing an integer from 0 to 2, and R 6 b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adarnentyl, quinoline, quinolone, dihydroquinolone, -NI-phenyl, phenylalkyl and cycloalkylalkyl, all these radicals being optionally substituted with a morpholino, piperidyl or phenyl radical itself optionally substituted with one or more radicals chosen from halogen atoms and the cyano, CF3, OCF 3 alkyl, phenyl-S(O)n-alk-phenyl, alkoxy, NH 2 NHalk, N(alk)2, S0 2

NH

2

SO

2 Nalk or SO2N(alk) 2 radical, all the alkyl, alkenyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 10 carbon atoms, all the phenyl radicals of the above radicals furthermore being optionally substituted with a dioxole radical, the said compounds of formula (IAb) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAb).

A subject of the present invention is thus in particular the compounds of formula as defined above corresponding to the formula (IAb) in which Ab represents a pyrazolyl or indazolyl radical optionally WO 03/035065 PCT/GB02/04763 -37substituted with one or more radicals chosen from halogen atoms and alkyl, alkoxy and thienyl radicals, Alb, Azb, A 3 b and A 4 b, which may be identical or different, are chosen from a hydrogen atom; halogen atoms; radicals of the following types: hydroxyl, alkyl, alkenyl optionally substituted with phenyl itself optionally substituted with one or more halogen atoms, alkoxy, nitro, cyano, furyl, thienyl optionally substituted with acyl COalk, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy which are optionally substituted; and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 bA 7 b such that either

A

6 b and A 7 b, which may be identical or different, are chosen from hydrogen and radicals of the following types alkyl, alkoxyalkyl containing not more than 6 carbon atoms, phenoxyalkyl optionally substituted with acylamino NH-C(O)alk, phenyl, optionally substituted phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl optionally substituted with one or more alkyl radicals, naphthylalkyl, thienylalkyl optionally substituted with alkyl or thienyl, piperidylalkyl optionally substituted with a carboxyl radical which is free, salified or esterified with an alkyl radical, pyridylalkyl optionally substituted with one or more radicals chosen from halogen and CF3, benzothienylalkyl, pyrazolylalkyl optionally substituted with one or more alkyl radicals, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl, and benzimidazolylalkyl optionally substituted with one or more alkyl radicals, or A 6 b and A 7 b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom with an alkyl radical, it being understood that two consecutive radicals among Alb, A 2 b, A 3 b and A 4 b can form, with the benzimidazole radical to which they are attached, an optionally substituted radical or an optionally substituted radical, Asa represents a hydrogen atom, the phenyl, phenoxy and phenylalkyl radicals above being optionally substituted with one or more radicals chosen from halogen atoms, hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and NII-COalk radicals, a carboxyl radical which is free, salified or esterified with an alkyl radical, and hydroxyalkyl, carboxyalkyl, phenoxyalkyl, alkylthio, SO 2 alk,

SO

2

NH

2 S0 2 -NH(alk), SO2-N(alk) 2

CF

3

OCF

3

NO

2 CN, phenyl, itself optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C(=0)-NH(alk), C(=O)-N(alk) 2 and C(O)CH 3 radicals, WO 03/035065 PCT/GB02/04763 -38all the alkyl or alk, alkenyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 4 carbon atoms, all the phenyl radicals of the above radicals furthermore being optionally substituted with a dioxole radical, the said compounds of formula (IAb) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAb).

A subject of the present invention is thus in particular the compounds of formula as defined above corresponding to the formula (IAb) in which Ab, Alb, Ab, A 3 b, A 4 b and A 5 b have any of the meanings indicated hereinabove, and when one of Alb, A 2 b, A 3 b and A 4 b represents a carboxyl radical amidated with a radical

NA

6 bA 7 b, then either one of A 6 b and A'b represents a hydrogen atom or an alkyl radical and the other of A'b and A 7 b is chosen from the values defined for A 6 b and A 7 b, or A'b and A 7 b form, together with the nitrogen atom to which they are attached, a 5- or 6-membered cyclic radical, the other substituents of the said compounds of formula having the any of the values indicated hereinabove, the said compounds of formula (IAb) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAb).

A subject of the present invention is thus in particular the compounds of formula as defined above in which X, W, Y and Z are such that two or three of them represent CH and the others are chosen from the values of CR 2 or CR 3 and, if appropriate, when two of them represent CH and CR 2 and

CR

3 are adjacent to each other, can form a dioxole radical,

R

2

R

3 and the other substituents of the said compounds of formula having any of the values as defined hereinabove, WO 03/035065 PCT/GB02/04763 -39the said compounds of formula being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula The present invention thus relates in particular to the compounds of formula (IA) as defined above in which A, A 2

A

3 and A 4 are such that two or three of them represent a hydrogen atom and the others are chosen from the values of A, A 2

A

3 and A 4 and, if appropriate, when two of them represent a hydrogen atom and the other two are on adjacent carbons, can form a dioxole radical, the other substituents of the compounds of formula (IA) having any of the values as defined hereinabove, the said compounds of formula (IA) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IA).

A subject of the present invention is also, more particularly, the compounds of formula as defined above, corresponding to the formula (IAa):

A

l a

A

2 a

N

A I Aa

A

3 a As 4 A (IAa) in which Aa represents a pyrazolyl, triazolyl or indazolyl radical, this heterocycle Aa being optionally substituted with one or more radicals XA', XA 2 or XA 3 chosen from halogen atoms, alkyl, alkoxy or alkylthio radicals and thienyl radicals optionally substituted with an alkyl radical, Ala, Aza, A 3 a and A 4 a, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 aA 7 a such that either A 6 a and A 7 a, which may be identical or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl radicals, or A 6 a and A'a form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, pyrazolidinyl, WO 03/035065 PCT/GB02/04763 pyrazolinyl, piperidyl, morpholino or piperazinyl radical optionally substituted on the second nitrogen atom with an alkyl or phenyl radical, which are themselves optionally substituted, it being understood that two consecutive radicals from among Ala, Aa, A 3 a and A 4 a may form, with the benzimidazole radical to which they are attached, an optionally substituted 5- to 6-membered carbon-based ring containing one or two oxygen atoms, represents a hydrogen atom or an alkyl radical, the phenyl and phenoxy radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salified or esterified carboxyl, and dioxole radicals, all the alkyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 6 carbon atoms, the said compounds of formula (IAa) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAa).

One subject of the present invention is, more particularly, the compounds of formula as defined above in which R represents a pyrazolyl or indazolyl radical, the other substituents having the values indicated above or below.

Among the preferred compounds that are particularly noted are the compounds of formula in which Aa represents a pyrazolyl or indazolyl radical optionally substituted as indicated above and below,

A

l a, A2a, A 3 a and A 4 a are chosen from the following values: Aa represents hydrogen or carboxyl or forms a ring with the adjacent member A~a

A

4 a represents hydrogen or carboxyl or forms a ring with the adjacent member A 3 a

A

2 a represents a carboxyl radical that is free, salified, esterified with an optionally substituted alkyl radical or an amidated carboxyl as indicated above or below,

A

2 a and A 3 a represent two optionally substituted alkyl radicals, As represents hydrogen.

One subject of the present invention is, even more particularly, the compounds of formula as defined above, corresponding to the formula (Ab): WO 03/035065 PCT/GB02/04763 -41-

A

2 b "N Abb AP\ N S(IAb)

A

3 b

A

4 b Ab (IAb) in which Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or more radicals chosen from halogen atoms and alkyl, alkoxy and thienyl radicals, Alb, Ab, A 3 b and A 4 b, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl and alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical that is free, salified, esterified with an alkyl radical or amidated with a radical NA'bA 7 b such that either A 6 b and A b, which may be identical or different, are chosen from alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and furylalkyl radicals, or A 6 b and A 7 b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical optionally substituted on the second nitrogen atom with an alkyl radical, it being understood that two consecutive radicals from among Alb, A 2 b, A 3 b and A 4 b may form, with the benzimidazole radical to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole radical or 4,5-methylenedioxybenzimidazole radical,

A

5 b represents a hydrogen atom, the phenyl and phenoxy radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and free, salified or esterified carboxyl radicals, all the alkyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 4 carbon atoms, the said compounds of formula (IAb) being in any possible racemic, enantiomeric or diastereoisomeric isomer from, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAb).

With reference to formula (Ix) above, the following are particular and preferred groupings:

R

1 may particularly represent optionally substituted heteroaryl. Exemplary optionally substituted heteroaryls include dihydrofuropyrazolyl, imidazolyl, indazolyl, indolyl, isoxazolyl, oxodihydropyridazinyl, oxodihydropyridinopyrazolyl, oxodihydropyridinyl, oxotetrahydropyrrolopyrazolyl, pyrazolyl, thiazolyl, thienopyrazolyl, tetrahydrocyclopentapyrazolyl, WO 03/035065 PCT/GB02/04763 -42tetrahydroindazolyl, tetrahydropyranopyrazolyl, tetahydropyridinopyrazolyl, tetrahydropyrrolopyrazolyl or triazolyl. Optional substituents include one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 4

-C(=O)R

4 -C(=O)NY1Y 2 -C(=0)OR 4

-N(R

6

)C(=O)R

4

-N(R

6

)C(=O)NY

1

Y

2

-N(R

6 )C(=0)OR 4 -N(R6)SO2R 4 -N(R6)SO2NY 1 Y 2

-NY

1 y 2

-OR

4

-OCF

2 H, -OCF 3

-OC(=O)R

4 -OC(=0)NY1Y 2 -S(O)nR 4 and -S(0)2NY 1 y 2 Ri more preferably represents a heteroaryl moiety in which R 7

R

8 and R 9 are as hereinbefore defined. It will be appreciated that compounds of formula (Ix) in which RI represents a heteroaryl moiety and R 7 is hydrogen can exist in the tautomeric forms

R

7

H

x4 N N N adR9 andi I IN NN

H

1 X N

NN

W H H W may particularly represent CH when X is CR 2 Y is CH or CR 3 and Z are CH or CR 3 W may also particularly represent CH when X is N, Y is CH or CR 3 and Z is CH or CR 3 W may also particularly represent N when X is CH or CR 2 Y is CH or CR 3 and Z is CH or CR 3 W may also particularly represent N when X is CH or CR 2 Y is CH or CR 3 and Z is N.

It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.

WO 03/035065 PCT/GB02/04763 -43- A particular group of compounds of the invention are compounds of formula (Ixa):-

R

9 7-

R

Y

X N H R (Ixa) in which W, X, Y, Z and R7 are as hereinbefore defined for compounds of formula and R8 and R 9 are independently selected from hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 4

-C(O)R

4 -C(=O)NYly2, -C(-0)OR 4

-N(R

6

)C(=O)R

4

-N(R

6

)C(=O)NY

1 2

-N(R

6 )C(=0)OR 4

-N(R

6 )S0 2

R

4

-NY

1 y 2

-OR

4

-OC(=O)R

4

-OC('O)NY

1

Y

2 -S(O)nR 4 and -S(0) 2

NY

1 y 2 and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixa) in which W represents CH, X represents CH, Y represents CH and Z represents CH or C-CH 3 are preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CH, Z represents CH and Y represents: C-C1- 4 alkyl C-CH 3

C-CI-H

2

CH

3

C-CH

2 CH2CH 3 or C-CH(CH 3 )21;

CH

3

CH,

(ii) C-aryl C ,C ,C CN CH 3

O

C CH3, C ,C ,C Cl, F o1 C or C Oj; (iii) C-CN; WO 031035065 PCT/GB02/04763 -44- (iv) C-NO 2 C-halo C-Br, C-Cl or C-Fl; (vi) C-haloalkyl C-CF 3

II;

N

(vii) C-heteroaryl C or C (viii) C-OR 4

C-OCH

3

C-OCH-

2

CH

3

C-OCHF

2

C-OCF

3 C-O O C-O-CH2-- or C-O-(C 2 N 02 (ix) C-C(0O)R 4 C-C(0O)o 1 C- C(=O)-NH-CHCH 3

C-C(=O)-NH-CH(CH

3 2 c-C(=O)-NH-C(CH 3 2 -CHiOH, C-C(=O)-NH-CHCH 2

CN'

C-C(=O)-NH-CH2CH2OCH3, C-C( O)-NH-CH2

CH

3 CH 3 C-C(=O)-NH CH 2 C-C(=O)-NHftCH 2 CH 3 C-C(=-O)-NHftCH 2 C-C(=O)-NIICH, C-C( O)-NHL(CH.4 2 )2N 0 C-C(O)NH(CH 2 No WO 031035065 PCT/GB02/04763

H

_N 2 11j, C-C(=O)-NH-(Cfl)i C-C(=O)-NH-(CH 2 or C-C(0)-NH (xi) C-C(=D)OR 4 C-C(=O)OH or C-C('=O)OCH3]; (xii) C-NHC(--O)R 4 jeg. C-NHC( Q)CH 3 C-NHiC(=D)CH-(CH 3 )2, C-NH-C(=O) or C-NH-C&=O)-CH 2 0 or (xiii) C-CH(OH)aryl C-CH(OH)-- j; (xiv) C-S(O) 2 )NYly 2 C-SO-N.H-CH 2 (xv) C-S(O)nR 4 Le.g. C-SO 2

CH

3 are also preferred.

Compounds of formula (Ixa) in which W represents CH, X represents C-CH 3 C-CH2CH 3

C-CH(CI-

3 2

C-OCH

3

C-OCH

2

CH

3 C-Br or C-Cl, Y represents C-CH 3

C-CH

2

CH

3

C-OCH

3 C-Br, C-Cl, C-F, C or C-C(=O)-NE-HCII and Z represents CHI are also preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CII, Y represents C-CH 3 and Z represents C-CH 3 are also preferred.

Compounds of formula (Ixa) in which W represents CH-, X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH2-O-CH 2 and Z represents CHI are also preferred.

WO 031035065 PCT/GB02/04763 -46- Compounds of formula (Ixa) in which W represents CH-, X represents CR 2 and Y represents CR 3 where R2 and R3 form the group -CH, 2

-CH

2

-CH

2 and Z represents CH are also preferred.

Compounds of formula (Ixa) in which R7 represents hydrogen are preferred.

Compounds of formula (Ixa) in which R8 represents: hydrogen; (ii) C 1 4 alkyl CH 3

CH

2

CH

3

CH(CH

3 2 or CH(CH 3

)CH

2

CH

3 1; (iii) -SR 4 leg-. -S-CH, -S-HCI-11 or -S-CH 2 -S-CH 2

OCH

3 N s -S-CI1CH, -S-C- 2 or -S-CH 9 (iv) -Nl'yY 2 -N O;r

-OR

5 -OCHoCH 3 are preferred.

Compounds of formula (Ixa) in which R 9 represents: hydrogen; (ii) Ctu-'nlky1 -CH 3 -CH2CH 2

CH

3

-CH(CH

3 2 or -CI{ 2

-CH

2

-CH(CH

3 2 (iii) aryl Le.g. phenyl]; (iv) -C(=O)NY'Y 2

-C(=O)-NH-CHCH

3

-C(=O)-NH-C

2

CH

2

CH

3

-C(=O)-NH-CH

2

CH(CH,)

2

-C(=O)-NH-CH(CH

3 2 -NT- C(CH 3 3

-C(=O)-MI--C(CH

3 )2 C1 2 0H, -C(=O)-NH-CH 2 CHOCH 3 C(=O)-N(CH 3 2

-C(=O)-N(CHCH

3 -C(O)NH1 I C(0)NHTCH2< or -C(=O<NiH-I0] WO 031035065 PCT/GB02/04763 -47- 6

=O)R

4 particularly -INHC(=O)R 4 in which R 4 is alkyl optionally substituted by aryl, cycloalkyl, heteroaryl, heterocycloalkyl, N"Y Iy 2 or -OR 5 [e.g.

-NH-C(=O)-CHT 3 3 -~NI-C&0)-CH(CH 3 2 -NH-C(=O)-C(CH 3 3 -NI-C(=O)-C-lCH(CI 3

Y,,

-NH-fC(=O)-CH(CH 3

)CH.

2

CH

3 -NH-C(=O)-CH,C(CH 3 3

-NH-CO)-CH

2

-NH-C(=O)-CHF<

-NH-C(=O)-CH-N N' -NHC(=O)-CHTN(CH9) 2 -NH-C(=O)CHTN ,NH-C(0)-CHIr 0 or -NH-C(>)CH 2

CH

3

R

4 is aryl [e.g.

H

3

C

I~ -NH-C( O) b or CH 3 1' R 4 is cycloalkyl or R 4 is heteroaryl -NH-CQ=O) 1I 0 -NNHCCQ0) or

H

3 C I-HC-O- 0 o -NH-CCO) N or heterocycloalkyl [e.g.

WO 031035065 PCT/GB02/04763 -48- -N(R 6 )C(=O)Ny'y 2 particularly -NHC(=O)NY'Y 2 Ije.g. -NH- C&O)-NHCH 3

-NH-C=O)-NHCHCH

3

-NH--C=O-NHCH(CH

3 2

-NH-C(=O)-NHC

2

.CH(CH

3 2

-NH-C(=O)-NHC(CH

3 3 -NH-C(=O)-N(CH 3 2 -NH-C(=O)-N(CHCH 3 2 -NH-C&0)NHCH -NH-C(=O)-NH-CH, 0 -NH-C(=O)-NH -NI-C(=O)-N0 N-CH 3 or -NH-C& 0)-N1 0]; (vii) -NYlY 2

-NH

9 Or (viii) alkyl substituted by -N(R6)C(=OJNYly 2

-CH

2

-NH-CQ=O)-CH(CH

3 )2 Or -CH 0; are preferred.

A preferred group of compounds of the invention are compounds of formula (Ixa) in which:- W represents CH; X represents CH; Y represents CH; Z represents CH or C-CH 3 R7 represents hydrogen; R 8 represents hydrogen, (ii) C I 4 alkyl CH 3

CH

2

CH

3

CH(CH

3 2 or

CH(CH

3 )CH9)CH3], (iii) -SR 4

-S-CH

2

-S-CHCH

3 or -S-CHj-_ j

-S-CH

9 SCH 2 CH 3 -S-CH 2 CHT 2 -SCH r--C 2 (iv) -NY IY 2 or -OR Le.g. -OCH2CH 3 1; R 9 represents hydrogen; (ii) C 1 7 alkyl -CH 3

-CH

2

CH

2

CH

3

-CH(CH

3 2 or -CH 2

-CH

2

-CH(CH

3 (iii) aryl phenyl];l (iv) -C(=O)NYlY 2 [e.g.

WO 031035065 PCT/GB02/04763 -49- -CQO)NlI-C 2

C

3 ,-C(=O)-NH-CHCHC 3 -C(O)-NH-HC4C 3 2

-C(=O)-NH-CH(CH

3 2

-C"=)-NH-C(CH

3 3

=O)-NH-C(CH

3 2

CH

2

OH,

-C(=O)-NH-CHCHOC-

3 A -C(=O)-N(CHCH 3 2 ,1 C(=O)-NHCH< or -C=O)IN- 0]

-N(R

6

)C@=O)R

4 e, particularly -NHC(=O)R 4 in which R4 is allcyl optionally substituted by aryl, cycloalkyl, heteroaryi, heterocycloalkyl, NY 1

Y

2 or -OR 5 g. -N4T-C(=O)-CH 3 -NH-C(=O)-(CH4,)2CH 3

-NH-C(=O)-CH(CH

3 2 -NH-C(=0)-C(CH 3 ,3 -NH- C(-O)-CHCH(CH 3 2 ,1 -NH-C(O)-CH(CH 3

)CHCH

3

-NH-C(=O)-CHC(CH

3 3 2 N I -NI-C(=O)-CH-N(CI 3 2 2No -NH-C(=O)-CI1 or -NH-C(0)-CHOCH 3 R4 is aryl [e.g.

H

3

C

-NH-C(0) b or -NH4-CQ=O)

CR

3 1

R

4 is cycloalkyl or

R

4 is heteroaryl Ieg Hf -NH-C or -NH-CQ=O) C N] or heterocycloalkyl -NLIC(=O) 0 1; WO 031035065 PCT/GB02/04763 (vi) -N(R 6 )C(0)NY y 2 particularly -NHCQ=O)NY'Y 2

-NH-C(=O)-NHCH

3

-N-H-C(=O)HCH

2

CH

3

-NI-C(=O)-NHC-(CH

3 9 1' -NH-C(O)-HCH2CH(CH3)1'

-N-.-CQ=O)-NH-C(CH

3 3 3 -NH-C(--0O)-N(CH-CH 3 2 -NH-C(=O)N CHF<, -NH--CQ=O)-NH-CH 2 1 -NH-C(=O)-NH -NH-CC=0)-N

N-CH

3 or -HC O- (vii) -NY 1

Y

2

-NH

2 or (viii) alkyl substituted by -N(R 6 )C(=O)Nyly 2

-CH

2

CH(CH

3 2 Or -CH--NH-C(=0y-N and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixa) in which:- W represents CH; X represents CH; Z represents CH; Y represents C-Cl 1 4 alky1 C-CH 3 CH 3

C-CH

2

CH

3

C-CH

2

CH

2

CH

3 or C-CH4(CH 3 2 (ii) C-aryl C ,C en 3 CN CH-O C6 0/ CH 3 ,c F0 C-0C or C (iii) C-ON, (iv) C-N02, C-halo C-Br, C-Cl or (vi) C-haloalkyl C-CF 3 1, (vii) C-heteroaryl C \N or WO 031035065 PCT/GB02/04763 -51c '(viii) C-OR 4 C-OC-H C-OCH CH 3 C-OCHF, C-OCF, 2\ c-o C-O-CH 2 or C-O-(CH 2_-N 01, (ix) C-C(=0)R 4 [e.g.

C-C(=O)o C-C=O)NYly 2 [eg. C-C(=O)-NH-CH- 3 C-C(=0)-N(CH A,

C-C(=O)-NH-CI

2

CH

3 C-C(=O)-NH-CH(CH 3 2 C-CQ==O)-NH-C(CH 3 2

-CH

2 01" C-C( 0)-NH-CH 2 CH 2 CN' C-C(=O)-NH-CH 2

CJ

2

OCH

3 cH 3 C-C(=O)-NI-I-CH 2 9

CH

3

C-C(=O)-NH-CH

2 ,C-C(=O)-NH-CH 2

CH

3

C-C(=QJ-NH-CH

2 C-c(=O)-NW-CH

O-

C-C(=O)-NH-(CH29 9 I 0, C-C(=O)-NH-(CH.,rNo C-C(=O)-NH-(CH 2 H 0 or C-C(=O)-NH0 1 (xi) C-C(=O)0R 4 C-C(-O)OH or C-C(0)OCH 3 (xii) C-N-HC(--0)R 4

C-NHC(=O)CH

3 or C-NHC(=O)CH(CH 3 2 C-bll-C(0) or WO 031035065 PCT/GB02/04763 -52- C-NH-C( 0)-C(=0)-CH 2 (xiii) C-CH(OH)aryl C-CH(OH)-- 11 (xiv) C-S(0) 2 NYly 2 C-S02--I-I-CI-I 2 /0 or (xv) C-S(0)nR 4

C-SO

2

CH

3

R

7 represents hydrogen; R 8 represents hydrogen, GOi C 1 4 alkyl CH 3 CH2CH 3

CH(CH

3 )2 or

CH(CH

3 )CH2CH 3 (iii) -SR 4 -S-CE3 -SC C2o SC -S-CR, ,S-CR, OCH 3 -S-CH2-CI-1 2 or ci-i -b4Y 1

Y

2 0 or -OR

-OCHCH

3 I; R 9 represents hydrogen; (ii) C1p 7 alkyl -CH 3 -CH2CH2CH 3

-CH(CH

3 2 or -CH 2

-CH-

2

-CH(CFI

3 2 1; (iii) aryl phenyl]; (iv) -C(=0)Nyly 2 [e.g.

-C(-0)-NH-CHCH 3

-C(=O)-NH-CHCH

2

CH

3 -C(=O)-NH-CH,CH(CH39 2 -C(=0)-NH-CH(CH 3 9 -C(=0)-NH-C(CH3) 3 -C(=0)-NH-C(CH 3

),CHOH,

-C(=O)-NH-CHCH

9

OCE

3 -C(=O0YN(CHf,, -C(0)-N(CHCH), -C(O)-NH I -C(=0)NH-CH 2 or -C O)NT1 0]

-N(R

6 4 particularly -NHC(--O)R 4 in which R 4 is alkyl optionally substituted by aryl, cycloalkyl, heteroaryl, heterocycloalkyl, Nyly 2 or -OR 5

-NH-CQ=O)-CH

3 -NH-C(0> )CH 2

CH(CH

3 2

CH(CH

3

)CH

2

CH

3

-NH-C(=O)-CH

2

C(CH

3 3 -MI-C(=0)-CH 2 I -NH-C(=0-C1127<j -NH-C(=O)-CH2 N 11N'N -NI-C&O)-CH2-N(CH 3 2 WO 031035065 PCT/GB02/04763 -53- -NH-=0)-CH-N3 -NH-C&=0)-CHTN F-0 or -N1-C(--)-CHCCH 3

R

4 is aryl [e.g.

-NH-C( 0)o I NI I- /O or CH 3 1,

R

4 is cycloalkyl or -NH-C(0O)-

R

4 is H3

N/

heteroaryljeg. 0

HC

or -NH-C(0O) N or heterocycloalkyl -NH-CQ=0)- 1 (vi) -N(R 6 particularly -NHC(=0ThYlY 2 -NH-C(=0)-N4CH 3 -NH-C(--0)-NCH 2 CH 3 -NH-C(0)-NHCH(CH 3 2 -NH-CONHCHCH(CH 3 2 -NH-C(0)-NHC(CH 3 3 -NI-I-C=0)-N(CH 3 2

-NH-C(O-N(CHCH

3 2 -NH-C(=C)-NIFK2,

-NH-C&O)-NH-CTTK<

NH-C(-=0)-NH -Nfl-C(=0)-N0 N-ET Or -1 01, (vii) -ISJyly 2

-NH

2 I or (viii) alkyl substituted by -N(R6%C(=0)NY 1

Y

2 -C11 2

-INI-C(=O)-

CH(CH

3 2 or o] ;and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisosteres.

WO 031035065 PCT/GB02/04763 -54- A further preferred group of compounds of the invention are compounds of formula (Ixa) in which: W represents CH; X represents C-CH 3

C-CH

2

CH

3 C-CH(CHf 3 2

C-OCH

3 C-OCH2C- 3 C-Br or C-Cl; Y represents C-CH 3 C-CH-2CH 3

C-OCH

3 C-Br, C-Cl, C-F, C or

C-CQ=O)-NII-CH

9 Z represents CH; R7 represents hydrogen; R 8 represents (i) (ii) Clp 4 alkyl CH-, CH 2

CH

3

CH(CH

3 or CH(CH3)CH 2

CH

3 I, (iii) -SR 4 [e.g.

-S-CH 3

-S-CHCH

3 or S-CT2 ,S-CH 2 0

N

-S-CH

9 OCH 3

CH

2 1 ,-s-CH2- or -S-CE (iv) -NY 1

Y

2 eg-N 0 or -OR 5

-OCH

2

CH

3 1; R 9 represents hydrogen; (ii) C 1 7 alkyl -CH 3

-CH

2 CH2CH 3

-CH(CH

3 2 or -CH2-CH2-

CH(CH

3 2 (iii) aryl phenyl]; (iv) -C(=O)NY 1

Y

2 -C(=O)-NJ-CHCH3'

-C(=O)-NH-CH

2 CHCH., C(=O)-NHI-CHCH( CH 3 2

-CQ=-O)-NH-CH(CH

3 2

-C(=O)-NH-C(CH)

3 1 -C(=O)-NH-C(CH 3

)'CH

9 011 -C(=O)-NH-CCH 2- OCH3 -C(=OYNHCHK< or 0 01; -N(R 6 )C(0O)R 4 particularly -NHC( O)R, in which R 4 is alkyl optionally substituted by aryl, cycloalkyl, heteroaryl, heterocycloalkyl, NY 1

Y

2 or -OR 5 3 -NH-C()(CH 2

)CH

3

-NHC(~)-C(CH)

2 ,-NI-C(=O)-C(CH3) 3 -NI-C(-O)-HCH CH 2

-N{-C(=O)-CH(CH

3

)C

2 H, -MNH C(_O)-CH 2

(CH

3 HCH, NH-C(O CH 2 C(H' N

N

WO 031035065 PCT/GB02/04763 -Nl-C =0)-CH-N(CH 3 2 -NH--C(=0)-CHT-NO -NH-C(zO)-CH--N C or -NH-C&0)-CH 2 0CH 3

R

4 is aryl [e.g.

H

3

C

I or -NH-CQ0O) CH 3

R

4 is cycloalkyl or -NH-C(=0)o

R

4 is 0/ heteroaryl[e.g. -NH-C( O) j 0

HC

or Nlor heterocycloalkyl -N1-C(C) 0] (vi) -N(R 6 )C(0)NYlY 2 particularly -N7HC(=0)NY'Y 2 -NI-C(0)-NCH 3 -NH-C(=)NHCH,C14 3 1 -NHa-C(=0)-NCH(CH,),' -NH-C(=0)-NHCHCH(CH3)2

NH-C(=)NHC(CH

3 3 -NH-C(=O)-N(CH 3 )2 -NH-C(,=0)-N(CH 2

CH)

2 -NH-C&)NH1<, -NH-C=OftNH-CH 2 -NH-C(=0)-NH-CH 2 1

I

NH-C(=0)-N N-H r-NH-C(=0)-N 1 (vii) NYly 2

-NH

2 or (viii) alkyl substituted by -N(R6%C(0)Nyly 2 -CHa)-NH-C&=O)-

CH(CH

3 2 Or -CH2 ol and their corresponding N-oxides, and their WO 031035065 PCT/GB02/04763 -56prodrugs, and their acid bloisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisosteres.

A fuirther preferred group of compounds of the invention are compounds of formula (Ixa) in which: -W represents CH; X represents CH; Y represents C-CH 3 Z represents C-CH 3

R

7 represents hydrogen;

R

8 represents hydrogen, GiO Cp- 4 alkyl je.g. CH 3

CH

2

CH

3

CH(CH

3 2 or CH(CH 3

)CH

2

CH

3 (iii)

-SR

4

-S-C-

3

-S-CHCH

3 or S-CH 2

S-C-I.

N

-S-CR, 2OOCH 3 7 -SCC2,

-S-CH

2 -O or

S

-C C (iv) -NYlY 2 -N 0or -OR 5 -OCH2CH 3

R

9 represents hydrogen; GOi CIj'alky1 -CH 3

-CH

2

CH

2

CH

3

-CH(CH

3 )2 or -CH 2 -CH2-

CH(CH

3 )21; (iii) aryl phenyl]; (iv) -C(=O)Nyly 2 [e.g.

-C(=O)-NH-CHCH 3

-C(=O)-NH-CH)C.H,CIH

3

-C(=O)-NH-CHCH(CH

3 -C(=O)-NH-CH(CH3) 2

-C(=O)-KHB-C(CH

3 3

-C(Q)-NH-C(CH

3

,-CH

2

OH,

2 lCH 2

,OCH

3 I -C(=O)-N(CH 3 X2, -CQ=O)-N(CI-1,CH4,, CQ0O)-NH-CH 2 or 0];

-N(R

6 4 particularly -NHC(0O)R 4 in which R 4 is alkyl optionally substituted by aryl, cycloalkyl, heteroat-yl, heterocycloalkyl, Nyly 2 or -OR 5 -N1-C(--O)-CH 3

-NHC(O)-CH)

2

C

3

O)-CH(CH)

2

-NH-C(=O)-C(CH

3 3 2 CH(C1 3 2

-NI-C(=O)-CH(CH

3 lCH 2

CH

3

-NI-C=O)-CH

2

C(CH

3 3

-NH-C(-O)-CH

2 1 -NH-C&=O)-CHT<, -NH-C(=O)-CHTNN \N I-KH-C(=O)-CH-N(CH 3 2

N

WO 031035065 PCT/GB02/04763 -57- -NEIj-Ce 0)-CHTN3 -NH-C(=OD)-CH;-N 0 or -NH-C&=0)-CH,0CH 3

R

4 is aryl [e.g.

H

3

C

b or 1. il] R4 is cycloalkyl or R:4 is 3C 0/ heteroaryl[e.g. -NH-C(0O)- 3 or 'IN] or heterocycloalkyl 1 (vi) -N(R6%C(0O)Ny'y 2 particularly -NHC&0O)NYly 2 -NH-C(--O)-NICH 3 -N--C(=0)-NT-CH,CH 3

-NH-C(=O)-NHCH(CH

3 2 -NH-C(=0)-NHCHCH(CH3).,' -NH-C(=0)-NHC(CH 3 3 -NH-C-O)-N(CH 3 2 -NH-C(=)-N(CHCH 3 2

-NH-C(=O)-NH-CHKJ,

-NH-C(=O)-NHCH2 -NH-C(O)NH -NH-C(=0O)-No -NH-C(=-OYN N-C-I or -NH-C( 0)-N (vii) KNyly 2 -1N1 2 1 or (viii) alkyl substituted by -N(R 6 )C(=O)NYlY 2

-CH

2 -NH-CQ O)-

CH-(CH

3 2 or -CHT-2NH-C&=O)--N o] and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisosteres.

WO 031035065 PCT/GB02/04763 -58- A further preferred group of compounds of the invention are compounds of formula (Ixa) in which:-W represenits CH; X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group

-CH

2 -O-CH9 Z represents CH; R 7 represents hydrogeni; R 8 represents hydrogen, GOi C 1 4 alkyl

CH

3

CH

2

CH

3

CH(CH

3 2 or CH(C11 3

)CH

2

CH

3 (iii) -SR 4 -S-CH 3 -S-CH 2 CH 3 or CH., -S-CH, QOCH, N

S

-S-CH--CH-

2 -e-i Or -S-CH 2 (iv) -N~yly 2 [e.g.

-N 0]or -OR 5

-CCH

2

CH

3

R

9 represents hydrogen; (ii) Cp- 7 alkyl -CH 3

-CH

2

CH

2

CH

3 -CH(CI-1 3 )2 or -CH 2

-CH

2

-CH(CH

3 (iii) aryl phenyl]; (iv) _C(-O)Ny 1 y 2 [e.g.

-C(0>)NH-CHCH, -C(=O)-NH-CH 2

H

2 C 3 -C(=0)--NH-CHCH(CH 3 )-1 -C(-=O)-N11-CH(CH 3 2 ,1 -C(=0)-NI-C(CH 3 -C(=O)-NH-C(CH 3 )2CH 2

OH,

-C(=O)-NH-CH 2

CH

7 OCH 3

-C(=O)-N(CH

3

-C(=O)-N(CI

2 CH 3 2 -C~)NJK2 -C(=O)-NH-CH 2 or 0];

-N(R

6

(O)R

4 particularly -NHCQ=O)R 4 in which R 4 is alkyl optionally substituted by aryl, cycloalkyl, heteroaryl, heterocycloalkyl, N-Y 1

Y

2 or -OR 5 -11-C(0)-CH 3 -NII-C(=O)-(CH A CH 3 -NH-C&=O)-C(CH 3 3 -NH-C(=O)-CH 2 CH(CH 3 )2 CH(CH 3 )CH 2

CH,

-NH-C=O)-CH

2 C(CH 3 3 1 -NH-C(=O)-CH 2 -NH-C(=O>-CH 2 <j

-N

-NHC&O>)CllTN0 -NH-C(=O)-CH-TN 0 or WO 031035065 PCT/GB02/04763 -59- -NE-C(?=0)-CH,0CH 3 1, R4 is aryl [e-g.

H-

3

C

0\ I b or CH 3 1 R4 is cycloalkyl or 1, R4 is heteroaryl[e.g. -NH-CQ=0) I,-N C(0 or -NH-C( 0) or heterocycloalkyl -NH-C(0O)01 (vi) -N(R6%C(0)Nyly 2 particularly -NHC(0)NY 1 y 2 -NH--C(0)-NHCH 3 -NH-C&0)-NHCH,CH 3 -NH-C(=)-NHCH(CFI)2,' -N--C(=0)-NHCHCH(CH 3 2 -NH-C(=0)-NHC(CH 3 3 -NI-I-C(=0)-N(CH 3 -NH-C=0)-N(CH 2

CH

3 -NH-C(0)-NH< -NH-C(=0)-NHCH2 <?j -NH-C(=O)-NH -CH- -NH-C(=0)-No -NH-Cc)-N N-CH 3 Or 01O, (vii) -NY 1 y 2

-NH

2 or (viii) alkyl substituted by -N(R 6 )C(=O)I'.yly 2 [e.g.

-CH

2 -NH-C(=0)-CH(CH 3 2 or -CFFN- -Ce=o)-N 01 and their corresponding N-oxidcs, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisosteres.

WO 031035065 PCT/GB02/04763 A further preferred group of compounds of the invention are compounds of formula (hxa) in which:-W represents CH; X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group

-CH

2

-CH

9 -C11 2 Z represcnts CH; R 7 represents hydrogen; R 8 represents hydrogen, (ii) C 1 4 alkyl

CH

3

CH

2

CH

3

CH(CH

3 2 or CH(CH- 3

)CH

2

CH

3 I, (iii) -SR 4

-S-CH

3

-S-CH

2

CH

3 or -S-CH 2

-S-CH

2

OOCH

3 N s S-CHT H C ,o SC 2 (iv) -NYly 2 [e.g.

-N 01or -OR 5

-OCH

2

CH

3

R

9 represents hydrogen; (ii) Clj 7 alkyl -CH 3

-CH

2

CH

2

CH

3

-CH(CH

3 2 or -CH?-CH 9

)-CH(CH

3 2 1; (iii) aryl phenyl]; (iv) [e.g.

-C(=0)-NH-CHCH- 3 -C(=0)-NH-CHCHCH,, -C(=0>-NHCHC(CH) 2 -C(=0)-NH-CH(CH 3 2 3 3 3 2

CH

2 0H,

CH

2

CH

2

OCH

3 3 -C(=0)-N(CHCH4 3 2 1 -C(=0)-Nfl -C&D)NHCH2KI or -C(0)NH 01;

-N(R

6 )C&'0)R 4 particularly -NHC('=O)R 4 in which R 4 is alkyl optionally substituted by aryl, cycloalkyl, heteroaryl, heterocycloalkyl, INY 1

Y

2 or -OR 5 -NI-C(=0)-CH 3 -NH-C(=0)-(CH2)2CH 3

-NH-C=O)-CH(CH

3 2 -NHlT-C(-=)-C(CH 3 3

-NH-C=OC)-C

2

CH(CH

3 2 -NH-C(--0)-CH(CH)CH.,CH 3

-MI-C(O)-CH

2

C(CH

3 3 -NH-Q=OYCH 2 -NH-C(=0O)-CH-N~ N' -NE-(=0)-C12N(CH) 2 C()CHTN0 -NH-Q=O)-CH-N 0 or

-NH-C(=O)-CH

2 C-I' R 4 is aryl [e.g.

WO 031035065 PCT/GB02/04763 -61- -NH-C(=0)o I -b or -NH-C&0) CH 3 b1 R4 is cycloalkyl or -NH-C(=0)o

R

4 is

H

3

C

-N/

heteroarylieg. -NH-C(0O) I-NH-CQ=0) or NHC 0) N]or heterocycloalkyl 1 (vi) -N(R 6 )C(=O)Nyly 2 particularly -NHC( 0)NY 1 y 2 -NH-C&0>)NICH,

-NH-C(=O)-NHCHCH

3 -N--C(=0)-NICH(CH 3 2 -~NH-Cez0)-NHCHCH(CH 3 2 -NH-C(=Oy-NHC(CH 3 3 -NH-C(=0)-N(CH 3 2 -NH-C(0)-N(CHCH 3 X,1 -NH-C(=0Y-NH-Kj, -NH-C(=0)-NH-CH 2 -NH-C(=0)-NH -Ch-1/1 -NH-C(0)NH 0 /I -NH-C(=0)-No -NH-Cj=0)-N N-CH 3 o N 1 (vii) -INyly 2

NH

2 1 or (viii) alkyl substituted by -N(R 6 )C(--0)Nyly 2 [e.g.

-CH

2 -NII-C(=0)-CH(CH 3 2 or -CH2 NH-C(=O)-N o] and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixa) in which R 8 is hydrogen or -CH 3 and R 9 is -C1' 2

-CH

2

-CH(CH

3 2 WO 031035065 PCT/GB02/04763 -62- -C(=0)-NH-CHCH 3

C=)N-C

2 H H -C(=0)-NH-CH(CH), =0)-NH-C(CH, 3 3 -C(=0)-NH-C(CH 3 2 CH_,OH, -C(=0D)-NH}I -C(0-NHCH~HOH 3 2

-C(=)-N(CHCH,

-C(=0)-NHC 0, -NT{-C(=0)-C1 3

-NH--C(=O)-CH(CH

3

-NH-C(=O)-C(CH

3 3

-NH-C(-O)-CH

2

CH(CH

3 2

CH(CH

3

)CH

2

CH

3 -NH- C(=0O)-CH 2

C(CH

3 3

-NH-C(=O>CH

2 -NUH-C(=0Y-CH2-, -NH-C(=0-CHT-Nl

N.

-N-H-C(0-)-CHN(CH 3 2N 0, -NHI-C(=)-CHOCH 3

HC

-G CH 3 -NH-C(0o)-<

H

3

C

-NH-CQ=0) NH-C(=0) NH- /0O

H

3

C

/0 -fC(0)-1CH 3 -NH-C(=0NiHCH-CH 3 -NM--C(--0)-NHC(CH 3 2 -NH-C(=0)-NHC(CH 3 3

-NH-C=O)-N(CH

3 2

-NH-C(=)-N(CH

2

CH

3 2

-NH-C()NH<

-NH-C(=)-NH-CHF2 -NH-C(=O)-NI{CH 2 WO 031035065 PCT/GB02/04763 -63- -NH-C(=O)-NH

NH-C(=O)-N

N-CH

3 0 -CH 2 -NH-C(=-0)-CH(CH 3 2 Or CH 2NI-I 0are particularly preferred.

Compounds of formula (Ixa) in which R 9 represents hydrogen and R 8 represents -CH(CH 3 )2,

-S--CH

3

,-S-CHCH

3 or -S-CH 2 are also particularly preferred.

Compounds of formula (Ixa) in which W is CH, X is CH, Y is CH, C-CH2CH 3

C-CH-)CH

2

CH

3 CN F 0 C 0 ,C-CN, C-Br, C-CF 3 C (-OCH, C-0CI 2

CH

3

C-OCHF

2

C-OCF,

C-0-CH 2 0 1C-C(=0)-N1-CH 3 C-Cq=)-H-CHCH 3 C-C(=-O)-NH-CH(CH 3 2

C(CH

3 2 1-CHOH, C-C(-O)-NHi-CHCH 2

CN'

C-C(=r0)-M1-CHCH 2 OCfl 3 C-C(0)-NH-CH,

CH

3 CH 3 C-C&=O)-NH-CH 2 2 6/ C-C(z=0)-NH-CH 2 CH 3 C- C(=0)-NH-(CH 2 2 0 WO 031035065 PCT/GB02/04763 -64- 0, C-C(=O)-N~H-(CH 2 )2 N

N--N

C-C(-0)--NH-(CH 2 )2 I -N

N-N

C-C(=O)-NH-CH

2 C-C(=0)-NH-CH 2 0 C-C( 0)-NH-(CH 2 C-C(=0)OCH 3 C-C(=0)0H, C-H(O) -SO 2

H

3 r C-0-N and Z is CH are particularly preferred.

Compounds of formula (Ixa) in which W is CH, X is C-CH 3 or C-CH 2

CH

3 Y is C-CH 3

C-CH',CH

3

C-CH(CH

3 2 C-Br, C-Cl, C-F, C or C-C(=0)-N-H-CH 2 ,and Z is CH are also particularly preferred.

Compounds of formula (Ixa) in which W is CH, X is C-OCH 3 Y is CH, C-CH 3

C-CH

2

CH

3 C-Cl or

C-OCH

3 and Z is CH are also particularly preferred.

Compounds of formula (Ixa) in which W is CH, X is C-0CH 2

CH

3 Y is C-F and Z is CH are also particularly preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R 3 atoms form the group -CH 2

-CH

2

-CH

2 and Z represents CH are also particularly preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CR 2 and Y represents CR 3 where R2 and R 3 form the group -CH2-0-CH 2 and Z represents CH are also particularly preferred.

WO 031035065 PCT/GB02/04763 Compounds of formula (Ixa) in which R 8 is hydrogen or -CH 3 and R 9 is -C(=zO)NH-CHCH, -C(0)-NH-CHCH,CH 3 C(=D)-NH-CH(CH 3 C(=0)-NiI-CHCH(CH 3 3 3 3 )_1CH,0H, -C(=)-N(CHCH 3 )2, I -C(=0)-NH-CH2 -C(O)-KEI 0, -C(=O)-NH-CH)CH,0CH 3 I -N1-C(=0)-(CH2,-CH 3 -NH-C(=0)-CH(CH3jY, -NH-C(=0)-C(CH 3 3 -NH-C=0)-CHCH(CH 3 2 ,1

-NH-C(=)-CH(CH)CHCH

3 -NH1-C(=0)-CH 2 C(CH9 3 -NHl-C(=O)CH-'<j

/N

-NH-C( 0)O I ,-NLI-C(=0)o I 0/ -NH-C(O0) I -NHE--C(--0)-NHCH 3 -NH-C(=)-NHCHCH3, -NH-C(--VKN4HCH(CH 3 2 -Nl-C(=0Y)NHC(CH 3 3 -NH-C(=)-N(C1 3 2

-NH-C(=>-N(CH

2

CH

3 2 -NHC(0>NHK2 -NH-C(0>O)NH-H -N{-C(0)-NH-CI 2 -NH-C(=0)-NH0

I

-NH-C(0)-No -NH-CQ=0)-N

N-CH

3 or 0 are especially preferred.

WO 03/035065 PCT/GB02/04763 -66- Compounds of formula (Ixa) in which W is CH, X is CH, Y is C-OCH 3

C-OCH

2

CH

3

C-OCHF

2

C-CF

3

C-C(=O)-NH-CH

2 or C-C(O)-NH-CH 2 N and Z is CH are especially preferred.

Compounds of formula (Ixa) in which W is CH, X is C-CH 3 or C-CH 2

CH

3 Y is C-CH 3 or C-CH2CH 3 C-C1 or C-F and Z is CH are also especially preferred.

Compounds of formula (Ixa) in which W is CH, X is C-OCH 3 Y is C-CH 3

C-CH

2

CH

3 C-Cl, C-F or

C-OCH

3 and Z is CH are also especially preferred.

Compounds of formula (Ixa) in which W is CH, X is C-OCH2CH 3 Y is C-C1 or C-F and Z is CH are also especially preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH 2 -CH2-CH 2 and Z represents CH are also especially preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH 2

-O-CH

2 and Z represents CH are also especially preferred.

Another particular group of compounds of the invention are compounds of formula (Ix) wherein R 1 is a

R

9

R

heteroaryl moiety in which R 8 and R 9 together with the carbon atoms to which they N are attached form an optionally substituted phenyl ring, i.e. compounds of formula (Ixb):- (R)p 4 6 (Rio

N

W N N \R XW II R7 WO 031035065 PCT/GB02/04763 -67- (Ixb) in which W, X, Y, Z and R 7 are as hereinbefore defined for compounds of formula RIO is carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R.

4

-C(=O)R

4 -C(=O)NYly 2 -C(=O)0R 4

-N(R

6

)C(=O)R

4

-N(R

6 )C(=O)Ny 1 y 2

-N(R

6 )C(=O)0R 4

-N(R

6 )S09R 4 -N(R6%SO2NYly 2 -Nyly 2

-OR

4 -OCF2HB, -GeE 3 -OC( O)R 4 -OC@=O)Nyly 2

-S(O)

11

R

4 or -S(O)2N'Y 1

Y

2 and p is zero, or an integer 1; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixb) in which W represents CH, X represents CH, Y represents CH and Z represents CH or C-CH 3 are preferred.

Compounds of formula (Ixb) in which W represents CH, X represents CH, Z represents CH- and Y represents:

C-C

1 4 alkyl C-CH 3

C-CH

2

CH

3

C-CH

2

CH

2

CH

3 or C-CH(CH 3 )21;

CH

3

CH

3 (ii) C-aryl -C-b C-d I c CN CH 3 0 F 0 C Ci'C or C (iii) C-CN; (iv) C-NO 2 C-halo C-Br, C-Cl or C-F]; (vi) C-haloalkyl C-CF 3 1; (vii) C-heteroaryl N or C WO 031035065 PCT/GB02/04763 -68- (viii) C-OR 4 C-0CH 3

C-OCHCH

3

COCHF

2 5 COCF 3 0 '0 C-O-CH, or C-O-(CH)TT-N Oi; (ix) C-C(=O)R 4 i;

C-C=O)NY

1 y 2

C--C(=O)-NI{-CH

3 C-C(=O)-N(CH 3 C-C(=O)-N-CHCH 3 C-C( O)-NH-CH(CH 3 2 3 2 -CH 2

OH,

C-C(=O)-NH-CH 2 CHCN, C-C(=O)-NH-CH 2

H

2 OfCH 3 C-C(-O)-Nl-CH 2

,C-C(=O)-NHCH

2

CH

3 1

C-C(=O)-NH-CH

9 CH 3 C-C(=O)-NH-CH

'C-C(=O)-NH-CH

9 /2

C-C(=O)-NH-(CH)

2 C-C(=O)-NH-(Cl- 2 0 kN A C(=O-I(H 2 2

I

N--N

0 N

(CH.

9 3N or C-C(=O 4II 1; WO 031035065 PCT/GB02/04763 -69- (xi) C-CQ=-O)0R 4 [e.g.C-C(=O)OH orC-C(=O)OCH 3

];I

(xii) C-NHC("'O)R 4

C-NHC(=O)CH

3

C-NH-C(=O)CH(CH

3 2 C-NH-C(0D) or C-NH-C(=O)-CH 20 (xiii) C-CH(OH)aryl C-CH(OH) O 1 C-S(O))2NY ly 2 C-SO NH-CH 2 (xv) C-S(O)nR 4

C-SO

2

CH

3 1; are also preferred.

Compounds of formula (lxb) in which W represents CH, X represents C-CH 3 C-CF12CH 3

C-CH(CHL

3 2

C-OCH

3

C-OCH

2

CH

3 C-Br or C-Cl, Y represents C-CH 3

C-CH

2

CH

3

C-OCH

3 C-Br, C-Cl, C-F, C or C-C( O)-NHTCH 2 0/ and Z represents CH are also preferred.

Compounds of formula (Txb) in which W represents CH, X represents CH-, Y represents C-CH 3 and Z represents C-CH 3 are also preferred.

Compounds of formula (Ixb) in which W represents CH, X represents CR 2 and Y represents CR 3 where R-9 and R 3 form the group -CH-C-CH 2 and Z represents CH are also preferred.

Compouinds of formula (lxb) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH 2

-CH

2 -CH2-, and Z represents CH are also preferred.

Compounds of formula (Ixb) in which R 7 represents hydrogen are preferred.

Compounds of formula (Ixb) in which p is zero or one are preferred.

WO 03/035065 PCT/GB02/04763 Compounds of formula (Ixb) in which R 10 represents: cyano (ii) halo chloro, fluoro]; (iii) C 1 4 alkyl methyl, (iv) -OR 4

-OCH

3

-OCH

2

CH

3 or

-C(=O)NY

1

Y

2

-C(=O)-NH

2

-C(=O)-NHCH(CH

3

-C(=O)-N(CH

3 2 are preferred.

A preferred group of compounds of the invention are compounds of formula (Ixb) in which:- WV represents CH: X represents CH; Y represents CH; Z represents CH or C-CH 3

R

7 represents hydrogen; R 1 0 represents cyano, (ii) halo chloro, fluoro], (iii) Cl-4alkyl methyl], (iv)

-OR

4

-OCH

3 or -OCH 2

CH

3 or -C(=O)NY 1

Y

2 NH2 -C(=O)-NHCH(CH 3 2 or

-C(=O)-N(CH

3 2 and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CH; Z represents CH; Y represents C-C 1 -4alkyl C-CH3,

CH,

C-CH

2

CH

3

C-CH

2

CH

2

CH

3 or C-CH(CH 3 2 (ii) C-aryl C C I

CH

3 CN CH O C ,C CH-, C ,C F 0o C CC or C O (iii) C-CN, (iv) C-N02, C-halo C-Br, C-Cl or (vi) C-haloalkyl C-CF 3 (vii) C-heteroaryl CN or

N

C (viii) C-OR 4

C-OCH

3

C-OCHCH

3 C-OCHF,, C-OCF WO 031035065 PCT/GB02/04763 -71c-0 C-O-CHT, or C-O-(CH,)i-N (ix) C-C(=0)R 4 [e.g.

C-C(=0)o C-C=0)NY'Y 2 l C-C(=O)-NII-CH 3 C-C(zz0)-N(CH 3 2

C-C(=O)-NH-CH

2 CH 3

C-C(=O)-NH-CH(CH

3 2 C-C(=0)-NI-L-C(CH 3 2

-CH

2 0H,

C-C(=QO)-NH-CH

2

CH

2 CN' C-C(=0)-NH-CH CH2OCH3' C-C(=O)-N-J-CH 2 2 b CH 3 C-C(=O)-NIIh-CH 2 C-CQ=0)-NH-CH 2 0/, CH 3 C-C( O)-NH-CH 2 C-C(=0)-NH-1(CH 2 9 I C-C(=0)-N-I-(CH2 )N 0, C-C(=0)HC 2 O

-C=)-NH-(CCHH-

AN

11, N

,N

0 C- (CH 2 )3 N or C-CQ=O)-NII 1, (xi) -C(=O)0R 4 C-C(=O)OH or C-C(0)OCH 3 (xii) C-NHC(=0)R 4 C-NHC(0O)C.H 3 or C-NHC( O)CH(CH 3 2 C-NI-C(0O) -O or C-1NH-C(=O)CHi 0 (xiii) C-CH(OH)aryl C-CH(OH) G 1 (xiv) WO 03/035065 PCT/GB02/04763 -72- C-S(0) 2 NYy 2 C-SO-NH-CH2 or (xv) C-S()nR 4

C-SO

2

CH

3

R

7 represents hydrogen; p is zero or one; R 10 represents cyano, (ii) halo chloro, fluoro], (iii) Cl.

4 alkyl methyl], (iv) -OR 4

-OCH

3 or -OCH 2 CH3] or -C(=O)NY1y 2 [e.g.

-C(=O)-NH

2

-C(=O)-NHCH(CH

3 2 or -C(=0)-N(CH 3 2 and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g.

hydrates) of compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisostcres.

A further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents C-CH 3 C-CH2CH 3

C-CH(CH

3 2

C-OCH

3 C-OCH2CH 3 C-Br or C-C1; Y represents C-CH 3

C-CH

2

CH

3

C-OCH

3 C-Br, C-C1, C-F, C- or C-C(=O)-NH-CH2- Z represents CH; R 7 represents hydrogen; p is zero or one; R 10 represents cyano, (ii) halo chloro, fluoro], (iii) Cl_ 4 alkyl methyl], (iv) -OR 4

-OCH

3 or -OCH 2

CH

3 or -C(=O)NY 1 y 2

-C(=O)-NHCH(CH

3 2 or and their corresponding N-oxides, and their prodrgs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CH; Y represents C-CH 3 Z represents C-CH 3

R

7 represents hydrogen; p is zero or one; R 1 0 represents cyano, (ii) halo chloro, fluoro], (iii) C1-4alkyl methyl], (iv)

-OR

4

-OCH

3 or -OCH 2

CH

3 or -C(=O)NY 1 y 2

-C(=O)-NH

2

-C(=O)-NHCH(CH

3 2 or

-C(=O)-N(CH

3 2 and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group WO 03/035065 PCT/GB02/04763 -73- -CH2-O-CH2-; Z represents CH; R 7 represents hydrogen; p is zero or one; R 1 0 represents cyano, (ii) halo chloro, fluoro], (iii) C1-4alkyl methyl], (iv) -OR4 -OCH 3 or -OCI-1 2

CH

3 or

-C(=O)NY

1

Y

2

-C(=O)-NH

2

-C(=O)-NHCH(CH

3 2 or -C(=O)-N(CH 3 2 and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CR2 and Y represents CR 3 where R 2 and R 3 form the group

-CH

2

-CH

2 -CH- Z represents CH; R 7 represents hydrogen; p is zero or one; R 10 represents (i) cyano, (ii) halo chloro, fluoro], (iii) C1-4alkyl methyl], (iv) -OR 4

-OCH

3 or -OCH2CH 3 or -C(=O)NYlY 2

-C(=O)-NH

2

-C(=O)-NHCH(CH

3 2 or -C(=O)-N(CH 3 2 1; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixb) in which R 7 represents hydrogen and p is zero are particularly preferred.

Compounds of formula (Ixb) in which R 7 represents hydrogen; p is one and R 10 represents cyano, chloro, fluoro, methyl, -OCH 3

-OCH

2

CH

3 -C(=O)-NfI 2

-C(=O)-NHCH(CI-H

3 2 or

-C(=O)-N(CH

3 )2 are also particularly preferred.

Compounds of fornula (Ixb) in which W is CH, X is CH, Y is CH, C-CH 2

CH

3 C-CH2CH 2 CH3, CN F 0 C O ,C N C- C- 0 C-CN, C-Br, C-CF 3 C NC C-OCH, C-OCHCH, C-OCHF 2

C-OCF,

C /-C3 C\C23 C-OCH C C(=0o)-N--CH 3 C-C(0)-NH-CH 2 CH3'

C-C(=O)-NH-CH(CH

3

C-C(=O)-NH-C(CH)

2 -CH20H, C-C(=O)-NH-CHCH 2 CN WO 031035065 WO 03/35065PCT/GB02/04763 -74-

C-C(=O)-NI-CHCHOCH

3 C-CQ=O)-NT1-CH 2 CH 3 C-C(=O)-NH-CH 2

C-C(=D)-NH-

O)-NH-

C- C(=O)-NH- C- C(=O)-NH- -CHi- -Ci 2 CH, C-C(=O)-NH-(CH)

-(CIH

2 2 C-CQ=O)-NH-(CH 2 )2NO

H

-(CH4N 11 2 /T A N'

_N

0 -(Cli 9 )r b C-C&0O)-NH C-C(=0)0CH 3 C-C(=O)0H, C-H(H, I C-SO 2

CH

3 Or 0-SO--NH-OH -C and Z is CHi are particularly preferred.

Compounds of formula (Ixb) in which W is CH, X is C-CH 3 or C-OH 2

CH

3 Y is C-OH 3

C-CH

2

OH

3

C-OH(CH

3 C-Br, C-Cl, C-F, C C C -C(=0)-NII-CH 2 and Z is CHi are also particularly preferred.

Compounds of formula (Ixb) in which W is CH, X is C-00H 3 Y is OH, C-CH 3

C-CH

2 0H 3 C-Cl or 0-00113 and Z is CH are also particularly preferred- WO 03/035065 PCT/GB02/04763 Compounds of formula (Ixb) in which W is CH, X is C-OCH 2

CH

3 Y is C-F and Z is CH are also particularly preferred.

Compounds of formula (Ixb) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH2-CH 2

-CH

2 and Z represents CH are also particularly preferred.

Compounds of formula (Ixb) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH2-O-CH2-, and Z represents CH are also particularly preferred.

Compounds of formula (Ixb) in which R 7 represents hydrogen and p is zero are especially preferred.

Compounds of formula (Ixb) in which R 7 represents hydrogen; p is one and R 10 represents -OCH 3 -OCH2CH 3 or -C(=O)-NIICH(CH 3 2 attached to position 5 of the indazolyl ring are also especially preferred.

Compounds of formula (Ixb) in which W is CH, X is C-CH 3 or C-CH2CH 3 Y is C-CH 3 or C-CH2CH 3 and Z is CH are also especially preferred.

Another particular group of compounds of the invention are compounds of formula (Ix) wherein R 1 is a

R

9

R'

pyrazolyl moiety in which RS and R 9 together with the carbon atoms to which they

N

R

7 are attached form an optionally substituted C_ 5 8 cycloalkyl ring, i.e. compounds of formula (Ixc):- 1(R 1 2 )q (Ixc) WO 031035065 PCT/GB02/04763 -76in which W, X, Y, Z, X and p are as hereinbefore defined for compounds of formula AD is a

C

5 -Scycloalkyl ring and R 1 2 is acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or an acid bioisostere), cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluorornethyl, -C(=OyyY 2 -NY' -CQ=O)alkY1, -NY' So 2 alkyl,- Ny 1 y 2 -SO2NY 1 y 2 or alkyl, alkenyl or alkynyl each optionally substituted with aryl, cycloalkyl, heteroaryl, hydroxy, -C(='O)0R 6 -C('=O)Nyl y 2 -INy 1 y 2 or -OR 5 and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixc) in which W represents CH, X represents CH, Y represents CH and Z represents CH or C-CH 3 are preferred.

Compounds of formula (Ixc) in which W represents CH, X represents CH, Z represents CH and Y represents: 0i) C-Cl 1 4 alkyl C-CH 3 C-CH2CH 3 C-CH2CH2CH 3 or C-CH(CH 3 2 CH, CH 3 (ii) C-arl[e.g. C C c CN CH 3 0 C CH 3 i F 0 c~ or (iii) C-CN; (iv) C-N02); C-halo C-Br, C-Cl or C-F]; (vi) C-haloalkyl C-CF 3 1; WO 031035065 PCT/GB02/04763 -77-

_N

(vii) C-heteroaryl C or C i; (viii) C-OR 4

C-OCH

3

C-OCHCF

3 C- OCHF 9 COCF3' C-0O C-O-CH 2 or C-O-(CH 2 0 (ix) C-C(=O)R 4 C-C(=O)o J C-C=O)Ny 1 y 2

C-C(=O)-N(CH

3 2 1'

C-C(-O)-NH-CHCH

3 C-C(=O)-NH-CH(CH 3 C-C(=O)-NH-C(CH 3 2

-CH

2

OH,

C-C(--=O)-NH-CHf2CH 2 CN, C-C(=O)-N{CH,CH,OCH 3

CH

3 C-C(=O)-NH--1 2

C-C(=-O)-NH-CH

2 CH3

C-C(=O)-NH-CH

2 I C-C(=O)-NH-CH 2

CH

3

C-C(=O)-NHCH

2 /D C-C(=O)-KW(CH)N 0 C-C(=O)-NH-(CH4N- I C-C(=O)-NH--(CH 2 )Td \O

NN

WO 031035065 PCT/GB02/04763 -78- 0

(CH

2 i-N/ C-C(O)-NH-(CH 9 or C-C(=O)-NH 1; (xi) C-C(=0)0R 4 C-C(=O)OH or C-C(=O)OCH 3 (xii) C-NH-C(=0)R 4

C.-NHC(=O)CH

3 C-NIIC(0)CH(CH 3 2 C-NHI-C(0O) -G or C-NH-CQ-'0)-CH, 2- or (xiii) C-CH(OH)aryl C-CH(OH)-- 1 (xiv) C-S(0) 2 Ny'y 2 C-S0;-NH-CH,O i; (xv) C-S(0) 1 1

R

4

C-SO

2

CH

3 are also preferred.

Compounds of formula (Ixc) in which W represents CH, X represents C-CH 3

C-CH

2

CH

3

C-CH(CH

3 2

C-OCH

3 C-OCH2CH 3 C-Br or C-Cl, Y represents C-CH 3

C-CH

2

CH

3

C-OCH

3 C-Br, C-Cl, C-F, C-/0 or C-C(=0)-NH-CH 2 0 and Z represents CH are also preferred.

Compounds of formula (Ixc) in which W represents CH, X represents CH, Y represents C-CH 3 and Z represents C-CH 3 are also preferred.

Compounds of formula (Ixe) in which WV represents CH, X represents CR 2 and Y represents CR_ 3 where R 2 and R.

3 form the group -CH 2 -0-CH 2 and Z represents CH are also preferred.

WO 03/035065 PCT/GB02/04763 -79- Compounds of formula (Ixc) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH 2 -CH2-CH2-, and Z represents CH are also preferred.

Compounds of formula (Ixc) in which R 7 represents hydrogen are preferred.

Compounds of formula (Ixc) in which A represents a cyclopentyl, cyclohexyl and cycloheptyl, especially cyclohexyl, ring are preferred.

Compounds of formula (Ixc) in which q is zero are preferred.

A preferred group of compounds of the invention are compounds of formula (Ixc) in which:- W represents CH; X represents CH; Y represents CH; Z represents CH or C-CH 3

R

7 represents hydrogen; A represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixc) in which:- W represents CH; X represents CH; Z represents CH; Y represents C-Cl_ 4 alkyl C-CH 3

CH

3 C-CH2CH 3

C-CH

2

CH

2

CH

3 or C-CH(CH 3 2 (ii) C-aryl C C- CH, CN CHO C /6 ,C -CHC,, C ,C F 0 C- C- or C- 0 (iii) C-CN, (iv) C-N0 2 C-halo WO 031035065 PCT/GB02/04763 C-Br, C-Cl or (vi) C-haloalkyl C-CF 3 1, (vii) C-heteroaryl N or

/N

C 1~(viii) C-OR 4

C-OCH

3

C-OCHCH

3 C- OCHF,, C-OCF 3 C-0 C-O--CH2 or C-G-(CH-)yN (ix) C-C(=O)R 4 [e.g.

C-C(0) C-C=O)NylY 2 C-C(=O)-NM1-CH 3

C-C(-=O)-N(CH

3 2 C-C(=O)-NH-CHCH 3 C-C (=O)-N~H-CH(CH 3 9 C-C(=0)-TH-C(CH 3 2

-CH

2 0H, C-C(=O)-NH--CHCHCN, C-C(=O)-NH-CH,CH 2

OCHT

3 cH 3 C-C(=O)-NH-CH2 C-C(=O)-NH-CH 2 b

CH

3

C-C(=O)-NL-CH

2

C-C(=O)-NH-CH

2 CH 3 C-C(=O)-NT-CH2 C-C(=O)-NFH 2 2

C-C(=O)-NH-(CH-

2 )-TN 0,

C-CQ=O)-NH-(CH

2 )TN C-C(=O)-NH-(CH 2 )3 N1 N0 C-C(=O)-Nfl-(CH9 2 2\ C-C(=O)-NH-(CH 2

)TN

or C-C(=0)-NU1 1 (xi) -C(=O)OR 4 C-C(=O)OH or C-C( O)OCH 3 1, (xii) WO 03/035065 PCT/GB02/04763 -81-

C-NHC(=O)R

4

C-NHC(=O)CH

3 or C-NHC(=O)CH(CH 3 2 or

C-NH-C(=O)-CH

2 (xiii) C-CH(OH)aryl C-CH(OH) (xiv) C-S(0) 2 NY1y2 C-SO-NH-CH or (xv) C-S(0)nR 4

C-SO

2

CH

3

R

7 represents hydrogen; A represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixc) in which:- W represents CH; X represents C-CH 3 C-CH2CH 3

C-CH(CI-

3

C-OCH

3

C-OCH

2

CH

3 C-Br or C-Cl; Y represents C-CH 3

C-CH

2

CH

3 C-OCH3, C-Br, C-OC C C, C-F, C or C-C(=O)-NH-CH- Z represents CH; R 7 represents hydrogen; A represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixc) in which:-W represents CH; X represents CH; Y represents C-CH 3 Z represents C-CH3; R 7 represents hydrogen; 0 represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisosteres.

WO 03/035065 PCT/GB02/04763 -82- A further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH2-O-CH2-; Z represents CH; R 7 represents hydrogen; A represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixc) and their N-oxides and their prodrgs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group

-CH

2

-CH

2

CH

2 Z represents CH; R 7 represents hydrogen; A represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixc) in which R 7 represents hydrogen and p is zero are particularly preferred.

Compounds of formula (Ixc) in which W is CH, X is C-CH 3 Y is C-CH 3 and Z is CH are also particularly preferred.

Compounds of formula (Ixc) in which A is a cyclopentyl ring are particularly preferred.

Another particular group of compounds of the invention are compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety in which R 8 and R 9 together with the carbon atoms to which they

S

are attached form an optionally substituted heterocycloalkyl ring, i.e. compounds of formula (Ixd):- WO 03/035065 PCT/GB02/04763 -83- X1 (R 1) lZ N SW H R7 (Ixd) in which W, X, Y, Z and X are as hereinbefore defined for compounds of formula X 1 is O, S, SO2, or NY 5 (where Y 5 is hydrogen, R 4

-C(=O)R

4

-C(=O)NY

1

Y

2

-C(=O)OR

4 or -S 2

R

4 r is zero or an integer one or two and R 1 3 is alkyl or two RI3 groups attached to the same carbon atom form an oxo group; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixd) and their N-oxides and their prodirugs, and their acid bioisosteres.

Compounds of formula (Ixd) in which W represents CH, X represents CII, Y represents CH and Z represents CH or C-CH 3 are preferred.

Compounds of formula (Ixd) in which W represents CH, X represents CH, Z represents CH and Y represents: C-C1- 4 alkyl C-CH 3 C-CH2CH 3

C-CH

2

CH

2

CH

3 or C-CH(CH 3 2 j; CH 3

CH,

(ii) C-aryl C C CN CHO 3 0 C/ \CH 3 6 ,b -0 Cl, F 0 C or CO (iii) C-CN; (iv) C-N02; C-halo C-Br, C-Cl or C-F]; (vi) C-haloalkyl C-CF 3 WO 031035065 PCT/GB02/04763 -84-

/-N

(vii) C-hecteroaryl C N or C (viii) C-OR 4 C-OCH C-OCHCH C-OCHF C-OCF, C-0O

C-O-CH

2 or C-O-(CH)i-Nf- 0]; (ix) C-C(0)R 4 C-C(=C)o 1 C-C=O)Nyly 2 C-C( O)-N1-CH 3

C-C(=O)-N(CH

3 C- CH 2

CH

3 C-C( -O)-N1--CH(CHO 3 C- C(CH 3

)'-CH

2 OH, C- C( CH 2

CHCN,

C-C(=O)-N1-CHCH 2

ODCH

3

CH

3 CH 3

C-C(=O)-NH-CH

2 C-C(=O)-NHftCH 2 CH

C-C(=O)-NHCH

2 2 9,N C-CQ=O)-NH-(CH2) 2

II

N--N

WO 031035065 PCT/GB02/04763 0 (CH,)rN1- C-C(=0)-NH-(CH)yN or C-C&=0)-NH1 1; (xi) C-C(=0)0R 4 C-C(=0)OH- or C-C(=0)OCH 3 (xii) C-NIIC(=O)R 4 C-NHC(=0)CH- 3 C-NHC(=0)CH(CH 3 2 C-NH-C(=0) or C-INI-I-C(=-O)-CH 9 2 (xiii) C-CEJ(OH)aryl [eg. C-CH(OH) O 1 (xi) 2 yY 2

C-SO-NH-CH

2 0 ];or (xv) C-S(O),R 4

C-SO

9

CH

3

I;

are also preferred.

Compounds of form-Lla (Ixd) in which W represents CH, X represents C-CU 3

C-CJ-

2 C1Ig,

C-CH(CH

3 2

C-CCH

3

C-OCH

2

CH

3 C-Br or C-Cl, Y represents C-CH 3

C-CH

2

CH

3 C-0C11 3 C-Br, C-Cl, C-F, C or C-C(=0)-NII-CH., and Z represents CH are also preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CHI, Y represents C-CH 3 and Z represents C-CH3 are also preferred.

Compounds of formula (Ixd) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH 2

-O-CH

2 and Z represents CH are also preferred.

WO 031035065 PCT/GB02/04763 -86- Compounds of formula (Ixd) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH2-CH 2 -CH2-, and Z represents CH are also preferred.

Compounds of formula (Ixd) in which R 7 represents hydrogen are preferred.

Compounds of formula (Ixd) in which X I is: 0; (ii) N-C(=0)R 4 [e.gY. N-C(0C)CH 3 N-C&0O)CH 2

CH(CH

3 N-C(=0)CH(CH 3 2 Or N-C(=0)C(CH 3 3 or 1; (iii) N-C(=O)NY

T

y 2 N-C(0)N(CH 3 2 N-C( 0)NCH(CH 3 2 N-C(=0)N(CH- 2

CH

3 2 N-(C=0)-NC N-(C=0)-No or 1; (iv) N-C(=O)0R 4 N-C(=0)OCH 3 or N-C(=0)OCH 2

CH

3 or N-S0 2

R

4 N-SO92CH 3 or N-SO 2

CH(CH

3 2 are preferred.

Compounds of formula (Ixd) in which r is zero are preferred.

A preferred group of compounds of the invention are compounds of formula (Lxd) in which:- W represents CH; X represents CH; Y represents CH; Z represents CHI or C-CH 3

R

7 represents hydrogen; XI is 0; (ii) N-C(=0)R 4 N-C(=0)CH2CH(CH 3

N-

C(=0)CH(CH 3 2 or N-C(0)C(CH 3 3 or (iii) N-C(=O)Nyly 2 [e.g.

N-C(=O)'N(CH

3 2 N-C(=O)NCH(CI1 3 2

N-C(=O)N(CH

2

CH

3 2

N-(C=O)-NC

N-(C=O)-OOr (iv) N-CQ=O)0R 4

N-C(=O)OCH

3 or

N-C(=O)OCH

2

CH

3 1; or N-S09)R 4

N-SO

2

CH

3 or N-SO 2 CH(CH3) 2 and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically WO 031035065 PCT/GB02/04763 -87acceptable salts and solvates hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid biolsosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixd) in which:- W represents CHI; X represents CHI; Z represents CH; Y represents C-C 1 4 alkyl C-CH 3

C-CH

2

CH

3

C-CH

2

CH

2

CH

3 or C-CH(CH 3 2 GOi C-arYl C-/0 CH 3

C-

CH

3 C-d CN CH 3

O

-CH

3 C-/6 F 0o Cl, or C-6/ 0 (iii) C-CN, (iv) C-NO 2 C-halo C-Br, C-Cl or (vi) C-haloalkyl C-CF 3 1, (vii) C-heteroaryl N or

N

C (viii) C-OR 4 C-OCH, C-OCH 2 IC-OCHF 2 C-OCF 3 O

I

C-O-CH or C-O-(CH 2 1 (ix) C-C(=0)R 4 [e.g.

C-C( -O C-C0)NYly 2

C-C@=O)--HT-CH

3

C-C(-=O)-N(CH

3 2

C-C(=O)-NH-CH

2

C'H

3 C-CQ=O)-N4-CH(CH3) 2

C-C(=O)-NI-C(CH

3 2

-CH

2

OH,

C-C&=O)-NHI-CH

2

CH

2 CN, C-C(=0)-N-CH 2

CH

2

OCH

3 C-C(=O)-NII-CH,- C-C( O)-NH-CH2 WO 031035065 WO 03/35065PCT/GB02/04763 C-C(=O)-NH-CH, /2

C-C(=O)-NH-(CH

2 )2 C- C(=O)-NH-(CH 2 No 11, -88- 2

CH

3 C-Q( O)-NH-CH.

O

0 C-C( (CH2)3Nb or C-C( 0)-NH O (xi) -C(=O)0R 4 C-C(=0)OH or C-C(=0)OCH 3 I, (xii) C-NHCQ=0)R, 4 C-NHC(=0)CH 3 or C-NHC(=0)CFL(CH 3 C-N}T-CQ=O) or C-NH-C(=0)-CH 2 (xiii) C-CH(OH)aryl C-CH(OH) j, (Xiv) 2 'NYtY 2 C7-1;Q-NHI-l-., or (xv) C-S(0)nR 4

C-SO

2

CH

3 1; R 7 represents hydrogen; Xl is 0; (ii) N-C('=0)R 4 N-C(0)CH 3 N-C(=0)CH 2

CH(CH

3 2

N-

C(-=O)CH(CH

3 2 or N-C(=0)C(CH 3 3 or ]ZIjI; (iii) N-C( =O)NYly 2 [e.g.

N-C(=O)N(CHI)

2 N-C(=0)NCH(CH3) 2 N-C(=0)N(CH 2

CH

3 2 N-(C=0)-NC or 0;(vN-CQ=0)0R 4 N-C(=0)OCH 3 or N-C(=O)0CH 2

CH

3 or N-S0 2

R

4

N-SO

2

CH

3 or N-SO 2

CH(CH

3 2 and r is zero; and their WO 031035065 PCT/GB02/04763 -89corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixd) in which:- W represents CHi; X represents C-CH 3

C-CH

2 CH-, C-CH(CH 3 2

C-OCH

3 C-OCH2)CH 3 C-Br or c-ci; Y represents C-CH 3

C-CH

2

CH

3

C-OCH

3 C-Br, C-Cl, C-F, C or C-C()-N1-CH 2 ;Z represents CH; R 7 represents hydrogen; XI is 0; (ii) N-C(0O)R le-g. N-C(=0)CH 3 N-C(=0)CH 2

CH(CH

3 N-C(=0)CH(CH 3 2 or N-C(=O)C(CH 3 3 or N-(C0C)< (iii) N-C(=O)Ny Iy 2 N-C(=0)N(CH 3 N-C(=0)NCH(CH 3 2 N-C(=0)N(CH2CH 3 2 N-(C=O)-NC or 0]1; (iv) N-C(=0)0R 4

N-C(=OC)OCH

3 or N-CQ=0)0CH 2

CH

3 or (v N-S02R 4

N-SO

2

CH

3 or

N-SO

2 CH(CI-1 3 2 and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formnula (Ixd) in wvhich: -W represents CH; X represents CH; Y represents C-CH 3 Z represents C-CH 3

R

7 represents hydrogen; X1 is 0; (ii) N-C(=0)R 4 N-C(=0)CH 3 N-C(0)CH 2

CH(CH

3 2 N-C('=0)CH(CH 3 2 or N-C( 0)C(CH 3 3 or (iii) N-CQ=0)NY 1

Y

2 N-C(0)N(CH 3 2

N-

C('=0)NCH(CH 3 2

N-C(=O)N(CH

2

CH

3 2 N-(C=0)-No or N-(C0)-N N-C=O0)0R 4 N-CQ=0)OCH 3 or N-C(=0)OCH2CH 3 or (v) N-S0 2

R

4

N-SO

2

CH

3 or N-SO 2

CH(CH

3 2 and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid hioisosteres; and pharmaceutically acceptable salts and solvates (e.g.

WO 031035065 PCT/GB02/04763 hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixd) in which:-W represents CH; X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH2-O-CH 2 Z represents CH; R 7 represents hydrogen; XI is 0; (ii) N-C(=0)R 4

N-

CQ=O)CH

3 N-C(=0)CH 2

CH(CH

3 2 N-C(=0)CH(CH 3 2 or N-C(0)C(CH 3 3 Or N-C(=0)NYly 2

N-C(=-O)N(CH

3 N-C(=O)NCH(CH1 3 2 N-C(=0)N(CH2CH 3 )2 I or 01 (iv) N-C(=O)0R 4 [e.gy. N-C(=0O)OCH 3 Or N-C(=O)OCH 2

CH

3 J; or N-S02)R 4

N-SO

2

CH

3 or

N-SO

2

)CH(CH

3 2 and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (lxd) and their N-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds of formula (Ixd) in which: -W represents CH; X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group

-CH-

2

-CH

2

-CH

2 Z represents CH; R7 represents hydrogen; XI is 0; (ii) N-C(--0)R 4

N-

C(0)CH 3 N-C(-0)CH 2 CH(CH3)2, N-C(0)CH(CH 3 2 or N-C(=0)CC 3 3 or (iii) N-C(0)Nyly 2 N-C(=0)N(CH 3 2 N-C(=0)NCH(CH 3 2 N-C(=O)N(CH2CH 3 N-(C=O)-NC N-(C=0)-No or 0 1; (iv) N--C(=0)0R 4 N-C(=0)OCH 3 or N-C(=0)CH 2

CH

3 Or N-S0 2

R

4

N-SO

2

CH

3 or

N-SO

2

CH(CH

3 )21 and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixd) in which XI is N-C( 0)CH(CH 3 2 N-C(0)CH 2

CH(CH

3 2 N-C( =O)C(CH 3 3 I N-C(=0)N(CH 3 2 N-C(=0)NCH(CH 3 2 WO 031035065 PCT/GB02/04763 -91-

N-C(=-O)N(CH

2

CH

3 N-(C=OY-N 0, N-C(0)CCH 3 or N-CQ O)OCFI 2

CH

3 and r is zero are particularly preferred.

Compounds of formula (Ixd) in which W is CH, X is CH, Y is CHT, C-CH 2

CH

3

C-CH

2

CH

2

CH

3 C0

CN

IC-CN, C-Br, C-CF 3 C

-N

C /\,C-OCH 3

C-OCH

2

CH

3 C-OCHF,, C-CCF_,, C-O-C- CC=)N-HC3 C-C(=o)-NH-CH(CH 3

.H-C(CH

3

-CH

2 OH, C-(O-H-HC2N

C-C(=O)-NH-CH)CHCH

3 C-C(=0)-NI-CL1 2 0

CH

3 C14 3 C-C(=Qj)-NH-CH, O)-NH-CH.,/ C-C(0')-WCH 2

CH

3 2 Cc(=0)-NH(CH 2 )2 N 0, C-C(=0)-NH-(CH 2 )yNo

C-C(=O)-NH-(CH,)WN/

C-C('0)-NH-CH 2

N

2

I

N--N

C-C(=0)-N~HCH 9 WO 03/035065 PCT/GB02/04763 -92- 0 C-C(=0)-NH C-C(=0)OCH 3 C-C(=0)OH C-CH(OH)/

C-SO

2

CH

3 or C-SOjNH2-CH and Z is CH are particularly preferred.

Compounds of formula (Ixd) in which W is CH, X is C-CH 3 or C-CH 2

CH

3 Y is C-CH 3 C-CH2CH 3

C-CH(CH

3 C-Br, C-Cl, C-F, C C-C(=0)-NH-CH2/ and Z is CH are also particularly preferred.

Compounds of formula (Ixa) in which W is CH, X is C-OCH 3 Y is CH, C-CH 3 C-CH2CH-I 3 C-Cl or

C-OCH

3 and Z is CH are also particularly preferred.

Compounds of formula (Ixd) in which W is CH, X is C-OCH 2

CH

3 Y is C-F and Z is CH are also particularly preferred.

Compounds of formula (Ixd) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R 3 form the group -CH 2

-CH

2

-CH

2 and Z represents CH are also particularly preferred.

Compounds of formula (Ixd) in which W represents CH, X represents CR 2 and Y represents CR 3 where R 2 and R3 form the group -CH2-O-CH 2 and Z represents CH are also particularly preferred.

Compounds of formula (Ixd) in which X 1 is N-C(=0)N(CH 3 2 N-C(=0)NCH(CH 3 2

N-C(=O)N(CH

2

CH

3 or and r is zero are especially preferred.

WO 03/035065 PCT/GB02/04763 -93- Compounds of formula (Ixd) in which W represents CH, X represents C-CH 3 Y represents C-CH 3 or C-C1 and Z represents CH are especially preferred.

Particular compounds of the invention of formula (Ix) are selected from the compounds formed by joining the carbon atom of one of the benzoimidazole, or imidazo[4,5-b]pyrazine fragments (Al to A110) shown in Table 1 to the carbon atom in the heteroaryl moiety of one of the fragments (B1 to B 168) shown in Table 2.

Particular compounds of the invention of formula (Ixa) are selected from the compounds formed by joining the carbon atom of one of the benzoimidazole, or imidazo[4,5-b]pyrazine fragments (Al to A110) shown in Table 1 to the carbon atom in the pyrazole ring of one of the fragments (B1 to B48, B74 to B107, B124 to B127, 130 to 142 or 144 to 150) shown in Table 2.

Particular compounds of the invention of formula (Ixb) are also selected from the compounds formed by joining the carbon atom of one of the benzoimidazole, or imidazo[4,5-b]pyrazine fragments (Al to A110) shown in Table 1 to the carbon atom in the five membered ring of one of the fragments (B63 to B73, B108 to B 14, B128 or B151) shown in Table 2.

Particular compounds of the invention of formula (Ixc) are selected from the compounds formed by joining the carbon atom of one of the benzoimidazole, or imidazo[4,5-b]pyrazine fragments (Al to A110) shown in Table 1 to the carbon atom in the five membered ring of one of the fragments (B56, B59 or B129) shown in Table 2.

Particular compounds of the invention of formula (Ixd) are selected from the compounds formed by joining the carbon atom of one of the benzoimidazole, imidazo[4,5-c]pyridine or imidazo[4,5-b]pyrazine fragments (Al to A110) shown in Table 1 to the carbon atom in the five membered ring of one of the fragments (B115 to B123 or B157) shown in Table 2.

WO 031035065 PCT/GB02/04763 -94- TABLE I WO 03/035065 PCT/GB02104763 A23 CH 3 0 N A24 (CH 2 N N CHO 0:I( p

(CH

3 )2 N NA2 N N N j' N 1 H H WO 031035065 PCT/GB02/04763 WO 031035065 WO 03/35065PCT/GB02/04763

H

INI

N

WO 031035065 PCT/GB02/04763 WO 031035065 WO 03/35065PCT/GB02/04763 A105 H H A106 14N H C- I c( C H C H 0 0

HH

A107 ~A108

N~

H A109 l N II TABLE 2 WO 031035065 WO 03/35065PCT/GB02/04763 -100- B13 B 14

**CNIN

B 15 N B 16 C 3 C NNH B17 HOCH, B18 HOCH 2

CH,

*c N"N NH B 19 CHOCH, *c NHH B21 _N B22 0

CNH

*Cl IINH B23 N(CH,) 2 M24 NH(CH 2

),OH

NH *c -NINH

NHC(CH

3 2

CH

2 0H 26 00 B26 No ,N H~ 0

,N-I

B27

H

2 N\ B28

(CH

3 2 CHNH4 ~C 'Nl NEI *C 'N'NH WO 031035065 WO 03/35065PCT/GB02/04763 -101-

HN

Ck IINH

H

C-N

FIN

N

FIN

,NH

HN

0C'

'-N

0

I-IN

"NH4 0

ANN

R N

RN

NH

IFIN

*C ,NHl

NXI

0

RN

NH

N

0

N

HN

*-N

WO 031035065 WO 03/35065PCT/GB02/04763 -102- 0 7 NIN CHCH-,CH, SP H3

*"N'N

(CI-I

3 XH S-

NH

S

,NH

WO 031035065 PCT/GB02/04763 -103-

N

*CNZ ,NH

N

WO 031035065 WO 03/35065PCT/GB02/04763 -104- 0Z-

NH

S

'N'N

HN

-o

*K

7

N-

NC

0 CH-(CH 3 )-1

HN

C-

NH

OH-

HN

*K N ANH

HN

*K ,-vNH WO 031035065 WO 03/35065PCT/GB02/04763 -105-

HN

HN

INH

0

HN

,NH

0 N-

HN

,NH

0

N

HN

*C V ,N-I 0 14N

N

,NH

0

N-

HN

IINH

WO 031035065 WO 03/35065PCT/GB02/04763 -106-

FP

.c NH

N'

cl WO 031035065 WO 03/35065PCT/GB02/04763 0= *C MNH 0

HN

o pr

HN

HN

N

Br 7 ,1Nf WO 031035065 WO 03/35065PCT/GB02/04763 -108o HiC CH 3 HN

OH

IN CH, *C N114% 0

HN

,NH

NHC(CHJ),CJ4,OH 0= *C INH 0 NzN *C NH WO 031035065 WO 03/35065PCT/GB02/04763 -109c N/,NH RNP -0 *C NH 0

NH

H

0 WO 031035065 WO 03/35065PCT/GB02/04763 -110- Particular compounds of the invention of formnula (Ix) denoted as the product of the combination of group Al to Al10in Table 1 with Bi to B169 in Tablec2 are illustrated below: Al-BI; Al-B32; Al-B3; Al-B4; A1-B5; Al-B36; A1-B7; Al-B8; Al-B9; Al-BlO; Al-Bli; A1-B12; AI-B13; A1-B14; Al-B15; Al-B16; A1-B17; At-BiS8; A1-B19; Al-B20; Al-B21; A1.-B22; Al-B23; Al-B324; Al-B26; Al-B27; Al-B28; Al-B29; A1-B31; AI-B32; A1-B33; A1-B34; A1-B35; AI-B36; A1-B37; Al-B38; AI1B39; A1-B40; A1-B41; Al-B42; AI-B43; A1-B44; A1-B45; A1-B46; A1-B47; A1-B48; AI-B49; A1-B50; Al-B51; A1-B52; Al-B53; A1-B54; A1-B56; Al-B57; A1-B58; A1B59; A1-B60; Al-B61; A1-B62; Al1-1363; AI-B64;, A1-B65; AI-B66; Al-1367; A1-B68; A1-B69; Al-B70; Al-B71; Al-B72; AI-B73; A1-B74; A1-B75; A1-B76; A1-B77; Al-B78; Al-B79; AI-B80; AI-BS1; Al-B82; AI-B83; Al-B84; 1B6 Al-B 87; Al J WO 031035065 WO 03/35065PCT/GB02/04763 -111- A1-B91; A1-B92; AI-1393; AI-B94; A 1-B95; A1-B96; A1-B97; A1-B98; A 1-B99; A1-BI00; Al-BlOl;- AI-B102; AI-B103; A1I-B 104; A1I-B 105; AlI-B 106; A1-B107; Al-BLOS; A1-B109; Al-BIlO; Al-Bitl; Al -B 112; Al-B113; AI-Btl4; Al-B 11, AI-BI16; A1-B117; Al-BuS8; A1-B119; AI-B120;- A1-B121; At-B122; Al1-B 123; Al-B124; Al-B125; AI-BI26; Al-B127; AI-B128; A1-B129; Al-B130; Al-B131; AI-B132; A1-B133; At-B134; Al-B135; Al-B136; AT-B137; AI-B138; Al-B139; A1-B140; A1-B141; Al-B142; AlI-B 143; A1-B144; A1-B145; A1-B146; AI-B147; A1-B149; A1-B149; A1-B150; AI-BI51; Al-B152; AI-BI53; A1-B154; Al-B155; Al-B156; At-B163; A1-B164; A1-B165; 7;A1 B1 6 6 A1-B167; A1-B168; A1-B169; A2-B1; A2-B2;2-3 A2-B4; A2-B6; A2-B7; A2-BS; A2-B9; A2-B 10; A2-BlT; A2-B 12; A2-B 13; A2-B14; A2-B15; A2-B 16; A2-B17; A2-B 18 A2-B19; A2-B20; A2-B2 1; A2-B22; A2-B23; A2-B24; A2-B25; A2-B26; A2-B27; A2-B28; A2-B29; A2-B30; A2-B3 1; A2-B32; A2-B33; A2-B34- A2-B35; A2-B36; A2-B37; A2-B38; A2-B39; A2-B40; A2-B41; A2-B42; A2-B43; A2-B44; A2-B45; A2-B46; A2-B47; A2-B48; A2-B49; A2-B50; A2-B5 1; A2-B52; A2-B53; A2-B54; A2-B55; A2-B56; A2-B57; A2-B58; A2-B59; A2-B60; A2-B61; A2-B62; A2-B63; A2-B64; A2-B65; A2-B66; A2-B67; A2-B68; A2-B69; A2-B70; A2-B71; A2-B72; A2-B73; A2-B74; A2-B75; A2-B76; A2-B77; A2-B78; A2-B79; A2-B80; A2-B81; A2-B82; A2-B83; A2-B84; A2-B85; A2-B86; A2-B87; A2-B88; A2-B89; A2-B90; A2-B91; A2-B92; A2-B93; A2-B94; A2-B95; A2-B96; A2-B97; A2-B98; A2-B99; A2-BlO; A2BOl; A2-B102; A2-B103; A2-B 104; A2-B 105; A2-B106; A2-B107;1 A2-B108; A2-B109; A2-BIlO; A2-B I11; A2-B 112; A2-B 113; A2-B 114; A2-B 115; A2-B 116; A2-B 117; A2-B 118; A2-B 119; A2-B 120; A2-B12l; A2-Bt22; AI-123; A2-B t24; A2-B125; A2-B 126; A2-B127; A2-B128) A2-B129; A2-B 130; A2-B131; WO 031035065 WO 03/35065PCT/GB02/04763 -112- A2-B132; A2-B 133; A2-B 134; A2-B 135; A2-BI36; A2-B137; A2-B138; A2-B 13 9; A2-B 140; A2-B14 1; A2-B 142; A2-BI43;- A2-B144; A2-B 145; A2-B 146; A2-B 147; A2-B 148; A2-B149; A2-B150;, A2-B 15 1; A2-B 152; A2-B153; A2-B 154; A2-B155;- A2-B156; A2-B 15 7; A2-B158; A2-B 159; A2-B160; A2-B161; A2-B 162; A2-B163; A2-B 164; A2-B 165; A2-B 166; A2-B167; A2-B 168; A2-B169; A3-B 1; A3-B2; A3-B3; A3-B4; A3-B6; A3-B7; A3-B8; A3-B9; A3-B1O; A3-B 11; A3-B12; A3-B 13; A3-B14; A' 15; A3-B16;, A3 -B17; A3-Blg; A3-B 19; A3-B20; A3-B21; A3-B22; A3-B23; A3-B24; A3-B25; A3-B26; A3-B27; A3-B28; A3-B29; A3-B30; A3-B31; A3-B32; A3-B33; A3-B3)4; A3-B35; A3-B36; A3-B37; A3-B38; A3-B39; A3-B40; A3-B4f; A3-B42; A3-B43; A3-B44; A3-B45; A3-B46; A3-B47; A3-B48; A3-B49; A-I-B50; A3-B51; A3-B52; A3-B53; A3-B54; A3-B55; A3-B56; A3-B57; A3-B58; A3-B59; A3-B60; A3-B61; A3-BS2; A3-B63; A3-B64; A3-B65; A3-B66; A3-B61; A3-B68; A3-B69; A3-B70; A3-B71; A3-B72; A3-B73; A3-B74; A3-B75; A3-B76;- A3-B77; A3-B78; A3-B79; A3-B80; A3-B8 1; A3-B82; A3-B83; A3-B84; A3-B85; A3-B86; A3-B87; A3-B88; A3-B89; A3-B90; A3-B9 1; A3-B92; A3-B93; A3-B94; A3-B95; A3-B96; A3-B97; A3-B98; A3-B99; A3-B100; A3-B1O1; A3-B102; A3 -B 103; A3-B 104; A3-B105; A3-B 106; A3 -B107; A3 -B10 8; A3 -B 109; A3-BI1O; A3-B111; A3-13112; A3 -B113; A3 -B 114; A3 -B 115; A3-B116; A3-B 117; A3-B 118; A3-B 119; A3-B1QO; A3-BI21; A3 -B 122; A3-BI23; A3-B124; A3-B125; A3-B126; A3-Bl27; A3-BI28; A3 -B 129; A3-B130; M3-B131; A3-B132; A3-B133; A3-B134; A3 -B 135; A3-B136; A3-B137; A3-B 13 8; A3-B139; A3-B140; A3-B 141; A3-B142; A3-Bl43; A3-B144; A3 -B 145; A3-B146; A3 -B 147; A3-B148; A3 -B 149; A3-B150; A3 -B15 1; A3-B 152; A3-BI53; A3-B154; A3 -B 155; A3-B156; A3-Bl57; A3-B159; A3-B159; A3-B160; A3 -B161; A3-1B162; A3-B163; A3-B164; A3-BI65; A3-B166; A3-B 167; A3-Bl68; A3-B169; A4-Bl; A4-B2; A4-B3; WO 031035065 WO 03/35065PCT/GB02/04763 -113- A4-B4; A4-B5; A4-B6; A4-B7; A4-B8; A4-B9; A4-B 10; A4-B 11; A4-BI2; A4-B13; A4-B 14; A4-B 16; A4-B 17; A4-B1S; A4-B 19; A4-B2O; A4-B21I A4-B22; A4-B23; A4-B24; A4-B25; A4-B26, A4-B27; A4-B28; A4-B29; A4-B30; A4-B3 1; A4-B332; A4-B3)3; A4-B34; A4-B35; A4-B36; A4-B37; A4-B38; A4-B39; A4-B40; A4-B41; A4-B42; A4-B43; A4-B44; A4-B45; A4-B46; A4-B47; A4-B48; A4-B49; A4-B50; A4-B51; A4-B52; A4-B51; A4-B54; A4-B55; A4-B56; A4-B57; A4-B58; A4-B59; A4-B60; A4-B61; A4-B62; A4-B63; A4-B64; A4-B65; A4-B66; A4-B67; A4-B68; A4-B69; A4-B70; A4-B71; A4-1B72; A4-B73; A4-B74; A4-B75; A4-B76; A4-B77; A4-B78; A4-B79; A4-B80; A4-BS1; A4-B82; A4-B83; A4-B84; A4-B85; A4-B86; A4-B87; A4-B88; A4-BR9; 4-0; A4-B9 1; A4-B92; A4-B93; A4-B94; A4-B95; A4-B96; A4-B97; A4-B98; A4-B99; A4-B 100; A4-B1O1; A4-B 102; A4-B 103; A4-B 104; A4-B105; A4-B 106; A4-Bl07; A4-B 108; A4-B 109; A4-BI1O; A4-Bl11; A4-B 112; A4-B 113; A4-B 114; A4B1; A4-B 116; A4-B 117; A4-B 118; A4-B 119; A4-B 120; A4-B121; A4-B 122; A4-B123; A4-B 124; A4-B125; A4-B 126; A4-B127; A4-B128; M4-B129;- A4-B 130; A4-B 13 1; A4-B3132; A4-B133; A4-B134; A4-B136; A4-B 137; A4-B138; A4-B 139; A4-B 140; A4-B1,41; A4-B 142; A4-B143; A4-B144; A4-B145; A4-B146; A4-B147; A4-B 148; A4-B149; A4-B 15 0; A4-Bl51; A4-B152; A4-B 153; A4-B 154; A4-B155; A4-B 15 6; A4-B157; A4-B158; A4-B 159; A4-B 160; A4-B161; A4-B 162; A4-B1t63; A4-B164; A4-B 165; A4-B166; A4-B167; A4-B168; A4-B169; A5-B1; A5-B2; A5-B3; A5-B4; A5-B5; A5-B6; A5-B7; A5-B8; A5-B9; A5-B1O; A5-Bl1; A5-B 12; A5-B13; A5-B14; A5-B15; A5-B16; A5-B17; A5-B 18; A5-B19; A5-B20; A5-B21; A5-B22; A5-B23; AX5-B24; A5-B25; A5-B26; A5-B27; A5-B28; A5-B29; A5-B30; A5-B31; A5-B32; A5-B33; A5-B34; A5 -B3 A5-B36; A5-B37; A5-B38; A5-B39; A5-B40; A5-B41; A5-B42; A5-B43; A5-B44; WO 031035065 PCT/GB02/04763 -114- A5-B45; A5-B46; A5-B51; fA5-B52; A5-B47; AS-B48; A5-B49; 1 -1 I- I- A5-B56; A5-B53; A5-B 54; A5-B55; AS-R57; A5-B58; A5-B59; A5-B60; A5-B61; A5-B62; A5-B63; A5-B64; A5-B65; A5-B66; A5-B67; A5-B68; A5-B69; A5-B70; A5-B71; A5-B72; A5-B73; AS )4; A5-B75; A5-B76; A5-B77; A5-B78; A5-B79; A5-Bg1; A5-B82; A5-B83; A5-B84; A5-B85; A5-B86, A5-BS7; A5-B 38; A5-B89; A5-B90; A5-B91; AS-B92; A5-B93; AS-B94; A5-B95; A5-B96; A5-B97; A5-B98; A5-B99; A5-BIOO; A5-BlOl; AS -B 102; A5-B103; A5-B 104; A5-Bl05; A5-B 106; AS -B 107; A5-BiOg; A5-B 109; A5-B 110; AS-Bill1; A5-B 112; ASX5-B1 13; A5-B 114; AS -B 11; A5 -B 116; AS -B 117; A5-B 118; A5 -B 119; A5-B120; A5-B121; A5-B 122; A5-B123; A5-B 124; A5-B 125; A5-B126; A5-B127; A5-B 128; A5-B129; A5-B130; A5-B 13 1; A5-B132; A5-B133; A5-B134; AS -B13 5; A5-B136; A5-B 137; A5-B138; AS -B 139; A5-B140; A5-B141; A5-B142; A5-B 143; AS-B144; A5-B 145; A5-B146; 147; AS-B 148; A5-B 149; A5-B150; AS -Bi15i; AS-B152; 153; A5-B154; A5-B3155; A5-B156; AS -B 157; A5-B158; A5-B159; AS-B160; A5-B161; A5-B162; A5-B 163; AS -B 164; AS-B 165; A5-B166; A5-B167; A5-B168; A5-B169; A6-Bl; A6-B2; A6-B3; A6-B4; A6-B5; A6-B6; A6-B7; A6-B8; A6-B9; A6-B1O; A6-Bll; A6-B12; A6-B13; A6-B14; A6-B20; A6-B26; [A6-B32; A6-B 15;

A&-B;

A6-B16; A6-B 17; A6-Bl8; AO-:51v; J 1 -I A6-B22; A6-B23; A6-B24; A6-B25; IL Ii A6-B27; A6-B33; A6-B28; A6-B29; A6-B30; A6-B3 1; I I- -w A6-B34; A6-B35; A6-B3 6; A6-B37; A6-B38; A6-B3-9; A6-B40; A6-B41; A6-B42; A6-B43; A6-B44; A6-B45; A6-B46; A6-B47; A6-B48; A6-B49; A6-B5l; A6-B52; A6-B53; A6-B54; A6-B55; A6-B56; A6-B57; A6-B58; A 6-B59, A6-B60; A6-B61; A6-B62; A6-B63; A6-B64; A6-B65; A6-B66; A6-B67; A6-B68; A6-B69; A6-B'70; A6-B71; A6-B72; A6-B73; A6-B74; A6-B75; A6-B76; A6-B77; A6-B78; A6-B79; A6-B80; A6-B81; A6-B82; A6-B83; A6-B84; A6-B85; WO 031035065 WO 03/35065PCT/GB02/04763 -115- A6-B86; A6-B87; A:6-B88; A6-B89; A6-B90; A6-B91; A6-B92; A6-B93; A6-B94; A6-B95; A6-B96)- A6-B97; A6-B98; A6-B99; A6-B 100; A6-B 101; A6-B 102; A6-B 103; A6-B 104; A6-B105; A-B 106; A6-B107; A6-B 108; A-B 109; A6-B11O; A6-B 111; A6-B 112; A6-B 113; A-B 114; A-B 115; A6-B 116; A6-B117- A-B 118; A6-B 119; A6-B120; A6-B 12 1; A6-B 122; A6-B123; A6-B 124; A-B 125; A-B 126; A6-B127; A6-B128; A6-B129; A6-B 130; A6-B131; A6-B132; A6-B133; A6-B134; A6-B 135; A6-B136; A-B 137; A6-B 13 8; A6-B139; A6-Bt40; A6-B 14 1; A6-B 142; A6-B 143; A6-B144; A6-B145; A6-B 146; A6-B147; A6iB148; A6-B149; A6-B150; A6-B 15 1; A6-B152; A6-B153; A-B 154; A6-B155; A6-B156; A6-B 157; A6-B158; A6-B159; A-B 160; A6-BI61; A-B 162; A-B 163; A6-B164; A6-BI65; A-B 16 6; A6-B 167; A6-B168; A6-B 169; A7-B1; A7-B2; A7-B3; A7-B4; A7-B5; A7-B6; A7-B7; A7-B8; A7-B9; A7-B1O; A7-Bl1; A7-B 12; A7-B13; A7-B 14; A7-B15; A7-B 16; A7-B17; A7-B1 S; A7-B 19; A7-B20; A7-B2 1; A7-B22; A7-B23; A7-B24; A7-B25; A7-B26; A7-B27; A7-B28;1 A7-B29; A7-B30; A7-B3 1; A7-B32; A7-B33; A7-B34; A7-B35; A7-B36; A7-B37; A7-B38; A7-B39; A7-B40; A7-B4 1; A7-B42; A7-B43; A7-B44; A7-B45; A7-B46; A7-B47; A7-B48; A7-B49; A7-B50; A7-B5 1; A7-B52; A7-B53; A7-B54; A7-B55; A7-B56; A7-B57; A7-B58; A7-B59; A7-B60; A7-B61; A7-B62; A7-B63; A7-B64; A7-B65; A7-B66; A7-B67; A7-B68; A7-B69; A?-B70; A7-B71; A7-B72; A7-B73; A7-B74; A7-B75; A'7-B76; A7-B77; A7-B78; A7-B79; A7-B80; A7-B81; A'7-B82; A7-B83; A7-B84; A7-B8-5; A7-B86; A7-B87; A-7-B88; A7-B89; A7-B90; A7-B91; A7-B92; A7-B93;- A'7-B94; A7-B95; A7-B96; A7-B97; A7-B98; A7-B99; A7-B100; A7-B1O1; A7-B 102; A7-B 103; A7-B 104; A7-B 105; Ali-B 106; A7-B107; A7-B 108; A7-B 109; A7-B11O; A7-B tI1; A7-B 112; A7-B 113; A7-B 114; A7-B 115; A7-B 116; A7-B 117; A7-Bl18; A7-B 119; A7-B 120; A7-B121; A7-B122; A7-BI23; A7-B 124; A7-B125; A7-B 126; WO 031035065 WO 03/35065PCT/GB02/04763 -116- A7-B127; A7-B 128; A7-D129; A7-B130; A-B 13 1; A7-B 132; A7-B133; A7-B 134; A7-B135; A7-B 13 6; A7-B137;- A7-Bt38; A7-BI39; A7-B 140; A7-B141; A7-B 142; A7-B143; A7-B t44; A7-B145; A7-B 146; A7-B 147, A7-B 148; A7-B 149; A7-B 150; A7-B151; A7-B 152; A7-B 153; AX7 -B1 54; A7-B 155; A7-BI56; A7-B 157; A7-B158; A7-B 159; A7-B160; A7-BI61; A7-B162; A7-B 163; A7-B 164; A7-B 165; A7B A'7-B167; A7-B168; A7-B 169; AS-BI; A8-B2; A8-B3; A8-B4; A8-B6; AR-B7; A8-B8; A8-B9; A8-B1O; AS-Bli; AS-B 12; AS-B13; A8-B 14; AS-B15; A8-B 16; A8-B17; A8-B 18; AS-B19; A8-B20; A8-B2 1; Ag-B22; A8-B23; A8-B24; AS-B25; AS-B26; A8-B27; A8-B28; A8-B29; A8-B30; AS-B3 1; A8-B32; A8-B33; A8-B34; A8-B35; A8-B36; A8-B37; A8-B38; A8-B39; A8-B40; A8-B4 1; A8-B42; A8-B43; A8-B44; A8-B45; A8-B46; A8-B41; A8-B49; AS-B49; A8-B50; A8-B5 1; Ag-B52; A8-B53; A8-B54; A8-B55; A8-B56; A8-B57; Ag-B58; A8-B59; A8-B60; A8-B6 1; A8-B62; AS78-B63; Ag-B64; A8-B65; A8-B66; A8-B67; A8-B68; A8-B69-; A8-B70; A8-B71; A8-B72; A8-B73; Ag-B74; A8-B75; AS-B76; A8-B77; A8-B78; A8-B79; AS-B80; A8-B831; A8-B82; A8-B83; A8-B84; A8-B85; A8-B86; A8-B87; A8-B88; A8-B89; A8-B90; A8-B91; A8-B92; A8-B93; A8-B94; A8-B96; A8-B97; A8-B98; A8-B99; A8-B100; AS-Bl10 A8-B102; A8-B103; A-B 104; AS8-B105; A8-B106; A8-B 107; A8-B108; A8-B109; A8-BI110; A8-BIll1; A8-B 112; A-B 113; A-B 114; AS-B115; A-B 116; A8-B 117; AS-Bi11; A8-B 119; Ag-B 120; AS-B 12 1; A8-B 122; A8-B123; A8-B 124; AS-B125; A8-B126; A8-B127; A-B 128; A8-B129; A8-B 130; AS-B 13 1; A8-B 132; A8-B133; A-B 134; A-B 13 5; AS-B136; A8-B137; Ag-B138; AS-B139; A8-B 140; A8-B141; A-B 142; A8-B143; A8-B 144; A8-B145; A8-B 146; A8-B147; A-B 148; A8-B 149; A8-Bl50; AS-B151; AS-B 152; AS8-BI53; AS-B 154; A8-B155; A-B 156; A8-B157; A8-B158; AS-B159; A8-B 160; AS-B161; A8-B162; AS-B163; A8-B 164; A8-B165; A8-B166; AS-B167; WO 031035065 WO 03/35065PCT/GB02/04763 -117- AS-B 168; A8-B 169; A9-Bl; A9-B2; A9-B3; A9-B4; A9-B6; A9-B7; A9-B8; A9-B9; A9-B A9-B 11; A9.-B 12; A9-B13); A9-B 14; A9-B15; A9-B 16; A9B1; 9-18; A-19; AB2; A9-B2 1; A9-B22; A9-B23; A9-B24 A9-B25 A9-B20; A9B7A-B8 A9-B29; A9-B30; A9-B21; A9-B2; A9-B33; A9-B24; A9-B35; A9-B36; A9-B371; A9-B38; A9-B39; A9-B34; A9-B41; A9-B42; A9-B3; A9-B44; A9-B45; A9-B40; A9-B47; A9-B42; A9-B43; A9-B44; A9-B5; A9-B52; A9-B53; A9-B4; A9-B56; A9-3571; A9-B52; A9-B59; A9-B60; A9-B655; A9-B56; A9-B53; A9-B64; A9-B5;1 A9-B60; A9-B67; A9-B68; A9-B69; A9-B70; A9-B71; A9-B72; A9-B7; A9-B74; A9-B69; A9-B70; A9-B717; A9-B78; A9-B79; A9-B70; A9-B71 A9-B82; A9-B83; A9-B8; A9-B79; A9-B80; A9-B87; A9-B82; A9-B83; AD-B90; A9-B91; A9-B92; A9-B93; A9-B94; A9-B9; A9-B90; A9-B91; A9-B98; A9-B93; A9-B10; A9-B1O; A9-B102; A9-B10; A9-Bl0; A9-B10; A9-B106; A9-B1; A9-B 102; A9-B 103; A9-B11O; A9-B 105; A9-B112; A9-B 107; A9-B114; A9-B115; A9-B116; A9-B I11; A9-B 112; A9-B 113; A9-B 114; A9-B 115; A9-B 116; A9-B 117; A9-B1184; A9-B 119; A9-B126; A9-B 1271; A9-B122; A9.-B123; A9-B 124; A9-B131; A9-B26; A9-B 127; A9-B134; A9-B135; A9-B 130; A9-B 1371; A9-B138; A9-B139; A9-B14; A9-B135; A9-B 136; A9-B13; A9-B144; A9-B 139; A9-B1406 A9-B1; A9-B 142; A9-B149; A9-B150; A9-B45; A9-B142; A9-B153; A9-B48; A9-B155; A9-B156; A9-BI17; A9-B158; A9-B159; A9-B 154; A9-B161; A9-B56; A9-B163; A- 9-B164; A9-B59; A9-B 160; A9-B167; A9-B168; A9-B 163; Al-Bi6; Al-B26; A1-B36; Al-B46; A1-B56; Al-B16; AlO-BI; AlO-B8; A1O-B9; AI-B; IOB5 AO-6; AI-B; A1-BS1; AIO-Bl; AIO-B1O; 16; AIO-Bil; Al10-B 17; Al0-B 12; A1O- 18;, A10-B 13; A10-B 19; AIO-B20; A10-B2 1; A1O-B27;

I

i

I

AIO-B22; AIO-B28;9 Al 0-B23; A10-B29; Al 0-B24; Al 0-B30; AlO-B25; AlO-B31; AlO-B 7; A1O-B26; Al 0-B 32; Al 0-B3 8; Al O-B3 3; Al 0-B39; Al 0-B34; A1O-B3 5; A10-B36; I WO 031035065 WO 03/35065PCT/GB02/04763 -118- A1O-B40; A1IO-B4 1; A1O-B42; A1O-B43; A1O-B44; A1O-B45; AIO-B46; A1O-B47; A1O-B48; A1O-B49; A1O-B50; A1O-B51; A1O-B52; A1O-B53; A1O-B54; A1O-B55; A1O-B56; AIO-B57; A1O-B58; AIO-B59; A1O-B60; A1O-B61; A1O-B62; A1C-B63; A1O-B64; AIO-B65; A10-B366; A1O-B67; A1O-B68; AIO-B69; AtO-B71; A1O-B72; A1O-B73; AIO-B74; A1O-B75; A1O-B76; A1O-B77; A1O-B78; A1O-B79; A1O-BS0; A1O-B81; AlO-B82; AIO-B83; A1O-B84; A1Q-B85; A1O-B86; A1O-B87; AlO-B88; A 104389; A1O-B90; A1O-B91; AI0-B92; AtO-B93; A1IO-B 94; A1O-B95; A1O-B96; A1O-B97; ATO-B98; A1O-B99; AlO-BIGO; AlO-BlOl; A1O-B102; A1O-B103; AlO-B104; AlO-BlOS; A1O-B106; A1O-B107; A1O-B108; A1O-B109; AlO-BIlO; AlO-Blil; AlO-BI 12; AI1O -Bi 1 AlO-BI 14; AlO-BI15; AlO-Bi 16; AlO-BI 17; AlO-BIlS; A1O-B119; A1O-B120; A1O-B121; A1O-B122; A1O-B123; AIO-B194; A10-B 125; AIO-B126; A1O-B 127; AIO-B128; A1O-B129; A1O-Bi.3O; A1O-B131; A1O-B132; A1O-BI33; AIO-B134; A1O-B135; AlO-B136; A1O-B137; AIO-B138; A1O-B139; A1O-B140; A1O-B141; AIO-B142; A1O-B143; A1O-B144; A10-B145; A1O-B146; Al1O-B 147; AIO-BI48; A10-B149; AlO-BiSO; A1O-B151; A1O-B152; A1O-B153; A1O-B154; AlO-BiSS; A1O-B156; A10-B157; A1O-BI58; AlO-B159; A10-B160; A1O-B161; AlO-B162; A10-B163; AIO-B164; AlO-B165; A1O-B166; A10-B167; A1O-B168; AlO-B169; All-Bi; A11-B2; Al1-B3; A11-B4; A11-B5; Al11-B6; Al1-B7; Al1I-BS; All-B9; Al 1-BlO; Al 1-fll; AllI-B12; Atl-B13; All-B14; Al1-B15; All-B16; Al1-B17; Al1-B18; All-B19; Al1-B20; All-B21; Al1-B22; Al 1-B23; AlI1-B24; Al1-B25; Al1-B26; All-B27; Al1I-B28; A 11 -B29; A11-B30; A11-B31; Al1-B32; A11-B33; Al1I-B34; Al1I-B35; A11-B36; Al11-B37; A11-B38; A11-B39; Al1-B40; Al I-B41; A11-B42; Al1I-B43; A11-B44; A11-B46; Al1I-B47; A11-B48; Al1-B49; Al1-B50; Al1-B51; A11-B52; Al11-B53; A11-B54; All-B55; AI1-B56; Al1-B57; A11-B58; Al1I-B59; A11-B60; All-B61; A11-B62; Al11-B63; A11-B64; Al1I-B65; All-B66; Al1I-B67; All-B68; Al 1-B69; All-B70; Al1-B71; All-B72; Al11-B73; Al -B74; A11-B75; Al1-B76; Al 1-B77; A11-B78; Al 1-B79; Al1-B80; WO 031035065 WO 03/35065PCT/GB02/04763 -119r .1 All-B81; A11-B87; All-BS2;- Al 1-B88; Al 1-B83; Al 1-B89; Al l-B84; Al I-B90; All -B85; All -B9 I; Al 1-B 86; Al l-B92; A l I-B93; AlI-B94; Al1-B95; Al1I-B96; All-B97; Al -B98; All-B99; All-BOG; All-BI0l; All-B102; All-B103; All-B104; All-B105; Al1-B106; All-B107; All-BiOS; All-B109; All-BIlO; All-Bill; All-B112; Al1-BI13; Al1-B114; All-Bll5; All-B116; AlI-B117; All-BI18; All-B119; All-B120; All-B121; All-B122; All1-B123; Al l-B124; All-B125; All-B126; Al l-B127; Al l-B128;- All-B129; All-B130; All-B131; All-B132, All-B133; All-B134; All-B135; Atl-B136; All-B137; Atl-B138; Al1t-B139; AlI-B140; A]1-B141; Atl-B142; All-Bl43; All-B144; All-B145; All-B146; AlI-B147; Al1-B 148; A11-B149;- All-B150; All-B151; Al1-BI52; All-B153; Al1-B3154; All-B155; All-B156; AllI-B157; All-B158; Al1-BI59; AlLI-B 160; All-B161; All-B162; All-B163; All-B164; All1-B 166; Al l-B167; All1-B 168; All-B169; A12-Bl; A12-B2; A12-B3; A12-B4; A12-B5; A12-B6; A12-B7; A 12-B 8; A12-B9; A12-BlO; A12-Bl1; A12-B12; A12-B13; A12-B14; A12-B 15; A12-B16; A12-B17; A12-B18; A12-B19; A12-B20; A12- 321; A12-B22 A12-B23; A12-B24; A12-B25; A12-B26; A12-B27; A12-B28; A12-B29; A12-B30; A12-B31; A12-B32; A12-B33; A12-B34; A12-B35; A12-B36; A12-B37; A12-B-8 A12-B39; A12-B40; A12-B41; A12-B42; A12-B43, A12-B44; A12-B45; A12-B46; A12-B47; A12-B48; A12-B49; A12-B50; A12-B51; A12-B52; A12-B53; A12-B54; A12-B55; A12-B56; A12-B57; A12-B58; A12-B59; A12-B360; A12-B61; A12-B62; A12-B63; A12-B64; A12-B65; A12-B66; A12-B67); A12-B68; A12-B69; A1-7; A12-B71; A12-B72; A12-B73; A12-B74; A12-B75; A12-B76; A12-B77; A12-B78; A12-B79; A12-B8O; A12-B81; A12-B382; A12-B83; A12-B84; A12-B85; A12-B86; A12-B87; A12-B88; A12-B89; A12-B90; A12-B9 1; A12-B92; A12-B93; A12-B394; A12-B95; A12-B96; A12-B97; A12-B98; A12-B99; A12-BlOO; A12-B1Ol; A12-BI02; A12-B103; A12-B104; A12-BI05; A12-BI06; A12-B107; A12-BIOS; A12-B109; A12-Bl1O; A12-Blll; A12-B112; A12-B 113; A12-B114; A12-Bl A12-BI16; A12-B 117; A12-B118; A12-B119; A12-B120; A12-B121; WO 031035065 WO 03/35065PCT/GB02/04763 -120- A12-B122; A12-B123; A12-BI24; A12-B125; A12-B126; A12-BI27; A12-B128; A12-B129; A12-B130; A12-B131; A12-B 132; A12-B133; A12-B134; A12-B135; A12-B 136; A12-B137; A12-B138; A12-BI39-; A12-B140; A12-B141; A12-B142; A12-B143; A12-B144; A12-B145; A12- 3146; A12-B 147; A12-B 148; A12-B149; A12-B 150; A12-B15 1; A12-B 152; A12-B153; A12-B154; A12-B155; A12-B156; A12-B157; A12-B158; A12-B159; A12-B160; A12-B161; A12-BI62; A12-B163; A12-B164; A12-B165; A12-B166; A12-BI67; A12-BI68; A12-B169; A13-BI; A13-B2; A13-B3; A13-B4; A13-B35; A13-B6; A13-B7; A13-B38; A13-B39; A13-B310; A13-B311; A13-B12; A13-B13; A13-B14; A13-B15; A13-B316; A13-B17; A13-B18; A13-B19; A13-B20; A13-B21; A13-B22% A13-B23; A13-B24; A13-B25; A13-B26; A13-B27; A13-B28; A13-B29; A13-B30; A13-B31; A13-B32; A13-B33; A13-B34; A13-B335; A13-B36; A13-B37; A13-B38; A13-B39; A13-B40; A13-B41; A 13 -B42; A13-B43; A13-B44; A13-B45; A13-B346; A13-B47; A13-B48;1 A13-349; A13-B50; A13-B51; A13-B52; A13-B53; A13-B54; A13-B55; A13-B56; A13-B57; A13-B58; A13-B59; A13-B60; A13-B61; A13-B62; A13-B63; A13-B64; A13-B65; A13-B66; A13-B67; A13-B68; A13-B69; A13-B70; A13-B371; A13-B72; A13-B73; A13-B74; A13-B75; A13-B76; A13-B77; A13-B78; A13-B79; A13-B80; A13)-B81; A13-B82; A13-B83; A13-B84; A13-BS5; A13-B86; A13-B87; A13-B88; A13-B89; A'13-B90; A13j-B9 1; A13-B92; A13-B93; A13-B94; A13-B95; A13-B96; A13-B97; A13-B98; A13-B99; A13-B100; A13-BIO1; A13-B102; A13-B103; A13-B104; A13-B105; A13-B106; A13-B3107; A13-B108; A13-B109; A13-BIl10; A13-B111; A13-B112; A13-BI13; A13-Bl114; A13-13115; A13-31 16; A13-31171; A13-B1 18; A13-B119; A13-B120; A13-B121; A13-B122; A13-B123; A13-B124; A13-B125; A13-BI26; A13-B127; A13-BI28; A13-B129; A13-B130; A13-B131; A13-B132; A13-B133; A13-B3134; A13-3135; A13-B136; A13-B137; A13-B138; A13-B 139; A13-B 140; Al 3-B 14 1; A13-BI42; A13-BI43; -I I- -t A13-B 149; A13-B145; jA13-B146; A13-B151; A13-B3152; A13-B157; A13-B158; A13-B147; Al 3-B 148; A13-B153; 1A13-B154; A13-3159; A13-B3160; AlI 3-B -150; Al 3-B 156; A1-BB162; A13-B155; Al 3-B 161; WO 031035065 WO 03/35065PCT/GB02/04763 -121-

I

A13-B163; Al 3-B 169; A14-B36; A 14-B 12; Al 3-B 164; A13-B 165; A13-B 166; A13-B167 A1-B168;, I r i A14-B1; A I4-B'7; A14-B2; A14-B8; A14-B3; Al 4-B 9; A14-B4; A14-B 10; Al 4-B A14-B 11; A1I4-B 17; A14-B 13; A14-B 14 A14-B1 5; A14-B 16;

I

A14-B3181 A 14-B 19; A14-B20; A14-B21; A14-B22; A14-B23; A14-B24; A14-B25; A14-B26; A14-B27; A14-B28; A14-B29; A14-B30; A14-B31; A14-B32; A14-B33; A14-B34; A14-B35; A14-B36; A 14 -B 37-; A14-B3M; A14-B09; A14-B4W; A14-B41; A 14-B342; A14-B43; A14-B44; A14-B45; A 14-B46; A14-B47; A14-B48; A14-B49; A14-B50; A14-B51; A14-B52; A14-B53; A14-B54; A14-B55; A14-B56; A14-B57; A14-B58; A14-B59; A14-B60; A14-B61; A14-B62; A14-1363; A14-B64; A14-B65; A14-B66; A14-B67; A14-B68; A14-B69; A14-B70; A14-B71; A14-B72; A14-B73; A14-B74; A14-B75; A14-B76; A14-B77; Ald1-B78; A14-B79; At4-BSO0 A14-B81; A14-B82; A14-B83; A14-B84; A14-B85; A14-B86; A14-B87; A14-B88; A14-B89; A14-B90; A14-B91; A14-B92; A14-B93; A14-B94; A14-B95; A14-B96; A14-B97; A14-B98; A14-B99; A14-BiOO0; A14-B101, A14-B 102; A14-B103; A14-B104; A14-B105; A14-B106; A14-B107; A14-B108; A14-B109; A14-B11O; A14-B11I; A14-B3112; A 14-B 113; A14-B1 114; A14-B1 15; A14-Bl 16; A1 l4 -B 117; A14-B 118; A14-BI 19; A14-B120; A14-B121; A14-B122; A14-B123; A14-B3124; A14-B125; A14-B126; A14-B127; A14-B128; A14-B129; A14-B130; A14-B131; A14-B132; A14-BI33; A14-B 134; A14-B135; A14-B136; A14-B137; A14-B138; A14-B139; A14-B140; A14-B141; A14-B142; A14-B143; A14-B144; A14-BI45; A14-B146; A14-B147; A14-B148; A14-B149; A14-B150; A14-B 151; A14-B152; A14-B 153; A14-BI54; 1 A14-B155; A 14-B 156; A14-B162; A 14-B 168; A15-B5; AlS-Bil; A14-B 157; A14-B 158; A14-B 159; A14-BI60; I -b 1 I A14-B167; A14-B163; A14-B 169; A14-B164; A14-B165; A14-B166; L -I 1 Al 5-B 3; Al 5-B 1; Al 5-B 2; Al 5-B3; AlS i A15-B17; A15-B23; A15-B29; Al 5-B 6; Al 5-B 12; Al15-B 18; A15-B24; Al 5-B30; A15-B7; Al 5-B 13; Al15-B 319; Al 5-B 8; A15-B9 A15-B14; A15-B15; AlS 3-20; A15-B21; 1A15-B22; A15-134; AlS-BIO; Al 5-B 16; A15-B325; 1 A5-B26; A15-B31; 1A15-B32; A15-B27; Al 5-B3 3; A15-B28; Al 5-B34; WO 031035065 WO 03/35065PCT/GB02/04763 -122- A15-B35; A15-B36; A15-B37; A15-B38; A15-B39; Al15-B40; A15-B41; A15-B42; A15-B43; A15-B44; A15-B45; A15-B46; A15-B47; A15-B48; A15-B49; A15-B50; A15-B51; A15-B52; A15-B53; A15-B54; A15-B55; A15-B56; A15-B57; A15-B58; A15-B59; A15-B60; A15-B61; A15-B62; A15-B63; A15-B64; A15-B65; A15-B66; A15-B67; A15-B68; AI5-B69; A15-B70; A15-B71; A15-B72; A15-B73; A15-B74; A15-B75; A15-B76; A15-B77; A15-B78; A15-B79; A15-B80; A15-B81; A15-B82; A15-B83; A15-B84; A15-B85; A15-B86; A15-B87; A15-B88; A15-B89; A15-B90; A15-B91; A15-B92; A15-B93;, A15-B94; A15-B95; A15-B96; A15-B97; A15-B98; A15-B99; A15-B100; A15-B1O1; A15-B102,1 A15-B103; A15-B104; A15-B105; A15-B106; A15-3107; AI-B1OS; A15-B109; A15-B11O; A15-B111; A15-B112; A15-B113; A15-B114; A15-B15 A15-BI16; A15-BI17; A15-B1S; A15-B119; A15-B120; A15-B121; A15-B122; A15-B123; A15-BI24; A15-B125; A15-B126; A15-B127; A15-B128; A15-B129; A15-B130; A15-B131; A15-.B132; A15-B133; A15-B134; A15-B135; A15-B136; A15-B137; Al 5-313 8; A15-B139; A15-B140; AIS-B141; A15-B142; A15-BI43; A15-B144; A15-B145; A15-B146-; A15-BI47; A15-B148; A15-B149; A15-B150; A15-B151; A15-B152; A15-B153; A15-B154; A15-B155; A15-B156; k15-B157, A15-BI58; A15-B159; A15-B160; A15-BI61; A15-B162; A15-B163; A15-B164; A15-B165; A15-B166; A15-B167; A15-B168; A15-B169; A16-B1; A16-B2; A16-B3, A16-B4; A16-B5; A16-B6; A16-B7; A16-BS; A16-B9; A16-B1O; A16-Bl1; A16-B12; A16-B13; A16-B14; A16-B15; A16-B16; A16-B17; A16-B18; A16-B19; A16-B20; A16-B21; A16-B22; A16-B'23; A16-B24; A16-B25; Al 6-B26; A16-B27; A16-B28; A16-B29; A16-B30; A16-B31; Al16-B32; A16-B33; A16-B34; A16-B35; A16-B336; A16-B37; A16-B38; A16-B39; A16-B40; A16-B341; A16-B42; A16-B43; A16-B44; A16-B45; A16-B46; A16-B47; Al 6-B48; A16-B49; A16-B50; A16-B5 1; A16-B52; A16-B53; A16-B54; A16-B55; A16-B56; A16-B57; A16-B58; A16-B59; A16-B60; A16-B61; A16-B62; A16-B63; A16-B64; A16-B65; A16-B66; A16-B67; A16-B68; A16-B69; A16-B70; A16-B71; A16-B72; A16-B73; A16-B74; A16-B75; WO 031035065 WO 03/35065PCT/GB02/04763 -123- A16-B76; A I6-B77; A16-B78; A16-B79; A16-B80; A16-B81; Al16-B82; A16-B83; A16-B384; A16-B85; A16-B86; A16-B87; A16-B88; A16-B89; A16-B90; A16-B91; A16-B92; A16-B93; A16-B94; A16-B95; A16-B96; A16-B97; A16-B98; A16-B99; A16-B100; A16-B1O1; A16-B 102; A16-B103; A16-B104; A16-B105; A16-B106; A16-B107; A16-B1OS; Al16-B 109; A16-B11O; Al16-B I11; A16-B112; A16-B113; Al16-B 114; A16-B1 15; A16-BI16; A16-B1 17; A16-B1S; A16-B119; A16-B120; A16-B121; A16-B122; A16-B123; Al16-B124; A I6-B 125; A16-B126; A16-B127; A16-B128; A16-B129; A16-B130; A16-B131; A16-B132; A16-B133; A16-B134; A16-B135; A16-BI36; A16-B137; A16-B138; A16-B139; A16-B140; A16-B141; A16-BI42; A16-BI43; A1l6 B 4 4; A16-B145; A16-B146; A16-B147; A16-B148; A16-B149; A16-B150; A16-B151; A16-B152; A16-B153; A16-B154; A16-B155; A16-BI56; A16-B157; A16-B158; A16-B159; A16-B160; Al 6-Ri 61; AX16 -B16 A16-BI63; A16-B164; A16-B165; A16-BI66; A16-B167; A16-B168; A16-B169; A17-B1; A17-B2; A17-B3; A17-B4; A17-B5; A17-B6; A17-B7; A17-B8; A17-B9; A17-B1Q; A17-B11; A17-B12; A17-B13; A17-314; A17-B15; A1'7-B16; A17-B17; A17-B18; A17-B19; Al 7-B20; A17-B21; A17-B22; A17-B23; A17-B24; A17-B25; A17-B26; A17-B27; A17-B28; A17-B29; A17-B30; A17-B31; A17-B32; A17-B33; A17-B34; A17-B35; A17-B36; A17-B37; A17-B38; A17-B39; A17-B40; A17-B41; A17-B42; A17-B43; A17-B44; A17-B45; A17-B46;- A17-B47; A17-B48; AI'7-B49; A17-B50; A17-B5 1; A17-B52; A17-B53; A17-B54; A17-B55; A17-B56; A17-B57; A17-B58; A17-B59; A17-B60; A17-B61; A17-B62; A17-B63; A17-B64; A17-B65; A17-B66; A17-B67; A17-B68; A17-B69; A17-B70; A17-B7 1; A17-B72; A17-B73; A17-B74; A17-B75; A17-B76; A17-B77; A17-B78; A17-B79; A17-B8O; A17-B8I; A17-B82; A17-B83; A17-B84; A17-B85; A17-B86; A17-B87; A17-B88; A17-B89; A17-B90; A17-B91; A17-B92; A17-B93; At7-B94; A17-B95; A17-B96; A17-B97; A17-B98; A17-B99; A17-BI00; A17-B1O1; A17-B102; A17-B103; A17-B104; A17-B105; A17-B106; A17-B107; A17-B108; A17-B109; A17-BI A17-Bl11; A17-B112; A17-B113; A17-B114; A17-B115; A17-B116; WO 031035065 WO 03/35065PCT/GB02/04763 A17-B117; Al17-B 118; A17-B119; A17-B120; A17-B121; A17-B122; A17-B 123; Al 7-B 124; A17-B 125; A I7-B 126; A17-B 127; A1l 7-B 2 8; A17-BI29; A17-B130; A17-B131; A17-BI32; A17-BI33; A17-B134; A17-B 135; A17-B136; A17-B 137; A17-B138; A17-B139; Al17-B 140; A17-B141; A17-B142; A17-B143; A17-B144; A17-B145; A17-B146; A17-BI47; AI7-3148; A17-B149; A17-B1SO; A17-B151; A17-B152; A17-BI53; A17-B154; A17-B155; A17-B156; A17-B157; A17-B158; A17-Bt59; A17-B160; A17-Bt61; A17-BI62; A17-B163; A17-B164; A17-B165; A17-B166; A17-13167; Al')-B168; A17-B169; AlS-Bi; A18-B2; A18-B3; A18-B4; A1S-B5; A18-B6; A18-B7; A18-BS; A18-B9: AlS-BIO; A18-B11; A18-B12; A1S-B13; A18-B14; Al18-B 15; A18-B16; Al18-B 17; AI8-B18; A18-B19; A18-B20;, A18-B21; A1S-B22; Al18-B23; A18-B24; A18-B25; A18-B26; A18-B27; AIS-B28; A18-B29; A18-B30; A18-B31; A18-B32; A18-B33; A I -B34; A18-B35; A18-B36; Al 8-B37; A18-B38; A18-B39; A18-B40; A18-B41; A18-B42; A18-B43; A1S-B44; Al18-B45; A18-B46; A18-B47; A18-B48; A18-B49; A18-B51; A18-B52; A18-B53; A18-B54; A18-B55; A18-B56; Al8-B357; A18-B58; A18-B59; A18-B60; A18-B61; A18-B62; A18-B63; A18-B64; A18-B65; A18-B66; A1S-B67-) A1S-B68; A18-B69; AIS-B70; A18-B71; A18-B72; A18-B73; A18-B74; Alg-B75; ATS-B76; AIS-B77; A18-B78; A18-B79; A18-fl8O; AI8-B81; A18-B82; A1S-B83; A18-B84; A18-B86; AIS-BS7; A18-B88; A18-B89; A18-B90; AIS-B91; Al 8-B92; A18-B93; A18-B94; -A-1-B95; A18-B96; A18-B97; A18-B98; A18-B99; A18-BIOO; A18-B1O1; Al18-B 102; A18-B103;- A18-B104; A18-B105; Al18-B 106; A18-B107; Al 8-B 108; A18-B109, A18-BI1O; A18-B111; A18-B112; A18-3113; Al1S-B 114; AlS-BilS; A18-B116; A18-B1 17; A18-B118; A18-B1 19; A18-B120; A18-B121; A18-B122; A18-B123; A18-B124; A18-3125; A18-B126; A18-B127; A18-B128; AlS-B129; A1S-B130; A18-B131; A18-B132; A18-B133; Atg-B134; A18-B135; A18-B136; A18-B137; A18-B138; A18-B139; A18-B140; A18-B141; A18-B142; A18-B143; A18-B144; A18-B145; A18-B146; A18-B147; A18-B148; A18-B149; A18-BI50; Al 8-B151; At 8-B 152; Al18-BI153;1 A18-B154; Al 8-B 155; A18-B156; A18-B157; I J WO 031035065 WO 03/35065PCT/GB02/04763 -125- Al18-B 158; A18-B 164; A19-B1; A19-B7; A18-B159; A18-B 160; AlB-B 161; A18-B 162; .1 1 F A18-B165; A19-B2; A18-B 166; A18-B167; A18-B 168; Al 8-B 163; A18-B169; Al 9-B6; A19-B12; I r A19-B3); A19-B4; A19-B5; 1A19-B8; -t t F Al 9-B 9; A19-B 10; A19-B 11; A19-B13; A19-B14; A19-B15; A19-B1 6; ~A19-Bt7; A19-B18; A19-B19; A19-B20; A19-B21; A19-B22; ~A19-B23; A19-B24; A19-B25; A19-B26; A19-B27; A19-B28; A19-B29; A19-B30; A19-B31; A19-B32; A19-B33; A19-B34; A19-B35; A19-B36; A19-B37; A19-B38; A1I9-BI9; A19-B40; A19-B41; A19-B42; A19-B43; A19-B44; A19-B45; A19-B46; A19-B47; A19-B48;- A19-B49; A19-B50; A19-B51; A19-B52; A19-B53; A19-IB54; A19-B355; A19-B356; A19-B57; A19-B358; A19-B359; A19-B60; A19-B61; A19-B62; A19-B63; A19-B64; A19-B65; A19-B66; A19-B67; A19-B68; A19-B69; A19-B70; A19-B71; A19-B72; A19-B73; A19-B74; A19-B75; A19-B76; A19-B77; A19-B78; A19-B79; A19-B80; A19-B81; A19-BS2; A19-B83; A19-B84; A19-B85; A19-B86; A19-B87; A19-B88; A19-B89; A19-B90; A19-B91; A19-B92; A19-B93; A19-B94; A19-B95; A19-B96; A19-B97; A19-B98; A19-B99; A19-B10 A19-B1O1; A19-B102; A19-B103; A19-B104; A19-B105; A19-B106; A19-B107; A19-B1OS; A19-B109; A19-B11O; A19-Bl111; A 19-Bl112; A19-B3113; A19-B 114; A19-B1 15; A19-B116; A19-B117; A19-B1 18; Al19-B 119; A19-B120; A19-B121; A19-B122; A19-B123; A19-B124; A19-B125; A19-B126; A19-B127; A19-B128; A19-B129; A19-B130; Al19-B 13 1; A19-B132; A19-B133; A19-B134; A19-B135; A1l9-B136; A19-B137; A19-B138; A19-B139; A19- 1-40;- A19-B141; A19-B142; A19-B143; A19-B144; A19-BI45; A19-B146; A1I9-B 147; A19-B148; A19-B149; A19-B150; A19-B151; A19-BI52; A19-B153; A19-B3154; A19-B155; A19-B156; A19-B157; A19-B158; A19-B159; A19-B160; A19-B161; A19-B162; A19-B163; A19-B164; A19-B165; A19-B166; A19-B167; A19-B168; A19-B169; A20-B 1; A20-B2; A20-B3; A20-B4; A20-B5; A20-B6; A-20-B7; A20-B8; A20-B39; A20-B1O; A20-B 11; A20-B12; A20-B 13; A20-B14; 20 -B 15; A20-B16; A20-B17; A20O-B1S; A20-B19; A20-B24; -]A20-B25; A20-B20; A20-B21; A2U-B22; A20-B26;1 A20 E-B'27; A20-B28; A20-B29; WO 031035065 WO 03/35065PCT/GB02/04763 -126- A20B31 A20-B32; fA20-B33; jA20-B34; A20-B35; A20-B30;

I

ALU-B41; A20-B36; A20-B37; A20-B3 8; A20-B39; A20-B40; A20-B41; A20-B42; A20-B43; A20-B44; A20-B45; A20-B46; A20-B47; A20-B48; A20-B49; A20-B50; A20-B5 1; A20-B52; A20-B53; A20-B54; A20-B55; A20-B56; A20-B57; A20-B58; A20-B59, A20-B60; A20-B6 1; A20-B62; A20-B63; A20-B64; A20-B65; A20-B66; A20-B67; A20-B68; A20-B69; A20-B70; A20-B71; A20-B72; A20-B73; A20-B74; A20-B75; A20-B76; A20-B77; A20-B78; A20-B79; A20-B90; A20-B81; A20-B82; A20-BS3; A20-B84; A20-B85; A20-B86; A20-B87; A20-B88; A20-B89; A20-B90; A20-B91; A20-B92; A20-B93; A20-B94; A20-B95; A20-B96; A20-B97; A20-B98; A 20-B99; A20-B100; A20-Bl01; 102; A20)-B 103; A20-B 104;- A20-B 105; A 2 0 -B 10 6; A20-B 107; A20-BI08; A20-B 109; A20-B110; A20-B I11; A20-BI12; A20-B 113; 114; A20-B115; A20-B1 116; A20-B 117; A20-B 118; A20-B 119; 120; A20-B 121; A20-B122; A20-B123; A20-B124; A20-B125-, A20-B126; A20-B 127; A20-B128; A20-B 129; A20-B130; A20-BI31; A20-B132; A20-B 133; A20-B134; A20-B 135; A20-B136; A20-B137; A20-B1 38; A20-B 139; A20-B 140; A20-B 141t; A20-B142; A20-B 143; 144; A20-B 145; A20-B 146; A20-B3 147; A20-B 148; A20-B 149; A20-B150; A20-B 15 1; A20-B 1, 52; A20-BI53;, A20-B 154; A20-B 155; A20-B156; A20-B157; A20-B3158; A20-B159; A20-B 160; A20-B161; 162; A20-B 163; A20-B 164; A20-B 165; A20-B 166; A20-B 167; A20-B168; A20-B169; A21-B1; A21-B2; A21-B3; A21-B4; A21-B5; A21-B6; A21-B7; A21-B8; A21-B9; A21-B1O; A21-B1T; A21-B12; A21I-B 13; A21I-B 14; A21I-B 15; A21-B16; A2 1-B 17; A21-B18; A2 1-B 19; A21-B20; A21-B21; A21-B22; A21-B23; A21-B24; A21I-B25; A21-B26; A21I-B27; A21-B28; A21-B29; A21-B30; A21-B31; A21-B32; A21.-B33; A21-B34; A21-B35; A21-B36; A21-B37; A21-B338; A21-B39; A21-B40; A21-B41; A21-B342; A21-B343; A21-B344; A21-B45; A21-B46; A21-B47; A21-B48; A21-B49; A21-B50; A21-B51; A21I-B52; A21-B353; A21-B54; A-91 -B 55; A2141356; A21-B57; A21-B58; A21-B59; A2 1-B65; A21-B60; A-21 -B6 1; A21- 36'2; A21-B63; A21-B70;

I

A2 1-B 66; A21-B67; A21-B68; I-A21-B69;

I

WO 031035065 WO 03/35065PCT/GB02/04763 -127- A21-B71;, A21-B72; A21-B73; A21-B74; A21-B75; A'21-B76; A21-B77; A21-B78; A21-B79; A21-B80; A21-B81; A'21-B82; A21-B83; A21-B84; A21-B85; A21-B86; A21-B87; A21-B88; A21-B89; A21-B90; A21-B91; A21 -B 92; A21-B93; A2 I-B 94; A21-B95; A21-B96; A21-B97; A21-B98; A21-B99; A21-B100; A21-B1OI; A21-B102; A21-BI03; A2 1-B 104; A21-B105; A2t-B106; A21-B107; A21-BIOS; A21-B109; A21-BI1O; A2 I-B I11; A21-3112; A21 -B 113; A21-B114, A21-BI15; A21-B116; A21-B117; A21-BI1S; A2 I-B 119; A21I-B 120; A21-B121; A21I-B 122; A21-B123; A21 -B 124; A21-B125; A21-B126; A21-B127; A21-B128; sk2l-B129; A21-B130; A21-BI31; A21I-B 132; A21-B133; A21-B134; A21-BI35; A21-B136; A21-BI37; A'21-B 138;- A21-B139; A2 t-B 140; A21-B141; A21-B142; A21-B143; A21I-B 144; A21I-B 145; A21-B146; A21I-B 147; A21-B148; A21-B149; A21-B150; A21-B151; A21-13152; A21-BI53; A21-BI54; A2)1-BI55; A21 -B156; A21-B157; A21-B158; A21-B159; A21I-B 160; A21-B161; A21-BI62; A21-BI63; A21t-B 164; A21-B165; A21-B166; A21-BI67; A21-BI68; A21I-B 169; A22-B 1; A22-B2; A22-B3; A22-B4; A22-B5; A22-B6; A22-B7; A22-B8; A22-B9; A22-B 10; A22-B 11; A22-B 12; A22-B 13; A22-B 14; A22-B A22-B 16; A22-B17; A22-B 18; A22-B19; A22-B20; A22-B2 1; A22-B22; A22-B23; A22-B24; A22-B25; A22-B26; A22-B27; A22-B28; A22-B29; A'22-B30; A22-B3 1; A22-B32; A22-B33; A22-B34; A22-B35; A22-B36; A22-B37; A22-B38; A22-B39; A22-B40; A22-B41; A22-B42; A22-B43; A22-B44; A22-B45; A22-B46; A22-B47; A22-B48; A22-B49; A22-B50; A22-B5 1; A22-B52; A22-B53; A22-B54; A22-B55; A22-B56; A22-B57; A22-B5S; A22-]359; A22-B60; A22-B6 1; A22-B62; A22-B63; A22-B64; A22-B65; A22-B66; A22-B67; A22-B68; A22-B69; A22-B70; A22-B71; A22-B72; A22-B73; A22-B74; A22-B75; A22-B76; A22-B77; A22.-B78; A22-B79; A22-B80; A22-B81; A22-B82; A22-B83; A22-B84; A22-B85; A22-B86; A22-B87;- A22-B88; A22-B89; A22-B90; A;2 2 -B9 1, A22-B92; A22-B93; A22-B94; A22-B95; A22-B96; A22-B97; A22-B98; A22-B99; A22-B100; A22-BlO1; A22-B 102; A22-B 103; A22-B 104; A22-B105; A'22-B106; A22-B107; A22-B108; A22-B109; A22-B11O; A22-B 111; WO 031035065 WO 03/35065PCT/GB02/04763 -128- A22-B 12; A22-B 13; A22-B 114; A22-B 15; A22-B 116; A22-B 117; A22-B 118; A22-B 119; A22-B 120; A22-B 12 1; A22-B 122; A22-B123; A22-B 124; A22-B 125; A22-B126; A22-B127; A22-B128; A22-B 129; A22-B 130; A22-B 13 1; A22-B L32; A22-B 133; A222-B 134; A22-B 135; A22-B136; A22-B 137; A22-B 13 8; A22-B139; A22-B140; A22-BI41; A22-B 142; A22-B 143; A22-B 144; A22-B 145; A22-B146; A22-B 147; A22-B148; A22-B 149; A22-B 150; A22-B151; A22-B152; A22-B153; A22-B 154; A22-B 155; A22-B156; A22-B157; A22-B158; A22-B159;- A22-B 160; A 2- 16 61; A22-B 162; A22-B 163; A22-B164; A22-B 165; A22-B 166; A22-B167; A22-B168; A22-B 169; A23-B1; A23)-B2; A23-B3; A23-B4; A23-B5; A23-B6; A23-B37; A23-B8; A23-B9; A23-B1O; A23-B11; A23-B12; A23-B13; A23-B 14; A23-B 15; A23-B 16; A23-B17; A23-B 18; A23-B19; A23-B20; A23-B21; A23-B22; A23-B23; A23-B24; A23-B25; A23-B26; A23-B27; A23-B28; A23-B29; A23-B30; A23-B3 1; A23-B32; A23-B33; A23-B34; A23-B35; A23-B336; A23-B37; A23-B38; A23-B39; A23-1340; A23-B41; A23-B42; A23-B43; A23-B44; A23-B45; A23-B46; A23-B47; A23-B48; A23-B49; A23-B50; A23-B5 1; A23-B52; A23-B53; A23-B54; A23-B55; A23-B56; A23-B57; A23-B58; A23-B59; A23-B60; A23-B61; A23-B62; A23-B63; A23-B64; A23-B65; A23-B66; A23-B67; A23-B68; A23-B69; A23-B70; A23-B71; A23-B72; A23-B73; A23-B74; A23-B75; A23-B76; A23-B77; A23-B78; A23-B79; A23-B80; A23 -B 81; A23-B82; A23-B83; A23-B84; A23-B85; A23-B86; A23-B87; A23-B88; A23-B89; A23-B90; A23-B91; A23-B92; A23-B93; A23-B94; A23-B395; A23-B96; A23-B97; A23-B98; A23-B99; A23-B 100; A23-B 101; A23-B 102; A23-B 103; A23-B 104; A23-B105; A23-B106; A23-B 107; A23-BIOS; A23-B109; A23-B11O; A23-B1 11; A23-13112; A23-B 113; A23-B114; A23-B115; A23-B 116; A23-B1 17; A23-B I 13; A23-B 119; A2-3-Bl2D; A23-B121; A23-B122; ,A23-B123; A23-B124; A23-B125; A23-B126; A23-B127- A23-B128; A23-B129; A23-B130; A23-B 13 1; A23-B132; A23-B133; A23-B134; A23-B135; A23-B136; A23-B137; A3B138; A23-B139; A23-B140; A23-B141; A-23-B142; A23-B143; A23 -B 144; A23-B145; A23-B146; A23-B 147; A23-B148; A23-B149; A23-B150; A23-B151; A23-B152; WO 031035065 WO 03/35065PCT/GB02/04763 A23-B153; A23-B154; A23-B155; A23-B156; A21-B157; A23-B 158; A23)-B159; A23-B160; A23 -B1'61; A23-B162; A23-B 163; A23-B 164; A23-B165; A23-B166; A23-B 167; A23-B168; A23-B169; A24-B 1; A24-B2; A24-B3; A24-B4; A24-B5; A24-B6; A24-B7; A24-Bg; A24-B9; A24-B 10; A24-B 11; A24-B12; A24-B 13; A24-B 14; A24-B15; A24-B 16; A24-B17; A24-B 18; A24-B19; A24-B20; A24-B2 1; A24-B22; A24-B23; A24-B24; A24-B25; A24-B26; A24-B27; A24-B28; A24-B29; A24-B30; A24-B3 1; A24-B32; A24-B33; A24-B34; A24-B35; A24-B36; A24-B37; A24-B38; A24-B39; A24-B40; A24-B41; A24-B42; A24-B43; A24-B44; A24-B45; A24-B46; A24-B47; A24-B48; A24-B49; A24-B50; A24-B5 1; A24-B52; A24-B53; A24-B54; A24-B55; A24-B56; A24-B57; A24-B58; A24-B59; A24-B60; A24-B61; A24-B62; A24-B63; A24-B64; A24-B65; A24-B66; A24-B67; A24-B68; A24-B69; A24-B70; A24-B71; A24-B72; A24-B73; A24-B74; A24-B75; A24-B76; A24-B77; A24-B78; A24-B79; A24-B8O; A24-B81; A24-B82; A24-BS3; A24-BS4; A24-B85; A24-B86; A24-B87; A24-B88; A24-B89; A24-B90; A24-B91; A24-B92; A24-B93; A24-B94; A24-B95; A24-B96; A24-B97; A24-B98; A24-B99; A24-B 100; A24-BIO1; A24-B 102; A24-B 103; A24-B 104; A24-B 105; A24-B 106; A24-B 107; A24-B 108; A24-B 109; A24-B1 1t0; A24-B 111; A24-B 112; A24-B 113; A24-B 114; A24-B 115; A24-B 116; A24-B 117; A24-B1 18; A24-B1t 19; A24-B120; A24-B121; A24-B 122; A24-B 123; A24-B 124; A24-B 125; A'24-B 126; A24-B 127; A24-BI28; A24-B129; A24-B130; A24-B131; A24-B132; A24-B 133; A24-BI34; A24-B135; A24-B136; A24-B137; A24-B 13 8; A24-B139; A24-B 140; A24-B 141; A24-B 142; A24-B 143; A24-B144; A24-B 145; A24-B146; A24-B147; A24-B148; A24-B149; A24-B150; A24-B151; A24-BR152; A24-B153; A24-B154; A24-B155; A24-B156; A24-B157; A24-B158; A24-B159; A24-B160; A24-B 16 1; A24-B162; A24-B 163; A24-B1 64; A24-B 165; A24-B 166; A24-B 167; A24-B 168; A24-B1 69; A25-B1; A25-B2; A25-B3; A25-B4; A25-B5; A25-B6; A25-B7; A25-B8; A25-B9; A25-B1O; A25-B 11; A25-B12; A25-B13; A25-B14; A25-1B15; A25-B16; A25-B17; A25-B18; A25-B19; A25-B20; A25-B21; A25-B22; A25-B23; A25-B24; WO 031035065 WO 03/35065PCT/GB02/04763 -130- A25-B25; A25-B3 1; A25-B26;- A25-B32; A25-B27; A25-B33; A25-B28, IA2 5-B 2 9; A 25 A25-B37; A25-B43; A25-B349; A25-B55; A25-B61; A25-B67; A25-B73; A2 5-B79; A25-B85; A25-B91; A25-B97; A2 5-B 103; 109; 3115; A25-BV11 A25-B127; 133; A25-B139; A25-B145; A25-B151; A25-B1 57; A25-B163; 169; A26-B6; A26-B 12; A25-B338; A25-B44; A25-B50; A25-B356; A25-B62; A25-B68; A) 5-B74; A5-B 39; A25-B45; A2-5-B51; A25-B57; A25-B63; A25-B69; A25-B75; A25-B34; A25-B40; A25-B46; A25-B52; A25-B5 8; A25-B64; A25-B70; A25-B76; A25-B3 5; A25-B41; A25-B47; A25-B53; A25-B59; A25-B65; A25-B7 1; A25-B77; A25-B3 6; A25-B42; A25-B48; A25-B54; A25-B A25-B 66; A25-B72; A25-B78; A25-B84; A25-B 4 1 v T A25-B80, A25-B 86; A25-B8 1; A25-B87; A25-B82; A25-B88; A2 5-B 83; A25-B 89; .1 t A25-B92; A25-B98; A25-B 104; A25-B1 1t0; A25-B1 16; A25-B93; A25-B99; A25-B 105; A25-B 111; A25-B94; A25-B 100; A25-B 106; A25-B 112; S2-B95; A25-B 101; A25-B107; A25-B113, A25-B96; A25-B 102; A25-B 108; A25-B1 114; I -t A25-B 117; A25-B1 18; A25-B1 19; 1 4 F -i A25-B 122; A25-B 128; A25-B 134; A25-B 140; A25-B 146; A25 -B 152; A25-B 158; A25-B 164; A26-B1; A26-B7; A26-B 13; A25-B 123; A25-B 129; A25-B135; A25-B141; A25-B147; A25-B 153; A25-B159; A25-B165; A26-B32; A26-BS; A26-B 14; A2 5-B 124; A25-B 130; A25-B 136; A2 5-B 142; A25-B 3148; A25-B 154; A25-B 160; A;25-B 166; A26-B3 A26-B9; A26-B 15; A25-B 125; A25-B131; A25 -B 137; A25-B 143; A25-B 149; A25-B155; A25-B 16 1; A25-B 167; A26-B4; A26-B 10; A26-B 16; A25-B 120; A25-B 126; A25-B 132; A25-B 138; A25-B 144; A25-B 150; A25-B 156; A25-B 162; A25-B 168; A26-B5; A26-Bl1; A26-B 17; A26-B23; A26-B29; A26-B35; A26-B41; I T A26-B 18; A26-B 19; A26-B20, A2b-II 4~ 1 A26-B24; A26-B25; A26-B26; A26-B27; A26-B2 2; A26-BT98; A26-B34; A26-B40; 4- A26-B30; A26-B3 1; A26-B32; A26-B33; F -1- A26-B36; A26-B342; A26-B37; A26-B3 8; A.26-B39; L 4 4 A26-B43; A26-B44; A26-B45; A26-B46; A26-B52; A26-B47; A26-B53; 4 4 t A26-B48; A26-B54; A26-B60; A26-B49; A26-B55; A26-B50; A26-B56; A26-B5 1; A26-B57; A26-B63; A26-361; -A26-B62; A26-B58; A26-B59; A26-B64; A26-B65; WO 031035065 WO 03/35065PCT/GB02/04763 -131- A26-B 66; A26-B72; A26-B37R; A26-BS4; A26- 390; A26-B96; A26-B 102; A26-B 108; A26-31 14; A26-B 120; A26-B 126; A26-B 132; A26-B 138; A26-B 144; A26-B 150; A26-B156; A26-B 162;1 A26-B168; A27-B5; A27-B 11; A27-B 17; A27-B23; A27-B29; A27-B35; A'27-B41; A27-B47; A27-B53; A27-B59; A27-B 65; A27-B71; A27-B77; A27-B83; A26-B 67;- A26-B73; A26-B379; A26-B85; A26-B9 1; A26-B97; A26-B103; A26-B 109; A26-B 15; A26-B 12I; A26-B3127; A26-B 133; A26-B 13 9; A26-B 145; A26-B 15 1; A26-B 157; A26-B 163: A26-B 169; A27-B6; A27-B 312; A27-B 18; A27-B24; A27-B 30; A27-B36; A27-BW2; A27-B48-; A27.-B54; A26-B68; A26-B74; A26-B80; A9 6-B86; A26-B9M; A26-B98; A26-B 104; A26-B1I 10; A26-B 116; A26- 3122; A26-B 128; A26-B 134; A26-B 140; A26-B 146; A26-B 152; A26-B 158; A26-B 164; A27-B1; A27-B7; A27-B13; A27-B 19; A27-B25; A27-B3 1; A27-B37; A27-B43; A27-B49; +A27-B55;, A26-B69; A26-B75; A26-B81; A26-B 87; A26-B93;, A26-B99; A26-B 105; A26-B1 111; A26-B 117; A26-B1M3; A26-B129; A26-B135; A26-B 141; A26-B 3147; A26-B 153; A26-B 159; A26-B 165; A27-B2; A27-B 8; A27-B 14; A27-B20; A27-B26; A27-B32; A27-B3 8; A27-B44; A27-B50; A27-B56; A27-B 62; A27-B68; A27-B74; A26-B70; A26-B76; A2 6 -B 82; A26-B88; A26-B94; A26-B 100; A26-B 106; A26-B 112; A26-B 118; A26-B1M4; A26-B130; A26-B7 1; A26-B77; A26-B83; A26-B89; A26-B95; X2 6 -B10 t; A26-B 107; A26-B113; A26-B119; A26-B 125; A26-B 13 1; A26-B136; A26-B142; A26- 3148; A26-B154; [A26-B160; A26-B137; A26-B 143; A26-B 149; A26-B 155; A26-B 161; A26-B 167; A27-B3; A27-B9; A27-B 15; A27-B2 1; A27-B27; A27-B33; A27-B39; A27-B45; A27-B5 11 A27-B57; A27-B63; A27-B69; A27-B75; A27-B4; A27-B A27-B 16; A27-B22; A27-B2 8; A27-B34; A27-B40; A27-B46; A27-B52; A27-B58; A27-B 64; A27-B70; A27-B76; A27-B60; A27-B66; A27-B72; A27-B78; A27-B84; A27-B61; A27-B67; A27-B73; A27-B81; A27-B82; A27-B79; A27-B85; A27-BSO; A27-B81

_I

A27-B 86; A27-B89; A27-B90; A27-B95; A27-B96; A27-B1O1; A27-3102; A27-B91; _A27-B92; A27-B97; A27-B98; A27-B 103; A27-B104; A27-BS7; A27-B93; A27-B99; -A27 -B10 5; A27-B94; A27-B100; A27-B 106; WO 031035065 WO 03/35065PCT/GB02/04763 -132- A27-B107; IA27-Bt 18 A27-B 109; A27-B 110; i X27 -B 13; IA27-B 114; A27-B1 15; A27-B1 16; A27-B I1; A27-B 117; A27-B 123; A27-B 129; L -I t A27-B 119; A27-B125; A27-B 120; A27-B 126; A27-B 12 1; A 27-B 127;

I

A27-B 122; A27-B 128; A27- 3112; A27-B 118; A27-B 124; A27-B 130; A27-B 136; A27-B 142; A27-B 148; I A27-B 13 1; A27-B 137; A27-B 143; A27-B 149; A27-B 155; A27-B 132; A27-B 13 8; A27-B 144; A27-B 150; A2- 133 A27-B 139; A27-B 145; A27-B 134; AX27-B 140; A27-B 146; A27-B 135; A27-B 141; A27-B 147; 1 4 t A27-B 154; A27-B 15 1; A27-B 152; A27-B 153; A27-B 154; 4 F 4 A27-B 160; A27-B 156; A27-B 157; A27-B15 8; A27-B 159; A27-B160; A27-B 16 1; A27-B 162; A27-B 163; A27-B164; A27-B165; A27-B166; A27-B 167; A27-B 168; A27-B 169; A28-B 1; A28-B2; A28-B3; A28-B4; A28-B5; A28-B6; A28-B7; A28-B8; A28-B9; A28-B10; A28-B 11; A28-B12; A28-B13; A28-B314; A28-B315; A28-B16; A28-B 17; A28-B318; A28-B19; A28-B20; A28-B21; A2)8-B229 A28-B23; A28-B24; A28-B25; A28-B26; A28-B27; A28-B28; A28-B29; A28-B30; A28-B31; A28-B32; A28-B33; A28-B34; A28-B335; A28-B336; A28-B37; A28-B39; A28-339; A28-B40; A28-B41; A28-B342; A28- 143; A28-B44; A29-B45; A28-B46; A28-B47; A28-B48; A28-B49; A28-B50; A28-B51; A28-B52; A28-B53; A28-B54; A28-B55; A28-B56; A28-B57; A28-B58; A28-fl59; A28-B60; A28-B61; A28-B62; A28-B63; A28-B64; A28-B65; A28-B66; A29-B67; A28-B68; A28-B69; A28-B70; A28-B71; A28-B72; A29-B73; A28-B74; A28-B75; A28-B76; A28-B77; A28-B78; A28-B79; A28-B380; A28-B81; A28-B82; A28-B83; A28-B84; A28-B85; A28-386i; A28-B87; A28-B88; A28-B89; A28-B9M; A28-B391; A28-B92; A28-B93; A28-B94; A29-B95; A28:696, A28-B397; A28-B98; A28-B99; A28-B100; A28-B1O1; A28-B102; A28-B103; A28-B 104; A28-B105; A28-B106; A28-B107; A28-B108; A28-B109; A28-B11O; A28-B111; A28-B112; A28-B113; A28-B114; A28-B115; A28-B 116; A28-B117; A28-B118; A28-B 119; A28-B3120; A28-B3121; A28-B122; A28-B123; A2?5IilZi; A~-I5iz~; .1~OIZ.

A28-B 124; A28-B 125; A28-B 13 1; A28-B 126; I IA/ Z5-J5 6; A28-B136; A28-B137; A28-B142; A28-B143; A28-B3132; A28-B133; 1A28-B134; A28-B135; A28-B3138; A28-B139; A28-B140; A28-B141; A28-B 144; A28-B145; A28-B 146; A28-B 147; WO 031035065 WO 03/35065PCT/GB02/04763 -133-

I

A2 A28-B 148;- A28-BI49; A28-B 150; A28-B 151; SA'28-B 152; A28 -153; A28-B154; A28-B155; A28-B156; A'-8-B157); A28-B158; A28-B159; A28-B160; A28-BI1; A28-B162; A28-B163; A28-B 164; A28-B165; A28-B166; A"-S-B167; A28-B168; A28-BI69; A29-B1; A29-B2; A29-B3; A2,9-B4; A29-B5; A29-B6; A29-B7; A29-B8; A29-B9; A29-B1O; A29-BI11; A29-B12; A29-B 13; A29-B 14; A29-B 15; A29-B16; A29-B 17; A29-B 18; A29-B 19; A29-B20; A29-B2 1; A29-B22; A29-B23; A29-B24; A29-B25; A29-B26; A'29-B27; A29-B28; A2-9-B29;, A29-B30; A29-B31; A29-B32; A29-B33; A29-B34; A29-B35; A29-B36; A29-B37; A29-B38; A29-B39; A29-B40; A29-B41; A29-B42; A29-B43; A29-B44; A29-B45; A29-B46; A29-B47; A29-B48; A29-B49; A29-B50; A29-B51; A29-B52; A29-B53; A29-B54; A29-B55; A29-B56; A29-B57; A29-B58; A29-B59; A29-B60; A29-B61; A29-B62; A29-B63; A29-B64; A29-B65; A29-B66; A29-B67; A29-B68; A29-B69; A29-B70; A29-B71; A29-B72; A29-B73; A29-B74; A29-B75; A29-B76; A29-B77; A29-B78; A29-B79; A29-B380; A29-BS1; A29-B82; A29-BS3; A29-B84; A29-B85; A29-B86; A29-B87; A29-B88; A29-BS9; A29-B90; A29-B9 1; A29-B92; A29-B93; A29-B94; A29-B95; A29-B96; A29-B97; A29-B98; A29-B99; A29-BIOO; A29-BIO1; A29-B 102; A29-B103; A29-B104; A29-B105; A29-B 106; A29-B107; X2-9-B 108; A29-B109; A29-B1O; A29-Bl11; A29-B112; A29-BI113; A29-B 114; A29-B 115; A29-B 116; A29-B 117; A29-B1 18; A29-B 119; A29-B 120; A29-B3121; A29-B3122; A29-BI23; A29-B 124; A29-BI25; A29-B 126; A29-B 127; A29-B 128; A29-B129; A29-B130; A29-B 13 1; A29-B132; A29-B 133; A29-B134; A29-B 135; A29-B 136; A29-B 137; A29-B 138; A29-B 139; A29-B 140; A29-B141; A29-B142; A29-B 143; A29-B144; A29-B145; A29-B 146; A29-B147; A29-B148; A29-B 149; A29-B150; A29-B 15 1; A29-B152; A29-BI53; A29-B 154; A29-B155; A29-B156; A29-B 157; A29-B158; A29-B159; A29-B 160; A29-B 16 1; A29-B162; A29-B163; A29-B 164; A29-B165; A29-B166; A29-B 167; A29-B168; A29-B169; A30-B1; A30-B2; A30-B3; A30-B4; A30-B5; A30-B6; A30-B7; A30-B8; A30-B9; A30-B1O; A30-B11; A30-B12; A3 0-B 13; 14; A30-B15; A30-B16; A30-B 17; A30-B18; A30-1319; WO 031035065 WO 03/35065PCT/GB02/04763 -134- A;3-0-B20; A30-B21; -A30-B22; A30-B23; A30-B24; A30-B25; A30-B26; A30-B27; A30-B28; A3C-B29;5 A30-B30; A30-B3 1; A3O-B32, A30-B33; A30-B34; A30-B35; A30-B36; A30-B37; A30-B38; A30-B39; A30-B40; A30-B41; A30-B42; A30-B43; A30-B44; A30-B45; A30-B46; A30-B47; A30-B48; A30-B49; A30-B50; A30-B5 1; A30-B52; A30-B53; A30-B54; A30-B55; A30-B56; A30-B57; A30-B58; A30-B59; A30-B60; A30-B61; A30-B62; A30-B63; A30-B64; A30-B65; A30-B366; A30-B67; A30-B68; A30-B69; A30-B70; A30-B71; A30-B72; A30-B73; A30-B74; A30-B'15; A30-B76; A30-B77; A30-B78; A30-B79; A30-B80; A30-B81; A30-BS2; A30-B83; A30O-B84; A30-B85; A30-B86; A30-B87; A30-BSS; A30-B89; A30-B90; A30-B91; A30-B92; A30-B93; A30-B94; A30-B95; A30-B96; A30-B97; A30-B98; A30-B99; A30-B100; A30-B1OI; A30-B102; A30-B103; A30-B104; A30-B 105; A30-B106, A30-B 107; A30-B108; A30-B109; A3O-B11O; A30-B I11; A30-BI 12; A30-B 113; A30-B 114; A30-B 115; 116; A30-B 117; A30-B 118; A30-B119; A30-B120; A30-B121; A30-B122; A30-B 123; A30-B124; A30-B 125; A30-DB126; A30-BI27; A30-B128; A30-B 129; A30-B130-; A30-B 13 1; A30-B 132; A30-B 133; A30-B134; A30-B135; A30-B136; A30-B137; A30-B3138; A30-B139; A30-B140; A30-B 14 1; A30-BI42; A30-B143; A30O-B 144; A30-B 145; A30-B146; A30-B147; A30-B148; A30-B149; A30-B150; A30-BI5l; A30-B152; A30-B 15 3; A30-B154; A30-B155; A30-B156; A30-B157; A30-B158; A30-B159; A30-B160; A30-B 16 1; A30-B162; A30-B163; A30-BI64; A30-BI65; A30-B 166; A30-B167; A30-B168; A30-BI69; A31-B1; A31I-B2; A31-B3; A31-B4; A31-B5; A31-B6; A3 I-B7; A31-B8; A31-B9; A31-B1O; A31-Bll; A31I-B 12; A3 1-B13; A3 I-B 14; A31I-B 15; A31I-B 16; A31I-B 17; A31-B1S; A31-B19; A31-B20; A31-B21; A31-B22; A31-B23; A3 1-B24; A3 t-B25; A3 1-B26; A3 I1-B27; A31-B28; A3 1-B29; A3 1-B30; A31-B31; A31-B32; A31-B33; A31-B34; A31-B35; A31-B36; A31-B37; A31I-B3 8; A31-B39; A31-B40; A3 I-B4 1; A31I-B42; A3 I-B43; A31-B44; A31-B45; A31-B46; A31I-B47; A31-B48; A3 1-B49; A31-B50; A31-B51; A31-B52; A31-B53; A31-B54; A31-B-55; A31-B56; A31-B57; A31-B58; A31-B59; A3 1-B60; WO 031035065 WO 03/35065PCT/GB02/04763 -135- A3 1-B6 1; A3 l-B67; A31-B73; A3 1-B79; A3 I-B62; A3 I1-B68; A3 1-B74; A31-B63; A3 1-B69; A3 I-B75; A3 I1-B64; A3 1-B70; A31I-B76; A31-B65; A31-B66; A31-B71; A31-B72; A31-B'77; A31-B78; I- I I- A3 1-B80; A3 1-B8 1; A3 I1-B 82; I- -l I- A31-B85; A31-B86; A31-B87; A31-B88; -4- A3 1-B9 1; A31-B397; A3 1-B 103; A3 1-B92; A3 1-B98; A31-B3104; A31-B93; A31-B99; A3 1-B 105; A3 1-B94; A31-B100; A3 1-B 106; A3 1-B 83; A-31 -B89; A31I-B95; A3 1-B 101; A31-B107; A3- 1-B 1 13;, A3 I1-B 109; A3 I1-B 115; A3 1-B 121; 1A31I-BiI 1; A3 1-Bill; A3 1-B 112; A3 I1-B 84; A3 A31 l0B6; A3 1 -B 102; A3 1-B 108; A3 1-B 114; A3 1-B 120; A3 1-B 126; A31-B 132; A3 1-B 138; A3 I1-B 144; A31I-B 1 16; A31I-B 117; A3 1-B 118; A31-B1 19; A3 1-B125; A31-B122; A3 1-B 123; A3 1-B 124; L 4 -4- A3 I1-B 127; A3 1-B 133; A31-B 139; A31-B 145; A3 1-B 151; A3 1-B 157; A3 1-B 128; A3 1-B 134; A3 I1-B 140; A3 I1-B 129; A3 1-B 135; A3 1-B 14t; A3 1-B 130; A3 1-B 136;- A3 1-B 142; A3 1-B 131; A3 1-B 137; A3 1-B 143; -l r A3 1-B 150; A3 1-B 146; A31-B 152; A31-B147; A3 1-B 148; A3 1-B 149; A3 I -B 150; 1 4- t A3 1-B 156; A31-B153; A3 1-B 154; A3 1-B 155; A31-BI56; I A'3 1-B 162; 1A31-B158; A3 1-B 159; A3 1-B 160; A3 1-B 161; A3 I -B 162; A31-B163; A31I-B 164; A31-B165; A3 1-B 166; A31-B167; A31-B168; A3 1-B 169; A32-B 1; A32-B2; A32-B3; A32-B4; A32-B5; A32-B6; A32-B7; A32-B8; A32-B9; A32-B 10; A32-B 11; A32-B12; A32-B 13; A32-B14; A32-B1S; A32-B 16; A32-B17; A32-B18; A32-B19; A32-B20; A32-B21; A32-B22; A32-B23; A32-B24; A32-B25; A32-B26; A32-B27; A32-B28; A32-B29; A32-B30; A32-B3 1; A32-B32; A32-B33; A32-B34; A32-B35; A32-B316; A32-B37; A32-B38; A32-B39; A32-B40; A32-B41; A32-B42; A32-B43; A32-B44; A32-B45; A32-B46; A32-B47); A32-B48; A32-B49; A32-B50; A3-5; A32-B52; A32-B53; A32-B54; A32-B55; A32-B56; A32-B57; A32-B58; A32-B59; A32-B60; A32-B61; A32-B62; A32-B63; A32-B64; A32-B65; A32-B66; A32-B67; A32-B68; A32-B69; A32-B70; A32-B71; A32-B72; A32-B73; A32-B74; A32-B75; A32-B76; A32-B77; A3-B8 A2B7; A32-B80; A32-B81; A32-B82; A32-B83; A32-B84; A32-B85; A32-B86; A32-B87; A32-B88; A32-B89; A32-B90; A32-B91; A32-B92; A32-B91; A32-B399; A32-B10; A32-B 101; A32 3 9-, A32B96 1A3 2-B97; A32-B93; WO 031035065 WO 03/35065PCT/GB02/04763 -136- A32-B 102; A32-B10J;- A32-B 104; A32-B 105; A32-B1 06; A32-B 107; A32-B3108; A32-B109; A32-BIIO; A32-B I11; A32-B 112; A3-1; A32- 31 14; A32-B 115: A32-B1 116; A'3)2-B 117; A32-B 118; A32-B 119; A32-B120; A' )2-B 12 1; A32-B 122; A32-B123; A32-B 124; A32-B 125; A32-B 126; A32-B127; A32-B 128; A32-B129; A32-B 130; A32-B 13 1; A32-B 132; A3 2-B 13 3; A32-B134; A32-B135; A32-B 136; A32-B 137; A32-B3138; A32-B139; A-B4; A32-B141; A32-B 142; A'12-B143; A32-BI44; A32-B145; A32-B 146; A32-B147; A32-B 148; A32-B149;- A32-B 150; A32-B151; A32-B152; A32-B153; A32-B 154; A3B15 A32-B156; A32-B157; A32-Bt58; A32-B3159; A32-B160; A32-B161; A32-B162; A32-B163; A32-B 164; A32-B165; A32-B166; A32-BI67; A32-B168, A32-B 169; A33-B1; A33-B2; A33-B3; A33-134; A33-B5; A33-B6; A33-B7; A33-B8; A33-B9; A33-B1O; A33-B11; A33-B12; A33-B13; A3 3-B 14; A33-B15; A33-B16; A33-B317; A33-B18; A33I-B]9, A33-B320; A33-B21; A33-B22; A33-B23; A33-B24; A33-B325; A-B6 A33-B27; A33-B28; A33-B29; A33-B30; A33-B3 1; A33-B32; A33-B33; A33-1334; A33-B35; A33-B36; A33-B37; A33-B38; A33-B39; A33-B40; A33-B4 1; A33-B42; A33-B43; A33-B44; A33-B45; A33-B46; A33-B47; A33-B48; A33-B49; A33-B50; A33-B5i1; A33-B52; A33-B53; A33-B54; A33-B55; A33-B56; A33-B57; A33-B58; A33-B59; A33-B60; A33-B61; A33-B62; A33-B63; A33-B64; A33-B65; A33-B66; A33-B67; A33-B68; A33-B69; A33-B70; A33-B7 1; A33-B72; A33-B373; A33-B74; A33--B75; A33-B76; A33-B77; A33-B78; A33-B79; A33-BSO; A33-B81; A33-B82; A33-B83; A33-BS4; A33-B85; A33-B86; A33-B87; A33-B88; A33-B89; A33-B390; A33-B91; A33-392; A33-B93; A33-B94; A33-B95; A33-B96; A33-B97; A3-3-B98; A33-B99; A33-B100; A33-B1Ol; A33-B102; A33-B103; A-33-BI104; A33-B105; A33-B106; A33-B107; A33-B1OS; A33-B109; A33-Bl1O; A33-B1t11; A33-B112; A33-B113; A33-B114; A33-B115; A33-B116; A33-B117; A33-B118; A33-B119; A33-B120; A33-B121; A33-BI22; A33-B123; A33-B124; A33-B125; A33-B126; A33-B127; A33-B128; A33-B129; A33-B130; A33-B131; A33-B132; A33-B133; A33-B134; A33-B135; A33-B136; A33-B137; A33-B138; A33-B139; A33-B140; A33-B141; A33-B142; WO 031035065 WO 03/35065PCT/GB02/04763 -137- A33-B143; A33-B144; A33-B145; A33-B146; A3 3-B 147; A33-B148; A33-B 149; A33-B150; A33-B151; A33-B152; A33-B 153; A33-B154; A33-B1-55; A-33-B156; A33-B157; A33-B158; A33-B 159; A33-B160; A33-B 161; A33-B162; A3-3-B163; A33-B164; A33-B 165; A33-B166; A33-B 167; A33-B16S; A33-B 169; A34-131; A34-B2; A34-133; A34-B4; A34-B5; A34-B6; A34-B7 3-8 A34-B9; A34-B 10; A34-B 11; A34-B 12; A34-B13; A34-B 14; A34-B A34-B 16; A34-B17; A34-B 18; A34-B 19; A34-B20; A34-B21; A34-B22; A34-B23; A34-B24; A34-B25; A34-B26; A34-B27; A34-B28; A34-B29; A34-B30; A34-B3 1; A34-B32; A34-B33; A34-B34; A34-D35; A34-B36; A34-B37; A34-B38; A34-B39; A34-B40; A34-B41; A34-B42; A34-B43; A34-B44; A34-B45; A34-B46; A34-B347; A34-B48; A34-B49; A34-B50; A34-B5 1; A34-B52; A34-B53; A34-B54; A34-B55; A34-B56; A34-B57; A34-B58; A34-B59; A34-fl60; A34-B61; A34-B362; A34-B63; A34-B64; A34-B65; A34-B66; A34-B367; A34-B68; A34-B69; A34-B70; A34-B71; A34-B72; A34-B73; A34-B74; A34-B75; A34-B76; A34-B77; A34-B78; A34-B79; A34-B80; A34-B81; A34-B82; A34-B83; A34-B84; A34-B85; A34-B86; A34-B87;- A34-B88; A34-B89; A34-B90; A34-B91; A34-B92; A34-B93; A34-B94; A34-B95; A34-B96; A34-B97; A34-B98; A34-B99; A34-B100; A34-B1O1; A34-B102; A34-B 103; A34-B 104; A34-B105; A34-B 106; A34-B 107; A34-B 3108; A34-B 109; A34-B 110; A34-B 1 11; A34-B 112; A34-B113; A34-B 114; A34-B 115; A34-B 116; A34-B 117; A34-B 18; A34-B 119; A34-B 120; A34-BI21; A34-B122; A34-B 123; A34-B124; A34-B125; A34-B 126; A34-B127; A34-B128; A34-B 129; A34-B130; A34-B131; A34-B 132; A34-B133; A34-B 134; A34-B135; A34-B136; A34-B137; A34-BI38; A34-B139; A34-B 140; A34-B141; A34-BI142;P A34-B 143; A34-B 144; A34-B 145; A34-B 146; A34-B147; A34-B 148; A34-B149; A34-B150; A34-B151; A34-B 152; A34-B153; A34-B 154; A34-B3160; A34-B166; A35-B3; A35-B9; A34-B 155; A34- 3161; A34-B 156; A34-B162; A34-B 157; A34-B 163; A34-B 164; A34-B 167; A34-B168; A35-B4; A35-B5; A35-310; A35-B111; A34-B 169; A35-B6; AX35 -B 12;

I

A3 5-B 1; A34-B 165; A35-B2; A35-B8; A35-B 14; A35-B7; A35-B 13; WO 031035065 WO 03/35065PCT/GB02/04763 -138- A3 5-B 15; A35-B16; A35-B 17; A3 5-B 18; A35-B19; A35-B20; A35-B21; A35-B22 A35-B23; A35-B24; A35-B25; A35-B26; A35-182'7- A35-B28; A35-B29; A35-B30; A35-B3 1; A35-B32; A35-B33; A35-B34; A35-B35; A35-B36; A35-B37; A35-B38; A35-B39; A35-B40; A35-B41; A35-B42; A35-B43; A35-B44; A35-B45; A35-B46; A35-B47; A35-B48; A35-B349; A35-B50; A35-B5 1; A35-B52; A35-B53; A35-B54; A35-B55; A35-B56; A35-B57; A35-B58; A35-B59; A35-B60; A35-B61; A35-B62; A35-B63; A35-B64; A-35-B65; A35-B66; A35-B67; A35-B68; A35-B69; A35-B70; A35-B7 1; A35-B72; A35-B73; A35-B74; A35-B75; A35-B76; A35-B77; A35-B78; A35-B79; A35-B8O; A35-BS81; A35-B82; A35-B83; A35-B84: A35-B85; A35-B86; A35-B87; A35-B88; A35-B89; A35-B901 A35-B91; A35-B92; A35-B93; A35-B94; A35-B95; A35-B96; A35-B97; A35-B98; A35-B99; A35-B100; A35-BI01; A35-B102; A35-B 103; A35-BI04; A35-B105; A35-B106; A3 5-B 107; A35-B 108; A35-B 109; A35-B1 11; A35-B112; A35-BI13; A35-B114; A35-B115; A35-B116; 117; A3 5-B 118; A35-B119; A35-BI20; A35-B121; A35-B122; A35-B123; A35-B124; A35-B125; A35-B126; A35-B127; A35-BI28; A35-BI29; A35-B130; A35-BI31; A35-B132; A35-BI33; A35-B134; A3 5-B1 35; A35-B136; A35-B3137; A35-B138; A35-B139; A35-B140; 141; A35-B 142; A35-B 143; A35- 3144; A35-B 145; A35-B 146; A3 5-B 147; A35-B148; A35-B149; A35-B150; A35-B151; A35-B152; A35-B153; A35-B154; A35-B155; A35-B 156; A35-B157; A35-B158; A35-B159; A35-B160; A35-B161; A35-B162; A35-B163; A35-B164; A35-B165; A35-B166; A35-B167; A35-B168; A35-B169; A36-B1; A36-B2; A36-B3; A36-B4; A36-B5; A36-B6; A36-B7; A36-B8; A36-B9; A36-B310; A36-B11; A36-B12; A36-B13; A36-BI4; A36-B15; A3 6-B 16; A36-B17; A36-B1S; A36-B19; A36-B20; A36-B21; A36-B22; A36-B23; A36-B24; A36-B25; A36-B26; A36-B27; A36-B28; A36-B29; A36-B30; A36-B31; A36-B32; A36-B33; A36-B34; A36-B35; A36-B36; A36-B37; A36-B38; A36-B39; A36-B40; A36-B41; A36-B42; A36-B43; A36-B44; A36-B45; A36-B46; A36-B47; A36-B48; A36-B49; A36-B50; A36-B51; A36-B52; A36-B53; A36-B54; A36-B55; WO 031035065 WO 03/35065PCT/GB02/04763 -139- A36-B56; A36-B57; A36-B58; A36-B59; A36-B60; A36-B61; A3-62 3-B6 A36-B64; A36-B65; A36-B66; A36-B67; A36-B69; A36-B69; A36-B70; A36-B71; A36-B72; A36-B73;1 A36-B74; A36-B75; A36-B76; A36-B77; A36-B78; A36-B379; A36-B8O; A36-B81; A36-B82; A36-B83; A36-B94; A36-B85; A36-B86; A36-B87; A36-BS8; A36-B89; K3-6-B90; A36-B91; A36-B92; A36-B393; A36-B94; A36-B95; A36-B96; A36-B97; A36-B98; A36-B99; A36-BIOO; A36-B1O1; A36-B102; A36-B103; A36-B104; A36-B1O0 A3-B06 A36-B1O'7; A36-B108; A36-B 109; A36-BI1O; A36-BI111; A36-B1'> A36-3113; A3 6-B 114; A36-B 115; A36-B1-6 A36-B3117; A36-B118; A36-B119; A36-B120; A36-B121; A36-B122; A36-B123; A36-B124; k3 6 -B12 5; A36-1B126; A36-B127; A36-BI28; A36-BI29; A36-B130; A3 6-B 13 1; A36-B132; A36-B133; A36-B 134; A36-B 135; A36-BI36; A36-B137; A36-B138; A36-B139; A36-B 140; A36-B141; A36-B142; A36-BI43; A36-B144; A36-B145; A36-B146; A36-B 147; A36-B148; A36-B149; A36-B150; A36-B15 1; A36-B152; A36-B 153; A36-B154; A-36-B155; A36-B3156; A3-17; A36-B158; A36-B159; A36-B160; A36-B161; A36-fl162; A36-B163; A36-B164; A36-B3165; A36-B3166; A36-B167; A36-B18 A36-BI69; A37-B1; A37-B2; A37-B3; A37-B4; A37-B5; A37-B6; A37-B7; A37-BS; A3-7-B9; A37-BIO; A37-B 11; A37-B 12; A37-B 13; A37-B14; A37-B 15; A37-B16; A37-B17; X3-7-B18, A37-B19; A37-B20; A37-B321; A37-B22; A37-B23; A37-B24; A37-B25; A37-B26; A37-B27; A37-B28; A37-B29; A37-B30; A37-B3 1; A37-B32; A37-B33; A37-B34; A37-B35; A37-B36; A37-B37; A37-B'18; A37-B39; A37-B40; A37-B41; A37-B42; A37-B43; A37-B44; A37-B45; A37-B46; A37-B47; A37-B48, A37-B49; A37-BS0; A37-B51; A37-B52; A37-B53; A37-B54; A37-B55; A37-B56; A37-B57; A37-B58; A37-B59; A37-B60; A37-B61; A37-B62; A37-B63; A37-B64; A37-B65; A37-B66; A37-B67; A37-B68; A37-B69; A37-B70; A37-B71; A37-B72; A37-B73; A37-B74; A37-B75; A37-B76; A37-B77; A37-B78; A37-B79; A37-B8O; A37-B81; A37-B82; A37-B83; A37-B84; A37-B85; A37-B86; A3'7-B87; A37-B88; A37-B89; A37-B90; A37-B91; A37-B392; A37-1B93; AX3-7-B94; A37-B95; A37-B96; WO 031035065 WO 03/35065PCT/GB02/04763 -140- A37-B97; A37-B98; A37-B99; A37-BI00; A37-BIO1; A37-B102; A37-B103; A37-B104; A37-B 105; A37-B 106; A37-B 107; A,37-B108; A37-B109; A37-BI10O; A37-B 111; A37-B112; A37-B 113; A37-BI14; A37-B1 15; A3 7-B 116; A37-BI 117; A37-B 118; A37-BI 19; A37-B190; A37-B121; A37-B 122; A37-B t23; A37-B124; A37-B 125; A37-B126; A37-B 127; A37-B128; A37-BI29; A37-B130; A37-B131; A37-B132; A37-B133; A37-B134; A37-B 135; A37-B136; A37-B137; A37-B138; A3 7-B 13 9; A37-B 140; A' 7-B 14 1; A3'7-B 142; A37-B143; A37-B144; A37-B 145; A3'7-B 146; A 37 -B 14 7, A37-B 3148; A37-B149; A37-B 150; A37-B 15 1; A37-B 152; A37-B153; A37-B 154; A37-B155; A37-B 156; A37-B157; A37-BI58; A37-BI59; A37-B160; A37-B161; A3'7-B 162; A37-B163; A37-B164; A37-B165; A37-B166;- A37-B167; A37-B 168; A37-B 169; A38S-B 1; A38-B2; A38-B3; A38-B4; A38-B5; A38-B6; A38-B7; A38-B8; A38-B9; A38-BIO; A38-Bl1; A38-B12; A3 S-B 13; A38-B14; A38-B15; A38-B16; A38-B17; A38-B18; A38-B19; A38-B20; A38-B21; A38-B22; A38-B23; A38-B24; A38-B25; A38-B26; A38-B27; A38-B28; A38-B29; A38-B30; A3 8-B3 1; A38-B32; A38-B33; A38-B34; A38-B35; A38-B36; A38-B37; A38-B38; A38-B39; A38-B40;- A38-B41; A38-B42; A38-B43; A38-B44; A38-B45; A38-B46; A38-B47; A38-B48; A38-B49; A38-BS0; A39-B51; A38-B52; A38-B53; A38-B54; A38-B55; A38-B56; A38-B57; A38-B59; A38-B59; A38-B60; A38-B61; A38-B62; A38-B63; A38-B64; A38-B65; A38-B66; A38-B67; A38-B68; A38-B69;) A38-B70; A38-B71; A38-B72; A38-B73; A38-B74; A38-B75; A38-B76; A38-B77; A38-B78; A38-B79; A38-B80; A38-B8 1; A38-B82; A38-B83; A38-B84; A38-B85; A38-B96; A38-B87; A38-B88; A38-BS9; A38-B90; A38-B91; A38-B92; A38-B93; A38-B94; A38-B95; A38-B96; A38-B97; A38-B98; A38-B99; A38-B100; A38-B1O1; A38-B102; A38-B103; A3 8-B 104; A38-B105; A3 8-B 106; A38-B107; A38-B108; A38-BI09; A38-B11O; A38-Bll1; A38-B112; A38-BI113; A38-B114; A38-B115; A38-B116; A38-BI17; A39-B118; A38-Bl119; A38-B120; A38-B121; A38-B122; A38-B123; A38-B124; A38-B125; A38-B126; A38-B127; A38-B128; A38-B129; A38-B130; A38-B131; A38-B132; A38-B133; A38-B134; A38-B135; A38-B136; A38-BI37; WO 031035065 WO 03/35065PCT/GB02/04763 A38-BI38; A38-B139; A38-BI40-; A38-B141; A38-B142; A38-B143; A38-B 144; A38-B145; A38-BI46; A38-B147; A38-B148; A38-B149;- A3S-B]150; A38-B151; A38-B152; A38-B 153; A38-B154; A38-B155; A38-B156; A38-B157; A38-B158; A38-B159; A38S-B 160; A38-BI61; A38-B162; A38-B163; A38-B164; A38-BI65; A38-B166; A38-B167; A38-BI68; A38-BI69; A39-B1; A39-B2; A39-B3; A39-B4; A39-B5; A39-B6; A39-B7; A39-B8; A39-B9; A39-B A39-B11; A3 9-B 12; A39-B13; A39-B14; A39-B15; A3 9-B 16; A39-B17; A39-BI8; A39-B]9; A39-B20; A39-B21; A39-B22; A39-B23; A39-B24; A39-B25; A39-B26; A39-B27; A39-B28; A39-B29; A39-B30; A39-B3 1; A39-B32; A3)9-B33; A39-B34; A39-B35; A39-B36; A39-B37; A39-B38; A39-B39; A39-B40; A39-B4 1; A39-B42; A39-B43; A39-B44; A39-B45; A39-B46; A39-B47; A39-B48; A39-B49; A39-B50; A39-B51t A39-B52; A39-B53; A39-B54; A39-B55;, A39-B56; A39-B57; A39-B58; A39-B59; A39-B60; A39-B61; A39-B62; A39-B363; A39-B64; A39-B65; A39-B66; A39-B67; A39-B68; A39-B69; A39-B70; A39-B7 1; A39-B72; A39-B73; A39-B74; A39-B75; A39-B76; A39-B77; A39-B78; A39-B79; A39-B8O; A39-BS1;l A39-B82; A39-B83; A39-B84; A39-B85; A39-B86; A39-B87; A39-B88; A39-B89; A39-B90; A39-B91; A39-B92; A39-B93; A39-B94; A39-B95; A39-B96; A39-B97; A39-B98; A39-B99; A39-B100; A39-B1O1; A39-BI02; A39-B103; A39-BI04; A39-B105; A39-B106; A39-B107; A39-BI08; A3 9-B 109; A39-B 110; A39-B 111; A39-B112; A39-B113; A39-B 114; A39-B 115; A39-B 116; A39-B117; A39-BI18S; A39-B 1 19; A39-B120; A39-B121; A39-B122; A39-B 123; A39-B124; A39-B125; A39-B126; A39-B127; A9B 128; A9B2; A39-BI30; A39-B131; A39-BI32; A39-B133; A39-B 134; A3 9-B 13 5; A39-B136; A3 9-.B137; A39-B138; A39-BI39; A39-B 140; A39-B141; A39-B142; A39-B143; A39-B 144; A39-B145; A39-B146; A39-B147; A39-BI48; A39-BI49; A39-B 150; A39-B151; A39-B152; A39-B153; A39-B154; A3 9-B 15 5; A39-B 156; A39-B157; A39-B158; A39-BI59; A39-B160; A3 9-B 16 1; A39-B 162; A39-B163; A39-B164; A39-B165; A39-B166; A39-B167; A39-B168; A39-B169; A40-B1; A40-B2; A40-B3; A40-B4; A40-B5; A40-B6- A 4-0-B7; A40-B8-, A40-B9; WO 031035065 WO 03/35065PCT/GB02/04763 -142- A40-B 11; A40-B 12; A40-B13; A40-B14; A40-B 16; A40-B17; A40-B 18; A40-B 19; A40-B20; A40-B2 1; A40-B22; A40-B23; A40-B24; A40-B25; A40-B26; A40-B27; A40-B28; A40-B29; A40-B30; A40-B3 1; A40-B32; A40-B33; A40-B34; A40-B35; A40-336; A40-B37; A40-B38; A40-B39; A40-B40; A40-B41; A40-B42; A40-B43; A40-B44; A40-B45; A40-B46; A40-B47; A40-B48; A40-B49; A40-B50; A40-B5 1; A40-B52; A40-B53; A40-B54; A40-B55; A40-B56; A40-B57; A40-B58; A40-B59; A40-B60; A40-B61; A40-B62; A40-B63; A40-B64; A40-B65; A40-B66; A40-B67; A40-B68; A40-B69; A40-B70; A40-B71; A40-B72; A40-B73; A40-B74; A40-B75; A40-B76; A40-B77; A40-B78; A40-B79; A40-B80; A40-B81; A40-B82; A40-B383; A40-B84; A40-B85; A40-1886; A40-B87; A40-B88; A40-B89; A40-B90; A40-B9 1; A40-B92; A40-B93; A40-B94; A40-B95; A40-B96; A40-B97; A40-B98; A40-B99; 100; A40-B 101; A40-B 102; A40-B 103; A40-B 104; A40-B 105; 106; A40-B 107; A40-B 108; A40-B 109; A40-B 110; A40-B 111; 112; A40-B 113; A40-B 114; A40-B 115; A40-B 116; A40-B 117; 118; A40-B 119; A40-B 120; A40-B121; A40-B 122; A40-B123; A40-BI24; A40-B 125; A40-B 126; A40-B 127; A40-B 128; A40-B 129; A40-B130; A40-B13 t; A40-B 132; A40-B133; A40-B 134; A40-B135; A40-B136; A40-B137; A40-B138; A40-B139; A40-B 140; A40-B141; 142; A40-B 143; A40-B 144; A40-B 145; A40-B 146; A40-B147; A40-B148; A40-B 149; A40-B 150; A40-B151; A40-B152; A40-B153; 154; A40-B155; A40-B 15 6; A40-B 157; A40-B 15 8; A40-B 159; 160; A40-B1 61; A40-B 162; A40-B 163; A40-B 164; A40-B1 166; A40-B 167; A40-B168; 4 0 -B 16 9; A41-B1; A41-B2, A41-B3; A41-B4; A41-B5; A41-B6; A41-B7; A41-B8; A41-B9; A41-B1O; A41-Bl1; A41 B 12; A41-B13; A41-B14; A4 I-B 15; A41 -B 16; A41-B 17; A41-B18; A41-B19; A41-B20; A41-B21; A41-B22; A41-B23; A41-B24; A41-B25; A41-B26; A41I-B27; A41-B28; A41-B29; A41-B3C; A41-B31; A41-B32; A41-B33; A41-B34; A41-B05; A41-B36; A41-B37; A41-B38; A41-B39; A41-B40; A41-B41; A41-B42; A41-B43; A4 I-B44; A41-B45; A41-B46; A41-B47) A41-B48; A41-B49; A41-B50; WO 031035065 WO 03/35065PCT/GB02/04763 -143- A4 1 -B5 1; A4 1-B52; A4 1-B53; A41-B54; IA41 -B 55; A41-B56;

I-I

A4 1-B 57; A4 1-B5 8; A4 1-B5 9; A41-B60; A41 -B 61; A41-1362; A41 -B63; A41-B64; A41-B65; A41-B66; A41-B67; A41-B68; A41-B69; A41-B70; A41 -B7 1; A41-B72; A41-B73; A41-B74; A41 -B75; A41-B76; A41-B77; A41-B78; A41-B79; A41-BSO; A41-B81; A41-B82; A41-B83; A41-B84; A41-B85; A41-B86; A41-B87; A41-B88; A41-B89; A41-B90; A41-KB91; A41-B92; A41-B93; A41-B94; A41-B95; A41-B96; A41-B97; A41-B98; A41-B99; A41-BI00; A41I-B tO01; A41-B102; A41-B103; A41-B104; A41 -B 105; A41-B106; A4 1-B 107; A41-B108; A41-B109; A41-B11O; A41-Blll; A41-D112; A41-B113; A41-B114; A41-B115; A41-B116; A41-B117; A41-BI18; A41-B119; A41-B120; A41-B121; A41-B3122; A41-B123; A41I-B 124; A41-B125; A41-B126; A41-B127;- A41-B128; A41 -B 129, A41I-B 130; A41-B131; A41 -B 132; A41-B133; A4 1-B 134; A41-B135; A41-B136; A41-B137; A41-B138; A41-B139; A41I-B 140; A41-B141; A41I-B 142; A41-B143; A4 I-B 144; A41I-B 145; A41 -B 146; A41-B147-; A41-B148; A41-B149; A41-B150; A41-B151; A41-B152; A41-B153; A41-B154; A41-B155; A41-B156; A41-B157; A41-B158; A41-B159; A41-B160; A41-B161; A4 1-B 162; A41 -B 163; A41-B164; A41-B165; A41-B166; A41-B167; A41-B168; A41-B169; A42-Bt; A42-B2; A42-B3; A42-B4; A42-B5; A42-B6; A42-B7; A42-B8; A42-B9; A42-B1O; A42-B 11; A42-B 12; A42-B13; A42-B14; A42-B15; A42-B16; A42-B 17; A42-B 18; A42-B19; A42-B20; A42-B21; A42-B22; A42-B23; A42-B24; A42-B25; A42-B26; A42-B27; A42-B28; A42-B29; A42-B30; A42-B3 1; A42-B32; A42-B33; A42-B34; A42-B35; A42-B36; A42-B37; A42-B38; A42-B39; A42-B40; A42-B41; A42-B42; A42-B43; A42-B44; A42-B45; A42-B46; A42-B47; A42-B48; A42-B49; A42-B50; A42-B5 1; A42-B52; A42-B53; A42-B54; A42-B55; A42-B56; A42-B57; A42-B58; A42-B59; A42-B60; A42-B61; A42-B62; A42-B63; A42-B64; A42-B65; A42-B66; A42-B67; A42-B68; A42-B69; A42-B70; A42-B71; A42-B72; A42-B73; A42-B74; A42-B75; A42-B76; A42-B77; A42-B78; A42-B79; A42-B8O; A42-B81; A42-B82; A42-B83; A42-B84; A42-B85; A42-B86; A42-B87; A42-B88; A42-BS9; A42-B90; WO 031035065 WO 03/35065PCT/GB02/04763 -144- A42-B92; A42-B93; A42-B94; A42-B95; A42-B96; A42-B97; A42-B98; A42-B99; A42-B 100; A42-B 10 1; A42-B 102;- A4 2 -B 103; A42-B104; A42-B 105; A42-B 106; A42-B107; A42-B108; A42-B109; A42-B11O; A42-B 111; A42-B t 12; A42 -B 113; A42-B 114; A42-B 115; A42-B 116; A42-B 117; A42-BI 18; A42-B 119; A42-B 120; A42-B121; A42-B 122; A42- 3123; A42-B 1 24; A42-B 125; A42-B126; A42-B127; A42-BI28; A42-B 129; A42-B130; A42-B 13 1; A42-B132; A42-B133; A42-B134; A42-B 135; A42-BI36; A42-B 137; A42-B138; A42-B139; A42-BI40; A42-BI41; A42-B142; A42-B 143; A42-B144; A42-B 145; A42-B146; A42-B 14'7; A42-B148; A42-B 149; A42-B 150; A42-B 15 1; A42-B152; A42-B153; A42-B154; A42-B 155; A42-B156; A42-B 157; A42-B158; A42-B 159; A42-B160; A42-B 16 1; A42-B162; A42-B 163; A42-B164; A42-B 165; A42-B166; A42-B 167; A42-BI68; A42-B 169; A43-Bl; A43-B2; A43-B3; A43-B4; A43-B5; A43-B6; A43-B7; A43-B8; A43-B9; A43-B1O; A43 -B 11; A43 -B 12; A43 -B 13; A43-B14; A43-BI5; A43 -B 16; A43 -B 17; A43-BI8; A43-B19; A43-B20; A43 -B2 1; A43-B22; A43-B23; A43-B24; A43-B25; A43-B26; A43-B27; A43-B28; A43-B29; A43-B30; A43 -B3 1; A43-B32; A43-B313; A43-B34; A43-B35;- A43-B36; A43-B37; A43-B38; A43-B39; A43-B40; A43-B41; A43-B42; A43-B43; A43-B44; A43-B45; A43-B46; A43-B47; A43-B48; A43-B49; A43-B50; A43-B51; A43-B52; A43-B53; A43-B54; A43-B55; A43-B56; A43-B57; A43-B58; A43-B59; A43-B60; A43-B61; A43-B62; A43-B63; A43-B64; A43-B65; A43-B66; A43-B67; A43-B68; A43-B69; A43-B70; A43-B71; A43-B72; A43-B73; A43-B74; A43-B75; A43-B76; A43-B77; A43-B78; A43-B79; A43-B80; A43-B91; AX43-B82; A43-B83; A43-B84; A43-B85; A43-B86; A43-B87; A43-B88; A43-B89; A43-B90; A43-B91; A43-B92; A43-B93; A43-B94; A43-B95; A43-B96; A43-B97; A43-B98; A43-B99; A43 -B 100; A43-B1O1; A43-B102; A43-B103; A43-B 104; A43-B105; A43-BI06; A43-B107; A43-B1OS; A43-B109; A43-B 110; A43-B 111; A3 -B 112; A43-B 1 13; A43 -B 114; A43-B115; A43 -B 116; A43-B117; A43-B11S; A43-B 119; A43-B120; A43-B121; A43 -B 122; A43-B123; A43-B124; A43-B125; A43-B126; A43-B127; A43-B128; A43-BI29; A43-B130; A43-B 13 1; A43-B132; WO 031035065 WO 03/35065PCT/GB02/04763 -145- A-43-B 13 3 A43-B 134; A43-B135; A43-BI36; A43-B137; A43-B 138; A43-B139; A43-B 140; A43-B141; A43-B 142; A43-B143; A43-BI44;- A43-B 145; A43-B 146; A43-B147; A43-B148; A43-B149; A43-B150; A43-B151; A43-B 152; A43-B153; A43-B t54; A43-B155; A43-B156; A43-B157; A43-B158; A43-B159; A43-B160; A43 -B 161; A43-B162; A43-B163-) A43-B 164; A43-B165; A43-B166; A43-B167; A43-B168; A43-B 169; A44-BI1; A44-B2; A44-B3; A44-B4; A44-B5; A44-B6; A44-B7; A44-BS; A44-B9; A44-B 10; A44-B 11; A44-B12; A44-B 13; A44-B14; A44-B 15; A44-B 16; A44-B 17; A44-B1IS; A44-B 19; A44-B20; A44-B21; A44-B22; A44-B23; A44-B24; A44-B25; A44-B26; A44-B27; A44-B28; A44-B29; A44-B30; A44-B331; A44-B32; A44-B33; A44-B34; A44-B35; A44-B36; A44-B3'1; A44-B38; A44-B39; A44-B40; A44-B41; A44-B42; A44-B43; A44-B44; A44-B45; A44-B46; A44-B47, A44-B48; A44-B49; A44-B50; A44-BS51; A44-B52; A44-B53; A44-B54; A44-B55; A44-B56; A44-B57; A44-B58; A44-B59; Ak44-B60; A44-B 61; A44-B62; A44-B63; A44-B64; A44-B65; A44-B66; A44-B67; A44-B68; A44-B69; A44-B70; A44-B71; A44-B72; A44-B73; A44-B74; A44-B75; A44-B76;- A44-B77; A44-B78; A44-B79; A44-B80; A44-B81; A44-B82; A44-B83; A44-B84; A44-BBS; A44-B86; A44-B87; A44-B88; A44-B89; A44-B90; A44-B91; A44-B92; A44-B93; A44-B94; A44-B95; A44-B96; A44-B97; A44-B98; A44-B99; A44-B 100; A44-B1O1; A44-B 102; A44-B 103; A44-B 104; A44-B 105; A44-B 106; A44-B 107; A44-B 108; A44-B109; A44-BI 10; A44-B1I11; A44-B 112; A44-B 113; A44-B 114; A44-B 115; A44-B 116; A44-B 117; A44-B 118; A44-B 119; A44-B 120; A44-B 121; A44-B3 122; A44-B 123; A44-B 124; A44-B 125, A44-B 126; A44-B127; A44-B 12 8; A44-B129; A44-B 130; A44-B131; A44-B 132; A44-B133; A44-B 134; A44-B 135; A44-B 13 6; A44-B137; A44-B 13 8; A44-B 13 9; A44-B 140;- A44-B 141; A44-B 142; A44-B143; A44-B144; A44-B 145; A44-B146; A44-B 147; A44-B148; A44-B 149; A44-B 150; A44-B 15 1; A44-B152; A44-B 153; A44-B 154; A44-B 155; A44-B156; A44-B 157; A44-B158; Z4 4 -Bt15 9 A44-B 160; A44-B161; A44-B 162; A44-B 163; A44-B 164; A44-B 165; A44-B 166; A44-B 167; A44-B168; A44-B 169; A45-B1; A4-5-B2;, A45-B3; A45-B4; WO 031035065 WO 03/35065PCT/GB02/04763 -146- A45-B5; A45-B6; A45-B7; A45-B8; A45-B9; A45-B1O; 11; A45-B 12; A45-B13; A45-B14; A45-B15-; A45-B16; 17; A45-B18; A45-B19; A45-B20; A45 -B2 1; A45-B22; A45-B23; A45-B24; A45-B25; A45-B26, A45-B27; A45-B28; A45-B29; A45-B30; A45-B3 1; A45-B32; A45-B33; A45-B34; A45-B35; A45-B36; A45-B37; A45-B38; A45-B39; A45-B40; A45-B41; A45-B42; A45-B43; A45-B44; A45-1345; A45-B46; A45-B47; A45-B48; A45-B49; A45-B50; A45-B5 1; A45-B52; A45-B53; A45-B54; A45-B55; A45-B56; A45-B57; A45-B58; A45-B59; A45-B60; A45-B61; A45-B62; A45-B63; A45-B64; A45-B65; A45-B66; A45-B67; A45-B68; A45-B69; A45-B70; A45-B7 1; A45-B'72; A45-B73; A45-B74; A45-B75; A45-B76; A45-B77; A45-B78; A45-B79; A45-B8O; A45-B81; A45-B82; A45-B83; A45-B84; A45-B85; A45-B86; A45-B87; A45-B88; A45-B89; A45-B90; A45-BR91; AX45-B92; A45-B93; A45-B94; A45-B95; A45-B96; A45-B97; A45-B98; A45-B99; A45-B1O1; A45-B 102; A45-B 103; A45 -B 104; A45-B 105; A45-Bt06; A45-B107; A45-B 108; A45-B 109; A45-B1IO; A45-Bl11; A45-B112; A45-Bl113; A45-B 114; A45-B 115; A45-B 116; A45-B117; A45 -B 118; 119; A45-B120; A45-B 12 1; A45-BI22; A45-B123; A45-B124; A45-B125; A45-B126; A45-B 127; A45-B128; A45-B129; A45-B130; A45-B131; A45-B132; A45-BI33; A45-B134; A45-B135; A45-B136; A45-B137; A45-BI38; A45-B139; A45-B140; A45-B 141; A45-B142; 143; A45-B144; A45-B145; A5B6; A45-B 147; A45-B148; 149; A45-B150; A45-B 15 1; A45-B152; A45-B153; A45-B 154; A45-B155; A45-B156; A45-B 157; A45-B158; A45-B159; A45-BI60; A45-B161; A45-B162; A45-B163; A45-BI64; A45-B165; A45-BI66; 167; A45-B168; A45-B169; A46-B1; A46-B2; A46-B3; A46-B4; A46-B5; A46-B6; A46-B7; A46-B8; A46-B9; A46-B1O; A46-B 11; A46-B12; A46-Bt3; A46-B14; A46-B15; A46-B16; A46-B 17; A46-B 18; A46-B19; A46-B20; A46-B21; A46-B22; A46-B23; A46-B24; A46-B25; A46-B26; A46-B27; A46-B28; A46-B29; A46-B30; A46-l3 1; A46-B32; A46-B33; A46-B34; A46-B35; A46-B36; A46-B37; A46-B38; A46-B39; A46-B40; A46-B41; A46-B42; A46-B343; A46-B44; A46-B45; WO 031035065 WO 03/35065PCT/GB02/04763 -147- A46-B46; A46-B47; A46-B48;- A46-B49; A46-B50; A46-B51; A46-B52; A46-B53; A46-B54; A46-B55; A46-B56; A46-B57; A46-B59; A46-B59; A46-B60; A46-B61; A46-B62; A46-B63; A46-B64; A46-B65; A46-B66; A46-B67; A46-B68; A46-B69; A46-B70; A46-B71; A46-B72; A46-B'73; A46-B74; A46-B75; A46-B76; A46-B77; A46-B78; A46-B79; A46-B8O; A46-B81; A46-B82; A46-B83; A46-1B84; A46-B85; A,46-B86;- A46-B87; A46-B88; A46-B89; A46-B90; A46-B91; A46-B92; A46-B93; A46-B94; A46-B95; A46-T396; A46-B97; A46-B98:, A46-B99; A46-B100; A46-B1O1; A46-B 102; A46-BI03; A46-B 104; A46-B 105; A46-B106; A46-B 107; A46-B 108; A46-B109; A46-B 1 10; A46-B1 111; A46-BT 112; A46-B 13; A46-B 114; A46-B1 15; A46-B 116; A46-B 117; A46-BI118; A46-B 119; A46-B 120; A46-B121; A46-B122; A46-B123; A46-B124; A46-B 125; A46-B126; A46-B 127; A46-B 128; A46-B129; A46-B 130; A46-B 13 t; A46- 13 32; A46-B133; A46-B 134; A46-BI35; A46-B136; A46-B 137; A46-B138; A46-B139; A46-B 140; A46-B 14 1; A46-B 142; A46-B 143; A46-B 144; A46-B 145; A46-B 146; A46-B 147; A46-B148; A46-B 149; A46-B 150; A46-B 151 A46-B 152; A46-B 153; A46-B 154; A46-BI55; A46-B156; A46-B157; A46-B158; A46-B159; A46-B 160; A46-B161; A46-B162; A46-B163; A46-B 164; A46-B 165; A46-B 166; A46-B 167; A46-fl168; A46-B 169; A47-B1; A47-B2; A47-B3; A47-B4; A47-B5; A47-B6; A47-B7; A47-B8; A47-B9; A47-B 10; A47-B 11; A47-B 12; A47-B 13; A47-B14; A47-B 15; A47-B 16; A47-B17;- A47-B 18; A47-B 19; A47-B20; A47-B21; A47-B22; A47-B23; A47-B24; A47-B25; A47-B26; A47-B27; A47-B28; A47-B29; A47-B30; A47-B31; A47-B32; A47-B333; A47-B34; A47-B35; A47-B36; A47-B37; A47-B38; A47-B39; A47-B40; A47-B41; A47-B42; A47-B43; A47-B44; A47-B45; A47-B46; A47-B47; A47-B48; A47-B49; A47-B50; A47-B5 1; A47-B52; A4'7-B53; A47-B54;) A47-B55; A47-B56; A47-B57; A47-B58; A47-B59; A47-B60; A47-B6 1; A47-B62; A47-B63; A47-B64; A47-B65; A47-B66; A47-B67; A47-B68; A47-B69; A47-B70; A47-B'71; A 4-7-B72; A47-B73; A47-B74; A47-B75; A47-B76; A47-B77; A47-B78; A47-B79; A47-B8O; A47-B81; A47-B82; A47-B83; A7B84; A47-B85; A47-B386; WO 031035065 WO 03/35065PCT/GB02/04763 -148- A47-B87; A47-B88; A47-B89; A47-B90; A47-B91; A47-B92; A47-B93; A47-B94; A47-B95; A47-B96; A47-B97; A47-B98; A47-1399; A47-B100; A47-B1OI; A47-B102; A47-B103; A47-B 104; A47-B 105; A47-B 106; A47-B107; A4'7-B 108; A47-BI09; A47-B1 A47-B I11; A47-B 112; A47-B113; A47-B 114; A47-B115; A47-B 116; A47-B 117; A47-B 118; A47-B119; A47-B 120; A,47-BI21; A47-B 122; A47-B 123; A47-B 124; A47-B125; A47-B126;- A,47-B127; A47-B128; A47-B 129; A47-B130; A47-B131; A47-B 132; A47-B133; A47-B 134; A47-B135; A47-B 1 36; A47-B137; A47-B138; A47-B139, A47-B 140; A47-B141; A47-B 142; A47-B143; A47-B 144;, A47-B145; A47-B 146; A47-B147; A47-B 148; A4'7-BI49; A47-B150; A47-B151; A47-B 152; A47-B153; A47-B 154; A47-B155; A47-B156; A47-B157; A47-B158; A47-B159; A47-B 160; A47-B 16 1; A47-B 162; A47-B 163; A47-B 164; A47-B 165; A47-B166; A47-B 167; A47-B 168; A47-B 169; A48-B1; A48-B2; A48-B3; A48-B4; A48-B5; A48-B6; A48-B7; A48-Bg; A48-B9; A48-BIO; A49-B 11; A48-B12; A48-B 13; A48-B14; A48-B15; A48-B 16; A4 S-B 17; A48-B18; A48-B 19; A48-B20; A48-B21; A48-B22; A48-B23; A48-B24; A48-B25; A48-B26; A48-B27; A48-B28; A48-B29; A48-B30;- A48-B3 1; A48-B32; A48-B33; A48-B34; A48-B35; A48-B36; A48-B37; A48-B38; A48-B39; A48-B40; A48-B41; A48-B42; A48-B43; A48-B44; A48-B45; A48-B46; A48-B47; A48-B48; A48-B49; A48-B50; A48-B5 1; A48-B52; A48-B53; A48-B54; A48-B55; A48-B56; A48-B57; A48-B58; A48-B59; A48-B60; A48-B61; A48-B62; A48-B63; A48-B64; A48-B65; A48-B66; A48-B67; A48-B68; A48-B69; A48-B70; A48-B7 1; A48-B72; A48-B73; A48-B74; A48-B75; A48-B76; A48-B77; A48-B78; A48-B79; A48-BSO; A48-B81; A48-B82; A48-B83; A48-B84; A48-B85; A48-B86; A48-B87; A48-B88; A48-B89; A48-B90; A48-B91; A48-B92; A48-B93; A48-B94; A48-B95; A48-B96; A48-B97; A48-B98; A48-B99; A48-B 100; A48-B 101; A48-B 102; W4 8 -B 10 3; A48-B 104; A48-B105; A48-B106; A48-B 107; A48-BI08; A48-B109; A48-B1O; A48-B 111; A48-B112; A48-'B113; A48-B114; A48-BI15; A48-B1 16; A48-B 1 17; A48-B1S; A48-B1 19; A48-B120; A48-B121; A48-B122; A48-B123; A48-B124; A48-B125; A48-B126; A48-B127; WO 031035065 WO 03/35065PCT/GB02/04763 A48-B 128; A48-B 129; A48-B 130; A48-B13 1; A48-B132; A48-B 133; A48-B 134; A48-B135; A48-B136; A48-B137; A48-B138; A48-B 139; A48-B 140; A48-B 141; A48-B 142; A48-B 143; A48-B 144; A48-B 145; A48-B146; A48-B 147; A48-B148; A48-B 149; A48-B150; A48-B 15 1; A48-B152; A48-B153; A48-B154; A48-B 3155; A48-B156; A49-B 157; A48-B158; A48-B159; A48-B160; A48-B 16 1; A48-B162; A48-B163; A48-B164; A48-B165; A48-B166; A48-B167; A48-B168; A48-B169; A49-BI1; A49-B2; A49-B3; A49-B4; A49-B5; A49-B6;- A49-B7; A49-BRg A49-B9; A49-B1O; A49-B 11; A49-B 12; A49-B 13; A49-B 14; A49-B15; A49-B 16; A49-B17; A49-B 18; A49-B 19; A49-B20; A49-B2 1; A49-B22; A49-B23; A49-B24; A49-B25; A49-B26; A49-B27; A49-B28; A49-B29; A49-B30; A49-B3 1; A49-B32; A49-B33; A49-B34; A49-B35; A49-B36; A49-B37; A49-B38; A49-B39; A49-B40; A49-B41; A49-B42; A49-B43; A49-B44; A49-B45; A49-B46; A49-B347; A49-B48; A49-B49; A49-b50; A49-B5 1; A49-B52; A49-B53; A49-B54; A49-B55; A49-B56; A49-B57; A49-B58; A49-B59; A49-B60; A49-B6 1; A49-B62; A49-B63; A49-B64; A49-B65; A49-B66; A49-B67; A49-B68; A49-B69; A49-B70; A49-B71; A49-B72; A49-B73; A49-B74; A49-B75; A49-B76; A49-B77; A49-B78; A49-B79; A49-BSO; A49-B81; A49-B82; A49-B83; A49-B84; A49-B95; A49-B86; A49-B87; A49-B88; A49-B89; A49-B90; A49-B91; A49-B92; A49-B93; A49-B94; A49-B95; A49-B96; A49-B97; A49-B98; A49-B99; A49-B100; A49-B1O1; A49-B102; A49-B 103; A49-B 104; A49-B 105; A49-B 106; A49-B107; A49-B108; A49-B 109; A49-B1 10; A49-B1 11; A49-B 112; A49-B1 13; A49-B 114; A49-B1I15; A49-B 116; A49-B 117; A49-B 118; A49-B119; A49-B 120; A49-B 12 1; A49-B 122; A49-B 123; A49-B 124; A49-B 125; A49-B 126; A49-B 127; A49-B 128; A49-B 129; A49-B 130; A49-B 13 1; A4 9- B13 3; A49-B133; A49-B 134; A49-B135; A49-B136; A49-B137; A49-B138; A49-B 13 9; A49-B3140; A49-B141; A49-B142; A49-B143; A49-B 144; A49-B145; A49-B 146; A49-B147; A49-B148; A49-B149; A49-B150; A49-B151; A49-B t52; A49-B153; A49-B154; A49-B155; A49-Bt56; A49-B157; A49-B158; A49-B 15 9; A-4-9-B 160; A49-B161; A49-B162; A49-B163; SA49-B 164; A49-B 165; A49-B 166; A49-B 167; A49-B168; j J WO 031035065 WO 03/35065PCT/GB02/04763 -150- A49-B 169; A50-Bi1 A50-B2; A50-B3; A50-B4; A50-B5; A50-B6; A50-B7; A50-B8; A50-B9; A50-B1O; A50-B 11; A50-B12; A50-B 13; A50-B14; A50-B315; A50-B16; A50-B17; 18; A50-B 19; A50-B20; A50-B21; A50-B22; A50-B23; A50-B24; A50-B25; A50-B26; A50-B27; A50-B2QS AS0-B29; A50-B30; A50-B31; A50-B32; A50-B33; A50-B34; A50-B35; A50-B36; A50-B37; A50-B38; A50-B39; A50-B40; A50-B41; A50-B42; A50-B43; A50-B44; A50-B45; A50-B46; A50-B47; A50-B48; A50-B49; A50-B50; A50-B5 1; A50-B52; A50-B53; A50-B54; A50-B55; A50-B56; A50-B57; A50-B58; A50-B59; A50-B60; A50-B61; A50-B62; A50-B63; A50-B64; A50-B65; A50-B66; A50-B67; A50-B68; A50-B69; A50-B70; A50-B71; A50-B72; A50-B73; A50-B74; A50-B75; A50-B76; A50-B77; A50-B78; A50-B79; A50-B80; A50O-B 81; A50-B82; A50-B83, A50-B84; A50-BR5; A50-B86; A50-B87; A50-B88; A50-B89; A50-B90; AS 0-B 91; A50-B92; A50-B93; A50-B94; A50-B95; A50-B96; A50-B97; A50-B98; A50-B99; A50-BIOO; 102; A50-B103; AS50-B 104; AS50O-Bl10 A50-B 106; ASO-B 107; 108; A50-BI09; A50-B11O; A50-B Il1; A50-B112; A50-B113; A50-B114; A50-Bl115; A50-B 116; A50O-B 117; A50-BI18; A50-B 119; A50-B120; A50-B121; A50-B 122; A50-B123; A50-B 124; A50-BI25; A50-B126; A50-B 127; A50-B128; A50-B129; A50-B 13 0; A50-B131; A50-B132; A50-B133; A50-B134; A50-B135; AS0-B 13 6; A50-B137; 13 8; A50-B139; A50-B140; A50-BI41; A50-B142; A50-B1343; 144; A50-B 145; A50-B146; A50-B 147; A50-B148; A50-B149; A50-Bi15i; A50-B152; A50-B 153; A50-B154; A50-B155; 156; A50-B 157; A50-B158; A50-B 159; A50-B160; A50-B161; A50-B162; A50-B163; A50-B164; A50-B 165; A50-B166; A50-B167; A50-B168; A50-B169; A51-B1; A51-B2; A51-B3; A 1 -B4; AS 1-B5; A51-B6; A51-B7; A51-B8; A51-B9; A51-BIO; A5 1-B 12; A51I-B 13; A5 1-B 14; A5i-BI5; A51-B16; A51I-B 17; AS I-B 18; AS I-B 19; A51-B20; AS I-B2 1; A51I-B22; A51-B23; A 1 -B24; A5 I-B25; A51-B26; A;5 1 -B27, A51-B28; A51I-B29; A51-B30; A51-B31; A51-B32; A51-B33; A51I-B34; A51-B35; A51-B36; A51-B37; A51-B38; A51-B3)9; AS 1-B40; WO 031035065 WO 03/35065PCT/GB02/04763 -151- A51I-B4 1; A5 1-B42; A51-B43; A51I-B44; A51-B45; A51-B46; 1-B47; A51-B48; A51-B49; A51I-B50; A51-B51; A51-B352; A51-B53; A5 I-B54; A51-B55; A5 I-B56; A51-B57; A51I-B58; A51-B59; A51-B60; A51-B61; A51-B62; A51-B63; A5 I-B64; A51-B65; A51-B66; A51-B67; A51-B68; A51-B69; A51I-B70; A51-B71; A51-B72; A51I-B73; A51-B74; A51-B75; A51I-B76; I-B77; A51-B78; A51-B79; A51-B380; A51-B81; A51-B82; A51-B83; A51-B84; A51-B85; A51I-B86; A51-B87; A51-B88; A51-B89; A51-B90; A51 9 1; A51-B92; A51-B93; A51-B94; A51-B95; A51-B96; A5 1-B 97; A51-B98; A51-B99; A51-B100; A51-BIOI; A51-B102; A51-B103; A51I-B 104; A51-B105; A51-B106; A51-B113; A51-B114; A5 I-B 109; A51-Bl16; A51-Bl17; A51-B112; A51-B119; A51-B120; A51-B121; A5 I-B 122; A51-B123; A51I-B 124; A51-B125; A51-B19&; A51127; A5 1-B 128; A51-B129; A51-BI30; A51-B131; A5 1-B132; A51-B133; A51I-B 134; A51-B135; A51-B136; A51-B137; A51-B138; A51-B139; A51-B140; A51-B141; A51I-B 142; A51-BI43; A5 I-B 144; A51-BI45; A51-BI46; A51-B147; A51-B148; A51-BI49; A51-B150; A51-B151; A51-B152; A51-B153; A51-B154; A51-B155; A51-B156; A51-B157; A51-BI58; A51-B159; A51-B160; A51-B161; A51-B162; A51-B163; A5I B 164; A51-B165; A51-B166; A51-B167; A51-BI68; A51-BI69; A52-B1; A52-B2; A52-B3; A52-B4; A52-B5; A52-B36; A52-B7; A52-B8; A52-B9; A52-B1O; A52-B11; A52-B 12; A52-B13; A52-B 14; A52-B15; A52-B16; A52-B17; A52-B tS; A52-B19; A52-B20; A52-B21; A52-B22; A52-B23; A52-B24; A52-B25; A52-B26; A52-B27; A52-B28; A52-B29; A524330; A52-B3 1; A52-B32; A52-B33; A52-B34; A52-B35; A52-B36; A52-B37; A52-B38; A52-B39; A52-B40; A52-B41; A52-B42; A52-B43; A52-B44; A52-B45; A52-B46; A52-B47; A52-B48; A52-B49; A52-B50; A52-B5 1, A52-B52; A52-B53; A52-B54; A52-B55; A52-B56; A52-B57; A52-B58; A52-B59; A52-B60; A52-B61; A52-B62; A52-B63; A52-B64; A52-B65; A52-B66; A52-B67; A52-B68; A52-B69; A52-B70; A52-B71; A52-B72; A52-B73; A52-B74; A52-B375; A52-B76; A52-B77; A52-B78; A52-B79; A52-B80; A52-B81; WO 031035065 WO 03/35065PCT/GB02/04763 -152- A52-B82; A52-B83; A52-B84; A52-B85; A52-B86; A52-B87; A52-B88; A52-B89; A52-B90; A52-B91; A52-B92; A52-B93; A52-BR94; A52-B95; A52-B96; A52-B97; A52-B98; A52-B99; A52-B100; A52-BIO1; A52-B102; A52-B 103; A52-B104; A52-B105; A52-B 106; A52-B 107; A52-B 108; A52-B 109; A52-B11O; A52-B111; A52-B 112; A52-B 113; A52-B 114; A52-B 115; A52-B116; A52-B 117; A52-B1 18; A52-B 119; A52-B 120; A52-B121; A52-BI22-; A52-B123; A52-B 124; A52-B 125; A52-B 126; A52-B 127; A52-B128; A52-BI29; A52-B130; A52-B 13 1; A52-Bl32; A52-B 133; A52-B134; A52-B135; A52-BI36; A52-DB137; A52-B138; A52-B 139; A52-B140; A52-B3141; A52-BI42; A52-B 143; A52-B144; A52-B 145; A52-B146; A52-B 147; A52-B148; A52-B 149; A52-B150; A52-B 151; A52-B152; A52-B 153; A52-B 154; A52-BI55; A52-B156; A52-B 157; A52-B158; A52-BI159;1 A52'-BI60 A52-B 16 1 A52-B162; A52-B 163; A52-B164; A52-B 165; A52-B 166; A52-B 167; A52-B1]68; A52-B 169; A53-B1; A53-B2; A53-B3; A53-B4; A53-B5; A53-B6; A53-B7; A53-Bg; A53-B9; A53-B1O; A53-BI11; A5 3-B 12; A5 3-B 13; A53-B14;- A53-B15; A5 3-B 16; A53-B17; A5 3-B 18; A53-B19; A53-B20; A53-B21; A53-B22; A53-B23; A53-B24; A53-B25; A53-B26; A53-B27; A53-B28; A53-B29; A53-B30; A53-B3 1; A53-B32; A53-B33; A53-B34; A53-B35; A53-B36; A53-B37; A53-B38; A53-B39; A53-B40; A5 3-B4 1; A53-B42; A53-B43; A53-B44; A53-B45; A53-B46; A53-B47; A53-B48; A53-B49; A53-B50; A53-B5 1; A53-B52; A53-B53; A53-B54;) A53-B55; A53-B56; A53-B57; A53-B58; A53-B59; A53-B60; A53-B61; A53-B62; A53.-B63; A53-B64; A53-B65; A53-B66; A53-B67; A53-B68; A53-B69; A53-B70; A53-B71; A53-B72; A53-B73; A53-B74; A53-B75; A53-B76; A53-B77; A53-B78; A53-B79; A53-BSO; A53-B81; A53-B82; A53-B83; A53-B84; A53-B85; A53-B86; A53-B87; A53-B88; A53-B89; A53-B90; A53-B91; A53-B92; A53-B93; A53-B94; A53-B95; A53-B96; A53-B97; A53-B98; A53-B99; A53-B100; A53-B 101; A5 3-B 102; A53-B103; A53-B104; A53-B105; A53-B106; A53-B107; A53-B1OS; A53-B109; A53-B 110; A53-B111; A53-B 112; A53-B113; A53-B114; A53-B115; A53 -B 116; A53-B1 17; A53-B1 18; A53-B1 19; A53-B120; A53-B121; A53-B122; WO 031035065 WO 03/35065PCT/GB02/04763 -153- A53-B123; A53-B124;- A53-B125; A53-B126; A5 3-B 127; A53-B128; A53-B129; A53-B130; A53-B131; A53-B132; A53-B133; A53-B134; A53-B 135; A53-B136:, A53-B137; A53-B138; A53-B139; A53-B 140; A53-B 141; A53-B 142; A53-B 143; A5 3-B 144; A53-B 145; A53-B 146; A53-1B147; A53-B148; A53-B149; A53-B150; A53-B151; A53-B152; A53-B153; A53-B154; A53-B 155; A53-B156; A53-B157; A53-B158; A53-B159; A53-B160; A53-B161; A53-B162; A53-BI63; A53-B164; A53-B165; A53-B166; A53-B167; A53-B168; A53-B169; A54-B 1; A54-B2; A54-B3; A54-B4; A54-B5; A54-B6; A54-B7; A54-BS; A54-B9; A54-B t0; A54-B 11; A54-B12; A54-B 13; A54-B 14; A54-B 15; A54-Bt6; A54-B 17; A54-B 18; A54-B 19; A54-B20; A54-B21; A54-B22; A54-B23; A54-B24; A54--B25; A54-B26; A54-B27; A54-B 2 8; A 54-B29; A54-B30; A54-B3 1; A54-B32; A54-B33; A54-B34; A54-B35; A54-B36; A54-B37; A54-B38; A54-B39; A54-B40; A54-B41; A54-B42; A54-B43; A54-B44; A54-B45; A54-B46; A54-B47; A54-B48; A54-B49; A54-B50; A54-B51; A54-B52; A54-B53; A54-B54; A54-B55- A54-B56; A54-B57; A54-B58; A54-B59; A54-B60; A54-B61; A54-B62; A54-B63; A54-B64; A54-B65; A54-B66; A54-B67; A54-B68; A54-B69; A54-B70; A54-B71; A54-B72; A54-B73; A54-B74; A54-B75; A54-B76; A54-B77; A54-B78; A54-B79; A54-B8O; A54-B81; A54-B82; A54-B83; A54-B84; A54-B85; A54-BS6; A54-B87; A54-B89; A54-B89; A54-B90; A54-B9 1; A54-B92; A54-B93; A54-B94; A54-B95; A54-B96; A54-B97; A54-B98; A54-B99; A54-B 100; A54-B 101; A54-B 102; A54-B 103; A54-B 104; A54-B 105; A54-B 106; A54-B 107; A54-B 108; A54-B 109; A54-B1 10; A54-B1 11; A 54-1 12; A54-B 113; A54-B 114; A54-B 115; A54-B116; A54-B117; A54-B 118; A54-B 119; A54-B 120; A54-B121; A54-B 122; A54-BI23; A54-B 124; A54-B 125; A54-B 126; A54-B127; A54-B128; A54-B129; A54-B130; A54-B 13 1; A54-B132; A54-B133; A54-B 134; A54-B135; A54-B136; A54-B 137; A54-B138; A54-B139; A54-B 140; A54-B 14 1; A54-B 142; A54-B143; A54-B144; A54-B 145; A54-B 146; A54-B 147; A54-B 148; A54-B149; A54-BI50; A54-B 15 1; A54-B 152; A54-B 153; A54-B 154; A54-B1 55; A54-B 156; A54-B157; A54-B158; A54-BI59; A54-B160; A54-B161; A54-B162; A54-B163; WO 031035065 WO 03/35065PCT/GB02/04763 -154- A54-B 164; A54-B 165;- A54-B 166; A54-B 167; A54-B 168; A54-B 169; A55-B1; A55-B2; A55-B3; A55-B4; A55-B5; A55-B6; A55-B7; ASS-ES; A55-B9, A55-BlO; A55-BIt1; A5 5-B 12; A55-B13; A5 5-B314; A55-B15; A55-B 16; A5 5-B 17; A55-B1S; 5-B 19; A55-B20; A55-B21; A55-B22; A55-B23; ASS-B24; A55-B25; A55-B26; A55-B27. A55-B28; A55-B29; A55-B30; A55-B31; A55-B332; A55-B33; A55-B34; A55-B35; A55-B36; A55-B337; A55-B38; A55-B39; A55-B40; A55-B41; A55-B42; A55-B43; A55-B44; A55-B45; A55-B46; A55-B347; A55-B48; A55-B49; A55-B5O; A55-B5 1; A55-B52; A55-B53; A55-B54; A55-B55; A55-B56; A55-B57; A55-B58; A55-B59; A55-B360; A55-B61; A55-B62; A55-B63; A55-B64; A55-B65; A55-B66; A55-B67; A55-B68; A55-B69; A55-B70; A55-B71; A55-B72; A55-B73; A55-B74; A55-B75; A55-B76; A55-B77; A55-B78; A55-B79; A55-B80; A5-5-BR 1; A55-B82; A55-B83; A55-B84; A55-B85; A55--8-6 A55-B387; A55-B88; A55-B89; A55-B90; A55-B9 t; A55-B92; A55-B93; A55-B94; A55-B95; A55-B96; A55-B97; A55-B98; A55-B99; A55-BlOO; A55-BlOl; A55-B102; A55-B103; A55-B104; A55-B105; A55-B106; A55-B 107; A55-BI09; A55-BilO; A55-BIll1; A55-B112; A55-B 113; A55-BI14; 11; ASS-B116; A55-B 117; A55-B11S; A55-B119; A55-B120; A55-B121; A55-B 122; A55-B 123; ASS-B 124; ASS-B 125; A55-B126; A55-B127;- A55-B128; A55-B129; A55-B130; A5S-B131; A55-B132; A55-B133; A55-B134; A55-B135; A55-B136; ASS-BI37; ASS-Bl38; ASS-B139; A55-B140; A55-B141; -A55-B142; A55-B 143; A55-B144; A5S-B145; ASS-B146; ASS-BI47; A5S-B148; A55-B149; 1; A55-B152; A55-B153; A55-B154; ASS-BiSS; A55-B156; ASS-B157; ASS-BISS; A55-B159; A55-B160; A55-B161; A55-B162; ASS-B163; ASS-B164; A55-B165; A55-B166; A55-B167; ASS-B168; ASS-B169; A56-B1; A56-B2; A56-B3; A56-B4; A56-BS; A56-B6; A56-B7; A56-B8; A56-B9; A56-B1O; A56-Bl1; A56-B12; A56-B13; A56-B14; A56-B15; A56-B16; A56-B17; A56-B18; A56-B19; A56-B20; A56-B21; A56-B22; A56-B23; A56-B24; A56-B25; A56-B26; A56-B27; A56-B28; A56-B29; A56-B30; i A56-B31; A-30 A5B1; A56-B32; A56-B33; IA56-B34; I A56-B35; WO 031035065 WO 03/35065PCT/GB02/04763 -155- A56-B36; A56-B37; A56-B38; A56-B39; A56-B40; A56-B41; A56-B42; A56-B43; A56-B44; A56-B45; A56-B46; A56-B47; A56-B48; A,56-B49; A56-B50; A56-B51; A56-B52; A-,5-6-B53; A56-B54; A56-B55; A56-B56; A56-B57; A5-5; A56-B59; A56-B60; A56-B61; A56-B62; A56-B63; A56-B64; A56-B65; A56-B66; A56-B67; A56-B68; A56-B69;- A56-B70; A56-B71; A56-B72; A56-B73; A56-B74; A56-B75; A56-B76;- A56-B77; A56-B78; A56-B79; A56-B80; A56-B81; A56-B82; A56-B83; A56-B84; A56-B85; A56-B86; A56-B87; A56-B88; A56-B89; A56-B90; A56-B91; A56-B92; A56-B93; A56-B94; A56-B95; A56-B96; A56-B97; A56-B98; A56-B99; A56-B100; A56-B1O1; A56-BI02; A56-B 103; A56-BI04; A56-B105; A56-B106; A56-B107; A56-B1OS; A56-B109; A56-BI10O; 5 6 -B 111; A56-Bl112; A56-B 113; A56-B114; A56-B115; A56-B 116; A56-B117; A56-B 118; A56-B 119; A56-B120; A5 6-B 12 1; A56-BI22; A56-B123; A56-B124; A56-B125; A56-B126; A56-BI27; A56-B128; A56-B129; A56-B 130; A56-BI31; A56-B132; A56-B133; A56-BI34; A56-BI35; A56-B136; A56-B 137; A56-BI38; A56-B139; A56-BI40; A5 6-B 14 1; A56-BI42; A56-B143; A56-B144; A56-BI45; A56-B146; A 56-B147; A56-B 148; A5 6-B 149; A56-B150; A56-B15t; A56-BI52; A56-BI53; K5 6-B 154, A5 6-B 15 A56-BI56; A56-B157; A5 6-B 15 8; A56-BI59; A56-B160; A56-B161; A56-B162; A56-BI63; A56-B164; A56-B165; A56-B166; A56-B167; A56-B168; A56-B 169; A57-Bl; A57-B2; A57-B3; A57-B4; A57-B5; A57-B6; A57-B7; A57-B8; A57-B9; A57-B1O; A57-Bl1; A57-B 12; A5 7-B 13; A57-B 14; A57-B 15; A57-B16; A57-B17; A57-B 18; A57-B19; A57-B20; A57-B2M; A57-B22; A57-B23; A57-B24; A57-B25; AX5-7-B26; A57-B27; A57-B28; A57-B29; A57-B30; A57-B31; A57-B32; A57-B33; A57-B34; A57-B35; A57-B36; A57-B37; A57-B38; A57-B39; A57-B40; A57-B41; A57-B42; A57-B43; A57-B44; A57-B45; A57-B46; A57-B47; A57-B48; A57-B49; A57-350; A57-B51; A57-B52; A57-B53; A57-B54; A57-B55; A57-B56; A57-B57; A57-B58; A57-B59; A57-B60; A57-B61; A57-B62; A57-1363; A57-B64; A57-B65; A57-B66; A5'7-B67; 5-7-B68; A57-B69; A57-B70; A5'7-B7 1; A57-B72; A57-B73; A7B74; A57-B75; A57-B76; WO 031035065 WO 03/35065PCT/GB02/04763 -156- A57-B77; A57-B78; A57-B79; A57-B80; A57TB81; A57-B82; A57-B83; A57-B84; A57-B85; A57-BS6; A57-B87; A57-B88; A57-B89; A57-B90; A57-B91; A57-B92; A57-B93; A57-B94; A57-B95; A57-B96; A57-B97; A5'7-B98; A57-B99; A57-B 100; A57-B 101; A57-B102; A57-B 103; A5'7-B 104; A57-B105; A57-B 106; A57-B107; A57-BI08; A57-B109; A57-B 110; A57-Bl 11; A57-B 112; A57-B 113; A5'7-B 114; A57-B115; A57-B 116; A57-B117; A57-B1 18; A57-B1 19; A57-B 120; A57-B121; A5 7-B 122; A57-B123; A57-B 124; A57-B125; A57--B196 A57-BI27; A57-B 128; A57-BI29; A57-B 130; A57-B131; A57-B 132; A57-B133; A57-B 134; A57-B135; A57-B136; A57-B137; A57-B138; A57-B139; A57-B140; A57-B141; A57-B 142; A57-B143; A57-B 144; A57-BI45; A57-B 146; A57-B147; A57-B148; A57-B149; A57-B150; A57-B151; A57-B 152; A57-B153; A57-B154; A57-B155; A57-B 156; A57-B157; A57-B158; A57-BI59; A57-B 160; A57-B161; A-57 -B 162; A57-BI63; A57-B 164; A57-B165; A57-B166; A57-B167; A57-B168; A5'1-B169; A58-BI; A58-B2; A58-B3; A58-B4; A58-B5; A58-B6; A58-B7; A58-B8; A58-B9; A58-B1O; A58-B11; A58-B12; A5 S-B 13; A58-B14; A58-B15; A58-B16; A58-B17; A58-B18; A5 S-B 19; A58-B20; A58-B21; A58-B22; A58-B23; A58-B24; A58-B25; A58-B26; A58-B27; A58-B28; A58-B29; A58-B30; A58-B31; A58-B32; A58-B33; A58-B'04; A58-B35; A58-B36; A58-B37; A58-B38; A58-B39; A58-B40; A58-B41; A5 8-B42; A5 S-B43; A58-B44; A58-B45; A58-B46; A5 8-B47; A58-B48; A58-B49; A58-B50; A58-B5 1; A58-B52; A58-B53; A58-B54; A58-B55; A58-B56; A58-B57; A58-B58; A58-B59; A58-B60; A58-B61; A58-B62; A58-B63; A58-B64; A58-B65; A58-B66; A58-B67; A58-B68; A58-B69; A58-B70; A58-B71; A58-B72; A58-B'73; A58.-B74; A58-B75; A58-B76; A58-B77; A58-B78; A58-B79; A58-B80; A58-B81; A58-B82; A58-B83; A58-B84; A58-B85; ASS-B86; A58-B87; A58-B88; A58-B89; A58-B90; A 5-8-B9 t; A58-B92; A58-B93; A58-B94; A58-B95; A58-B96; 5-8-B97; A58-B98; A58-B99; A59-B100; A58-BlOl; A58-B102; A58-B103; A5 S-B 104; A58-BI05; A58-B106; A58-B107; A58-BIOS; A58-B109; A58-B1 10; A58-B1 11; AZ "l1 I A ZQ D 11. 4 ArQ P1 1'7 S-B I1 22; IOJDO-1 11.; .1 I WO 031035065 WO 03/35065PCT/GB02/04763 -157- A58-B1S; A58-B119; A58-B120; A58-B121; A58-BI22; A58-B123; A58-B 124; A58-B 125; A58-B126; A58-B 127; A58-BI28; A58-B 129; ASS-B130; A58-B131; A58-B132; A58-B133; A58-BI34; A58-B135; A58-B136; A58-B137; A58-BI38; A59-B139; A58-BI40; A58-BI41; A58-B142; A58-B143; A58-B144; A58-B145; A58-B146; A5 8-B 147; A58-BI48; A58-B149; A58-B150; A58-BI5i; ASS-B152; ASS-B153; A58-B154; A58-B155; A58-B156; A58-B157; A58-1B158; A58-B159; A58-B160; A58-B161; A58-B162; A58-B163; A58-B164; A5B-B165; A58-B166; A5S-B 167; A58-B168; A58-B169; A59-B 1; A59-B2; A59-B3; A59-B4; A59-B5; A59-B6; A59-B7; A59-Bg; A59-B9; A59-BIO; A59-B 11; A59-B12; A5 9-B 13; A59-B14; A59-B15; A59-B16; A59-B 17; A59-B1S; A59-B 19; A59-B20; A59-B2 1; A59-B22; A59-B23; A59-B24; A59-B25; A59-B26; A59-B27; A59-B28; A59-B29; A59-B30; A59-B3 1; A59-B32, A59-B33; A59-B347: A59-B35; A59-B36; A59-B37; A59-B38; A59-B39; A59-B40; A59-B41; A59-B42; A59-B43; A59-B44; A59-B45; A59-B46; A59-B47; A59-B48; A59-B49; A59-B50; A59-B5 1; A59-B52; A59-B53; A59-B54; A59-B55; A59-B56; A59-B57; A59-B58; A59-B59; A59-B60; A59-B61 A59-B62; A59-B63; A59-B64; A59-B65; A59-B66; A59-B67; A59-B68; A59-B69; A59-B70; A59-B71; A59-B'12; A59-B73; A59-B74; A59-B75; A59-B76; A59-B77; A59-B78; A59-B79; A59-B8O; A59-B81; A59-B82; A59-B83; A59-B84; A59-B85; A59-B86, A59-B87; A59-B88; A59-B89; A59-B90; A59-B91; A59-B92; A59-B93; A59-B94; A59-B95; A59-B96; A59-B97; A59-B98; A59-B99; A59-B100; A59-B1O1; A59-B 102; A59-B103; A59-B104; A59-B105; A59-B106; A59-B107; A59-B 108; A59-BI09; A59-B11O; A59-B111; A59-B 112; A59-B113; A59-B 114; A59-B115; A59-B 116; A59-B117; A59-B 118; A59-B119; A59-B120; A59-B121; A59-BI22; A59-B 123; A59-B124; A59-B125; A59-B126;- A59-B127; A59-B128; A59-B129; A59-B 130; A59-B131; A59-B132; A59-BI33; A59-BI34-; A59-BI35; A59-B136; A59-B137; A59-B138; A59-B139; A59-B140; 9-B 14 1; A59-B142; A59-B143; A59-B144; A59-B145; A59-BI46; A59-B147; A59-B148; A59-B149; A59-B150; A59-B151; A59-B152; 9-B 15 3; A59-B154)- A59-B155; A59-BI56; A59-B157; A59-B158; WO 031035065 WO 03/35065PCT/GB02/04763 -158- I T I A59-13t64; A59-B 159; A59-B 165; A60-B2; A60-B8; A59-B 160; A59-B 166; IA59-B 161; IA59-BI 62; A 9-B13 A59-BI64; 4 4 A59-B 167; IA59-B 168; A59-B 169; A60-B 1;

I

I A60-B3; A60-B9; A60-B4; A60-B 10; IA60-B5; A60-B6; A60-B7; L 4 -I A60-B 11; A60-B12; A60-B 13; 14; A60-B15; A60-B 16; A60-B17; A60-B1t8; A0B9 A60-B20; A60-B2 1; A60-B22; A60-B23; A60-B24; A60-B25; A60-B26; A60-B27; A60-B28; A60-B29; A60-B30; A60-B31; A60-B32; A60-B33; A60-B34; A60-B35; A60-B36; A60-B37; A60-B38; A60-B39; A60-B40; A60-B41; A60-B42; A60-B43; A60-B44; A60-B45; A60-B46; A60-B47; A60-B48; A60-B49; A60-B50; A60-B5 1; A60-B52; A60-B53; A60-B54; A60-B55; A60-B56; A60-B57; A6-5; A60-B59; A60-Bi6-0 A60-B 61; A60-B62; A60-B63; A60-B64; A60-B65; A60-B66-, A60-B67; A60-B68; A60-B69; A60-Bi7-0 A60-B7 1; A60-B72, -A60-B73; A60-1374; A60-B75, A60-B76; A60-B77; A60-B78; A60-B79; A60-B81; A60-B82; A60-BS3; A60-BS4; A60-B85; A60-B86; A60-B87; A60-B388; A60-B89; A60-B90; A60-B91; A60-B92; A60-B93; A60-B94; A60-B95; A60-B96; A60-B97; A60-B98; A60-B99; A60-B1 00; A60-B 101; A60-B102; A60-B 103; 104; A60-B 105; A60-B 106; A60-B 107; A60-B 108; A60-B 109; 110; A60-B 11 1; A60-B 112; A60-B 113; A60-B 114; A60-B 115; A60-B116; A60-B 117; A60-B 118; A60-B 119; A60-B 120; A60-B121; A60-B122; A60-B 123; A60-B124; A60-B 125; A60-B 126; A60-B 127; 128; A60-B 129; A60-B130; A60-B 13 1; A60-B132; A60-B 13 3; A60-B134; A60-B 135; A60-B136; A60-B137; A60-B138; A60-B139; 140; A60-B 141; A60-B 142; A60-B 143; A60-B 144; A60-B 145; A60-B146; A60-B 147; A60-B 148; A60-B 149; A60-B 150; A60-B 15 1; A60-B152; A60-3153; A60-B154; A60-B155; A60-B156; A60-Bt57; A60-B158; A60-3159; A60-B 160; A60-B161; A60-B162; A60-B163; 164; A60-B 3165; A60-B 166; A60-B 167; A60-13168; A60-B1 69; A61-B1; A61-B2; A61-B3; A61-B4; A61-B5; A61-B6; A61-B7; A61-BS; A61-B9; A61-B1O; A61-B11; A61I-B 12; A61I-B 13; A61I-B 14; A61-B15; A61I-B 16; A61I-B 17; A61-B18; A61-B19; A61-B20; A61-B21; A61-B22; A61-B23; A61-B24; A61-B25; A61-B26; A61-B27; A61-B28; A61-B29; A61-B30; WO 031035065 WO 03/35065PCT/GB02/04763 -159- A61-B31; A61-B32; A61-B33; A6 1-B 34; A61-B35; A61-B36; A61-B37; A61-B38; A61-B39; A61-B40; A61 -B4 1; A61-B42; A61-B43; A61-B44; A6 1-B45; A61-B46; A61-B47; A6 1-B4 8; A6 1-B49; A61-B50; A61-B51; A61-B52; A61-B53; A61-B54; A61-B55; A61-B56; A61-B57; A61-B59; A61-B59; A61-B60; A61-B61; A61-B62; A61-B63; A61-B64; A61-B365; A61-B366; A61-B67; A61-B68; A61-B69; A61-B70; A61-B71; A61-B72; A61-B73; A61-B74; A61-B75; A61-B76; A61-B77; A61-B78; A61-B79; A61-B80; A61-B81; A61-B82; A61-B83; A61-B84; A61-B85; A61-B86; A61 -B8'7; A61-B88; A61-B89; A61-B90; A61-B91; A61-B92; A61-B93; A6 I-B 94; A61-B95; A61-B96; A61-B97; A61-B98; A61-B99; A61-BI00; A61-B1O1; A6 I-B 102; A61-BI03; A61I-B 104; A61-BI05; A61I-B 106; A61-B107; A61-B108; A61-B109; A61-B11O; A61-B11I; A61-B112; A61-B113; A61-B114; A61-B115; A61-B116; A61-B117; A61-B118; A61-B119; A61I-B 120; A61-B121; A6 I-B 122 A61-B123; A61I-B124; 4k61-B125; A61-B126; A61-B127; A61-B3128, A61-B3129; A61-B130; A61-B131; A61-B132; A61-B133; A61-B134; A61-B135; A61-B136; A61-B137; A61-B138; A61-BI39; A6 1-B 140; A61 -B 141; A6t B 142; A61-B143; A61-BI44; A61-B145; A61-B146; A61-B147; A61-B148; A61-B149; A61-B150; A61-B151; A61-B152; A61-B153; A61-B154; A61-B155; A61-BI56; A61-BI57; A61-B158; A61-BI59; A61-B160; A61-B161; A61-B162; A61-B163; A61I-B 164; A61-B165; A61-B166; A61I-B 167; A61-B168; A651-B 169; A62-B 1; A62-B2; A62-B3; A62-B4; A62-B5; A62-B6; A62-B7; A62-B8; A62-B9; A62-B1O; A62-B 11; A62-B 12; A62-B313; A62-B 14; A62-B 15; A6B1; A217 A62-B 18; A62-B19; A62-B20; A62-B2 1; A62-B22; A62-B23; A62-B24; A62-B25; A62-B26; A62-B27; A62-B28; A62-B29; A62-B30; A62-B3 1; A62-B32; A62-B33; A62-B34; A62-B35; A62-B36; A62-B37; A62-B38; A62-B39; A62-B40; A62-B41; A62-B42; A62-B43; A62-B44; A62-B45; A62-B46;- A62-B47; A62-B48; A62-B49; A62-B50; A62-B51; A62-B52; A62-B53; A62-B54; A62-B55; A62-B56; A62-B57; A62-B58; A-62-B59; A62-B60; A62-B61; A62-B62; A62-B63; A62-B64; A62- A -6 A6-B67; tA62--B68; rA-62-B69; A62-B70; A62- B7 1; WO 031035065 WO 03/35065PCT/GB02/04763 -160r r A62-B72 A62-B73; A62-B74; A62-1375; A62-B76; A62-B77; A62-B78; A62-B79;- A62-Bb0; A62-B81; A62-B82; A62-B83; A62-B84;, A62-B85; A62-B86; A62-B81; A62-388; A62-B89; A62-B90; A62-B91; A62-B92; A62-B93; A62-B94; A62-B95; A62-B96; A62-B97; A62-B98; A62-B99; A62-B 100; A62-B1O1; A62-B 102; A62-B 103; A62-B 104; A62-B 105; A62-B 106; A2B17 A62-B108; A62-B 109; A62-B1 10; A62-B1 111; A62-B 112; A62-B 113; A62-B3114; A62-3115; A62-B 116; A62-B3117; A62-B 118; A62-B119; A62-B 120; A62-B12 1; A62-B 122; A62-B3123; A62-B 124; A62-B125; A62-B 126; A62-B 127; A62-B 128; A62-B129; A62-B130; A62-B 13 1; A62-B 132; A62-B133; A62-B 134; A62-B135; A62-B136; A62-B137; A62-B 313 8; A62-B 3139; A62-B 140; A62-B 141; A62-B142; A62-B 143; A62-B 144; A62-B 145; A62-B 146; A6-11-B 147; A62-B148; A62-B 149; A62-B 150; A62-B 15 1; A62-B 152; A62-B3153; A62 3154; A62-BI55; A62-B3156; A62-B 157; A62-13158; A62-B 159; A62-B160; A62-B 16 1; A62-B 162; A62-B 163; A62-B 164; A62-B 3165; A62- 3166; A62-B 167; A62-B168;- A62-B3169; A63-B1; A63-B2; A63-B3; A63-B4; A63-B5; A63-B6; A63-B7; A63-BS; A63-B9; A3BO A63-B 11; A63-B 12; A63-B13; A63 -B 14; A63-B15; A63-B 16; A63-B17; A63-B18; A63-B19; A63-B20; A63-B2 1; A63-B22; A63-B23; A63-B24; A63-B25; A63-B26; A63-B27; A63-B28; A63-B29; A63-B30; A63 -B3 1; A63-B32; A63-B33; A63-B34; A63-B35; A63-B336; A63-B37; A63-B38; A63-B39; A63-B40; A63-B41; A63-B42, A63-B43; A63-B44; A63-B45; A63-B46; A63-B47; A63-B48; A63-B49; A63-B50; A63-B51; A63-B52; A63-B53; A63-B54; A63-B55; A63-B56; A63-B57; A63-B58;- A63-B59; A63-B60; A63-1361; A63-B62; -I I- A63-B69; A63-B65; A63-B66; A63-B 67; A63-B68; A63-B71; A63-B72; A63-B73; A63-B74; A63-B75; A63-B77; A63-B78; A63-B79; A63-B80; A63-BS1; A63-B83; A63-B84; A63-B85; A63-B86; 1A63-BS7; A63-B89; A63-B90; A63-B91; A63-B92; A63-B93; A63-B70; A63-376; A63-B 82; A63-B8 8; A63-B94; A A63-B95; A63-B1O1; A63-B107; A63B6 A63-B97; A63-B98; A63-B99; A63 -B 102; jA63-B103; A63-B108; A63-B3109; A63-B104; A63-B105; jA63-B106; A63-B110; A63-B111; A63-B112; WO 031035065 WO 03/35065PCT/GB02/04763 -161- A63-B 113; A63-B 114; A63-13115; ]A63-B116; [A63-BI17; A63-B118; A63-B 124; I_ 4 A63-B 119; A63-B120; A63-B 121; A63-B 122; A63-B1231

I

A61-BR125; A63-b126; A63-B 127; A63-BI28; A63-B129; A63-B130; A63-3131; A63-BI32; A63-B 133; A63-B134; A63-B135; A63-B136; A63-B 137; A63-B138; A63-B 139; A63-B 140; A63-B141; ,KZ3-B142; A63-B143; A63-B 144; A63-B145; A63-B 146; A63-B147; A63-B148; A63-B149; A63-B150; A63-B151; A63-B3152; A63-BI53; A63-B154; A63-B 155; A63-B156; A63-BI57; A63-B158; A63-B159; A63-B 160; A63-B 16 1; A63-B 162; A63-B163; A63-B 164; A63-B165; A63-B 166; A63-B167; A63-B 168; A63-B3169; A64-B 1; A64-B2; A64-B3; A64-B4; A64-B5; A64-B6; A64-B7; A64-BS; A64-B9; A64-BIO; A64-B 11; A64-B12; A64-B 13; A64-B14; A64-B A64-B16; A64-B 17; AX64-B 18, A64-B 19; A64-B20; A64-B2 1; A64-B22; A64-B23; A64-B24; A64-B25; A64-B26; A64-B27; A64-B28; A64-B29; A64-fl30; A64-B 31; A64-B32; A64-B33; A64-B34; A64-B35; A64-B36; A64-B37; A64-B38; A64-B39; A64-B40; A64-B41; A64-B42; A64-B43; A64-B44; A64-B45; A64-B46; A64-B47; A64-B48; A64-B9 A64-B50; A64-B5 1; A64-B52; A64-B53; A64-B54; A64-B55; A64-B56; A64-B57; A64-B58; A64-B59; A64-B60; A64-B6 1; A64-B62; A64-B63; A64-B64; A64-B65; A64-B66; A64-B367; A64-B68; A64-B69; A64-B70; A64-B7 1; A64-B72; A64-B73; A64-B74; A64-B75; A64-B76; A64-B77; A64-B78; A64-B79; A64-BSO; A64-B81; A64-B82; A64-B83; A64-B84; A64-B85; A64-B86; A64-B87; A64-B88; A64-B89; A64-B90; A64-B91; A64-B92; A64-B93; A64-B94; A64-B95; A64-B196; A64-B97; A64-B98; A64-B99; A64-B 100; A64-B 101; A64-B 102; A64-B 103; A64-B 104; A64-B 105; A64-B 106; A64-B 107; A64-B1OS; A64-B 109; A64-B 110; A64-B 111; A64-B 12; A64-B 113; A64-B 114; A64-B 115; A64-B 116; A64-B 117; A64-B 118; A64-B 119; A64-B 120; A64-B12 1; A64-B122; A64-B 123; A64-B 124; A64-B 125; A64-B 126; A64-B127; A64-B128; A64-B 129; A64-B 13 0; A64-B 13 1; A64-B 132; A64-B133; A64-B 134; A64-B135; A64-B136; A64-B 137; A64-B 13 S; A64-B139; A64-B140; A64-B141; A64-B142; A64-B 143; A64-D 144; AK64-B 145; A64-B 146; A64-B 147; A64-B148; A64-B 149; A64-B 150; A64-B151; A64-B152; A64-B153; WO 031035065 WO 03/35065PCT/GB02/04763 -162- A64-B 154; A64-BI55;- A64-B156) A64-B 157; A64-B158; A64-B 159; A64-B 160; A64-B 16 1; A64-B 162; A64-B163; A64-B 164; A64-B 1 A64-B 166; A64-13 167; A;6 4 -B16 8; A64-B 169; A65-B1; A65-B2; A65-B3; A65-B4; A65-B5; A65-B6; A65-B7; A65-B8; A65-B9; A65-B1O; A65-B11; A65-B 12; A65-B13; A65-B14; A65-B15;, A65-B16; A65 -B 17; A65-B18; A65-B t9; A65-B20; A65-B21; A65-B22; A65-B23; A65-B24; A65-B25; A65-B26; A65-B27; A65-B28; A65-B329; A65-B30; A65-B31; A65-B32; A65-B33; A65-B3 4; A65-B35; A65-B36; A65-B37; A65-B38; A65-B39; A65-B40; A65-B41; A65-B42; A65-B43; A5-B44; A65-B45; A65-B46; A65-B47; A65-B48; A65-B49; A65-B50; A65-B5 1; A65-B52; A65-B5M; A65-B54; A65-B55; A65-B56; A65-B57; A65-B58; A65-B59; A65-B60; A65-B61; A65-B62; A65-B63; A65-B64; A65-B65; A65-B66; A65-B67; A65-B68, A65-B69; A65-B70; A65-B71; A65-B72; A65-B73; A65-B74; A65-B75; A65-B76; A65-B77; A65-B78; A65-B79; A65-B80; A65-B81; A65-B82; A65-B83; A65-B84; A65-B85; A65-B86; A65-B87; A65-B88; A65-B89; A65-B90; A65-B9 1; A65-B92; A65-B93; A65-B94; A65-B95; A65-B96; A65-B97;1 A65-B98; A65-B99; A65-B100; A65-B1O1; A65-B 102; A65-B103; A6 5-B 104; A65-B105; A65-B 106; A65-B107; A6-5-B1OS; A65-B109; A65-B11O; A65-B1 11; A65-B1 12; A65-D 113; A65-B 114; A65-B 1 1 5; A65-B 116; A65-BI117; A65-B11S; A65-BI19; A65-B120; A65-B121; A65-BI22; A65-B123; A65-B124; A65-BI25; A65-BM6; A65-B 127; A65-B128; A65-B129; A65-B130; A65-B 131; A65-B132; A65-B 133; A65-B 134; A65-B[15; A65-B136; A65-B 137; A65-BI38; A65-B 139; A65-B140; A65-B141; A65-BI42; A65-B 143; A65 -B 144; A65-B 145; A65-B146, A65-B147; A65-B148; A65-B 149; A65-B150; A65-B151; A65-B152; A65-B153; A65-B 154; A65-B155; A65-B156; A65-B157; A65-B158; A65-B159; A65-B 160; A65-B161; A65-B162; A65-B163; A65-B164; A65-B165; A65-B166; A65-B167; A65-B168; A65-B169; A66-B1; A66-B2; A66-B3; A66-B4; A66-B5; A66-B6; A66-B7; A66-B8; A66-B9; A66-B1O; A66-Bl1; A66-B12; A66-B 13; A66-B14; A66-B 15; A66-B 16; A66-B17; A66-B18; A66-B19; A66-B20; A66-B21; A66-B22; A66-B323; A66-B24; A66-B25; WO 031035065 WO 03/35065PCT/GB02/04763 -163- A66-B26; rA66-B32;

I

A66-B27-; A66-B33; A66-B28; A66-B29; A66-B30; A66-B31; 1 -I I. -f A66-B34; A66-B35; A66-B36; A66-B37; A66-B39; A66-B39; A66-B40; A66-B41; A66-B42; A66-B43; A66-B44; A66-B45; A66-B46; A66-B47; A66-B48; A66-B49; A66-B50; A66-B51; A66-B52; A66-B53; A66-B54; A66-B55; A66-B56; A66-B57; A66-B58; A66-B59; A66-B60; A6 6-B 61; A66-B62; A66-B63; A66-B64; A66-B65; A66-B66; A66-B67, A66-B68; A66-B69; A66-B70; A66-B7 1; A66-B72; A66-B73; A66-B74; A66-B75; A66-B76; A66-B77; A66-B78; A66-B79; A66-B80; A66-B81; A66-B82; A66-B83; A66-B84; A66-B85; A66-B86; A66-B87; A66-B88; A66-B89; A66-BR90; A66-B91; A66-B92; A66-B93; A66-B94; A66-B95; A66-B96; A66-B97; A66-B98; A66-B99; A66-B 100; A66-B 101; A66-B 102; A66-B 103; A66-B 104; A66-B 105; A66-B 106; A66-B 107; A66-B 108; A66-B 109; A66-B1 10; A66-B1I 11; A66-B 112; A66-B 113; A66-B 114; A66-B 115; A66-B 116; A66-B 117; A66-B1 18; A66-B 119; A66-B120; A66-B121; A66-B 122; A66-B 123; A66-B 124; A66-B 125; A66-B3126; A66-B 127; A66-B 128; A66-B 3129; A66-B130; A66-B 13 1; A66-B1 32; A66-B 133; A66-B 134; A66-B 135; A66-B1 36; A66-B 137; A66-B 138; A66-B 139; A66-B 140; A66-B 141; A66-B142; A66-B 143; A66-B144; A66-B 145; A66-B146; A66-B147; A66-B148; A66-B 149; A66-B150; A66-B151; A66-B152; A66-B153; A66-B154; A66-B155; A66-B156; A66-B157; A66-B158; A66-B159; A66-B160; A66-B 16 1; A66-B162; A66-B 163; A66-B1 64; A66-B 165; A66-B 166; A66-B 167; A66-B3168; A66-B 169; A67-B1; A67-B2; A67-B3; A67-B4; A67-B5; A67-B6; A67-B7; A67-B8; A67-B9; A67-B 10; A67-B 11; A67-B12;- A67-B13; A67-B14; A67-B 15; A67-B 16; A67-B 17; A67-B18; A67-B19; A67-B20; A67-B21; A67-B22; A67-B23; A67-B24; A67-B25; A67-B26; A67-B327; A67-B28; A67-B29; A67-B30; A67-B3 1; A67-B32; A67-B33; A67-B34; A67-B35; A67-B36; A67-B37; A67-B38; A67-B39; A67-B40; A67-B41; A67-B42; A67-B43; A67-B44; A67-B45; A67-B46; A67-B47; A67-B48; A67-B49; A67-BS0; A67-B5 1; A67-B52; A67-B53; A67-B54; A67-B55 A7-B56; A67-B57; A67-B58; A67-B59; A67-B60;- A67-B61; A67-B62;

I

A67-B63; A67-B64; A67-B65; A67-B66; WO 031035065 WO 03/35065PCT/GB02/04763 -164- A67-B67; A67-B68; A67-B69; A67-B70; A67-B71; A67-B72; A67-B'73; A67-B74; A67-B75; A67-B76; A67-B77; A67-B78; A67-B79; A67-B80; A67-B81; A67-B82; A67-B83; A67-B84; A67-B85; A67-B86; A67-B87; A6'7-B88; A67-B89; A67-B90; A67-B91; A67-B92; A67-B93; A67-B94; A67-B95; A67-B96; A67-B97; A67-B98; A67-B99; A67 -B 100; A67-BIOI; A67-B 102; A67-B 103; A67-B1 04; A67-B 105; A6'7-B 106; A67-B 107; A67-B 108; A67-B 109; A67-B 110; A67-B1I 11; A61) -B 112; A67-B 113; A67-B 114; A67-B3115; A67-Bl16(; A67-B 117; A6'7-B 118; A67-B119; A67-B 120; A67-BI21; A67-B 122; A67-B123; A67-B 124; A67-B125; A67-B 126; A67-B 127; A67-B128; A67-B129; A67-B 130; A67-B131; A67-B132; A67-B 133; A67-B 134; A 67 -B 13 5; A67-B136; A67-B137; A67-B 138; A67-B139; A67-B140; A67-B141; A67-B 142; A67-B 143; A67-B 144; A67-B145; A67-B 146; A67-B147; A67-BI48; A67-B 149; A67-B 150; A67-B151; A67-B152; A67-B153; A67-B 154; A67-B155; A67-B156; A67-B157; A67-B 158; A67-B159; A67-B 160; A67-B 16 1; A67-B 162; A67-B163; A6'7-B 164; A67-B165; A67-B 166; A67-B 167; A67-B169; A67-B 169; A68-B1; A68-B2; A68-B3; A68-B4; A68-B5; A68-B6; A68-B7; A68-B8; A68-B9; A68-B1O;l A68-B11; A68-B 12; A68-B13; A68-B14; A6S-B15; A68-B16; A68-B17; A68-B 18; A6 9-B 19; A68-B20; A68-B21; A68-B22; A68-B23; A68-B24; A68-B25; A68-B26; A68-B27; A68-B29; A68-B29; A68-B30; A68-B31; A68-B32; A69-B33; A68-B34; A68-B35, A68-B36; A68-B37; A68-fl38; A68-B39; A68-B40; A68-B41; A68-B42; A68-B43; A68-B44; A69-B45; A68-B46; A68-B47; A68-B48; A68-B49; A68-B50; A68-B5 1; A68-B52; A68-B53; A68-B54; A68-B55; A68-B56; A68-B57; A68-B58; A68-B59, A68-B60; A68-B61; A68-B62; A68-B63; A68-B64; A68-B65; A68-B66; A68-B67; A68-B68; A68-B69; A68-B70; A68-B71; A68-B72; A68-B73; A68-B74;- A68-B75;- A68-B76; A68-B77; A68-B78; A68-B79; A68-B80; A68-B81; A68-B82; A68-B83; A68-B384; A68-B85; A68-B86; A68-BS7; A68-B88; A68-B89; A68-B90; A68-B9 1; A68-B92; A68-B93; A68-B94; A68-B95; A68-B96; A68-B97; A68-B98; A68-B99; A68-B100; A68-B1O1; A68-B102; A68-B103; A68-B104; A68-B 105; A68-B106; A68-B107; WO 031035065 WO 03/35065PCT/GB02/04763 -165- A68-B1OS; A68-B109; A68-B1 10; A68-Bl 11; A68-BI 112; A68-B1 13; A68-B114; A68-B 115; A68-B 116; A68-B117; A68-B t18; A68-B119; A68-B120; A68-B121; A68-B 122; A68-3123; A68-B124; A68-B125; A68-B126; A68-B127; A68-B 129; A68-B129; A68-B130O; A68-B131, A68-B132; A68-BI33; A68-B134; A68-B135; A69-B136; A68-B137; A68-B138; A68-B139; A68-B 140; A68-B141; A68-B142; A68-B143; A68-B 144; A68-B145; A68-B 146; A68-B147; A68-BI48; A68-B149; A68-B 150; A68-B15 1; A68-Bt52; A68-B153; A68-B154; A68-B155; A68-B156; A68-B 1-57; A68-BI58; A68-B159; A68-B160; A68-B161; A68-B 162; A68-DB163; A68-B 164; A68-B165; A68-B166; A68-B167; A68-B 168; A68-B 169; A69-B1; A69-B2; A69-B3; A69-B4; A69-B5; A69-B6; A69-B7; A69-B8; A69-B9; A69-B A69-B 11; A69-B 12; A69-B13; A69-B 14; A69-B15; A69-B 16; A69-B 17; A69-B 18; A69-B19; A69-B20; A69-B2 1; A69-B22, A69-B23; A69-B24; A69-B25; A69-B26; A69-B27; A69-B28; A69-B29; A69-B30; A69-B3 1; A69-B32; A69-B33; A69-B34; A69-B35; A69-B36; A69-B3'7; A69-B38; A69-B39; A69-B40; A69-B4 1; A69-B342; A69-B43; A69-B44; A69-B45; A69-B46; A69-B47; A69-B48; A69-B49; A69-B50; A69-B5 1; A69-B52; A69-B53; A69-B54; A69-B55; A69-B56; A69-B57; A69-B58; A69-B59; A69-B60; A69-B6 1; A69-B62; A69-B63; A69-B64; A69-B65; A69-B66; A69-B67; A69-B68; A69-B69; A69-B70; A69-B71; A69-B72; A69-B73; A69-B74; A69-B75; A69-B76, A69-B77; A69-B78; A69-B79; A69-BSO; A69-BgI; A69-B82; A69-B83; A69-B84; A69-B85; A69-B86; A69-B87; A69-B88; A69-B89; A69-B90; A69-B91; A69-B92; A69-B93; A69-B94; A69-B95; A69-B96; A69-B97; A69-B98; A69-B99; A69-B 100, A69-B1O1; A69-B102; A69-B103; A69-B104; A69-B105; A69-B106; A69-B107; A69-B108; A69-B 109; A69-B11O; A69-B 111; A69-B 112; A69-B 113; A69-B 114; A69-B 115; A69-B 116; A69-B 117; A69-Bl118; A69-B 119; A69-B 120; A69-B 12 1; A69-B122; A69-B123; A69-B124; A69-B125; A69-B 126; A69-B127; A69-B 128; A69-BI29; A69-B130; A69-B 13 1; A69-B132; A69-B133; A69-BI34;, A69-B135; A69-B136; A69-B 137; A69-B 138; A69-B 139; A69-B 140; A69-B 141; A69-B 142; A6-143; A69-B 144; A69-B145; W6-9-B146;, A69-B147; A69-BI48; WO 031035065 WO 03/35065PCT/GB02/04763 -166- A69-B149; A69-B150; A69-B 15 1; A69-B 152; A69-B153; A69-B 154; A69-B155; A69-B156; A69-B157; A69-B158; A69-B159; A69-B 160; A69-B 16 1; A69-B 162; A69-B 163; A69-B 164; A69-B 165; A 6 9 -B 166; A69-B 167; A69-B168; A69- 3169; A70-B 1; A7O-B2; A70-B3; A70-D4; A70-B5; A70-B6; A70-B7; A7O-Bg; A70-B9; A70-B10; A70-B 11; A70-B 12; A70-B13; A70-B 14; A70-B15; 16; A7O-B17; A70-B 18; A70-B19; A70-B20; A70-B21; A70-B22; A70-B23; A70-B24; A70-B25; A70-B26; A70-B27); A70-B28; A70-B9 A70-B30; A70-B3 1; A70-B32; A70-B33; A70-B314; A70-B35; A70-B36; A70-B37; A70-B38; A70-B39; A70-B40; A70-B41; A70-B42; A70-B43; A70-B44; A70-B45; A70-B46; A70-B47;, A70-B48; A70-B49; A70-B50; A70-B51; A70-B52; A70-B53; A70-B54; A70-B55; A70-B56; A70-B57; A70-B58; A70-B59; A70-B60; A70-B61; A70-B62; A70-B63; A70-B64; A70-B65; A70-B66; A70-B367; A70-B68; A70-B69; A70-B70; A70-B71; A70-B72; A70-B373; A70-B74; A70-B75; A70-B76; A70-B77; A70-B78; A70-B79; A70-B8O; A70-B81; A70-B82; A70-B83; A70-B84; A70-B85; A70-B86; A70-B87; A70-B88; A70-B89; A70-B90; A70-B91; A70-B92; A70-B93; A70-B94; A70-B95; A70-B396; A70-B97; A70-B98; A70-B99; 100; A70-B 101; A70-B 102; A70-B 103; A70-B 104; A70-B 105; 106; A70-B10O7; A70-B 108; A70-B 109; A70-B1 10; A70-B1 111; 112; A70-B 113; A70-B 114; A70-B 115; A70-B 116; A70-B 117; A'70-B1 18; A70-B 1 -19; A70-B120; A70-B 12 1; A70-B 122; A70-B 123; 124; A70-B125; A70-B 16; A'70-B 127; A70-B 128; A70-B129; A70-B130; A70-B 13 1; A70-B132; A70-B133; A70-B 134; A70-B135; A70-B136;. A70-B137; A70-B138; A70-B139; A70-B 140; A70-B141; 142; A70-B143; A70-B 144; A70-BI45; A70-B146; A70-B147; 148; A70-B149; A70-B150; A70-B151; A70-B 152; A70-B153; 154; A70-B155; A70-B156; A70-B157; A70-B158; A70-B159; 160; A70B 3161; A70-B 162; A 7 0 -B 16 3; A70-B 164; A70-B1 A70-BI66; A70-B 167; A70-B168; A70-B 169; A71-Bl; A71-B2; A71-B3; A71-B4; A71-B5; A71'-B6; A71-B7; A71-BS; A71-B9; A71 -B 10; A71-B11; A71I-B 12; A71I-B 13; A71 -B 14; A71-B15; A71 -B 16; A71-B17; A71-BI8; A71-B19; A71-B20; WO 031035065 WO 03/35065PCT/GB02/04763 -167- A71-B21; A'71-B22; -A71-B23; A71 -B24; A71 -B2 5; A71-B26; A71-B27; A71-B28; A71I-B29; A71-B30; A71-B31; A71-B32; A71-B33% A71-B34; A71-B35; A71-B36; A71-B37; A7 1-B38; A71-B39; A71-B40; A71-B41; A71-B42; A71-B43; A71I-B44; A71-B45; A71-B46; A71I-B47; A71-B48; A71-B49; A71-B50; A71-B51; A71-B52; A71-B53; A71-B54; A71 -B 55; A71-B56; A71-B57; A71-B58; A71-B59; A71-B60; A71-B61; A71-B62; A71-B63; A71-B64; A71-B65; A71-B66; A71-B67; A71-B68; A71-B69; A71-B70; A71-B71; A71-B72; A71-B73; A71-B74; A71-B75; A71-B'76; A71 -B77; A71-B379- A7 1-B79; A71I-B80; A71 -B 81; A71-B82; A71-B83; A71-B84; A71-BS5; A71-B86; A71-B87; A71-B88; A71-B89; A71-B90; A71-B91; A71-B92; A71-B93;, A71-B94; A71-B95; A71-B96; A71-B97; A71-B98; A71-B99; A71-BIO0; A71-BtOl; A7 I-B 102; A71-B103; A7 I-B 104; A71-.B105; A71-B106; A71 -B 107; A7 1-B 108; A71-B109; A71-B1 A71-B111; A71-B112; A71-B113; A71-B3114; A71-B115; A71-B116; A71 -B 117; A71-B118; A71-BI19; A71I-B 120; A71-B121; A7 I-B 122; A71 -B 123; A71I-B 124; A71-B125; A71-B126; A71-B127; A71-BI28; A71-B129; A71-B130; A71-B131; A'71-BI32; A71-B133; A71I-B 134; A71-B135; A71-B136; A71-B137; A71-B138; A71-B139; A71I-B 140; A71-B141; A7 1-B 142; A71-B143; A71I-B 144; A71-B145; A71-B146; A71-B147; A71-B148; A71-B149; A7t-B150; A71-B151; A71-B152; A71-B153; A71-B154; A71-B155; A71-B156; A71-B157; A71-B159; A71-B159; A71-B160; A71-B161; A71-B162; A71-B163; A71t-B 164; A71-B165; A71-B166; A71-B167; I71-B 168S; A71-B169; A72-BI; A72-B2; A72-B3; A72-B4; A72-B5; A72-B6; A72-B7; A'72-B8; A72-B9; A72-B1O; A72-B 11; A72-B12; A72-Bti3; A'72-B14; A72-B15; A72-B316; A72-B17; A72-B1IS; A72-B1t9; A72-B20; A72-B21; A72-B22; A72-B23; A72-B24; A72-B25; A72-B26; A72-B27; A72-B28; A72-B29; A72-B30; A72-B3 1, A72-B32; A72-B33; A72-B34; A72-B35; A72-B36; A72-B37; A72-B38; A72-B39; A72-B40; A72-B41; A72-B42; A72-B43; A72-B44; A72-B45; A72-B46; A72-B47; A72-B48; A72-B49; A72-B50; A72-BS 1; A72-B52; A72-B53; A72-B54; A72-B55; A7-56; A72-B57; A72-B58; A72-B59; A72-B60; A72-B61; WO 031035065 WO 03/35065PCT/GB02/04763 -168- A72-1362; A72-B68; I ~r A72-B63;- A72-B69; A72-B64; A72-B 65; A72-B66; A72-B67; I- -I I- A72-B70; A72-B71; A72-B72; A72-B73; A72-1374; A72-B75; A72-B76; A72-1377; A72-B78; A72-B79; A72-1380; A72-B81; A72-BS2; A72-B83; A72-B84; A72-1385; A72-BS6; A72-B387; A72-B88; A72-B89; A72-B90; A72-B91; A72-B92; A72-B93; A72-B94; A72-B95; A72-B96; A72-B97; A72-1398; A72-1399; A72-B1 00; A72-B 101; A72-B 102; A72-B 103; A72-B104; A72-B 105; A72-B 106; A72-B 107; A72-B108; A72-B 109; A72-B1 10; A72-B 1i1; A72-B 112; A72-B 113; A72-B 114; A72-B 115; A72-B 16; A72-B 117; A72-B1 18I; A72-B 119; A72-B 120; A72-B 12 1; A72-B122; A72-13123; A72-B 124; A72-B125; A72-B 126; A72-B 127; A72-B128; A72-13129; A72-B130; A72-B131; A72-B 132; A72-BI33; A72-B134; A72-B135; A72-B136; A72-B137; A72-B138; A72-13139; A72-B 140; A72-B 14 1; A72-B 142; A72-B143; A72-B 144; A72-B145; A72-B 146; A72-B 147; A72-B 148; A72-B 149; A72-B 150; A72-B 15 1; A72-13152; A72-B153; A72-B 154; A72-B155; A72-B 1 56; A72-B157; A72-13158; A72-13159; A72-B 160; A72-B161; A72-B 162; A72-B163; A72-B 164; A72-B 165; A72-B 166; A72-B 167; A72-B 168; A72-B 169; A73-B1; A73-B2; A73-B3; A73-B4; A73-B5; A73-B6; A73-B7; A73-B8; A73-B9; A73-B1O; A73-B 11; A73-B12; A73-B13; A73 -B 14; A73-B15; A73-B 16; A73-B17; A73-B18; A73-B19; A73-B20; A73-B21; A73-B22; A73-B23; A'73-B24; A73-B25; A73-B26; A73-B27; A73-B28; A73-B29; A73-B30; A73-131; A73-B32; A73-B33; A73-B34; A73-B35; A73-B36; A73-B37; A73-B38; A73-B39; A73-B40; A73-B41; A73-B42; A73-B43; A73-B44; A73-B45; A73-B46; A73-B47; A73-B48; A73-B49; A73-B50; A73-B51; A73-B52; A73-B53; A73-B54; A73-B55; A73-B56; A73-B57; A73-B58; A73-B59; A73-B60; A73-B61; A73-B62; A73-B63; A73-B64; A73-B65; A73-B66; A73-B67; A73-B68; A73-B69; A73-B70; A73-B71; A73-B72; A73-B73; A73-B74; A73-B75; A 73-B76; A73-B77; A73-1378; A73-B79; A73-BS0; A73-B81; A73-1382; A73-B83; A73-B84; A73-B85; A73-BS6; A73-B87; A73-B88; A73-B89; A73-1390; A73-B91; A73-B92; A73-B93; A73-1394; A73-B95; A73-B96; A73-B97; A73-B98)- A73-B99; A73-B 100; A73-B1O1; A73-B 102; I I WO 031035065 WO 03/35065PCT/GB02/04763 -169- A73-B1U~S; A73-B 103; A73-B 109; A73-B104;- A'73-B1 10; A73-B 105; A73-B 106; A73-B 107; L I I- F A73-B I111; A73-B1 12; A73-B 113; A73 -B 119; A73-B1 14; A73-B 120; I* -t A73-B1 115; A73-B116; A73-B 117; A73-BI18; A73-B121; A73-B122; A73-B193; A73-B124; A73-B125; A73-B126; A73-B 127; A73-B128; A73-B 129; A73-B3130; A'73-B131; A73-B132; A73-B133; A73-BI34; A73-B135; A73-B136; A73-B137; A73-B138; A73-B139; A73-B140; A73-B141; A73-B 142; A73-B143; A73 -B 144; A73-B 145; A73-B146; A73-B147; A73-B 148; A73-B149; A73-B150; A73-B 15 1; A73-31,52; A73-B153; A7' 154; A73-B155; A73-B156; A73-B157; A73-B158; A73-B159; A73-B160; A73-B161; A73-B162; A73-B163; A73-B164; A73-B165; A73-B166; A73-B167; A73-B 168; A73-B169; A74- 31; A74-B2; A74-B3; A74-B4; A74-B5; A74-B6; A74-B7; A74-B8; A74-B9; A74-B1O; A74-B 11; A74-B12; A74-B 13; A74-B14; A74-B 15; A74-B 16; A74-B17; A74-B 18; A74-B319; A74-B20; A74-B21; A74-B22; A74-B23; A74-B24; A74-B25; A74-B26; A74-B27; A74-B28; A74-B29; A74-B30; A74-B3 1; A74-B32; A74-B33; A74-B34; A74-B35;- A74-B36; A74-B37; A74-B38; A74-B39; A74-B340; A74-B41; A74-B42; A74-B43; A74-B44; A74-B45;- A74-B46; A74-B47; A74-B48; A74-B349; A74-B50; A74-B5 1; A74-B52; A74-B53; A74-B54; A74-.B55; A74-B56; A74-B57; A74-B58; A74-B59; A74-B60; A74-B6 1; A74-B62; A74-B63; A74-B64; A74-B65; A74-B66; A74-B67; A74-B68; A74-B69; A74-B70; A74-B7 1; A74-B72; A74-B73; A74-B74; A74-B75; 'A74-B76; A74-B77; A74-B78; A74-B79; A74-BSO; A74-B 81; A74-B82; A74-BS3; A74-B84; A74-B85; A74-B86; A74-B87; A74-B88; A74-B89; A74-B90; A74-B9 1; A74-B92; A74-B93; A74-B94; A74-B95; A74-B96; A74-B97; A74-B98; A74-B399; A74-B100; A74-B1O1; A74-B 102; A74-B 103; A74-B 3104; A74-B 105; A74-B 106; A74-B 107; A74-BI08; A74-B 109; A74-B11O; A74-B1I 11; A74-B 112; A74-Bl 13; A74-B 114; A74-B 115; A74-B 116; A74-B 117; A74-B118; A74-B 119; A74-B 120; A74-B 12 1; A74-B 122; A74-B 123; A74-B 124; A74-B125; A74-B 126; A74-B 127; A74-B129; AX74-B129; A74-B130; A74-B 13 1; A74-B132; A74-B 138; A74-B133; A74-B 13 9; A74-B134; A74-B 140; A74-B335; A74-B14 1; A74-B136; A 14-1.5 1 A74-B142; A74-B 143;

I

WO 031035065 WO 03/35065PCT/GB02/04763 -170- -I F A74-B 144; A'74-B 145; A74-B 146; A74-B 147; A74-B 148; SA74-B 1; A74-B 150; A74-B 15 1; A74-B 152; A74-B 15 3; A74-B 154; A74-B155; A74-B 156; A74-B157; A74-B 158; A74-B159; A74-B 160; A74-B 16 1; A74-B 162; A74-B 163; A7-4-B 164; A74-B 165; A74-B 166; A74-B 167; A74-B168; A74-B 169; A75-Bl1; A75-B2; A75-B3; A75-B4; A75-B5; A75-B6; A75-B7; A75-B8; A75-B9; A75-B 11; A75-B12; A75-B13; A75-B14; A75-B15; A75-B16; A7 5-B 17; A75-BIS; A75-B 19; A75-B20; A75-B21; A75-B22; A75-B23; A75-B24; A75-B25; A75-B26; A75-B27; A75-B28; A75-B29; A75-B30; A75-B3 1; A75-B32; A75-B33; A75-B34; A75-B35; A75-B36; A75-B37; A75-B38; A75-B39; A75-B40; A75-B4 1; A75-B42; A75-B43; A75-B44; A75-B45; A75-B46; A75-B47; A75-B48; A75-B49; A75-B50; A75-B5 1; A75-B52; A75-B53; A75-B54; A75-B55; A75-B56; A75-B57; A75-B58; A75-B59; A75-B60; A'75-B61; A75-B62; A75-B363; A75-B64, A75-B65; A75-B66; A75-B67; A75-B68; A75-B69; A75-B70; A75-B71; A75-B72; A75-B73; A75-B74; A75-B75; A75-B76; A75-B77; A75-B78; A75-B79; A75-B80; A75-BS1; A75-B82; A75-B83; A75-B84; A75-B85; A75-B86; A75-B387; A75-B88; A75-B89; A75-B90; A75-B91; A75-B92; A75-B93; A75-B94; A75-B95; A75-B96; A75-B97; A75-B98; A75-B99; A75-B 100; A75-B1O1; A75-B102; A75-B103; A75-B104; A75-B 105; A75-B106; A75-B107; A75-B108; A75-B109; A75-B11O; A75-B1 11; A75-B1 112; A75-BI13; A75-B114; A75-B115; A75-B116; A75-DB117; A75-BI1S; 119; A75-B120; A75-B 12 1; A75-B122; A75-B 123; A75-B 124; A75-B125; A75-B126; A75-B127; A75-B128; A75-B129; A75-B130; A75-B131; A75-B132; A75-B133; A75-B134; A75-B3135; A75-B136; A75-B137; A75-B138; A75-BI39; A75-B140; A75-B141; A75-B142, A75-B143;) A75-B144; A75-B 145; A75-B146; A75-B147; A75-B148; A75-B149; A75-B150; A75-B 15 1; A75-B152; A75-B153; A75-B154; A75-B155; A75-BI56; A75-B157; A75-B158; A75-B159; A75-B160; A75-B161; A75-B 162; A75-B163; A705 -B 164; A75-B165; A75-B166; A75-B167; A75-B168; A75-B169; A76-B 1; A76-B2; A76-B3; A76-B4; A76-B5; A76-B6; A76-B7; A76-BS; A76-B9; A76-B1O; A76-B 11 A76-B12; A76-B13; A76-B14; A76-B15; WO 031035065 WO 03/35065PCT/GB02/04763 -171- A76-B 16; A76-B17; A76-B1 S; A76-B19; A76-B20; A76-B21; A76-B22; A-16-B23; A76-B24; A76-B25; A76-B26; A76-B27;- A76-B28; A76-B29; A76-B30; A76-B331; A76-B32; A76-B33; A76-B34; A76-B35; A76-B36; A76-B37; A76-B38, A76-B39; A76-B40; A76-B41; A76-B42; A76-B43; A76-B44; A76-B45; A76-B46; A76-B47; A76-B48; A76-B49; A76-B50; A76-B5 1; A76-B52; A76-B53; A76-B54; A76-B55;- A76-B56; A76-B57; A76-B58; A76-B59; A76-B60; A76-B61; A76-B62; A76-B63; A76-B64; A76-B65; A76-B66; A76-B67, A76-B68; A76-B69; A76-B70; A76-B71; A76-B72; A76-B73; A76-B74; A76-B75; A76-B76; A76-B77; A76-B78; A76-B79; A76-B80; A76-B81; A76-B82; A76-B83; A76-B84; A76-B85; A76-B86; A76-B87; A76-B88; A76-B89; A76-B90; A76-B91; A76-B92;1 A76-B93; A76-B94; A76-B95; A76-B96; A76-B97; A76-B98; A76-B99; A76-BIOO; A76-B1OI; A76-BI 02; A76-B 103; A76-BI04; A76-B 105; A76-B106; A76-B107; A76-B108; A76-B109; A76-Bl 10; A76-B1 11; A76-B 112; A76-B 113; A76-B 114; A76-B 115; A76-B 116; A76-B117; A76-B 18; A76-B 119; A76-B120; A76-B 12 1; A76-B 122; A76-B123; A76-B 124; A76-B125; A76-B126; A76-B 127; A76-B128; A76-B 129; A76-B130; A76-B 13 1; A76-B132; A7-6-BI33; A76-B 134; A76-B135; A76-B136; A76-B137; A76-BI38; A76-B139; A76-B 140; A76-B141; A76-B142; A76-B 143; A76-B144; A76-B 145; A76-B 146; A76-B 147; A76-B148; A76-B 149; A76-B 150; A76-B15 1; A76-B 152; A76-B 153; A76-B154; A'76-B155; A76-B156; A76-B157; A76-B158; A76-B 159; A76-BI60; A76-BI61; A76-B162; A76-BI63; A76-B 164; A76-B 165; A76-B 166; A76-B167; A76-B 168; A76-B 169; A77-B 1; A77-B2; A77-B3; A77-B4; A77-135; A77-B6; A77-B7; A77-B8; A77-B9; A77-B1O; A77-BI11; A77-B12; A77-B 13; A77-B14; A77-B15; A77-B16; A77-B 17; A77-B 18; A77-B 19; A77-B20; A77-B21; A77-B22; A77-B23;- A77-B24; A77-B25; A77-B26; A77-B27; A77-B28; A77-B29; A77-B30; A77-B31; A77-B32; A77-B33; A77-B34; A77-B35; A7'7-B36; A77-B37; A77-B38; A77-B39; A77-B40; A77-B41; A77-1342; A77-B43; A77-B44; A77-B45; A77-B46; A77-B47; A77-B48; A77-B49; A77-B50; A77-B51; A77-B52; A77-B53; A77-B54; A77-B55; A77-B56; WO 031035065 WO 03/35065PCT/GB02/04763 -172- A77-B57; A77-B58; A77-B59; A77-B60; A77-B61; A77-B62; A77-B63; A77-B64; A77-B65; A77-B66; A77-B67; A77-B68; A77-B69; A77-B70; A77-B71; A77-B72; A77-B73; A77-B74; A77-B75; A77-B76; A77-B77; A77-B78; A77-B79; A77-BSO; A'77-B8 1; A77-B82; A77-B83; A77-B84; A77-B85; A77-fl86; A77-B87; A77-B88; A77-BS9; A77-B90; A77-B91; A77-B92; A77-B93; A77-B94; A77-B95; A77-B96; A77-B97; A77-B98; A77-B99; A77-B 100; A77-B 101; A77-B 102; A77-B 103; A77-B 104; A77-B105; A77-B 106; A77-B 107; A77-B1OS; A77-B 109; A77-B11O; A77-B 111; A77-B 112; A77-B 113; A77-BI14; A77-B 115; A77-B 116; A77-B 117; A77-B 118; A77-B 119; A77-B120; A77-B 12 1; A77-B 122 A77-B123; A77-BI24; A77-B125; A77-B 126; A77-B 127; A77-B128; A77-B129; A77-B130; A77-B 13 1; A77-BI32-; A77-B133; A77-B134; A77-B135; A77-B136; A77-B137; A77-B138; A77-B139; A77-B140; A77-B141; A77-B 142; A77-B 143; A77-B144;, A77-B 145; A77-B146; A77-B 147; A77-B 148; A77-B 149; A77-B 150; A77-B 15 1; A77-B 152; A'77-B 153; A77-B 154; A77-B155; A77-B156; A77-B157; A77-B158; A77-B159; A77-B 160; A77-B161; A77-B 162; A77-B 163; A77-B 164; A77-B165; A77-B 166; A77-B 167; A77-B 168; A77-B169; A78-B1; A78-B2; A78-B3; A78-B4; A78-B5; A78-B6; A78-B7; A78-Bg; A78-B9; A78-B1O; A78-B 11; A78-B12; A78-B13; A7 8-B 14; A78-B15; A78-316; A78-B17; A78-B18; A78-B19; A7S-B20; A78-B21; A78-B22; A'78-B23; A78-B24; A78-B25; A78-B26; A78-B27; A78-B28; A78-B29; A78-B30; A78-B3 1; A78-B32; A78-B33; A78-B34; A78-B35; A78-B36; A78-B37; A78-B38; A78-B39; A78-B40; A78-B41; A78-B42; A78-B43; A79-B44; A78-B45; A78-B46; A78-B47; A78-B48; A78-B49; A78-B50; A78-B51; A78-B52; A78-B53; A78-B54; A78-B55; A78-B56; A78-B57; A78-B58; A78-B59; A78-B60; A78-B61; A78-B62; A78-B63; A78-B64; A78-B65; A78-B66; A78-B67; A78-B68; A78-B69; A78-B70; A78-B71; A78-B72; A78-B73; A78-B74; A78-B75; A78-B76; A78-B77; A78-B78; A78-B79; A78-B80; A78-BSI; A79-B82; AX78-B83; A78-B84; A78-B85; A78-B86; A79-B87; A78-B88; A78-B89; A78-B90; A78-B91; A78-B92; A78-B93; A78-B94; A78-B95; A78-B96; A78-B97; WO 031035065 WO 03/35065PCT/GB02/04763 -173- A78-B98; A'78-B399; -A78-B100; A79-B1O1; A78-B102; A78-B103; A78-B 104-, A78-B105; A78-B106; A78-B107; A79-B108; A78-B109; A78-B1 10; A78-B1 11; A78-B112; A78-B1 13; A78-B114; A78-B115; A78-BI16; A78-B1 t7; A78-BI18; A78-B 119; A78-B120; A78-B 12 1; A7 8-B 122; A78-B123; A79-B 124; A78-B125; A78-B126; A78-B127; A78-B128; A78-B 129; A78-B 130; A78-B131; A'78-B132; A78-B133; A78-B134; A78-B135; A78-BI36; A78-B137; A78-B138; A78-BI39; A78-B3 140; A78-B 14 1; A78-B 142; A78-B 143;- A78-B144; A78-B 145; A78-B146; A78-B 147; A78-Bt48; A78-B149; A78-B150; A78-B 151; A78-B152; A78-B 153; A78-B154; A78-B 155; A78-B156; A78-B157; A78-B158; A78-B 159; A78-B160; A78-B 161; A78-B162; A78-B 163; A78-B164; A78-B165; A78-B166; A78-B167; A78-B168; A78-B169; A79-B1; A79-B2; A79-B3; A79-B4; A79-B5; A79-B6; A79-B7; A79-B8; A79-B9; A79-B 10; A79-B11; A79-B 12; A79-B 13; A79-B14K A79-B15; A79-B 16; A79-B17; A79-B 18;1 A79-B 19; A79-B20; A79-B2 1; A79-B22; A79-B23; A79-B24; A79-B25; A'79-B26; A79-B27; A79-B28; A79-B29; A79-B30; A79-B3 1; A79-B32; A79-B33; A79-B34; A79-B35; A79-B36; A79-B37; A79-B38; A79-B39; A'19-B40; A79-B4 1; A79-B42; A79-B43; A79-B44; A79-B45; A79-B46; A79-B47; A79-B48; A79-B49; A79-B50; A79-B5 1; A79-B52; A79-B53; A79-B54; A79-B55; A79-B56; A79-B57; A79-B58; A79-B59; A79-B60; A79-B61; A79-B62; A79-B63; A79-B64; A79-B65; A79-B66; A79-B67; A79:§68, A79-B69; A79-B70; A79-B71; A79-B72; A79-B73; A79-B74; A79-B75; A79-B76; A79-B77; A79-B78; A79-B79; A79-B80; A79-B81; A79-B82;) A79-B83; A79-B84; A79-B85; A79-B86; A79-B87; A79-B88; A79-B89; A79-B90, A'19-B91; A79-B92; A79-B93; A79-B94; A79-B95; A79-B96; A79-B97; A79-B98; A79-B99; A79-B100; A79-B1O1; A79-B 102; A79-B 103; A79-B 104; A79-B 105; A79-B 106; A79-B 107; A79-B108; A79-B 109; A79-B1 10; A79-B1 11; A79-B 112; A79-B 113; A79-B3114; A79-B 115; A79-B 116; A79-B 117; A79-B 118; A79-BI19-; A79-B120; A79-B121; A79-B 122; A79-B123; A79-B124; A79-B125; A79-B126; A79-B 127; A79-B 128; A79-B129; A79-B 130; A79-B13 1; A79-B 132; A79-B133; A79-B134; A79-B135; A79-B136; A79-B137; A79-B3138; WO 031035065 WO 03/35065PCT/GB02/04763 -174- A79-B139; A79-B140; A79-B141; A79-B 142; A79-B 143; A79-B144; A79-B 145; A79-B 146; A;7 9 BI 4 7 A79-B148; A79-B 149; A79-B150; A79-B 15 1; A79-B152; A79-B 153; A79-B154; A79-B 155; A79-B156; A79-B 157; A79-B158; A79-B 159; A79-B160; A79-B 161; A79-B 162; A79-B 163; A79-B 164; A79-B 165; A79-B 166; A79-B 167; A79-B 168; A79-B 169; A8O-BI; A80-B2; A80-B3; A80-B4; A80-B5; A80-B6; A80-B7; A80-B8; A80-B9; A80-B1O; A80-B 11; AS0-B 12; AS0-B 13; A80-B314; A80-B 15; A80-B16; AS0-B 17; 18; A80-B 19; AS0-B20; ASO-B21; A80-B22; A8O-B23; A80-B24; A90-B25; ASO-B 26; AS0-B27; A80-B28; A80-B29; A80-B30; AS0-B31; A80-B32; A8O-B33; A80-B34; A8O-B35; A80-B36; ASO-B37; A80-B38; A80-B39; A80-B40; ASO-B4 1; A80-B42; AS0-B43; A80-B44; A8O-B45; A80-B46; A80-B47; A80-B48; A80-B49; A80-B50; A80-B5 1; A80-B52; A80-B53, A80-B54; A80-B55; AXO-BS6; A80-B57; A80-B58; ASO-B59; AS0-B60; AS0-B61; A80-B62; A80-B63; A90-B64; A80-B65; A80-B66; A80-B67; A80-B68; A80-B69; ASO-B70; A80-B7 1; A80-B72; A80-B73; A80-B74; A80-B75; A80-B76; A80-B77; A80-B78; A80-B79; A80-B80; A80-B81; A80-B82; A80-B83; A80-B84; A80-B85; A80-B86; A80-B87; A80-B88; A80-B89; A80-B90; A80-B91; A80-B92; A80-B93; ASO-B94; A80-B95; A80-B96; ASO-B97; A80-B98; A80-B99; A90-B 100; A80-B1O1; AS0-B 102; A80-B 103; A80-B 104; A80-B 105; ASO-B 106; A90-B 107; A80-B108; A80-B109; A80-B Il1; A80-Bill; A80-B 112; A80-B 113; 114; A80-B 115; A80-B 116; A80-B1 117; A80-B 118; A80-B 119; ASO-B 120; A80-B12 1; A80-B 122; ASO-B 123; A80-B 124; A80-B 125; 126; A80-B127; A90-D128; A80-B129; A80-B130; A80-B131; A80-B132; A80-B133; A80-B 134; A80-B3135; A80-B136; A80-B 137; A80-B138; A80-B139; A80-B 140; A80-3141; A8O-B142; A80-B143; 144; A80-B 145; A80-B 146; A80-B 147; A80-B 148; A8O-B149; A80-B150; A80-B151; A80-B152; A80-B 153; A80-B154; A8O-B156; A80-B 157; A80-B158; A80-B 159; A80-B 160; A80-Bl61; 162; A80-B 163; A80-B 164; ASO-B 165; A80-B 166; A8O-B 167; A80-B168; A80-B 169; A8 1-Bi1; ASI-B2; A81-B3; AS1-B4; A81-B5; A81-B6; AS I-B7; A81-B38; A81-B39; A8i-BlO; WO 031035065 WO 03/35065PCT/GB02/04763 A81-Bl1; AS1-B12; A81-B13; A81I-B 14; A81-B15; A81-B16; A81-B17; ASI-B1S; A81I-B 19; A81-B20; A81-B21; A81-B22; AR1-B23; AB1-B24; A81-B25; A81-B26; A81-B27; A81-B28; A81-B29; A81-B30; A81-B31; A81-B32; A81-B33; A81-B34;- A81-B35; ASI-B36; A81-B37; A81-B38; A81-B39; A81-B40:, A81-B41; A81-B342; A81-B43; A81 -B44; AS1I-B45; AS I-B46; A81-B47; A81-B48; A81-B49; AS I-B50; A81-B51; A81-B52; A81-B53; A81I-B 54; ASl-B55; A81-B56; A81-B57; A81-B58;) A81-B59; AS 1:-60; AS I-B6 1; A81-B62; A81-B63; A81-B64; A81-B65; A81-B66; A81-B67; A81-B68; A81-B69; A81-B70; A81-B71; A81I-B72; AS I-B73; A81-B74; A81-B75; AS1-B76; A81-B77; A81-B78; A81-B79; A81-B80; A81-B8I; A81-BS2; A81-BS3; A81-B84; ASI-B85; A81-B86; A81-B87;- A81-B88; AS1-B89; A81-B90; A81I-B9 1; A81-B92; A81-B93; A81-B94, A81-B95; A81-B96; AS I-B97; A81-B98; AS1I-B99; A81-B100; A81-B1O1; Ag1-BI02; AS I-B 103; A81-B104; A81-B105; A81-B106; AS I-B 107; A81-B108; A81-B3109; A81-BI 10; A81-BI11; A81-B112; A81-BI13; A81-BI14; A81-BI15; A81-B116; A81-B117; A81-B1IS; A81-B119; A81-B120; A 1 -B 121; A81I-B 122; A81-B123; A81-BI24; A81-B125; A81-B126; A81-B12'1; A81-B128; A81-B129; A81-B130; A81-B131; A81-B132; ASI-B133: A81-B134; A81-B135; A81-B136; A81-B137; A81-B138; A81-B139; A81-B140; A81-B141; A81-B142; AS1I-B 143; AS I-B 144; A81-B145; A81I-B 146; A81-B147; A81-B148, A81-BI49; ASI-B3150; A81-B151; A81-BI52; A81-B153; AS1-B154; A81-B155; A81 -B15 6; A81-B157; A81-BI58; A81-B159; A81-B160; Agl-B161; A81 -B 162; A81-B163; ASI-B164; A81-B165; A81-B166; A81-B167; A81-B168; Ag1-B169; A82-Bl; A82-B2; A82-B3, A82-B4; A82-B5; A82-B36; A82-B7; A82-B8; A82-B9; A82-B1O; A82-B 11; A82-B12; A82-B13; A82-B14; A82-B15; A82-B16; A82-B 17; A82-B1S; A82-B19; A82-B20; A82-B21; A82-B22; A82-B23; A82-B24; X8-2-B25; A82-B26; A82-B27; A82-B28; A82-B29; A82-B30; A78-2-M 1, A82-B32; A82-B33; A82-B34; A82-B35; A82-B36; A82-1337; A82-B38; A82-B39; A82-B40; A82-B41; A82-B42; A82-B43; A82-B44; A82-B45; A82-B46; A82-B47; A82-B48; A82-B49; A82-B50; A82-B5 1; WO 031035065 WO 03/35065PCT/GB02/04763 -176- A82-B52; A82-B53; A82-B54; A82-B55; A82-B56; A82-B57; A82-B58; A92-B59; A82-B60; A82-B61; A82-B62;) A82-B63; A82-B64; A82-B65; A82-B66; A82-B67; A82-B68; A82-B69; A82-B70; A92-B71; A82-B72; A82-B73; A82-B74; A82-B75; A82-B76; A92-B77; A82-B78; A82-B79; A82-B80; A82-B81; A82-B82; A82-B83; A82-B84; A82-B85; A82-B86; A82-B87; A82-B88; A82-B89; A82-B90; A82-B91; A82-B92; A82-B93; A82-B94; A82-B95; A82-B96; A82-B97; A82-B98; A82-B99; A82-B 100; A82-B 101; A82-B102; A82-B 103; A82-B104; A82-B 105; A82-B106; A82-B 107; A82-B108; A82-B109; A92-B1I 10; A82-B1 11; A82-B 112; A82-B 113; A82-Bl114; A82-B 115; A82-B 116; A82-B 117; A82-B 118; A82-B119; A82-B120; A82-B 12 t; A82-B 122; A82-B193; A82-BI24; A82-B 125; A82-B126; A82-B127; A82-B 128; A82-B129; A82-B130; A82-B 13 1; A82-B 132; A82-B133; A82-B 134; A82-B135; A82-B136; A92-B 137; A82-B138; A82-BI39; A82-B3140; A82-B141; A82-B142; A82-B 143; A82-B 144; A82-B145; A82-B 146; A82-B147; A82-B 148; A82-B 149; A82-B 150; A82-B 15 1; A82-B 152; A82-B 153; A82-B 154; A82-BI55; A82-B156; A82-B157; A82-BI58; A82-B 159; A82-B160; A82-B 16 1; A82-B 162; A82-B 163; A82-B 164; A82-B 165; A82-B 166; A82-B 167; A82-B 163; A82-B 169; A83-B 1; A83-B2; A83-B3; A83-B4; A83-B5; A83-B6; A83-B7; A83-B8; A83-B9; A83-B1O; A83-BI11; A83-B12; A83-B13; A83-B14; A83-B15; A83-B16; A83-B17; A83-B18; A83-B19; A83-B20; A83-B21; A83-B22; A83-B23; A83-B24; A83-B25; A83-B26; A83-B27; A83-B28; A83-B29; A83-B30; A83-B31; A83-B32; A83-B33; A83-B34; A83-B35; A83-B36; A83-B37; A83-B38; A83-B39; A83-B40; A83-B41; A83-B42; A83-B43; A83-B44; A83-B45; A83-B46; A83-B47; A83-B48; A83-B49; A83-B50; A83-B51; A83-B52; A83-B53; A83-B54; A83-B55; A83-B56; A83-B57; A83-B58; A83-B59; A83-B60; A83-B61; A83-B62; A83-B63; A83-B64; A83-B65; A83-B66; A83-B67; A83-B68; A93-B69; A83-B70; A83-B71; A83-B72; A83-B73; A83-B74; A83-B75; A83-B76; A83-B77; A83-B78; A83-B79; A83-B80; A83-BS1; A83-382; A83-B83; A83-B384; A83-B85; A83-B86; Q*2. I O D0V1 A Q2 D Y).

A83-BS A6i-Ii6b; t"O.)-Doy; AO-5-K)YU; J J WO 031035065 WO 03/35065PCT/GB02/04763 -177- A83-B93; A83-B94; A83-B95; A83-B96; A83-B97; A83-B98; A83-B99; A83-B100; A83-BIO1; A83-B102; A83-B103; A83-B 104; A8-B1 05; A83-B106; A83-B 107; A83-B108; A83-BI09; A83-B1 A83-B1I11; A83-B 112; A83 -B1I1'3; A83-B 114; A83 -B 115; A83-B 116; A83-B 117; A93-B 1 18; A83-B 119; A83-B 120; A83-B 121; A93-B 122; A83-B123; A83-B124; A83-B125; A83-B126; A83-B127; A83-B128; A83-B129; A83-B130; A83-B 131; A93-B132- A83-B133; A83-B134; A83-B135; A83-B136; A83-B137; A83-BI38; A83-B139; A83-B140; A83-B 141; A83-B142; A93-B3 143; A83- 3144; A83-B 145; A83-B 146; A83-B 147; A83-B 148; A83-B 149; A83-B 150; A83-B151; A83-B 152; A83-B153; A83-B154; A83-B155; A83-B16 A83-B157; A83-B158; A83-B159; A83-B160; A83-B16t); A83-B162; A83-B163; A83-B164; A83-B 165; A83-B 166; A83-B167; A83-B 168; A83-B169; A84-B1; A84-B2; A84-B3; A84-B4; A84-B5; A84-B6; A84-B7; A84-B8; A84-B9; A84-B10; 8-4-B 11; A84-B12; A84-B 13; A84-B 14; A84-B 15; A84-B 16; A84-B 17; A84-B18; A84-B 19; A84-B20; A84-B21; A84-B22; A84-B23; A84-B24; A84-B25; A84-B26; A84-B27; A84-B28; A84-B29; A84-B30; A84-B3 1 A84-B32; A84-B33; A84-B34; A84-B35; A84-B36; A84-B37); A84-B3 8; A84-B39; A84-B40; A84-B4 1; A84-B42; A84-B43; A84-B44; A84-B45; A94-B46; A84-B47; A84-B48; A84-B49; A84-B50; A84-B51; A84-B352; A84-B53' A84-B54; A84-B55; A84-B56; A84-B57; A84-B59; A84-B59; A84-B360; A84-B61; A84-B62; A84-B63; A84-B64; A84-B65; A94-B66; A84-B67; A84-B68; A84-B69; A84-B70; A84-B371; A84-B72; A84-B73; A84-B74; A84-B75; A84-B76; A84-B77; A84-B78; A84-B79; A84-BS0; A94-B8 1; A84-B82; A84-BS3; A84-B84; A84-B A84-B86; A84-B87; A84-B88; A84-B89; A84-B90; A84-B91; A84-B92; A84-B93; A84-B94; A84-B95; A84-B96; A84-B97; A84-B98; A84-B99; A84-B100; A84-B1O1; A84-B102; A84-B 103; A84-B 104; A84-B 105; A84-B 106; A84-B 107; A84-BI108; A84-B 109; A84-B1I 10; A84-B1 111; A84-B 112; A84-B 113; A84-B 114; A84-B 115; A94-B 116; A84-B 117; A84-B 118; A84-B 119; A84-B 120; A84-B121; A84-B 122; A84-B 123; A94-B 124; A84-B 125; A84-B 126; A84-B127; A84-B18 A8-B 129; A8 4-B 13 0; 1A84-B 131; A84-B 13 2; A84-B133; WO 031035065 WO 03/35065PCT/GB02/04763 -178- A84-B 134; A84-B135; A84-Bt36; A84-B137; A84-B138; A84-B139; A84-B 140; A84-B 14 1; A84-B 142; A84-B 143; A84-B 144; A84-B 145; A84-B 146; A84-B 147; A84-B 148; A84-B 149; A84-B 150; A84-B 15 1; A84-B 152; A84-B 153; A84-B 154; A84-B155; A84-B156; A84-B 157; A84-3158; A84-B159; A84-B160; A84-BI61; A84-B162; A84-B 163; A84-B 164; A84-B 165; A84-B166; A94-B 167; A84-B168; A84-B 169; 1; A85-B2; A85-B3; A85-B4; A85-B5; A85-B6; A85-B7; A85-B8; A85-B9; A85-B1O; A85-Bl11; A85-B12; 13; A95-B 14; A85-B15. A85-B16; A85-B17; A8 5-B 18; 19; A85-B20; A85-B21; A85-B22; A85-B23; A85-B24; A85-B25; A85-B26; A85-B27; A85-B28; A85-B29; A85-B30; A85-B3 1; A85-B32; A85-B33; A85-B34; A85-B35; A85-B36; A85-B37; A85-B38; A85-B39; A85-B40; A85-B41; A85-B42; A85-B43; A85-B44; A85-B45; A85-B46; A85-B47; A85-B48, A85-B49; A85-B50; A85-B51; A85-B52; A85-B53; A85-B54; A85-B55; A85-B56; A85-B57; A85-B58; A95-B59; A85-B60; A85-B61; A85-1362; A85-B63; A85-B64; A85-B65; A85-B66; A85-B67; A85-B68; A85-B69; A85-B70; A85-B7 t; A85-B72; A85-B73; A85-B74; A85-B75; A85-B76; A85-B77; A85-B78; A85-B79; A85-B80; A85-B81; A85-B82; A85-B83; A85-B84; A85-B85; A95-B86; A85-B87; A85-B88; A85-B89; A85-B90; A85-B91; A85-B92; A85-B93; A85-B94; A85-B95; A85-B96; A85-B97; A85-B98; A85-B99; A85-B 100; A85-B 101; A85-B 102; A8 5-B 103; A85-B104; A85-BiOS; A85-B106; A85-B107; ASS-BIOS; A85-B109; A85-B I 10; AS-Bill; A85-B1 12; A85-B 113; A85 -B 114; 15; A85-B1 16; A85-BI 17; A85-B I 18; A85-B 119; A85-B120; A85-B121; A85-B122; A85-B123; A85-B124; A85-B125; A85-B126; ASS-B127; A85-BI28; A85-BI29; A85-B130; A85-B131; A85-B132; A85-B133; A85-B134; A8 5-B 13 5; A85-B136; A85-B137; A85-BI38; A85-B139; A85-B140; A85-B141; A85 -B 142; A85-B143; A85-B144; A85-B145; A85-B146; A85-B147; A85-B148; A85-B149;- A85-B15O; A85-B151; A85-B152; A85-B153; A85-B154; A85-B155; A85-B156; A85-B157; A85-B158; A85-B159; AS--B160; A85-B161; A85-B162; 163; A8 5-B 164; A85-B165; A85-B166; A85-B167; A85-B168; A55-B1; A8-B 1; A86-B2; A86-B3; A5g-6-B4; A86-B5; WO 031035065 WO 03/35065PCT/GB02/04763 -179- A86-B6; A36-B7; A86-BS; A86-B9; A86-BIO; A86-B 11; A86-B12; A96-B 13; A86-B14; A86-B 15; A86-B16; A86-B 17; A96-B 18; AB6-B 19; A86-B20; A86-B21; A86-B22; A86-B23; A86-B24; A86-B25; A86-B26; A86-B27; A86-B28; A86-B29; A86-B30; A86-B31; A86-B32; A86-B33; A86-B34; A86-B35; A86-B36; A86-B37; A86-B38; A86-B39; '86-B40; A86-B41; A86-B42; A86-B43; A86-B44; A86-B45; A86-B46; A86-B47; A86-B48; A86-B49; A86-B50; A86-B51; A86-B52; A86-B53; A86-B54; A86-BR55; A86-B56; A86-B57; A86-B58; A86-B59; A86-B60; A86-B61; A86-B62; A86-B63; A86-B64; A86-B65; A86-B66; A86-B67; A86-B68; A86-B69; A86-B70; A86-B71; A86-B72; A86-B373; A86-B74; A86-B75; A86-B76; A86-B77; A86-B78; A86-B79; A86-B8O; A86-B81; A86-B82; A86-B83; A86-B84; A86-B85; A86-B86; A86-B87; A86-B88; A86-B89, A86-B90; A86-B91; A86-B92; A86-B93; A86-B94; A86-B95; A86-B96; A86-B97; A86-B98; A86-B99; A86-B100; A86-B1O1; A86-BI02; A86-B 103; A86-B 104; A86-B105; A86-BI06; A86-B107; A86-B1OS; A86-B109; A86-B 110; A86-B111; A86-B 112; A86-Bl 13; A86-B 114; A86-B 115; A86-B 116; A86-B117-; A86-B118; A86-B 119; A86-B120; A86-B121; A86-B 122; A86-B123; A86-B124; A86-B3125; A86-B126; A86-B127; A86-BI28; A86-B 129; A86-B130; A86-BI31; A86-B132; A86-B133; A86-B 134; A86-B135; A86-BI36; A86-B137; A86-B138; A86-B139; A86-B 140; A86-BI41; A86-B142; A86-B143; A86-B144; A86-B 145; A86-B146; A86-BI47; A86-B149; A86-B149; A86-BI50; A86-B1 51; A86-B152; A86-B 153; A86-B154; A86-BI55; A86-B156; A86-B 157; A86-B 15 8; A86-B 159; A86-B160; A86-B161; A86-B162; A86-B 163; A86-B164; A86-B 165; A86-B166; A86-B167; A86-B168; A86-B 169; A87-B1; A87-B2; A87-B3; A87-B4; A87-B5; A87-B6; A87-B7; A87-Bg; A87-B9; M 7 -B A87-B 11; A87-B 12; A87-B 13; A87-B14; A87-B15; A87-B16; A87-B17; A87-B t8; A87-B19; A87-B2O; A87-B21; A87-B22; A87-B23; A87-B24; A87-B25; A87-B26; A87-B27; A87-B28; A87-B29; A87-B30; A87-B31; A87-B32; A87-B33; A87-B34; A87-B35; A87-B36; AS'7-B37; A87-B38; A87-B39; A97-B40; A87-B41; A87-B42; A87-B43; A87-B44; A87-B45; A87-B46; WO 031035065 WO 03/35065PCT/GB02/04763 -180- A87-B47; A87-B53; A87-B59; A87-B48; A87-B49; A87-B50; A87-B5 1; A87-B52; A87-B58; 4 1 1 A87-B54; A97-B60; A87-B55; A87 -B5 6; A87-B57; A87-B6 1; A87-B62; A87-B63; A87-B69; A87-B64; A97-B70; AS'7-B65; A87-B'71; A87-B77; A87-B66; A87-B72; A87-B67; A87-B68; A87-B73; A87-074 A7-B 75; A 7-B76;, I L r A~ 1-11151; IX~ i-1i~z; A87-B78; A87-B79; A87-J380; A87-BS1; A87-BS2, A87-B83; A87-B84; A87-B85; A87-B86; A87-BS7; A87-B88; A87-B89; A87-B90; A87-B91; A87-B92; A87-B93; A87-B94; A87-B95; A87- 9-6 A97-1397; A87-B98; A87-B99; A87-B 100; A87-B1O1; A87-B 102; A87-Bt03; AU -B 104; A87-B105; A87-B 106; A87-B 107; A87-B1OS; A87-B t09; A87-B110; A87-B111; A87-BI12; A87-B 113; A87-B 114; A87-B 115; A87-B 116; A87-B 117; A97-BI1S; A87-B 119; A87-B 120; A87-B 12 1; A8'7-B 122; A87-B123; A87-B124; A87-B125; A87-B 126; A87-B127; A87-B 128; A87-B129; A87-B130; A87-B 13 1; A87-B 132; A87-BI 33; A87-B 134; A87-B135; A87-B136; A87-B137; A87-B138; A87-BI39; A87-B3140; A97-B141; A87-B 142; A87-B 143; A87-B 144; A87-BI45; A87-B 146; A87-B147; A87-B 148; A87-B149; A87-B 150; A87-B151; A87-B 152; A87-B 153; A87-B 154; A87-BI55; A87-B156; A87-B157; A87-B158; A87-B 159; A87-B 160; A8-B6; 8 -B162; 87-B163; A87-B 164; A87-B 165; A87-B166, A87-B167; A87-B168; A97-B 169; A88-Bl; A88-B32; A88-B 3; A88-B4; A88-B5; A88-B6; A88-B7; A88-B8; ASS-B9; A88-B1O; A88-B11; A88-B12; A88-B13; AS88-B 14; A88-B16; A88-B17; A88-B18; A88-B19; A88-B20;, A88-B21; A88-B22; A88-B23; A88-B24; A88-B25; A88-B26; A88-B27; A88-B28; A88-B29; A88-B30; A88-B31; A88-B32; A88-B33; A88-B34; AS8-B35; A88-B36; Aj8 8 -B 37; A88-B338; A88-B39; A88-B40; A88-B41; A88-B42; A88-B43; A88-B44; A88-B45; A88-B46; A88-B47; A88-B48; A88-B49; A88-B50; A88-B5 1; A88-B52; A88-B53; A88-B54; A88-355; A88-B56; A88-B57; A88-B58; A88-B59; A88-B60; A88-B361; A88-B62; A88-B63; ASS-B64; A88-B65; A88-B66; A88-B 6'; A88-B68; A88-B70; A88-B76; A88-B7 1; [A88-B72; 1A88-B77; A88-B78; A88-B73; A88-B74; A88-B79; A88-BSO; A88-B85; A88-BS6; A88-B75; A88-B8 1; A88-B87; A8H-B82; A88-B83;- [AB84; WO 031035065 WO 03/35065PCT/GB02/04763 -181- A88-B88; A88-B89; A88-B90; IA88-1391; 4 1 A88-B94; A88-B95; A88-B96; IA88-B97; A88-B92; A88-B9 8; A88-B 104; A8 S-B93; A8S-B99; A88-B 105; I 1 ASS-BR 100; A8 8-B 101; A88-B 102; AS S-B 103 A88-B3106; Ag8-B107; A88-B 108; A88-B109; A8S-B I 10; A8B 1 A88-D112; A88-Bl113; ASS-B 114; A88-B115; A88-B 116; A98-B117; A88-B118; A88-B119; A88-B 120; A88-B121; A88-B122; A98-B123; A88-B124; A88-B125; A88-B126; A88-B127; A88-13128; A88-B129; A88-B 130; A88-B131; A88-B132; A88-B133; A88-B 134; A88-B135; A89-B136; A88-B137; ASS-B 138; A88-B139; A88-B140; A88-B141; A88-B142; ASS-B 143; AS8-B144; A85-B 145; A88-B146; A88-B147; A88-B148; A38-13149; ASS-B 150; ASS-B151; A88-B152; A88-B153; A88-B154; A88-BiSS; A88-B156;- A88-B157; A88-B158; A88-B159; A88-B160; A88-B161; A88-B 162; ASS8-8-B 163; A88-B164; A88-B165; A88-B166; A88-B167; A88-Bt68; A88-B169; A89-B1; A89-B2; A89-B3; A89-B4; A89-B5; A89-B6; A89-B7; A89-B8; A89-B9; A89-B 10; A89-B 11; A89-B 12; A89-B1; A89-B 14; A89-B15; A89-B 16; A89-B 17; A89-B 18; A89-B19; A89-B20; A89-B2 1; A89-B22; A89-B23; A89-B24; A89-B25; A89-B26; A89-B27; A89-B28; A89-B29; A89-B30; A89-B3 1; AS9-B32; A89-B33; A89-B34; A89-B35; A89-B36; A89-B37; A89-B38; A89-B39; A89-B40; A89-B4 1; A89-B42; A89-B43; A89-B44; A89-B45; A89-B46; A89-B47; A89-B48; A89-B49; A89-B50; A89-B5 1; A89-B52; A89-B53; A89-B54; A99-B55; A89-B56; A89-B57; A89-B58; A89-B59; A89-B60; A;U9 -B6 t; AS9-B62; A89-B63; A89-B64; A89-B65; A89-B66; A89-B67; A89-B68; A89-B69-; A89-B70; A89-B7 1; A89-B72; A89-B73; A89-B74; A89-B75; A89-B76; A89-B77; A89-B78; A89-B79; A89-B8O; A89-B81; A89-B82; A89-B83; A89-B84; A89-B85; A89-B86; A89-B87; A89-B88; A89-B89; A89-B90; A89-B91; A89-B92; A89-B93; A89-B94; A89-B95; A89-B96; A89-B97; A89-B98; A89-B99; A89-B 100; A89-B 101; A-i89-B 102; A89-B 103; A89-B 104; A89-B105; A89-B106; A89-B 107; A89-B1O; A9B09; A 8-9-B10; A89-B1 11; A89-B3112; A89-B1 13; A89-B 114; A89-B 115; A89-Bl 16; A89-B1 17; A89-B 1 IS; A99-B 19; A89-B120; A89-B 12 1; A89-B122; A89-B 123; A89-B124; A89-B 125; A89-B126; A89-B127; A89-B128; WO 031035065 WO 03/35065PCT/GB02/04763 -182- A89-B 129; A89-B130; A89-B 131; A89-B132; A89-B 133; A89-BI34; A89-B135; A89-B136; A89-B 137; A89-B138; A89-B 139; A89-B140; A89-BI1P A89-B142; A89-B 143; A8 9-B 144; A89-B 145; A89-B146; A89-B 147; A89-B148; A89-B 149; A89-B150; A89-B 15 1; A89-B 152; A89-B 153; A89-B154; A89-B 155; A89-B156; A89-B 157; A89-B158; A89-B159; A89-B 160; A89-B161; A99-B12 A8 13; A89-B164; A89-B165; A89-B 166; A89-B167; A89-B3168; A89-B169; A90-B1; A90-B2; A90-B3; A90-B4; A90-B5; A90-B6; A90-B7; A90-B9; A90-BIO;0 A90-B 11, A90-B12; A90-B13; 14; A90-B 15; A90-B 16; A90-B 17; A90-B18; A90-B19; A90-B20; A90-B2 1; A90-B22; A90-B23; A90-B24; A90-B25; A90-B26; A90-B27; A90-B28; A90-B29; A90-B30; A90-B3i1; A90-B32; A90-B33; A90-B34; A90-B35; A90-B36; A90-B37; A90-B38; A90-B39; A90-B40; A90-B4 1; A90-B42; A90-B43; A90-B44; A90-B45; A-j90-B46; A90-B47; A90-B48; A90-B49; A90-B50; A90-B51; A90-B52; A90-B53; A90-B54; A90-B55; A90-B56; A90-B57; A90-B58; A90-B59; A90-B60; A90-B61; A90-B62; A90-B363; A90-B64; A90-B65; A90-B66; A90-B67; A90-B68; A90-B69; A90-B70; A90-B71; A90-B72; A90-B73; A90-B74; A90-B75; A90-B76; A90-B77; A90-B78; A90-B79; A90-B8O; A90-B81; A90-B82; A90-B83; A90-B84; A90-B85; A90-B86; A90-B87; A90-B88; A90-B89; A90-B90; A90-B91; A90-B92; A90-B93; A90-B94; A90-B95; A90-B96; A90-B97; A90-B98; A90-B99, A90-B 100; A90 B101; A90-B 102; A90-B103; 104; A90-B 105; A90-B 106; A90-B107; A90-B108; A90-B109; A90-B11O; A90-Bl11t; A90-B 112; A90-B 113; A90-B 114; A90-B115;- 116; A90-B117; A90-B 118; A90-B 119; A90-B 120; A90-Bl21, 122; A90-B 123; A90-B 124; A90-B 125; A90-B 126; A90-B 127; A90-B128; A90-B129; A90-B130; A90-B131; A90-B3132; A90-B133; 134; A90-B135; A90-B136; A90-B 137; A90-B138; A90-B139; 140; A90-B141; A90-B 142; A90-B 143; A90-B144; A90-B145; A90-B146; A90-B 147; A90-B148; A,9-0-B 149; A90-B150; A90-B151; 152; A90-B 153; A90-B 154; A90-B 155; A90-B156; A90-B1 57; A90-B158; A90-B 159; A90-B 160; A90-B 161; A90-B 162; A90-B 163; 164; A90-B 165; A90-B166; A90-B167; A90-B168; A90-B169; WO 031035065 WO 03/35065PCT/GB02/04763 -183- A91-B1; A91-B2; A91-B3; A91-B4; A91-B5; A91-B6; A91-B7; A91-B8; A91-B9; A91-BIO; A91-B1I; A91I-B 12; A91I-B 13; A91I-B 14; A91-B15; A9 1-B 16; A91-B17; A91-B18; A9 1-B 19; A9 I-B20; A91-B21; A91-B22; A91-B23; A91I-B24; A91-B25; A91-B26; A91-B27; A91-B28; A91-B29; A91-B30; A91-B31; A91-B32; A91-B33; A91-B34; A91-B35; A91 -B 36; A91-B37-; A91-B38; A91 -B3 9; A9 I-B40; A91-B41; A91I-B42; A91-B43; A9 1-B44; A91 -B45; A91-B46;- A91-1347; A91-B48; A9 I-B49; A91-B350; A91-B51; A91-B52; A91-B53; A91-B54;- A91-B55; A91-B56; A91-B57; A91-B58; A91-B59; A91-B60; A91-B61; A91I-B62; A91-B63; A91I-B 64; A91-B65; A91-B66; A91-B67; A91-B68; A91-B69; A91-B70; A91-B'11; A91-B72; A91-B73; A91-B74; A91-B75; A91-B76; A91-B77; A91-B78; A91-B79; A91-B8O; A91-B81; A91-B82; A91-B83; A91-B84; A91-B85; A91-B86; A91-B8'1; A91-B88; A91-B89; A91-B90; A91-B91; A91-B92; A91-B93; A91-B94; A91-B95; A91-B96; A91-B97; A91-B98; A91-B99; A91-B100; A91-B1O1; A91-B102; A91 -B 103; A91t-B 104; A91-BI05; A91-B106; A91I-B 107; A91-B108; A91-B109; A91-B11O; A91-B111; A91-BI t2; A91-B113; A91-B114; A91-BI 15; A91-Bl116; A91I-B 117; A91 -B 118; A91-B119; A91-B190; A91-B121; A91-B122; A91-B123; A91-B124; A91-B125; A91-B126; A91-BI27; A91-B128; A91-B129; A91-B130; A91-BI31; A91-B132; A91-B133; A91-B134; A91-B135; A91 -B 136; A91-B137; A91-B138; A91-B139; A91-B140; A91-B141; A91 -B 142; A91-B143; A91-B144; A91-B145; A91 -B 146; A91-B147; A91-B148; A91-B149; A91-B150; A91-B151; A91 -B 152; A91-B153; A91-B154-) A91-B155; A91-13156; A91-B157; A91-B158; A91-B159; A91-B160; A91-B161; A91-B162; A91-BM63; A91 -B 164; A91-B165; A91-B166; A91-B167; A91-B168; A91-B169; A92-B 1; A92-B2; A92-B3; A92-B4; A92-B5; A92-B6; A92-B7; A92-B8; AX9-2-B9; A92-B1O; A92-B11; A92-B 12; A92-B 13; A92-B14; AX9 2 -B 15; A92-B16; A92-B17; A92-B 19; A92-B1t9; A92-B20; A92-B21; A92-B22; A92-B23; A92-B24; A92-B25; A92-B26; A92-B27; A92-B28; A92-B29; A92-B30; A92-B31; A92-B32; AX9-2-B33; A92-B34; A92-B35; A92-B36; A92-B37; A92-B38; A92-B39; A92-B40; A92-B41; WO 031035065 WO 03/35065PCT/GB02/04763 -184- A92-B42; A92-B43; A92-B44; A92-B45; A92-B46; A92-B47; A92-B48; A92-B49; A92-B50; A92-B5 1; A92-B52; A92-1B53; A92-B54; A92-B55; A92-B56; A92-B57; A92-B58; A92-B59; A92-B60; A92-B61; A92-B62; A92-B63; A92-B64; A92-B65; A92-B66; A92-B67; A92-B68; A92-B69; A92-B70; A92-B71; A92-B72; A92-B73; A92-B74; A92-B75; A92-B76; A92-B77; A92-B78; A92-B79; A92-B80; A92-B381; A92-B82; A92-B83; A92-B84; A92-B85; A92-B86; A92-B87; A92-B88; A92-B89; A92-B90; A92-B91; A92-B92; A92-B93; A92-B94; A92-B95; A92-B96; A92-B97; A92-B98; A92-B99; A92-B 100; A92-B 101; A92-B 102; A92-B 103; A92-B 104; A92-B 105; A92-B 106; A92-B 107; A92-B108; A92-B 109; A92-B11O; A92-B111; A-92-B 112; A92-B 113; A92-B 114; A92-B 115; A92-B 116; A92-BI11 A92-B 118; A92-B119; A92-B t20; A92-B 12 1; A92-Bt22 A92-BI23; A92-B 124; A92-B125; A92-B126; A92-B1?7; A92-B3 128; A92-BI29; A92-B130; A92-B 131; A92-B 132; A92-B 13 3; A92-B 134; A92-B135; A92-B 136; A2 -B 137; A92-B 13 S; A92-B139; A92-B 140; A92-B 141; A92-B 142; A92-B 143; A92-B 144; A92-B 145; A92-B 146; A92-B 147; A92-B 148; A92-B 149; A92-B150; A92-B 15 1; A92-B152; A92-B153; A92-B154; A92-B155; A92-B156; A92-B 157; A92-3158; A92-B159; A92-B160; A92-B 161; A92-B 1 62 A92-B 163; A92-B 164; A92-B 165; A92-B 166; A92-B 167; A92-B168; A92-B 169; A93-B31; A93-B2; A93-B3; A93-B4; A93-B5; A93-B6; A93-B7; A93-B8; A93-B9; A93-B1O; A93-B1 1; A93-B12; A93-B13; A93-B14; A93-B15; A93-B16; A93-B17; A93-B18; A93 -B 19; A93-B20; A93-B21; A93-B22; A93-B23; A93-B24; A93-B25; A93-B26; A93-B27; A93-B28); A93--B29; A93-B30; A93-B31; A93-B32; A93-B33; A93-B34; A93-B35; A93-B36; A93-B37; A93-B38; A93-B39; A93-B40; A93-B41; A93-B42; A93-B43; A93-B44; A93-B45; A93-B46; A93-B47; A93-B48; A93-B49; A93-B50; A93-B51; A93-B52; A93-B53; A93-B54; A93-B55; A93-B56; A93-B57; A93-B58; A93-B59; A93-B60; A93-B61; A93-B62; A93-B63; A93-B64; A93-B65; A93-B66; A93-B67; A93-B68; A93-B69; A93-B70; A93-B71; A93-B72; A93-B73; A93-B74; A93-B75; A93-B76; A93-B77; I A93-B78 A93-B79; A93-BSO; A93-B81; A93-B82; WO 031035065 WO 03/35065PCT/GB02/04763 -185- A93-B83; A93-B84; A93-BS57 A93-B86; A93-B87; A93-B88; A93-B89; A93-B90; A93-B91; A93-B92; A93-B93; A93-B94; A93-B95; A93-B96; A93-B97; A93-B98; A93-B99; A93-BI00; A93-BIOI; A93-B102; A93-B103; A93 -B 104; A93-B105; A93-B106; A93-B 107; A93-B108; A93-BI09; A93-BI1O; A93-B 111; A93-B112; A93-B113; A93-B114; A93-Bl115; A93-B116; A93-Bl117; A93-B 118; A93-B1 19; A93-B120; A93-B121; A93-B122 A93-B123; A93-B124; A93-B125; A93-B126; A93-B127; A93-B 128; A93-BI29; A93-B130; A93-B131; A93-B132; A93-B133; A93-B134; A93-B135; A93-B 136; A93-B137; A93-B138; A93-B139; A93-BI40; A93-B141; A93-B142; A93-B143; A93-B144; A93-B145; A93-B 146; A93 -B 147; A93-BI48; A93-B149; A93-BI50; A93-B151; A93-B 152; A93-B 153; A93-B154; A93-B155; A93-B3156; A93-B157; A93-B158; A93-B 159; A93-B160; A93-B161; A93-B162; A93-B163; A93-B 164; A93-B 165; A93-B 166; A93-B167; A93-B168; A93-B169; A94-B1; A94-B2; A94-B3; A94-B4; A94-B5; A94-B6; A94-B7; A94-B8; A94-B9; A94-BlO-; A94-B 11; A94-B 12; A94-B 13; A94-B 14; A94-B A94-B 16; A94-B17; A94-B 18; A94-B 19; A94-B20; A94-B2 1; A94-B22; A94-B23; A94-B24; A94-B25; A94-B26; A94-B27;- A94-B28; A94-B29; A94-B30; A94-B3 1; A94-B32; A94-B33; A94-B34; A94-B35; A94-B36; A94-B37; A94-B38; A94-B39; A94-B40; A94-B4 1; A94-B42; A94-B43; A94-B44; A94-B45; A94-B46; A94-B47; A94-B48; A94-B49; A94-B50; A94-B5 1; A94-B52; A94-B53; A94-B54; A94-B55;) A94-B56; A94-B57; A94-B58; A94-B59; A94-B60; A94-B6 1; A94-B62; A94-B63; A94-B64; A94-B65; A94-B66; A94-B67; A94-B68; A94-B69; A94-B70; A94-B7 1; A94-B72; A94-B73; A94-B74; A94-B75, A94-B76; A94-B77; A94-B78; A94-B79; A94-B80; A94-B8 1; A94-B82; A94-BS3; A94-B84; A94-B85; A94-B86; A94-B87; A94-B88; A94-B89; A94-B90; A94-B91; A94-B92; A94-B93; A94-B94; A94-B95; A94-B96; A94-B97; A94-B98; A94-B99; A94-B100; A94-B1O1; A94-B102; A94-B103; A94-B 104; A94-B 105; A94-B 106; A94-B 107; A94-B 108; A94-B 109; A94-B 1 10; A94-B 111; A94-B 112; A94-B 113; A94-B 14; A94-B 115; A94-B 116; A94-B 117; A94-B 118; A94-B 119; A94-B 120; A94-B 12 1; A94-B 122; A94-B 123; WO 031035065 WO 03/35065PCT/GB02/04763 -186r 1 r A94-B 124; A94-B 125; A94-B126;- A94-B 127; A94-B 128; A94-BEl 129 A94-B130; A94-B131; A94-B132; A94-B 13 3; A94-B134; -A94-B135; A94-BI36; A94-B 137; A94-B138; A94-B139; A94-B 140; A94-B 14 1; A94-B 142; A94-B 143; A94-B144; A94-B 145; A94-B 146; A94-B 147; A94-Bf4-8; A94-B 149; A94-B150; A94-B 15 1; A94-B 152; A94-B153; A94-B 154; A94-B 155; A94-B156; A94-B157; A94-BI58; A94-B 159; A94-B 160; A94-B 16 1; A94-B162; A94-B 163; A94-B 164; A94-B 165; A94-B166; A94-B167; A94-B168; A94-B169; A95-B 1; A95-B2; A95-B3; A95-B4; A95-B5; A95-B6; A95-B7; A95-B8; A95-B9; A95-B1O; A95-B 11; A95-B 12; A95-B 13; A95-B14; A95-B15; A9 5-B 16; A9 5-B 17; A95-B18; A95-B 19; A95-B20; A95-B2 1; A95-B22; A95-B23; A95-B24; A95-B25; A95-B26; A95-B27; A95-B28; A95-B29; A95-B30; A95-B31; A95-B32; A95-B33; A95-B34; A95-B35; A95-B36; A95-B37; A95-B38; A95-B39; A95-B40; A95-R4P; A95-B42; A95-B43; A95-B44; A95-B45; A95-B46; A95-B47; A95-B48; A95-B49; A95-B50; A95-B51; A95-B52; A95-B53; A95-B54; A95-B55; A95-B56; A95-B57; A95-B58; A95-B59; A95-B60; A95-B61; A95-B62; A95-B63; A95-B64; A95-B65; A95-B66; A95-B67; A95-B68; A95-B69; A95-B70; A95-B71; A95-B72; A95-B73; A95-B74; A95-B75; A95-B76; A95-1377; A95-B78; A95-B79; A95-B8O; A95-B81; A95-B82; A95-B83; A95-B84; A95-BS5; A95-B86; A95-B87; A95-B88; A95-B89; A95-B90; A95-B91; A95-B92; A95-B93; A95-B94; A95-B95; A95-B96; A95-B97; A95-B98; A95-B99; A95-B100; A95-B1OI; A9 5-B 102; A95-B103; A95-B104; A95-B105; A95-B106; A95-B107; A95-BI08; A95-B109; A95-B11O; A95-B1 11; A95-B 112; A95-B1 13; A95-B1 14; A95-B1 15; A95-B1 16; 117; A95-B118; A95-B119; A95-B120; A95-B121; A95-B122, A95-B123-; A95 -B 124; A95-BI25; A95-B126; A95-B127; A95-B128; A95-B129; A95-B130; A95-B 13 1; A95-B132; A95-B133;- A95-B134; A95-B135; A95-B136; A95-B137; A95-B138; A95-BI39; A95-B140; A95-B141; A95-B142; A95-B143; A95-B144; A95-B145; A95-B146; A95-B147; A95-B148; A95-B149; A95-B150; A95-B151; A95-B 152; A95-B153; A95-B154; A95-B155; A95-B156; A95-BI57; A95-B158; A95-B159; A95-B160; A95-B161; X9-5-B162; A95-13163; A95-B164; WO 031035065 WO 03/35065PCT/GB02/04763 -187- A95-B165; A95-B16 A95-B 167;- A95-B 168; A95-B 169; A96-Bl; A96-B2; A96-B3; A96-B4; A96-B5; A96-B6; A96-B7;5 A96-138; A96-B9; A96-B1O; A96-B11; A96-B 12; A96-B 13; A96-B14; A96-B 15; A96-B 16; A96-B17; A96-B1IS; A96-B 19; A96-B20; A96-B21; A96-B22; A96-B23; A96-B24; A96-B25; A96-B26; A96-B27; A96-B28; A96-B29; A96-B30; A96-B3 1; A96-B32; A96-B33; A96-B34; A96-B35; A96-B36;- A96-B37; A96-B38; A96-B39; A96-B40; A96-B41; A96-B42; A96-B43; A96-B44; A96-B45; A964346; A96-B47; A96-B48; A96-B49; A96-B50; A96-B5 1; A96-B52; A96-B53; A96-B54; A96-B55; A96-B56; A96-B57; A96-B58; A96-B59; A96-B60; A96-B6 1; A96-B62; A96-B63; A96-B64; A96-B65;- A96-B66; A96-B67; A96-B68; A96-B69; A96-B70; A96-B71; A96-B72; A96-B73; A96-B74; A96-B75; A96-B76; A96-B77; A96-B78; A96-B79; A96-BSO; A96-B81; A96-B2; A96-B83; A96-B84; A96-B85; A96-B86; A96-B87; A96-BSS; A96-B89; A96-B90; A96-B91; A96-B92; A96-B93; A96-B94; A96-B95; A96-B96; A96-B97; A96-B98; A96-B99; A96-B 100; A96-B 101; A96-B 102; A96-B 103; A96-B 104; A96-B 105; A96-B 106; A96-B 107; A96-B1OS; A96-BI109;1 A96-B11O; A96-B111; A96-B112; A96-B113; A96-B114; A96-B 115; A96-B 116; A96-B 117; A96-B118; A96-B 119; A96-B120; A96-B121; A96-BI22; A96-B 123; A96-B124; A96-B125; A96-B126; A96-B127; A96-B128; A96-B 129; A96-B130; A96-B131; A96-B132; A96-B133; A96-B 134; A96-B135; A96-B136; A96-B137; A96-B138; A96-B139; A96-B 140; A96-B 14 1; A96-B 142; A96-B143; A96-B 144; A96-B 145; A96-B146; A96-B147; A96-B148; A96-B149; A96-B150; A96-B151; A96-B 152; A96-BI53; A96-B154; A96-B155; A96-B156; A96-B157; A96-B158; A96-B159; A96-B160; A96-B161; A96-B162; A96-B163; A96-B1 64; A96-B 165; A96-B 166; A96-B 167; A96-B 168; A96-B 169; A97-B 1; A97-B2; A97-B3; A97-B4; A97-B5; A97-B6; A97-B7; A97-BS; A97-B9; A97-B1O; A97-B 11; A97-B 12; A9'7-B 13; A97-B14; A97-B15; A97-B 16; A97-B17; A97-B 18; A97-B 19; A97-B20; A97-B21; A97-B22; A97-B23; A97-B24; A97 -B325; A97-B26; A97-B27; A97-B28; A97-B29; A97-B30; A97-B31; A97-B32; A97-B33; A97-B34; A97-B35; A97-B36; WO 031035065 WO 03/35065PCT/GB02/04763 -188- A97-B37;- A97-B38; A97-B39; A97-B40; A97-B41; A97-B42; A97-B43; A97-B44; A97-B45; A97-B46; A97-B47; A97-B48; A97-B49; A97-B50; A97-B5 1; A97-B52; A97-B53; A97-B54; A97-B55; A97-B56; A97-B57; A97-B58; A97-B59; A97-B60; A97-B6 1; A97-B62; A97-B63; A97-B64; A97-B65; A97-B66; A97-B67; A97-B68; A97-B69; A9'7-B70; A97-B7 1; A97-B72; A97-B73; A97-B74; A97-B75; A97-B76;P A97-B77; A97-B78; A97-B79; A97-B8O; A97-B8 1; A97-B82; A97-B83; A97-B84; A97-B85; A97-B96; A97-BS7; A97-B88; A97-B89; A97-B90; A97-B9 1; A97-B92; A97-B93; A97-B94; A97-B95; A97-B96; A97-B97; A97-B98; A97-B99; A97-BLOO; A97-B1O1; A97-B 102; A97-B103; A97-B 104; A97-B105; A97-B 106; A97-BI07; A97-B108; A97-B109; A97-B11O; A97-Bl111; A97-B 112; A97-B 113; A97-B 114; A97-B 115; A97-B 116, A97-B 117; A97-B1I 18; A97-B3 119; A97-B 120; A97-B121; A97-B 122, A97-B 123; A97-B 124; A97-B 125, A97-B 126; A9'7-B 127; A97-B128; A97-B129; A97-BI30; A97-B 13 1; A97-B132; A97-B133; A97-B134; A97-B135; A97-B136; A97-B 137; A97-B 138; A97-B 139; A97-B 140; A97-B 141; A97-B 142; A97-B 143; A97-B 144; A97-B 145; A97-B 146; A97-B 147; A97-B 148; A97-B 149; A97-B 150; A97-B 15 1; A97-B152; A97-B 153; A97-B 154; A97-B155; A97-B156; A97-B 157; A97-BI59; A97-B159; A97-B160; A97-B 16 1; A97-B 162; A97-B 163; A9'7-B 164; A97-B 165; A97-B 166; A97-B 167; A97-B 168; A97-B169; A98-B1; A98-B2; A98-B3; A98-B4; A98-B5; A98-B6; A98-B7; A98-B8; A98-B9; A98-B1O; A98-B 11; A98-B12; A98-B13; A98-B 14; A98-B 15; A98-B 16; A98-B17; A98-B18; A98-B19; A98-B20; A98-B2 1; A98-B22; A98-B23; A98-B24; A98-B25; A98-B26; A98-B27; A98-B28; A98-B29; A98-B30; A98-B3 1; A98-B32; A98-B33; A98-B34; A98-B35; A98-B36; A98-B37; A98-B38; A98-B39; A98-B40; A98-B41; A98-B42; A98-B43; A98-B44; A98-B45; A98-B46; A98-B47; A98-B48; A98-B49; A98-B50; A98-B5 1; A98-B52; A98-B53; A98-B54; A98-B55; A98-B56; A98-B57; A98-B58; A98-B59; A98-B60; A98-B61; A98-B62; A-X98-63; A98-B64; A98-B65; A98-B66; A98-B67; A98-B68; A98-B69; A98-B70; A98-B71; A98-B72; A98-B373; A98-B74; A98-B75; A98-376; A98-B77; WO 031035065 WO 03/35065PCT/GB02/04763 -189- A98-B78; A98-B79; A98-B80;l A98-B81; A98-B82; A98-B83; A98384; A98-B85; A98-B86; A98-B87; A98-B88; A98-B89; A99-B90; A98-B91; A98-B92; A98-B93; A98-B94; A98-B95; A98-B96; A98-B97; A98-B98; A98-B99; A98-B100; A98-B101;, A98-B102; A98-B103; A98-B104; A98-B 105; A98-B106; A98-B107; A98-B1OS; A98-B109;) A98-B110; A98-BI11; A98-B112; A98-B113; A98-B 114; A98-B 115; A98-B 116; A98-B117; A98-BI IS; A98-B119; A98-B120; A98-B121; A98-B122; A99-B123; A98-B124; A98-B125; A98-B 126; A98-B127; A99-B]29; A98-B 129; A98-B130; A98-B13 1; A98-B132; A98-B133; A98-B134; A98-B 135; A98-B13)6; A98-B 137; A98-B138; A98-B139; A98-B140; A98-B141; A98-B142; A98-B143; A98-B144; A98-BI45; A98-B146; A98-B147; A98-B148; A98-B149; A98-B150; A98-B151; A98-B152; A98-B153; A98-B154; A98-B155; A98-BI56; A98-B157; A98-B158; A98-B 159; A98-B160; A98-B161; A98-B162; A98-B 163; A98-B1 64; A98-B165; A98-BI66; A98-B 167; A98-B 168; A98-B169; A99-B1; A99-B2; A99-B3; A99-B4; A99-B5; A99-B6; A99-B7; A99-B8; A99-B9; A99-B A99-B 11; A99-B 12; A99-B13; A99-B14;- A99-B 15; A99-B 16; A99-B17; A99-B 18; A99-B19; A99-B20; A99-1321; A99-B22; A99-B23; A99-B24; A99-B25; A99-B26; A99-B27; A99-B28; A99-B9 A99-B30; A99-B3 1; A99-B32; A99-B33; A99-B34; A99-B35; A99-B36; A99-B37; A99-B38; A99-B39; A99-B40; A99-B41; A99-B42; A99-B43; A99-B44; A99-B45; A99-B46; A99-B47; A99-B48; A99-B49; A99-B50; A99-B5 1; A99-B52; A99-B53; A99-B54; A99-B55; A99-B56; A99-B57; A99-B58; A99-B59; A99-B60; A99-B6 1; A99-B62; A99-B63; A99-B64; A99-B65; A99-B66; A99-B67; A99-B68; A99-B69; A99-B70; A99-B71; A99-1372; A99-B73; A99-B74; A99-B75; A99-B76; A99-B77; A99-B78; A99-B79; A99-B80; A99-B81; A99-B82; A99-B83; A99-B84; A99-B85; A99-B86; A99-B87; A99-B88; A99-B89; A99-B90; A99-B91; A99-B92; A99-B93; A99-B94; A99-B95; A99-B96; A99-B97; A99-B98; A99-B99; A99-B 100; A99-B 101; A99-B 102; A99-13103; A99-B 104; A99-B 105; A99-B 106; A99-B 107; A99-B 108; A99-B 109; A99-B 110; A99-B 1 11; A99-B 112; A99-B113; A99-B 114; A99-B 115; A99-B116; A99-B 117; A99-B 118; WO 031035065 WO 03/35065PCT/GB02/04763 -190- A99-B 119; A99-B 120; A99-B 121; A99-B 122; A99-B123; A99-B 124; A99-B 125; A99-B126; A99-B 127; A99-B 128; A99-B129; A99-B130; A99-B 13 1 A99-B 1 32; A99-BI133; A99-B 134; A99-B135; A99-B 136; A99-B137; A99-B138; A99-B19; A99-B 140; A99-B141; A9-12 A99-B 143; A99-B 144; A99-B145; A99-B 146; A99-B147; A99-B 148; A99-B149; A99-B 150; A99-B15 1; A99-B 152; A99-B153; A99-B154; A99-B155; A99-BI56; A99-B157; A99-B158; A99-B159; A99-B 160; A99-B 16 1 A99-B 162; A99-BI63; A99-B 164; A99-B165; A99-B166; A99-B167; A99-B 168; A99-B169; A100-B1; AIOO-B2; AI00-B3; A100-B4; A100-B5; A100-B6; AlOO-B7, AIOO-B8; AlOO-B9; A100-B1O; AlOO-B1 1; AlOO-B12; A100-B13; A100-B14; AlOC-BiS; AIOO-B16; AlOO-B17; AlOO-BI8; AI00-B19; A100-B20; AlOO-B21; AIOO-B22; AIOO-B23; AlOO-B24; A100-B25; AlOO-B26; AlOG-B27; A100-B28; A100-B29; A100-B30; A100-B31; A100-B32; A100-B33; A100-B34; AlOO-B35; A100-B36; AlI 00-B37; A100-B38; A100-B39; A100-B40; Al 00-B4 I; AlOO-B42; A100-B43; AIOO-B44; AlI 00-B45; A100-B46;- Al 00-B47; A100-B48; Al 00-B49; AIOO-B50; AlDO0-B5 1; AlOO-B52; AlOO-B53; AlOO-B54; A100-B55; AlOO-B56; AlOO-B57; AlOO-B58; A100-B59; AlOO-B60; A100-B61; A100-B62; AlOO-B63;- AlOO-B64; Al 0O-B65; AlOO-B66; Al OO-B67; Al 00-B68; Al 00-B69; AlOO-B71; AlOO-B72; A100-B73; AlOO-B74; AlOO-B76; AlOO-B77; A100-B78; Al O0-B79; Al 00-B80; A100-B8 1; AIOO-B82; A100-B83; AlOO-B84; AIOO-B85; A100-B86; A100-B87; A100-B88; A100-B89; AlOO-B90; A100-B91; AlOO-B92; A100-B93; AIOO-B94; Al 00-B95; Al O0-B96; AIO0-B97; Al 00-B98; A100-B99; AlOO-BlOO; A100-B1Ql; A100-B102; A100-B103; AlOO-BlO4; A100-B 105; A100-B106; A100-B107; AlOO-B1OS; AlOO-B109; AlOG-BlI 1; AlOO-B Ill1; AlOO-B112; A1OO-B113; A100-B114; AlOO-BI15; AlO00-B 116; AlOO-B117; AlOO-Bllg; A100-B119; A100-B120; AIOO-B121; AlOO-B122; A100-B123; AlOO-B124; A100-B125; AlOO-B126; AlOO-B127; AlOO-B128; A100-B 129; A100-B131; AlOO-BI32; A100-B133; AlOO-B134; AlOO-B135; AIOO-B136; A1OO-B137; A100-Bl38; A100-B139; A100-B140; AI00-BI41; A100-B142; AlOO-B143; AlOO-B144; A100-B145; AtOO-B146; A100-B147; A100-B148; AlOO-B149; A100-B150; AlOO-Bl5l; A100-B152; AIOO-B153; A100-B154; A1OO-B155; A100-B156; A100-B157; 1A100-B158; A100-Bl59; WO 031035065 WO 03/35065PCT/GB02/04763 -191- A100-B160; A100-B161; A100-B162; A100-B163; A100-B164; A100-B165; AlOO-B166; A100-B167; AIOO-B168; A100-B169; Al0l-Bi; A1O1-B21 A1O1-B3; A1O1-B4; AIO1-B5; A1O1-B6; A1O1-B7; A1OI-B8; A1OI-B9; AlOl-BlO; AlOI-Bli; AlO1-B12; A101-B13; A1O1-B14; A1OI-B15; A1OI-B16; A1O1-B17; A1O1-B18; AIO1-B19; A1O1-B20; A1O1-B21; A1O1-B22; ALOI-B23; A1O1-B24; A1O1-B25; AlO1-B26; A1O1-B27; A1O1-B28; A1OI-B29; AlO1-B30; A1OT-B31;1 AIO1-B32; A1O1-B33; A1O1-B34; A1O1-B35; A1O1-B36; A1O1-B37; A1O1-B38; A1OI-B39; A1O1-B40; A1O1-9141; A1O1-B42; A1O1-B43; A1OI-B44; A1O1-B45; AIO1-B46; A1O1-B47; A1OI-B48; A1OI-B49; A101-B50; A1O1-B51; A1O1-B52; A1O1-B53; AIO1-B54; AIOI-B55; A1O1-B56; A1O1-B57; AT0l-B58; AlOI-B59; A1Ol-B60; A1O1-B61; A1O1-B62; AIOI-B63; A1OI-B64; AlOI-B65; AlO1-B66; A1O1-B67; A1O1-B68;- AlOI-B69; A1O1-B70; A1O1-B71; A1O1-B72; AIO1-B73; A1OI-B74; A1Ot-B75; A1Ol-B76; A101-877; AIOI-B78; A1O1-B79; A1OI-B80; A1OI-B81; A101-B1392 A1O1-B83; A1O1.-B84; A1OI-BS5; A1OI-B86; A1OI-BS'7; A1OI-B88; A1O1-B89; AtI-B90; AlO1-B91; AIOl-B92; A1O1-B93; AIO1-B94; A1O1-B95; A1O1-B96; A1O1-B97; A1OI-B98; A1O1-B105; A1O1-B106; AtO1-B107; A1OI-B108; A1OI-B109; AlOl-BI Al0l-Bill; A1O1-BI19 A1O1-BIl3; A1O1-B114; A1O1-B115; AIO1-B116; AlO1-B117; AI0l-BIiS; A1O1-B119; A1O1-B120; AlOl-B121; A101-B122; A101-B123; A1O1-B124; A1O1-B125; A101-B126; A1Ol-B127; A1O1-B128; AIOl-B135; A101-B136; A1O1-B137; A1O1-B138; A1Ol-B139; A1OI-B140; A101-B141; A101-B142; A1O1-B143; A1O1-BI44; A1O1-B145; A101-B146; A1O1-B147; A101-B148; A101-B149; A101-B150; A1O1-B151; A1OI-B152; A1O1-B153; AlO1-B154; A1O1-B155; A101-B156; A101-B157; A1O1-B158; A101-B159; Al0l-B160; A1O1-B161; AlO1-B162; A1O1-B163; A101-B164; AtOl-B165; AlOl-B166; A1Ol-B167; AIO1-B168; A1O1-BI69; A102-B1; A102-B2; A102-B3; A102-B4; A102-B5; A102-B6; A102-B7; A102-Bg; A102-B9; A102-B1O; A102-Bl1; A102-B12; A102-B13; A102-B14; A102-B15; A102-B16; A1 02)B 17; A102-B18; A102-B19; A102-B20; A102-B2 1; A102-B22; Al 02-B23; A102-B24; A102-B25; A102-B26; A102-B27; A102-B28; Al 102-B29; A102-B30; A102-B3 1; WO 031035065 WO 03/35065PCT/GB02/04763 -192- A102-B32; A102-B33; A102-B34;- Al 02-B35; Al 02-B36; A102-B37; A102-B38; A102-B39; A102-B40; A102-B41; A102-B42; A102-B43; AlO'2-B44; A I02-B45; A102-B46; A102-B47; A102-B48; A102-B49; A102-B50;, A102-B51; A102-B52; A102-B53 A102-B54; A102-B55; A102-B56; A102-B57; A102-B58; A102-B59; A102-B60; A102-B61; A102-B62; A102-B63; A102-B64; A102-B65; A102-B66; A102-B67; A102-B68; A102-B69; A102-B70; A102-B7 1; A102-B72-; A102-B73; At102-B74; A102-B75; A102-B76; Al 02-B77; Al 02-B78; A102-B79; A102-BSO; A102-B81; A102-B82; Al1 02-BS3; A102-B84; A102-B85; A102-B86; A102-B87; A102-B88; A102-B89; A102-B90; A102-B91; A102-B92; A102-B93; A102-B94; A102-B95; A102-B96; A102-B97; A102-B98; A102-B99; A102-BlOO; A102-BlO1; A102-B102; A102-B103; A102-B104, A102-B105; A102-B106; A102-B107; A102-B1OS; A102-B109; A102-BllO; A102-Bl 11; A102-B 112; A 102-B 113; Al102-B 114; A102-B115; A102-B116; A 102-Bl117; A102-Bll8; A1I02-B 119; A102-B120; A102-B121; A102-B122; A102-B123; A102-B 124; A102-B125; A102-B t26; A102-B127; A102-B128-; A102-B129; A102-B130; A102-B131; A102-B132; A102-B133; A102-B134; A102-B135; A102-B136; A102-B137;- A102-B138; A102-B139; A102-B140; A102-B141; A102-B142; A102-B143; A102-B144; A102-B145;- A102-B146; A102-B147; A102-B148; A102-B149; A102-B150; A102-B151; A102-B152; A102-B153; A102XR154; A102-B155; A102-B156; A102-B157; A102-B158; A102-,B159; A102-B160; A102-B161; A102-B162; A102-B163; A102-B164; A1I02-B 165; A102-B166; A102-B167; A102-B168; A102-B169; A103-Bl; A103-B2; A103-B3; A103-B4; A103-B5; A103'-B6; A103-B7; A103-B8; A103-B9; A103-BlO; A103-BIl1; A 103-B 12; A103-B13; A103-B14; A103-B15; A103-B 16; A103-Bl7; A103-BlS; A103-B19; A103-B20; A103-B21; A103-B22; A103-B23; A103-B24; A103-B25; A103-B26; A103-B27; A103-B28; A103-B29; A103-B30; A103-B31; A103-B32; A103-B33; A103-B34; A103-B35; A103-B36; A103-B37; A103-B38; A103-B39; A103-B40; A103-B41; A103-B42; Al 03-B43; A103-B44; A103-B45; A103-B46; A103-B47; A103-B48; A103-B49; A103-B50; A103-B51; A103-B52; A103-B53; A103-B54; A103-B55; A103-B56; A103-B57; A103-B58; A103-B59; A103-B60; A103-B61; A103-B62; A103-B63; 1-03-B64; A103-B65; A103-B66; A103-B67; A103-B68; A103-B69; A1-03-B70; A103-B71; A103-B72; WO 031035065 WO 03/35065PCT/GB02/04763 -193- A103-B73; A103-B74; A103-B75; A103-B76; A103-B77; A103-B78; A103-B79; A103-B80; A103-B81; A103-B82; A103-B83; A103-B84; A103-BS5; AtO3-B86; A103-B87; A103-B88; A103-B89; A103-B90; A103-B91; At03-B92; A103-B93; A103-B94; A103-B95; A103-B96; A103-B97; A103-B98; A103-B99; A103-BIOO; A103-BIO1; A103-.B102; A103-B103; At03-Bl04; A103-BI05-; A103-B106; A103-B107; A103-B108; A103-B109; A103-B1 10; A103-Bl1 1; A103-B112; A103.-B1 13; A103-B114; A103-B115; A103-B1 16; A103-Bl 17; A103-B1 18; A103-B 119; A103-B120; A103-B121; A103-B1Th; A 10343123; A103-B124; A103-B125; A103-B126; A103-B127; A103-B128; A103-B129; A103-B130; A103-B131; A103-B132; A103-B133; A103-B134; A103-B135; A103-B136; A103-B 137; A103-B138; A103-B 139; A103-B140; A103-B141; A103-B142; A103-B 143; A103-B144; A103-B145; A103-B146; A103-B 147; A103-B148; A103-B149; A103-B150; A103-Bl5l; A103-B152; A103-B153; A103-B154; A103-B155; A103-BI56; A103-B157; A103-B1SS; A103-B1 59; A103-B160; At03-Bt6l; A103-B162; A103-B163; A103-B164; A103-B165; A103-B166; A103-B167; A103-B16S; A103-B 169; A104-B1; A104-B2; A104-B3; A104-B4; A104-B5; A104-B6; A104-B7; A104-BS; A104-B9; A104-B1O; A104-B1I; A 104-B 12; A104-B13; A1I04-B 14; A104-B15; A104-B16;- A104-B17; A104-B18; A104-B19; A104-B20; A104-B21; A104-B22; A104-B23; A104-B24; Al 04-B25; A104-B26; A104-B27; A104-B28; A104-B29; A104-B30; A104-B31; A104-B32; A104-B33; A104-B34; A104-B35; A104-B36; A104-B37; A104-B38; A104-B39; A104-B40; A104-B41; A104-B42; A104-B43; A104-B44; A104-B45; A104-B46; A104-B47; A104-B48; A104-B49; A104-B50; A104-B51; A104-B52; A104-B53; Al 04-B54; Al 04-B55; Al 04-B56; A104-B57; Al 04-B58; A104-B59; Al 04-B60; A104-B61; Al 04-B62; A104-B63; Al 04-B64; A104-B65; A104-B66; A104-B67; A104-B68; A104-B69; A104-B70; A104-B71; A104-B72; A104-B73; A104-B74; A104-B75; A104-B76; A104-B77; Al 04-B78; A104-B79; Al 04-B80; A104-B81; Al 04-B82; A104-B83; Al 04-B84; A104-B85; Al 04-B86; A14B7 A148; Al0-39 A104-B90; A104-B91; A104-B92; A104-B93; A104-B94; A104-B95; A104-B96; A104-B97; A104-B98; A104-B99; A104-BlOO; A104-BlOt; A104-B102; A104-B103; A1 04-B 104; A104-B105; A104-B106; A104.-B107; Al104-B 108; A104-B109; A104-BllO; A104-Blll; A104-B112; A104-B113; WO 031035065 WO 03/35065PCT/GB02/04763 -194- A1I04-B 114; A104-B115; A104-B116; A104-B117; A104-B1S; A104-B119; A104-B120; A104-B121; A104-B122; A104-B123; A104-B124; A104-B125; A104-B126; A104-B127; A104-B128; A104-B129; A104-B130; A104-B131; A104-B132; A104-B133; A104-B134; A104-B135; A1I04-B 13 6; A104-B137; A104-B138; A104-B139; A104-B140; A104-B141; A104-B142; A104-B143; A104-B144; Al104-B 145; A104-B146; A104-B147; A1I04-B 14 8; A104-B149; A104-B150; A104-B15 1; A104-B152; A104-B153; A 104-B 154; A104-B1SS; A104-B156; A104-B157; A104-B158; A104-B159; A104-B160; A104-B161; A104-B162; A104-B163; A104-B164 A104-B165; A104-B166; A104-B167; A104-B168; A104-B169; A105-BI; A105-B2; A105-B3; A1OS-B4; A105-B5; A105-B6; A105-B7; A105-BS; A1OS-B9; A105-B1O; A105-B11; A105-B12; A105-B13; A105-B14; A105-B1S; A105-B16; A105-B1; A105-B1S; A105-B19; A105-B20;- A105-B21; A105-B22; A105-B23; A105-B24; A105-B25; A105-B26; A105-B27; A105-B28; A105-B29; A105-B30; A105-B31; A105-B32; A105-B33; A105-B34; A105-B35; A105-B36; A105-B37; A105-B38; A105-B39; A105-B41; A105-B42; A105-B43; A105-B44; A105-B45; A105-B46; A105-B47; A1OS.-B48; A105-B49; A105-B50; A105-B51; A105-B52; A105-B53; A105-B54;- A105-B55;- A105-B56; A105-B57; A105-B58; A105-B59; A105-B60; A105-B61; A105-B62; A105-B63; A105-B64; A105-B65; A105-B66; A105-B67; A105-B68; A105-B69; A105-B70; A105-B71; A1OS-B72; A105-B73; A105-B74; A1.05-B75; AIOS-B76; A105-B77; A105-B78; A105-B79; A105-B8O; A105-B81; A105-B82; A105-B83; A105-B84; A105-B85; A105-BS6; A105-B87; A105-B88; A105-B89; A105-B90; A105-B91; A105-B92; A105-B93; A105-B94; A105-B95; A105-B96; A105-B97; A105-B98; A105-B99; A105-B100; A105-B1O1; A105-B102; A105-B103; A105-B104; A105-B105; A105-BI06; A105-B107; A105-B108; A105-B109; A105-B1 10; A105-B1 11; A105-B1 12; A105-Bl113; A105-B114; A1OS-B115; A105-B116; A105-B117; A1OS-B118; A105-B1 19; A105-B120; A105-B121; A105-B122; A105-B123; A105-B124; A105-B125; A105-B126; A105-B127; A105-B128; A105-B129; A105-B130; A105-BI31; A105-B132; A105-B133; A105-B134; A105-B135; A105-B136; A105-B137; A105-B138; A105-B139; A105-B140; A105-B141; A105-B142; A105-B143; A105-B144; A105-B145; A105-B146; A105-B147; A105-B148; A105-B149; A105-B150; A105-B151; A105-B152; A105-B1531; A105-B154; WO 031035065 WO 03/35065PCT/GB02/04763 -195- A105-B155; A105-B156; A105-B157; A105-D158; A1OS-B159; A105-B160; A105-B161; A105-B162; A105-B163; A105-B164; A105-B165; A105-B166; A105-B167; A105-B168; A105-B169; A106-Bl; A106-B2; A106-B3; A106-B4; A106-B5; A106-B6; A106-B7; A106-Bg; A106-B9; A106-BIO; Al106-Bl11; A106-B12; A106-B13; A106-B14; A106-B15; A106-B16; A106-B17; A106-B18;- A106-B19; A106-B20; A106-B21; A106-B22; Al 06-B23; A106-B24; Al 06-B25; A106-B26; Al 06-B27; A106-B28; A106-B29; A106-B30; AlO6-B3 1; A106-1332; A106-B33; A106-B34; A106-B35; A106-fl36; A106-B37; A106-B38; A106-B39; A106-B40; Al 06-B4 1; A106-B42; AlI 06-B43; A106-B44; Al 06-B45; A106-B46; Al 06-B47; AlO6-B48; A106-B49; A106-B50; Al 06-B5 1; A106-B52; A106-B53; A106-B54; AlO6-B55; A106-B56; A106-B57; A106-B58; A106-B59; A106-B60; A106-B61; A106-B62; AlO&-B63; A106-B64; Al 06-B65; A106-B66; Al 06-B67; Al 06-B68; Al 06-B69; A106-B70; Al 06-B7 1; AlI 06-B72; Al 06-B73; A106-B74; A106-B75; A106-B76; Al 06-B77; A106-B78; Al 06-B79; A1O6-B80; Al OC-B8 1; A1O6-B82; A106-B83; A1O6-B84; A106-B85; A106-B86; A106-B87; A106-B88; A106-B89; A106-B90; A106-B91;- A106-B92; A106-B93; A1O6-B94; Al 06-B95; AlOG-B96; Al 06-B97; A106-B98; A1O6-B99; AlO6-BlOO; A106-BlOl; AlO6-B102; A1O6-B103; A106-BI04; AlQ6-B105; A106-B 106; A106-BlO'7; AlO6-BIOS; AlO6-B109; A106-BllO; AlO6-Blll; AlO6-B112; A106-B113; AlO6-Bll4; AlO6-Bll5; AlO6-B116; A106-Bll7; AlO6-Bl 18; A106-Bl 19; A106-B120; A106-B121; AlO6-B122; AlO6-B123; A106-B124; AlO6-B125; AlO6Bl26;- A106-Bl27; A106-Bl28; A106-B129; AlO6-B130; A106-B131; A106-B132; A106-B133; AlO6-B134; A106-Bl35; A106-Bl36; A106-B 137; AlO6-Bl38; A106-B139; A106-B140; A106-B 141; A106-B142; A106-Bl43; A106-]B144; A106-Bl45; AlO6-B146; A106-B147; AlO6.-BI4S; A106-B149; A106-B150; A106-B151; A106-B152; AlO6-B153; A106-B154; A106-B155; AlO6-B156; AJA6-Bl57; A106-B158; A106-B 159; A106-B160; A106-BI61; A106-B162; A106-BI63;5 A106-B164; AlO6-B165; A106-B166; A106-B167; AlO6-Bl68; A106-B169; A107-Bl; A107-B2; A107-B3; A107-B4; AlO7-B5; A107-B6; A107-B7; A107-B8; A107-B9; A107-B1O; A107-Bll; A107-B12; AlO'7-B13; A107-B 14; A107-B15; A107-B16; A107-Bl7; A1 l0 7-B 18; A107-B19; A107-B20; A1O7-B21; A107-B22; A107-B23; A107-B24; A107-B25; A107-B26; WO 031035065 WO 03/35065PCT/GB02/04763 -196- A107-B27; At07-B28; A107-B29; A107-B30; A107-B31; A107-B32; A107-B33; A107-B34; A107-B35; A107-B36; A107-B37; At07-B38; A1C7-B39; A107-B40; A107-B41; A1O7-B42; A107-B43; A107-B44; A107-B45; A107-B46; A107-B47; A107-B48; A107-B49; A107-B50; A107-B51; A107-B52; A107-B53; A107-B54; A107-B55; A107-B56; A107-B57; A107-B58; A107-B59; A107-B60; A107-B61; A107-B62; Al O'-B63; A107-B64; A107-B65; A107-B66; Al 07-B67; Al 07-B68; AlO7-B69; A107-B70; A107-B7 1; A107-B72; Al 07-B'73; A107-B74; A107-B75; Al 07-B76; A107-1877; A107-B78; Al 07-B79; A107-B80; A107-B8l; A107-B92; A107-B83; A107-B84; A107-B85; A107-B86, A107-B87; A107-B88; AlOV-B89; A107-B90; A107-B91; A107-B92; A107-B93; A107-B94; A 107-B95; A107-B96; A107-B97; A107-B98; A107-B99; A107-BlOO; A107-BIOI; A107-B102; A107-BI03; A107-B104; A107-B105; A107-B106; A107-B107; A107-B108; A107-B109; A107-BlO1; A107-Blll; A107-BI19 A107-B113; A1I07-B 114; A1I07-B 115; A107-B116; AIO'7-Bl 17; A107-Bl 18; A107-Bl 19; A107-B120; A107-B121; A107-B122; A107-B 123; A107-B124; A107-B125; A107-B126; A107-B127; A107-B128; A107-B129; A107-B130; A107-B131; A107-B132; A107-B133; A107-B134; A107-B135; A107-B136; AtO7-BI37; A107-B138; A107-B139; A107-B140; A107-B141; A107-B142; A107-B143; A107-B144; A107-B145; A107-B146; A107-B147; A107-B148; A107-B149; A107-B150; A107-Bt51; A107-B152; A107-B153; A107-B154; A107-B155; A107-B156; A107-B157; A107-B158; A107-B159; A107-B160; A107-B161; A 107-B 162; A107-B163; A107-B164; A107-B165; A107-B165; A107-B167; A107-B168; A107-B169; AlOS-Bi; AIOS-B2; A108-B3; A1OS-B4; A108-B5; A1OS-B6; AlOS-B7; AlOS-B8; A1OS-B9; AlOS-BlO; A108-B1 1; A108-B12; A108-B13; A1OS-B14; A1OS-B15; N1OS-B16; AiOS-B17; A108-B1S; A1OS-B19; A108-B21; A108-B22; A108-B23; AlOS-B24; A108-B25; Al 08-B26; Al 08-B27; A108-B28; AlOS-B29; A108-B30; A108-B3 1; A108-B32; A108-B33; AlOS-B34; AlOS-B35; A108-B36; A108-B37; A1OS-B38; AlOS-B39; AlOS-B40; AlOS-B41; A1OS-B42; AIOS-B43; Al O8-B44; AIOS-B45; Al 08-B46; A1OS-B47; A1OS-B48; A108-B49; A1OS-B50; A108-B51; A108-B52; A108-B53; A108-B54; AlOS-B56; AlOS-B57; A108-B58; A108-B59; Al 08-B60; A108-B61; AlOS-B62; A108-B63; A1OS-B64; A108-B65; A108-B66; A108-B67; WO 031035065 WO 03/35065PCT/GB02/04763 -197- A108-B68; A108-B69; AlO8-B70; A108-B71; A108-B72; A108-B73; A108-B74; AI08-B75; A108-B76; A108-B77; A108-B78; A108-B79; A108-BR0; A108-B8l; A108-B82; A108-B83; A108-B84; A108-B85; A108-B86; A1OS-B81; A108-B88; A108-B89; A108-B90; A108-B91; A108-B92; A108-B93; A108-B94; A108-B95; A108-B96; A1OS-B97; A1OS-B98; A108-B99; A108-B 100; A108-BlO1; A1OS-BI02; A108-B103; A108-B104; AlOS-BlOS; A108-B106; A108-B107; A108-BI08-; A108-B109; A108-BIlO; A108-B1 11; AlOS-BI 12; A108-Bl 13H; A108-BI 14; AlOS-Bi AlOS-BI 16; AlO8-Bi 17; Al109-B] 18; AJOS-BI 19; A108-B120; A108-B121; A108-B122; A108-B123; A108-B124; A1OS-B125; A108-B126; A108-B127; A108-B128; A108-B129; A108-B130; A108-B131; A1OS-B132; A108-B133; A108-B134; A108-B135; AlOS-B136; A108-B137; A108-B138; A108-B139; A108-B140; A108-B141; AIOS-B142; A108-B143; A1OS-B144; A10S-B 145; AIOS-B 146; A108-B 147; A108-B148; A108-B149; A108-B150; A108-B151; AlOS-B152; A1OS-B153; A1OS-R154; A108-B155; A108-B156; A108-B157; AIOS-BI58; A108-B159; A108-B160; A108-B161; A108-B162; A108-B163; A1OS-B164; A1OS-B165; A108-B166; A108-B167; A108-B168; A108-B169; A109-B1; A109-B2; A109-B3; A109-B4;- A109-B5; A109-B6; A109-B7; A109-B8; A109-B9; A109-B 10; A109-Bl 1; A109-B 12; A109-B13; A109-B14; A109-B15; A109-B16; A109-B17; A109-B1S; A109-B19; A109-B20; A109-B21; A109-B22; A109-B23; A109-B24; Al 09-B25; A109-B26; Al 09-B27; A109-B28; Al 09-B29; A109-B30; A109-B31; A109-B32; A109-B33; A109-B34; A109-B35; A109-B36; A109-B37; A109-B38; A109-B39; A109-B40; A109-B41; A109-B42; Al 09-B43; A109-B44; Al 09-B45; A109-B46; Al 09-B47; A109-B48; A109-B49; A109-B50; A109-B51; A109-B52; A109-B53; A109-B54; A109-B55; A109-B56; A109-1357; A109-B58; A109-B59; A109-B60; Al 09-B6 1; A109-B62; Al 09-B63; A109-B64; A109-B65; A109-B66, A109-B67; A109-B68; A109-B69; A109-B70; A109-B71; A109-B72; A109-B73; A109-B74; A109-B75; A109-B76; A109-B77; A109-B78; A109-B79; A109-B80; A109-BS 1; A109-BS2; A109-B83; Al 09-B84; A109-B85; A109-B86; A109-B87; 4A109-B88; A109-B89; A109-B90; A109-B91; A109-B92; A109-B93; 4A109-B94; A109-B95; A109-B96; A109-B97; A109-B98; Al 09-B99; Al I 09-B 100; A109-B 101; Al 09-B 102; Al109-B 103; A109-B104;- A109-B105; A109-B106; A109-B107; A109-B1OS; WO 031035065 WO 03/35065PCT/GB02/04763 -198- A109-BlO9; Al09-BIl10; A109-B111; A109-B112; A109-B113; A109-B114; Al09-B115; Al09-B 116; A109-B117; Al109-BI118; A1I09-B 119; A109-B120;) A109-11 A109-B122; A109-B 123; AlO9-B124; AlO9-B125; A109-B126; A109-B127; A109-B128; A109-B129; A109-Bl3O; A109-Bl31; A109-B132; A109-B133; A109-B134; A109-B 135; AlO9-B136; Al09-B137; A109-B138; A109-B139; A109-B140; A109-B141; A109-B142; A109-B143; A109-B144; A109-B145; A109-B146; A109-B147; A109-B148; A109-B49;- A109-B150; A109-B151; A109-B152; A109-B153; A109-B154; A109-B155; AlO9-B156; A109-B157; A109-B158; Al 09-Bi 59; A109-B160; A109-B161; A109-B162; A109-B163; A109-B164; A109-B165; A109-B166; A109-B167; A109-B168; A109-B169; AllO1-B I; AllO-B2; AIlO-B3; All10-B4; AllO-B6; All10-B7; AlO1-B8- A1lO-B9; AllO-BlO; All10-Bli1; Al 1O-B12; A IIO-B 13; A IIO-B 14; AllO-B15; Al lO-B16; AllO-B17;- Al IO-B18; All10-B19; A1lO-B20; AllO-B21; All10-B22; AIlO-B23; At10O-B24; AllO-B25; Al10-B26; A1IO-B27; All10-B28; Al1O-B29; A 11O-B30; All10-B31; AlI10-B32; AllO-B33; AlL10-B34; A1lO-B35; At10O-B36; AIlO-B37; Al 10-B38; AllO-B39; All10-B40; AIlO-B41; AllO-B42; AllO-B43; AllO-B44; AllIO-B45; All10-B46; AllO-B47; Al lO-B48; Al 1O-B49; Al 10-B50; Al lO-B51; Al lO-B52; Al lO-B53; Al Il1-B54; Al lO-B55; Al 10-B56; Al lO-B57; Al lO-B58; Al lO-B59; Al lO-B60; Al lO-B61; Al 10-B62; Al lO-B63; Al lO-B64; Al1O0-B65; At 10-B66; A1lO-B67; Al 10-B68; AI1O-B69; AI1O-B70; A1lO-B71; Al lO-B72; All -B73; Al 10-B74; All O-B75; Al lO-B76; All O-B77; Al1O0-B78; Al l0-B79; Al lO-BSO; Al lO-BSI; Al lO-B82; Al lO-B83; At 10-B84; AllO-B85; A11O-B86; AIlO-B87; AIlO-B88; AllO-B89; Al lO-B90; Al lO-B91; Al lO-B92; A IIO-B93; Al lO-1B94; Al l0-B95; Al 10-B96; Al lO-B97; Al lO-B98; Al 10-B99; A1lO-BlOO; Al lO-BiOl; AllO-B102; AllO-BlO3; AllO-B104; AllO-BIOS; AllO-B106; AllO-B107; 108; A1lO-B109; A1lO-BllO; AllO-Blll; AllO-B112; AllO-B113; AllO-BIl4; AllO-B115; AllO-B116; AllO-B117; AllO-B118; AllO-Bll9; Al110-B120; Al lO-Bl2l; AllO-B122; Al 10-B123; AllIO-B 124; Al110-B125; A110-B126; Al lO-B127; Al lO-B128; Al 1O-B129; Al l0-BI30; Al lO-B131; A110-B132; Al lO-B133; A1lO-B134; Al lO-B135; Al lO-B136; Al110-B137; AlIO-B138; AllO-B139; AllO-B140; A110-B141; AllIO-B 142; AllO-B143; Al lO-B144; Al lO-B145; Al lO-B146; Al lO-B147; AllO-B148; Al lO-B149; WO 031035065 WO 03/35065PCT/GB02104763 -199- A11O-B150; A11O-B151; A11O-B152; AllO-B153; Al1O-Bl154; A1TO-B155; A11O-B156; A11O-B157; A1IO-B158; Al 10-B159; AlI1O-B 160; AIIO-B161; A11IO-B 162; A11O-B3163; Al 1O-B164; Al11O-B3165-: AI1O-B166; A11IO-B 167; A11O-13168; AllO0-B169.

Thus, for example, in the above list the compound denoted as A9-B9 is the product of the combination of group A9 in Table I and B9 in Table 2, namely

H

3 C N SCH 3 1,NH H Example 230(a) hereinafter described.

Particular compounds of the invention of formula (Ix) for the inhibition of SYK are: 2-(1H-indazol-3-yl)- 1H-benzirnidazole-5-carboxylic acid benzylamide; 1H-indazol-3-yI)- I H-benzimidazole>,5-carboxylie acid N-methylnmide; 1H-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-ethylamide; IIH-indazol-3 -yl)-l H-benzimidazole-5-carboxylic acid N-isopropylamide; 1H-indazol-3-yl)- 1H-benzimidazole-5-carboxylie acid N-phenylnmide; 2-(l1 H-indazol-3 l H-benzimidazole-5-carboxylie acid N-phenethylamide; 5,6-dimethyl-2-(5 -methylsulfanyl-1IH-pyrazol-3 1 H-benzohnidazole; 6-chloro-5-m-ethyl-2-(5-methylsulfanyl-1H-pyrazol-3 lH-benzoimidazole; 6-ehloro-2-(5 -etbylsulfanyl-1IH-pyrazol-3 -yl)-5-methyl- IMH-beozoimidazole; -methylsulfanyl-1IH-pyrazol-3 -yl)-5-trifluoromethyl- 1 H-benzoimidazole; -cyclopropylniethylsul fniiyl- 1 HT-pyrazol-3 -yl)-5,6-dimethyl- 1H-benzoimidazole; 2-(5-ethylsulfanyl- W-pyrazol-3-yl)-5,6-dimethyl- IH-benzoimidazole; 5,6-dimethyl-2-f5 -(pyridin-3 -ylmethylsulfnnyl)- 1H-pyrazol-3 -yl] 1H-benzoimidazole; 5-fhxaoro-2-j5-methylsulfanyl)-1H-pyrazol-3-yl]- TH-benzoim-idazole; 5,6-dimethyl-2-(5 -phenethylsulfanyl-1 H-pyrazol-3-yl)-1H-benzoimidazole; 4-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)- 1H-benzoimidazole; 5,6-dimethyl-2-(5-benzylsulfanyl-H-pyrazol-3-y)-H-benZOllfidaZOle; 6-chloro-5-methyl-2-(5-morpholin-4-yl- 1H-pyrazol-3-yl)- 1H-benzoimidazole; 5,6-dimethyl-2-[5 -(thiophen-2-ylmethylsulfanyl)-H-pyrazol-3 -YI- 1 H-benzoimidazole; H-pyrazol-3-yl)-5-methoxy- 1H-benzoimidazole hydrochloride; 5-methyl-2-(5-methylsulfanyl-4-propyl-1 H-pyrazol-3-yl)-1H-benzoiinidazole; 2-(5-(4-mnethoxy-be-nzylsulfany1)-4-propy1-1H-pyrazol- 3 5-methyl-1JJ-benzoimidazole; WO 031035065 WO 03/35065PCT/GB02104763 -200- 2-(5-benzylsulfanyl-4-isopropyl- 11--pyrazol-3-yl)-5-methyl- lHu-benzoimidazole; 2-(5-methylsulfanyl-4-rnethyl- 2-(5-methylsulfanyl-4-metliyl- 1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazOle; 1H-benzoimidazol-2-yl)-1H-pyrazol- 4 -ylamirle; 3-(5 ,6-dichloro- IHJ-benzoimidazol-2-yl)- 1H-pyrazol-4-ylamine; 3-(5,6-diinethyl- 1H-benzoirnidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5-ethyl-6-methiyl-1H-benzoimidazol-2-yl)- 1H-pyrazol-4-ylamine; 3-(6-chloro-5-methoxy- 1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylafile; 1 H-benzoimidazol-2-yl)-1H-pyraZOl-4-ylamifle 3-(5-ethoxy-1H-benzoimidazol-2-yl)- 1 H-pyrazol-4-ylamine; 3-(5-fluoro-6-methyl-1 H-benzoirnidazol-2-yl)-1H-pyrazol-4-Ylamhfe; 1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-ylaniine; 3 -trifluoromethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4-ylamine; 24(4-amino-i1 H-pyrazol-3-yl)- 1 H-benzoimidazote-5-carboxylic acid methyl ester; 3-(1H-benzoimnidazol-2-yl)- I1H-indazole; 1H-benzoimidazol-2-yl)-1H-indazole; Il2-indazol-3-yl)-1H-benzoinidazOl-5-YLI -phenyl-methanone; 2-phenyl- 1 H-imidazol[4,5 -b]pyrazine; 3-(5 ,6-dimethyl-1 H-benzoimidazol-2-yl)- I H-indazole; 2-(1 H-indazol-3-yl)-3H--imidazo[4,5-cliiyridine; 2-(l1H-indazole-3-y1)-3H-imidazoFI4,5-b]pyridifle 2-(l1H-pyrazol-3y1)- 1H-benzoimidazole; 3-(5,6-dimiethiyl-1J-benzoimnidazo1-2-yl)-5-methoxy-H-ildazole; 3-(5 -ethyl-6-methyl- 1 H-benzoimidlazol-2-yl)-5 -methoxy- 1H-indazole; ,6-dimethyl- 1H-benzoimidazol-2-yl)-5-fluoro- 1H-indazole;, 3-(5.6-dimethy1-1H-benzoinidazo-2-y)-6-fLUOO-ifl-indazole; 3-(5,6-dimethyl-TH-tenzoimidazol-2-yl)-5-netiYl- 1H-indazole; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-6-methoxy- 1H-indazole; 5,6-dimethyl-2-(4-pheny1-1H-pyrazo-3-yl)-H-benOiTidazole; 3-(5-ethyl-1H-benzoimidazol-2-yl)-11-indazole; 3-(5-ethiyl-6-rnethyl-II-benzoimidazol-2-yl)- iR-indazole; -isopropyl-6-methyl-1H-benzoimidazo-2-yl)-H-ildazole; 3 -(5-bromo-6-methyl- 1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-bromo-lH-benzoimidazol-2-yl)-1H-indazole; 3-(5-(3-cyanlo)phenyl-11I-benzoimidazol-2-yl)- 1H-indazole; WO 031035065 PCT/GB02/04763 -201- 3-(5-(pyrid-3 -yl)-lH-benzoimidazol-2-yl)- I H-indazole; 3-(6-rnethyl-5-phenyl- 1 H-b enzoimidazot-2-yl)- lH-indazole; 3-(5-phenyl-l1H-benzoimidazol-2-yl)-1 H-indazole; 3 -(5-(2-fluoro)phenyl- 1 H-benzoimidazol-2-yl)- 1H-indazole; 3-(5-(5,6-methylenedioxy)phenyl- 1H-ben7Oimidazol-2-yl)- 11--indazole; 3-(5-(2-methoxy)phenyl- 1H-benzoimidazol-2-yl)- lH-indlazole; 3-(5-(4-chloro)phenyl- lH-benzoimidazol-2-yl)- 1H-indazole; 3-(5-(4-methyl)pheniyl- 1H-benzoirnidazol-2-yl)-lfl-indazole; 1H-beinzoimidazol-2-yl)- 1H-indazole; 3-(5,6-methylenedioxy- 1H-benzoimidazol-2-yl)- 1 H-indazole; ,6-dirnethoxy- IH-benzoirnidazol-2-yl)- 1 H-indazole; ,6-diethyl-1H-benzoimidazol-2-yl)- 1H-indazole; 3-(4,5-dimethy1- 1H-benzoil-nidazol-2-yl)-l1H-indazole; 2-(I-I-indazol-3D-yl)- 3-(5 -methoxycarbonyl- 1 H-benzoiinidazol-2-yl)- 1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-ethoxy- 1H-indazole; ,6-dimethyl- I benzoirnidazol-2-yl)-pyrazole-4-carboxylic acid ethyl ester; 2-(4-isopropylcarbamoyl- 1H-pyrazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid methyl ester;, ,6-dimethyl- 1H-benzoirnidazol-2-yl)-5-methyl-pyrazole-4-carboxylic acid ethyl ester; 1,5 ,6,7-tetrahydro-1 ,3-diaza-s-indacen-2-yl)- 1H-pyrazole-4-carboxylic acid cyclopropylamide; 3 -(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid isopropylamide; 3-45-(2-morpholin-4-yl-ethoxy)-1H-benzoimnidazol-2-yl]- lH-indazole; 3 .6-dimethyl- lH-benzoimidazol-2-yl)-IH-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide; 3-(5.6-dimethyl-1I--benzoimidazol-2-yl)-lH-pyrazole-4-carboxylic acid propylamide; 3-(5 ,6-dimethyl- 1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-y1)-amnide; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-l1H-inidazole-5-carboniitrile; 3 -(5-difluoromethoxy-1H-benzoimidazol-2-yl)-l1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5-difluoromethoxy-1 I-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid cyclopropylamide; 3-6ehl5mtoyI-eziiazl2y)l-yaoe4croyi acid isopropylamide; 3-(5 ,6-dimethyl- 1H-benzoimidazol1-2-yl)-1H-indazole-5-carbonitrile; 2-(5-methyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 2-(5-cthoxy-1H-pyrazol-3-y1)- 1H-benzoimidazole; 2-(5-methylsulfanyl-isoxazol-3-yl)- lI1-benzoimidazole; 5-chloro-2-(4-nitro- 1H-pyrazol-3-yl)-1H-benzoimidazole;, 5,6-dichloro-2-(4-nitro- 1H-pyrazol-3-yl)-1H-benzoimidazole; (benzoimidazol-2-yl)-5-methylthio-3-pyrazole; WO 031035065 PCT/GB02/04763 -202- 3-(5,6-dimethyl- IH-benzoimidazol-2-yl)-4,5,6,7-tetralhydro-1H-indazole; 2-(5-isopropy1-1 H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 1H-pyrazol-3-yl)-5,6-dimethyl- 1H-benzoimidazole; 5,6-dimethyl-2-( 1,4,5,6-tetrahydro-cyclopentapyrazol-3 1H-benzoimidazole; 3-(5,6-dimethyl- I1H-benzoimidazol-2-yl)-4-fluoro- 1 H-indazole; 4-chloro-3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-indazole; 3-(5,6-dimethiyl-IH-benzoimidazol-2-yl)-5-chloro-l1H-indazole; 3-(5,6-dimethyl-11i-benzoirnidazol-2-yl)- -n-propyl- I1H-benzoirnidazo 1-2-yl)-1IH-indazole; 1H-indazol-3 -yfl)-1H-benzoimidazole-5-sulfonic acid benzylamide; -methane sulfonyl- 1H-benzoimidazol-2-yl)-1H-indazole; [2-(indazol-3-yl)- [2-(indazol-3-yl)-l1H-benzoimidazol-5-yl]-carboxylic acid; [2-(indazol-3-yl)- 1H-benzoimiclazol-5-yll -carboxylic acid, methylamide; [2-(indazol-3-yl)- 1H-benzoimidazol-5-yl] -carboxylic acid, dimethylamide; [2-(inidazo]-3-yl)- 1H-benzoimida7ol-5-yl] -carboxylic acid, isopropylamide; acid, benzylamide; [2-(indazol-3-yl)-l1H-benzoimidazol-5-yl]-carboxylic acid, benzamide; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- IH-pyrazole-4-carboxylic acid isopropylamide; 3-(5 ,6-dimethyl- IH-benzoimidazol-2-y1)- IH-pyrazole-4-carboxylic acid (2-hydroxy- 1, -dimethylethyl)-amide; 2-(4-isopropylcarbamoyl- IH-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridiin-3-ylrnethyl)amide; ,6-dimethyl- 1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide; 2-(4-isopropylcarbamoyl- 1H-pyrazol-3-yl)-IH-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 2-(4-isopropylcarbamoyl-1 H-pyrazul-3-yl)-lIH-beiizoirnidazole-5-carboxylic acid (pyridin-2-ylmethyl)amide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methyl-benzylainide; 1H-indazol-3-yl)-1H-benz.oimidazole-5-carboxylic acid 4-methyl-benzylamide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 13-(2-oxo-pyrrolidin-1I-yl)-propyll-amide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 2-(1 H-indazol-3-yl)-1 H-benzoimnidazole-5-carboxylic acid (2-rnethoxy-ethyl)-amide; 1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl)-amide; 2-(1 H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (2-hydroxy-1 ,1-dimethyl-ethyl)-amide; 1H-Indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl)-amide; WO 031035065 PCT/GB02/04763 -203- 6-dime~thyl- 1H-benzoirnidazol-2-yl)- 1H-pyrazole-4-carboxylic acid isobutyl-amide; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid isopropylarnide; 3-(5,6-dimethyl- IH-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylmethyl-ainide; 3-(5,6-dimethyl- IH-benzoimidazol-2-yl)-5-methyl- 1H-pyrazole-4-carboxylic acid tert-butylamide; 3-(5,6-.dimethyl- 1H-benzoirnidazol-2-yl)- 1H-indazole-5-carboxylic acid dimethylamicle; 2-(4-isobutyrylamino- 1H-pyrazol-3-yl)- 1H-benzoimidazole-5.-carboxylic acid benzylamide; [2-(indazol-3-y1)-1H-benzoimidazol-5-yll-carboxylic acid; 3-(5,6-dimethyl- 1H-benzoimidazol-5-yl)-pyrazole-4-carboxylic acid; 2-(4-isopropylcarbamoyl-I H-pyrazol-3-yl)- 1H-benizoimidazole-5-carboxylic acid; 3-(5,6-dimethyl- IH-benzoimidazol-2-yl)-5-methyl-pyrazole-4-caboxylic acid; N-1j3-(5,6-dimethyl-l1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-isobutyramide; N-[3-(5,6-dimethyl- 1H-benzoimidlazol-2-yl)- 1H-pyrazol-4-yl]-3-rnethyl-butyramide; N-[3-(5,6-diirnethyl- IH-benzoirnidazol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide; cyclopropanearboxylic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; methoxyacetic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -amide; cyclopentanecarboxylic acid [3-(5,6-dirncthyl-1 H-benzoimidazol-2-yI)- 1H-pyrazol-4-yl] -amide; trirnethylacetic acid [3 -(5,6-dimethyl-1 H-benzoimidazol-2-y1)-1H-pyrazol-4-yl]-amide; tert-butylacetic acid [3-(5,6-dimethyl- 1H-benzoimnidazol-2-yl)- 1H-pyrazol-4-yl]-arnide;I butanoic acid ,6-dimethyl- IH-benzoirnidazol-2-yl)-1H-pyrazol-4-fl]-amide; isoxazole-5-carboxylic acid [3-(5.6-dimethyl-1h-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-amide; S(+)-2-methylbutanoic acid .6-dimethyl-1 H-benzoimidazol-2-yl)- H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -amide; piperidine-1 -carboxylic acid[3-(6-chloro-5-methoxy-l1H-benzoimidazol-2-y1)- 1H-pyrazol-4-yl]-amide; 3-[3-(6-chloro-5-methoxy- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]- 1,1-dimethylurea; cyclopropanecarboxylic acid [3-(5-methoxy- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide;, cyclopropanecarboxylic acid [3-(5-ethoxy- 1H-benizoirnidazol-2-yl)- 1fl-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-fluoro-6-methyl- 1H-benzoimidazol-2-y1)-1H-pyrazol-4-yll-arnide; cyclopropanecarboxylic acid [3-(5-trifluoromethoxy- IH-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-trifluoroinethyl- 1H-benzoimnidazol-2-yl)- 1H-pyrazol-4-yl]-amide; N-[3-(5-trifluLoromethyl- 1H-benzoimidazol-2-yI)- 1H-pyrazol-4-yl]-isobutyramide; cyclopropanecarboxylie acid [3-(5-chloro-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; 3,5-dimethyl-isoxazole-4-carboxylic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-1H-pyrazol-4-y1]amide; N-[3-(5,6-dimethyl-l1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-acetainide; furan-3-carboxylic acid [3-(5-chloro-6-metliyl-1H-benzoimidazol-2-yl)-l1H-pyrazo1-4-yl]-amidde; N-1i3-(5,6-dirnethyl- 1H-benzoim-idazol-2-yl)- 1H-pyrazol-4-y11-4-methyl-benzamide; WO 031035065 PCT/GB02/04763 -204- 5,6-dimethyl-2-(4-nitro- 1H-pyrazol-3-yl)- 1H-benzoimidazole; 5-ethyl-6-methyl-2-(4-nitro- 1H-pyrazol-3-yl)- lH-benzoimidazole; 6-chloro-5-methoxy-2-(4-nitro-1H-pyrazol-3-y1)- 1H-benzoimidazole; 5-fluoro-6-methyl-2--(4-nitro- 1H-pyrazol-3-yl)- 1H-benzoimidazole; 2-(4-nitro-1 H-pyrazol-3-yl)-5-trifluoromethoxy- IH-benzoimidazole; 2-(4-nitro-1 H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole; 5-chloro-6-methyl-2-(4-nitro-1H-pyrazol-3 1H-benzoimidazole; 2-(4-nitro-1 H-pyrazol-3-yl)- 1H-benzoiiuidazole-5-carboxylic acid methyl ester; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl> 1 ,4,6,7-tetrah-ydro-pyrazololi4,3-clpyridine-5-carboxylic acid isopropylamide; cyclopropyl-[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1 4,6,7-tetrahydro-pyrazolo[4,3 methanone; isopropyl-[3-(5,6-dimethyl-1H-beInzoimidazol-2-yl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl] methanone; l-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-clpyridin-5-yl] dimethyl-propan-1- -one; 3-(5,6-dirnethyl- 1H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester; ,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine; 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazoloL4,3-c]pyridine; 3-[5-(2-morpholin-4-yl-ethoxy)- 1 H-benzoimidazol-2-yll-4,5,6,7-tetrahydro- 1Hpyrazolo[4,3-cjpyridine; 1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-clpyridine; 3-(5,6-dimethyl-1 I--benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-clpyridine-5-carboxylic acid tert-butyl ester; 5-methoxy-2-(4-nitro- 1H-pyrazol-3-yl)- lH-benzoimidazole;, 5-ethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1 H-benzoimidazole; 3-(5-chloro-6-methyl-ll1-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolof4,3-clpyridine-5-carboxylic acid tert-butyl ester; 3-[5-(2-morpholin-4-yl-ethoxy)- 1H-benzoimidazol-2-yl]-1 ,4,6,7-tetrahydro-pyrazolo[4,3-clpyridine-5carboxylic acid tert-butyl ester; 3 -(5,6-dimcthyl- IH-benzoim-idazol-2-yl)-1I,4,6,7-tetrahydro-pyrano[4,3-clpyrazole; 3-(5-trifluoromethyl-1 H-benzoimlidazol-2-yl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester; ,6-dimetlhyl-1H-benizoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholifl-4-yl-acetamide; 2-dimethylamino-N-[3-(5,6-dimethyl-1H-bcnzoimidazol-2-y1)- 1H-pyrazol-4-yll-acetamide; WO 031035065 PCT/GB02/04763 -205- N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]- ,2,3J,4-tetraazcl- 1-ylU-acctamide; N-[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-isonicotinamide; 2-cyclopropyl-N-[3 -(5,6-dimethyl-l1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-acetamide; 1 ,6-dimethyl- 1H-benzoimiclazol-2-yl)- 1H-pyrazol-4-yl]-3-methyl-urea; 1 -[3-(5,6-dimethyl-l1H--benzoimilazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea; 1 -[3-(5,6-dimethyl- I H-benzoimidazol-2-yl)-1 F-pyrazol-4-yl] -3-phenyl-urea; 1 -benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-l1H-pyrazol-4-yll-urea; ,6-dimethyl-l1H-benzoimidazol-2-yl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-S-carboxylic acid isopropylamide; cyclopropanecarboxylic acidjl3-(5 -ethoxy-6-ethyl- IH-benzoimidazol-2-yI)-lH-pyrazol-4-yllamide; 3-(1I,5,6,7-tetrahydro- 1,3 -diaza-s-indacen-2-yl)-1H-pyrazol-4-ylamiine; 4-methylpiperazine-lI-carboxylic acid 1,5,6,7-tetrahyvdro- 1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4yl]amide; 1,1 -dimethyl-3-[3-( 1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl] urea; cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl)- 1H-pyrazol-4-yllamide; tetrahydropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro- 1H-benzirnidazol-2-yl)- IH-pyrazole-4ylaride; morpholine-4-carboxylic acid[3-(6-ethoxy-5-fluoro- 1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; piperidine-4-carboxylic acid[3-(6-ethoxy-5-fiuoro-1H-benzimidazol-2-yl)-1 H-pyrazol-4-yl]ar-nide; 3-[6-ethoxy-5-fluoro- 1H-benziinidazol-2-yl)- 1H-pyrazol-4-yl]-1, 1-diethylurea; 5-methoxy-2-(4-nitro-1 H-pyrazol-3-yl)- 1H-benzoimidazole; morpholine-4-carboxylic acid [3 -(5,6-dimethyl- 1H-benzoimidazol-2-yl)-lIH-pyrazol-4-ylmethyllamide; 3-[3-(5-difluorometboxy-I-I-benzoimidazol-2-yl)-1 H-pyrazot-4-yl]- 1,1-diethyl-urea; piperidine-1 -carboxylic acid [3-(5-difluoromethioxy-1H-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(6-chloro-5-rnethoxy- 1H-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid 1,5,6,7-tetrahydro-1 ,3-diaza-s-indacen-2-yl)- 1H-pyrazol-4-yl~amide; morpholine-4-carboxylic acid[3-( 1,5,6,7-tetrahydro- 1,3-diaza-s-indacen-2-yl)- IH-pyrazol-4-yll-amide; piperidine- 1-carboxylic acid [3-(5-methoxy-1H-benzoimidao-2-y1)-1H-pyrazo1-4-yI]-arnde; 3-[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]- 1 -dimnetiyl -urea; piperidine-1-carboxylic acid [3-(5-ethiyl-6-methyl-11--benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; 3-[3-(5-fluoro-6-mcthyl- 1H-bcnzoimidazol-2-yl)- 1H-pyrazol-1-yl] -dimethyl-urea; morpholine-4-carboxylic acid [3 -trifluorornethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-clpyridine-5-carboxylic acid diethylamide; WO 031035065 PCT/GB02/04763 -206- [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)- 1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridlin-5-yl]-pyrrolidin- 1yl-m(-thanone; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)- 1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1yl-methanione; [3-(5,6-dimethy1-1H-benzomidazo-2-y)- 1,4,6,7-tetrah-ydro-pyrazolo[4,3-c]pyridin-5-yl]-morpholin-4yl-mathanone; 3 -chloro-6-methyl- 1 H-benzoimidazol-2 1 ,4,6,7-tetrahydro-pyrazolo [4,3-c]pyridine-5 -carboxylic acid diethylamide; morpholine-4-carboxylic acid [3-(5,6-dimethyl-tIH-benzoimidazol-2-yl)-1I--pyrazol-4-yl] -arnide; piperidine-l1-carboxylic acid [3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -amide; 3-[5-(2-morpholin-4-yl-ethoxy)- 1H-benzcimidazol-2-yll- 1,4,6,'7-tetrahydro-pyrazolo carboxylic acid diethylamide; 1H-benizoirnidazol-2-yl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid [2-(2H-tetrazol-5-yl)-ethyl]-amide; 1 -cyclopropyl-3-[3-(5-ethyl-6-methyl- 1H-benzoimidazol-2-yl)- 11H-pyrazol-4-yl]-urea; 1 -[3-(5-ethyl-6-mezhyl- 1H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl] -3-methyl-urea; 4-methyl-piperazine-l1-carboxylic acid [3 -(5-ethyl-6-methyl- IH-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide; piperidine-l1-carboxylic acid [3-(5-fluoro-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; 1 -[3-(5-tluoro-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-3-methyl-urea; morpholine-4-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazo1-4-yl]-amide; 4-methyl-piperazine-l1-carboxylic acid [3-(5-fluoro-6-rnethiyl-1H-benzoirnidazol-2-yl)-I--pyrazol-4yl]-amide; 1 -methyl-3 -(5-triftuoromethyl- 1H-benzoimnidazol-2-yl)-1I--pyrazol-4-yl]-urea; 1 -[3-(5-chloro-6-methyl-1 H-benzoimidazol-2-yl)-1 H-pyrazul-4-yll-3-rnietliyl-urea; 4-methyl-piperazine-l1-carhoxylic acid [3-(5-chloro-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4yl]-amide; 1 -tert-butyl-3-[3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-urea; 1 -[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yI]-3-ethyl-urea; 4-methyl-p iperazinie-1 -carboxylic acid [3-(5,6-dimethyl-1 I-benzoimidazol-2-yl)-1H-pyrazol-4-yl] amide; 1 -cyclopropyl-3-f3-(5 ,6-dirnethiyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-urea; 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-1, 1-diethyl-urea;, 1-[3-(5,6-diiniethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl] -3-isobutyl-urea; 1-cyclopropylmethyl-3-[3-(5,6-dimethy1-1H-benzoimidazo-2-y1)- 1H-pyrazol-4-yl]-urea; WO 031035065 PCT/GB02/04763 -207- 3-(5-chloro)-6methyl-1H-benizoinidazol-2-y)- 1H-pyrazol-4-ylamine; 3-(5-ethyl-6-metbyl- 1H-benzoimidazol-2-yl)- 1H-indazole-5-carboxylic acid amide dihydrochioride; ,6-dimethyl-1H-benzoimidazol-2-yl)- 1H-indazole-5-carboxylic acid; 2-(4-isobutyrylamino-l1H-pyrazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid; 3-[3-(5,6-dimethyl-1H-benzoirnidazol-2-yl)- 1H-pyrazol-4-yl]- 1,1-dimethyl-urea; 3-(5-nitro-1 H-benzoimidazol-2-yl)-IH-indazole; 1H-Indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2-piperidin- 1-yl-ethyl)-amide; 1H-Indazol-3 -yl)-l H-benizoimidazole-5-carboxylic acid (pyridin-2-ylmethyl)-amide; 1H-Indazol-3-yl)- 1H-beazoiiniidazole-5-carboxylic acid [3-(4-methyl-piperazin-1-yl.)-propyl]-amide; IH-Indazol-3-yl)- IH-benzoimidazol-5-ylJ -isobutyramide; N-[3-(5,6-Dimethyl-l1H-benzoiinidazoL-2-yl)- 1H-pyrazol-4-ylj-2-piperidin- 1-yL-acetamide; 1H-indazol-3 piperidine-1 -carboxylic acid ,6-dimethiyl-1H-benzoimidazol-2-yij- 1H-pyrazol-4-yl] -amide; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixa) of the invention for the inhibition of SYK are:- 1H-indazol-3-yl)- 1H-beazimidazole-5-carboxylic acid beazylamide; 1H-indazol-3 1H-benzimidazole-5-carboxylic acid N-methylamide; 1H-indazol-3-yl)-l1H-benzimidazole-5-carboxylic acid N-ethylamide; 1 H-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-isopropylamide; 1H-indazol-3I-yl)-1H-benzimidazole-5-carboxylic acid N-phenylamide; 2-(1H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-phenethylarnide; 5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)- 1H-benzoimidazole; 6-chtoro-5-rnethyl-2-(5-rnethylsulfaayl-1 H-pyrazol-3-yl)-1H-benzoimidazole; 6-chloro-2-(5-ethylsulfanyl- 1H-pyrazol-3-yl)-5-methyl-1H-benizoimnidazole;, 2-(5-rnethylsulfanyl-1H-pyrazol-3J-yl)-5-trifluoromethyl-l1I--benzoimidazole; IH-pyrazol-3-yl)-5 ,6-dimethyl- 1H-benzoimidazole; 1H-pyrazol-3 -yl)-5,6-dimethyl-1 H-benzoimidazole; 5,6-dimethyl-2-[5-(pyridin-3-ylrnethyls-ulfanyl)-1H-pyrazol-3l-y]- 1 -henzoirnidazole; 5-fl-uoro-2-[5-methylsulfanyl)- 1H-pyrazol-3-yl]- 1H-benzoimidazole; 5,6-dimethyl-2-(5-phenethylsulfanyl-1H-pyrazol-3-y)- 1H-benzoimidazole; 4-methiyl-2-(5-methylsulfanyl- 1H-pyrazol-3-yl)-1I--benzoimidazole; 5,6-dimethyl-2-(5-benzylsulfanyl- 1H-pyrazol-3-yl)-1H-benzoimidazole; 5,6-dimetbyl-2-[5-(thiophen-2-ylmethylsulfanyl)- IHI-pyrazol-3-y1]- 1H-bcnzoimidazole; 2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole hydrochloride; WO 031035065 PCT/GB02/04763 -208- -rnethyl-2-(5-rnethiylsulfaniyl-4-propyl- 1 H-pyrazol-3 1 H-benzoimidazole; 2-(5-(4-methoxy-benzylsulfanyl)-4-propyl- 1H-pyrazol-3-y1)- 5-methyl-i H-benzoimiclazole; 2-(5-benzylsulfanyl-4-isopropyl- IH-pyrazol-3-yl)-5-methyl- IH-benzoimidazole; 2-(5-methylsulfanyl-4-methyl- 1H-pyrazol-3-yl)-5-methcxy-1H-benzoimidazole; 2-(5-methylsulfanyl-4-methyl- 1H-pyrazol-3-yl)-5-methyl-IH4-benzoimidazole; 1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5,6-dichloro- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-ylamine; 5,6-dimethyl-2-(4-phenyl- 1H-pyrazol-3 -yl)-l H-benzoimidazolc; 1,5 ,6,7-tetrahydro-1 ,3-diaza-s-indacen-2-yl)-1I--pyrazole-4-carboxylic acid cyclopropylamide; 3-(5-methoxy-6-methyl- 1H-benzoimidazol-2-yl)-l1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid propylamide; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide; IH-benzoimidazol-2-yl)- IH-pyrazoleA4-carboxylic acid isopropylamide; 3-(5-difluoromethioxy- 1H-benzoimidazol-2-yl)- IH-pyrazole-4-carboxylic acid cyclopropylamide; 3-(6-ethyl-5-m-ethioxy- 1H-belizoirnidazol-2-yl)- 1H-pyrazole-4-carboxylic acid isopropylamide; 2-(5-ethoxy-1H-pyrazol-3 1H-benzoimidazole; (benzoimidazol-2-yl)-5-methylthio-3 -pyrazole; 2-(5-isopropyl-1 H-pyrazol-3-yl)-5,6-dimethyl-IH-benzoimidazole; 2-(5 -ethyl- 1 H-pyrazol-3-y1)-5 ,6-dimethyl- 1 H-benzoimidazole; .3-(5,6-dimethyl- IH-benzoimidazo-2-yl)-1H-pyrazoe-4-carboxylic acid isopropylamide; .3-(5,6-dimethyl- 1 H-benzoimidazol-2-yl)-1IH-pyrazole-4-carboxylic acid (2-hydroxy- 1, 1 -dimethylethyl)-ainide; 2-(4-isopropylearbamoyl- 1H-pyrazol-3-yl)-I H-benzoimidazole--5-carboxylic acid (pyridin-3 -ylmethyl)amide; 3-(5,6-dimethyl- 1H-benzoimiidazol-2-yl)-5-iniethiyl- 1H-pyrazole-4-carboxylic acid cyclopropylam-ide; 2-(4-isopropylcarbamoyl- 1H-pyrazol-3 -yl)-l H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid isobutyl-amide; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimetiyl -1 H-benzoimidazol-2-yl)-1 H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-5 -methyl- 1H-pyrazole-4-carboxylic acid tert-butylamide; 2-(4-isobutyrylamino- 1H-pyrazolb3-y1)- 1 H-benzoimidazole-5-carboxylic acid benzylamide; N-[3-(5,6-dimethyl- 1H-benizoimidazol-2-yl)-1H-pyrazol-4-yl]-isobuityramide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl] -3-meth-yl-butyramnide;- N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yfl-2-phenyl-acetamide; cyclopropanearboxylic acid [3-(5,6-dimethyl- I H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl]-amide; WO 031035065 PCT/GB02/04763 -209rnethoxyacetic acid [3-(5,6-dimaethyl-1 H-benzoimidazol-2-yl)--1H-pyrazol-4-ylj-amide; cyclopentanecarboxylic acid [3-(5,6-dimethyl- IH-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -amide; trimethylacetic acid [3-(5,6-dlimethyl-1H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-amide; tert-butylacetic acid [3 -(5,6-dimethyl- 1H-benzoimidazo[-2-yl)- IH-pyrazol-4-yl]-amide; butanoic acid [3-(5,6-dimethyl-1H-benzoimida7Ol-2-yl)- 1H-pyrazol-4-yl]-amide; acid [3 -(5,6-dimethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl] -amide; S(+)-2-methylbutanoic acid [3 -(5,6-dimethyl-1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-ethyl-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; piperidine-l1-carboxylic acid[3-(6-chloro-5-methoxy- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -amide; 3)-[3-(6-chloro-5-mnethoxy- IH-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]- 1,1-dimethylurea; cyclopropanecarboxylic acid [3J-(5-methoxy-1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3)-(5-ethoxy- 1H-benzoimidazol-2-yl)-1 H-pyrazol-4-yll-amide; cyclopropanecarboxylic acid [3 -(5-fluoro-6-methyl- 1 H-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3 -(5-trifluoromethoxy- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-trifluaoromethyl-1 H-benzoimidazol-2-yl)-tIH-pyrazol-4-yl]-amide; IH-benizoimidazol-2-yl)- 1H-pyrazol-4-yl]-isobutyramide; cyclopropanecarboxylic acid -chloro-6-methyl-1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amiide; 3,5-dimethyl-isoxazole-4-carboxylic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- IH-pyrazol-4-yl]amide; ,6-dimethyl-l1H-benzoiinidazol-2-yl)-1H-pyrazol-4-ylj -acetamide; furan-3-carboxylic acid [3-(5-chloro-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; ,6-dimethyt- 1H-benzoimidazol-2-yl)-1H-pyrazOl-4-yl]-4-methyl-benzamide; N-[3-(5,6-dimethyl- 1H-benzoirnidazol-2-yl)- 1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide; 2-dimethylamino-IN-[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yI]-acetamide; N-[3'-(5,6-dirnethiyl-l1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl] 2-(1H-tI,2,3,4-tetraazol- 1-yl)-acetamide; ,6-dimnethyl- 1H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-isoniicotiniaiide; 2-cyclopropy1-N-[3-(5,6-dimethy1-1H-benzoimidazol-2-y1)- 1H-pyrazol-4-yl]-acetamide; 1 -[3-(5,6-dimethyl-IH-benzoimidazol-2-yl)- 1H-pyrazol-4-yll-3-methyl-uarea; 1 -[3-(5,6-dimethyl-IH-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-3-isopropyl-urea; 1 -[3-(5,6-dimethyl-1H-benzoini dazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-urea; I1-benzyl-3 -[3-(5,6-dimethyl- 1 H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]--area; cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethy-1H-benzoimidazo-2-y)- 1H-pyrazol-4-yl] amide; 4-r-nethlylpiperazin-1 -carboxylic acid ,5,6,7-tetrahydro- 1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4ylamide; 1, 1-dimethyl-3-[3-(1 ,5,6,7-tetrahydro-s-indaceni-2-yl)-l1H-pyrazol-4-yl]urea; cyclopropanecarboxylic acid 13-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yllamide; WO 031035065 PCT/GB02/04763 -210tetrah-ydropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl)- 1H-pyrazole-4ylamide; morpholine-4-carboxyliC acid[3-(6-ethoxy-5-fluoro 1 H-benzimidazol-2-yl)- 1H-pyrazol-4-ylllamide; piperidine-4-carboxylic acidL3-(6-ethoxy-5 -fluoro- 11--benzimnidazol-2-yl)I1H-pyrazol-4-ytlamide; 3-[6-ethoxy-5-fluoro-IH-beflzimidazol 2 -yl) H-pyrazol-4-yl]-1, 1-diethylurea; morpholine-4-carboxylic acid ,6-dirnethyl-1 H-benzoimidazol-2-yl)- 1H-pyrazol-4-ylmethyl]amide; 3-[3-(5-difluoromethoxy- 1H-benzoimidazol-2-yI')- 1H-pyrazol-4-yI]- 1, -diethyl-urea; piperidine-1 -carboxytio acid [3-(5-difluoromnethoxy-1I-I-benzoimidazol-2-yl)- 1H-pyrazol-4-y1I-amide; cyclopropanecarboxylic acid [3.-(6-3hloro-5-methoxy--I-benzoimidazol-2-yl)-l H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid ,5,6,7-tetrahydro- 1,3daasidcn2y -Hprz14y~~ie m-orpholine-4-carboxylic acid[3-(1 ,5,6,7-tetrahydro- 1,3-diaza-s-indacen-2-y1)-I H-pyrazol-4-yll-amide; piperidine-1 -carboxylic acid [3-(5-rnethoxy-1H-beflzoimfidazol-2-yl)-lH-pyrazol-4-y1]-amide; 3 -[3-(5-methoxy-l1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yll-l,1I-dimethyl-urea;I piperidine-l1-carboxylic acid [3-(5-ethy1-6-methy1- 1H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl] -amide; 3 -[3-(5-fluoro-6-methyl- 1H-benzoimidazol-2-yl)-l H-pyrazol-4-yl]- 1,1 -dimethyl-urea; morpholine-4-carboxylic acid [3-(5-trifluoromethyl- Hbnomdzl2y)IHprzl4y]aie morpholine-4-carboxyliC acid j3-(5 ,6-dimethyl-l1H-benzoimidazol-2-yl)-l H-pyrazol-4-yl]-anide; piperidine- 1-carboxylic acid E3-(5,6-dimethyl- 1H-benzoimidazol-2-Yl) 1H-pyrazol-4-yll-amide; 1 -cyclopropyl- 3 -[3-(5-ethyl-6-methyl- lH-benzoirnidazo1-2-yl)-I1Wpyrazol 4 -yl]-urea; 1 -ethyl-6-methyl- 1 noiidzl2y)-Hprzl--i--ety-~ra 4-methyl-piperazine-l1-carboxylic acid [3-(5-ethiyl-6-methyl- 1H-ben-zoimidazol-2-yI)- 1H-pyrazol-4-yl]amide; piperidine-l1-carboxylic acid -fluoro-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide; 1 -Ii3-(5-fluoro-6-methy1- 1H-benzoimidazol-2-yl)- IH-pyrazo1-4-y]-3-methy1-uIrea; mOrphOline-4-carboxylic acid [3-(5-fluoro-6-methyl-l1H-benz7oimidazoI-2-yl)-1H-pyrazo14-yll-amide; 4-methyl-piperazine-l1-carboxylic acid [3-(5-fluoro-6-methyl- 1H-benzoimidazol-2-yD- H-pyrazol-4yl]-amide; 1 -methyl-3-j3-(5-trifluoromethyl-be1 mdzl2-l-Hprzo--l-ra 1 3(-clr--mty-I-ezimdz 1--l-H-pyrazo1-4-yl]-3-methy1-Urea; 4-methyl-piperazine-l1-carboxylic acid [3-(5-choro6mthy[IHbeflzeimidazol2y)lH-pyrazol- 4 yl]-amide; 1-otbtl3[-56drehll-eziiac12y)I-yao--i-ra 1 -[3-(5,6-diimethy1-1H-bcflzoimidazo[2-yl) ifl-pyrazo-4-y1-3-ethylurea; 4-methyl-piperazine-1 -carboxylic acid [3-(5,6-dimethy1-1H-bel2oimidazol- 2 -yI) 1H-pyrazol-4-yl1amide; WO 031035065 PCT/GB02/04763 -211- I-cyclopropy1-3-[3-(5,6-dimethyl- 1 H-benzoimidazo-2-y1)-1IH-pyaZOl-4-yl]-urea; ,6-dimethyl- 1H-benzoirnidazol-2-yl)- 1 I1-pyrazol-4-yl]- 1, 1 -diethyl-urea; 1-f 3-(5 ,6-dimethyl- 1H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl]-3-isobutyl-urea; 1 -cyclopropylmethyl-3 5 ,6-dimethyl- 1 H-benzoimidazol-2-yl)- I1H-pyrazol-4-yl] -u-rca; 3-[3I-(5 ,6-dimethyl- 1 H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]- 1,1 -dimethyl-urea; 1H-indazol-3-yl)- 1H-benzoimidazole-5-caboxylic acid (2-piperidin-1I-yl-ethyl)-amide; 2-(l1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxyliC acid (pyridin-2-ylmethyl)-amide; N-[2-(l1H-indazol-3-yl)- N-[3-(5,6-dimethytl1H-benzoimidazol-2-yl)-l H-pyrazo1-4-y]-2-piperidifl-l-yl-acetamnide; 1H-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-morpholinoamide; 1H-indazol-3-yl)-1 H-benzimidazole-5-carbOXylic acid N-(N'-methylpiperazino)amide; 1H-indazol-3 -yI)-1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide; 2-(I--indazol-3-ylD- 1H-benzimidazole-5-carbOXYlic acid N-(isobutyl)amide; 2-(1H-indazol-3-yl)- 1l--benzimidazole-5-carboxylic acid N-(cyctohexylmethyl)amide; 1H-indazol-3-yl)-l1H-benzimidazole-5-carboxylic acid N-(2-furfuaryl)amide; 2-(l1H-indazol-3-yl)- 1 H-benzimidazole-5-caboxylic acid N-benzyl-N-mnethylarnidle; methyl 1H-indazol-3-y1)-3H-beflzimidazole- 5 carboxylate; 5,6-dirnethyl-2-(1 H-indazol-3-yl)- 1 H-benzimidazole; Hidzl3y)3-eziiaoe4croyi acid; 2-(5-ethoxy-2H-pyrazol-3-yl)- 1H-benzimidazole-4-carboxylic acid; 5,6-dimethyl-2-(5-methyl-2H-pyrazol- 3 -yl)l H-benzimnidazole; 5,-iehl2(-hohn2y-H-yao--l-Hbniiaoe 2-(4-bromno-2H-pyrazol-3-yl)-5,6-dimethyl-il-benzimidazole; -ethyl-2H-pyrazo1-3-y1)-5,6-dimethyl- 1H-benzimidazole; 2-(5-ethyl-2H-pyrazol-3-yl)-4,5-ehiyleedioxy- 1H-benzimidazole; 2-(5-tthyl-2H-pyrazo-3-y)-5-mcthoxy- I H-benzimidazole; 2-(5-ethy-2H-pyrazol-3-yl)-4-hydroxy-l H-benzimidazole 2-(5-ethy1-2H-pyrazol-3-yl)-5-bromo-l H-benzimidazole; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of formula (Ixa) of the invention for the inhibition of SYK are:- 2-(1 H-indazol-3-yl)- 1H-henzirnidazole-5-carboxylic acid benzylamide, Example 1; 2-(1H-indazol-3-yl)- 1U-benzimidazole-5-carboxylic acid N-methylamide, Example 2; 2-l-nao--l-Hbniiaoe5croyi acid N-ethylamide, Example 3; acid N-isopropylamide, Example 4; WO 031035065 PCT/GB02/04763 -212- 2-(IH-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-phenylamide, Example 1H-indazol-3-yl)-1H-belnzimnidazole-5-carboxylic acid N-phenethylamide, Example 6 5,6-diniethyl-2-(5-methylsulfanyl- 1H-pyrazol-3-yl)- IH-benzoimi-idazole, (compound denoted as A9-B9), Example 230(a); 6-chloro-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-methyl- 1H-benzoimidazole, (compound denoted as A12-B9), Example 230(b); 6-chloro-2-(5-ethylsulfanyl-1 H-pyrazol-3-yl)-5-rnethyl- lH-benizoimidazole, (compound denoted as A12-B 10), Example 230(c); 11-pyrazol-3-yl)-5-trifluoromethyl-l1H-benzoimidazole, (compound denoted as A4-B9), Example 230(d); -cyclopropylmethylsulfanyl- lH-pyrazol-3-yl)-5,6-dimethyl-l1H-beazoimidazole, (compound denoted as A9-13 11), Example 230O(e); 2-(5-ethylsulfanyl-tIH-pyrazol-3 -yl)-5,6-dimethyl-1H-benzoimidazole, (compound denoted as A9-B Example 230(f); 1,5 ,6,7-tetrahydro- 1,3-diaza-s-indacen-2-yl)- IH-pyrazole-4-carboxylic acid cyclopropylamide, Example 235(ah); 3-(5-methoxy-6-methyl- lH-benzoimidazol-2-yl)-1H--pyrazole-4-carboxylic acid isopropylamide, Example 235(ai);- 3 .6-dimethyl- IH-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide, Example 235(ak); .6-dimethyl- IH-benzoimidazol-2-yl)- IH-pyrazole-4-carboxylic acid propylamide, Example 235(al); 3-(5,6-dimethyl- 1H-benzoimnidazol-2-yl)- IH-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide, Example 235(am); 3-(5-difltuoromethoxy- 1H-benzoimidazol-2-yl)- 1H-pyrazote-4-carboxylic acid isopropylamide, Example 235(ao); 3-(5-difluoromethioxy-1H-benizoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid cyclopropylamide, Example 235(ap); 3-(6-ethyl-5-i-ethioxy-1 H-benzoimidazol-2-yl)-1I-pyrazole-4-carboxylic acid isopropylamide, Example 235(aq)l; 1H-pyrazol-3-yl)-5 ,6-dimethyl- 1H-benzoimidazole, (compound denoted as A9-B83), Example 24 1(b); 3-(5,6-dimethyl-l1H-benzoimidazol-2-yl)-lI--pyrazole-4-carboxylic acid isopropylamnide, (compound denoted as A9-B106), Example 246(g); 3 -(5,6-dimethyl- IH-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (2-hydroxy-1, 1-dimethylethyl)-amide, (compound denoted as A9-B25), Example 246(h); WO 031035065 PCT/GB02/04763 -213- 2-(4-isopropylcarbamoyl- lH-pyrazol-3 1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)amide, (compound denoted as A40-B 106), Example 246(i); 3-(5,6-dimethyl- 1H-bcnzciinidazol-2-yl)-5-methyl- 1H-pyrazole-4-carboxylic acid cyclopropylamide, (compound denoted as A9-B 105), Example 2460); 2-(4-isopropylcarbamoyl- IH-pyrazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide, (compound denoted as A17-B 106), Example 246(k); 6-dimethyl-1 H-benzoimidazol-2-yl)-lH-pyrazole-4-carboxylic acid isobutyl-amide, Example 246(v); 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- lH-pyrazole-4-carboxylic acid isopropylamide, Example 246(w); 3-(5,6-diinethyl- 1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide, Example 246(x); 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-5-methyl-l H-pyrazcle-4-carboxylic acid tert-butylamide, Example 246(y); 2-(4-isobutyrylamnino- 1H-pyrazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid benzylamide, Example 246(aa); ,6-dimethyl-lH-ben7oimidazol-2-yl)-1 H-pyrazol-4-yl]-isobutyramide, (compound denoted as A9-B85), Example 248(a); N-[3-(5,6-dimethyl-lH-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-3-methyl-butyramide, (compound denoted as A9-B 86), Example 248(b); N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-2-phenyl-acetamide, (compound denoted as A9-B36), Example 248(c); cyclopropanecarboxylic acid [3-(5,6-dimethyl- IH-benzoimidazol-2-yl)-1H-pyrazol-4-yl] -amnide, (compound denoted as A9-B 89), Example 248(d); methoxyacetic acid 13-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide, (compound denoted as A9-B94), Example 2d48(e); cyclopentanecarboxylic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-l H-pyrazol-4-yl]-amide, (compound denoted as A9-B87), Example 248(f);trimethylacetic acid [3-(5,6-dimcthyl- 1H-benzcimidazol-2-yl)-1H-pyrazol-4-yl]-amide, (compound denoted as A9-B88), Example 248(g); tert-butylacetic acid [3-(5,6-dimethyl-1H-benzoimnidazcl-2-yl)- 1H-pyrazol-4-yl] -amide, (compound denoted as A9-B90), Example 248(h); butanoic acid [3-(5,6-dimethyl- 1I-benzoimiidazol-2-yl)-1H-pyrazol-4-yl]-amide, (compound denoted as A9-B9 Example 248(i); isoxazole-5-carboxylic acid [3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)-lH-pyrazol-4-yll-amide, (compound denoted as A9-B96), Example 248(j); WO 031035065 PCT/GB02/04763 -214- S(+i)-2-methylbutanoic acid [3-(5,6-dim-ethyl-lH-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-amide, (compound denoted as A9-B393), Example 248(k); cyclopropanecarboxylic acid [3-(5-ethyl-6-methyl-11 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-amide, (compound denoted as A55-.B89), Example 248(1); pipeidine- I -carboxylic acid[3-(6-chloro-5-methoxy- IH-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example 248(m); 3-1j3-(6-chloro-5-methoxy- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-1,tI-dimethiylurea, Example 248(n); cyclopropanecarboxylic acid [3-(5-methoxy- IH-benzoirnidazol-2-yl)-1 H-pyrazol-4-y1]-amide, Example 248(o); cyclopropanearboxylic acid [3-(5-ethoxy- I fI-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-amide, Example cyclopropanecarboxylic acid [3-(5-fluoro-6-mnetlhyl- 1H-benzoimaidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example 248(q); cyclopropanecarboxylic acid [3-(5-trifluoromethoxy-lH-benzoimidazol-2-yl)- I H-pyrazol-4-ylj-amide, Example 248(r), cyclopropaqnecarboxylic acid [3-(5-trifluoromethyl- 1 H-benzoiimidazo]-2-yl)-1 H-pyrazol-4-yl]-amide, Example 248(s); N-[3-(5-trifluoromethyl-1 H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-isobuatyraniide, Example 248(t); cyclopropanecarboxylic acid [3-(5-chloro-6-mietlhyl- 1H-benizoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example 248(u); 3,5-dimethyl-isoxazole-4-carboxylic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- lH-pyrazol-4-yljamide, Example 248(v); N-[3-(5,6-dimethyl-lH-benzoimidazol-2-yl)-1I-I-pyrazol-4-yl]-acetamide, Example 249(w); furan-3-carboxylic acid [3-(5-chlor~o-6-methyl-1 H-benzoimidazol-2-yl)-1H-pyrazol-4-vl]-amide, Example 248(x); N-[3-(5,6-dimethyl-1H-bezoimidazol-2-y)-H-pyrazol4yl-4methylbenamide, Example 248(y); N-f 3-(5,6-dimethyl-1ll-benzoimidazol-2-y)-1 H-pyrazol-4-yl]-2-morpliolin-4-yl-acetamide, (compound denoted as A9-B99), Example 253; N-f 3-(5,6-dimnethyl-1H-benzoimidazol-2-yl) lH-pyrazol-4-yl]- 1H-l ,2,3,4-tetraazol- 1-yl)-acetamide, (compound denoted as A9-1397), Example 254(a); N-f 3-(5,6-dimethyl- lH-benzoimidazol-2-yl)-1 H-pyrazol-4-ylj-isonicotinamide; Example 254(b); 2-cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-acetamide; Example 254(c); 1-f 3-(5,6-dimethyl-I H-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-3-methyl-urea, (compound denoted as A9-B38), Example 255(a); WO 031035065 PCT/GB02/04763 -215- 1 -[3-(5,6-dimethyl-I H-benzoimidazol-2-yl)-l1H-pyrazo1-4-y11-3-isopropy1-urea, (compound denoted as A9-B 103), Example 255 I -[3-(5,6-dimethy1- 1H-benzoimidazol-2-yl)-l1H-pyrazol-4-yl]-3-pheni-yl-urea, (compound denoted as A9-1340), Example 255(c); 1 -benzyl-3-[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- lH-pyrazol-4-yljJ-urea, (compound denoted as A9-B39), Example 255(d); cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoii-nidazol-2-yl)-I--pyrazol-4-yl]amide, Example 256(a); 4-methylpiperazine-1 -carboxylic acid ,5 ,6,7-tetrahydro-1I,3-diaza-s-indacen-2-yl)-1H-pyrazol-4yllamide, Example 256(c); 1, 1 -dimethyl-3-[3-(1 ,5,6,7-tetrahydro-s-indacen-2-yl)- 1 H-pyrazol-4-yllurea, Example 256(d); cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-beazimidazol-2-yl)- 1H-pyrazol-4-yl] amide, Example 257(a); tetrahiydropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4yflamide, Example 257(b); morpholine-4-carboxylic acidL3-(6-ethoxy-5-fluoro-l1H-benzimidazol-2-yl)-l1H-pyrazol-4-yl]amide, Example 257(c); piperidine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benizimidazol-2-yl)- I-pyrazol-4-yl]amide, Example 257(d); 3-[6-ethoxy-5-fluoro- IH-benzimidazol-2-yl)- lH-pyrazol-4-yl]- 1,1 -diethylurea, Example 257(e); morpholine-4-carboxylic acid [3-(5,6-dimethyl-tIH-benzo~imidazol-2-yl)- IH-pyra7zol-4-ylmethyl]-amide, Example 257(g); 3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-1, 1-diethyl-urea, Example 257(h); piperidine-l1-carboxylic acid [3-(5-dlifluoromethoxy- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -amnide, Example 257(i); cyclopropanecarboxylic acid [3-(6-chloro-5-methoxy-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-amnide, Example 258(a); cyclopropanecarboxylic acid ,5,6,7-tetrahydro-1 ,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-ytlamide, Example 258(b); morpholine-4-carboxylic acid[3-(1 ,5,6,7-tetrahydro- 1,3-diaza-s-indacen-2-yl)-l1H-pyrazol-4-yl]-amide, Example 258(c); piperidine-I1-carboxylic acid [3-(5-methoxy-1H-benzoirnidazol-2-yl)-l1H-pyraz.ol-4-yl]-amide, Example 258(d); 3-[3-(5-m-ethoxy- 1H-benzoinmidazol-2-yl)-1H-pyrazol-4-yl]-Il,1-dimethyl-urea, Example 258(e); piperidine-l1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide, Example 258(f); WO 031035065 PCT/GB02/04763 -216- 3-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)- TH-pyrazol-4-yl]-1.1 -dimethyl-urea, Example 258(g); morpholine-4-carboxylic acid [3-(5-trifluoromethyl- 1H-benzoimnidazol-2-yl)- lI--pyrazol-4-yl]-amide, Example 258(h); morpholine-4-carboxylic acid [3-(5,6-dimethyl-tIH-benzoimidazol-2-yl)- 1H-pyrazol-4-yt]-amide, Example 258(n): piperidine-lI-carboxylic acid [3 ,6-dimethyl- 1H-benzoimidazol-2-yl)- IH-pyrazol-4-yll-amide, Example 258(o); 1 -cyclopropyl-3-[3-(5-ethyl-6-methyl- lH-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-urea, Example 260(a); 1 -(5-ethyl-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-3O-methyl-urea, Example 260(b); 4-methyl-piperazine-1 -carboxylic acid [3-(5-ethyl-6-methyl- IH-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide, Example 260(c); piperidine-l1-carboxylic acid [3-(5-fluoro-6-methyl-lH-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-amide, Example 260(d); 1- 3 -(5-fluoro-6-methyl-l1H-benizoimidazol-2-yl)- lH-pyrazol-4-yl]-3 -methyl-uirea, Example 260(e); morpholine-4-carboxylic acid [3-(5-fluoro-6-methyl- lH-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -amide, Example 260(f); 4-methiyl-piperazine-l1-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)- 1H-pyrazol-4yl]-amide, Exampte 260(g); 1 -methyl-3-[3-(5-trifluoromethyl-l1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -urea, Example 260(h); 1 -[3-(5-chloro-6-methyl- IH-benzoimidazol-2-yl)-1 H-pyrazol-4-yll-3-methyl-urea, Example 260(i); 4-methyl-piperazine-l1-carboxylic acid [3-(5-chloro-6-methyl- 1H-benzoirnidazol-2-yl)-lH-pyrazol-4yl]-amide, Example 260(j); 1 -tert-butyl-3-[3-(5,6-dimethyl-l1H-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-urea, Example 260(k); 1 -[3-(5,6-dimethiyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -3-ethyl-urea, Example 260(l); 4-methyl-piperazine-1 -carboxylic acid ,6-dimethyl- lH-benzoirnidazol-2-yl)-1H-pyrazol-4-yl]ainide, Example 260(m1); 1 -cyclopropyl-3-[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-urea, Example 260(n); 3-f 3-(5,6-dimethyl- IH-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1, 1-diethyl-urea, Example 260(o);- 1 -[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-3-isobutyl-urea, Example 260(p); 1 -cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-urea, Example 260(q); 3-[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-1, 1-dimeth-yl-virea, Examp]le 259(r); 2-(1H-Indazol-3-yl)-1 H-benzoimidazole-5-carhoxylic acid (2-piperidin- 1-yl-ethyl)-amide, Example 246(ab); 1H-Indazol-3-yl)-1 H-beinzoimidazole-5-carboxylic acid (pyridiin-2-ylmethyl)-ainide, Example 246(ac); WO 031035065 PCT/GB02/04763 -217- N-[3-(5,6-Dimethyl-1 H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -2-piperidin-l1-yl-acetamide, Example 253(c); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Especially preferred compounds of formula (Ixa), denoted as the product of the combination of group Al1 in Table 1 and B I in Table 2, of the invention for tbe inhibition of SYK are: 3-(1,5,6,7-tetrahydro- 1,3-diaza-s-indacen-2-yl)- 1H-pyrazole-4-carboxylic acid cyclopropylamide, Example 235(ah); 3-(5-methoxy-6-mnethyl- IH-benzoimidazol-2-yl)-IH-pyrazole-4-carhoxylic acid isopropylamide, Example 235(ai); ,6-dimethyl-1H-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide, Example 235(ak); 3-(5,6-dimethyl-1H-benzoimnidazol-2-yl)- 1H-pyrazole-4-carboxylic acid propylamide, Example 235(al); 3-(5,6-dimethyl- IH-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide, Example 235(am); 1I-benzoimidazol-2-yl)-lH-pyrazole-4-carboxylic acid isopropylamide, Example 235(ao); 3-(5-difluoromethoxy- lH-benzoimidazol-2-yl)- lH-pyrazole-4-carboxylic acid cyclopropylamide, Example 235(ap); 3-(6-ethyl-5-methoxy-1H-benzoimidazol-2-yl)-lH-pyrazole-4-carboxylic acid isopropylamide, Example 235 (aq); 3-(5,6-dimethyl-lH-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid isopropylamide, (compound denoted as A9-B 106), Example 2 46(g); 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)- 1H-pyrazolc-4-carboxylic acid (2-hydroxy-l, I-dimethylethyl)-amide, (compound denoted as A9-B25), Example 246(h); 2-(4-isopropylcarbamoyl- 1H-pyrazol-3-yl)- 1H-benizoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)amide, (compound denoted as A40-B 106), Example 246(i); 3-(5,6-dimethyl-1H-benzoimnidazol-2-yt)-5-methyl-lH-pyrazote-4-carboxylic acid cyclopropylamide, (compound denoted as A9-B 105), Example 246(j); 2-(4-isopropylcarbamoyl-IH-pyrazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide, (compound denoted as A17-13106), Example 246(k); 6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid isobutyl-amide, Example 246(v); WO 031035065 PCT/GB02/04763 -218- 3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid isopropylamide, Example 246(w); 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide, Example 246(x); 3-(5,6-dimethyl-l H-benzoimidazol-2-yl)-5-methyl- 1H-pyrazole-4-carbcoxylic acid tert-butylamide, Example 246(y); 2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid beuzylamide, Example 246(aa); N-[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-isobutyramide, (compound denoted as A9-B85), Example 248(a); ,6-dimethyl- 1H-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-3-r-nethyl-butyramide, (compound denoted as A9-B386), Example 248(b); cyclopropanecarboxylic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -amide, (compound denoted as A9-1389), Example 248(d); mnethoxyacetic acid [3 -(5,6-diniethyl- 1H-benzoimidazol-2-yl)-1I pyrazol-4-yl]-amide, (compound denoted as A9-1394), Example 248(e); cyclopentanecarboxylic acid [3J-(5,6-dimethyl- 1H-bcnzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide, (compound denoted as A9-B87), Example 248(f); trimethylacetic acid [3-(5,6-dimethyl- lH-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide, (compound denoted as A9-BS8), Example 248(g); tert-butylacetic acid [3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)- 1H-pyrazol-4-yll-amide, (compound denoted as A9-B90), Example 248(h); butanoic acid [3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl] -amide, (compound denoted as A9-B9 Example 248(i); isoxazole-5-carboxylic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-1H-pyraz-ol-4-yl]-ainide, (compound denoted as A9-1396), Example 248(j); S(+)-2-methylbutanoic acid [3-(5,6-dinmethyl- 1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, (compound denoted as A9-B93), Example 248(k); cyclopropanecarboxylic acid [3-(5-ethyl-6-inethiyl-1 H-benzoimidazol-2-yl)- lH-pyrazol1-4-yl]-amide, (compound denoted as A55-1389), Example 248(1); piperidine-1 -carboxylic acid[3-(6-chloro-5-methoxy- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide, Example 248(m); 3-[3-(6-chloro-5-mnethoxy- lH-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]- 1,1 -dimethyl-urea, Example 248(n); cyclopropanecarboxylic acid [3-(5-methoxy-1H-benzoimnidazol-2-yl)-1H-pyrazol-4-yt]-anmide, Example 248(o); WO 031035065 PCT/GB02/04763 -219cyclopropanecarboxylic acid [3-(5-ethoxy- 1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example 248(p); cyclopropanecarboxylic acid [3-(5-fluoro-6-methyl- IH-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example 248(q); cyclopropanearboxylic acid {3-(5-trifluoromethyl-lH-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-amide, Example 248(s); 1H-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-isobutyramide, Example 248(t); cyclopropanecarboxylic acid [3-(5-chloro-6-methyl-1H-benizoimidazol-2-yl)-l1H-pyrazol-4-yl]-amide, Example 248(u); 3 1,5-dimethyl-isoxazole-4-carboxylic acid [3-(5,6-dimethyl- IH-benzoimidazol-2-yl)-IH-pyrazol-4-yl] amide, Example 248(v); furan-3 -carboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)- 1L--pyrazol-4-ylJ -amide, Example 248(x); ,6-dimethyl-1 H-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-2-morpholiin-4-yl-acetamide, (compound denoted as A9-B99), Example 253; N-[3-(5,6-dimethy]- lH-benzoimidazol-2-yl)- lH-pyrazol-4-yl] 1H- 1,2,3 ,4-tetraazol-l -yl)-acetamide, (compound denoted as A9-B97), Example 254(a); N-[3-(5,6-dimethyl- lH-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-isonicotinamide;, Example 254(b);- 2-cyclopropyl-N-[3)-(5,6-dirnethytl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide; Example 254(c); 1 -[3-(5,6-dimethyl- IH-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-3-methyl-urea, (compound denoted as A9-1338), Example 255(a); 1 -[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl] -3-isopropyl-urea, (compound denoted as A9-B 103), Example 255(b); 1 -[3-(5,6-dimnethyl-l1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl] -3-phenyl-uirea, (compound denoted as A9-1340), Example 255(c); 1 -benzyl-3-13-(5,6-dimethyl-l H-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-urea, (compound denoted as A9-B39), Example 255(d); cyclopropanecarboxylic acidll3-(5-ethoxy-6-ethyl-1 H-benzoimnidazol-2-yl)-l H-pyrazol-4-yllamide, Example 256(a); 4-methylpiperazine-l1-carboxylic acid 1,5,6,7-tetrahydro-1 ,3-diaza-s-indacen-2-yl)-lH-pyrazol-4ylamide, Example 256(c); 1,1 -dimethyl-3-[3-( 1,5,6,7-tetrah-ydro-s-indacen-2-yl)-1H-pyrazol-4-yllurea, Example 256(d); cyclopropanecarbexylic acid [3-(6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl)- lH-pyrazol-4-yljamnide, Example 257(a); WO 031035065 PCT/GB02/04763 -220tetrahydropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro- 1H-benzimridazol-2-yl)-1 H-pyrazole-4yljamicle, Example 257(b); morpholine-4-carboxylic acid[3-(6-ethoxy-5-ftuoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide, Example 257(c); piperidinle-4-carboxylic acid[3-(6-ethoxy-5-fluoro- 1H-benzimidazol-2-yl)-1 H-pyrazol-4-yl]amide, Example 257(d); 3-[6-ethoxy-5-fluoro- 1H-benzimidazol-2-yl)- 1H-pyrazol-4-yl]-1, 1-diethylurea, Example 257(e); 3-[3-(5-difluoromethoxy-I1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]- 1,1-diethyl-urea, Example 257(h); piperidine- I-carboxylic acid -difluoronwtboxy- lH-benzoimidazo[-2-yt)- 1H-pyrazol-4-yl]-amide, Example 257(i); cyclopropanecarboxylic acid [3-(6-chloro)-5-methoxy-1 H-benrzoimidazol-2-yl)- 1H-pyrazol-4-yl] -amnide, Example 25 8(a); cyclopropanecarboxylic acid 1,5 ,6,7-tetrahydro- 1,3-diaza-s-iadacen-2-yl)-I H-pyrazol-4-yl]amide, Example 25 8(b); rnorpholine-4-carboxylic acid[3-( 1,5,6,7-retrahydro-1 ,3-diaza-s-indacen-2-yl)-l1I--pyrazol-4-yl]-amide, Example 258(c); piperidine-l1-carboxylic acid -methoxy- 1H-benzoimidazol-2-yl)- lH-pyrazol-4-yll-amide, Example 258(d); 3-{3-(5-methoxy- 1H-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-l,1I-dimethyl-urea, Example 258(e); piperidine-lI-carboxylic acid [3-(5-ethiyl-6-methyl-IH-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -amnide, Example 258(t); 3-[3-(5-fluoro-6-rneth-yl- 1H-benzoim-iidazol-2-yl)- 1H-pyrazol-4-yl]- 1,1-dimetbyl-urea, Example 258(g); morpholinc-4-carboxylic acid L3-(5-trifluoromcthyl-1H-benzoimidazol-2-yl)- 1 F-pyrazol-4-ylJ -amide, Example 258(h); morpholine-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yI)-1H-pyrazol-4-yl]-amide, Example 258(n); piperidine- I-carboxylic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-yl}-1H-pyrazol-4-yl] -amide, Example 258(o); 1 -cyclopropyl-3-[3-(5-etliyl-6-methyl- 1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylj -urea, Example 260(a); 1 -[3-(5-ethyl-6-methyl- lH-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea, Example 260(b); 4-mnethyl-piperazine-l1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]amide, Example 260(c); piperidine-1 -carboxylic acid [3-(5-fluoro-6-methyl- 1H-benzoimidazol-2-yl)-IH-pyrazol-4-yl]-atmde-, Example 260(d); 1 -[3-(5-fluoro-6-mnethyl-l H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea, Example 260(e); WO 031035065 PCT/GB02/04763 -221morpholine-4-carboxylic acid f3-(5 -fluoro-6-methyl-1H-benzoimidazol- 2 1H-pyrazol-4-yljj-amide, Example 260(0-; 1 -methyl-3 -[3-(5-trifluoromethiyl- 1H-benzoimidazol-2-yl)-I--pyrazol-4-yll-urea, Example 260(h); 1 -[3-(5-chloro-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-3-inethyl-uLrea, Example 260(i); 4-methyl-piperazine-l-carboxyliC acid [3-(5-chloro-6-methyl-1H-belzoim-idaZOl-2-Y1)4IH-pYrazolP 4 yl]-amide, Example 260(j); 1 -tert-butyl--{3-(5,6-dimetbyl-1I-benzoimidazol-2-yl)-H-pyrazOl- 4 -yl1 -urea, Example 260(k); 1 ,6-dimi-ethyl- 1H-benzoimnidazot-2-yl)- lH-pyrazol-4-yl]-3-ethyl-urea, Example 260(1); 4-methyl-piperazine-l -carboxylic acid ,6-dimethyl-1H-benzoimidazOl-2-yl)- 1H-pyrazol-4-yljamide, Example 260(m); 1 -cyclopropyl-3-1 3 -(5,6-dimethyl-tII--benzoiinidazol-2-yI)- 1H-pyrazol-4-yl]-urea, Example 260(n); ,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -1,1 -diethyl-urea, Example 260(o); 1 -j3-(5,6-dimethyl- IH eziiao--y)I-yao--t]3iouy-r Example 260(p); 1 -cyclopropymethyl- 3 -1 3 I-(S ,6-dinethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl] -urea, Example 260(q); 3-[3-{5,6-dlimethyl- IH-benzoimidazol-2-yl)- 1H-pyrazol-4-yll- 1,1 -dimnethyl-urea, (compound denoted as A9-13142), Example 258(r); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

More especially preferred compounds of formula (Ixa) of the invention for the inhibition of SYK are:- 3-(5-methoxy-6-methyh 1 H-benzoimidazol-2-yl)- lH-pyrazole-4-carboxylic acid isopropylamide, Example 235(ai); 1,5,6,7-tetrahydro- 1,3-diaza-s-indacen-2-yl)- 1H-pyrazote-4-carboxylic acid cyclopropylamide, Example 235(ah); ,6-dimethyl-1 H-bcnzoimidazol-2-yl)- 1H-pyrazole-4-carboxylic acid (retrahydro-pyran-4-yl)-amide, Example 235(am); 6-dimerhyl-1H-benzoimidazol-2-yl)-1 H-pyrazole-4-carboxylic acid isobutyl-amide, Example 246(v); cyclopropanecarboxylic acd3(-toy6ehll-eziidzl2y)l-yao--laie Example 25 6(a); 1,1 -dimethyl-3-[3-(l ,5 ,6,7-tetrahydro-s-indacen-2-yl)-H-pyrazo1- 4 -yl]urea, Example 256(d); piperidine-4-carboxylic acid[3-(6-ethoxy-5-fluoro- 1H-benzimidazol-2-yl)- 1H-pyrazol-4-yl] amiide, Example 257(d); 3-[6-ethoxy-5-fluoro-1H-benzimidaZOl-2-yl)-l l-pyrazol- 4 1,1 -diethylurca, Example 257(e); 3-[3-(5-difluoromethoxy-11I-belzoirnidazo-2-yl)-1H-PYrazol 4 tl]lIl-diethyl-urea, Example 257(h); WO 031035065 PCT/GB02/04763 -222piperidine-l1-carboxylic acid [3-(5-difluoro~methoxy-1 H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-arnide, Example 257(i); cyclopropanecarboxylic acid 1,5,6,7-tetrahydro- 1,3-diaza-s-indacen-2-yl)- 1I-pyrazol-4-yl]amide, Example 25 8(b); piperidine-lI-carboxylic acid [3-(5-methoxy-l1H-benzoimidazol-2-yl)-1H-pyrazol-4-y1-amide, Example 258(d); piperidine-l1-carboxylic acid [3-(5-etlhyl-6-methyl-I--benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amnide, Example 258(f); piperidine-tI-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-H-pyrazol-4-yl-amidlC, Example 25 8(o); I -cyclopropyl-3-[3-(5-ethyl-6-meth-yl-l H-benzoim-idazol-2-yl)-1H-pyrazol-4-yl]-utea, Example 260(a); piperidine- 1-carboxylic acid [3-(5-fluoro-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-amide, Example 260(d); 1 -tert-butyl-3-[3-(5,6-dimethyl- 1H-benzoirnidazol-2-yl)- 1H-pyrazol-4-yl]-urea, Example 260(k); 1 -cyclopropyl- 3 3 -(5,6-dimethyl- 1H-benzoin-idazol-2-yl)- 1H-pyrazol-4-yl]-urea, Example 260(n); 3D-[3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-l, 1-diethyl-urea, Example 260(o); 1-cyclopropylmethyl-3-[3-(5 ,6-dimethyl-1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-urea, Example 260(q); 3-[3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)- 1H-pyrazol-4-yll- 1,1-dimethyl-urea, Example 258(r); and the corresponding N-oxides, and their prodrugs; and pharmnaueutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixb) of the invention for the inhibition of SYK are:lH-benzoimidazol-2-yl)-IH-indazole; 3-(5-methoxy-lH-benzoimidazol-2-yl)-l H-indazole; [2-(indazol-3-yl)-l1H-benzoimidazol-5-yl] -phenyl-methanone; 1H-indazol-3-yl)-3H-beiizoimidazol-4-ol; ,6-dimethyl-1 H-benzoirnidazol-2-yl)- IB-indazole; 1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine; 2-(1H-indazole-3-yl)-3H-imidazo[4,5-bllpyridine; ,6-dimethyl- 1H-benzoimidazol-2-yl)-5-methoxy- 1H-indazole; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-5-fliioro-I H-indazole; 3-(5,6-dim-ethyl-1 H-benzoimidazol-2-yl)-6-fluoro-1H-indazole; 3-(5,6-dimethyl- 1H-benzoimnidazol-2-yl)-5-methyl- lH-iadazole; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-6-methoxy-Hf-indazolC; 3-(5-ethyl-lH-benzoimidazol-2-yl)- 1H-indazole; WO 031035065 WO 03/35065PCT/GB02104763 -223- 3-(5-ethyl-6-nwthyl- 1H-benzoimidazol-2-yl)- 1 H-inclazole; 3 -isopropyl-6-rnethyl- 1PH-benizoirnidazol-2-yl)-1IH-indazole; 3-(5-bromo-6-methyl-1IH-benzoimidazol-2-yl)- IH-indazole; -bromo- I H-benzoim-idazol-2-yl)- 1I--indazole; 3-(5 -(3-cyano)phenyl- 1 H-benzoimnidazol-2-yl)-1IH-indazole; 3-(5-(pyrid-3-yl)- 1 H-benzoimidazol-2-yl)- I H-indazole; 3-(6-methyl-5-phenyl- 1H-benzoimidazol-2-yl)-1H-indazole; IF-I-benzoimidazol-2-yl)- 1 H-indazote; 3-(5-(2-fluoro)phenyl- I H-benzoimidazol-2-yl)- I H-indazolc; 3-(5-(5,6-methylenedioxy)phenyl- IH-benzoimidazol-2-yl)- 1 H-inldazole;- 3.-(5-(2-methoxy)phenyl-l1H-benzoimidazol-2-yI)-1 H-indazole; -(4-chloro)phenyl- 1 H-benzoimidazol-2-yl)- t H-indazole; 3-(5-(4-methyl)phenyl- 1H-benzoimidazol-2-yl)- iB-indazole; -beozyloxy- 1H-benzoimidazol-2-yl)- 1 H-indazole; 3-(5.6-rnethylenedioxy-1 H-benzoimidazol-2-yl)- IH-indazole; 3-(5,6-dimethoxy- I H-benizoimnidazol-2-yl)-1IH-indazole; .6-diethyl- IH-benzointdazol-2-yI)- 1H-indazole; 2-(l1H-indazol-3 -yl)-l 1H-benzoimidazol-2-yl)- 1H-indazole; 3-(5 ,6-dimethyl- 1H-benzoimidazol-2-yl)-5-ethoxy- 1H-indazole; 3-[5-(2-morpholin-4-yI-ethoxy)- 1H-benzoimidazol-2-y1- IH-indazole; 3 -ethyl-6-methyl- 1 I--benzoimidazol-2-yl)- 1 3-(5,6-dimethyl- 1 3-(5,6-dimethyl- 1 H-benzoimidazol-2-yl)-4-fluioro-1H-indazole; 3-(5,6-dimethyl- 1H-benzoimridazol-2-yl)-5-chloro-1 H-inldazole; 3-(5-n-propyl-1 H-benzoimidazol-2-yl)- IH-indazolc; 241 H-indazol.-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide; 3-(5-methanesulfonyl-1TI-benzoimidazol-2-y)-1Iz-indazole; r2-(iiidazol-3-y1)-1H-ben-zoimidazol-5-y11-phenyl-methanol; [2-(indazo1-3-y1)- 1H-benzoimidazol-5-yl]-carboxylic acid; r2-(indazol-3-yl)- 1H-benzoimidazol-5-yl]-carboxylic acid, methylamide; [2-(indazol-3)-yl)- 1H-benzoimidazol-5-yl]-carboxylic acid, dimethylamidle; [2-(inidazol-3-yl)-l1H-benzoimidazol-5-yl]-carboxylic acid, isopropylamide; [2-(indazol-3-yl)-1H-bcnzoimidazol-5-yl]-carboxylic acid, benizylamide; [2-(inidazol-3-yl)- 1H-benzoimidazol-5-ylj-carboxylic acid, benzamide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethy1)-amide;- WO 031035065 PCT/GB02/04763 -224- 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-methyl-henzylamide; 1 H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [3-(2-oxo-pyrrolidin- 1-yl)-propyll-amide; 1H-indazol-3-yl)- lH-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl)-amide; 2-(11I--iidazol-3-yl)-IH-benzoimidazole-5-carboxylic acid (2-hydlroxy- 1,1 -dimethyl-ethyl)-amide; 1H-Tndazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3 -imidazoI-l -yl-propyl)-amide; 3-(5,6-dimethyl- 1 I--benzoimidazol-2-yl)-lH-indazole-5-carboxylic acid dimethylamide; [2-(indazol-3-yl)- 1H-benzoimidazol-5-yl]-carboxylic acid; 3-(5-ethyl-6-methyl-I--benzoirnidazol-2-yl)- 1 H-indazole-5-carboxylic acid amide dihydrochioride; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Par-icularly preferred compounds of formula (Ixb), denoted as the product of the combination of group Al in Table 1 and B I in Table 2, of the invention for the inhibition of SYK are:- 3-(1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted as A1-B63), Example 234(a); 3-(5-methoxy-lI--benzoimidazol-2-yl)- 1 indazole, (compound denoted as A6-B63), Example 234(b); 3 -(5,6-dimethyl- IH-benzoimidazol-2-yl)-l1H-indazole, (compound denoted as A9-B363), Example 234(f); 3-(5,6-dimietlhyl- 1H-benzoimidazol-2-yl)-5-methoxy- 1H-indazole, (compound denoted as A9-B68), Example 235(b); 3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)-5-fluoro- 1H-indazole, (compound denoted as A9-B70), Example 235(d); 3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)-6-fluoro- 1H-inidazole, (compound denoted as A9-B7 1), Example 235(e); 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl- 1H-indazole, (compound denoted as A9-B 64), Example 235(0); 3-(5,6-dimnethyl-1H-benzoimidazol-2-yl)-6-methoxy-l H-indazole, (compound denoted as A9-B69), Example 235(g); -ethyl- 1lH-benzoimidazol-2-yl)-1 H-indazole, (compound denoted as A27-B63), Example 235(i); 3-(5-ethyl-6-rnethyl -1 H-ben7oimidcazol-2-yl)-lH-indazole, (compound denoted as A55-B63), Example 235(j); 3-(5-isopro~pyl-6-methyl-l1H-benzoimidazol-2-yl)- IH-indazole, (compound denoted as A54-1363), Example 235(k); WO 031035065 PCT/GB02/04763 -225- 3-(5-bromo-6-methyl-IH-benzoiidazol-2-yl)- 1H-indazole, (compound denoted as A58-1363), Example 235(l); 1H-benzoimidazol-2-yl)- lH-indazole, (compound denoted as A32-1363), Example 23 3-(5-(3-cyano)phenyl- 1H-benzoimidazol-2-yl)-1 H-indazole, (compound denoted as A68-1363), Example 235(n); -(pyrid-3-yl)- 1H-benzoimidazol-2-yl)- IE-indazole, (compound denoted as A69-1363), Example 235(c); 3-(6-methyl-5-phenvl-1I benzoimidazol-2-yl)-1H-indazole, (compound denoted as A57-1363), Example 235(p); 3-(5 -phenyl- IH-benzoiinidazol-2-yl)- IH-iadazole, (compound denoted as A60-1363), Example 235(q); 3-(5-(2-fluoro)phenyl-1H-benzoimidazol-2-yl)- 1H-indazole, (compound denoted as A65-1363), Example 235(r); -meth-ylenedioxy)phenyl- IH-benzoimidazol-2-yl)-IH-indazole, (compound denoted as A66-1363), Example 235(s); 3-(5-benzyloxy- 1H-benzoimidazol-2-yl)- IH-indazole, (compound denoted as A74-B363), Example 235(w);- 3-(5,6-methylenedioxy-l H-benzoimidazol-2-yl)-l H-indazole, (compound denoted as A22-1363), Example 235(x); 3-(5,6-dimethoxy-I1 -benzoimidazol-2-yl)- 11--inidazole, (compound denoted as A23-B63), Example 235(y); 3 -(5,6-diethyl- IH-benzoimidazol-2-yl)- 1H-indazole, (compound denoted as AS 6-B63), Example 235(z); 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carbonitrile, (compound denoted as A33-B363), Example 235(ab); 3-(5-methoxycarbonyl-l I--benzoimidazol-2-yl)-1H-indazole, (compound denoted as A35-1363), Example 235(ac); 3-(5,6-dim-iethyl-1Ii1-benzoimidazol-2-yl)-5-ethoxy-lH-indazole, (compound denoted as A9-1363), (compound denoted as A9-112), Example 235(ad); 3-[5-(2-morpholin-4-yl-ethoxy)- 1H-benzoimidazol-2-y11-1H-indazole, Example 235 (aj); 3-(5-ethyl-6-methytl 1I--henzoimidazol-2-yl)- 1H-indazole-5-carbonitrile, Example 235(an); 3-(5,6-dimethyl-I1-benzoimidazol-2-yl)-IH-indazole-5-caboflitrile, Example 235(ar); 3-(5,6-dimethyl- lH-benzoimidazol-2-yl)-4-fiuoro-1 H-indazole, (compound denoted as A9-13 110), Example 242(a);- 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-chloro-1H-indazole, (compound denoted as A9-13 109), Example 242(c); WO 031035065 PCT/GB02/04763 -226- 3-(5-n-propyl-I--benzoimidazol-.2"-yl)-l1H-indazole, (compound denoted as A28-B63), Example 244(a); 2-.(IH-indazol-3-yl)- IH-benzoimidazole-5-sulfonic acid benzylamide, Exarnple244(b);I lH-benzoimidazol-2-yl)- 1H-indazole; Example 244(c) [2-(indazol-3-yl)- 1H-benzoimidazol-5-yl]-phenyl-methanol, (compound denoted as A34-1363), Example 245; [2-(indazol-3-yl)- IH-benzoimidazol-5-yl]-carboxylic acid, ethylamide, (compound denoted as A36-B63), Example 246(a); [2-(indazol-3-yl)- 1H-benzoimidazol-5-yl]-carboxylic acid, methylamide, (compound denoted as A15-B63), Example 246(b); [2-(indazol-3'-yl)- 1 H-benzoimnidazol-5-yl]-carboxylic acid, isopropylamide, (compound denoted as A16-B63), Example 246(d); [2-(indazol-3-yl)- I H-benzoimidazol-5-yl]-carboxylic acid, beazylamide, (compound denoted as A17-B63), Example 246(e); [2-(indazol-3-yl)-lH-benzoimidazol-5-yl]-carboxylic acid, benzamide, (compound denoted as A52-B63), Example 246(f); 2-(tIH-indazol-3D-yl)- lH-benzoimidazole-5-carboxylic acid (pyridin-3 -ylmethyl)-amide, Example 246(m); 2 H-indazol-3-yl)- lH-benzoimidazole-5-carboxylic acid 3-meothyl-beuzylamide, Example 246(n); 2-(lH-indazol-3-ylD-lH-benzoimidazole-5-carboxylic acid 4-methyl-benzylamide, Example 246(o); 2-(l1H-indazol-3-yl)-lH-benzoimidazole-5-carboxylic acid f3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide, Example 246(p); 2-(1H-indazol-3-yl)- lH-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide, Example 246(q); 2-(1H-indlazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-arnide, Example 246(r); 2-(lH-inidazol-3-yl)- 1H-belizoimidazole-5-carboxylic acid (2-cyano-ethyl)-amide, Example 246(s); 2-(1H-indazol-3-yl)- lH-benzoimidazole-5-carboxylic acid (2-h-ydroxy-1, 1-dimethyl-ethyl)-amide, Example 246(t); 2-(1H-Jndazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (3-imidazol- 1-yl-propyl)-amnide, Example 246(u), 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)- 1H-indazole-5-carboxylic acid dimethylamide, Example 24 6(x); [2-(indazol-3-yl)-1 H-benzoimidazol-5-yl]-carboxylic acid, (compound denoted as A14-1363), Example 247(a); 3-(5-ethyl-6-mcthyl- 1H-benzoimidazol-2-yl)- 1H-indazole-5-carboxylic acid amide dihydrochioride, Example 262; WO 03/035065 PCT/GB02/04763 -227and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Especially preferred compounds of formula (Ixb) of the invention for the inhibition of SYK are:- 3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)-5-methoxy- 1H-indazole, (compound denoted as A9-B68), Example 235(b); 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted as A55-B63), Example 235(j); 3-(5,6-diethyl-1 H-benzoimidazol-2-yl)-I1H-indazole, (compound denoted as A56-B63), Example 235(z); 3-(5,6-dimethyl- IH-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid dimethylamide, Example 246(x); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixc) of the invention for the inhibition of SYK are:- 3-(5,6-dimiethyl- 1H-benzoimidazol-2-y)-4,5,6,7-tetrahydro- H-indazole; 5,6-dimethyl-2-(1,4,5,6-tetrahydro-cyclopentapyrazol- 3 1H-benzoimidazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,5,6,7,8-hexahydro-cycloheptapyrazole; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of formula (Ixc), denoted as the product of the combination of group Al in Table I and Bl in Table 2, of the invention for the inhibition of SYK are:- 3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro- H-indazole, (compound denoted as A9-B59), Example 241(a); 5,6-dimethyl-2-(1,4,5,6-tetrahydro-cyclopentapyrazol- 3 -yl)-1H-benzoimidazole, (compound denoted as A9-B56), Example 241(d); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixd) of the invention for the inhibition of SYK are:- 3-(5,6-dimethyl-H-benzoimidazol-2-yl)- 1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; cyclopropyl-[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]methanone; WO 031035065 PCT/GB02/04763 -228isopropyl-L3-(5,6-dimethyl- IH-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]methanone; 1 -[3-(5,6-dimethyl- 1H-benzoimnidazo1-2-y)- 1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin- 5 -yll -ethanone; 1 -[3-(5,6-dirnethyl- IHJ-benzoimidazol-2-y)-1 ,4,6,'7-tetrahydro-pyrazolo[4,3-c~pyridin-5-yl]-2-methyIpropan-1-one; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-pyridine-5-Carboxylic acid methyl ester; 3-(5,6-dimethyl- 1H-benzoimidazol-2-yU- 1 ,4,6,'1-tetrahydro-pyrazoo[4,3-cpyridile-5-carboxylic acid dimethylarnide; 1 -[3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]Fyridin-5-yl]-3-methylbutan- 1-one; 1 -[3-(5,6-dirnethyl-1H-benzoimnidazol-2-yl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-clpyridifl-5-yl]-2, 2 dimethyl-propan-I -one; ,6-dimethyl-l1H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester; 3-(5,6-dimethyl-1H-benzoimidazol-2-yD- 1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1IB-benzoirnidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; ['3-(5,6-dimethyl- IH-benzoimida7zol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridil-5-y]-pyr-Tolidifl-lyl-methanone; ,6-dimethiyl-l H-benzoimidazol-2-yl)-1I,4,6,7-tetrahydro-pyrazolo4,3-c]pyridil-5-y]-piperidilyl-methanone; 13-(5,6-dimethyl-l1H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-morpholifl- 4 yl-methanone; 3 -(5-chloro-6-methyl-l1T1benzoimidazo1-2-y)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridile- 5 -carboxyliC acid diethylamide; 3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-y]-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine- 5 carboxylic acid diethylarnide; 3-(5-trifluoromethyl- 1H-benzoimidazol-2-yl)-1 ,4,6,'1-tetrahydro-pyrazolo[4,3-c]pyriine-5-carboxylic acid diethylarnide; 1 -[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-1 ,4,6,7-tetr-ahydro-pyrazolo[4,3-c]pyridin-5-yl] -2,2dimethyl-propan- 1 -one; 3-(5,6-dirnethiyl-1 H-benzoimidazol-2-y)-5-(propane-2-sulfonyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3c]pyridine; 3-(5,6-dimethyl-1H-benzoiniidazol-2-yl)-1 ,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole; WO 031035065 PCT/GB02/04763 -229and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Particularly prefer-red compounds of formula (Ixd), denoted as the product of the combination of group Al1 ini Table 1 and B I in Table 2, of the invention for the inhibition of SYK are:- 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide, (compound denoted as A9-B 12 Example 250(a); cyclopropyt-[ 3 -(5,6-dirnethiyl- 1ll-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-clpyridin-5-yl] methanone, (compound denoted as A9-13 122); isopropyl-F3-(5,6-dimethyl- lH-benzoimidazol-2-yl)-l ,4,6,7-tetrallydro-pyrazolo[4,3-c]pyridin-5-yl]methanone; 1 -[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yll-2,2dimethyl-prop an-i -one; 3-(5,6-dimethyl- lH-benzoimidazol-2-yl)-1I,4,6,7-tetrahydro-pyrazolo[4,3-c~pyridine-5-carboxylic acid methyl ester; ,6-dimethyl- lH-benzoimidazol-2-ylU-1I,4,6,'7-tetrahydro-pyrazolo[j4,3-cpyridine-5-carboxylic acid isopropylamide; 26(e) prepared 3-(5,6-dimethyl- 1H-benzoimuidazol-2-yl)-1I,4,6,7-tetralhydro-pyrazolo[4,3-c]pyridine-5carboxylic acid diethylamide; [3-(5,6-dimethyl-IH-benzoimidazol-2-yl)- 1,4,6, 7-tetrahaydro-pyrazolo[4,3-c]pyridin-5-yl] -pyrrolidin- 1yl-mathanone; jj3-(5,6-dimethyl-1H-benz~oirnidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-clpyridin-5-yl] -piperidin-1 yl-methanone; [3 -(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3I-c]pyridin-S-yl]-morpholin-4yl-methanone; 3-(5-chloro-6-methyl-l-benzoimidazol-2-yl)- 1,4,6,7-tctrahydro-pyrazolo[4,3-c]pyridiae-5-carboxylic acid diethylamide; 3-[5-(2-morpholin-4-yl-ethoxy)- 1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5carboxylic acid diethylamide; 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-l ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; 3-(5,6-dimethyl- 1H-benzoirnidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c~pyridine-5-carboxylic acid dimethylamide, (compound denoted as A9-B3 119); 1 -[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-cpyridil-5-yl -2-methylpropan- I-one, (compound denoted as A9-B 117); WO 031035065 PCT/GB02/04763 -230- 3-(5,6-dimethyl-l H-benzoimidazol-2-yl)- acid methyl ester, (compound denoted as A9-B120); 1-[3-(5,6-dimethyl- IH-benzoimidazol-2-yl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3-methylbutan-l-one, (compound denoted as A9-BI 18); 1-[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2, 2 dimethyl-propan- 1-one, (compound denoted as A9-B123); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Especially preferred compounds of formula (Ixd), denoted as the product of the combination of group Al in Table 1 and BI in Table 2, of the invention for the inhibition of SYK are:- 3 -(5,6-dimethyl-I H-benzoimidazol-2-yl)-I,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide, (compound denoted as A9-B121), Example 250(a); cyclopropyl-[3-(5,6-dimethyl-1H-henzoimidazol-2-yl)-1 4,6,7-tetrahydro-pyrazolo[4,3-cjpyridin-5-yl]metbanone, (compound denoted as A9-B 122); Example 250(b); 3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-clpyridine-5-carboxylic acid isopropylamide, Example 255(e); prepared 3-(5,6-dimethyl- 1 -benzoimidazol-2-yl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5carboxylic acid diethylamide, Example 258(i); f3-(5,6-dimethyl-1H-benzoimidazol-2-yI)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-pyrrolidin-lyl-methanone, Example 2580); [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-clpyridin-5-yl]-piperidin-1yl-methanone, Example 258(k); 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)- I ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide, Example 258(m); 3-(5.6-dimcthyl-1H-benzoimidazol-2j1)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid dimethylamide, (compound denoted as A9-B 119); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Particular compounds of formula (Ix) of the invention for the inhibition of KDR are:- 2-(1H-indazol-3-yl)-1H-benzimi dazole-5-cahoxylic acid benzylamide; 2-(1H-indazol-3-yl)-1-benzimidazole-5-carboxylic acid N-methylamide; 2-(1 1-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide; 2-(1H-indazoi-3-yl)-1H-benzimidazole-5-carboxylic acid N-isopropylamide; 2-(IH-indazol-3-yl)-lH-benzimidazole-5-carboxylic acid N-phenylamide; WO 031035065 PCT/GB02/04763 -231- 2-(1 H-indazol-3-yl)- 1H-benzimidazolc-5-carboxylic acid N-phenethylamide; 2-(l1H-indazol-3-yl)-1IH-benzimidazole-5-carboxylic acid N-morpholinoamfide; 2-(lI H-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-(N'-methylpiperazino)amide;, 2-(1 H-indazol-3I-yl)-1H-benzirnidazole-5-carboxylic acid N-pyrrolidinoamidc; 2-(1 H-indazol-3-yl)- 1I-I-benzimidazole-5-carboxylic acid N-(isobutyl)amide; 1H-indazol-3-yl)- H-benzimidazole-5-carboxylic acid N-(cyclohexylmethyl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(2-furfuryl)aniide; 2-(1 H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide; methyl 2-(1H-indazol-3-yl)-3H-bcnizimidazole-5- carboxylate; 5,6-dimethyt-2-( 1H-indazol-3-yl)- 1H-benzimidazole; 5-methoxy-2-( 1H-indazol-3-yl)-IH-benzimidazole; 2-(1H-indazol-3 -yl)-3H-benzimidazole-4-carboxylic acid; 2-(1H-indazol-3-yI)-3H-benzimidazole; 2-(5-ethoxy-2H-pyrazol-3-yl)- 1H-benzimidazole-4-carboxylic acid; 5,6-dimethyl-2-(5-methyl-2H-pyrazol-3-yl)- 1H-benzirnidazole; 5,6-dimetbyl-2-(5-thlophen-2-yl-2H-pyrazol-3-yl)- 1H-benzimidazole; 2-(4-bromo-2H-pyrazol-3-yl)-5,6-dimethyl-H-benzimidazole; 2-(5-ethyl-2H-pyrazol-3-yl)-5,6-dimethyl- 1H-benzimidazole;, 2-(5-ethyl-2H-pyrazol-3 -yl)-4,5-ethylenedioxy- IH-benzim-idazole; 2-(5-ethy1-2H-pyrazol-3-yl)-5-meth-oxy- IH-benzimidazole; 2-(5-ethyl-2H-pyrazol-3 -yl)-4-hydroxy-1 H-b enzimidazote 2-(5-ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzinidazole; 1H-inidazol-3-yl)- 1H-benzoirridazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (3-ethoxy-propyl)-amide; 2-(1H-indazol-3-yl)- 1H-benzoim-idazole-5-carboxylic acid 4-bromo-benzylamide; 1H-indazol-3-yl)- 1H-benzoimiidazole-5-carboxylic acid 4-methancsulfonyl-benzylainide; 2-(1H-indazol-3-yl)-1 H-bcnzoimidazole-5-carboxylic acid (naphthalen- 1-ylmethyl)-amide; JH-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-trifluoromethyl-benzylamide; 2-(1H-indazol-3-yl)-l1H-benzoimidazole-5-carboxylic acid (thiophen-2-ylmethyl)-amide; 1H-inda7,oI-3-yl)-l1H-benzoimidazole-5-carboxylic acid 4-dimethylamino-benzylamide; 2-(l H-nao- 1y) Hbnomdzl--abnl aioI-ehl-ieiie -carboxylic acid tert-butyl ester; IH-indazol-3-yl)- 1H-benzoiiriidazole-5-carboxylic acid 4-nitro-benzylaniide; 2-(l1H-indazol-3-yl)- 1H-benzoimuidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 3-bromo-benzylamide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methoxy-beuzylamide; WO 031035065 PCT/GB02/04763 -232- 2-(1H-indazol-3-y1)-l1H-benzoimidazole-5-carboxylic acid (benzo[ 1,3] 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (benzo[b]thiophen-3 -ylmethyl)-amide; 1H-indazol-3 -yl)-l H-benzoimidazole-5-carboxylic acid (1,3-dimethyl-1 H-pyrazol-4-ylrnethyl)amide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 2-trifluoromethoxy-benzylamide; 2-(l1H-indazol-3-yl)-l1H-benzoimidazole-5-carboxylic acid 2-methyl-benzylamide; 1H-indazol-3-yl)- 1H-beiizoirnidazole-5-carboxylic acid (3-methyl-thiophen-2-ylmethyl)-amide; 1I-I-indazol-3 -yl)-l H-benzoimidazole-5-carboxylic acid 2-trifluoromethyl-benzylamide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 4-phenoxy-benzylamide; 1H-inidazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 3-trifluoromethoxy-beinzylarnide; 1H-indazol-3-yl)- 1H-benzoirnidazole-5-carboxylic acid (3-isopropoxy-propyl)-amide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (1 -methyl-1H-pyrazol-4-ylmethyl)-amide; 1H-indazol-3-y1)- IH-benzoimidazole-5-carboxylic acid 4-isopropyl-benzylamide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2,5-dimethyl-furan-3-ylmethyl)-amide; 2-(l1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (benzo[b]thiophen-2-ylmethyl)-amide; 2-(l1H-indazol-3-y1)- IH-benzoimidazole-5-carboxylic acid [3-(3-acetylamino-phenoxy)-propyl]-amide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl)-arnide; 1H-indazol-3-yl)- lI-I-benzoli-ndazole-5-carboxylic acid ([2,2']bithiophenyl-5-ylmethyl)-amide; 2-(tIH-indazol-3-yl)-l1H-benzoimidazole-5-carboxylic acid (2,3-dihiydro-benzofuran-5-ylmethyl)amide; 2-(1I-indazol-3-yl)- IH-benzoimidazole-5-carboxylic acid 4-cyalio-benzylamide; 2-(11I--indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (5-chloro-benzo[b]thiophen-3-ylmethyl)amide; 1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid 3-trifluorornetliyl-benzylamide; 1H-indazol-3-yI)- 1H-benzOirnidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (benzo[blthiophen-3-ylmethyl)-amide; 1H-indazol-3-yI)-1H-benzoirnlidazole-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide; 1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benlzo[ 1,4]dioxin-2-ylmethyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimfidazole-5-carboxylic acid (fiiran-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoiniidazole-5-carboxylic acid 2-nitro-benzylamide; 1H-indazol-3-yl)-1H-benzoimidazole-5-caqrbnxylic acid (thiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-(1H-indazol-3-yl)- IH-benzoimidazolc-5-carboxylic acid (1 -methyl-TH-benzoimidazol-2-ylmethyl)amide-, 2-(1H-indazol-3-yl)-1H-benzoimnidazole-5-carboxylic acid 3-methyl-benzylamide; WO 031035065 PCT/GB02/04763 -233- 1H-indazol-3 -yl)-l H-benzoimidazole-5-carboxylic acid 3-chioro-benzylamide; 1 T-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 4-sulfainoyl-benzylarnide,; 1H-indazol-3-yl)-3H-benzoirnidazole-4-carbo xylic acid (3-ethoxy-propyl)-arnide; 1H-indazol-3 -yl)-3H-benzoimidazole-4-carboxylic acid 4-bromo-benzylamide; 1H-indazol-3-yl)-3 H-benzoimidazole-4-carboxylic acid (liaphthalen- 1-ylmethyl)-amide; 2-(l1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (thiophen-2-ylmethyl)-amide; 2-(l1 H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 4-dimethylamino-benzylamide; 1H-indazol-3-yl)-3H-bcnzoimidazole-4-carboxylic acid 4-nitro-benzylamide; 1H-indazol-3-yl)-3 H-benzoimidazole-4-carboxylic acid (pyridin-3 -vlmethyl)-amide; 2-(l1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-bromo-benzylamide; IH-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-methoxy-benzylamide; IH-indazol-3-yl)-3 H-benzoimidazole-4-carboxylic acid (benzofblthiophen-3-ylmethyl)-amide; 2-(l1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 4-phenoxy-benzylamide; 1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-trifluorornethoxy-belizylamide; 1H--indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide; 1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (2,3-dihydro-benzofuran-5 -ylmethyl)amide; 2-(I-I-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-trifluoromethyl-benzylamide; 1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (furan-3 -ylnethyl)-amnide;- IH-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-nitro-benzylamide; 1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-chloro-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carbcoxylic acid phenylamide; 1H-indazol-3-yl)-3H--benzoimidazole-4-carboxylic acid benzylamide; 2-(1H-indazol-3 -yl)-3H-benzoimidazole-4-carboxylic acid phenethyl-amide; 3-(6-phenyl- 1H-benzoimidazol-2-yl)-2H--indazole; 3-[6-(2,4-dichloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-(6-naphthalen-1 -yl- 1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(4-fluoro-phenyl)- 1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-chloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-methoxy-phenyl)- 1H-henz7Oimidazol-2-yl] -211-indazole; 3-[6-(3D-chloro-4-fluoro-phenyl)-1H-benzoimidazol-2-y]-2H-indazole; 3-[6-(3,5-dichloro-phenyl)- 1H-benzoimidazol-2-yl]-2H-indazole; 3-(6-thianthren- l-yl- 1H-benzoimidazol-2-yl)-21--indazole; 3-(6-biphenyl-4-yl-lH-benzoiiidazol-2-yl)-2H-indazol; WO 031035065 WO 03/35065PCT/GB02104763 -234- 3 -(6-p-tolyt- 1 H-benzoimidazol-2-yl)-2H-indazole; 3-(6-m-tolyl- 1 H-benzoimidazol-2-yl)-2H-indazole; 3 -(6-o-tolyl-1 I-benzoimidazol-2-yl)-2H-indazole; 3-(6-thiophen-3-yl- 1 H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(3-trifiuoromethyl-phenyl)- 1H-henzoimidazol-2-yl]-2H-indazole; 3-[6-(4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl] -2H-indazole; 3-[6-(3-chloro-phenyl)- 1H-benzoimidazol-2-yl] -211-indazole; -methoxy-phenyl)- 1 H-benzoimnidazol-2-yl]-2H-indazole; 3 -f6-(3 ,5-dimethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazote; 3-[6-(3,4-dimnethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-i-ndazole; 3 -(6-benzo[ 1,3] dioxol-5 -yl-1IH-benzoimnidazol-2-yl)-2H-indazole; 3-f 6-(4-tert-butyl-phenyl)- IH-benzoimidazol-2-yl]-2H-indazole; 3-(6-hex- 1 -enyl- 1 H-benzoimidazol-2-yl)-2H-indazole; ,4-dimethoxy-pheniyl)-l1H-benzoim-idazol-2-yl]-2--indazole; 31-f2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl] -phenol; 4-f 2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl] -phenol; 3-16-(3,4-dichloro-phenyl)-l1H-benzoimiidazol-2-yl] -2H-indazole; 3 -[6-(4-trifiuoromethoxy-phenyl)- 1H-benzoimidazol-2-ylJ -2H1-indazole; 1- {4-[2-(2H-indazol-3-yl)-3H-benzoirnicazol-5-yll-phenyl} -ethanone; 3-(6-benzo[b]thiophen-2-yl- 1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(3,4,5-trimethoxy-phenyl)- 1 H-benizoimidazol-2-yl]-2H-indazole; 1 t{5-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-thiophen-2-yl} -ethanone; 1- -3-r2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl} -ethanone; 3-[6-(4-henzyloxy-phenyl)- 1H-benzoimnicazol-2-yl]-2H-inldazole; 3-[6-(2-fluoro-biphenyl-4-yl)- 1H-benzoimidazol-2-yl]-2H-indazole; 34(6-benzo[b]thiophen-3-yl- lH-benzoimidazol-2-yl)-2H-indazole; {3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl} -methanol; 3-[6-(4-etlhylsutfanyl-phen-yl)-1H-henzoimidazol-2-yl-21-indazole; 3-[6-(2,4-difiuoro-phenyl)- 1H-benzoimidazol-2-yl] -2H-indazole; 3-[6-(3-trifluoromethoxy-phenyl)- 1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-fluoro-2-methyl-phenyl)-1H-henzoimidazol-2-yl -2H-indazole; 3-{6-[2-(4-fluom--plienyl)-vinyl]-1 HT-benizoimidazol-2-yl} -2H-indazole; 3-{6-[2-(4-ehloro-phenyl)-vinytj- 1H-benzoimidazol-2-yl} -2H-indazole; 3- {4-[242H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl} -propionic acid; {4-[2-(2H-indazol-3-yl)-311-henzoimidazol-5-yl]-pheny.} -methanol; 3-(6-furan-2-yl-1H-benzoimnidazol-2-yl)-2H-indazole; WO 031035065 PCT/GB02/04763 -235- 3-[6-(3-benzyloxy-phenyl)- 1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-isopropyl-phenyl)- IH-benzoimidlazol-2-yl]-2H-indazole; 3-[6-(4-r-nethanesulfonyl-phenyl)- 1H-benzoimidazol-2-yl]-2H-indazole; 1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (tetrahydro-pyran-4-ylrnethyl)-amide;, 1H-indazol-3-yD-1H-benzoimidazole-5-carboxylic acid 4-acetylamino-benzylamide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methylamide; 1H-indazol-3-yI)- 1H-benzoimidazole-5-carboxylic acid isopropylamide; 1H-indazol-3-yl)-1 H-benzoimidazo1-5-y1]-morpholin-4-y1-methanone; 1H-indazol-3-yl)- 1 1-benzoimidazol-5-yl]-(4-methyl-piperazin-1 -yl)-methanone; 1H-indazol-3-yl)- 1H-benzoirnidazole-5-carboxylic acid benzyl-miethyl-amide; 1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid 3-nitro-beazylamide; 1H-indazol-3-yI)-1 H-benzoimidazole-5-carboxylic acid 2-fluoro-benzylamide; 1H-indazol-3-yl)- 1H-benzoirfidazole-5-carboxylic acid 2,4-difluoro-beazylamide;- 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,6-difluoro-benzylamide; 1H-indazol-3-y1)- 1 F-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2-(1H-indazol-3 -yl)-lI H-benzoimidazole-S-carboxylic acid 4-chloro-2-fiuoro-benzylamide; 2-(1H-indazol-3-yI)-1 H-benzoimidazole-5-carboxylic acid 4-brorno-2-fluoro-benzylarnide; 2-.(I--indazol-3-yl)- 1H-benzoimcidazole-5-carboxylic acid 3,4-difluoro-benzylamide; 2-(1H-indazol-3 -yl)-l H-benzoimidazole-5-carboxylic acid 3,4,5-trifluoro-benzylamide; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (4'-chloro-bipleniy1-4-ylimethiy1)-amide; 2-(IH-indazol-3 -yl)-I H-benzoimidazole-5-carboxylic acid (3',5 t -dichloro-biphenyl-4-ylmethyl)-amide; 2-(1H-indazol-3-yt)- IH-benzoimidazole-5-carboxylic acid (4'-fluoro-biphenyl-4-ylmethyl)-amide; 1H-indazol-3J-yl)-l1H-benzoimidazole-5-carboxylic acid 2-fluoro-benzylamide; 2-(1H-indazol-3'-yl)- 1H-benzoirmidazole-5-carboxylic acid 2,6-difluoro-3-methyl-benzylaniide; 2-(1H-indazol-3-yl)-l1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2-(1H-indazol-3-yl)- 1H-benzoirnidazole-5-carboxylic acid 4-chloro-benzylamide; 2-(1H-indazol-3-yl)- Ill-benzoimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 4-fluoro-benizylamide; 1H-indazol-3-yl)- 1H-benzoimidazolc-5-carboxylic acid (2'-chloro-biphenyl-4-ylmethyl)-am-ide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (6-trifluoromethyl-pyridin-3-ylmethyl)arnide; 1H-indazol-3-yl)-1H-benzoimida7Ole-5-carlboxylic acid (5-pyridin-2-yl-thiophea-2-ylmcthyl)amide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl)-amide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carbonyl]-piperazine-l1-carboxylic acid tert-butyl ester; 2-(1 H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl)arnide; WO 031035065 PCT/GB02/04763 -236- 2-(1 H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2,4-dichloro--fluoro-benzy1)amide; 1H-indazol-3 1H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl)amide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2-fluoro-4-chloro-6-mnethyl-beinzyl)amlide; 1H-iindazol-3-yl)- IH-benzoirnidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmcthyl)-amide; 2-15-(bnzyloxy)-2H-pyrazol-3I-yl]- 1H-benzoimidazole; 2-[5-(3-phenyl-allyloxy)2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(2-methyl-allyloxy)2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3,7-dimnethyl-octa-2,6-dienyloxy)-2H-pyrazol-3-yl]-I--benzoimidazole; 2-[5-(3-bromo-benzyloxy)-2H-pyrazo-3-y]-1H-benzoimidazole; 1H-benizoimidazol-2-yl)-1 H-pyrazol-3-yloxymethyl]-benzonitrile; 2-[5-(4-trifluoromethyl-benzyloxy)-2H-pyrazol-3-yl]- 1H-benzoimidazole; 2-[5-(3,4-dichloro-benzyloxy)-2H-pyrazol-3-yl]- 1H-benzoimidazole;, 2-[5-pentafluorophenylmethoxy)-2H-pyrazol-3-yl-H-benzoinidazole; 2-[5-(4-ter-t-butyl-benzyloxy)-2H-pyfrazol-3-yl]- 1H-benzoimidazole; 2-[5-(2-benzenesiilfonylmethyl-bezyloxy)-2H-pyrazol-3-yl-i-benzoimidazole; 4-[5-(1H-benzoimidazol-2-y1)- IH-pyrazol-3-yloxymethyl]-benzonitrile; 2-r5-(biphenyl-4-ylmethoxy)-2H-pyrazol-3-y]- IH-bcnzoirnidazolc; 2,3-dlichioro-benzenesulfonic acid 1 H-beinzoimiidazol-2-yl)-1H-pyrazol-3-y ester; 2-[5-(2-rnorpholin-4-yl-ethoxy)-2H-pyrazol-3-yl]- 1H-benzoinaidazole; 2-[5-(2-piperidin-1I-yl-ethoxy)-2H-pyrazol-3-yll- 1H-benzoimidazole; 2-[5-(3-methoxy-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoinidazole; 2-[5-(1H-benzoimidazol-2-yl)- 1H-pyrazol-3-yloxy]-1 -p-tolyl-ethanone; 1-[5-(1H-benzoimidazol-2-yl)- 1H-pyrazol-3-yloxy]-3,3,4,4,4-pentafluoro-butan-2-one; 2-r5-(1H-benoimidazo-2-y)-1H-pyrazo1-3-yloxy]- 1-biphenyl-4-yl-ethanone; 1 -[5-(1H-benzoimiclazol-2-yl)-ilH-pyrazol-3-yloxy]-butan-2-one; 1H-benizoimidazol-2-yl)- 1 1-pyrazol-3-yloxyj- 1-(4-dimcthiylamino-phenyl)-cthanonc; 2-[5-(1H-benzoimidazol-2-yl)- IH-pyrazol-3-yloxyi- 1-(3-phenyl-isoxazol-5-yl)-ethanone;, 1H-benzoimidazol-2-yl)-1H-pyrazol-3-ylo~xy]-N-phenyl-acetamide; 1H-benzoimidazol-2-yl)-1 H-pyrazol-3-ylcoxy]-3,3-dimethyl-butan-2-one; 1 -adamantan-1-yI-2-[5-(1H-benzoiicazol-2-yl)-IH-pyrazol-3-yloxyl-ethanone; 2-[5-(1H-benzoimidazol-2-yl)- 1H-pyrazol-3-yloxy]-1 -naphthalen-2-yl-ethanone; 4- {2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-acetyl} -benzonitrile; 6-12[ I-eziidzl2y)-Hprzl3yoy-ctl-34dhdoI-unln2oe 2-[5-(1H-benzoirmidazol-2-yl)-1H-pyrazol-3-yloxy-1-(4-trifluoromethoxy-phenyl)-ethanone; 5- {2-[5-(1H-benzoirmidazol-2-yl)-1H-pyrazol-3-yloxyl-acetyl} -2-chloro-1benzeesulfonainide; 2-[5-(1H-betizoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1 -(4-methoxy-phenyl)-ethanone; WO 031035065 PCT/GB02/04763 -237- IH-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]- 1 -cyolopropyl-ethanone; isonicotinic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; 2,2-dimethyl-propionic acid 5-(IH-benzoimnidazol-2-yl)- 1H-pyrazol-3-yl ester;, benzyloxy-acetic acid 1H-benzoimi'dazol-2-yl)-1H-pyrazol-3-yl ester; benzoic acid 5-(lH-benzoiinidazol-2-yl)-1H-pyrazol-3-yl ester; 4-methoxy-benzoic acid IH-benzoimidazol-2-yI)-1H-pyrazol-3-yl ester; phenyl-acetic acid 5-(1H-benzoimidazol-2-y[)-1H-pyrazol-3-yl ester; 2,3,4,5,6-Pentafluoro-benzoic acid lH-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; cyclopropanecarboxylic acid 5-(lH--benzoinilidazol-2-yl)- 1H-pyrazol-3-yl ester; 2,2,3,3,4,4,4-heptafluoro-butyric acid 5-(1H-benzoimidazol-2-yl)-IH-pyrazol-3-yl ester;, cyclopentanecarboxylic acid 5-(1H-benzoiniidazol-2-yl)-1H-pyrazol-3-yl ester; 3-phenyl-propionic acid 5-(1I--benzoimidazol-2-yD)-1H-pyrazol-3-yl ester; biphenyl-4-carboxylic acid 5-(1H-benzoimiidazol-2-yl)-lH-pyrazot-3 -yl ester; acid 5-(1H-benzoimidazol-2-yl)-lH-pyrazol-3-yl ester; 4-trifluoromethyl-benzoic acid 5-(tIH-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; thiophene-2-carboxylic acid 1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

201 Preferred compounds of formula (Ixa), denoted as the product of the combination of group Al in Table 1 and Bi1 in Table 2, of the invention for the inhibition of KDR are:- 2-(5-ethyl-2H-pyrazol-3-yl>-5,6-dimethyl- 1I--benzimidazole, (compound denoted as A9-133); 2-(5-methyl-2H-pyrazol-3 -yl)-5,6-dimethyl-1 H-benzimidazole (compound denoted as A9-B2); and the corresponding N-oxides, and their prodrugs; and pharmaceutically accepflable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Lxb), denoted as the product of the combination of group Al in Table I and B 1 in Table 2, of the invention for the inhibition of KDR are: 2-(l1H-indazol-3-yl)- 1H-benzimiidazole-5-carhoxylic acid benzylamide, (compound denoted as A17-1363); 1H-indazol-3 1H-benziniidazole-5-carboxylic acid N-methylamide, (compound denoted as Al 5-B63); 1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide, (compound denoted as A36-B63); 2-(1H-indazol-3-yl)-lH-benzimidazole-5-carboxylic acid N-isopropylamide, (compound denoted as A37-B63); WO 031035065 PCT/GB02/04763 -238- 1H-indazol-3-yl)- IH-benzim-iidazole-5-carboxylic acid N-phenylamide, (compound denoted as A52-B63);- 2-(l1H-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-phenethylamide, (compound denoted as A51-B63); 1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-morpholinoamide, (compound denoted as A92-B 63); 1H-indazol-3-yl)-1H-benzimnidazole-5-carboxylic acid N-(N'-methylpiperazino)amide, (compound denoted as A93-B63); 1H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide, (compound denoted as A91-B63); 1H-indazol-3-yl)- 1H-benzimidazole-5 -carboxylic acid N-(isobutyl)amide, (compound denoted as A82-B 63); 1H-indazol-3-yl)- 1H-benzimidazole-5 -carboxylic acid N-(cyclohexylmethyl)amide, (compound denoted as A83-B63); 2-(IH-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-(2-furfuryl)amide, (compound denoted as A84-B63); 2-(1H-indazol-3-yl)- 1H-benzimidazole-5 -carboxylic acid N-benzyl-N-methylamide, (comnpound denoted as A90-B63);l 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 2,4-dichioro-benzylamnide; 1H-indazol-3-yl)-IH-benzoimidazole-5-carboxylic acid (3-ethoxy-propyl)-amide;, IH-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-benzylamide; IH-indazol-3 1H-benzoimidazole-5-carboxylic acid 4-methanesulfonyl-benzylamide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (naphthalen- 1-ylmethyl)-amide; 1H-indazol-3-yl)-IH-benzoimidazole-5-carboxylic acid 4-trifltioromethyl-benzylamide; 1H-indazol-3-yI)-1H-benzoimidazole-5-carboxylic acid (thiophen-2-ylmethyl)-amide; 1H-indazol-3-yl)-1 I--benzoimidazotc-5-carboxylic acid 4-dimethylamino-benzylamide; 1H-indazol-3-yl)- IH-benzoimidazole-5-carbonyl]-amino} -methyl)-piperidine-l1-carboxylic acid tert-butyl ester; 2-(1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid 4-nitro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridiin-3-ylmethyl)-amide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 3-bromo-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methoxy-benzylacide; 1H-indazol-3-yl)-1 H-benzoimnidazole-5-carboxylic acid (benzo[ 1,3]dioxol-5-ylmethyl)-amide; 1H-indazol-3 1H-benzoimidazole-5-carboxylic acid (benzo[blthiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (1 ,3-dimethlyl-1H-pyrazol-4-ylmethyl)amide; WO 031035065 PCT/GB02/04763 -239- IH-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid 2-trifiuoromethoxy-benzylamide; 2-(l1H-indazol-3-yl)-l1H-benzoimidazole-5-carboxylic acid 2-methyl-benzylamide; 1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (3-methyl-thlophen-2-ylmethyl)-amide; IH-indazol-3-yl)- 1H-benzoimidazote-5-carboxylic acid 2-trifluoromethyl-benzylamide; 1H-indazol-3-ylD- 1 H-benzoimidazole-5-carboxylic acid 4-phenoxy-benzylamide; 2-(1 H-indazol-3 -yl)-l H-benzoimidazole-5-carboxylic acid 3-trifluoromethoxy-benzylamide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-isopropoxy-propyl)-amnide; 2-(I--indazol-3-yI)-1 H-benzoimidazole-5-carboxylic acid (1-methyl-I H-pyrazol-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-isopropyl-benzylamide; 1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (2,5-dim-ethyl-furan-3-ylmethyl)-amide; 1H-indazol-3-y])-1 H-benzoirnidazole-5-carboxylic acid (benzo[b]thiophen-2-ylmethyl)-amide; 1H-indazol-3-yl)- 1H-benzoimaidazole-5-carboxylic acid [3-(3-acetylamino-ph-enoxy)-propyl]-amide; 2-(1H-indazol-3-yl)-1 H-benzoimi dazole-5-carboxylic acid (6-chloro-pyridin-3 -ylmethyl)-amide; IH-indazol-3 -yl)-l H-benzoimidazole-5-carboxylic acid ([2,2']bithiophenyl-5-ylmethyl)-amide; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2,3-dihydro-ben7ofuran-5-ylmethyl)amide; 1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid 4-cyano-benzylamide; 1H-indazol-3-yl)- lI-I-benzoirnidazole-5-carboxylic acid 2-methylsulfanyl-benzylamidc; 2-(1H-indazol-3-yl)-1 H-benzoimnidazole-5-carboxylic acid (benzo[b]thiophen-3 -ylrnethiyl)-arnide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-an-ide; 2-(1H-indazol-3 -yl)-l H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzo 1 ,4]dioxin-2-ylmethyl)amide; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (furan-3-ylmethyl)-amide; 1H-indazol-3-yl)-l1H-benzoimidazole-5-carboxylic acid 2-nitro-benzylamide; 1H-indazol-3-yl)-l1H-benzoimidazole-5-carboxylic acid (thiophen-3-ylmethyl)-amide; IH-indazol-3-yl)- IH-bcnzoimidazole-5-carboxylic acid 2-{I H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (1-methyl-I H-benzoimidazol-2-ylmcthyl)amide; IE-indazol-3-yl)- IH-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 2-(lH-indazol-3-yl)- 1H-benzoimridazole-5-carboxylic acid 3-chloro-benzylamide; 1H-inda2Ol-3-yl)-31-I-benzoimidazole-4-carboxylic acid 4-sulfamoyl-benzylamide; IH-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (pyridin-3-ylmethyl)-arnide; 1 H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-methoxy-benzylamide; 1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; 2-(l H-indazol-3-yl)-3H-benzoimnidazole-4-carboxylic acid (furan-3-ylmethyl)-amide; 1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-nitro-benzylamide; WO 031035065 PCT/GB02/04763 -240- 2-(l1H-indazol-3 -yl)-3H-benzoimidazole-4-carboxylic acid 2-(IH-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid phenylarnide; 3-[6-(4-fluoro-phenyl)-1H-benzoirnidazol-2-yl]-2H-indazole; 3-[6-(4-methoxy-phenyl)-1H-benzoimidazol-2-y]-2H-indazote; 3-[6-(3-chloro-4-fluoro-phenyl)-1H-benzoimidazol-2-ylj -2H-indazole; 3-(6-m-tolyl-.1H-benzoimidazol-2-yl)-2H-indazote; 3-(6-o-tolyl-1H-benzoiinidazol-2-yl)-2H-indazole; 3-(6-thiophen-3-yl- 1I--benzoimidlazol-2-yl)-2H-indazole; 3-[6-(3-chloro-pheniyl)-1 H-benzoimidazol-2-yll-2H-indazole; 3-[6-(3-methoxy-phenyl)- IH-benizoirnicazol-2-yl]-2H-indazole; 3-[6-(3,5-dimetby1-pheniyl)-1H-benzoimidazol-2-y1]-2H-indazole; 3-(6-benzo[ 1,3]dioxol-5-yl-1 H-benzoimidazol-2-yl)-2H-indazole; 3-(6 -hex-i -enyl- 1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(3,4-dimethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[2 -(2H-indazol-3 4-[2-(2H-indazol-3 -yl)-3H-benzoirnidazol-5 -yl] -phenol; 3-[6-(3,4,5-trimethoxy-phenyl)-1 H-benzoimidazol-2-yl]-2H-indazole; 1 -{5-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl] -thiophen-2-yl} -ethanone; {3-[2-(2H-indazo1-3-y1)-3H-benzoimidazo-5-yl]-pheny -methanol; 3-[6-(2,4-difluoro-phenyl)- 1 Li-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-fluoro-2-methyl-phenyl)- I H-benzoimidazol-2-yl] -2H-indazole; {4-[2-(2H-indazol-3-yl)-3H-berizoimidazol-5-yl]-phenylt -methaaol; 3-(6-furan-2-yl- 1 H-benzoimidazol-2-yl)-2H-indazole; 3-6(-spoy-hnl-Hbnziiao--l-Hidtoe 2-(l1H-indazol-3-yl)- 1H-benzoirnidazole-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide; 1H-indazol-3-yl)- 1H-beazoimidazole-5-carboxylic acid 4-acetylamino-benzylamide; 1H-in-dazol-3-yl)- 1H-belizoimidazole-5-carboxylic acid methylamide; 2-(l1H-indazol-3-yl)-1 H-benzoimidazole--5-carboxylic acid isopropylamide;- IH-indazol-3-yl)-I--benzoimidazol-5-yl]-morpholin-4-yl-methanone; [2-(1H-indazol-3I-yl)- 1H-benzoimnidazol-5-yl]-(4-methyl-piperazin- 1-yl)-methanone; 2-(l1 H-indazol-3 1 H-benzoimidazole-5 -carboxylic acid benzyl-methyl-amide; 1H-indazol-3-yl)- 1H-benzoimidaz.ole-5-carboxyl ic acid 3-niitro-benzylamide; 2-(l1H-indazol-3-yl)- 1H-benzoimidazolc-5-carboxylic acid 2-fluoro-benzylamide; 1H-indazot-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,4-difluoro-benzylamide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,6-difluoro-benzylamide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; WO 031035065 PCT/GB02/04763 1H-indazol-3-yl)- 1H-benzoimidazolc-5-carboxylic acid 4-chloro-2-fluoro-benzylamide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamiide; 1H-indazol-3-yl)-1H-benzoimidazole-5 -carboxylic acid 3 ,4-difluoro-benzylatnide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 3 1H-inda7ol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 2,6-difluoro-3-methyl-benzylamide; IH-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylaniide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-benzylamide; IH-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide; 1H-indazol-3-yl)-I--benzoimidazole-5-carboxylic acid 4-fluoro-benzylamide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2'-chloro-biphenyl-4-ylmethiyl)-arnide; 1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (6-trifluoromethyl-pyridini-3-ylrnethyl)amide; 2-(tIH-indazol-3-yl)-1H-benzoimidazole-5 -carboxylic acid (5-pyridin-2-yl-thiophen-2-ylmethyl)-amide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (3-imidazol- 1-yl-propyl)-amide; 4-[2-(1H-indazol-3-yl)-l1H-benzoimiudazole-5-carbonyfl-piperazine-l1-carboxylic acid tert-butyl ester; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (9_6-difluoro-4-chloro-benzyl)amide; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl)amide; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benizyl)arnide; 2-(1H-indazol-3-yl)- 1H-benizoiinidazole-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl)amide; 2-(1H-indazcl-3-yl>- 11--benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3 -ylmethyl)-amide; 2-[5-(benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3-pheny1-allyloxy)2H-pyrazol-3-y1]-1H-benzoilnidazole; 2-[5-(3,7-dirnetl-iy1-octa-2,6-dienyoxy)-21-pyrazo-3-y]-H-benoiridazole; -(3-bromo-benzyloxy)-2H-pyrazol-3-yl-H-benzoimidazole; 2-[5-(3,4-dichloro-benzyloxy)-2H-pyrazo-3-yl-H-benzoi-idazole; 2-[5-(2-benzenesulfoylietlyl-benzyloxy)-2H-pyrazol-3-yl]-H-bezoimdazolC; 2-[5-(biphenyl-4-ylmethoxy)-2H-pyrazl-3-yl]-1H-benzoimidazole; 2-L5-(3-methoxy-benzyloxy)-2H-pyrazol-3-y]- 1H-benzoimcidazole; isonicotinic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-y ester; benzoic: acid 5-(1 1-benzoirnidazol-2-yl)-lfl-pyrazol-3-y ester; 3-phenyl-propionic acid 1H-benzoimidazo1-2-yl)-1H-pyrazol-3-yl ester; methyl 241 H-indazol-3-yl)-3H-benzimidazole-5- carboxylate; 5-methoxy-2-(1H-indazot-3-yl)- 1H-benzimidazole; 1H-indazol.-3-yl)-3H-benzimidazole, (compound denoted as A32-B363); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

WO 031035065 PCT/GB02/04763 -242- Particularly preferred compounds of fornnula (Ixb) of the invention for the inhibition of KDR are: 1H-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-(cyclohexylmethyl)amide; IH-indazol-3-yl)-I--benzimidazole-5-carboxylic acid N-(2-furfuryl)amide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 4-bromo-benzylarmide; 1H-indazol-3 -yl)-l H-benzoimidazole-5-carboxylic acid 4-inethanesulfonyt-benzylamide; 2-(1 H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-nitro-benzylamide; 1H-indazol-3-yl)-1I-benzoimidazole-5-carboxylic acid 2-methyl-benzylamide; IH-indazol-3-yl)-1H-ben-zoimidazole-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide; 2-(1 H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmnethyl)-amide; 2-(l H-Indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide; 1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (benzo[b]thiophen-3-ytmethyl)-amide; 2- (1 H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid 3-methyl-benzylarnide; 1H-indazol-3-yl)- 1H-benzoimnidazole-5-carboxylic acid 3-chloro-benzylamide; 2-(1 H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; 1I--indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2-(1H-indazol-3-yl)- 1H-benizoirnidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2-(I--indazol-3-yl)- 1 H-benzoirnidazole-5-carboxylic acid 4-chioro-beazylamide; 2-(IH-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylan-iide; 2-(1H-indazol-3-yl)-1 H-benizoimidazole-5-carboxylic acid (2,6-difluoro-4-clloro-benzyl)anmide; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl)amide; 2-(1H-indazol-3-yl) 1H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl)amide; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl)amide; 2-(1H-indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3-yhnethyl)-amide; and the corresponding N-oxides, and thcir prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

Particular compounds of formula (Ix) of the invention for the inhibition of IlK are:- 2-(1H-Indazol-3-yl)- lH-benzoimidazole-5-carboxylic acid (2-piperidin-l-yl-ethyl)-amide, Example 246(ab); 2-(1H-Indazol-3 1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylrnetlhyl)-amide, Example 246(ac); 2-(1H-Indazol-3-yl)- 1H-benzoimidazolc-5-carboxylic acid r3-(4-methyl-piperazin-1-yl)-propyl]-amide, Example 246(ad); N-[2-(tH-Indazol-3-yl)- 1H-benzoimidazol-5-yl]-isobutyramide, Example 246(ae) WO 03/035065 PCT/GB02/04763 -243- N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-l-yl-acetamide, Example 253(c) and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates hydrates) of such compounds and their N-oxides and prodrugs.

The compounds of formula (Ix) of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of formula (Ix) of the invention and compositions containing compounds of formula (Ix) of the invention for use in therapy.

Compounds of formula (Ix) within the scope of the present invention block kinase catalytic activity according to tests described in the literature and in vitro procedures described hereinafter, and which tests results are believed to correlate to pharmacological activity in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of formula (Ix) of the invention and compositions containing compounds of formula (Ix) of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of protein kinase inhibitors Syk, KDR, tie2 or ITK). For example, compounds of formula (Ix) of the present invention are useful in the treatment of inflammatory diseases, for example asthma: atopic dermatitis, inflammatory dermatoses psoriasis, dematitis herpetiformis, eczema, necrotizing and cutaneous vasculitis, bullous disease, acute and chronic urticaria,); allergic rhinitis and allergic conjunctivitis; joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. The compounds of formula (Ix) are also useful in the treatment of Chronic Obstructive Pulmonary Disease (COPD), adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, diabetes, multiple sclerosis, restenosis, myocarditis, B cell lymphomas, systemic lupus erythematosus, viral infections, bacterial infections, parasitic infections, graft v host disease and other transplant associated rejection events, reperfusion injury, Crohn's disease and ulcerative colitis, cancers and tumours (such as colorectal, prostate, breast, thyroid, colon and lung cancers), atherosclerosis, degenerative muscle diseases, obesity, conjestive heart failure, Parkinson's, depression, schizophrenia, stroke, head trauma, spinal cord injury, Alzheimer's, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis, fibrotic diseases of the viscera, and inflammatory bowel disease.

WO 03/035065 PCT/GB02/04763 -244- The products of the present patent application as SYK inhibitors may be used for the treatment of diseases chosen from the following: asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, acute and chronic urticaria, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, diabetes, multiple sclerosis, systemic lupus erythromatosis, viral infections, bacterial infections, parasitic infections, graft vs. host disease, organ transplant rejection, reperfusion injury, Crohn's disease and ulcerative colitis.

The products of the present patent application as KDR inhibitors may be used especially for the treatment or prevention of diseases chosen from the following group: cancers, especially breast, colon, lung and prostate cancer, atherosclerosis, degenerative muscle diseases, obesity, conjestive heart failure, Parkinson's, depression, schizophrenia, stroke, head trauma, spinal cord injury, Alzheimer's, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis and fibrotic diseases of the viscera.

A special embodiment of the therapeutic methods of the present invention is the treating of asthma.

Another special embodiment of the therapeutic methods of the present invention is the treating of psoriasis.

Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.

Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.

Another special embodiment of the therapeutic methods of the present invention is the treating of cancers and tumours.

According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of a protein kinase inhibitor Syk, KDR, tie2 or ITK) for example conditions as hereinbefore described, which comprises the administration to the patient of an effective amount of compound of the invention or a composition containing a compound of the invention. "Effective WO 03/035065 PCT/GB02/04763 -245amount" is meant to describe an amount of compound of the present invention effective in inhibiting the catalytic activity a protein kinase, such as. Syk, KDR, tie2 or ITK, and thus producing the desired therapeutic effect.

References herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.

The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of formula (Ix) of the invention, as defined above, or a pharmaceutically acceptable salt or a prodrug, in association, where appropriate, with a pharmaceutically acceptable carrier or excipient.

Pharmaceutical compositions of the present invention for the treatment of KDR or tie2 associated disease states can also, where appropriate, contain active principles of other antimitotic medicinal products such as, in particular, those based on taxol, cis-platin, DNA-intercalating agents and the like.

Compounds of formula (Ix) of the invention may be administered by any suitable means. In practice compounds of formula (Ix) of the present invention may generally be administered parenterally, locally by topical application to the skin and mucous membranes, rectally, orally, by inhalation, or by intravenous or intramuscular injection, especially by the oral rouLte.

Compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets.

To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols.

When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate WO 03/035065 PCT/GB02/04763 -246suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.

For topical administration, gels (water or alcohol based), creams or ointments containing compounds of formula (Ix) of the invention may be used. Compounds of formula (Ix) of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.

For administration by inhalation compounds of formula (Ix) of the invention may be dissolved or suslended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.

Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.

The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained.

Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, WO 03/035065 PCT/GB02/04763 -247weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.

The compounds of formula (Ix) according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.

Compounds of formula (Ix) of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R.C.Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

Compounds of formula (Ix) wherein W, X, Y, Z and R 1 are as hereinbefore defined for compounds of formula (Ix) and A 5 is H, may be prepared by reaction of compounds of formula (IIx):- Z NH, II (IIx) 5W NH 2 in which W, X, Y and Z are as hereinbefore defined for compounds of formula with acids of formula (IIIx):- R- CO2H (IIIx) in which R 1 is as hereinbefore defined for compounds of formula at a temperature at about 160'C.

Alternatively the reaction may be carried in the presence of hydrochloric acid at about reflux WO 03/035065 PCT/GB02/04763 -248temperature, or polyphosphoric acid at a temperature at about 160 0 C or (ii) be carried out in a microwave oven.

Compounds of formula (Ix) wherein W, X, Y, Z and R 1 are as hereinbefore defined and A 5 is H, may be prepared by reaction of compounds of formula (IIx) in which W, X, Y and Z are as hereinbefore defined for compounds of formula with aldehydes of formula (IVx):-

R-CHO

(IVx) in which R 1 is as hereinbefore defined for compounds of formula in the presence of in inert solvent, such as dimethylformamide or nitrobenzene, and at a temperature up to about 145 0

C.

Alternatively the reaction may be carried in the presence of sodium bisulfite at a temperature at about reflux temperature or (ii) be carried out in a microwave oven at a temperature up to about 200 0

C.

Compounds of formula (Ix) wherein W, X, Y, Z and R 1 are as hereinbefore defined for compounds of formula (Ix) and A 5 is H, may be prepared by cyclisation of compounds of formula i I W R (Vx) wherein W, X, Y, Z and R 1 are as hereinbefore defined for compounds of formula The cyclisation may be carried out by heating in the presence of an acid catalyst, such as acetic acid, and at a temperature up to about 120 0

C.

Compounds of formula (Ixa) wherein W, X, Y and Z are as hereinbefore defined for compounds of formula (Ix) and R 1 is in which R 9 is as hereinbefore defined for compounds of formula R 7 is hydrogen and R 8 is SR 4 i.e. compounds of formula (Ixaa), may be prepared as shown in scheme 1.

WO 031035065 WO 03/35065PCT/GB02/04763 -249- Scheme 1 IZ NH 2 (lix) Step 1 Step 2

N

(VJLx) (VIx) I Step Ia Step 3 Step 2a

H

(TXx) Step 3\a (Vllx) Step 4 (Xx) (Xix) Step Step 6 (Xlx) (Ixaa) WO 03/035065 PCT/GB02/04763 -250- For example diamines of formula (IIx), wherein W, X, Y and Z are as hereinbefore defined for compounds of formula may be treated, in Step 1, with formic acid in the presence of hydrochloric acid at a temperature at about 50°C. The imino group of the resulting compounds of formula (VIx) wherein W, X, Y and Z are as hereinbefore defined for compounds of formula may then be protected, in Step 2, with a suitable protecting group, for example when this is a 2-(trimethylsilanyl)ethoxymethyl group the protection is conveniently carried out by reaction with sodium hydride in dimethylformamide then (ii) reaction with 2-(trimethylsilanyl)ethoxymethyl chloride. The resulting compounds of formula (VIIx), wherein W, X, Y and Z are as hereinbefore defined for compounds of formula (Ix) and R 1 1 is a suitable protecting group, such as a 2-(trimethylsilanyl)ethoxymethyl group, may then be treated, in Step 3, with lithium diisopropylamide, in an inert solvent, such as tetrahydrofuran, and at a temperature at about -78 0

C,

then (ii) acetamides of formula R 9

-C(=O)-N(CH

3 )2 [in which R 9 is as hereinbefore defined for compounds of formula The resulting compounds of formula wherein W, X, Y, Z, R 9 and

R

1 1 are as hereinbefore defined for compounds of formula [alternatively prepared by reaction of diamines of formula (IIx) with P-hydroxy-acids of formula R 9

CH

2 CH(OH)CO2H [in which R 9 is as hereinbefore defined for compounds of formula in Step la, at a temperature at about 70°C, (ii) oxidation, in Step 2a, of the resulting compounds of formula (VIIIx) with manganese dioxide in an inert solvent, such as chloroform, and at a temperature at about 60°C and (iii) protection of the imino group, in Step 3a, as described in Step 2 above)] may then be treated, in Step 4, with sodium tertiary butoxide, in an inert solvent, such as benzene or tetrahydrofuran, at -50C, then (ii) carbon disulfide and then (iii) compounds of formula R 4

-X

1 [in which R 4 is as hereinbefore defined for compounds of formula and X 1 is halo. The resulting compounds of formula (XIx), wherein W, X, Y, Z, R 4

R

9 and R 1 1 are as hereinbefore defined for compounds of formula may then be treated, in Step with hydrazine, in an inert solvent, such as ethanol, and at a temperature from about room temperature to about reflux temperature. The resulting compounds of formula (XIIx), wherein W, X, Y, Z, R 4

R

9 and R 1 1 are as hereinbefore defined for compounds of formula may then be deprotected {for example when R 11 is a 2-(trimethylsilanyl)ethoxymethyl group by treatment with hydrochloric acid in an inert solvent, such as ethanol, and at a temperature from about room temperature to about reflux temperature}, in Step 6, to liberate the pyrazoles of general formula (Ixaa), wherein W, X, Y, Z, R 4 and R 9 are as hereinbefore defined for compounds of formula Compounds of formula (XIx) in which R 1 1 is a tetrahydropyran-2-yl protecting group may be deprotected by treatment with an acid, such as p-toluenesulfonic acid, in water at reflux temperature and subsequently treated with hydrazine, in an inert solvent, such as ethanol, and at a temperature from about room temperature to about reflux WO 03/035065 PCT/GB02/04763 -251temperature to give pyrazoles of general formula (Ixaa), wherein W, X, Y, Z, R 4 and R 9 are as hereinbefore defined for compounds of formula (Ix).

Compounds of formula (Ix) wherein W, X, Y and Z are as hereinbefore defined for compounds of formula (Ix) and A 5 is H, and R 1 is ,in which R 9 is as hereinbefore defined for compounds of formula R 7 is hydrogen and R 8 is OR 4 i.e. compounds of formula (Ixab), may be prepared as shown in scheme 2.

Scheme 2 Step 1 (XIx) (XIIIx) Step 2 (Ixab) For example compounds of formula (XIx), wherein W, X, Y, Z, R 9

R

1 1 are as hereinbefore defined for compounds of formula and R4 is lower alkyl, may be treated, in Step 1, with the sodium salt of an alcohol of formula R 4 -OH (in which R 4 is lower alkyl), such as sodium ethoxide, followed by treatment with hydrazine as described hereinabove for scheme 1. The resulting compounds of formula (XIIIx), wherein W, X, Y, Z, R 4

R

9 and R 1 1 are as hereinbefore defined for compounds of formula may then be deprotected [for example when R 11 is a 2-(trimethylsilanyl)ethoxymethyl group by WO 03/035065 PCT/GB02/04763 -252treatment with trifluoroacetic acid at about 50 0 in Step 2, to liberate the pyrazoles of general formula (Ixab).

Compounds of formula (Ix) wherein W, X, Y and Z are as hereinbefore defined for compounds of formula (Ix) and A 5 is H, and R 1 is in which R 9 is as hereinbefore defined for compounds of formula R 7 is hydrogen and R 8 is -NY 1

Y

2 i.e. compounds of formula (Ixac), may be prepared as shown in scheme 3.

Scheme 3

R

9

NY'Y

2 Step 1 Y Z -N SR X/^N O 11

R

(XIVx) Step 2 i (XIx) Step 3 (Ixac) (XVx) For example compounds of formula (XIx), wherein W, X, Y, Z, R 9 and R 1 1 are as hereinbefore defined for compounds of formula and R 4 is lower alkyl, may be treated, in Step 1, with an amine of formula HNY 1

Y

2 [in which Y 1 and Y2 are as hereinbefore defined for compounds of formula e.g. morpholine. The resulting compounds of formula (XIVx), wherein W, X, Y, Z, R 9

R

1 1, yl and Y2 are as hereinbefore defined for compounds of formula and R 4 is lower alkyl, may then be treated, in step 2, with hydrazine as described hereinabove for scheme 1. The resulting compounds of WO 03/035065 PCT/GB02/04763 -253formula (XVx), wherein W, X, Y, Z, R 9

R

1 1 yl and Y 2 are as hereinbefore defined for compounds of formula may then be deprotected as described hereinabove, in Step 3, to liberate the pyrazoles of general formula (Ixac).

Compounds of formula (Ix) wherein W, X, Y and Z are as hereinbefore defined for compounds of formula (Ix) and A 5 is H, and R 1 is prepared as shown in scheme 4.

i.e. compounds of formula (Ixad), may be Scheme 4 Step 1 (XIx) (XVIx) Step 2 (Ixad) For example compounds of formula (XIx), wherein W, X, Y, Z, R 9 and R 11 are as hereinbefore defined for compounds of formula and R 4 is lower alkyl, may be treated, in Step 1, with hydroxylamine in the presence of sodium methoxide and in methanol at reflux temperature. The resulting compounds of formula (XVIx), wherein W, X, Y, Z, R 4

R

9 and R 1 1 are as hereinbefore defined for compounds of formula may then be deprotected as described hereinabove, in Step 2, to liberate the isoxazoles of general formula (Ixad).

WO 03/035065 PCT/GB02/04763 -254- Compounds of the invention of formula (Ix) may also be prepared by interconversion of other compounds of the invention.

Thus, for example, compounds of formula (Ix) containing a carboxy group may be prepared by hydrolysis of the corresponding esters. The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50 0 C to about As another example compounds of formula (Ix) containing a carboxy group may be prepared by acid catalysed removal of the tert-butyl group of the corresponding tert-butyl esters using standard reaction conditions, for example reaction with trifluoroacetic acid at a temperature at about room temperature.

As another example compounds of formula (Ix) containing a carboxy group may be prepared by hydrogenation of the corresponding benzyl esters. The reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature at about reflux temperature. The reaction may alternatively be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.

As another example compounds of formula (Ix) containing a carboxy group may be prepared by treatment of compounds of formula I(x) containing a cyano group with hydrochloric acid in acetic acid at a temperature at about 100 0

C.

As another example of the interconversion process, compounds of formula (Ix) containing a -C(=O)-NY1Y 2 group may be prepared by reaction of compounds of formula (Ix) containing a carboxy group with an amine of formula HNY 1

Y

2 to give an amide bond using standard peptide coupling procedures, for example coupling in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydroxybenzotriazole and di-isopropylethylamine in an inert solvent, such as dimethylformamide and a temperature up to about 80 0 C. The reaction may alternatively be carried out in the presence of O-(7-azabenzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide) at room temperature.

WO 03/035065 PCT/GB02/04763 -255- As another example of the interconversion process, compounds of formula (Ix) containing a

-NH-C(=O)-R

4 group may be prepared by: coupling compounds of formula (Ix) containing an amino group with acids of formula R 4

-CO

2 H using standard coupling conditions as described above; or (ii) by reaction of compounds of formula (Ix) containing an amino group with acid chlorides of formula R 4 in the presence of a tertiary base, such as di-isopropylethylamine, in an inert solvent, such a dichloromethane, and at a temperature at about room temperature. In some instances a bis-acylated derivative is obtained by reaction of compounds of formula (Ix) containing an amino group and in which A 5 is H, with acid chlorides of formula R 4 These bis-acylated derivatives may be converted to compounds of formula (Ix) containing a -NH-C(=O)-R 4 group and in which A 5 is H, by treatment with potassium hydroxide in aqueous methanol at a temperature at about 0

C.

As another example of the interconversion process, compounds of formula (Ix) wherein R 1 is a 9 pyrazolyl moiety in which R 8 and R 9 together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing a NY 5 group (where Y 5 is

-C(=O)R

4 may be prepared by reaction of compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety in which R 8 and R 9 together with the carbon atoms to which they are N \7 attached form a 5 or 6 membered heterocyclic ring containing a NY 5 group (where Y 5 is hydrogen) with acid chlorides of formula R 4 in the presence of a tertiary base, such as di-isopropylethylamine, in an inert solvent, such a dichloromethane, and at a temperature at about room temperature.

WO 03/035065 PCT/GB02/04763 -256- As another example of the interconversion process, compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety in which R 8 and R 9 together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing a NY 5 group (where Y 5 is

-C(=O)NY

1

Y

2 may be prepared by reaction of compounds of formula (Ix) wherein R 1 is a pyrazolyl

R

moiety in which R 8 and R 9 together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing a NY 5 group (where Y 5 is hydrogen) with carbamoyl chlorides of formula Y1y 2 N-C(=O)-Cl in the presence of a tertiary base, such as diisopropylethylamine, in an inert solvent, such a dichloromethane, and at a temperature at about room temperature.

As another example of the interconversion process, compounds of formula (Ix) wherein R 1 is a

R

9 pyrazolyl moiety R

R

7 in which R 8 and R 9 together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing a NY 5 group (where Y 5 is -C(=0)OR 4 may be prepared by reaction of compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety in which R 8 and R 9 together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing a NY 5 group (where Y 5 is hydrogen) with chloroformates of formula R40-C(=O)-Cl in the presence of a tertiary base, such as diisopropylethylamine, in an inert solvent, such a dichloromethane, and at a temperature at about room temperature.

WO 03/035065 PCT/GB02/04763 -257- As another example of the interconversion process, compounds of formula (Ix) wherein R 1 is a N R7 are attached form a 5 or 6 membered heterocyclic ring containing a NY 5 group (where Y 5 is -S0 2

R

4 may be prepared by reaction of compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety

R

9 in which R 8 and R 9 together with the carbon atoms to which they are attached form N

R

7 a 5 or 6 membered heterocyclic ring containing a NY 5 group (where Y 5 is hydrogen) with sulfonyl chlorides of formula R 4 S0 2 -Cl in the presence of a tertiary base, such as diisopropylethylamine, in an inert solvent, such a dichloromethane, and at a temperature at about room temperature.

As another example of the interconversion process, compounds of formula (Ix) containing a

-NH-C(=O)-R

4 group, in which R 4 is alkyl substituted by NY 1

Y

2 may be prepared by coupling compounds of formula (Ix) containing an amino group with the appropriate chloroalkyl acid chloride, in the presence of a tertiary base, such as di-isopropylethylamine, in an inert solvent, such a dichloromethane, and at a temperature at about room temperature, followed by (ii) reaction with an amine of formula HNY 1

Y

2 As another example of the interconversion process, compounds of formula (Ix) containing a

-N(R

6 )C(=O)NY1y 2 group [in which R 6 is hydrogen, Y 1 is hydrogen and Y 2 is alkenyl, aryl, cycloalkyl, heteroaryl, or optionally substituted alkyl] may be prepared by reaction of compounds of formula (Ix) containing an amino group with isocyanates of formula Y 2 N=C=O [in which Y 2 is alkenyl, aryl, cycloalkyl, heteroaryl, or optionally substituted alkyl], in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature.

As another example of the interconversion process, compounds of formula (Ix) containing a

-N(R

6

)C(=O)NY

1

Y

2 group [in which R 6 is hydrogen] may be prepared by reaction of compounds of formula (Ix) containing an amino group with 1,1-carbonyldiimidazole in an inert solvent such as WO 03/035065 PCT/GB02/04763 -258tetrahydrofuran and at a temperature at about 60 0 C followed by reaction with an amine of formula HNY1y 2 As another example of the interconversion process, compounds of formula (Ix) containing an amino group may be prepared by reduction of the corresponding compounds of formula (Ix) containing a nitro group. For example, the reduction may conveniently be carried out by hydrogenation in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol. The reduction may also conveniently be carried out by means of reaction with tin chloride, in an inert solvent, such as methanol or ethanol, and at a temperature at about reflux temperature. Alternatively the reaction with tin chloride may be carried out in a microwave oven at a temperature at about 140 0

C.

As another example of the interconversion process, compounds of formula (Ix) containing a -CH2OH group may be prepared by the reduction of corresponding compounds of formula (Ix) containing a -CHO or -CO 2 lower alkyl group. For example, the reduction may conveniently be carried out by means of reaction with lithium aluminium hydride, in an inert solvent, such as tetrahydrofuran, and at a temperature from about room temperature to about reflux temperature.

As another example of the interconversion process, compounds of formula (Ix) containing a

-CH(OH)R

4 group may be prepared by treating compounds of formula (Ix) containing a -C(=O)R 4 group with diisobutylaluminium hydride, in an inert solvent, such as tetrahydrofuran, and at a temperature from about -78°C to about room temperature.

As another example of the interconversion process, compounds of formula (Ix) in which RI is aryl or heteroaryl substituted by hydroxy may be prepared by reaction of the corresponding compounds of formula (Ix) in which R 1 is aryl or heteroaryl substituted by methoxy with a Lewis acid, such as boron tribromide, in an inert solvent, such as dichloromethane, and at a temperature from about 0°C to about room temperature.

As another example of the interconversion process, compounds of formula (Ix) containing sulfoxide linkages may be prepared by the oxidation of corresponding compounds containing linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g.

3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulfate in a medium WO 03/035065 PCT/GB02/04763 -259such as aqueous methanol, buffered to about pH 5, at temperatures between about 0°C and room temperature. This latter method is preferred for compounds containing an acid-labile group.

As another example of the interconversion process, compounds of formula (Ix) containing sulfone linkages may be prepared by the oxidation of corresponding compounds containing or sulfoxide linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.

As another example of the interconversion process, compounds of formula (Ix) containing a cyano group may be prepared by reaction of the corresponding compounds of formula (Ix) containing a

-C(=O)-NH

2 group with phosphorus pentachloride in the presence of triethylamine. The reaction may conveniently be carried out in an inert solvent, such as tetrahydrofuran, and at a temperature at about reflux temperature.

As another example of the interconversion process, compounds of formula (Ix) containing a -C(=O)-NH2 group may be prepared by reaction of the corresponding compounds of formula (Ix) containing a cyano group with hydrogen peroxide in the presence of sodium hydroxide. The reaction may conveniently be carried out in methanol at a temperature at about room temperature. Alternatively compounds of formula (Ix) containing a -C(=O)-NH 2 group may be prepared by reaction of the corresponding compounds of formula (Ix) containing a cyano group with hydrochloric acid in acetic acid at a temperature from about 80'C to about 100 0

C.

As another example of the interconversion process, compounds of formula (Ix) containing a tetrazolyl group may be prepared by reaction of the corresponding compounds of formula (Ix) containing a cyano group with azidotributyltin. The reaction may conveniently be carried out in an inert solvent, such as toluene, and at a temperature at about reflux temperature.

According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

WO 03/035065 PCT/GB02/04763 -260- Compounds of this invention can be regenerated from their acid addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.

According to a further feature of the invention, base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

Compounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.

Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.

The starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.

Intermediates of formula (IIx), wherein W, X, Y and Z are as hereinbefore defined for compounds of formula may be prepared by reduction of the corresponding nitro compounds of formula yZ N02 Y N

II

0 (1) W NH 2 wherein W, X, Y and Z are as hereinbefore defined for compounds of formula For example, the reduction may conveniently be carried out by means of reaction with tin chloride, in an inert solvent, WO 03/035065 PCT/GB02/04763 -261such as methanol or ethanol, and at a temperature at about reflux temperature. Alternatively the reaction may be carried out in a microwave oven at a temperature at about 140 0

C.

Intermediates of formula (IIx), wherein W, X, Y and Z are as hereinbefore defined for compounds of formula may also be prepared by reduction of the corresponding dinitro compounds of formula

II

1/ NO(2) W

NO

2 wherein W, X, Y and Z are as hereinbefore defined for compounds of formula with tin chloride as above.

Nitro compounds of formula wherein W is CH, X is C-R 2 Y is C-R 3 and Z is CH [in which R 3 is as hereinbefore defined for compounds of formula may be prepared from the corresponding anilines of formula (3) NH2 (3) wherein X is C-R 2 and Y is C-R 3 [in which R 3 is as hereinbefore defined for compounds of formula by reaction with acetic anhydride in the presence of triethylamine, in an inert solvent, such as dichloromethane, and at a temperature from about 0°C to about room temperature, (ii) reaction with nitric acid in the presence of acetic acid and acetic anhydride at a temperature at about -5"C and (iii) reaction with an alkali metal alkoxide, such as sodium methoxide, in methanol and at room temperature.

Nitro compounds of formula wherein W is CH, X is C-R 2 (in which R 2 is alkyl), Y is C-R 3 (in which R 3 is an aryl or heteroaryl group) and Z is CH may be prepared by reaction of compounds of formula WO 03/035065 PCT/GB02/04763 -262wherein X is C-R 2 (in which R 2 is alkyl) and X 2 is bromo or iodo, with an aryl (or heteroaryl) boronic acid in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium, in an inert solvent, such as tetrahydrofuran, and at a temperature at about 85 0

C.

Intermediates of formula (IIIx), wherein R 1 is in which R 7 is hydrogen, R 8 is alkyl and R 9 is hydrogen or alkyl may be prepared by reaction of compounds of formula

R

9 COEt

R-

0 0 wherein R 8 is alkyl and R 9 is hydrogen, with hydrazine in the presence of acetic acid at reflux temperature, followed by hydrolysis.

Intermediates of formula (IIIx), wherein R 1 is in which R 7 is hydrogen and R 8 and

R

9 together with the carbon atoms to which they are attached form a 5, 6 or 7 membered carbocyclic ring may be similarly prepared by reaction of compounds of formula wherein R 8 and R 9 together with the carbon atoms to which they are attached form a 5, 6 or 7 membered carbocyclic ring, with hydrazine, followed by hydrolysis.

WO 03/035065 PCT/GB02/04763 -263- Intermediates of formula (IIIx), wherein R 1 is R 7/ in which R 7 is hydrogen, R 13 is alkyl and X 1 is O, S, SO 2 or NY 5 (where Y 5 is R 4

-C(=O)R

4 -C(=O)NY1Y 2 -C(=0)OR 4 or -S0 2

R

4 may be similarly prepared by reaction of compounds of formula

X

(R

1 3 )7

X

CO,Et 0 (6) wherein R 13 is alkyl and X 1 is O, S S 2 or NY 5 (where Y 5 is R 4

-C(=O)R

4 -C(=O)NY1y 2 -C(=0)OR 4 or -SO2R 4 with hydrazine, followed by hydrolysis.

Compounds of formula wherein R 8 is alkyl and R 9 is hydrogen, may be prepared by reaction of compounds of formula

CH

3 R8-2 wherein R 8 is alkyi, with diethyl oxalate, in the presence of an alkali metal alkoxide, such as sodium ethoxide, in an inert solvent, such as ethanol, and at a temperature at about 60 0

C.

Compounds of formula wherein R 8 and R 9 together with the carbon atoms to which they are attached form a 5, 6 or 7 membered carbocyclic ring may be similarly prepared by reaction of cyclopentanone, or cyclohexanone, with diethyl oxalate.

Compounds of formula wherein R 13 is alkyl and X 1 is O, S, SO 2 or NY 5 (where Y 5 is R 4

-C(=O)R

4 -C(O)NY1y 2 -C(=0)OR 4 or -S0 2

R

4 may be similarly prepared by reaction of compounds of formula WO 03/035065 PCT/GB02/04763 -264-

(R

1 3 0 (8) wherein R 13 is alkyl and X 1 is 0, S, SO 2 or NY 5 (where Y 5 is R 4

-C(=O)R

4

-C(=O)NY

1 y 2 -C(=0)OR 4 or -S0 2

R

4 with diethyl oxalate.

Intermediates of formula (IVx), wherein R 1 is as hereinbefore defined for compounds of formula (Ix), may be prepared by oxidation of compounds of formula

R

1

-C

H 2

OH

wherein R I is as hereinbefore defined for compounds of formula The oxidation may conveniently be carried out with manganese dioxide, or pyridinium chlorochromatc, in an inert solvent, such as chloroform, or dichloromethane, and at a temperature at about 60'C. This procedure is particularly suitable for intermediates of formula (IVx) wherein R 1 is (in which R10 and p are as hereinbefore defined).

Compounds of formula wherein R 1 is as hereinbefore defined for compounds of formula may be prepared by reduction of acids of formula

R

1

-CO

2

H

wherein R 1 is as hereinbefore defined for compounds of formula The reduction may conveniently be carried out with lithium aluminium hydride, in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature.

Compounds of formula wherein R 1 is as hereinbefore defined for compounds of formula may be prepared by reduction of alkyl esters of formula Rl-CO 2 alkyl (loa) WO 03/035065 PCT/GB02/04763 -265wherein R 1 is as hereinbefore defined for compounds of formula The reduction may conveniently be carried out with lithium aluminium hydride, in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature.

Acids of formula wherein R 1 is (in which R 1 0 and p are as hereinbefore defined), may be prepared by reaction of indole-diones of formula (11):

(R'I>

P

wherein R 10 and p are as hereinbefore defined, with sodium hydroxide at 50 0 C, (ii) sodium nitrite then sulfuric acid at 5 0 C and (iii) tin (II) chloride.

Indole-diones of formula wherein R 10 is as hereinbefore defined and p is one, may be prepared by reaction of compounds of formula (12):

\NOH

0 wherein R 1 0 is as hereinbefore defined, with polyphosphoric acid at a temperature at about Compounds of formula wherein R 1 0 is as hereinbefore defined, may be prepared by reaction of anilines of formula (13): WO 03/035065 PCT/GB02/04763 -266- NH (13) wherein R 10 is as hereinbefore defined, with chloral hydrate and hydroxylamine in the presence of hydrochloric acid at a temperature at about 80 0

C.

Intermediates of formula wherein W, X, Y, Z and R 1 are as hereinbefore defined for compounds of formula may be prepared by reaction of compounds of formula with acid chlorides of formula R 1 optionally in the presence of a tertiary base, such as pyridine, and in an inert solvent, such as dichloromethane, at a temperature at about room temperature.

The following references are also cited, which may be used for the preparation of benzimidazoles, pyrazoles or indazoles in the context of the present invention: G. R. Newkome, W.W. Paudler, Comtemporary Heterocyclic Chemistry, Syntheses, Reactions and Applications, J. Wiley, 1982 Preston, Heterocyclic Compounds, Benzimidazoles and congeneric tricyclic compounds, J. Wiley, 1981 Behr, Fusco, Jarboe, Heterocyclic Compounds, Pyrazoles, Pyrazolines, Pyrazolidines, indazoles and condensed rings, J. Wiley, 1967.

The following schemes, schemes 5 to 13, illustrate the synthesis of specific examples within the specification using the processes hereinbefore described with the use of appropriate protecting groups where necessary.

WO 031035065 WO 03/35065PCT/GB02/04763 -267- Scheme EtO H LiAIH 4 0 0 -b HO N-NH HS 4 Eto N-~NH TH Mn0 2 3- 0 HO N-NH H ~N-NH J;(NH2 nitrobenzene, 145'C

N/H

2 or NaHS0 3 DME, reflux

-~N

N

N

H

Example Scheme 6 0 OH EtBr, KCO, 0 QEt LIAIH, ORt mn0 2 0 Cit KI. acetone THFN EtO C~H 2Ph Eto NNCHPh H Nj -N.P H CH 2Ph PhCHNH-NH, AcOH, reflux EtOOC CO 2 .Et 1nitrobenzene, 145'C NaHSO, DMF, reflex 0 HO" N\ OEt N -NH

H

Example 19 WO 031035065 WO 03/35065PCT/GB02/04763 -268- Scheme 7 0 NHNH, 0 UAIH 4 M0 EtO 0 EtO N.NH THE HO N-NH H N-NH nitrobenzene, 145'C

N.H-SO

3 DMF, reflux N 1 N

'NNH

Example 23 Scheme 8

HOH

-a N N-N OME

H

Example I WO 031035065 PCT/GB02/04763 -269- Scheme 9

OCI-

2

CH

3

SCH

2

CH

3 ,CHC1H 3 0CH 2

H

3

SCH

2

CH,

O,N

NH 2 OH2 C3 SCH 2 CH 3 0 N

OCH

2

CH,

'~CH,CH

3 0 NH CH 3

CH

2

C[-

3

CH'

CH1 3

CH

2 C H 3

C

Example 256(a) WO 031035065 WO 03/35065PCT/GB02/04763 -270- Scheme 0~~ Ci NH 2 0~~ C1 NH 2 0 C1 H 2N#

NH,

OZZN/0

NN

N N~N

H

Example 248(m) WO 031035065 WO 03/35065PCT/GB02/04763 -271- Scheme 11 o 0

NH

2 H

NH

2

NI

0

NH

2 C

N

N

Example 256(c) Scheme 12 00 H 0 H H NN

NH

2

H

1 H N 2 H WO 031035065 PCT/GB02/04763 -272- Scherme 13 F 'NNH 2

CH

3

CH

2 0O

NH

2 o 0 0 H NzzN

N

+iN CH CHO 0 H 0 0

CH

3

CH

2 0 N~ N N F N. -N

NH

2 H N CH 3

CH

2 0 N N6

H

1 0

H

N

F N0 CHCH 2 0 O: N N H N

H

Example 257(b) WO 031035065 PCT/GB02/04763 -273- Scheme 14 0 0

ONH,

N

N

0 0

C

0 0

OCH,

CHO

NH

CECH,O,

NN0 S/ OMe MeO r0

N

CH

3 N N 3 H Example 257(?) WO 03/035065 PCT/GB02/04763 -274- The present invention is further exemplified but not limited by the following illustrative Examples and Reference Examples.

400M Hz 1H nuclear magnetic resonance spectra (NMR) were recorded on a Varian Unity INOVA machine. In the nuclear magnetic resonance spectra (NMR) the chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations have the following significances: s singlet; d doublet; t triplet; m multiplet; q quartet; dd doublet of doublets; ddd doublet of double doublets.

The thin layer chromatography (TLC) RF values were determined using Merck silica plates.

High Pressure Liquid Chromatography Mass Spectrometry (LC-MS) conditions for determination of retention times (RT) and associated mass ions were as follows:- METHOD A: Mass Spectrometer (MS) LCT Time-of-Flight (Micromass UK Ltd) Serial No. KA014 [Ionization Mode: Electrospray (Positive Ion); Scan: TofMS (Full Scan m/z 100 1200, sum for 0.4 s 50us/scan) Centroid Mode]. Liquid Chromatograph Hewlett Packard HP 1100 Series Binary Pump (Serial US80301343)& Degasser (serial JP73008973).

Hypersil BDS C-18, 3L (4.6mm x 50mm), Reverse Phase Column operated under gradient elution conditions using water containing 0.05% trifluoroacetic acid and acetonitrile containing 0.05% trifluoroacetic acid as the mobile phase (gradient: 0.00 minutes, 100%A; linear gradient to 100% B at 2 minutes; then hold until 1.5 minutes); flow rate Iml/minute to column to UV detector, flow split after UV detector such that 0.75ml/minute to ELS detector and 0.25ml/minute to mass spectrometer; injection volume 10 1 l; Auxiliary Detectors: Hewlett Packard Model HP1100 Series UV detector (serial JP73704703) wavelength 220nm; (ii) Sedere (France) Model SEDEX 75 Evaporative Light Scattering (ELS) detector (serial 9970002A); temperature 46 0 C, Nitrogen pressure 4bar; Autosampler Injector: Gilson Model 215 Liquid Handler with Model 819 injection valve (serial 259E8280).

METHOD B: Waters Symmetry C8 3.5ptm HPLC colunm operated under gradient conditions with mixtures *of water containing 0.1% formic and acetonitrile containing 0.1% formic acid as the mobile phase (gradient: 0.00 minutes, 95%A:5%B; 0.75minutes, 95%A:5%B; 3.00 minutes 100%B; 4.00 minutes 100%B; 4.25 minutes 95%A:5%B); flow rate 1.5ml/minute with approximately 200Ll/minute split to the Mass Spectrometer; injection volume 201l; in line WO 03/035065 PCT/GB02/04763 -275- Diode Array (210-300nm), in line Evaporative light scattering (ELS) detection ELS temperature 40'C, Gain 7 1.5ml/minute; Source temperature 150 0

C.

METHOD C: Waters Symmetry C8 3.5gim HPLC column operated under gradient conditions with mixtures of(A) water containing 10mM ammonium acetate and methanol containing ammonium acetate as the mobile phase (gradient 0.00 minutes, 95%A:5%B; 0.75minutes, 95%A:5%B; 3.00 minutes 100%B; 4.00 minutes 100%B; 4.25 minutes 95%A:5%B); flow rate with approximately 200gl/minute split to the Mass Spectrometer; injection volume 20ul; in line Diode Array (210-300nm), in line Evaporative light scattering (ELS) detection ELS temperature 400C, Gain 7 1.5ml/minute; Source temperature 1500C.

METHOD D: C8 Phenomenex Luna 5pm (250 x 4.6mm) HPLC column operated under gradient conditions with mixtures of methanol containing 10mM ammonium acetate and water containing.

ammonium acetate as the mobile phase (gradient: 0 to 2 minutes 10%A:90%B; 2 to 23 minutes ramp up to 100%A; 23 to 30 minutes 100%A; 30 to 37 minutes 10%A:90%B); flow rate Iml/minute.

METHOD E: Mass Spectrometer (MS) LCT Time-of-Flight (Micromass UK Ltd) Serial No. KA014 [Ionization Mode: Electrospray (Positive Ion); Scan: Tof MS (Full Scan m/z 100 1200, sum for 0.4 s 50us/scan) Centroid Mode]. Liquid Chromatograph Hewlett Packard HP1100 Series Binary Pump (Serial US80301343)& Degasser (serial JP73008973).

Synergi 2U Hydro reverse phase 20X4 mm column, solvent A 0.1% trifluoroacetic acid in water; Solvent B 0.1% trifluoroacetic acid in acetonitrile. Gradient 5%B at time 0 to 90% B at time 2 minutes to 100% B at 5 minutes; flow rate Iml/minute to column to UV detector, flow split after UV detector such that 0.75ml!minute to ELS detector and 0.25ml/minute to mass spectrometer; injection volume 10l; Auxiliary Detectors: Hewlett Packard Model HP1100 Series UV detector (serial JP73704703) wavelength 220nm; (ii) Sedere (France) Model SEDEX 75 Evaporative Light Scattering (ELS) detector (serial 9970002A); temperature 46°C, Nitrogen pressure 4bar; Autosampler Injector: Gilson Model 215 Liquid Handler with Model 819 injection valve (serial 259E8280).

METHOD F: Agilent 1100 Series HPLC with a YMC CombiScreen Pro C 18 5.5 gm 4.6 mm by 33 mm reverse phase column using gradient elution with a mixture of acetonitrile/0.1% trifluoroacetic acid and water/0.1% trifluoroacetic acid (5%A:95%B to 95%A:5%B over WO 03/035065 PCT/GB02/04763 -276- 5.1 minutes) with a 1.2 mL/minute flow rate; Agilent 1100 Series wellplate autosampler with 2 gL injection; Agilent 1100 Series diode array detector with 215, 254 and 300 nM wavelength detection; Hewlett Packard 1100 Series mass spectrometer with electrospray and positive ionisation.

METHOD G: Rainin HPXL dual pump HPLC system with a Rainin Dynamax UV-D II detector for 254 nM wavelength, C18 Metachem Monochrom 10pM (100 x 4.6mm) column using gradient elution with a mixture of water with 0.1% trifluoroacetic acid and acetonitrile as the mobile phase (90%A: 10%B to 0%A in 12 minutes) with a flow rate of 1.0 ml/minute C18 Phenomenex Luna 5jiM (150 x 4.6mm) column using gradient elution with a mixture of methanol and water with 10mM ammonium acetate as the mobile phase (0-2 minutes 10%A:90%B; 2-25 minutes ramp up to 100%A; 25-32 minutes 100%A; 32-33 minutes 10%A:90%B) with a flow rate of 1.0 ml/minute.

METHOD H: Waters Symmetry C8 3.5tM Column (50 x 4.6mm) using gradient elution with a mixture of water/0.1% formic acid and acetonitrile/0.1% formic acid (5%B:95%A to 100%B in 100%Bfor 1 min, 100%B to 5%B:95%A in 0.1min, Equilibrate 5%B:95%A 0.49 minutes, Total run time 5 min)with a flow rate of 1.5mL/minute; Detection 210-300nM, 2nM range interval; Column Temp 30 0 C; Mass Spec Quadrupole, Electrospray, cone ion switching, centroid data, 140 to 850 Da 0.6 sec scan, 0.4 sec inter scan delay.

METHOD J: Waters Symmetry C8 3.5JtM Column (50 x 4.6mm) using gradient elution with a mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile (5%B:95%A 0.75 minutes to 100%B in 4 minutes, 100%Bfor 0.5 minutes, 100%B to 5%B:95%A in 1 minute, Total run time 5 minutes with a flow rate of 1.5mL/minute; Detection 210-300nM, 2nM range interval; Column Temp 30 0 C; Mass Spec Quadrupole, Electrospray, cone voltage25V, ion switching, centroid data, 140 to 850 Da, 0.6 sec scan, 0.4 sec inter scan delay.

METHOD K: Waters Symmetry C8 3.5g Column (50 x 4.6mm) using gradient elution with a mixture of (A) ammonium acetate in water and 10mM ammonium acetate in methanol (5%B:95%A 0.75 minutes to 100%B in 4 minutes, 100%Bfor 0.5 minutes, 100%B to 5%B:95%A in 1 minute, Total run time 5 min)with a flow rate of 1.5mL/minute; Detection WO 03/035065 PCT/GB02/04763 -277- 210-300nM, 2nm range interval; Column Temp 30°C; Mass Spec Quadrupole, Electrospray, cone voltage25V, ion switching, centroid data, 140 to 850 Da, 0.6 sec scan, 0.4 sec inter scan delay.

METHOD L: Phenomenex Luna C18(2) 3gM Column (150 x 4.6mm) using gradient elution with a mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile (20%B:80%A to 100%B in 10 minutes, 100%Bfor 2 minutes, 100%B to 20%B:80%A in 0.5 minutes, 20%B:80%A for 3.5 minutes, Total run time 16 minutes with a flow rate of 210-300nM, 220 and 254nM extracted and ELSD; Column Temp 30 0 C; Mass Spec Quadrupole, Electrospray, cone voltage25V, ion switching, centroid data, 100 to 900 Da, 0.6 sec scan, 0.4 sec inter scan delay.

METHOD M: Phenomenex Luna C18(2) 3LM Column (150 x 4.6mm) using gradient elution with a mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile (5%B:95%A to 60%B:40%A in 10 minutes, 60%B:40%A for 2 minutes, 60%B:40%A to 5%B:95%A in minutes, 5%B:95%A for 3.5 minutes, Total run time 16 minutes with a flow rate of 1.OmL/minute; 210-300nM, 220 and 254nM extracted and ELSD; Column Temp 30°C; Mass Spec Quadrupole, Electrospray, cone voltage25V, ion switching, centroid data, 100 to 900 Da, 0.6 sec scan, 0.4 sec inter scan delay.

METHOD N: Waters Symmetry C8 3.5gM Column (50 x 4.6mm) using gradient elution with a mixture of 10mM ammonium acetate in water and 10 mM ammonium acetate in methanol (5%B:95%A to 100%B in 3.5minutes, 100%Bfor 1 minute, 100%B to 5%B:95%A in 0. minute, Equilibrate 5%B:95%A 0.49 minutes, Total run time 5 minutes)with a flow rate of Detection 210-300nM, 2nM range interval; Column Temp 30 0 C; Mass Spec Quadrupole, Electrospray, cone voltage25V, ion switching, centroid data, 140 to 850 Da, 0.6 sec scan, 0.4 sec inter scan delay.

METHOD P: Phenomenex Luna C18(2) 3pM Column (150 x 4.6mm) using gradient elution with a mixture of 10mm ammonium acetate in water and 10mm ammonium acetate in methanol (5%B:95%A to 60%B:40%A in 10 minutes, 60%B:40%A for 2 minutes, 60%B:40%A to 5%B:95%A in 0.5 minutes, 5%B:95%A for 3.5 minutes, Total run time 16 minutes with a flow WO 03/035065 PCT/GB02/04763 -278rate of 1.0mL/minute; 210-300nM, 220 and 254nM extracted and ELSD; Column Temp 30 0

C;

Mass Spec Quadrupole, Electrospray, cone voltage25V, ion switching, centroid data, 100 to 900 Da 0.6 sec scan, 0.4 sec inter scan delay.

METHOD Q: Phenomenex Luna C18(2) 3|gM Column (150 x 4.6mm) using gradient elution with a mixture of 10mm ammonium acetate in water and 10mm ammonium acetate in methanol (20%B:80%A to 100%B in 10 minutes, 100%Bfor 2 minutes, 100%B to 20%B:80%A in minutes, 20%B:80%A for 3.5 minutes, Total run time 16 minutes with a flow rate of 1.0mL/minute; 210-300nM, 220 and 254nM extracted and ELSD; Column Temp 30 0 C; Mass Spec Quadrupole, Electrospray, cone voltage25V, ion switching, centroid data, 100 to 900 Da, 0.6 sec scan, 0.4 sec inter scan delay.

METHOD R: Phenomenex Luna C18(2) 5gM Column (150 x 4.6mm) using gradient elution with a mixture of 10mm ammonium acetate in water and 10mm ammonium acetate in methanol (40%B:60%A to 100%B in 10 minutes, 100%Bfor 2 minutes, i00%B to 40%B:60%A in minutes, 40%B:60%A for 3.5 minutes, Total run time 16 minutes with a flow rate of 210-300nM, 220 and 254nM extracted and ELSD; Column Temp 30°C; Mass Spec Quadrupole, Electrospray, cone voltage25V, ion switching, centroid data, 100 to 900 Da, 0.6 sec scan, 0.4 sec inter scan delay.

High Pressure Liquid Chromatography conditions for determination of retention times (RT) were as follows:- METHOD Al: YMC ODS-AQ (2 x 50mm) column using gradient elution conditions with mixtures of acetonitrile, water and formic acid as the mobile phase [95/5/0.1% to 5/95/0.1%] and a flow rate of 0.4mL/minute.

METHOD Bl: C18 Phenomenex Luna 5liM (150 x 4.6mm) column using gradient elution with a mixtures of acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid as the mobile phase (gradient: 0-2 minutes 10%A:90%B; 2-25 minutes ramp up to 100%A; 25-32 minutes 100%A; 32-33 minutes 10%A:90%B) with a flow rate of 1.0 ml/minute.

METHOD C1: WO 03/035065 PCT/GB02/04763 -279- C18 Phenomenex Luna 5pM (150 x 4.6mm) column using gradient elution with a mixture of methanol and water with 10mM ammonium acetate as the mobile phase (0-2 minutes 10%A:90%B; 2-25 minutes ramp up to 100%A; 25-32 minutes 100%A; 32-33 minutes 10%A:90%B) with a flow rate of 1.0 ml/minute.

METHOD Dl: C18 Phenomenex Luna 3pM (150 x 4.6mm) column using gradient elution with a mixture of acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid with a flow rate of 1.0 ml/minute METHOD El: C18 Phenomenex Luna 3gM (150 x 4.6mm) column using gradient elution with a mixture of methanol and water with 10mM ammonium acetate as the mobile phase (20%A:80%B to 100%A in 10 minutes; 100%A for 2 minutes; 100%Ato 20%A:80%B in 0.5 minutes; 20%A:80%B for 3.5 minutes) with a flow rate of 1.0 ml/minute.

METHOD Fl: C18 Phenomenex Luna 3gM (150 x 4.6mm) column using gradient elution with a mixture of acetonitrile and water with 0.1% formic acid.

METHOD G1: C18 Phenomenex Luna 3 M (150 x 4.6mm) column using gradient elution with a mixture of methanol and water with 10mM ammonium acetate as the mobile phase (5%A;95%B to 60%A:40%B in 10 minutes; 60%A:40%B for 2 minutes; 60%A:40%B to 5%A:95%B in minutes; 5%A:95%B for 3.5 minutes) with a flow rate of 1.5 ml/minute.

Gas Chromatography Mass Spectrometry (GC-MS) conditions for determination of retention times (RT) and associated mass ions were as follows: Varian 3800 Gas Chromatograph with Chrompack 0.25 mm diameter fused silica 30 m column using a 20 minute elution with 25°C /minute gradient from 50 to 300 0 C from time 1 to 11 minute; helium mobile phase with 1.2 mL/minute flow rate; 3-8 gtL injection volume with 50:50 injection split ratio; Varian 2000R mass spectrometer with electron impact detection for ions 40 to 650 m/z.

General method of LC-MS purification of examples 1 to 229: a Waters Fraction Lynx system is used, and the separations were carried out on a Waters Symmetry column (C18, 5 gM, 19x50 mm, catalogue number 186000210), eluting with a linear gradient of acetonitrile containing 0.07% Irifluoroacetic acid WO 03/035065 PCT/GB02/04763 -280in water containing 0.07% trifluoroacetic acid gradient rising from 5% to 95% of acetonitrile/ trifluoroacetic acid over 8 minutes, and then 2 minutes at 95% acetonitrile/ trifluoroacetic acid at a flow rate of 10 ml/minute. The products are injected in solution in dimethylsulfoxide, and collected according to the detection of their molecular weight.

Compound names were generated using an auto-nom plug in for ISIS2.3 or ISIS2.4.

EXAMPLE 1 2-(1H-indazol-3-vl)-1H-benzimidazole-5-carboxylic acid benzvlamide 0 PhCH,NH

H

2-(1 H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide may be prepared in the following manner.

A solution of 27.3 mg of HBTU in 0.2 ml of dimethylformamide is added, at a temperature in the region of 20 0 C, to a solution of 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid in 0.42 ml of anhydrous dimethylformamide. After stirring at a temperature in the region of 20 0 C for one hour, 15.7 ml of benzylamine are added, followed by addition of 12.4 ml of N,N-diisopropylethylamine dissolved in 0.32 ml of dimethylformamide. After 20 hours, at a temperature in the region of 20 0 C, the reaction medium is concentrated under reduced pressure, at a temperature in the region of 40°C. The crude residue obtained is dissolved in DMSO and purified by preparative LC-MS. The fractions containing the desired product are combined and concentrated under reduced pressure at a temperature in the region of 40 0 C. 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide are thus obtained in the form of a cream-coloured powder, the characteristics of which are as follows: LC-MS retention time 2.86 minutes 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid may be prepared in the following manner: 1.3 g of sodium metabisulphite and 1.04 g of 3,4-diaminobenzoic acid are added, at a temperature in the region of 20 0 C, to a solution of 1 g of 1H-indazole-3-carboxaldehyde in 10 ml of dimethylformamide. The reaction mixture is refluxed for one hour and then cooled to a temperature in the region of 20 0 C and diluted with dichloromethane, and the mixture is filtered. The collected filtrate is concentrated under reduced pressure. The brown lacquer obtained (340 mg) is purified by WO 03/035065 PCT/GB02/04763 -281preparative LC-MS. 138.8 mg of 2-(iH-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid are thus obtained in the form of a beige-coloured powder.

1H-Indazole-3-carboxaldehyde may be prepared in the following manner: A solution of 2.27 g of (1H-indazol-3-yl)methanol in 220 ml of 1,2-dimethoxyethane is added to 13.32 g of manganese dioxide. After one hour at a temperature in the region of 20 0 C, the reaction mixture is refluxed for 15 minutes. After cooling to a temperature in the region of 20 0 C, the reaction medium is filtered through a sinter funnel packed with Celite. The collected filtrate is concentrated under reduced pressure at a temperature in the region of 40"C. 2.02 g of 1H-indazole-3-carboxaldehyde are thus obtained in the form of a yellow powder, the characteristics of which are as follows: 1-INMR (DMSO d6, 400 MHz): 7.40 ppm (triplet, 1H); 7.55 ppm (triplet, 1H); 7.75 ppm (doublet, 1H); 8.18 ppm (doublet, 1H); 10.23 ppm (singlet, 1H); 14.2 ppm (multiplet, 1H).

(1H-Indazol-3-yl)methanol may be prepared in the following manner: 3.2 g of lithium aluminium hydride are added portionwise to a solution of 7.08 g of methyl 3-indazolecarboxylate in 80 ml of tetrahydrofuran, cooled to a temperature in the region of OC by an ice bath. After 4 hours at a temperature in the region of OC, 1.6 g of lithium aluminium hydride are added. After 2 hours at a temperature in the region of OC, the reaction medium is treated successively with 6 ml of water and then 6 ml of aqueous 1N sodium hydroxide solution and finally 18 ml of water.

The reaction mixture is filtered through paper and the aqueous filtrate is then extracted with dichloromethane. The collected organic fractions are combined, dried over magnesium sulphate and concentrated under reduced pressure at a temperature in the region of 40°C. 3.15 g of (IH-indazol-3yl)methanol are obtained in the form of an off-white powder, the characteristics of which are as follows: 1H NMR (DMSO d6, 400 MHz): 4.80 ppm (doublet, 2H); 5.25 ppm (triplet, 1H); 7.15 ppm (triplet, 1H); 7.35 ppm (triplet, 1H); 7.51 ppm (doublet, 1H); 7.87 ppm (doublet, 1H); 12.81 ppm (multiplet,

IH).

Methyl 3-indazolecarboxylate may be prepared in the following manner: 0.5 ml of concentrated sulphuric acid is added dropwise, at a temperature in the region of 20 0

C,

to a solution of 9.13 g of 3-indazolecarboxylic acid in 100 ml of methanol. After refluxing for WO 03/035065 PCT/GB02/04763 -282hours, the reaction medium is concentrated under reduced pressure at a temperature in the region of 0 C. The aqueous residue obtained is extracted with dichloromethane. The organic phases are combined, washed with water until neutral, dried over magnesium sulphate and then concentrated under reduced pressure at a temperature in the region of 40C. The yellow powder obtained is washed with ethyl ether. A white powder is obtained. The filtrate is concentrated under reduced pressure until a yellow powder is obtained. This yellow powder is washed again with ethyl ether until a white powder is obtained. The yellow filtrate is concentrated a third time under reduced pressure and the yellow powder collected is itself also washed with ethyl ether. All the fractions of white powder are combined.

7.08 g of methyl 3-indazolecarboxylate are thus obtained in the form of a white powder.

EXAMPLE 2 2-(1H-indazol-3-vl)- 1H-benzimidazole-5-carboxvlic acid N-methylamide CH NH N

H

2-(1H-Indazol-3-yl)-lH-benzimidazole-5-carboxylic acid N-methylamide may be prepared by following the procedure for the preparation of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1): Starting with 20 mg of 2-(1H-indazol-3-yl)-lH-benzimidazole-5-carboxylic acid and 71.8 1tl of a methylamine solution (2M in tetrahydrofaran), 14.8 mg of expected product are obtained.

EXAMPLE 3 2-(1H-Indazol-3-yl)- H-benzimidazole-5-carboxylic acid N-ethylamide o

CH

3

CH

2 NH N N N

H

2-(1H-Indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-ethylamide may be prepared by following the procedure for the preparation of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1): WO 031035065 PCT/GB02/04763 -283- Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid and 19.4 ml of an ethylamine solution (33% in water) 14.8 mg of 2-(1H-indazol-3-yl)-lH-benzimidazole-5-carboxylic acid N-ethylamaide are obtained.

EXAMPLE 4 1H-Indazol-3-yl)- IH-benzimidazole-5-carboxylic acid IN-isopropylamide 0

N

(CH

3 2 CHNH 1 N N-NH El 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-isopropylamide may be prepared by following the procedure for the preparation of 2-(IH-indazol-3-yl)-lH-benzimidazole-5-carboxylic acid N-benzylamide (Example 1): Starting with 20 mg of 2-(1H-indazol-3-yl)-lH-benzimidazole-5-carboxylic acid and 12.3 ml of isopropylamine, 16.5 mg of 2-(IH-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-isopropylamnide are obtained.

EXAMPLE 2-(IH-lndazol-3-yl)- IH-b enzimidazole-5-carboxylic acid N-phenylamide aN 0

N

I- Z

-NH

1H-Indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-phenylamide may be prepared by following the procedure for the preparation of 2-(1H-indazol-3-y1)-1H-benzimidazole-5-carboxylic acid N-benzylam-ide (Example 1): Starting with 20 mg of 2-(1H-indazol-3-yl)-l1-i-benzimidazole-5-carboxylic acid and 13.1 ml of aniline, 14.1 mg of 2-(1H-indazol1'3-yl)-1H-benzimidazole-5-carboxylic acid N-phenylarnide are obtained in the form of a white powder.

EXAMPLE 6 24(1H-Indazol-3-vl)-1H-benzimidazole-5-carboxvylic acid Niphenethylamide WO 031035065 PCT/GB02/04763 -284-

NN

2-(l1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenethylamide may be prepared by following the procedure for the preparation of 1H-indazol-3 -yl)-l H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1): Starting with 20 mg of 2-(lH-indazol-3-yl)-1H-bcnizimidazole-5-carboxylic acid and 18 ml of phenethylamine, 17.7 mg of 2-(lIH-iadazol-3 -yl)-l H-benziinidazole-5-carboxylic acid N-p henethylamide are obtained in the form of a white powder.

EXAMPLE 7 2-(lH-Indazol-3-yl)- 1H-benzimidazole-5-carboxvylic acid N-morcholinoamide 0 rN

N

H

2-(1H-Indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-morpholinoamide may be prepared by following the procedure for the preparation of 1H-indazol-3-yl)- 1H-benzimnidazole-5-carboxylic acid N-benzylamnide (Example 1): Starting with 20 mg of 2-(lH-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid and 12.5 ml of morpholine, 18.6 mg of IH-indazol-3-yl)- lH-benzimidaizole-5 -carboxylic acid N-morpholinoamide are obtained in the forrn of a pale yellow powder.

EXAMPLE 8 241 H-Indazol-3 IH-benzimidazole-5-carboxylic acid N-(jN'-methyltpiperazino)amide WO 031035065 PCT/GB02/04763 -285- IH-Indazol-3J-yl)-1H-benzirnidazole-5-carboxylic acid N-(N'-methyl-piperazino)amide may be prepared by following the procedure for the preparation of 2-(I--indazol-3-yl)- carboxylic acid N-benzylamide (Example 1): Starting with 20 mg of 2-(1H-indazol-3-yl)--1H-benzimidazole-5-carboxylic acid and 15.9 ml of N-methylpiperazine, 16.1 mg of 1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid methyl-piperazino)amide are obtained in the form of a yellow oil.

EXAMPLE 9 2-(IH-Indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-pyrrolidinoan-iide 0 Ny

N

1H-Indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide may be prepared by following the procedure for the preparation of 1H-indazol-3-yl)-1H-benzimnidazole-5-carboxylic acid N.-benzylamide (Example 1): Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-beniziimidazole-5-carboxylic acid and 12 ml of pyrrolidine, 17.7 mg of 1 H-indazol-3-yl)- IH-benzimidazole-5-carboxylic acid N-pyrrolidinoamide are obtained in the form of a pale yellow powder.

EXAMPLE 1H-Indazol-3-yl)- lf-benzimnidazole-5-carboxytic acid N-(isobutvllamide 0 (CH 3 2

CHCH

2 N IZ N 2-(1 H-Indazol-3-yl)-1H-benzimidlazole-5-carboxylic acid N-(isobutyl)amide may be prepared by following the procedure for the preparation of 2-(lH-indazol-3-yl)-1H-benzinidazole-5-carboxylic acid N-benzylamide (Example 1): WO 031035065 PCT/GB02/04763 -286- Starting with 20 mg of 2-(lH-indazol-3-yl)-1H-benizimidazole-5-carboxylic acid and 14.6 ml of isobutylamine, 7.6 mg of lH-indazol-3-yl)-l H-benzimidazote-5-carboxylic acid N-(isobutyl)amide are obtained in the form of a pale yellow powder.

EXAMPLE 11I lH-lndazol-3-ylV- TH-benzimidazole-5-carboxvlic acid N-(cyclohexylmethyl)amide 0 N N

NN

I-I

1H-Indazol-3-yl)- lH-benzimidazole-5-carboxylic acid N-(cyclohexvlmethyl)amide may be prepared by following the procedure for the preparation of lH-indazol-3-yl)- IH-benzimidazole-5 -carboxylic acid N-benzylamide (Example 1): Starting with 20 mg of 2-(1H-indazol-3-yl)-lH-benzimidazole-5-carboxylic acid and 18.7 ml of cyclohexylmethylamine, 16.1 ing of IH-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-(cyclohexylmethyl)amide are obtained in the form of a white powder.

EXAMPLE 12 2-(l1H-Indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-(2-fjrfuryl)amide 0 N N H j -Pv N N

N-

1H-Indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-(2-furfuryl)amide may be prepared by following the procedure for the preparation of 2-(IH-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-benzylarnide (Example 1): Starting with 20 mg of 2-(1H-indazol-3-yl)-lH-benzimidazole-5-carboxylic acid and 13.3 ml of 2-furfitrylamine, 14.8 mg of 2-(1IH-indazol-3-yl 1 H-heiizimidazole-5-carboxylic acid N-(2-furfuryl)amide are obtained in the form of a white powder.

EXAMPLE 13 2-(l1H-Indazol-3-yI)-1H-benzimidazole-5-carboxvlic acid N-benzyl-N-methylamide WO 03/035065 PCT/GB02/04763 -287o0

H

2-(1H-Indazol-3-yl)-H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide may be prepared by following the procedure for the preparation of 2-(1 H-indazol-3-yl)-H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1): Starting with 20 mIng of 2-(1I--indazol-3-yl)-1H-benzimidazole-5-carboxylic acid and 18.&6 ml of N-methylbenzylamine, 7.3 mg of 2-(1H-indazol-3-yl)- I H-benzimidazole-5-carboxylic acid N-benzyl- N-methylamide are obtained in the form of a pale yellow powder.

EXAMPLE 14 Methyl 2-(l H-indazol-3-vyl)-3H-benzimidazole-5-carboxvlate 0

CH

3 O I> N

N

H

Methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate may be prepared in the following manner: A mixture of 0.1 g of 1H-indazole-3-carboxaldehyde and 113.7 mg of methyl 3,4-diaminobenzoate in ml of nitrobenzene is maintained at a temperature in the region of 145'C for 3 hours and minutes. After cooling to a temperature in the region of 20'C, the reaction mixture is purified on SPE g of SCX phase, processing and washing with methanol, extraction with a 2N ammnoniacal methanol solution). The ammoniacal solution collected during the detachment is then concentrated under reduced pressure at a temperature in the region of 40 0 C. 198.3 mg of an orange lacquer are obtained and are purified by preparative LC-MS. 42.7 mg of methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5carboxylate are thus obtained in the form of a beige-coloured powder, the characteristics of which are as follows: 111 NMR (DMSO d6, 400 MHz): 3.95 ppm (singlet, 3H); 7.40 ppm (triplet, 1H); 7.55 ppm (triplet, 1H); 7.75 ppm (doublet, 1H); 7.77 ppm (doublet, 1H); 7.95 ppm (doublet, 1H); 8.57 ppm (doublet, 1H); 13.85 ppm (multiplet, 1H).

WO 031035065 PCT/GB02/04763 -288- EXAMPLE 5,6-dimethyl-2-( 1H-indazol-3-yl)-t1H-benzimidazole CH 3 N CH:: CN

N-NH

C

3

H

5,6-Dimethyl-2-(1H-indazol-3-yl)- 1I--benzimidazole may be prepared by following the proceduare for the preparation of methyl 2-(1H-indazol-3'Iy1)-3H-benzimidazoe-5-Carboxylate (Example 14): Starting with 200 mng of I1H-indazole-3-carboxaldehyde and 177 mg of 4,5-dimethyl- 1,2phenylenediamiine in 10 ml of nitrobenzene, 15.9 mg of 5,6-dimethyl-2-(lH-indazol-3-yl)-1Hbenzimidazole are obtained in the form of a dark red powder, the characteristics of which are as follows: 1 H INMR (DMS0 d6, 400 MHz): 2.60 ppmn (singlet, 6H); 7.42 ppm (triplet, 1H); 7.53 ppmn (singlet, 2H); 7.58 ppm (triplet, 1H); 7.78 ppmu (doublet, I1H); 8.52 ppmn (doublet, 1H); 14.05 ppm (multiplet,

IH).

5,6-Dimethyl-2-(lH-indazol-3-yl)-1H-benzimidazole may also be prepared according to the following procedure: 3189 mg of sodium metabisulphite are added, at a temperature in the region of 20'C, to a solution of 300 mg of 1H-indazole-3-carboxaldehyde and 279 mg of 4,5-diinethyl-1 ,2-phenylenediamine in 3 ml of dir-nethylfonmamide. The reaction mixture is refluxed for 4 hours and then cooled to a temperature in the region of 20'C and filtered through paper. The collected filtrate is concentrated under reduced pressure. The brown lacquer obtained (340 mg) is purified by preparative LC-MS. 138.3 mig of 5,6-dimethyl-2-(1H-indazol-3-yl)-1IH-benzimidazole are thus obtained in the form of a beige-coloured powder.

EXAMPLE 16 5-methoxv-2-(1H-inidazol-3-yl)- 1H-beriziinidazole WO 031035065 PCT/GB02/04763 -289-

CH

3 0 N

NN-N

H

5-Methoxy-2-(1H-indazol-3-yl)-IH-benzimidazole may be prepared by following the procedure for the preparation of methyl 1H-indazo1-3-yl)-3H-benzimidazole-5-carboxylate (Example 14): Starting with 200 mng of lH-indazole-3-carboxaldehyde and 274.4 mg of 4-methoxy-l,2phenylenediamine dihydrochiorid.- in 10 mnl of nitrobenzene, 45.6 mng of 5-methoxy-2-(lH-indazol-3yl)-1H-benzimidazole are obtained in the formn of a light brown powder, the characteristics of which are as follows: IH NMvR (DMSO d6, 400 MHz): 3.90 ppmn (singlet, 3H); 7.00 ppm (doublet, IlH); 7.18 ppm (doublet, lH); 7.40 ppm (triplet, lH); 7.55 ppm (triplet, lH); 7.64 ppm (doublet, IH); 7.73 ppm (doublet, IH); 8.52 ppmn (doublet, lH); 13.91 ppmn (multiplet, 1H).

EXAMPLE 17 2-Cl H-Indazol-3-yll-3H-benzimidazole-4-carboxylic acid 0 OH

N

N

N--NH

H

2-l-nao--l-Hbniiaoe4croyi acid may be prepared by following the procedure for the preparation of methyl lH-indazol-3 -yl)-3H-benzimidazole-5-carboxylate (Example 14): Starting with 237 mg of 11--indazole-3-carboxaldehyde and 305.5 mg of 2,3-diaminobenzoic acid hydrochloride in 10 ml of nitrobenzene, 20.5 mg of 1H-indazol-3-yl)-3H-benzimidazole-4carboxylic acid are obtained in the form of a beige-coloured powder, the characteristics of which are as follows: lH INMR, DMSO d6, 400 MHz: 7.40 ppm (triplet, 1H); 7.42 ppm (triplet, 1H); 7.55 ppm (triplet, lH); 7.72 ppm. (doublet, 1H); 7.90 ppmn (doublet, 1H); 8.02 ppmn (doublet, 8.52 ppm. (doublet, liI); 13.68 ppm (multiplet, 1H).

WO 031035065 PCT/GB02/04763 -290- EXAMPLE 18 5-bromo-2-( 1H-indazol-3-yl)-3H-benzimiidazole Br

N

N NNl 5-Bromo-2-(1H-indazol-3-yl)-3H-benzimidazole may be prepared by following the procedure for the preparation of 5,6-dimethyl-2-(l1H-.indazol-3-yl)-1 H-benzimidazole (Example Starting with 643 mg of 1H-indazole-3-carboxaldehyde, 816 mg of 4-bromo-1,2-phenylenediamine, and 836.5 mg of sodium metabisuiphite in 15 ml of dimethylforrnamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N anmmnacal methanol) followed by a chromatography under pressure on silica, 939 mg of 5-bromo-2-(lH-indazol-3-yl)-3H-benzimidazole are obtained in the form of a brick-red powder.

EXAMPLE 19 2-(5-Ethoxy-2H-pyrazol-3--ytb- H-benzimidazole-4-carboxylic acid 0 OH N OCH 2

CHI

3

H

2-(5-Ethoxy-2H-pyrazol-3-yl)- 1H-benzimidazole-4-carboxylic acid may be obtained from 2-(2-benzyl- 5-etboxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylic acid by deprotection of the benzyl group in the presence of hydrogen and a catalyst such as palladium.

2-(2-Benizyl-5-ethoxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylie acid may be prepared by following the procedure for the preparation of 5,6-dimethyl-2-(1H-indazol-3-yl)-1-benzimidazole (Example Starting with 21.6 mg of 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde, and 17.7 mg of 3,4diaminobenzoic acid hydrochloride in 1 ml of nitrobenzene, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 50.9 mng of 2-(2-benzyl-5-ethoxy- 2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylic acid are obtained in the form of a yellow lacquer.

WO 03/035065 PCT/GB02/04763 -291- 2-Benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde may be prepared in the following manner: 4 A molecular sieves are added to a solution of 45.7 mg of (2-benzyl-5-ethoxy-2H-pyrazol-3yl)methanol in 0.5 ml of dichloromethane, followed by addition of 43.1 mg of pyridinium chlorochromate. After 20 hours at a temperature in the region of 20 0 C, the reaction mixture is filtered through Celite. The insoluble material formed is rinsed with ethyl acetate and then with dichloromethane. The filtrate is washed with water. After separation of the phases by settling, the aqueous phase is re-extracted with dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated under reduced pressure. 21.6 mg of ethoxy-2H-pyrazole-3-carboxaldehyde are thus obtained in the form of a brown lacquer, the characteristics of which are as follows: 1 H NMR (DMSO d6, 400 MHz): 1.35 ppm (triplet, 3H); 4.25 ppm (quartet, 2H); 5.30 ppm (singlet, 2H); 6.30 ppm (singlet, 1H); 7.25-7.40 ppm (multiplet, 5H); 9.72 ppm (singlet, 1H).

(2-Benzyl-5-ethoxy-2H-pyrazol-3-yl)methanol may be prepared in the following manner: 11.1 mg of lithium aluminium hydride are added to a solution of 76 mg of methyl 2H-pyrazole-3-carboxylate in 0.75 ml of tetrahydrofuran, cooled to a temperature in the region of O°C by an ice bath. After 3 hours at a temperature in the region of 0°C, 22.2 mg of lithium aluminium hydride are added and the reaction medium is allowed to warm to a temperature in the region of 20 0

C.

After 30 minutes at a temperature in the region of 20 0 C, 10 ml of ice-cold water are added and the reaction mixture is then filtered through Celite. After separation of the phases by settling, the aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated under reduced pressure. 45.7 mg of (2-benzyl-5-ethoxy-2H-pyrazol-3-yl)methanol are thus obtained in the form of a brown lacquer, the characteristics of which are as follows: 1 H NMR (DMSO d6, 400 MHz): 1.35 ppm (triplet, 3H); 4.15 ppm (quartet, 2H); 4.30 ppm (doublet, 2H); 5.00 ppm (triplet, 1H); 5.08 ppm (singlet, 2H); 5.70 ppm (singlet, 1H); 7.20-7.40 ppm (multiplet, Methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate may be prepared in the following manner: mg of sodium iodide, 36 tl of bromoethane and 70 mg of potassium carbonate are added, at a temperature in the region of 20'C, to a solution of 100 mg of methyl 2-benzyl-5-hydroxy-2H-pyrazole- 3-carboxylate in 1 ml of acetone. The reaction mixture is refluxed for 9 hours, cooled to a temperature WO 03/035065 PCT/GB02/04763 -292in the region of 20 0 C and filtered. The filtrate is concentrated under reduced pressure. 76 mg of methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate are thus obtained in the form of a solid, the characteristics of which are as follows: 1 H NMR (DMSO d6, 400 MHz): 1.35 ppm (triplet, 3H); 3.50 ppm (singlet, 3H); 4.22 ppm (quartet, 2H); 5.22 ppm (singlet, 2H); 6.28 ppm (singlet, 1H); 7.20-7.40 ppm (multiplet, Methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate may be prepared in the following manner: 1.72 ml of dimethylacetylene dicarboxylate are added, at a temperature in the region of 20 0 C, to a solution of 2.73 g of benzylhydrazine dihydrochloride in 45 ml of glacial acetic acid. The reaction mixture is refluxed for 3 hours, cooled to a temperature in the region of 20 0 C and then concentrated under reduced pressure. After filtering off the insoluble material formed, 252 mg of methyl hydroxy-2H-pyrazole-3-carboxylate are collected in the form of a white powder, the characteristics of which are as follows: 1H NMR (DMSO d6, 400 MHz): 3.76 ppm (singlet, 3H); 5.19 ppm (singlet, 2H); 5.85 ppm (singlet, 1H); 7.25-7.45 ppm (multiplet, 511); 11.69 ppm (multiplet, 1H).

The filtrate may be purified by flash chromatography on 400 g of 20-45 ptm silica (applied in a 25/75 ethyl acetate/cyclohexane mixture; eluant: 25/75 and then 40/60 ethyl acetate/cyclohexane) to give an additional batch of methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate in the form of a white powder.

EXAMPLE 5.6-dimethvl-2-(5-methyl-2H-pyrazol-3-vl)-lH-benzimidazole

CH

3 N CH 3

CH

3 H 5,6-Dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-lH-benzimidazole may be prepared by following the procedure described for the preparation of 5,6-dimethyl-2-( H-indazol-3-yl)- H-benzimidazole (Example Starting with 53.3 mg of 5-methyl-2H-pyrazole-3-carboxaldehyde, 65.9 mg of 4,5-dimethyl-l,2phenylenediamine, and 92 mg of sodium metabisulphite, in 0.5 ml of ethanol and 1.5 ml of WO 031035065 PCT/GB02/04763 -293dimnethylformarnide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N amimoniacal methanol) followed by a chromatography under pressure on silica, 20.8 mng of 5,6-dimethyl-2-(5-methyl-2H-pyrazol-3-yl)- 1H-benzimidazole are obtained in the form of a white powder.

5-Methyl-2H-pyrazole-3-carboxaldehyde may be prepared from commercial ethyl 5-methyl-2Hpyrazole-3-carboxylate by following the procedure described for the preparation of 1H-indazole-3carboxaldehyde, starting with methyl 3-indazolecarboxylate.

EXAMPLE 21 5,6-dimethyl-2-( 5-thiophen-2-,yl-2H-pyrazol-3-yl)-l1H-benzimidazole

CH

3 N S N

C

3

H

,6-Dimetbyl-2-(5-thiophen-2-yl-2H-pyrazol-3-yl)-lH-benzimidazole may be prepared by following the procedure described for the preparation of 5,6-dimuethyl-2-(1IH-i-indazol-3-yl)-1ll-benzimidazole (Example Starting with 16.2 mg of 5-thiophen-2-yl-2H-pyrazole-3-carboxaldehyde, 12.4 mg of 4,5-dlimethyl- 1,2phenylenediamine, and 17.3 mng of sodium metabisulphite, in 0.2 ml of ethanol and 0.6 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal mnethanol) followed by a chromatography under pressure on silica and a purification by LC-MS, 5,6-dimethyl-2-(5-thiophien-2-yl-2H-p~yrazol-3-yl)-l H-benzimidazole is obtained in the form of a white powder.

5-Thiophen-2-yl-2H-pyrazole-3-carboxaldehyde may be prepared from commercial ethyl 5-thiophen-2yl-2H-pyrazole-3-carboxylate by following the procedure described for the preparation of 1H-indazole- 3-carboxaldehyde starting with methyl 3-indazolecarboxylate.

EXAMPLE 22 2-(4-bromo-2H-pyrazol-3-vl)-5,6-dimetlhyl-IH-benzimidazole WO 03/035065 PCT/GB02/04763 -294- Br CH 3

CH

3

H

2-(4-Bromo-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole may be prepared by following the procedure described for the preparation of 5,6-dimethyl-2-(1H-indazol-3-yl)-lH-benzimidazole (Example Starting with 100 mg of commercial 4-bromo-2H-pyrazole-3-carboxaldehyde, 77.8 mg of 1,2-phenylenediamine, and 108.6 mg of sodium metabisulphite, in 1 ml of ethanol and 2 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a chromatography under pressure on silica, 143.2 mg of 2-(4-bromo-2H-pyrazol-3-yl)-5,6-dimethyl-lH-benzimidazole are obtained in the form of a yellow foam.

EXAMPLE 23 2-(5-ethvl-2H-pyrazol-3-vl)-5.6-dimethvl-lH-benzimidazole CH 3N 2CH2CH3 HN' N

CH

3

H

2-(5-Ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole may be prepared by following the procedure described for the preparation of 5,6-dimethyl-2-(1H-indazol-3-yl)-lH-benzimidazole (Example Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 110 mg of 4,5-dimethyl-1,2phenylenediamine, and 153 mg of sodium metabisulphite, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm C18 phase, dimensions 100x25 mm, flow rate 20 ml/min, elution gradient acetonitrile/0.07% TFA water/0.07% TFA from 95 to 95-5 and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 82 mg of 2-(5-ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-lH-benzimidazole are obtained in the form of a beige-coloured powder, the characteristics of which are as follows: 1 H NMR (DMSO d6, 300 MHz): 1.26 J 7 Hz: 3H); 2.31 6H); 2.70 (broad q, J 7 Hz: 2H); 6.60 (broad s: 1H); 7.22 (mult: 1H); 7.36 (mult: 1H); 12.37 (mult: 1H); 12.92 (mult: IH).

WO 031035065 PCT/GB02/04763 -295- 5-Ethyl-2H-pyrazole-3-carboxaldehlyde may be prepared from ethyl 5-cthyl-2H-pyrazole-3-carboxylate by following the procedure described for the preparation of 1 H-indazole-3-carboxaldehyde starting with methyl 3-indazolecarboxylate.

Ethyl 5-ethyl-2H-pyrazole-3-carboxylate may be prepared according to the general procedure in the following reference: Kunio Seki et al., Chem. Pharm. Bull., 32(4), 1568-1577 (1984).

EXAMPLE 24 5-ethyl-2H-pyrazol-3-yI)-4,5-ethylenedioxy- 1H-benzimnidazole 0 N CH CH 3

NN

H

2-(5-Ethyl-2H-pyrazol-3-yl)-4,5-ethylenedioxy-H-belzimidazole may be prepared by following the procedure described for the preparation of 5,6-dirnethyl-2-(I1-indazol-3-yl)- 1 H-benzimidazole (Example Starting with 100 mg of 5-ethyl-2H-pyrazole-3-car~boxaldehiyde, 134 mg of 3,4-ethylenedioxy-1,2phenylenediamine, and 153 mg of sodium metabisuiphite, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (Sex phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mmn, C1 8 phase, dimensions 100x25 mml, flow rate 20 ml/min, elution gradient acetonitrile/0.07% IFA water/0.07% TFA from 5-95 to 95-5 and desalification by SPE (SCX phase, washing with methanol, extraction with 2N aromoniacal methanol), 60 mg of 2-(5-ethyl-211-pyrazol-3-yl)-4,5-ethylenedioxy- 1H-benzimidazole are obtained in the form of a brown lacquer, the characteristics of which are as follows: 1 H NVR (DMSO d6, 300 MHz): 1.27 J 7 Hz: 3H); 2.70 (broad q, J =7 Hz: 2H); from 4.20 to 4.45 (mt: 4H); 6.61 (broad s: 1H); 6.72 J 8 Hz: IB); 6.88 (broad d, J =8 Hz: 1H); 12.50 (nault: 111); 12.94 (mult: 1IM.

EXAMPLE 2-(5-ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole WO 031035065 PCT/GB02/04763 -296- CH 3 C_ N CH 2

CH

3

H

2-(5-Ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole may be prepared by following the procedure described for the preparation of 5,6-dimethyl-2-( 1H-indazol-3-yl)- lH-benzimidazole (Example Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 138 mg of 4-methoxy-1,2phenylenediamine, and 153mig of sodium metabisuiphite, in 1 nil of ethanol and 3 ml of diinethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm Cl 18 phase, dimensions 100x25 mm, flow rate 20 mI/mmn, elution gradient: acetonitrile/0.07% TFA water/0.07% TFA from 5-95 to 95-5 and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 61 mg of 2-(5-ethyl-2H-pyrazol-3-yl)-5-metboxy- 1H-benzimidazole are obtained in the form of a brown lacquer, the characteristics of which are as follows: IH NMR (DMSO d6 with addition of a few drops of CD 3 COOD, 300 MHz): 1.26 J =7 Hz: 3H); 2.70 J =7 Hz: 2H); 3.79 3H); 6.61 IlH); 6.81t (dd, J 8. 5 and 2.5 Hz: IlH); '7.03 (broad s: 1lH); 7.42 J 8.5 Hz: 1H).

EXAMPLE 26 2-(5-ethyl-2H-pyrazol-3-yl)-4-hydrox-1 H-benzimidnzote

OH

N

CH

2 CH3

N

H

2-(5-Ethyl-2H-pyrazol-3-yl)-4-hydroxy-1H-benzimidazole may be prepared by following the procedure described for the preparation of 5,6-dimnethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 100 mg of 2,3-diaminophenol, and 153 mg of sodium metabisuiphite, in I ml. of ethanol and 3 ml of dimethylfonnamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N aminioniacal methanol) followed by a reverse-phase HPLC (5 mm, C 18 phase, dimensions: 100x25 mm, flow rate 20 ml/min, elution gradient: acetonitrile/0.07%/ TFA water/0.07% TFA from 5-95 to 95-5 and desalification by 301 SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 16 mg of WO 03/035065 PCT/GB02/04763 -297- 2-(5-ethyl-2H-pyrazol-3-yl)-4-hydroxy-1H-benzimidazole are obtained in the form of a brown lacquer, the characteristics of which are as follows: 1 H NMR (DMSO d6 with addition of a few drops of CD 3 COOD, 300 MHz): 1.26 J= 7 Hz: 3H); 2.70 J= 7 Hz: 2H); 6.55 J 4.5 Hz: 1H); 6.66 1H); 6.96 (broad d, J 4.5 Hz: 2H).

EXAMPLE 27 2-(5-ethyl-2HI-pyrazol-3-vyl)-5-bromo-1H-benzimidazole Br N CH 2

CH

N N-NH

H

2-(5-Ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzimidazole may be prepared by following the procedure described for the preparation of 5,6-dimethyl-2-( 1H-indazol-3-yl)-l H-benzimidazole (Example Starting with 20 mg of 5-ethyl-2H-I-pyrazole-3-carboxaldehyde, 30 mg of 4-bromo-1,2phenylenediamine and 30 mg of sodium metabisulphite, in 1 ml of ethanol and 2 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm C18 phase, dimensions: 100x25 mm, flow rate 20 ml/min, elution gradient: acetonitrile/0.07% TFA water/0.07% TFA from 5-95 to 95-5 and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 21 img of 2-(5-ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzimidazole are obtained in the form of a yellow powder, the characteristics of which are as follows: 1 H NMR (DMSO d6, 300 MHz): 1.28 J 7 Hz: 31-H); 2.71 J= 7 Hz: 2H); 6.67 1H); 7.30 (dd, J 8.5 and 2.5 Hz: 1H); 7.49 (mt: 1H); 7.712 (broad s: IH); from 12.5 to 13.5 (broad mult: 2H).

The products of formula of the present application can also be prepared according to the following process: WO 03/035065 PCT/GB02/04763 -298- Br NH, CaSO, DMF I NH HOC r N NH NNH (ii) HCl/EtOH Y O0 0 Ac,O H I PhB(OH), Pd(0), Br N N Na,C0 3 Br N S N N-NH (ii) EtzN

N-

H

Y

0 The products of Examples 97 to 145 of the present application represented in the TABLE 3 below can be prepared according to the schemes indicated above and in particular according to the procedures indicated below.

EXAMPLE 97 3-(6-phenvl-1H-benzimidazol-2-yl)-2H-indazole Step 1 Synthesis of 3-(6-bromo-1H-benzimidazol-2-yl)-2H-indazole (other preparation of example 18) 4.25 g of 1-hydroxybenzotriazole and 4.3 g of calcium sulphate are added at ambient temperature to a solution of 4.6 g of indazole-3-carboxylic acid in 50 ml of dimethylformamide. The reaction mixture is cooled to approximately 0°C and then 4.9 ml of N,N-diisopropylcarbodiimide are slowly added. After stirring for 2 hours at ambient temperature, 5.9 g of 4-bromo-o-phenylenediamine are added. After stirring for 60 hours at ambient temperature, the reaction mixture is concentrated to dryness under reduced pressure. The brown oil obtained is taken up in 50 ml of water and extracted 3 times with 50 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and then concentrated to dryness under reduced pressure. 18 g of a brown oil are thus obtained, which oil is taken up in 100 ml of a 20% solution of hydrochloric acid in ethanol. The mixture is brought to reflux for 4 hours and then concentrated to dryness, the brown oil obtained is taken up in 20 ml of water, and an aqueous ammonia solution is run in until a pH of the mixture of about 8-9 is obtained. The aqueous phase is then extracted 3 times with 30 ml of ethyl acctate and the organic phases are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure. After purification by chromatography under pressure on silica (eluent water/acetonitrile), 5 g of 3-(6-bromo-1Hbenzimidazol-2-yl)-2H-indazole are thus obtained.

WO 03/035065 PCT/GB02/04763 -299- IR spectrum (KBr): characteristic bands at 1621, 1570, 1441, 1344, 1324, 1273, 1239, 1135, 1042, 914, 804, 774 and 746 cmu' Step 2 Synthesis of 1-[2-(1-acetyl-1H-indazol-3-yl)-5-bromobenzimidazol-l-yl]ethanone 5 g of 3-(6-bromo-1H-benzimidazol-2-yl)-2H-indazole are charged to a solution of 40 ml of acetic anhydride and 40 ml ofpyridine. The mixture is brought to reflux for 4 hours and then concentrated to dryness after returning to ambient temperature. The brown solid obtained is taken up in 50 ml of ethyl acetate and washed with 50 ml of a saturated sodium hydrogencarbonate solution until a pH of 7-8 is obtained. The organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The light brown solid obtained is triturated in 20 ml of ethyl acetate and then filtered off on a sintered glass funnel. 1.5 g of the compound 1-[2-(l-acetyl-lH-indazol-3-yl)are thus obtained. A second crop is obtained by chromatographing the filtrate obtained above under pressure on silica (eluent cyclohexane/ethyl acetate), i.e. 1.3 g of the same compound.

Characteristics of the compound: 1 H NMR spectrum (300 MHz, (CD 3 2 SO d6, 5 in ppm).

The mixture of the two positional isomers in the proportions 50/50 is observed.

2.61 and 2.62 (2 s, 3H in all); 2.80 3H); 7.62 (broad t, J 7.5 Hz, 1H); 7.68 and 7.71 (2 dd, J 9 and 2 Hz, 1H in all); 7.80 (ddd, J 8.5, 7.5 and 0.5 Hz, 1H); 7.91 and 8.01 (2 d, J 9 Hz, 1H); 8.18 and 8.20 (2 d, J 2 Hz, 1H in all); 8.27 and 8.30 (2 d, J 7.5 Hz, 1H in all); 8.46 J 8.5 Hz, 1H) IR spectrum (KBr): characteristic bands at 1727, 1610, 1450, 1405, 1374, 1326, 1290, 1198, 1176, 964 and 760 cm 1 Step 3 Synthesis of 3-(6-phenyl-1H-benzimidazol-2-yl)-2H-indazole mg of sodium carbonate, 7 mg of dihydrogendichlorobis(di-tert-butylphosphonite-cP)palladate(2-) (POPd[0]) and 46 mg ofphenylboronic acid are added under an argon atmosphere to a solution of mg of 1-[2-(l-acetyl-1H-indazol-3-yl)-5-bromobenzimidazol-1-yl]ethanone in 800 1 l of anhydrous tetrahydrofuran. The reaction mixture is brought to reflux for 3 hours and then cooled to ambient temperature. The mixture is then diluted with 3 ml of ethyl acetate and then washed with 2 times 2 ml of water. The organic phase is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. 48 mg of a brown solid are obtained, which solid is dissolved in 500 p1 of tetrahydrofuran, to which 500 pl of diethylamine are added. The reaction mixture is heated at 60 0 C for 4 hours and then allowed to return to ambient temperature. The mixture is then concentrated to dryness and then the brown solid obtained is purified by LC-MS to produce 12.5 mg of 3-(6-phenyl-1Hbenzimidazol-2-yl)-2H-indazolc analytical retention time 3.10, MS 311 WO 03/035065 PCT/GB02/04763 -300- The products of formula of the present application and in particular examples 98 to 145 can be prepared according to the following process S(i) RB(OH),, Pd(O), Br N Na 2

CO

3 N N (ii) Et 2

N

0 R N

H

The synthesis of examples 98 to 145 is carried out in a similar way to the synthesis of 3-(6-phenyl-1Hbenzimidazol-2-yl)-2H- indazole (example 97) but replacing phenylboronic acid with boronic acids of formula RB(OH)2.

Products of formula of the present application which constitute Examples 28 to 96 and 146 to 180 of the present application are represented in Table 3: these products can be prepared according to the schemes indicated above and in particular as indicated above for the product of Example 1.

TABLE 3 Example Molecular MS retention nubrSTRUCTURE

RNH

2 or RB(OH) 2 Frua MWV Characteristic time Nomenclature (minutes) 2-(1 H-Indazol-3-yI)- 1 H-benzoimidazole- 28 HNHIC22H18N603S 446.49 447 2.77 5croyi cd24 -N H 0dichloro-benzylamide H

H

2

N

0 2-(1 H-I ndazol-3-yI)- 29 NH C20H21N502 363.42 364 [M+H]f 2-8 1 -ezidao- 5-carboxylic acid (3- 0 N NN-N ethoxy-propyl)-amide H F I I F .IC22H 16BrN5O 1446.311I 447 1 .3 2-(1 H-Indazol-3-yI)- 1 H-benzoimidazole- 5-carboxylic acid 4bromo-benzylamide

H

2 Br 1 I 4 1 C23H19503S 445.50 446 [M+HI~j 2.81 2-(1 H-I ndazo V3-yI)- 1 H-benzoimidazole- 5-carboxylic acid 4methanesulfonylbenzylam ide 0 HCJNH 2 0 2-(1 H-Indazcl-3-yI)- P1 IH-benzoimidazole- HNC26H19N50 417.47 418 3.38 5-carboxylic acid N N -NH HZN (naphthalen-1 N lmethfl-am ide H C23HI16F3N50 1435-41 436 [M+H] t 3.41 1 H-benzoimidazole- 5-carboxylic acid 4trifiuoromethylbenzylamide

F

H

2 N

F

2-(l H-indazcl-3-yI)- 1 H-benzoimidazole- HN N N-N C2OHl5N50S 373.44 374 301 5-carboxylic acid 0 N H NN (thiophen-2- H ylmethyl)-amide 2-(l H-I ndazol-3-yi)- 1 H-benzoimidazole- C24H22N60 410.48 411 2.49 5-carboxylic acid 4- HNHCL dimethylaminoo0 N yN-NH /benzylamide H2 N H-Indazol-3yo y)-1 H- 36 yC26H30N603 474.56 475 [M+H]f 3.31 carbonylj-amino}- HN methyl)-piperidine-1 0 ]:-DCN 1~N 0 carboxylic acid tert- '~NN N "X butyl ester

H

2 C22H16N603 1412.41 1 413 [M+Hl+ 1 3.14 2-(l H-Indazol-3-y)- 1 H-benzoimidazole- 5-carboxylic acid 4nitro-benzylamide

HCI

H2N 0 I I I I C21H16N60 1368.401I 369 [M+HI' 2.39 2-(1 H-Indazol-3-yI)- 1 H-benzolmidazole- 5-carboxylic acid (pyridin-3-ylmethyl)amide NH,

N-

2-(l H-Indazol-3-yI)- 39 HN9C22H6BrN5O 446.31 447 3.36 I-eziiaoe N NNB r 5-carboxylic acid 3bromo-benzylamide

N

C23H19N502 1397.44 398 [M+H]f 2-(l H-Indazoi-3-yI)- I H-benzoimidazole- 5-carboxylic acid 3methoxybenzylamide HN I 0

HN

o I/ N NNH C23H17N503 1411.421 412 1 1 3.07 2-(1 H-I ndazol-3-yI)- 1 H-benzoimidazole- 5-carboxylic acid (benzo[1 ylmethyi)-amide

NH

2 F I I 42 C24H17N5OS 1423.50 424 [Mi-H] t 3.42 2-(1 H-I ndazol-3-yI)- I H-benzoimidazole- 5-carboxylic acid (benzo[b~thiophen-3ylmethyl)-amide

H

2

N

S

N-N 2-(l H-Indazol-3-yI)- I H-benzoimidazole- 43 HN:i C21 H 19N70 385.43 386 2.59 5-carboxylic acid (I ,3-dimethy-1 Ho N- pyrazol-4-ylmethyl)- VI amide

NH

2 F F

NH-

2 1 H-benzoimidazole- 44 FHN C23H16F3N502 451.41 452 [M+Hf- 3.44 5-carboxylic acid 2o 0 trifluoromethoxy- N benzylamide "aH F F 2-(l H-lndazol-3-yl)- HNC23H9N50 381.4 38 [M+f 3. 1 H-benzoimidazole- 4 NN N -N 2 H 9 5 8 .4 8 M H 3 2 5-carboxylic acid 2-

HH

2 methyl-benzylamide C21H17N5OS 1387.46 388 [M+H]I 3.16 s\ NH2 2-(1 H-Indazol-3-yi)- 1 H-benzoimidazole- 5-carboxylic acid (3methyl-thiophen-2ylmethyl)-amide 2-(l H-I ndazol-3-yI)- I H-benzoimidazoie- 5-carboxylic acid 2trifluoromethylbenzylamide 0 ~Jt ~Jt ijJ 023H16F3N50 1435.41 436 [M+H]f 3.38 r T 1 1 1 T T 028H21 N502 459.511 460 1IM±H]+ 3.56 2-(l H-Indazol-3-yl)- 1 H-benzoimidazole- 5-carboxyliG acid 4phenoxybenzylamide 0 ~Jt ~Jt 0' 0

NH

2 I t i i C23H1 6F3N5021 451.411 452 1 [M+Hf+ 3.46 2-(1 H-lndazol-3-yi)- I H-benzoimidazole- 5-carboxylic acid 3trifluoromethoxybenzylamide I .J 4. 0 2-(l H-Indazol-3-yl)- 1 H-benzoimidazole- NH C21 H23N502 377.45 378 LM+H]f 2.94 5-carboxylic acid (3- N N-H isopropoxy-propyl)- \1 amide 0 NH2

H

N -N 2-(l H-I ndazol-3-yI)- I H-benzoimidazole- 51 HNY C20Hl7N70 371.40 372 [M+Hf' 2.56 5-carboxylic acid (1- N NHNH 2 methyl-i H-pyrazol-4- H CNIN-ylmethyl)-amide 1 f I 1 2-(l H-Indazol-3-yI)- I H-benzoimidazole- 5-carboxylic acid 4isopropylbenzylamide C25H23N50 1 409.491 410 1 1 3.51

H

2 NH2 -i T i

C

022H19N502 1385.43 386 3.19 2-(l H-Indazol-3-yI)- I H-benzoimidazole- 5-carboxylic acid 3-ylmethyl)-amide 1 .1 .1 1~ T 1 1 1 54 C24H17N50S 1423.501I 424 I [M+H]l I 3.38 2-(l H-Indazol-3-yi)- 1 H-benzoimidazole- 5-carboxylic acid (benzo[b]thiophen-2ylmethyl)-amide

QS)\-

NH

2 I 1 t 1 C26H24N603 1468.521 469 1 1 2.92 2-(l H-Indazol-3-yI)- 1 H-benzoimidazoleacid [3- (3-acetylaminophenoxy)-propyl]amide H H C H I

I

1 1 T T r 1 1 56 C21H15CIN6O 402.84 j 2.92 2-(1 H-Iridazol-3-yI)- 1 H-benzoimidazole- 5-ca rboxylic acid (6chloro-pyridin-3ylmethyl)-amide 0 ~Jt ~Jt w

NH

2 2-(l H-Lndazol-3-yI)-

NH

1 H-benzoimidazole- 57 N C24H17N50S2 455.56 456 3.47 5-carboxylic, acid NH ([2,2']bithiophenyl-5ii I. NH 2 ylmethyl)-amide 0 2-(l H-lndazol-3-yI)- NH 1 H-benzoimidazoie- -N 5-carboxylic acid 58 N- G24H19N502 409.45 410 3.07 oNH (2,3-dihydro- H N H 2 ylmethyi)-amide 0 0 -N 1 H-benzoimidazole- 59 NN -N C23H16N60 392.42 393 3.03 5croyi cd4 NH 5croyi cd4 H cyano-benzylamide 0 NH 2 0 ~Jt ~Jt w I I I I II C24H16C1N50S 457.94 1 458 1[M-iH]* 3.55 2-(l H-Indazak-3-yI)- 1 H-benzoimidazoleacid chiorobenzo[b]thiophen-3ylmethyi)-amide

NH?

C23H16F3N50 1435.411 436 1 [M+H]f 3.41 2-(l H-Indazol-3-yI)- 1 H-benzoimidazole- 5-carboxylic acid 3trifluoromethylbenzylamide H2 N J -F

F

L r T I I 023Hl9N50S 1413.501 414 3.26 2-(l H-Indazol-3-yI)- 1 H-benzoimidazole- 5-carboxylic acid 2methylsulfanylbenzylamide s 4 I I t t C24H17N50S 1423.50 1 424 1 1 3.38

H

2

N

2-(1 H-Indazol-3-yl)- I H-benzoimidazole- 5-carboxylic acid (benzo[b]thiophen-3ylmethyl)-amide

I

1 r r r 1 2-(l H-Indazol-3-yi)- 1 H-benzoirnidazole- 5-carboxylic acid (tetra hydro-pyran-4ylmethyl)-amide C21H21N502 375.431 376 j 2.65

NH

2 0 I C24H19N503 425.45 426 [M+Hl+ 3.28 2-(l H-1 ndazol-3-yI)- 1 H-benzoimidazoleacid (2,3-dihydrobenzo[1,4]dioxin-2ylmethyl)-amide 0 ~Jt ~Jt U2

NH

2 0o I L I I I 1 r r r 1 C20H15N502 1357.371I 358 1 [M±HI+ 2.92 2-(1 H-Indazoi-3-yI)- 1 H-benzoimidazole- 5-carboxylic acid (furan-3-yl methyl) amide 0or NH 2 N'H 2-(1 H-Inclazol-3-yI)- N1 IH-benzoimidazoie- 67 N- C22H-16N603 412.41 413 3.14 NHI 5-carboxylic acid 2- J H NH 2 nitro-benzylamide

HGI

U1, N o 00 4 0 I I C2OHl5N5OS 1373.44 374 1[M+H]f 3.03 2-(1 H-I ndazol-3-yI)- 1 H-benzoimidazole- 5-carboxylic acid (thiophen-3ylmethyl)-amide 19 NH 2 I- I i i i C24H21N50 1 395.471 396 3.37 2-(1 H-Indazol-3-y)- 1 H-benzoimidazole- 5-carboxyi~c acid dimethylbenzylamide H N I J -l C24H19N70 1 421.461I 422 1 2.61 2-(l H-lndazol-3-yI)- 1 H-benzoimidazoleacid (1methyl-i Hbenzoimidazol-2ylmethyl)-amide

NH

I t t i 382 C23H19N50 1381.44 JM+HI 1 3.24 2-(l H-I ndazol-3-yi)- 1 H-benzoimidazoleb-carboxylic acid 3methyl-benzylamide 0

H

2 N,

N

I I I I I I I 022H16C1N50 1401.861I 402 1 I 3.29 2-(l H-Indazol-3-yl)- 1 H-benzoimidazole- 5-carboxylic acid 3chloro-benzylamide 72

H

2

N

-x 1 4 1 F f 1 0

NH

S-

N N HN

NH-

C22Hl8N603S 1446.49 447 1[+l

HCI

0

C==S

111 NH 2

H

2

N

3H-benzoimidazole- 4-carboxylic acid 4sulfamoylbenzylamide 74 C20H21 N502 363.42 364 3.45 2(HIdzl3y) 0 7-.3H-benzoimidazole- N 4-carboxylic acid (3- NH ethoxy-propyl)-amide 0

NH

S NHB C22H168rN5O 446.31 447 4.38 75 NH2-(l H-lndazol-3-yI)- N 3H-benzoimidazole-

NH

H

2 N Br 4-carboxylic acid 4brom o-benzylamide 0 /H 2-(1 H-1Indazol-3-yO)- 76NH C26H19N50 417.47 418 4.4bezimdzo

__N

NI- H 2 N 4-carboxylic acid (naphthalen-1 ylmethyl)-amide 0

NH

NH 2-(1 H-Indazol-3-yI)- 77 PSI C2OH15N5OS 373.44 374 3.9 3H-benzoimidazole- -N 4-carboxylic acid 2 N (thiophen-2- H2N/ /ylmethyl)-amide C0

NH

NH 2-(1 H-Indazol-3-yI)- 78 N-IHCI C24H22N60 410.48 411 tM±H]+ 2.93 3H-benzoimidazole- NHHC 4-carboxylic acid 4- NH N dimethylamino-

IH

2 N benzylamide 0 NilI 79 N-IC22H15N603 412.41 413 LM+H]+ 3.87 2-(1 H-Indazo-3-yI)- N \H7FCI 3H-benzoiniidazole- NH 07 NH 4-carboxylic acid 4- 0 nitro-benzylamide 0

NH

2-(1 H-I ndazol-3-yI)- Nl NH C21H16N60 368.40 369 2.4 3H-benzoimidazole-

N-N

_N 4-carboxylic acid NH NH, (pyridin-3-yimethyl)amide 1 T f 0 NH Br NH

NN-

Br

NH

2 022H1 CBrN5O 446.311I 447 1[M-IH]+ 1 4.18 2-(l H-Indazol-3-yi)- 3H-benzoimidazole- 4-ca rboxylic acid 3bromo-benzylamide 2-(1 H-lndazol-3-yI)- 3H-benzolmidazole- 4-carboxylic acid 3methoxybenzylamide I t t T I C23Hl9N502 1 397.44 1398 1 [M+Hf t 1 3.95

H

2 N ,,"a0 0

/H

NH 2-(l H-lndazol-3-yI)- 83 N-(C24H17N50S 423.50 424 4.68 3H-benzoimidazole- H 4-carboxylic acid I (benzo[bllthiophen-3s ~ylmethyl)-amide 0

NH

2-(l H-lndazol-3-yI)- 84 0C28H21 N502 459.51 460 4.5 3H-benzoimidazole- 4-carboxylic acid 4- NHZ phenoxy-

NI-]

2 benzylamide 0

NH

NH

NHP 2-(l H-ndazol-3-yl)-

NFH

2 N C23H15F3N502 451.41 452 4.4 3H-benzoimidazole- NV 0- FF 4-carboxylic acid 3- F trifluoromnethoxy- 0 F benzylamide 0

NH

N 2-(l H-Indazol-3-yi)- S Ni- 86 1 C, C21H15CIN6O 402.84 403 [M+H] 4 3.9 3H-benzoimidazole- -N 4-carboxylic acid (6- '.NH NH, chioro-pyridin-3- N a rN ylmethyl)-amide NH 2-(l H-Indazol-3-yI)- 87 o C4H1N502 409.5 40 [MH]~3H-benzoimidazole- S NH 87 N 1 C2H19N02 09.5 41 3.9 4-carboxylic acid (2,3-dihydro- NH HN 0

NHF

NH 2-(l H-Indazol-3-yl)-

NH

NH r 4-carboxylic acid 3-

H

2 F trifluoromethyl- F benzylamide 0 89 NHC2H95S 430 44 MH1 2-(1 H-I ndazol-3-yl)- 89 -I 231950S 41.5 44 M+L .9 3H-benzoimidazole- \NH- 4-carboxylic acid 2- I NH 2 methylsulfanylbenzylamide 1 r T r r 0

NH

NH

C20H15N502 1 357.371I 358 1[M+Hf+ 3.68 UoNH2 4 1- 1- r r r T 2-(l H-Indazol-3-yl)- 3H-benzoimidazole- 4-carboxylic acid (furan-3-ylmethyl)amide 2-(l H-Indazoi-3-y)- 3H-benzoimidazole- 4-carboxylic acid 2nitro-benzylamide 91 0 0 N

H

N

I IN

N

NH

C22H1 6N603 1412.411 413 1 [M+HIF 3.95

NH,

HCI

o 10 i i- i- t 024H21 N50 1395.471 396 4.45

H

2 N\ 2-(l H-Indazol-3-yI)- 3H-benzoimidazole- 4-carboxylic acid dimethylbenzylamide 0

NH

NH 2H6I5 418 0 MH 5.03

H

2 N C2H615 0.6 422-(1H-Indazol-3-yI)- N cl 3H-benzoimidazole-

NH

4-carboxylic acid 3chloro-benzylamide 0

N

H

94 NH C11N0 333 5 MIH~42 N- 2H55 5.8 34 42 2-(l H-indazoI-3-yi)- 3H-benzoimidazole-

NH

H

2 N 0 4-carboxylic acid phenyiamide 0

NH

N -IC22H17N50 367.41 368 3.9 2-(1H-Indazol-3-yI)- 3H-benzoimidazole-

NH

H

2 N 4-carboxylic acid benzylamide C23H19N50 1 381.441I 382 1 [MH] 4.01 H zN

\O

2-(l H-Indazol-3-yI)- 3H-benzoimidaZOle- 4-carboxylic acid phenethyl-amide N 3-(G-Phenyl-1 H- 97 N N" C20H14N4 310.36 311 3.14 benzoiirnidazo-2-yl)- N

H

H HO2H-indazole

HO

3-[6-(2,4-Dichloro- N /~NHO, OH phenyl)-1 H- 98 /\NB C20H12Cl2N4 379.25 379 3.53

H

H CIbenzoimidazol-2-yl]- 2H-indazoie

N

N

N"

N

H

H

C24H16N4 1360.421 361 I[M+H]+I 3.51 3-(6-Naphthalen-1 yI-l H-benzoimidazol- 2-yi)-2H-indazole

OH

HOBZ71 100N 3-[6-(4-Fluoro- N H C20H13FN4 328.35 329 3.21 hnI-H H benzoimidazo-2-yl]- 2H-indazole

FF

N 3-[6-(4-hloro- N IHO OH peylH 01N H B" C20H13CIN4 344.805 345 [M 3.44l)IH 101 Hbenzoimidazo-2-y]- 2H-indazole Gi a w uJ 3-[6-(4-Methoxy- 102N7J C21Hl6N4O 340.386 341 rM+H-s 3.14 hn)I- HNL benzoimidazol-2-yi]- 2H-indazole N. ~N3-[6-(3-Chloro-4- 103 N H C2OHl12CIFN4 362.795 362 3.51 fio-pey)1- H benzoimidazol-2-y]- HO 2H-indazole F clHO 104 C20H12C12N4 379.25 [378- [MH+ 3.81 phenyl)-I H- 380] benzoimidazol-2-y]- 2H-indazole N N NI_ 0 ~Jt ~Jt w

LJJ

T 1 1 1 T T T

[M+HI+

C26H18N4S2 1448.571I 449 3.91 3-(6-Thianthren-1 -yI- I H-benzoimidazol-2yl)-2H-I-ndazole aC 1:

S-

HO'BO

0 ~Jt ~Jt w F i I -1 C26H18N4 1386.4581 387 I[M-4H]-I- 3.78 3-(6-Biphenyl-4-yi- 1 H-benzoimidazol-2yI)-2H-indazole HOR

HO

I r r r 1 Ny

N

N H 0 ~Jt ~Jt HO_6 OH 021H16N4 1324.3871 324 3.38 3-(6-p-Tolyi-1 Hbenzoim idazol-2-yi)- 2H-indazole N /N 3-(6-m-Tolyi-1 H- 108 -N H C21 H1 ON4 324.387 325 3.41 benzoimidazo-2-yi)- H 2H-indazole

HO

N 3-(6-o-Toly-1 H- 19N' C21H16N4 324.387 325 3.41 benzoimidazol-2-yl)- NH 2H-indazole

HO

HO

w N ~N3-(6-Thiophen-3-yi- 110 N N HO CI8H12N4S 316.386 317 3.13 1H-benzoimidazol-2- S

S

N \Trif luorom ethyl- 111 N C21HI3F3N4 378.357 379 3.65 phenyl)-l H- N H F F OH F H benzoimidazol-2-ylI- F -F X TH2H-indazole N NI Trifiuoromethyl- 112 \N C21H13F3N4 378.357 379 3.68 phenyl)-l H- OH benzoimidazol-2-y]- FF 2H-indazole F F F 3-[6-(3-Chloro- 113 \N H OH C2OHl3CIN4 344.805 345 3.55l-1- H IB-O benzoimidazol-2-y]h 2 H i n d a z o l e ci ci N N 3-[6-(3-Methoxy- N pey)lH 114 N H 0old C21H16N40 340.386 341 [M+HJ+ 3.41 hn)-- H IbenzoimidaZOk-2-yi]y OH 2H-indazoe 0 ~Jt ~Jt

U-

C.

3-[6-(3,5-Dimethyl- N y)-lN 115 HC22H18N4 338.414 339 3.39 N(HH benzoimidazol-2-yII- HHidzl

HO

3-[6-(3,4-Dim ethyl- N

N

16/NC22H18N4 338.414 339 3.55 pey)lH 16N H OH H IIJ-benzoimidazol-2-yI]- 117 C21H14N402 354.369 354 3.18 yI-1 H-benzoimidazoi- 2-wyI)-2H-indazole N

N

N

0 ~Jt ~Jt N 3-[6-(4-tert-Butyl- N N phenyl)-1 H- 118 N~ OH C24H22N4 366.468 367 3.95omdao-2y] OH 2H-indazoie 3-(6-Hex-1-enyl-1 H- 11 NNC20H20N4 316.408 317 3.72 benzoimidazol-2-yi)- N OH H' H 2H-indazole H NOH N N 3-[6-(3,4-Dimethoxy- N N' phenyl)-1 H- 120 \N H C22H18N402 370.412 371 3.00 H H benzoimidazol-2-y]- 2H-indazole -00 B H /0 a 0 ~Jt ~Jt 00 N I> 3-[2-(2H-i ndazol-3- 121 H C20H14N40 326.359 327 2.92y)-H eH HOI phenol HO

OH

OH

4-[2-(2H-Indazol-3- 122 N N0N 20H14N40 326.359 327 [M+H]I 2.84 yl)-3H- H OH OH phenol HO H N ~N3-[6-(3,4-Dichloro- 123 H C20Hl2Cl2N4 379.25 378 3.82 hnl-H H H benzoimidazol-2-yJa B 2H-indazole N IN Trifluoromethoxy- 124 N H C21H13F3N40 394.356 395 3.72 phenyl)-l

H

OH benzoimidazol-2-yl]- F EF Fb OH 2H-indazole

FF

0 ~Jt ~Jt 1 -{4-[2-(2H-indazol- N N" N y)-H- 125 H OHC22H16N40 352.397 353 [M+HJ+ 3.08 benzoim BH phenyi}-ethanone 00 3-6

N

Benzo[b]thiophen-2- 126 \N Hi C22H14N4S 366.446 367 3.82 H yI-l H-benzoimidaZOl- SOH 2-yi)-2H-indazoie S OH N 127 N H C23H20N403 400.438 401 [M 3.02 TrmtoyhnI- H I1 H-benzoimidazol-2- "OH yII-2H-Indazole -(OlN N

M\

N H

H

0 C20Hl4N40S 1358-4231 359 13.09 1 -{5-[2-(2H-Indazol- 3-yI)-3Hthiophen-2-y}ethanone 0 OH C22H16N40 1352.3971 35 1 3.05 1 -{3-[2-(2H-Indazol- 3-yI)-3Hphenyll-etha none 4- t 0OH

OH

OH

4 4 1 t t C27H20N40 1416.484 417 [MH] 3.75 3-[6-(4-Benzyioxyphenyl)-1 HbenzoimidaZOl-2-y]- 2H-indazole L S 404.448 C26Hl7FN4 405 4.02 3-[6-(2-Fluorobiphenyl-4-y)-1 Hbenzoimidazol-2-y]- 2H-indazole

OH

BO

F'

N 132 N H022H14N4S 366.446 367 3.55b~hopen3 H HO ylIH-benzoimidazoi- S- B-OH 2-yi)-2 H-indazole r T F I T 1 F

C

C21H16N40 1340.3861 341 I[M+H]1- 2.79 {3-[2-(2H-IndazoI-3yi)-3Hphenyl}-methanol I 4 F -I I- I- N

N"N

N H

H

OH

OH

(C22H18N4S 1370A478[ 371 3.62 ~3-[b-(4-E-thylsulfanyphenyl)-1 Hbenzoimnidazol-2-y]- 2H-indazole I I S S S N/

N

N

NH

H

H

F

C20Hl2F2N4 1 346.341 347 I 3.29 3-[6-(2,4-Difluorophenyl)-1 Hbenzoim idazoi-2-yi]- 2H-indazole

OH

I

t' F F N N Trifluoromnethoxy- 136 N~C21H13F3N40 394.356 395 [M+Hl+ 3.66 phenyl)-l H- N

H

H OH benzoimidazo-2-yi]- F K0th H 2H-indazole FF F F 137

N/N

N'

N

H

H

F

C2IHl5FN4 1342.377 343 [IM+IHI-I- 3.36 3-[6-(4-Fluoro-2methyl-phenyl)-1 Hbenzoimidazol-2-y]- 2H-indazole

OH

OH

3-{6-[2-(4-Fluoro- N /h nl-vn H- 138 HC22H15FN4 354.388 355 [M+HJ+ 3y.49 e H benzoim idazoi-2-y}-

OH

FF

N

N

NN

H

H

cI C22H15C1N4 1370.8431 371 3.76 3-{6-[2-(4-Ghorophenyl)-vinyl]-1 Hbenzoimidazol-2-y}- 2H-ind2ZOle

CH

OH

r r T I 3.03 ndazol- 3-yl)-3Hbenzoim phenyl}-propionic acid C23H18N402 1382.4231 383 [H] i N

N

N H

HOH

OH

HO

O

0

OH

2 HO 4- F I r C21H16N40 1340.3861 341 2.72 {4-[2-(2H-Indazol-3yI)-3Hphenyl}-methanol 01 DCt IN~r 3-(6-Furan-2-y-1 H- 142 N C1BH12N4O 300.321 301 3.02 benzoimidazol-2-y)- N H 2 d z l 0 H BOH 2-ndzl 0 C~f

OH

3-[6-(3-Benzyloxyphenyl)-l Hbenzoim idazol-2-y]- 2H-indazole 3-[6-(4-Isopropylphenyl)-l H- C23H20N4

OH

xI H 2H-indazole

N

\N H4

H

0O Sl C21 HI N402S Methanesufonylphenyl)-1 Hbenzoimidazol-2-yl]- 2H-indazole

OH

'O

2-(l H-I ndazoI-3-yi)- HBr 1 H-benzoimidazole- 0 L C22Hl7N504 415.409 415 2.31 5-carboxylic acid 0N N 0 (tetra hydro-pyran-4- 0 H HN 0 ylmethyi)-amide 2-(l H-Indazol-3-yi)- H 1 H-benzoimidazole- 0 /a I 024H20N602 424.464 424 [MN 2.58 5-carboxylic acid 4- 0 -IN N" 0 N N >NH NHacetylamino- H H2benzylamide 2-(1 H-i ndazol-3-yI)- 0 1 H-benzoimidazole- _N -~C16H13N50 291.314 291 2.22 H -H H2NH N HN methylamide 2-(l H-Indazol-3-yI)- 0 1 H-benzoimidazole- N N\ C18H17N50 319.368 319 2.63

HN

H N isopropylamide H-I ndazol-3-y)- H 1 H-benzoimidazol-5- 150 0 N C19H17N502 347.378 347 2.23 N N N-NHyI]-morpholin-4-yI- 0HN methanone H-Indazol-3-yI)- N 1 151 N1I C20H2ON60 36U.421 361 [M-iH]f 1.94 yI]-(4-methyl- N piperazin-1 -yi)methanone 0 a -wNH HN N-

H

2-(l H-Indazol-3-yI)- 152 0 N C23H19N50 381.439 381 IM] 3.45 1 -ezidao- H -carboxylic acid 0 ~Jt ~Jt (jJ 2-(l H-lndazol-3-yi)- 0 1 H-benzoimidazole- S N N /Ha C22H16N603 412.409 412 3.32 H u a 5-carboxylic acid 3- N NH 1 H N- H 2 N N, nitro-benzylamide 0 OF 2-(1 H-Indazol-3-yI)- F 01 H-benzoimidazole- NHN C22H16FN50 385.402 385 [Il 2.96 H N 5-carboxylic acid 2- N NH fluoro-benzylamide H F 2-(1 H-Indazol-3-yI)- N 0~ C22H15F2N50 403.392 403 3.26 1H-benzoimidazole- NI-I /5-carboxylic acid 2,4- HF difluoro-benzylamide 2-(1 H-Indazol-3-yl)- F 07 1 H-benzoimidazole- N N C22H15F2N50 403.392 403 IM] 2.93 H 5-carboxylic acid 2,6- F -a N N- NH

H

2 N p FH F difluoro-benzylamide 2-(1 H-Indazol-3-yI)-

H

2 N Ha1 H-benzoimidazole- 219H 1, F C22Hl5BrFN5O 464.303 464 3.34 5-carboxylic acid 4- N N NH broma-2-fluaro- F 0benzyiamide

H

2 N 1 H-benzoimidazolea H C22Hl5CIFN5O 419.847 419 [Il 3.21 5-carboxyiic acid 4- N ~N NHchloro-2-fluoro- N N l-NHbenzylamide F 0a 2-(1 H-Indazol-3-yI)- I H-benzoimidazole- F 0 F NH 2 C22H15BrFN5O 464.303 464 [Il 3.31 5-carboxylic acid 4- N N~ bromo-2-fluoro- N N-NH benzylamide H B F 0 F 2-(l H-Indazol-3-ylQ- 'F N -O .N -N 1 H-benzoimidazole- HFC22H15F2N50 403.392 403 3.64 F N N-N 5-carboxylic acid 3,4-

H

difluoro-benzylamide 2-(l H-Indazol-3-yl)- H I H-benzoimidazole- 161 F N H 2 C22Hl4F3N50 421.382 421 .5 F N N N-N F 3,4,5-trifluoro- 0 F benzylamide 2-(l H-Indazol-3-yI)- 1 H-benzoimidazole- -N N C 28H2001N50 477.955 477 3.89 5-carboxylic acid 162 N. N -NH H I chloro-biphenyl-4- ,H HN ylmethyl)-amide C28Hl9C12N501 512.4 1 512 4.36 2-(l H-Indazol-3-y)- 1 H--benzoimidazoleacid biphenyl-4-ylmethyl)amide 2-(l H-Indazol-3-yI)- 1 H-benzoimidazole- 0 C28H20FN50 461.5 461 [Il 3.6 5-carboxylic acid N r- N fluoro-biphenyl-4- ~N NNH HIylmethyl)-amide F'o

H

2

N

2-(1 H-Indazo!-3-yi)- F N0 HU1 C22H16FN50 385.402 385 2.94 1 -ezidaoe H H H 5-carboxylic acid 2- H NH fluoro-benzylamide 2-(l H-Indazol-3-y)- H /F I H-benzoimidazole- H N NH 2 C23H17F2N50 417.419 417 [I 3.14 5-carboxylic acid 2,6- N N N NH difluoro-3-methyl-

F

F 0 benzylamide 2-(1 H-Indazol-3-yI)- Nl N0 2 2H5IN 3.0 3 M 1 H-benzoimidazole- H N 2\ C2lr1N04632 46 I 3.8 5-carboxylic acid 2,4- N -NH CI& N dichloro-benzylamide 2-(l1H-I ndazol-3-yI)o I H-benzoimidazole- N X N o C22H16ClN50 401.857 401 3.73 H '~N-NH H 2 N 5-carboxylic acid 4-

'HN

H chlorc-benzylamide 2-(1 H-I ndazol-3-yI)o I H-benzoimidazole- IH,% a C23H18C1N50 415.884 415 3.52 5-carboxylic acid 4- -l N N NH /chiloro-2-m ethyl-

H

_____benzylamide 2-(1 H-I ndozol-3-yI)- 0 I r,~H-benzoimidazole- N N C22H16FN50 385.402 385 3.09j -carboxylic acid 4- ,N ~NNH 11 2 F H \/fluoro-Denzylamide

NH

2 2-(1 H-I ndaZOl-3-yI)- 1 H-benzoimidazole- 0 -~HCI C28H20C1N50 477.955 477 3.9 5-carbcxylic acid H NNHchloro-biphenyl-4- H I~ylmethyl)-amide 436 C22H15F3N60 1436.397 2.93 2-(1 H-indazol-3-yI)- 1 H-benzoimidazoleacid (6trifluoromethylpyridin-3-y methyl)amide I'

'NH,

FXC

FF

C25Hl1 N6OS 1450.524 2.67

\N

H

2 N 00- 2-(1 H-Indazol-3-yI)- I H-benzoimidazole- 5-carboxylic acid pyridin-2-yi-thiophen- 2-yimethyl)-amide 2-(l H-Indazol-3-yI)- 1 H-benzoimidazole- 5-carboxylic acid (3irnidazol-1 -yi-propyl)amide 0 N

NH

H N NN C21H19N70 1385.4311 385

N

IN] 2.11 H-indazol-3o a yI)-l H- 17 N) 2H6634651 47 31 17N2 H 6 6 3 4 6 5 1 4 7 f A carbony ]-piperazineo N0 1-carboxylic acid tert- -a -N N N',Ok butyl ester

H

2-(l H-lndazol-3-yi)- 1 H-benzoimidazole- 176 438 [M+H]f 5-carboxylic acid F 0 6-difluoro-4- N HN- Nil 2 chloro-benzyl)amide I H NH ci FN N H a F 177 437 2-(1 H-Indazol-3-yI)- 1 H-benzoimidazole- 5-carboxyliC acid (2,4-dichloro-6fluoro-benzyl)amide ~N NH 2 F I 1 1 t F 1

H

2

F

420 1 M+H]+ 2-(l H-Indazol-3-yl)- I H-benzoimida7Ole- 5-carboxylic acid (3fluoro-4-chlorobenzyl)amide L i a i 1 1 T [Mi-Hl 2-(1 H-Indazo-3-yl)- 1 H-benzoimidazole- 5-carboxylic acid (2fluoro-4-chloro-6methyl-benzyI)amide a'6

F-NH

2 0 ~Jt ~Jt

C-'

I F I I_

N

NH 2 399 1 [M+Hf' 2-(l H-Indazol-3-yI>- 1 H-benzoimidazole- 5-carboxylic acid (6methoxy-pyridin-3yimethyl)-amide I WO 03/035065 PCT/GB02/04763 -361- The products of formula of the present application can also be prepared according to the following process: 3 1 H, E 100C Z3-t-O 0

SNH

2 OEt H 0

MEMCI

Z4

O

mem LDA Z A- L1 71,

I

AcOEt Z 0 mem z EtONa Z N Z1-X Z 0 mem

H

zi NH2-NH2 Z\~ ROH Z4 H

H

merr Cs2003

NMP

Z2-X

ZI

HCIIMeOH 13 Z4

H

mem z Z4 H H\ In the above scheme, the values of Z3 and Z4 are chosen from the values of R2 and R3 as defined above and the values of Z1 and -OZ2 are chosen from the values of X1, X2 or X3 with R1 representing a pyrazole radical, When Z1, Z3 and Z4 represent a hydrogen atom, it is possible in particular to prepare products of .0 formula of the present application according to the following synthesis scheme: D OH 0 i NaOH n l MH2-NH2H20 O NH O H 0 -0 40% 100% OH Ho z OH

H,

PPA H1I1~2 40% H RCOCH)r COCI RCH2r

H

H

R

R

H

0-1

H

H

Products of formula of the present application which constitute Examples 181 to 228 of the present application are represented in the table 4 hereinbelow: these products can be prepared according to the schemes indicated above and in particular the product of Example 181 can be prepared according to the WO 03/035065 PCT/GB02/04763 -362procedure indicated below. The products of Examples 182 to 228 can be prepared like the product of Example 181.

EXAMPLE 181 2-[5-(benzvloxy)-2H-pyrazol-3-yl- 1H-benzoimidazole Step 1: the cyclization is performed as in: Chem. Pharm. Bull., 31(4), 1228-1234 (1983); J. Org.

Chem., 47(2), 214-221 (1982).

Step 2: To the crude ester 1.015 g in 50 ml of MeOH, was added 5.5 ml of 6NNaOH and the mixture is heated to reflux during 2 h. After evaporation of most of the methanol, the medium is cooled and conc. HCI is carefully added until pH 2. After further evaporation to dryness, the solid is triturated three times with 30 ml of MeOH/AcOEt 1/1 and the filtrate evaporated to give 0.875 g of light brown solid after desiccation.

LC-MS: [gradient acetonitrile/water 0.1% HCOOH; Xterra RP18 2.1 x 50 nmm] retention time 0.53 minutes, MH+ 129, 95% pure Step 3: To 3.5 g ofPPA (polyphosphoric acid) were added 0.701 g of 1,2-phenylenediamine and 0.87 g of the step 2 acid. The mixture is heated to 150C during 1.5 h. After cooling, cone NH40H was added until pH 3. The green precipitate is filtered, washed with water and then with acetone. After one night drying under vacuum at 50C, 2.1 g of solid remains containing around 50% of mineral salts.

MS: EI 200.

Step 4: Ex. 181: To 80 mg of the step 3 solid in 4 ml of NMP were added caesium carbonate 137 mg and benzyl bromide 72 mg. After 2 h the mixture is hydrolysed with saturated KH2PO4 and extracted with AcOEt. After evaporation, the crude mixture was submitted to preparative LC-MS to give 8 mg of pure compound: LC-MS: [gradient acetonitrile/water 0.1% HCOOH; Xterra RP18 2.1 x 50 mm] retention time 3.17 minutes, MH+ 291. 97% pure In the same way, the step 4 is carried out with 15 benzyl or allyl bromides, 15 a-bromocarbonyl compounds and 15 acid chlorides in either DMF or NMP to give the expected compounds of TABLE 4. Examples 181 to 228 of the present application are represented in TABLE 4.

WO 031035065 WO 03/35065PCT/GB02/04763 -3 63- TABLE 4

CHEMISTRY

p 2-[5-(benzyloxy)-2H- ~Z<N181 pyrazol-3-yl]-1 H- IN benzoimidazole

N

henyl-al lyloxy)- -N182 2H-pyrazol-3-yI]-I H- H benzoimidazole 2-[5-(2-Methyl-allyloxy)- N ~183 2H-pyrazoi-3-yl]-1H- H H benzoimidazoie 7-Dim ethyl-octa- 184 2,6-dienyloxy)-2H- 184 pyrazol-3-yi]-1 Hbenzoimidazole H

N~

WO 031035065 WO 03/35065PCT/GB02/04763 -3 64- Br 2-[5-(3-Bromo- 185 benzyloxy)-2H-pyrazol-3 K N yIJ-1 H-benzoimidazole H

H

H-Benzoimidazol- 186 2-yi)-1 H-pyrazol-3yioxymethyl]-benzonitrile

N

H

H

F

F

2-[5-(4-Trifluoromethyl- 187 benzyloxy)-2H-pyrazol-3 K yl]-1 H-benzoimidazole

N

H

H

2-[5-(3,4-Dichloro- K 188 benzyloxy)-2H-pyrazol-3 yl]-1 H-benzoimidazole

N

H

H

WO 031035065 WO 03/35065PCT/GB02/04763 -3

F

F

19Pentaf Iuoro phenyl metho F 19 xy-2H-pyrazol-3-yi)-1 Hbenzoimidazole H

N

H H N 2-[5-(4-tert-Butyl- 190 benzyloxy)-2H-pyrazol-3 yl]-1 H-benzoimidazole H

H

Hn 191 Be nzenesuIfonyl methyl- 11benlzyloxy)-2H-pyrazol-3 yI]-l H-benzoimidazole N H

H

N H-Benzoimidazol- 192 2 -yI)-1 H-pyrazol-3yloxymethyI]-benzonitrile H

N

H

H

WO 031035065 WO 03/35065PCT/GB02/04763 -36 6- 2-[5-(Biphenyl-4- 193 ylmethoxy)-2H-pyrazol-3 yI]-I H-benzoimidazole N H

H

0 0 =S 2,3-Dichiorocl,, I 14benzenesulfonic acid C, ci 19 (1IH-benzoimidazol-2-y)- H N 1 H-pyrazol-3-yI ester H Cl2-[5-(2-Morphol in-4-yI- H CI 195 ethoxy)-2H-pyrazol-3-y] 1 H-benzoimidazole H Cl2-[5-(2-Piperid in-I -yI- I-i CI196 ethoxy)-2H-pyrazol-3-y] I H-benzeimidazole 2-[5-(3-Methoxy- 197 benzyloxy)-2H-pyrazol-3 yI]-1 H-benzoimidazole H N H H WO 031035065 WO 03/35065PCT/GB02/04763 -367- H-Benzoimidazol- 2-yI)-l H-pyrazoi-3-yloxy] I p-toly-etha none

F

F

F

1 H-Benzoimidazol- 0 199 2 -yI)-l H-pyrazol-3-yloxy] 3,3,4,4,4-pentaflucrobutan-2-one H N H H H-Benzoimidazol- 200 2-yI 1 H-pyrazol-3-yloxy].

1 -biphenyl-4-yi- 0 etha none H N2 H

H

o H-Benzoimidazol- K201 2-yI)-I H-pyrazol-3-yloxy] butan-2-one

N

H

H

WO 031035065 WO 03/35065PCT/GB02/04763 -368- '1 202 H-Benzoimidazol- 2-yI)-1 H-pyrazol-3-yloxy] 1 -(4-dimethylaminoph enyl)-etha nonie 0 H

H-

203 H-Benzoimidazol- 2-yI)-1 H-pyrazolk3-yloxy] I -(3-ph yl)-ethanone

CINH

H-Benzoimidazol- 0 204 2-yI I H-pyrazo I-3-yioxy] N-phenyl-acetamide 1 H-Benzoimidazol- 'K205 2-yI)-I H-pyrazol-3-yoxy] 3,3-diniethyl-butan-2one H H WO 031035065 WO 03/35065PCT/GB02/04763 -369- 0

H

1 -Adamantan-1 "H 206(I H-benzoimidazol-2-yI)- 1 H-pyrazo-3-yloxy]- H H 0 s- H-Benzoimidazol- 207 2-yl)-l H-pyrazol-3-yloxy] 1 -naphtha len-2-y- N -N ethanone H

H

N

H-

28Benzoimidazo-2-y!)-I

H-

08pyrazol-3-yloxy]-acetyl}o benzonitrile HI

H

0 H N

H-

Benzoimidazol-2-yl)-I H- 209 pyrazol-3-yloxy]-acetyl}- 0 3,4-dihydro-1 H-quinolin- /1 2-one

N

H

H

WO 031035065 WO 03/35065PCT/GB02/04763 -370- 210 H-Benzoimidazo- 2-yI)-1 H-pyrazol-3-yloxy] I -(4-trifi uoromethoxyphenyl)-ethanone 4 4 0 0 H

N

H H 211

H-

Benzoimidazol-2-y)-1 Hpyrazol-3-yloxy] -acetyl}- 2-ohlbrabenzenesulfonam ide 4 212 2-[15-(l H-Benzoimidazol- 2-yi)-l H-pyrazol-3-yoxy] I -(4-methoxy-phenyl)ethanone 0 H-Benzoimidazol- 213 2-yI)-1 H-pyrazol-3-yloxy] I -cyclopropyl-ethan one

N

H H WO 031035065 WO 03/35065PCT/GB02/04763 -371- 0H CI Isonicotinic acid 5-(l H- 214 benzoimidazol-2-y)-1 H- I pyrazol-3-yi ester N -N H

H

2,2-Di methyl-pro pion ic 215 acid 5-(l1H- 25benzoimidazol-2-y)-1 H- H 1 -N pyrazol-3-yI ester 0 H N Benzyloxy-acetic acid N H \216 (1 H-benzoimidazol-2-yi)- NH 1 H-pyrazo-3-y ester

N

0 4MehoBenzoic acid1H 217 8 -benzoimidazol-2-H yl- Hpyrazol-3-yI ester H

N

H H WO 031035065 WO 03/35065PCT/GB02/04763 -3'72- 0 I Phenyl-ac-etic acid 219 benzoimidazol-2-yI)-I H- H N -N pyrazol-3-yI ester

H

F

F

0 2,3,4,5,6-Pentafluoro- KF 220 benzoic acid 5-(l Hbenzoimidazo-2-y)-l H- H H pyraZOi3-yl ester Cyciopropanecarboxyl ic 221 acid 5-(l H- 21benzoimidazl-2-yl)-1 H- H H pyrazoi-3-yl ester F F F

F

F 2,2,3,3,4,4,4- K F Heptafluoro-butyric acid F 222 5-(l H-benzoimidazol-2- Nl N- yI)-l H-pyrazol-3-yi ester Cyclopentanecarboxylic K2 acid 5-(l1H- /22 benzoimidazcl-2-y)-l

H-

H N Npyrazol-3-yl ester WO 031035065 WO 03/35065PCT/GB02/04763 -373- 0o 3-Phenyl-propionic acid 224 5-(l H-benzoimidazol-2yI)-l H-pyrazol-3-y ester N H H 0i Biphenyl-4-carboxylic 225 acid 5-(l Hbenzoimidazo-2-y)-l H- I pyrazol-3-y ester H

N

H

F

F

F 3,5- Bis-trifl uorom ethyl- F F 226 benzoic acid 5-(1 H- F 2 benzoimidazol-2-yi)-1

H-

Lr pyrazol-3-yl ester H

H

F

F

0 4-Trifl uo rom ethyl- 227 benzoic acid 5-(l H- K 227benzoimidazol-2-yi)-1 Hpyrazol-3-yl ester N H H WO 031035065 WO 03/35065PCT/GB02/04763 -374- IS3 Y-OThiophene-2-carboxylic acid 5-(1 H- 228 benzoimidazo-2-y)-1

H-

H pyrazol-3-yl ester Example 229: pharmaceutical composition Tablets corresponding to the formula below were prepared: Product of Example 1 0.2 g Excipient for a finished tablet containing 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).

Example 1 is taken as pharmaceutical preparation example, it being possible for this preparation to be produced, if desired, with other products in examples in the presont application.

EXAMPLE 230 5 ,6-Dimethyl-2-(5-methylsulfanyl lH-pyrazol-3-yl)-H-benzoimidlazole A mixture of 5, 6 -dimethyl-2-(5-methylsulfanyl- 1H-pyrazol-3-yl)-1 2 -trimetlhylsilanyl-ethoxymethyl)lH-benzoimidazole [90mg, Reference Example hydrochloric acid (2niL, 4N) and ethanol (4rnL) was heated at reflux temperature for 16 hours then cooled to room temperature. The pH of the reaction mixture was adjusted to 7 by addition of saturated sodium bicarbonate solution. The resulting solid was filtered, then washed with water and then dried in a vacuum oven to give,5,6-dimethyl-2-(5methvlsulfanvyl-lH-pUyrazol-3-yl) 1 H-benzoimidazole (38mg). LC-MS (METHiOD RT =2.22 minutes; 259 6 -Chloro-5-methyl-2-(5-n-ethiylsulfanyl1mHpyrazol-3yl). H-benzoimidazole WO 031035065 WO 03/35065PCT/GB02/04763 -375- 'SCH 3 By proceeding in a similar manner to Example 230(a) above but using 6-chloro-5-mnethyl-2-(5methylsulfanyl- 1 H-pyrazol-3-yl)-1 -(2-trimethylsilanyl-ethoxymethyl)-1I--benzoimidazole [Reference Example there was prepared 6-chloro-5-methyl-2-(5-methylsulfanvl-1H-p razol-3-y1 -1Hbenzoimidazole.

6-Chloro-"-(5-ethylsulfanvyl- 1H-pvrazol-3-vl)-5-mietlhyl- 1 -1-benizoimiidazole HC N SCH 2 CH 3 Cl

H

By proceeding in a similar manner to Example 230(a) above but using 6-chloro-2-(5-ethylsulfaniyl-1Hpyrazol-3-yl)-5-r-nethyl-1 -(2-trimethylsilanyl-ethoxymethyl)-l1H-benzoiniidazole [Reference Example tbere was prepared 6-chloro-2-( 5-ethylsulfanyl- 1H-pyrazol-3-vl)-5-methyl-1H-benzoimidazole.

2-(5-methylsulfanvil- lH-pyrazol-3-vl)-5-trifluoromnethyl-l1H-benzoimidazole By proceeding in a similar manner to Example 230(a) above but using 2-(5-methylsulfanyl-1H-pyrazol- 3 -yl)-5-trifluoromethyl-l1-(2-trimethylsilanyl-ethoxymethyl)- 1H-benzoimidazole [Reference Example 1 there was prepared 2-(5-methylsulfanyl-1H-pyrazol-3-ylV5-trifluoromethvl- 1H-benzoimidazole.

5-CyclopropylmethylsulfanvI- H-pyrazol-3 -'l)-5,6-dimnethyl-1 H-b enzoimidazole By proceeding in a similar manner to Example 230(a) above but using 1 H-pyrazol-3-yl)-5,6-dimethyl-1-(2-trirnethylsilanyl-ethoxymethyl)-1H-benzoimidazole [Reference Example there was prepared 2-(5-cyclopropylmethylsulfanyl- 1H-pyrazol-3-yl)-5,6-dimetlivl-lHbenzoimnidazole. LC-MS (METHOD RT 2.47 minutes; 299 WO 031035065 PCT/GB02/04763 -376- 2-(5-Ethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-l1H-benzoimidazole H 3 C I: N SCH 2 CH 3 HN N N

H

3 C H By proceeding in a similar manner to Example 230(a) above but using 5,6-dimethyl-2-(5-ethylsulfanyl- 1H-pyrazol-3-yl)- 1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole [Reference Example 1I(f)] there was prepared 2-(5-ethylsulfanvyl- 1H-pyrazol-3-vl)-5 .6-dimethyl-lIH-benzoimidazole. LC-MS (METHOD RT =2.32 minutes; 273 5, 6-Dimethyl-2- F5-(pyridin-3-ylmethylsulfanyl)-1H-pyrazol-3-yll-1H-benzoimidazole

H

3 C j j NS

N

H

3 C H

N

By proceeding in a similar manner to Example 230(a) above but using 5,6-dimethyl-2,-[5-(pyridin-3yl)methylsulfanyl-l1H-pyrazol-3-yl]-I-(2-trii-nethylsilaniyl-ethoxymethyl)-1I-benzoimidazole [Reference Example there was prepared 5 ,6-dimethvl-2-F5-(Pvridin-3-vlmethylSLllfanyl)-l1Hpyrazol-3-yll-lH-benizoinmidazole as a colourless solid.

5-Fluoro-2-15-methylsulfanvyl)-1 H-:pvazol-3-yll -1H-benzoimidazole F ,C N SCH 3

N

H

By proceeding in a similar manner to Example 230(a) above but using 5-fluoro-2-(5-methylsulfanyllH-pyrazol-3-yl)- 1-(2-trimethylsilanyl-ethoxymethyl)-1 H-benzoimidazole [Reference Example 1 there was prepared 5-fluoro-2-F5-methylsulfanvl)- 1H-pvriazol-3-y.ll-1H-benzoimnidazole. MS: 249 ,6-Dimethyl-2-(5-:phceth-ylsulfanyl-l H-pvazol-3-:yl> benzoimidazole WO 031035065 PCT/GB02/04763 -377- By proceeding in a similar manner to Example 230(a) above but using 5,6-dimethyl-2-(5phenethylsulfanyl-1H-pyrazol-3-yl)-l1-(2-trimethylsilanyl-ethoxym-ethiyl)- 1I--benzoimidazole [Reference Example 1 (i)1 there was prepared 5,6-dimnethyl-2-(5 -phenethvylsulfanyl-1-pyrazol-3-vl)lH-benzoimidazole.

4-Methvl-2-( 5-methylsuLlfanvi- 1H-pvrazol-3-yl)-lH-benzoimidazole By proceeding in a similar manner to Example 230(a) above but using 4-rnethyl-2-(5-methylsulfanyl- 1H-pyrazol-3-yl)- 1-(2-trimethiylsilanyl-ethoxymethyl)-1H-benzoiflidazole [Reference Example there was prepared 4-meth L-2-(5-methylsulfanl-H-prazol-3-l)-H-benzoimidazole. MS: 245 5,6-Dimethyl-2-(5-benzlsulfail-H-pyrazol-3-yl)-l H-benzoimidazole By proceeding in a similar manner to Example 230(a) above but using 2-(5-benzylsulfanyl-1H-pyrazol- 3-yl)-5,6-dimethyl-l1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole [Reference Example 1(k)] there was prepared 5,6-dimnethvl-2-(5-benzylsulfanvyl-1 H-pyrazol-3-yl)- IH-benzoimidazole.

6-Chloro-5-methyl-2-(5-morpholin-4-yl- 1H-pyrazol-3-vl)- 1 F-benzoimidazole By proceeding in a similar manner to Example 230(a) above but using 6-chloro-5-methyl-2-(5morpholin-4-yl-l1H-pyrazol-3-yl)- 1-(2-trimethylsilanyl-ethoxymethyl)-1H-benizoimidazole [Reference Example there was prepared 6-chloro-5-methyl-2-(5-mo~pholin-4v1-1 H-pyrazol-3-vfl)-1Hbenzoimidazole.

WO 031035065 PCT/GB02/04763 -378- (in) 5,6-Dimethyl-2-[5-(thiophen-2-vlmethylsulfanl)-1 H-pyrazol-3-yl]- 1H-benzoimidazole

CH

3 N By proceeding in a similar manner to Example 230(a) above but using 5,6-dimethyl-2-[5-(thiophen-2ylmethylsulfanyl)- 1H-pyrazol-3-yl]- 1-(2-trimethiylsilanyl-ethoxynmethyt)- I I-benzoimidazole [Reference Example I1(m)] there was prepared 5,6-dimethyl-2-r5-(thiophen-2-ylmethvlsulfnl)- 1Hpyrazol-3-yll- lH-benzoimidazole.

EXAMPLE 231 (-5Ehlufn- Hpazl3l)5mto-1Hbeoiiaoehdchloride CH 3 O" N _C ,.SCH 2

CH

3

NN

H

A mixture of 3,3 -bis-ethylsulfanyl-1-[5-methoxy- 1-(2-trimethylsilanyl-ethoxymethyl)- lHbenzoimidazol-2-yll-propenone V-.78mmole, Reference Example 20)1 and hydrazine hydrate (500Vff) in ethanol (6niL) was heated at reflux temperature for 18 hours, then evaporated. The residue was purified on the Flashmaster to give 2-(5-ethylsulfanyl- 1H-pyrazol-3-yl)-5-methoxy-l1-(2triinethylsilanyl-ethoxymethyl)- 1 H-benzoimidazole which was treated with ethanol (6mL) and hydrochloric acid (3maL). This mixture was heated at reflux temperature for 18 hours and then evaporated to give 2-(5-ethylsulfanvyl-1H-:pyrazol-3-vl)-5-methoxy- 1H-benzoimidazole hydrochloride, LC-MS (METHOD RT 2.17 minutes; 275 EXAMPLE 232 5-Methyl-2-(5-methylsulfanyl-4-propyl-l1H-pyrazol-3-yl)-1H-benzoimidazole

CH

3 CHi, C1-I 2 CH 3 N SCH, N

N

H

A mixture of 2-(bis-methylsulfanyl-m~ethiylene)- 1 -(5-methyl-i1 H-b enzoimidazol-2-yl)-pentan-1 -one [I-0.49nimole, Reference Example and hydrazine hydrate (200p.1) in ethanol (6mL) was heated at reflux temperature for 2 days, then evaporated. The mixture was then treated with hydrochloric acid WO 031035065 PCT/GB02/04763 -379- (4mL, 4N) and heating was continued at reflux temperature for a further 24 hours. The reaction mixture was cooled, then neutralised by addition of sodium hydroxide solution (4N) and then extracted with dichioromethane. The extract was evaporated to give 5-methy1-2-(5-methylsulfanv1-4-propyl-1Hpyrazol-3-yl)-lH-benzoimidazole. MS: 287 2-(5-(4-miethoxv-benzylsulfanyl)-4-propvl- 1H-pyrazol-3-vl)- 5-methyl-i beazoimnidazole

OCH

3

CH

3

CH

2

CH,

CH_

N

By proceeding in a similar manner to Example 233(a) above but using 2-[bis-(4-metlioxyhenzylsulfanyl)-methylene]- 1-(5-methyl- IH-hcnzoimidazol-2-yl)-pentan- 1-one [Reference Example there was prepared 2-(5-(4-methoxy-ben-zylsulfai-vl)-4-1oropvl- 1H-pvrazol-3-vyl)- benzoimida7olC. MS: 393 2-('5-Benzvlsulfanyl-4-isopropyl-1 H-pvrazol-3-vl)-5-methyl-1 H-benzoimida2ole By proceeding in a similar manner to Example 232(a) above but using 2-(bis-benzylsulfanylmethylene)-3-methyl-1 -[5-methyl-i -(2-trimethylsilanyl--ethoxymethyl)-1H-benzoimidazol-2-yl]-butanl- 1-one [Reference Example there was prepared 2-(5-benzylsuifanyl-4-isopropyl-iH-pyrazol-3-vyl)- MS: 363 (d) 2-(5-Methylsulfanyl-4-methyl-1 H-pyrazol-3-yl)-5 -methoxy-1H-beazoimidazole By proceeding in a similar manner to Example 232(a) above hut using 1-[5-methoxy-1-(2trimiethylsilanyl-ethioxymnethyl)-1H-benizoimidazo-2-yj 2-methyl-3-(bis-methanesulfanyl)-1- WO 031035065 PCT/GB02/04763 -380propenione [Reference Example there was prepared 2-(5-methylsulfanyl-4-methyl-l H-pvrazol-3- 2-(5-Methylsulfanyl-4-methyl-IH-pyrazol-3-ylD-5-methyl-1 H-benzoimidazole By proceeding in a similar manner to Example 232(a) above but using l-[5-methyl-l1-(2trimethylsilanyl-ethoxymethyl)-l1H-benzoimidazol-2-yl]- 2-methyl-3-(bis-methanesulfanyi)- 1propenone [Reference Example there was prepared 2-(5-methylsulfanvyl-4-methvl-1 H-pyrazol-3lH-benzoimidazole.

EXAMPLE 233 3-(5-Chloro-l H-benzoimidazol-2-yl)-1 H-pyrazol-4-ylaimine A solution of 5-chloro-2-(4-nitro-lH-pyrazol-3-yl)-1H-benzoimidazole [91mg, Example 239(a)] in ethanol (4OmL), under nitrogen, was treated with palladium on carbon (spatula tip, The mixture was stir-red under hydrogen for 3 hours and then filtered through Celite. The filter pad was washed well with dichioromethane. The combined filtrate and washings were evaporated to give IH-benzoitmidazol-2-vl)-1H-pyrazol-4-'vlamine (I116mg). LC-MS (METHOD RT 2 minutes; 234 3-(5,6-Dichloro- 1H-benzoimidazol-2-yl)-1H-:pyrazol-4-ylamine By proceeding in a similar manner to Example 233(a) above but using 5,6-dichloro-2-(4-nitro-IHpyrazol-3 lH-henzoimidazole [Example 239(b)] there was prepared 3-(5,6-dichloro- Hbenzoimidazol-2-vl)-lH-py razol-4-vlamine. LC-MS (METHOD RT =2.37 minutes, 268 WO 031035065 WO 03/35065PCT/GB02/04763 -381- 3 .6-Dimethyl-1Hf-benzoimidazol-2-yi)-1I H-pyrazol-4-ylamine By proceeding in a similar manner to Example 233(a) above but using 5,6-dimethyl-2-(4-nitro-lHpyrazol-3-yl)- 1H-benzoimidazole [Example 249(a)] there was prepared 3-(5,6-dirnethyl- 1Hbenzoimidazol-2-yl)-1H-pyrazol-4-ylamine as a brown solid. LC-MS (METHOD B3): RT 2.29 mninates; 228.25 3-(5-Ethyl-6-methyl- 1H-benzoimidazol-2-yl)-l H-ipyrazol-4-ylamine

HN

CH

3 CH,

N

CH NH

C

3

H-

By proceeding in a similar manner to Example 233(a) above but using 5-ethyl-6-methyl-2-(4-nitro-1 Hpyrazol-3-yl)- 1H-benzoimidazole [Example 249(b)] there was prepared 5-ethyl-6-methyl-lIHbenzoimidazol-2-yl)-lH-pyrazol-4-vlamine as a brown solid. LC-MS (METHOD RT 2.14 minutes, 242.20 (e) 3 -(6-chloro-5-methoxv-I1 -benzoimidazol-2-yl)- lH-pyrazol-4-ylamine By proceeding in a similar manner to Example 233(a) above but using 6-chloro-5-methoxy-2-(4-nitrolH-pyrazol-3-yl)-1I-I-benzoimidazole [0.7g, Example 249(c)] there was prepared 3- methoxy-1H-benzoimidazol-2-vl)-1H-pyrazol-4-vlamine (0.54 g) as a brown foam. MS 264 3-(5-Methoxv-1H-benzoimidazol-2-yl)- 1H-wvyrazol-4-vlamine CH 3 0 WO 031035065 PCT/GB02/04763 -382- By proceeding in a similar manner to Example 233(a) above but using 5-methoxy-2-(4-nitro-1Hpyrazol-3-yl)-1H-benzoimidazole [373mg, Example 257(f)] there was prepared 3- 5-methox -1Hbenzoimidazol-2-vl)-IH-pyrazol-4-vlaminie (257mg) as a dark brown solid. LC-MS (Method RT 1.23 minutes, 230.25 228.25 3 -(5-Ethoxy-1H-benzoimidazol-2-yl)- lH-pyrazol-4-ylamine

-N

N

By proceeding in a manner similar to Example 233(a) above but using 5-ethoxy-2-(4-nitro-1H-pyrazol- 3-yl)-1H-benzoimidazole [407mg, Example 252(c)] there was prepared 2-yl)-1H-pyrazol-4-ylamine (375mg) as a dark brown oil. LC-MS (Method RT"= 1.43 minutes, 244.26 242.28 3-(5-Fluoro-6-methvl- 1H-benzoimidazol-2-yl)- IH-pyrazol-4-ylamine FH N

'N

C

3 H N H By proceeding in a manner similar to Example 233(a) above but using 5-fluoro-6-methyl-2-(4-nitro- 1H-pyrazol-3-yl)-1H-benzoimidazote [Example 249(d)] there was prepared 3-(5-fluoro-6-methyl-lHbenzoimidazol-2-yl)-lH-pyrazol-4-ylamine (0.590g) as a brown solid. LC-MS (METHOD RT 2.25 minutes, MS: 232.29 (i) 3-(5-Trifluorornethoxy-l1H-benzoimidazol-2-fl)-I1H-pvrazol-4-ylamine By proceeding in a manner simnilar to Example 233(a) above but using 5-trifluoromethoxy-2-(4-nitro- 1H-pyrazot-3)-yl)- 1H-benzoimidazole [Example 249(e)] there was prepared 3-(5-trifluoroi-nethoxy- Hbenazoimjidazol-2-fl)-1H-pyrazol-4-ylamine (0.920g) as a brown solid. LC-MS (METHOD RT 2.76 minutes, 284.23 WO 031035065 PCT/GB02/04763 -3 83- 3-(5-Trifluoromethyl- I H-benzoimidazol-2-yl)- 1H-ivrazol-4-ylamine CF 3 N

HN

By proceeding in a manner similar to Example 233(a) above but using 5-trifluoromethyl-2-(4-nitro-1Hpyrazol-3-yl)-1 H-benizoirnidazole [Example 249(f)] there was prepared 3-(5-trifluoromethyl- 1Hbenzoimidazol-2-yl)-1H-pyrazol-4-ylamine (0.150g) as a brown solid. LC-MS (METHOD RT 3.00 minutes, 268.16 2-(4-Amino- 1H-pyrazol-3-vyl)- 1H-benzoimidazole-5-carboxylic acid methyl ester 0

H

9

N

CH 3 0

N

N

-N

H

By proceeding in a manner similar to Example 233(a) above but using 2-(4nitro-lH-pyrazol-3-yl)-lHacid methyl ester [Example 249(h1)] there was prepared 2-(4-amino-lHacid methyl ester l0g) as an off-white solid, LC-MS (METHOD RT 2.40 minutes, 258.17 EXAMPLE 234 1H-Benzoimidazol-2-yl)-1H-indazole

N

jN

N-N

H

H

A mixture of 1 ,2-diamninohenzene (108mg), indazole-3-carboxylic acid (118mg) and polyphosphoric acid (lm-L) was heated at 150-160'C for 24 hours. The mixture was cooled, then diluted with ice water (1 OmL) and then treated with ethyl acetate (1 OmL). The aqueous layer was basified by addition of solid potassium carbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (l0mE). The combined organic phases were dried and then evaporated. The residue was subjected to chromatography on silica eluting with a mixture of heptane and ethyl acetate to give WO 031035065 PCT/GB02/04763 -3 84- 3-(lH-benzoimi dazol-2-yt)-1H-indazole (78mg), LC-MS (METHOD RT =1.28 minutes; 235 IH-benzoimidazol-2-yl)- IH-indazole By proceeding in a similar manner to Example 234(a) above but using 4-methoxy-1,2-diaminobenzene hydrochloride there was prepared 3-(5-methoxy- 1H-benzoimidazol-2-yl)- 1H-indazole as a solid.

LC-MS (METHOD RT =1.28 minutes; 265 (c) r2-(Indazol-3-yl> 1 By proceeding in a similar manner to Example 234(a) above but using 3,4-diaminobenzophenone there was prepared [2-(indazol-3-yl)-l H-benzoimiidazol1-5-yl]-phenyl-methanone as a solid.

LC-MS (METHOD RT =1.73 minutes; 339 2-(1H-Indazol-3- yl)-3H-benzoimidazol-4-oI

SN

N N H

N

H

OH

By proceeding in a similar manner to Example 234(a) above but using 2,3-diaminophenol there was prepared IH-indazol-3-:yl)-3H-benzoimidazol-4-oI as a solid. LC-MS (METHOD RT =1.63 minutes; 251 2-Phenvl-1H-imidazoI[4.5-blnDvrazine WO 031035065 PCT/GB02/04763 -385- N H By proceeding in a similar manner to Example 234(a) above but using 2,3-diaminopyrazine [Reference Example 9] and benzoic acid there was prepared 2-phenyl- 1H-imidazol[4,5-blpyrazine as a pale brown solid, mp 23 9-240'C. HPLC (METHOD Al1): RT 10. 18 minutes.

3-(5,6-Dirnethyl- IH-benzoimidazol-2-yl)-1H-indazole

CH

3 N By proceeding in a similar manner to Example 234(a) above but using 1 ,2-diamino-4,5dimethylbenzene there was prepared 3-(5 ,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-indazole (28mg).

LC-MS (METHOD A):RT 1.34 minutes; 263 1H-indazol-3 -yl)-3H-imidazoF4,5-clpyridine

N

N N-N H

H

By proceeding in a similar manner to Example 234(a) above but using 3,4-diaminopyridine there was prepared 2-(IH-indiazol-3-vl')-3H-imidazo[4,5-clpyridine as a solid. MS: 236 HPLC (METHOD RT 2.48 minutes.

1H-iindazole-3-vyl)-3H--imidazor4,5-blpyridine WO 031035065 PCT/GB02/04763 -386- By proceeding in a similar manner to Example 234(a) above but using 2 ,3.-diaminopyridine there was prepared 2 -(IH-indazole-3-yl)-3H-imidazor4,5..blpyridine as a solid. MS: 236 HPLC (METHOD RT 2.49 minutes.

EXAMPLE 235 2 -(lH-Pyrazol-3y1)-1H-benzoimidazole

_N

H

A mixture of 1H-pyrazole-3-carbaldehyde (0.961ig, Reference Example 10), o-phenylenediamine (0.

9 73g), sodium bisulfite (1.898g) and dry dimethylformamide (l0mL) was stirred at reflux for 2 hours, then cooled to room temperature and then poured onto cracked ice (35g). The mixture was filtered and the solid was washed with aqueous sodium bicarbonate and then with water. The solid was vacuum dried at 70'C and then recrystallised from ethanol to give 2-(1H-pyrazol-3yl)-1Hbenzoimidazole (0.645g) as a pahL yellowish solid, nip 335-338'C. [Elemental analysis:- C, 62.56%, H, 4.04%, N, 29. 14%. Calculated for Cl 0

H

8

N

4 C, 65.19%, H, 4.39%, N, 30.42%].

3 6 -Dimethl-1H-benzoimidazol2-y)-5methoxyvlHlndazole

CH

3

O

CH

3 N

CH

3 N N 3 H By proceeding in a similar manner to Example 235(a) above but using 3 -formyl-5-methoxy-indazole- 1carboxylic acid tert-butyl ester [Reference Example 20(a)] and 4,5-dimethylbenzene- 1,2-diamine there was prepared 3-(5 ,6-dimethyl- 1H-benzoimidazol-2-ylD-5-methoxy-lIHindazole as a white solid.

LC-MS (METHOD RT 2.35 minutes; 289 3-(5-Ethyl-6-methyl- 1H-benzoimidazol-2y)-5-methoylHindazole WO 031035065 WO 03/35065PCT/GB02/04763 -387- By proceeding in a manner similar to Example 235(a) above but using 3-formyl-5-methoxy-indazole-1carboxylic acid tert-butyl ester [Reference Example 20(a)] and 4-ethyl-5-methyl phenylene diamine [Reference Example 30], and subjecting the reaction product to flash column chromatography on silica cluting with a mixture of ethyl acetate and 40-60 petrol 1, there was prepared, 3-(5-ethyl-6methyl- IH-benzoimnidazol-2-vl)-5-meth-oxv-1H-indazole as a pale yellow solid.

LC-MS (METHOD RT= 2.48 minutes; 307 3-(5 .6-Dimethyl-tIH-benzoimidazol-2-yl)-5-fluoro- 1H-indazole By proceeding in a manner similar to Example 235(a) above but using 5-fluoro-1H-indazole-3carbaldehyde [Reference Example and 4,5-dimethylbenzene-1,2-diamine there was prepared 3 -(5,6-dimethyl- 1H-benzoimidazol-2-yl)-5-fluoro- 11--indazote as a brown solid.

LC-MS (METHOD RT 2.41 minutes; 281 .6-Din-ethyl-lI--benzoimidazol-2-vl')-6-fluoro- 1H-indazole By proceeding in a manner similar to Example 235(a) above but using 6-fluoro-1H-indazole-3carbaldehyde [Reference Example and 4,5-dimethylbenzerie-l,2-diamine there was prepared 3-(C5,6-dimethyl-lH-beiizoimiidazol-2--Vl)-6-fluoro-lH-indazole 104g) as a brown solid. MS: 281 HPLC (METHOD Bl1): RT 23.6 minutes.

WO 031035065 PCT/GB02/04763 -3 88- 3-(5,6-Dimethyl-l1H-benzoimidazol-2-yl)-5-inethlyl- lH-indazole CH 3

CH

3 N

CH

3 H H By proceeding in a manner similar to Example 235(a) above but using 5-methyl-I I--indazole-3carbaldehyde [Reference Example there was prepared 3-(5 ,6-dimethyl- 1H-benzoimidazol-2-yl)-5methyl-lH-indazole as a brown solid. LC-MS (METHOD RT= 2,35 minutes; 277 3-(5,6-Dimethyl- IH-benzoimidazol-2-yl)-6-methoy- lH-indazole OCH 3 CH 3 N

CH

3 N

N--NH

CH3

H

By proceeding in a maniner similar to Example 235(a) above but using 6-methoxy-1H-indazole-3carbaldehyde [Reference Example there was prepared 3-(5 ,6-dimethyl- I H-benizoimnidazol-2-yl)-6methoxy-1H-indazole as a pale orange solid. LC-MS (METHOD RT= 2.52 minutes; 293 5.6-Dimethvl-2-(4-Dhenvl-1H-pvrazol-3-vl)- 1H-benzoimidazole By proceeding in a manner similar to Example 235(a) above but using 4-phenyl-IH-pyrazole-3carbaldehyde [Reference Example there was prepared 5,6-dimethyl-2-(4-phenyl-1IH-pyrazol-3yl)-1H-benzoiniidazole as a white solid, LC-MS (METHOD RT =2.35 minutes; 289 3 -Ethyl- IlH-benzoimidazol-2-ylD-1H-indazole WO 031035065 WO 03/35065PCT/GB02/04763 -389- CH 3

CH

2 By proceeding in a manner similar to Example 235(a) above but using 4-ethyl-phenylene diamine [Reference Example a reaction temperature of 160'C and subjecting the reaction product to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane 1) there was prepared 34(5-ethyl-l1 H-benzoimidazol-2-yl)- IH-inclazole as an off-white solid. LC-MS (Method RT 23. 13 minutes, 263.3 3 -(5-Ethyl-6-miethyl-lH-benzoimidazol-2-yl)-1 H-indazole By proceeding in a manner similar to Example 235(i) above but using diamine [Reference Example 30O(a)] there was prepared 3-(5-ethyl-6-methvt-1 H-benzoimidazol-2-yl)- Ill-indazole as an off-white solid. LC-MS (Method RT =23.79 minutes, 277.3 3 4(5-Iso pro pyl-6-methyl-1 Ii-benzoimidazol-2-yl)-1I H-indazole By proceeding in a manner similar to Example 235(i) above but using diamine [Reference Example 30(b)] there was prepared 3-(5-isopropyl-6-methyl-1H-benzoimidazol-2yl-1 indazole as an off-white solid. NIS: 291.03 HPLC (METHOD B RT 23.39 minutes.

3-(5-Bromo-6-methyl-lH-benzoimidazol-2-vyl)-lH-indazole WO 031035065 WO 03/35065PCT/GB02/04763 -3 By proceeding in a manner similar to Example 23 5(i) above but using diamine [Reference Example 30(c)] there was prepared 3-(5-bromo-6-methyl-lIH-benzoimidazol-2-yl)lH-indazole as an off-white solid. MS: 329.09 HPLC (METHOD Bi): RT 22.74 minutes.

(in) 3-(5-Bromno-IH-benzoimidazol-2-yI -IH-indazole By proceeding in a manner similar to Example 23 5(i) above but using 4-bromo-phenylene diamine [Reference Example 30(e)] there was prepared 3-(5-bromo-l1{-benzoimidazol-2-yl)-lH-indazole as a brown solid. LC-MS (Method RT =23.46 minutes, 315.15 3-(5-(3-Cyano)phenvl-1 H-benzoimidazol-2-,vl)-lH-indazole By proceeding in a manner similar to Example 235 above but using 3',4'-diaminobiphenyl-3carbonitrile [Reference Example 30(f)] there was prepared 3-(5-(3-cvano)phenyl- 1H-benzoimidazot-2yl)-1H-indazole as a white solid. MS: 335.3 HPLC (METHOD Bi): RT =21.47 minutes.

3-(5-(Pyrid-3-yl)-1H-benzoimidazol-2-y)- 1H-indazole WO 031035065 PCT/GB02/04763 -39 1- By proceeding in a manner similar to Example 23 5(i) above but using 4-(pyridine-3-yl) benzene-1,2diamine [Reference Example 30(g)] there was prepared 3-(5-(pyrid-3-vl)-1H-benzoimidazol-2-yl)-l1Hindazole as a white solid. MS: 312.2 HPLC (METHOD Bi): RT =8.58 minutes.

3-('6-Methyl-5-phenyt-l H-benzoimidazol-2-yl)-1H-indazole By proceeding in a manner similar to Example 235(i) above but using 6-methylhiphenyl-3,4-diamine [Reference Example 30(h)] there was prepared 6-methyl-5-o~henyl-l1H-benzoimidazol-2-vl)-l1Hindazole as a white solid. MS: 325.3 HPLC (METHOD BI): RT =14.48 minutes.

3-(5-Phenyl-1H-benzoimidazol-2-vl)-1I-I-indazole By proceeding in a manner similar to Example 23 5(i) above but using 4-biphenyl-3,4-diamine [Reference Example 30(i)] there was prepared 3-(5-ponvl-IH-benzoimidazol-2-yl)-IH-indazole as a white solid. MS: 311.2 HPLC (Method RT 24.54 minutes.

3-(5-(2-Fluoro)phenyl-1I-l-benzoimidazol-2-yl)- 1H-indazole By proceeding in a manner similar to Example 23 5(i) above but using 2'-fluorobiphenyl-3,4-diamine diamine [Reference Example 300)] there was prepared 3-(5-(2-fluoro)phenyl- 1H--benzoimidazol-2- Yl- 1H-indazole as a white solid. MS: 329.2 (M+H)KI- HPLC (METHOD Bi): RT =22.54 minutes.

3 (5-(34-methylenedioxy)phenyl-1H-benzoimidazol-2-yl)1 il-indazole WO 031035065 WO 03/35065PCT/GB02/04763 -392- By proceeding in a manner similar to Example 235(i) above but using 4-benzo[l,3]dioxol-5-ylbenzene- 1 ,2-diamine [Reference Example 30(k)] there was prepared 3-(5-(5,6-methylenedioxy)phenvl-lHbenzoimidazol-2-vl)-1H-indazole as a white solid. MS: 355.2 HPLC (METHOD Bi): RT 22.04 minutes.

(t 3 -(5-(2-Methaoxy)phenyl- 1H-benzoimidazol-2-yl)- 1H-indazole OCH 3 By proceeding in a manner similar to Example 235(i) above but using 2'-methoxybiphenyl-3,4-diamine [Reference Example 30(1)] there was prepared 3-(5-(2-methoxy)phenyl-1 H-benzoimidazol-2-yl)-1 Hindazole as a white solid. MS: 341.2 HPLC (METHOD BI1): RT 22.09 minutes.

3-(5-(4-Chloro)phenvyl-1H-belnzoimidazol-2-vl)-1H-inda ole By proceeding in a manner similar to Example 235(i) above but using 4'-chlorobiphenyl-3,4-diamine [Reference Example 30(m)] there was prepared 3-(5-(4-chloro)pheniyl- 1H-benzoimidazol-2-yl)-1Hindazole as a white solid. MS: 345.2 (M+H) m HPLC (METHOD Bi): RT =23.71 minutes.

3 -(5-(4-Methyl)phenyl-1H-benzoimidazol-2-vl)- li-indazole WO 031035065 PCT/GB02/04763 -393- By proceeding in a manner similar to Example 235(i) above but using 4'-methylbipheniyl-3,4-diamine diamine [Reference Example 30(n)] there was prepared 3-(5-f'4-r-nethvl~phcEyl- 1H-benzoimidazol-2-.

I -lIH-indazole as a white solid. MS: 325.1 HPLC (METHOD Cl): RT 15.22 minutes.

3-(5-Benzyloxy- 1H-benzoimidazol-2-yl)- 1H-indazole

NN

By proceeding in a manner similar to Example 235(i) above but using 4-benzyloxybenzene-1,2-diamine [Reference Example 30(o)] there was prepared 3-(5-benzyloxv-1 H-ben2oimidazol-2-yl)-1 H-indazole as a white solid. MS: 33 9.3 HPLC (METHOD Bi1): RT 22.32 minutes.

3-(5,6-Methvlenedioxy- 1H-benzoimidazol-2-yl)- 1 i-idazole By proceeding in a manner similar to Example 235(i) above but using benzo[ 1,3]dioxole-5,6-diamine [Reference Example 30(p)] there was prepared 3 -(5,6-methylenedioxy-lH-benzoimidazol-2-yl)- 1Hindazole as a white solid. LC-MS (METHOD RT =2.25 minutes; 279.22 3 -(5,6-Dimethoxy-1 H-benzoimidazol-2-yl)-tIH-indazole By proceeding in a manner similar to Example 235(i) above but using 4,5-dimethoxybenzene-1,2diamine [Reference Example 30(q)] there was prepared 3 -(5,6-dimcthoxy- 1 I-benzoimnidazol-2-yl)-l Hindazole as a white solid. LC-MS (METHOD RT 2.16 minutes; 295.26 3-(5,6-Diethyl- 1H-benzoimidazol-2-yl]-1 H-indazole WO 031035065 WO 03/35065PCT/GB02/04763 -394- By proceeding in a manner similar to Example 235(i) above but using 4,5-diethylbenzene-1,2-diarnine [Reference Example 30(r)] there was prepared 3-(5,6-diethyl- 1H-benzoimidazol-2-yl)-l H-indazole as a white solid. LC-MS (METHOD RT =2.49 minutes; 291.32 (na) 3-(4,5-Dimethyl- IH-benzoimidazol-2-yl)- 1H-indazole By proceeding in a manner similar to Example 235(i) above but using 3,4-dimethylbenzene-1,2diamine there was prepared 3-(4,5-dimetlhyl- 1H-benzoimidazol-2-yl)- if-indazole as a white solid.

LC-MS (METHOD RT =2.31 minutes; 263.24 (ab) 2 -(lH-Indazol-3-yl)-1H-beazoimidazole-qcarbonitrile By proceeding in a manner similar to Example 235(i) above but using 3,4-diaminobenzonitrile amine there was prepared 2 -(lH-indazol-3-yl)-1H-benzoimidazole-5-carbonitrile as a white solid.

LC-MS (Method RT 21.81 minutes, MS: 260.1t0 (ac) 5-metlioxycarbonvl-1 H-benzoimidazol-2-:yl)- IH-indnzole WO 031035065 PCT/GB02/04763 -395- By proceeding in a manner similar to Example 235(i) above but using 3,4-diaminobenzojc acid, methyl ester there was prepared 3(5 -methoxycarbonyl- 1H-benzoimidazol-2-yl)-l 1 H-inclazole as a white solid.

LC-MS (Method RT =22.13 minutes, 293.16 (ad) 3-(5,6-Dimethyl- 1H-benzoimidazol-2-yl)-5-ethoxy-l H-indazole EtO

CH

3 N

CH

3

HN

By proceeding in a manner similar to Example 235(a) above but using 5-ethoxy-3-formyl-indazole-1carboxylic acid tert-butyl ester [Reference Example 20(d)] there was prepared 3-(5,6-dimethyl-lHas a pale orange solid. MS: 307 HPLC (METHOD BI1): RT= 13.5 8 minutes.

(ae) 3-(5 .6-Dirrethyl-1 H-beizoimidazol-2-yl)-Dyrazole-4carboxylic acid ethyl ester o OEt

CH

3 -N CH N

H

3 H By proceeding in a manner similar to Example 2 35(a) above but using 3 -formyl-pyrazole-4-carboxylic acid ethyl ester [Reference Example there was prepared 3-(5,6-dimethyl-lH-benzoimidazol-2-yl)pyrazole-4-carboxylic acid ethyl ester as a pale brown sclid. LC-MS (.METHOD 2.56 minutes; 285 (at) 2-( 4 -Isopropylcarbamovl-1H-pyrazol-3yl). H-benzoimidazole-5-carboxylic acid methyl ester 0 OC NH/H(CH 3 2

CH

3 O N H N H By proceeding in a manner similar to Example 235(a) above but using 3-formyl-pyrazole-4-carboxylic acid isopropylamide [Reference Example 60j)] and methyl-3,4-diamino benzoate there was prepared 2- WO 031035065 PCT/GB02/04763 -396- (4-isopropylcarbamoy-IHprol3y-1Hbnomiaoe5crolcaidehlesr as a yellow solid. LC-MS (METHOD 2.99 minutes; 328 (ag) 3-(5,6-Dimethyl- IH-benzoimidazol-2-yl)-5-methyl-prazole4carboxlic acid ethyl ester CH 3 N 0 1OtCH 3

CH

3 N N N By proceeding in a manner similar to Example 235(a) above but using 3 -forrnyl-5-methyl-pyrazole-4carboxylic acid ethyl ester [Reference Example there was prepared 3-(5,6-dimethyl-1Hbenzoimidazol-2-yl)-5-methyl-pyrazole4carboxylic acid ethyl ester as a white solid. LC-M4S (METHOD RT =2.59 minutes; 299 (ah) 3 ,5,6,7-Tetrahydro- 1,3-diaza-s-indacen-2-yl)- IHI-pyrazole-4-carboxylic acid cyclopropylamide

H

0

SN

H

By proceeding in a manner similar to Example 235(a) above but using indane-5,6-diamine (130mg) and 3-formyl- lH-pyrazole-4-carboxylic acid cyclopropylamide [150 mg, Reference Example and subjecting the reaction product to chromatography on silica [eluting with ethyl acetate! gradient 75 to 0%heptane] followed by trituration with acetone, there was prepared 1,5,6,7-tetrahvdro- I ,3-diaza-sindacen-2-yl)- IH-pvrazole-4-carboxylic acid cyclopropylamide (31lmg) as a white solid. LC-MS (Method RT 2.85 minutes, 308 (ai) 3-(5-Methoxv-6-methyl-lIH-benzoimidazol-2-yl)- TH-pyrazole-4-carboxylic acid isopropylamide INHCH(CH 3 )-1 WO 031035065 PCT/GB02/04763 -397- By proceeding in a manner similar to Example 235(a) above but using 3-foirmyl-pyrazole-4-carboxylic acid isopropylamide [198mg, Reference Example 60j)] and 4-methoxy-5-methyl-benzene- 1,2-diamine [1 66mg, Reference Example 29(b)] and subjecting the reaction product to flash chromatography on silica eluting with dichioromethane/methanol (95:5) followed by recrystallisation from a mixture of ethyl acetate and il-pentane there was prepared 3-(5-methoxy-6-methyl-lH-benzoimidazol-2-yl)- 1Hpyrazole-4-carboxylic acid isopropylamide (145mg) as a white solid. LC-MS (Method RT 2.09 minutes, 314.27 312.29 (aj) 3-[5-(2-Morp~holin-4-yl-ethoxy)-1 H-benzoimidazol-2-yl- 1 H-indazole

NN

0 N N NH By proceeding in a manner similar to Example 235(i) above but using 4-(2-morpholin-4-yl-ethoxy)benzene-l1,2-diamine [Reference Example 29(c)] and subjecting the reaction product to preparative LC-MS there was prepared 3-[5-(2-1-orpholin-4-yl-ethoxy)-1 H-benzoimidazol-2-yll -1H-indazole as a white solid. MS: 364 HPLC (METHOD Bi1): RT =19.38 minutes.

(ak) 3-(5,6-dimethyl- lH-benzoimidazol-2-yl)-l H-pyrazole-4-carboxylic acid (2-methoxv-ethyl)amide HT OCH N- 3 0 CH 3

C

3

H

By proceeding in a manner similar to Example 235(i) above but using 4,5-dimethylbenzene-1,2diamine and 3-fonmyl-lH--pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide [Reference Example there was prepared 3-(5,6-dimethvl-1H-benzoimidazol-2-yl)-1 H-pyrazole-4-carboxylic acid (2methoxy-ethyl)-amide (87mg) as a cream solid. LC-M-\S (METHOD RT 4.23 minutes, 314.2 (al) 3-(5,6-dimethyvl-1H-benzoimidazol1-2-yfl- lH-pvrazole-4-carboxvlic acid propvlamide WO 031035065 PCT/GB02/04763 -398-

H

NH

CH

3 a N

C

3

H

By proceeding in a manner similar to Example 6(i) above but using 4,5-dimethylbenzene-1,2-diamine and 3-formyl-1H-pyrazole-4-carboxylic acid propylamide [Reference Example there was prepared 3-(5.6-dimethyl- 1H-benzoimidazol-2-:yl)- IH-pyrazole-4-carboxylic acid propylamide (73mg) as a pale yellow solid. LC-MS (METHOD RT 4.94 minutes, 298.29 (am) 3-(5,6-dimethyl-1H-benzoimidazol-2-ylV 1 H-pyrazole-4-carboxylic acid (tetrahydro-pvran-4yl)-amide

N

O 0

CH

3 c N~N

CH

3

H

By proceeding in a manner similar to Example 235(i) above but using 4,5-dirnethyl-1_9phenylenediamnine and 3-formyl- 1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide [Reference Example 6 and recrystallising the reaction product from methanol there was prepared .6-dimethyl- 1H-benzoimidazol-2-yl)- IH-:pyrazole-4-carboxylic acid (tetrallydro-pyran-4-yl)-amide (228mg) as a white solid. LC-MS (METHOD RT 9.40 minutes, 360 (Mm (an) 3-(5-Ethyl-6-methyl- 1H-benzoimidazol-2-vl)-

NC

CCH

2 N CH 1 N N Nl 3 H By proceeding in a manner similar to Example 235(i) above but using, diamine [Reference Example 30(a)] and 3-formyl-1H-indazole-5-carbonitrile [Reference Example 68] WO 031035065 PCT/GB02/04763 -399there was prepared 3-(5-ethyl-6-methyl- 1H-benzoimidazol-2-:yl)-1 H-indazole-5-carbonitrile (133mg) as a pale yellow solid. MS: 302 HPLC (METHOD Bi): RT =16.45 minutes.

(ao) 3-(5-Difluoromethoxy- IH-benzoimidazol-2-vlY-lH-pvrazole-4-carboxylic acid isopropylamide FyF By proceeding in a manner similar to Example 23 5(i) above but using 4-diftuormethoxy-benzene- 1,2diamine [Reference Example 30 and 3-formyl-pyrazole-4-carboxylic acid isopropylamide [Reference Example 60j)] there was prepared 3-(5-difluoromethoxy- 1H-benzoimidazol-2-yl)- 1 H pyrazole-4-carboxylic acid isopropylamide (11I8mg) as a white solid. LC-MS (METHOD RT 10.46 minutes, 336.19 (ap) 3-(5-Difluoromethoxy- 1H-benzoimidazol-2-yl)- 1H-pvyrazole-4-carboxylic acid cyclopropylamide

H

F F

N

0 0

NN

H

By proceeding in a manner similar to Example 235(ao) above but using 3-formyl-1I-I-pyrazole-4carboxylic acid cyclopropylamide [Reference Example there was prepared I1I--benzoirnidazol-2-yl)-1 I--pyrazole-4-carboxylic acid cyclopropylamide (63mg) as a white solid.

LC-MS (METHOD RT =10. 18 minutes, 334.17 (aq) 3 6 -Ethyl-5-mnetlhoxv-1H-benzoimidazol-2yl). 1H-pyrazole-4-carboxylic acid isopropylamide

CH

3

CH-

By proceeding in a marnner similar to Example 235(i) but using 4-etbyl-5-methoxy-benzene-1,2diarnine [200 mg, Reference Example 30(z)] and 3-formyl-pyrazole-4-carboxylic acid isopropylamide WO 031035065 PCT/GB02/04763 -400- [Reference Example 60j)] there was prepared 3-(6-ethyl-5-methoxy- H-benzoimidazol-2-yl)- 1Hpyrazole-4-carboxylic acid isoropylamide (115 mg) as an off-white solid. LC-MS (METHOD RT 11.34 minutes, 328.24 (ar) 3-(5,6-Dimethyl-l1H-benzoimidazol-2-yl)- 1H-indazole-5-carbonitrile dihydrochioride

NC

CH 3 N

CH

3 N

NN

3H .2HCl By proceeding in a manner similar to Example 235(i) above but using diamine and 3-formnyl-1H-indazole-5-carbonitrile [Reference Example 68] (ii) treating a suspension of the reaction product in methanol with a solution of hydrochloric acid (4M) in 1,4-dioxane followed by evaporation of the mixture (iii) trituration of the residue with methanol and (iv) recrystallisation from diethyl ether, there was prepared 3-(5 ,6-dimethyl-1 H-benzoimidazol-2-vl)- dihydrochioride (I133mg) as an off-white solid. LC-MS (METHOD RT =2.32 minutes. MS: 288 (as) 3 -nitro- I1H-benzoimidazol-2-yl-1H-indazole 0 2

N.

By proceeding in a manner similar to Example 235(a) above but using 4-nitrophenylenediamnine there was prepared 3-(5 -nitro-1IH-benzoimidazol-2-yi)- IH-indazole as red solid. MS: 280.17 HPLC (Method BI1): RT =3.00 minutes.

EXAMPLE 236 -Methyl- lH-pvrazol-3-yl)-1H-benzoirnidazole WO 03/035065 PCT/GB02/04763 -401- A mixture of o-phenylenediamine (1.08g) and 5-methylpyrazole-3-carboxylic acid (1.266g) was finely ground and the finely ground material was heated at 160 0 C for 3 hours and then cooled to ambient temperature. The reaction mixture was recrystallised from ethyl alcohol (50mL) to give a light blue solid (0.27g). The filtrate gave another crop (0.lg) on standing. The combined solids were recrystallised from ethyl alcohol to give 2-(5-methyl-1H-pyrazol-3-vll- 1H-benzoimidazole (223mg) as a lilac coloured solid, mp 322-324 0 C. [Elemental analysis:- C, 66.54%; H, 4.80%; N, 28.14%.

Calculated for C 11

HIO

0

N

4 C, 66.64%; H, 5.09%; N, 28.27%].

EXAMPLE 237 2-(5-Ethox-1H-prazol-3-vl)-1H-benzoimidazole N OCHCH bi\NH

N

H

A mixture of trifluoroacetic acid (6mL) and 2-(5-ethoxy-lH-pyrazol-3-yl)-l-(2-trimethylsilanylethoxymethyl)-lH-benzoimidazole (300mg, Reference Example 11) was stirred at 50 0 C for 1.5 hours.

The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water (pH 10). The organic layer was dried and then evaporated. The residue was subjected to chromatography on silica eluting with a mixture of dichloromethane and methanol v/v) and then recrystallised from toluene to give 2-(5-ethoxv- IHI-pyvrazol-3-vl)-1-I-benzoimidazole (0.1 g) as a colourless solid, mp 217-219.5oC. [Elemental analysis:- C, 62.26%; H, 5.23%; N, 23.44%. Calculated for C 12

H

1 2N 4 C, 63.15%; H, 5.30%; N, 24.55%].

EXAMPLE 238 2-(5-Methylsulfanvl-isoxazol-3-vyl-l1H-benzoimidazole N SCH, 3 CN N'O

H

A mixture of 2-(5-methylsulfanyl-isoxazol-3-yl)-l -(2-trimethylsilanyl-ethoxymethyl)-1Hbenzoimidazole (160mg, Reference Example 12), methanol (l2mL) and concentrated aqueous hydrochloric acid (2.45mL) were heated at reflux for four hours, then cooled and then evaporated. The residue was treated with aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate.

The extracts were dried and then evaporated to give 2-(5-methlsulfanvl-isoxazol-3-vl)-1Hbenzoimidazole (96mg) as an off white solid, mnp 179-181-C. 1 H-NMR [(CD 3 2 SOJ: 84.65 3H), 9.00 1H), 9.15-9.6 (mn, 4H).

WO 031035065 WO 03/35065PCT/GB02/04763 -402- EXAMPLE 239 5-Chloro-2-(4-nitro I H-pyrazol-3-yl)-1H-benzoimidazole A solution of 4 -chloro-benzene-1,2-diamine (500ing) in hydrochloric acid was treated with 4 -nitro-pyrazole-3-carboxylic acid (826mg) then heated at reflux temperature, under nitrogen. The reaction mixture was cooled to room temperature when the pH was adjusted to 8 by addition of ainonium. hydroxide and the mixture was extracted with ethyl acetate. The extracts were evaporated to give 5-chloro-2-(4-nitro-l1H-pvrazol-3 -yfl- 11--henzoiinidazole.

to 5, 6 -dichloro-2-(4-nitro-lHpyrazl-3-yl)-1H-benzoimidaz-ole By proceeding in a similar manner to Example 239(a) above hut using 4,5-dichloro-1_9diaminohenzene there was prepared 5,6-dichloro-2-(4-niitro- 1H-pvrazcl-3 -ylv 1H-benzoimidazole, EXAMPLE 240 (Benzoimidazol-2-yl)-5-methylthio3pyrazole A mixture of 3 3 -bis(methylthio))benzoimidazol-2-yjpropen-2one [5.5g, Reference Example hydrazine hydrate (1 .02g) and acetonitrile (5OrnL) was stirred at reflux for 18 hours. The reaction mixture was cooled, and the precipitate was isolated by filtration. Recrystallisation from aqueous ethanol provided (benzoimidazol-2-vl)-5-methvlthio-3:pyrazole 3 3 6g) as a beige crystalline solid, m.p. 242'C. [Elemental analysis: Found: C 57.8; H- 4.5; N 24.0. Calculated for C 1

IHI

0

N

4 S: C 57.37; H 4.38; N 24.33].

EXAMPLE 241 3-(5,6-Dimethyl- IH-benzoimidazol-2-yl)-4,5,6,7tetrahydrol H-indazole WO 031035065 PCT/GB02/04763 -403-

CH

3 N

CH

3 H 1,2-diamine (90mg) and 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [110 mg, Reference Example 17(a)] were mixed in a glass vial then subjected to microwave radiation (900W, domestic oven) twice for two minutes. The resulting solid was subjected to flash colun chromatography on silica eluting with a mixture of ethyl acetate and hexane (85:15, vlv) to give 3-(5,6climethvl-1H-benzoimidazol-2-yfl-45,6,7-tetraliydro-lH-indazole (30mg) as a pale brown solid.

LC-MS (METHOD RT =2.28 minutes; 267 (M+HM+.

2-(5-Isopropvyl- IH-pvyrazol-3-yl)-5,6-dimethvl- 1H-benzoimidazole CH 3 N CH(CHA)

NN

ByC 3

H

Byproceeding in a manner similar to Example 241 above, but using 5-isopropyl-lH-pyrazole-3carboxylic acid [Reference Example 17(b)] there was prepared 2-(5-isopropvl- 1 H-pyrazol-3-vl)-5,6dimethyl-1H-benzoimidazole (80mg) as a brown solid. LC-MS (METHOD RT =2.27 minutes; 255 2-(5-Ethyl- lH-pvrazol-3-yl)-5,6-dimethyl- lH-benzoimidazole

CH

3 N CH 2

CH

3

CH

3 H N H By proceeding in a manner similar to Example 241(a) above but using 5 -ethyl- 1H-pyrazole-3carboxylic acid [Reference Example and triturating the brown solid reaction product with a mixture of ethyl acetate and hexane there was prepared 2-(5-ethyl-1H-pyIrazol-3-yl)-5 ,6dimethyl-IH-benzoimidazole as a light brown solid. LC-MS (METHOD RT =2.22 minutes; 241 5,6-Dimethyl-2-( 1 4,5,6-tetrahydro-cyclopentapyrazol-3-yl)- 1H-benzoimidazole WO 031035065 PCT/GB02/04763 -404-

CH

3 N

CH

3

N--NH

3 H By proceeding in a manner similar to Example 2 14(a) above but using 1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylic acid [Reference Example 17(f)] and triturating the reaction product with ethyl acetate, ether and methanol, there was prepared 5,6-dimethyl-2-(1,4,5,6-tetrahydrocvclopentapyrazol-3-yl)-1H-benzoimidazole (50mg) as an off-white solid. MS: 253 I-PLC (METHODBI1): RT 11. 17 minutes.

EXAMPLE 242 3 -(5,6-Dimethvl-1H-benzoimidazol-2-:yl)-4-fluoro- 1H-indazole

F

CH-I

-~NTN

C

3

H

A mixture of 4,5-dimethylbenzene-1,2-diamine (70ing) and 4-fluoro-lH-indazole-3-carbaldehyde Reference Example 20(b)] in dimethylfon-mamide (8mnl) was heated to 120'C for 30 minutes and then at 100'C for 16 hours. The reaction mixture was cooled, then diluted with ethyl acetate and then washed five times with brine. The organic phase was dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate v/v) to give 3-(5,6-dimethvl-lH-benzoimidazol-2-ylp-4fluoro-lIH-indazola (1 04mg) as a light brown solid. MS: 281 HPLC (METHOD Bi1): RT 10.08 minutes.

4-Chloro-3-(5,6-dimethyl-1H-benizoimidazol-2-yl)- 1H-indazole Cl CH 3 N

C

3

H

By proceeding in a manner similar to Example 242(a) above but using 4-chloro-3-formyl-indazole-1carboxylic acid tert-butyl ester [Reference Example 20(c)] there was prepared 4-chloro-3-(5,6- WO 031035065 PCT/GB02/04763 dimethyl-1H-benzoimidazol-2-YlV1IH-ildazole (25mg) as an off-white solid. MS: 299 HPLC (METHOD B RT =10. 59 minutes.

,6-Dimethvl-1H-benzoimidazol-2-l)-5-chloro-1I-indazole Cl CH 3

N

G

3 :cH

-N

By proceeding in a manner similar to Example 242(a) above but using 5-chloro-1H-indazole-3carbaldehyde [Reference Example there was prepared 3-(5,6-dimethvl-lH-benzoimidazol-2-yl)-5 chloro-1I--indazole (25mg) as a pale brown solid. LC-MS (METHOD RT =24.24 minutes, 299 EXAMPLE 243 3-(5,6-Dimethyl-I 1 H-benzoimidazol-2-yl)-1 H-indazol-5 -ol

HO

CH 3

N

"I P-NI CH

N'N

C

3

H

A solution of 3-(5 ,6-dimethayl- lH-benzoimidazol-2-yl)-5-methoxy- lH-indazole [34mg, Example 235(b)] at 0 0 C was treated with a solution of boron tribromide in dichioromethane (O.3OmL, IM). The mixture was then heated at reflux temperature for 4 hours, then cooled and then treated dropwise with water. The pH was adjusted to between 7 and 8 by the addition of saturated aqueous sodium bicarbonate solution and this mixture was then extracted twice with ethyl acetate. The combined extracts were washed with brine, then dried over magnesium sulfate and then evaporated. The pale yellow solid residue was subjected to flash columnn chromatography on silica eluting with a mixture of ethyl acetate and triethylamine (99: 1, v/v) to yield 3-(5,6-dimethyl-lH-benzoiniidazol-2-yl)-1H- (23mg) as a white solid. LC-MYS (METHOD RT =2.19 minutes; 279 WO 031035065 WO 03/35065PCT/GB02/04763 -406- EXAMPLE 244 3-(5-n-Propyl- 1 H-benzoimidazol-2-yl)- 1H-indazole A stirred solution of 4-propyl-benzenie-1,2-diamine [57mg, Reference Example 30(d)] and sodium bisulfite (40 rng) in dimiethylformarnide (2 ml) was treated with indazole-3-carboxaldehyde [Reference Example The reaction mixture was heated in a Smith Creator microwave at 200'C for t 3 minutes then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane 1) to give propyl-IH-benzoimidazol-2-yl)-IH-indazole (74 mg) as a pale brown solid. MS: 277.3 H-IPLC (METHOD Bi1): RT 12.81 minutes.

1 H-1-ndazol-3-yl)- lH-benzoimidazole-5-sulfonic acid benzylamide By proceeding in a manner similar to Example 244(a) above but using 3,4-diamino-N-benizylbenzenesul fonamide [Reference Example 30(x)] and heating at 230TC there was prepared 2-(LLHacid benzylamide (235mg) as a white solid. LC-MS (METHOD R 1 I 6.35 mnutes, 404.20 3-(5-Methaniesulfonyl- IH-benzoimidazol-2-yl)- 1H-indazole By proceeding in a manner similar to Example 244(a) above but using 4-methanesulfonyl-benzene-1,2diamine [Reference Example 49(o)] and heating at 2 10'C there was prepared 3-(5-methanesulfonyl- IH- WO 03/035065 PCT/GB02/04763 -407benzoimidazol-2-vl)-1H-indazole (105mg) as a white solid. LC-MS (METHOD RT 5.71 minutes, 313.23 EXAMPLE 245 [2-(indazol-3-yl)-

OH

N

NN

H

A stirred solution of [2-(indazol-3-yl)-lH-benzoimidazol-5-yl]-phenyl-methanone [200mg, Example 234(c)] in tetrahydrofuran (10nmL), at -78 0 C and under an atmosphere of nitrogen, was treated dropwise with a solution of diisobutylaluminium hydride in tetrahydrofuran (1.18mL, IN). The reaction mixture was warmed to ambient temperature, then stirred for 16 hours and then partitioned between ether and sodium hydroxide solution The organic phase was washed with water, then with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane v/v) to give [2-(indazol-3-vl)-IH-benzoimidazol-5-l1-phenl-methanol (161mg) as a white solid. LC-MS (Method RT 21.89 minutes, 341.3 EXAMPLE 246 [2-(Indazol-3-yl)- I 1-1-benzoimidazol-5-vll-carboxylic acid, ethylamide CH 3CH-,NFi N N N

H

A stirred solution of [2-(indazol-3-yl)-IH-benzoimidazol-5-yl]-carboxylic acid [130mg, Example 247(a)], hydroxybenzatriazole (189mg) and diisopropyl ethylamine (73211L) in dimethylformamide (3mrnL) was treated with ethylamine and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (267mg). The reaction mixture was heated at 80 0 C overnight and then partitioned between ethyl acetate and 5% citric acid. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, then with brine, then dried over magnesium sulfate and then evaporated. The residual oil was subjected to WO 031035065 PCT/GB02/04763 -408preparative H PLC to give I 2-(indazolI-3-yl)- I 1--benzoi midazol-5-yl -carboxylic acid, ethylamide as a white solid. LC-MS (METH-OD RT 2.37 minutes; 306.27 [2-(Indazol-3-yl)- IH-benzoifinidazol-5-yli]-carboxylic acid, inethylamide 0 CH 3 NHK rj' By proceeding in a mnanner similar to Example 246(a) above but using methylarnine, there was prepared [2-(indazol-3-yl)-ll-I-benzoimiidazol-5-yll-carboxylic acid, methylarnide as a white solid.

LC-MS (METHOD RT 2.28 minutes; 292.30 [2-(lndazol-3-yl)-tH-benzoimidazol-5-yll-carboxylic acid, dimethylamnide 0 (CH 3 2 N 1'

N

NH

N N

H

By proceeding in a manner similar to Example 246(a) above but using dimethylamine, there was prepared [24indazol-3-yl)-I H--henzoiniidazol-5-yll-carboxytic acid, dirmethylamide as a white solid.

bC-MS (METHIOD RT 2.38 minutes;, 306.27 [2-(Indazol-3-yl)- IH-benzoimidazol-5-yl] -carboxylic acid. isopropylamide

(CFI

3 2 CHNHf N

NI<NH

H

By proceeding ini a manner similar to Example 246(a) above but using isopropylamine, there was prepared [2-(indazol-3 1 H-benzoimidazol-5-yll -carboxylic acid. isopropylamide as a white solid.

LC-MS (METHOD RT 2.48 minutes; 320.30 f2-(Lndazol-3 1H-benzoimidazol-5-yll -carboxylic acid, benzylamide WO 031035065 PCT/GB02/04763 -409- 0

N

H

By proceeding in a manner similar to Example 246(a) above but using benzylamine, there was prepared [2-(indazol-3-yl)- IH-benzoimidazol-5-yll-carboxylic acid. benzylamide as a white solid.

LC-MS (METHOD RT 2.68 minutes; 368.27 [2-(lndazol-3-yl)- IH-benzoimidazol-5-yll-carboxylic acid, benzamide

O

PhNH N

-NH

N 1N

[I

By proceeding in a manner similar to Example 246 above but using aniline, there was prepared [2-(indazol-3-yl)-LH-benzoli-idazol-5-yll-carboxylic acid. benzarnide as a white solid.

bC-MS (METHOD RT 2.73 minutes; 354.26 6-Dimethyl-1H-benzoimidazol-2-ylIV1H-pyrazole-4-carboxy lie acid iso propy lamide

H-

0-

CH

3 N CHNN

NH

C

3

H

By proceeding in a manner similar to Example 246(a) above but using 3-(5,6-dimethyl-1Hbenzoimidazol-2-yI)-pyrazole-4-carboxylic acid [Example 247(b)] and isopropylamine, and subjecting the reaction product to flash chromatography on silica eluting with a mixture of dichioromethane and methanol (19: 1, there was prepared 3-(5,6-dimethyl-l1H-benzoimidazol-2-vl)- IH-pyrazole-4carboxylie acid isop ropy lamide as an off-white solid. LC-MS (METHOD RT 2.67 minutes; 298 3-(5 .6-Dimethyl- 1H-benzoirnidazol-2-yl)- 1H-pyrazole-4-carboxyl ic acid (2-hydroxy-l1.1 dimethyl-ethyl)-amide WO 031035065 PCT/GB02/04763 -4

OH

0

NH

CH

3 1:

N

CH

3 N

N

3 H By proceeding in a manner similar to Example 246(a) above but using 3-(5,6-dimethyl-lHbenizoimidazol-2-yl)-pyrazole-4-carboxylic acid [Example 247(b)] and 2-ainio-2-metrhyl- 1-propanol, and subjecting the reaction product to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (19: 1, there was prepared 3-(5,6-dim-ethyl-lH-benzoimidazol-2yl)- I T-1-pyrzole-4-carhoxyl ic acid (2-hydroxy- I -dirnerlil-ethyl)-amide as a pale yellow solid.

LC-MS (METHOD RT 2.63 minutes;, 328 0i) 2-(4-lsopropylcarbarnoyl- I H-pyrazol-3-yl)- I Hl-benzoimidazole-5-carboxylic acid (pyridin-3ylmethyl)-amide

NN

H

N

N-_NH

H

By proceeding in a manner similar to Example 246(a) above but using 2-(4-isopropylcarbamoyl-I Hpyrazol-3-yl)- I H-benzoimidazole-5-carboxylic acid [Example 247(c)] and 3-(aminomethyl)pyridine there was prepared 2-(4-isopropylcarbamoyl- 1 H--pyrazol-3-yl)- I H-benzoimidazole-5-carboxylie acid (pyridin-3-ylImethyl)-amide as a white solid. LC-MS (METHOD RT =2.49 minutes;, 404 3-(5 .6-Di methyl- I H-benzoimidazol-2-yl)-5-mnethyl- I H-tpyrazole-4-carboxvlic acid cyclopropylamide WO 031035065 PCT/GB02/04763 -411- By proceeding in a manner similar to Example 246(a) above but using 3-(5,6-dimethyl-IHbenzoimidazol-2-yI)-5-methyl-pyrazole-4-carboxylic acid [Example 247(d)] and cyclopropylamine, and subjecting the reaction product to flash chromatography on silica eluting- with a mixture of dichioromnethane and methanol (19: 1, there was prepared 3-(5,6-dimethvl- IH-benzoi-nidazol-2yI)-5-mcthyl-IH-12yrazole-4-carboxylic acid cyclopropylainide as a white solid. LC-MS (METHOD RT 2.67 minutes; 3 10 2-(4-l1sop ropylcarbamnoyl- t H-pyrazol I H-benzoi inidazole-5 -carboxyl ic acid phenylmethyl-amide 0 0- NHCH(CH 3 2 N N

HN

H -N N ~N A

H

By proceeding in a manner similar to Example 246(a) above but using 2-(4-isopropylcarbamoyl-1 Hacid [Example 247(c)] and benzylamine there was prepared 2-(4-isopropylcarbamoyl-IF1I-pyrazol-3 -yb-I H-benzoim--idazole-5 -carboxylic acid phenylmethyl-amide as a pale yellowv solid. LC-MS (METHOD RT 3.17 minutes; 403 (M+H) 7 Mh 2-(4-Thnnronvicarbamovl IH-nvrazol-3-vh)-1I-benzoimidazolc-5-carboxvlic acid (nvriclin-2yl methyl)-amide 0 0- NCH(CH 3 2 N N H H By proceeding in a manner similar to Example 246(a) above but using 2-(4-isopropylcarbamoyl-1Hpyrazol-3-yl)- I l--benzoimidazole-5-carboxylic acid [Example 247(c)] and 2-(aminomethyl)pyridine there was prepared 2-(4-isopropylcarbamoyl- IH-pyrazol-3 H-benzoimidazole-5-carboxyl ic acid (pyridin-2-ylmethyl)-amide as an off-white solid. LC-NIS (Method RT -9.33 minutes, 367.28 (in) 1H-Indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid (pyridin-3 -ylmethyl)-amide WO 031035065 WO 03/35065PCT/GB02/04763 -412- NC N'

H

By proceeding in a manner similar to Example 246(a) above but using 3-(aminomethyl)pyridine there was prepared 1H-indazol-3-yl)- IH-benzoimidazole-5 -carboxylic acid (pyrid in-3-ylmethyl)-amide (42.2mg) as an off white solid. LC-MS (Method RT 4.96 minutes, 367.19 2I( H-Indazol-3-yl)- I H-benzoimidazole-5-carboxylic acid 3-methyl-benzyl amide By proceeding in a manner similar to Example 246(a) above but using 3-methylbenzylamine there was prepared IH-indazol-3-yl)- I H-ben7oi midazole-5 -carboxylic acid 3 -miethyl -benzylamide (33.4mg) as a white solid. MS: 382.52 HPLC (Method BI1): R 1 16.22 minutes.

2-Cl H-Indazol-3 IH-benzoimidazole-5 -carboxylic acid 4-methyl-benzyl amide By proceeding in a manner similar to Example 246(a) above but usi ng 4-m-ethylbenzylan-ine there was prepared 2-(l1H-i ndazol-3-yl)- IH-benzoimidazole-5-carboxylic acid 4-methyl-benzylamide (63.5mg) as a white solid. MS: 382.54 HPLC (Method BI1): RT 16.14 minutes.

1H-Indazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid [3-(2-oxo-pyrrol idin- 1 -l)-propyllamide WO 03/035065 PCT/GB02/04763 -413- By proceeding in a manner similar to Example 246(a) above but using 1-(3-aminopropyl)-2pyrrolidinione there was prepared IH-indazol-3-yl)-1H-benzoimidazole-5-carbhoxylic acid r3-( 2 -oxopyrrolidin-l-vi)-propyll-amide (68.1mgn) as a white solid. MS: 401.13 HPLC (Method BI): RT =11.29 minutes.

IH-lndazol-3-yI)- 1H-benzoi midazole-5-carboxylic acid (2-morpholin-4-yi-ethyl)-amide 0 0 Hj N N Ni

H

By proceeding in a manner sim-illar to Example 246(a) above hut using 4-(2-aminoethyl)i-norpholine there was prepared 2-(lI 1-1-inda7.ol-3-yl)- I 1-1-enzoimidazole-5-carboxylic acid (2-imorphol in-4-yI ethyl)-arnide (70.8mg) as a white solid. MS: 389.12 HPLC (Method Bi1): Rj 1 8.51 minutes.

2-0 I lndazol-3-yl)- I H-benzoi midazole-5-carboxylic acid (2-methoxv-ethyl)-amide 0

N

H

N11 N NH

H

By proceeding in a manner similar to Example 246(a) above but using 2-miethoxyethylamine there was prepared 2-(1H-indazol-3-yl)-IH-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (55.2mg) as a white solid. MS: 336.52 HPLC (Method BI): RT= 11.30 minutes.

1H-Indazol-3-yl'i-l1H-benzoimidazole-5-carboxyl ic acid (2-cyano-ethyl)-amide o

N

H

N N NH By proceeding in a manner similar to Example 246(a) above but heating the reaction at 50'C and using 3-ami nopropion itrile there was prepared IH-indazol-3 -yv- 1H-bcnzoimidazolc-5-carboxylic acid (2cvano-ethyl)-amide (15.4mg) as a white solid. MS: 331.15 329.17 HPLC (Method Bi1): RT 12.72 minutes.

WO 031035065 PCT/GB02/04763 -414- 2-(tH-Indazol-3-yl)- IH-benzoimidazole-5-carboxylic acid (2-hydroxy-l,]I-dimethyl-ethyl)am ide 0 HO

N

-1 N N NH

H

By proceeding in a manner similar to Example 246(a) above but heating the reaction at 50'C and using 2-amino-2-metliyl-lI-propaniol there was prepared IH-inidazol-3-yl)-I H-benzoi acid (2-hydroxy- 1, 1-d imethyl-ethy ])-amid e (29.6mg) as a brown oil. LC-MS (Method RT 10.57 minutes, 3 50.16 348. 18 (M 2-(1I -1-lndaz.ol-3-yl)- I lI-benzoimidazole-5-carboxyl ic acid (3-imidazol-1 -yl-propyl)-amide

O

N N H N N -N l

H-

By proceeding in a manner similar to Example 246(a) above but using 1-(3-aminopropyl)imidazole there was prepared IH-Indazol-3-yl)- 1 H-benzoimida7ole-5-carboxylic acid (3-imidazol-1 -VI-pro~yl)amide (3 1.9mg) as a white solid. LC-MS (Method B3): Ri; 8.45 minutes, 386.22 (M 384.26 3-(5 .6-dimethyl- I H-benzoimidazol-2-yl)- 1 H-pyrazole-4-carboxyl ic acid isobutyl-ainide

H

WO 031035065 PCT/GB02/04763 -415- By proceeding in a manner similar to Example 246(g) above but using isobutylamine there was prepared 6-dimethyl-l H--benzoimidazol-2-yl')-1H-pyrazole-4-carboxylic acid isobutyl-amide (101mg) as a white solid. LC-MS (METHOD RT =9.38 minutes, 312 3-(5 6-litnethvl- 1 -b-enzoimidazol-2-vh)- I l-vrazole-4-carboxvlic acid isonronvlaniide

I

By proceeding in a manner similar to Example 246(g) above but using isopropylamine there was prepared 3-(5,6-dimrethyl-1H-benzoimidazol-2-yl)-I H-pyrazole-4-carboxylic acid isopropylamnide (I100mng) as a white solid. LC-MS (METHOD Rj, 7.21 minutes, 298 Wx 6-dimethyl- IH-benzoimnidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylimeth viami de

H

CH-,-N

By proceeding in a manner similar to Example 246(g) above but using (aminomethyl)cyclopropane there was prepared 3-(5,6-dimethyl- I H-benzoimidazol-2-yl)- I -nyrazole-4-carboxylic acid cycloprop~ylmethyl-amide (105mg) as a white solid. LC-MS (METHOD RT 8.77 minutes, 310 3 -(5,6-dimethyl- 1H-benzoimidazol-2-vl)-5-methyl-1 H-pyrazole-4-carboxylic acid tertbutylamide

H

CH

3 a-N; CH 3

CH

3 H N H WO 031035065 PCT/GB02/04763 -4 16- By proceeding in a manner similar to Example 2460) above but using tert-butylamine there was prepared 3-(5,6-dimethyl-l H-ben7.oimida7Ol-2-yl)-5-methyl- I H--pyra7.ole-4-carboxylic acid tertbutylamide (57mg) as an off-white solid. LC-MS (METHOD RT 13.86 minutes, 326 (M+H)7.

3-(5,6-Dimnethyl-1 H-benzoinmidazol-2-yl)- IH-indazole-5-carboxylic acid di methylamide dihydrochloride

CH

3 0 CH, CH 3 N

CH

3 N N--NH CH3H .2HCl By proceeding in a manner similar to Example 246(j) above, but using 3-(5,6-dimethyl-IHbenzoim-idazol-2-yl)-1l-l-indazole-5-carboxylic acid [97mg, Example 263] and dimethylamine hydrochloride (23mg), (ii) carrying out the reaction at amrbient temperature overnight, and (iii) subjecting the reaction product to flash column chromatography [eluting with ethyl acetate to ethyl acetate/methanol (97:3, followed by treatment with 4M hydrogen chloride in 1,4-dioxane and trituration with diebloromethane and diethyl ether there was prepared 3-(5,6-dimethyl- I Hbenzoimidazol-2-yl)- 1 H-inda7ole-5-carboxylic acid dimethylamide dihycirochloride (Sing) as a white solid. LC-MS (METHOD RT 9.37 minutes, 320 (aa) 2-(4-isobutvrylamino- IH-pyrazol-3-yl)- IH-benzoimidazole-5 -carboxylic acid benzylamide 0 0 N N

N

H

By proceeding in a manner similar to Example 246(a) above but using 2-(4-isobutyrylarmino-IHpyrazol-3-yl)- 1H-benzoimidazole-5-carboxylic acid [Reference Example 351 and benzylamine there was prepared 2-(4-Isobutyrylamino- IH-pyrazol-3-yl)- 1H-benzoimidazole-5-carboxyl ic acid benzylamide (1 7mg) as a white solid. LC-MS (METHOD RT 11.00 minutes, 403 WO 031035065 PCT/GB02/04763 -4 17- (ab) IH-Indazol-3-yl)-1 H-benzoimiclazole-5-carboxylic acid (2-piperidin-1 -yl-ethyfl-amide 0

NN

HN

N N N

H

By proceeding in a manner similar to Example 246(a) above but using 1-(2-aminoethyl)p iperi dine, and heating the reaction mixture at 50'C for 6 hours, there was prepared 2-(IH-indazol-3-Yl)- I Fiacid (2-piperidin- I-yl-ethyl)-amide as an oil. MS: 387.22 1IPLC (Method RT 5.03 minutes.

(ac) 1 H-Indazol-3-yl) -1H-benzoirniidazole-5-carboxylic acid (pyridin-2-ylrneth i) -amide 0

NN

N

N

I r

NH

H

By proceeding in a manner similar to Example 246(ab) above but using (2-aminomethyl)pyridine there was prepared I H-inidazol-3-yl)- IH-berizoimiidatzule-5 -carboxylic acid (pyridin-2-yliinethl y)-amlide as an off-white solid. MIS: 367.28 HPLC (Method BI1): RT =9.33 minutes.

(ad) 2-(1I I-lnclazol-3-yl)-11I-i-benzoiinidazole-5 -carboxylic acid [3-(4-rnethyl-piperazin- t-yj)propyll-amide 0

N

N N

H

N-NH

H

By proceeding in a manner similar to Example 246(ab) above but using 4-(3-(aminopropyl))-1 -methyl piperazine there was prepared IH-inidazol-3-yfl- IH-benizoim-idazole-5 -carboxylic acid P3-(4methylpiperazin- I-Yl)-propyll-amide as an oil. MS: 416.21 HPLC (Method RT 4.46 minutes.

(ac) 1H-Indazol-3 I WO 031035065 PCT/GB02/04763 -418- (CH 3 2 CH-r

N

0 N NNH

H

By proceeding in a manner similar to Example 246(ab) above but using isobutyric acid and 2-(1Hlindazol-3-yl)-3H-benzoimidazol-5-aminie [Example 265] there was prepared N-r2- I H-lndazol-3- I I H-benzoimidazol-5-yl]-isobutyramide as an off-white solid. MS: 320.23 I-IPLC (Method Bi1): RT 19.28 minutes.

EXAMPLE 247 12-(Indazol-3-yl)- i H-benzoim-idazol-5-yI -carboxylic acid o

N

HOH

A stirred solution of 3 -(5-m-ethoxycarbonyl-l1H-henzoimidazol-2-yl)- 11--indazole [84.5mg, Example 235(ac)] and sodium hydroxide (74mg) in tetrahydrofuran (4mL) and water (2mL) was heated at overnight. The reaction mixture was evaporated and the oily residue was partitioned between ethyl acetate and water, The aqueous layer was acidified to pH- 6 and extracted with ethyl acetate. The organic layers was dried over magnesium sulfate and then evaporated to give [2-(indazol-3-yl)-IHbenzoimidazol-5-yll-carboxylic acid (80mg) as an oil. MS: 279.14 HPLC (METHOD H): RT 2.81 minutes.

6-Dimethyl-IH-benzoimidazol-5-y )-pyrazole-4-carboxy lic acid 0

OH

CH

3 N N

CH

3

H

By proceeding in a manner similar to Example 247(a) above but using 3-(5,6-dimethyl-IHbenzoimidazol-2-yl)-pyrazole-4-carboxylic acid ethyl ester [Example 235(ae)] and carrying out the reaction at 60'C there was prepared 3-(5,6-dimethyl-IH-benzoimidazol-5-l)-pyrazole-4-carboxylic acid as a white solid. LC-MS (METHOD RT 2.17 minutes; 257 WO 031035065 PCT/GB02/04763 -419- 2-(4-Jsopropylcarbamoyl- I I-pyrazol-3-yl)-1 H-benzoimnidazole-5-carboxylic acid 0 NH-CH(CH 3 2 N

N-,NH

H

By proceeding in a manner similar to Example 247(a) above but using 2-(4-isopropylcarbamoyl- IHpyrazol-3-yl)- 1H-benizoimidazole-5-carboxylic acid methyl ester [Example 23 replacing the Stetrahydrofuran with methanol and carrying out the reaction at 65'C, there was prepared 2-(4-i sop ropylcarbaioyl I H-pyrazol-3 1 H-be nzoimnidazo le-5 -carboxyl ic acid as a pale brown solid which was used without further purification. LC-MS (METH-OD RT 2.67 minutes; 314 6-Dimethyl- I FI-benzoimidazol-2-vil -5-nmethyl-pyrazole-4-carboxylic acid 0 OH CHI- N CH 3 CH N N N 3I By proceeding in a mianner similar to Example 247(a) above but using 3-(5,6-dimethyl-IHbenzoimidazol-2-yI)-5-methyl-pyrazole-4-carboxylic acid ethyl ester [Example 235(ag)], replacing the tetrahydrofuran with methanol and carrying out the reaction at 65'C, there was prepared 34(5,6di methyl-iI--benzoimidazol-2-vl)-5-methvl- yrazole-4-carboxylic acid as a white solid. LC-MS (METHOD B3): RT 2.75 minutes; 271 (M±H)r.

EXAMPLE 248 N-[3-(5,6-Diinethvl-1I -1-benzoimidazol-2-yl)-l1H-pyrazol-4-yll-isobutyramnide 0 CH-(CI-1 3 2

HN

CH 3

)N

CHI H N NH A stirred solution of 5,6-dimethyl-I--benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [83mg, Example 233(c)] and diisopropylethylamine (256g~L) in dichloromethane (4nmh) was treated with isobutyryl chloride (I t 5ItL). The reaction mixture was stirred for 30 minutes at room temperature then treated with piperidine (500gtL) and stirring was continued for a further hour. The reaction mixture was WO 031035065 PCT/GB02/04763 -420partitioned between 5% citric acid. The organic layer was dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of hexane and ethyl acetate to give N-F3-(5,6-dirnethyl- I H-benzoimidazol-2-yl)-l H-pyrazol-4-y~lisobutyramnide (49mg) as a white solid. MS: 298.28 l-IPLC (METH-OD BI1): RT =14.66 minutes.

N-f3 -(5,6-Dimethyl- 1 11-benzoimidazol-2-yl)- I H-pyrazol-4-yll-3 -methyl-butyramide 0

CI

2 GCH(CH, 2

I-N

CH 3 N

C

3 H N H By proceeding in a manner similar to Example 248(a) above but using isovaleryl chloride there was prepared N-[3-(5.6-diimethyl- IH-benzoimidazol-2-yl)- 1H-pyrazol-4-vl]-3-methvyl-butyramide as a white solid. MS: 312.28 HPLC (METHODB RT 15.2 8 minutes.

N-[3 -(5,6-Dimethyl- 1 H-ben zoimi dazol 1 H-pyrazo 1-4-Vl -2 -p lenyl -acetam ide By proceeding in a manner similar to Examnple 248(a) above but using phenylacetyl chloride there was prepared .6-dimetbyl- IH-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-2-phenyl-acetamide as a white solid. LC-MS (METHOD RT 2.83 minutes, 346.18 Cyclopropanecarboxylic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yllamide WO 031035065 PCT/GB02/04763 -42 1- 0

HN

GH

3

N

C N N'N

C

3

H

.By proceeding in a manner simlar to Example 248(a) above but using cyclopropanecarbonyl chloride, there was prepared cyc lopropanecarboxyl ic acid [3-(5,6-dimethyl-lIH-benzoimidazol-2-yl)- 1H-pyrazol- 4-y1 -amide as a white solid. M4S: 296.28 HPLC (METHOD BHI): RT 13.50 minutes.

Methoxyacetic acid [3-(5,6-dimethyl- IH-benzoirnidazol-2-vl)- IH-pyrazol-4-yl]-amide 0 CH -0 2 0CH 3

CH

3

N

N

NNH

CH

3 H By proceeding in a manner similar to Example 248(a) above but using metlioxyacetyl chloride, there was prcpared methoxyacetic acid [3 ,6-dimethyl- I H-benzoi midazol-2-yl)- 1H-ciyrazol-4-yll-amide as a white solid. MS: 300.33 HPLC (METHOD Cl): RT =14.25 minutes.

Cyclopentaneccarboxylic acid f3-(5,6-dirnethyl-l1H-benzoimidazol-2-yl)-l1H-pyrazol-4-vl]-amide 0

TIN

CH

3 N

CH

3 N N'N CH3

H

By proceeding in a manner similar to Example 248(a) above but using cyclopentylcarbonyl chloride, there was prepared cyclopentanecarhoxylic acid. [3-(5,6-dimethyl- I H4-benzoimidazol-2-yl)-l1H-pyrazol- 4-yl]-arnide as a white solid. MS: 324.39 HPLC (METHOD B RT 17.64 minutes.

Trimethylacetic acid [3 -(5,6-dimethyl-1 H-benzoimidazol-2-yl)-l1H-pyrazol-4-yll-amide WO 031035065 WO 03/35065PCT/GB02/04763 -422- By proceeding in a manner similar to Example 248(a) above but using trimethylacetyl chloride, there was prepared trimethylacetic acid r3-(5,6-di methyl-I H-benzoimidazol-2-yfl- IH-pyrazol4-yll-amide as a white solid. MS: 312.39 HPLC (METHOD Bi1): RT -19.52 minutes.

tert-Butylacetic acid r3-(5,6-dIimethyl- 1H-benzoimidazot-2-yl)-tIH-pyrazol-4-yl]-amide 0 -CH 2 C(CH 3 3

NH

CH

3

NNH

By proceeding in a manner similar to Example 248(a) above but using tert-butylacetyl chloride, there was prepared tet-i-butylacetic acid r3-(5.6-dimethyl-H-benzoiniidazol-2-yl)-l1H-pyrazol-4-yl]-amide as a white solid. MIS: 326,29 HPLC (METHOD B1): RT 19.52 minutes.

Butanoic acid [3-(5,6-dimethvl- IH-benzoimidazol-2-yl)- IH-pyrazol-4-yll-amide By proceeding in a manner similar to Example 248(a) above but using butyryl chloride, there was prepared butanoic acid_[k-(5,6-dimet-hyl-11H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl I-amide as a white solid. MS: 298.34 HPLC (METHOD Bi1): RT 15.07 minutes.

0) Isoxazole-5 -carboxylic acid ,6-di methyl-I H-benzoi midazol-2-vl)-11 Drazol-4-yl1-amide WO 03/035065 PCT/GB02/04763 -423- 0 HN I CH 3 N

CH

3 HO N N'N By proceeding in a manner similar to Example 248(a) above but using isoxazole-5-carbonyl chloride, there was prepared isoxazole-5-carboxylic acid [3-(5,6-dimethyl- I H-benzoimidazol-2-yl)- 1H-pyra7zol- 4-yl]-amide as awhite solid. MS: 32316 H-PLC (METHODBl1): RT 10.01 m1inui-tes.

S(+)-2-Methwlbutanoic acid [3 .6-di miethiyl-I H-benizoi miidazol-2-yl- IH-pyrazol-4-yl]-am ide o CH 3 _ClI 14N

CHCH

3

CH

3 N

CH

3 IN N~N By proceeding in a manner similar to Example 248(a) above hut using S(±)-2-methyl hutyryl chloride, there was prepared S(+)-2-methylbutanoic acid r3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 11--pyrazol- 4-yll-amide as awhite solid. MS: 312. 18 HPLC (METHOD BI): RT 11. 15 minutes.

Cycloprop anecarboxylic acid [3-(5-eth y -6-meth vl-lH-benzoliidazol-2-y)-111-pyrazol-4y] amide 0 fiNY

CH

3

CH

2 N I \NH

C

3

H

By proceeding in a manner similar to Example 248(a) above but using 3-(5-ethyl-6-methyl-1Hbenzoimidazol-2-yl)- 1H-pyrazol-4-ylamine [Example 233(d)] and cyclopropanecarbonyl chloride, there was prepared cyclopropanecarboxylic acid [3-(5-ethyl-6-imethyl-1H-benzoitmidazol-2-yl)- IHpyrazol-4-yll-amide as a white solid. MS: 310.32 HPLC (METHOD BI): RT 8.88 minutes.

WO 03/035065 PCT/GB02/04763 -424- (in) Piperidine-lI-carboxyl ic ac il[3 -(6-chloro-5-methoxy- 1I--benzoirnidazol-2-yl)- 1H-pyrazol-4-yl]am ide 0 HN

N

CH

3 N ci

NNH

By proceeding in a manner similar to Example 248(a) above but treating a solution of 3-(6-chloro-5methoxy-IH-benzoimnidazol-2-yl)-l I--pyrazol-4-ylamine [0.2g, Example 233(e)] and diisopropylethylamine (392mg, 4 eq) in tetrahydrofuran (25mL) with piperidinecarbonyl chloride (450mg, 4 eq), stirring overnight at ambient temperature, and evaporating the reaction mixture, (ii) triturating the reaction product with water (30 mnL) and ethyl acetate (50 i-L) and extracting with aqueous layer with ethyl acetate, (iii) combining the organic phases, drying over magnesium sulfate, then evaporating (iv) chromnatographing the residue on silica gel (ethyl acetate), triturating the partially purified material with ethyl acetate (l5mL) for 1.5 hours and filtering, and (vi) evaporating the filtrate and chromatographing the residue on silica gel (ethyl acetate/heptane gradient of 20-0%) there was prepared piperidine-1 -carboxylic acid[3-(6-chloro-5-methoxy- 1 H--benzoimidazol-2-yl- H pyrazol-4-yll-amide (50 mg) as a yellow solid, nip >3 1 0 0 C. If-MS (Method E) RT 3 .25 minutes, 3-[3-6-Chloro-5-methoxy-I H-benzoir-nidazol-2-vl) -l1--pyrazol-4-yll-l. l-dimethvlurea

CH

3

NN

CH

3

I

Cl)O N N NH

H

By proceeding in a similar manner to Example 248(m) above but using N,N-dimethylcarbamnyl chloride 201 there was prepared 3-[3-(6-chloro-5-methoxy- 1H-benzoimidazol-2-vi 1- 1H-pyrazol-4-yll- 1,1 dimethylurea as a yellow solid, mp >300'C. LC-MS (Method RT =2.4 minutes, 335 Cyclopropanecarboxylic acid I 3-(5-mcthoxy-I1 -benzoimidazol-2-yl)-lIH-pvrazol-4-yl] -amide WO 03/035065 PCT/GB02/04763 -42 0 Cl-i 30,

N

N

-NH

H

By proceeding in a manner similar to Example 248(a) above but using 3-(5-methoxy- IHbenzoimidazol-2-yl)- IH-pyrazol-4-ylamine [282mg, Example 233(o] and cyclopropanecarbonyl chloride (0.558m1) there was prepared cyclopropanecarboxylic acid 2-yl)-I H-pyrazol-4-yi]-amide (761ng) as an off-white solid. LC-MS (Method RT= 5.25 minutes, 298.26 Cyclo prop anecarhoxyli1c acid [3-(5-ethioxy -IH-benzoimidazol-2-vl) -IH-pyrazol-4-yI] -arnide 0 C13 20-

N

N>

NHNV

H

By proceeding in a manner similar to Example 248(o) above but using 2 -yl)-IH-pyrazol-4-ylamine [187mg, Example 233(g)] there was prepared cyclopropanecarboxylic acid [3-(5-ethoxv-IH-benzoimidlazol-2-yl)-lH-pyrazol-4-yll-amidle (1 12mg) as a pale yellow solid. LC-MS (Method RT 2 2 6 minutes, 312,23 310.30 Cyc lopropanearboxyl ic acid [3 -(5-fluoro-6-methyl-l1H-benzoimidazol-2-yl- I H-pyrazol-4-ylamide 0

HN

F

N

N N'NH

C

3

H

By proceeding in a manner similar to Example 248(a) above but using 3-(5-fluoro-6-methyl-IHbenzoimidazol-2-yl)- 1H-pyrazol-4-ylamine [Example 233(h)] and cyc lopropanecarbonyl chloride there WO 031035065 PCT/GB02/04763 -42 6was prepared cyclopropanecarboxylic acid [3-(5-fluoro-6-inethyl-1 H-benzoimidazol-2-yl)- IH-pyrazol- 4-yll-arnidc (1 35mg) as a white solid. LC-MS (METHOD RT 11.31 minutes, 300,31 Cyclopropanecarboxyl ic acid [3 -(5-trifluoromethoxy- IH-benzoimidazol-2-yl IH-pyrazol-4yl]-arnide 0 CF 3 0N By proceeding in a manner similar to Example 248(a) above but using benzoi midazol-2-yl)- IH-pyrazol-4-ylamine [Example 233(i)] and cyclopropanecarbonyl chloride there was prepared cyclopropanecarboxylic acid [3-(5-trifluoromethoxy-lH-benzoimidazol-2-yl)- 1 -1 pyrazol-4-yl]-amide (275mg) as a white solid. LC-MS (METHOD RT =13.57 minutes, 352.22 Cyclopropanecarboxylic acid F3-(5 -trifluoromethyl- 1H-benzoimidazol IH-pyrazol-4-yl]arnide 0

CF

3 N N N -NH

H

By proceeding in a manner similar to Example 248(a) above but using 3-(5-trifluoromethyl- I Hbenzoimidazol-2-yl)- 1H-pyrazol-4-ylamine [Example 233(j)] and cyc lopropanecarbonyl chloride there was prepared cyclopropanecarboxylic acid [3-(5-trifluoromethyl-l1H-benzoimidazol-2-yij- 1H-pyrazol- 4-yl]-amide (88mg) as a white solid. LC-MS (METHOD RT 13.62 minutes, 338.12 Wt N-[3-(5-Trifluorom-ethiyl- IH-benizoi midazol-2-yl)-.I H--pyrazol-4-yfl-isobutyramide WO 031035065 WO 03/35065PCT/GB02/04763 0 CI-(CH 3)2 4

'N'I

By proceeding in a manner similar to Example 248(s) above but using isobutyryl chloride there was prepared -trifluoromethyl-l1H-benzoimidazol-2-yl)- I H-pyrazol-4-yfl-isobutyrarnide (7 1 mng) as a white solid. LC-MS (METH-OD RT =10. 11 minutes, 336.12 Cyclopropanecarboxylic acid [3-(5-chloro-6-methyl- 1H-benzoimidazol-2 I H--pyrazol-4-yllam ide 0 C1

N

CH

3 N NNH 3 H By proceeding in a manner similar to Example 248(a) above but using 3-(5-chloro-6-methyl-IHbenzoi midazol -2-yl)-lI H-pyrazol-4-ylamine [Example 2611] and cyclopropanecarbonyl chloride there was prepared cyclopropanecarboxylic acid [3-(5-cliloro-6-methyl- I H-benzoimnidazol-2-yl)- I H-pyrazol- 4-y1 -amide (46mg) as a white solid. LC-MS (METHOD RT 7.06 minutes, MS: 316.26 3,5-Dimethyl-isoxazole-4-carboxylic acid [3-(5,6-dirnethyl- I H-benzoimidazol-2-yl)-1 Hpyrazol-4-yl] -amide C~ I 3 CH 3"H By proceeding in a manner similar to Example 248(a) above but using 3,5-dimethylisoxazole-4carbonyl chloride there was prepared 3,5-dimethyl-isoxazole-4-carboxylic acid [3 -(5,6-dimethyl- 1H- WO 031035065 PCT/GB02/04763 -428- .benzoimidazol-2-vli3-1H-pvrazoI-4-vl]-amide (62mg) as a white solid. LC-MS (METHOD RT 8.45 minutes, 351.32 (N4-IH)+.

(wv) N-[3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)- 1H-pyraz.ol-4-yI]-acetamide

CH,

CH3 By proceeding in a manner similar to Example 248(a) above but using acetyl chloride there was prepared N-F3-(5,6-dimethiyl- 1H-benizoiimidazol-2-yl)- 1H-pyrazol-4-yIl-acetamide (25mg) as a white solid. LC-MS (METHOD RT 6.34 minutes, 270.14 Furan-3-carboxylic acid 6-imethylmetliyl- I H-benzo imidazol-2-yl -1 H-pyrazol-4- I]amide 0 HN

CH

3 N

N'NH

CH

3 H By proceedingo in a manner similar to Example 248 above hut using 3-furoylchloride there was prepared furan-3-carboxylic acid [3-(5,6-dimethyl- IH-benzoimidazol-2-yl)- 1 H-pyrazol--vl-amide (80mg) as a white solid. LC-MS (METHOD RT 7. 10 minutes, 322.31 ,6-Dimethyl- I I--benzoimi dazol-2-vl)- IH-pvrazol-4-vl]-4-methyl-benzamide WO 031035065 PCT/GB02/04763 -429- By proceeding in a manner similar to Example 248(a) above but using p-toluoyl chloride there was prepared N-r34-5 6-dimethyl- I H-benzoimidazol-2-yb)- 1 H-pyrazol-4-yll -4-m-ethyl-benzamide (42mg) as a white solid. LC-MS (METHOD RT 12.24 minutes, 346 EXAMPLE 249 5 ,6-Dimiethvl-2-(4-nitro- 1H-pyrazol-3-yl)- I H-henzoi midazole O2N

N

NT'H

CH

3 N N- A stirred solution of 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl)amnide [5.7g, Reference Example 36(a)] in acetic acid (IlO0rmL) was heated at 120'C for 1 hour, then cooled to ambient temnperature and then evaporated. The oily residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated to give 5,6-dimethyl- 2-(4-nitro-IH-pyrazol1-3-yl)-1l-I-benzoimidazole (5.70 g) as an orange solid. LC-MS (MEIHOD B): RT= 2.30 minutes, 258.11 5 -Ethyl-6-inethyl-2-(4-niitro- IH-pyrazol -3 1H-benzoimidazole 0 2

N

CH 3

CH

2 -N

CH

3 N

N-N

By proceeding in a manner similar to Example 249(a) above but using 4-nitro)-1H-pyrazole-3carboxylic acid (2-ami no-4-ethyl-5-methlylphenyl)amide [Reference Example 36(b)] there was prepared 5-ethyl-6-methyl-2-(4-nitro-t1H-pyrazol-3-yl)-1 H-benzoimidazole as a yellowv solid. bC-MIS (METHOD RT 2.61 minutes, 272.23 6-Chloro-5-methoxy-2-(4-nitro- 1H-pyrazol-3 -yl)-I 1--benzoimidazole O2N

CH

3 0

N

Cl N NN

H

By proceeding in a manner similar to Example 249(a) above but using 4-nitro-IH-pyrazole-3carboxylic acid (2-arnino-5-chloro-4-methoxyphenyl)amide 1.5g, Reference Example 36(c)] there was WO 03/035065 PCT/GB02/04763 -430prepared 6-chloro-5-methoxv-2-(4-nitro-1H-pyrazol-3-vl)-1H-benzoimidazole (0.7g) as a dark solid.

MS: 294 5-Flucoro-6-methyl-2-(4-nitro- IH-pyrazot-3-yl)- I 1-benzoimidazole O 2N CHI N N NH

H

By proceeding in a manner similar to Example 249(a) above but using 4-Nitro-1H-pyrazole-3carboxylic acid (2-amino-4-fluoro-5-metlhyl-phenyl)-amide [Reference Example 36(f)] there was prepared 5-fluoro-6-methyl-2-(4-nitro-IH-pyrazol-3-yl'l-lH-benzoimidazole (0.730g) as a red solid.

LC-MS (METH-OD RT 2.76 minutes, 26221 2-(4-Nitro- 1H-p yrazol-3-yl)-5 -trifIloromethoxy- 1I-benzoimidazole By proceeding in a manner similar to Example 249(a) above but using 4-nitro-IH-pyrazole-3carboxylic acid (2-amino-4-trifluoromethoxy-phenyl)-amnide [Reference Example 36(g)] there was prepared 2-(4-nitro- I H-pyrazol-3-yl)-5-trifluoromethoxy- 1 H-ben2oimidazole (1 .02g) as a red solid.

LC-MS (METHOD RT 3.32 minutes, 314.19 2-(4-Nitro- I H--prazol-3-yl)-5-trifluoromethyl- IH-benzoimidazolc By proceeding in a manner similar to Example 249(a) above but using 4-nitrolIH-pyrazole-3carboxylic acid (2-amino-4-trifluoromethyl-phenyl)-am~ide [Reference Example 36(h)] there was prepared 2-(4-nitro-IH-pVrazol-3-yl)-5-trifluoromethiyl- I H-benzoimidazole 195g) as an orange solid.

MS: 299.07 HPLC (METHOD RT 3.50 minutes.

-5-Chloro-6-methvi-2-(4-nitro- 1 H-nvra7zol-3-vh)- H-benzoimidazole WO 03/035065 PCT/GB02/04763 -43 1- 02 N Cl

N

C

3

H

By proceeding in a manner similar to Example 249(a) above but using 4-nitro- I H-pyrazole-3carboxylic acid (2-a mino-4-chloro-5 -methyl-phenyl)-amide [Reference Example 36(i)] there was prepared 5-chloro-6-methyl-2-(4-nitro-l1H-pyrazol-3 I H-benzoimidazole 3 2 0 g) as an orange solid. LC-MS (METH-OD RT =3.36minutes, 314.19 2-(4-N itro- IH-pyrazol-3-yI)- IH-benzoimidazole-5-carboxl ic acid methyl ester 0 02 N

CH

3 O N

N

N N~N

H

By proceeding in a manner similar to Example 249(a) above but using 3-amnino-4-[(4-itro- IHpyrazole-3-carbonyl)-aminoJ-benzoic acid methyl ester [Reference Example 36(j)] there was prepared 2-(4-n itro- IH-pyrazol-3-yl)- IH-benzoimidazole-5 -carboxylic acid methyl ester (2.50~g) as a yellow solid. LC-MS (METHOD RT 2.76 minutes, 288.12 EXAMPLE 250 3-(5,6-Dimethyl- IH-benzoimidazol-2-yl)- 1,4,6,7-tetrahvdro-pyrazolo[4,3-clpvridine-5carboxylic acid isopropylamide 0 N(C11 3 2

CH

3 )j :N N

_~NH

CH 3 H A solution of 3-(5,6-dimethyl- IH-benzoimidazol-2-yI)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridine [0.l150g, Example 25 in dimethyl formamide (4m1) was treated with diisopropylethylamine (O.54m1) and then with dimethyl carbamyl chloride (0.122m1). After stirring for 1 hour the reaction mixture was quenched by the addition of methanol Imi) and then diluted with ethyl acetate. This mixture was washed five times with brine and then evaporated. The residue was treated with tetrahydrofuran (9ml) and methanol (3ml) and the resulting solution was then treated with potassium WO 03/035065 PCT/GB02/04763 -4 32hydroxide (50mg). This mixture was stirred for 1 hour, then acidified by addition of hydrochloric acid I M) and then extracted three times with ethyl acetate. The aqueous layer was basified by addition of sodium carbonate and the resulting suspension was filtered, then washed with water, then dried in air and then azeotroped witli toluene to yield 3-(5,6-dirnethyl- I H-benzoimidazol-2-yl)-1I 4,6,7-tetrahydropyrazolo[4,3-clpyridinc-5-carboxylic acid isopropylamidc as a pale brown solid. MS: 339 HPLC (METHOD Fl1): RT 8.67 minutes.

Cyc lopropyl-[3 -(5,6-din-iethyl- 1I--benzoimidazol-2 -VI)-1I,4,6,7-tetrahydro-pyrazolo[4,3- N

N

By proceeding in a manner similar to Example 250(a) above, but using cyclopropancarbonyichioride and stirring the reaction mixture for 16 hours, there was prepared cyclopropyl-[3-(5,6-dirnethyl- I Hbenzoi midazol-2-yl)- 1.4.6.7-tetrahydro-pyrazolo[4,3-clpvyridi n-5 -yll-methianonie (68mg) as a pale yellow solid. LC-MS (METHOD RT 10.57 minutes, 336 Isopropyl-[3-(5,6-dimethyl- 1H-benzoi midazol-2-yl)- I 4.6,7-tetrahydro-pyrazolor4,3-clpyridin- 0

N

CH

3 N

C

3 H N K By proceeding in a manner similar to Example 250(b) above, but using isopropylcarbonyl chloride, cyclopropylcarbonylchloride there was prepared isopropyl-r3 .6-dimethyl- IH-benzoimidazol-2-yl)- WO 03/035065 PCT/GB02/04763 -433- 1,4,6,7-tetrahydro-pyrazolof4,3-clpyridin-5-yll-methanone (68mg) as a white solid. LC-MS (METHOD RT 9.28 minutes, 338 I -3-(5,6-Dimethyl- I H-benzoimidazol-2-vl)- I,4,6,7-tetrahydro-pyrazolo[4,3-elpyridin-5-yll- 2,2-dimethyl-propan-I -one CH

N

CH N NH

C

3 H By proceeding in a manner similar to Example 250(b) above, but using trimethylacetyl chloride and filtering the precipitate formed upon basification with sodium carbonate, followed by azeotroping with toluene there was prepared 1- 6-dirnethy l-IH-benzoimidazol-2-yl)-1,4,6. 7-tetrahydropyraizolor4,3-clpyridin-5-yll-2,2-dimethyl-propan- I-one (49mg) as a pale yellow solid, LC-MS (METHOD RT =11.39 minutes, 352 (M+H) m 3-(5 6-Dirnethyl- I H--benzoimidazol-2-yl-1 4,6,7-tetrahydro-pvrazolo[4,3-clpyridine-5carboxylic acid methyl ester Oz e

N

CH

3 N

CH

3 H

N-N

By proceeding in a manner similar to Example 2 50(b) above but using methylchloroformate there was prepared 3-(5,6-dimethvl- 1H-benzoimidazol-2-yl)-tI 4,6,7-tetrahydro-pyrazolo[4,3-clpvridi carhoxylic acid m-ethyl ester (89mg) as a pale brown solid. LC-MS (METHOD RT -99 minutes, 326 EXAMPLE 251 3 .6-Dimethyl- 1H-bonzoimidazol-2-yl)-4,5,6,7-tetraliydro- lH-pyrazolor4,3-clpyridine WO 031035065 PCT/GB02/04763 -434-

H

CH

3 N

C

3

H

A solution of 3-(5,6-dimethyl-1 H-benzoimnidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5carboxylic acid tert-butyl ester [1.0 14g, Example 252(a)] in methanol (2Oml) was treated with a solution of hydrogen chloride in dioxane (5m1, 4M). After stirring for 16 hours the reaction mixture was evaporated. The resulting beig-e solid was triturated with methanol to yield 3-(5,6-dimethyl-1Hbenzoimidazol-2-yl)-4,5,6,7-tetraihydro- I H-pyrazolo[4,3-clpyridine (0.523g) as a pale yellow solid.

LC-MS (METHOD RT 0.63 minutes; 269 3-(5-Chloro-6-methyl-IH-benzoimidazol-2-yl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-clpyridine 11

N

NH

C

3

H

By proceeding in a mann er simi lar to Example 2 5 1(a) above, but using 3 -chloro-6-methyl- IHbenzoimidazol-2-yl)- I ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxyl ic acid tert-butyl ester [Example 252(d)] there was prepared 3-(5-ch oro-6-mcthyl-IH-bcnzoimidazol-2-yl)-4.5,6,7-tetrahydro- I--pyrazolor4,3-c-lpyridine (223mg) as a white solid. LC-MS (METHOD RT 3.91 minutes, 288/290 3-r5-(2-Morohol in-4-yl-ethoxy)-I1-benzoirnidazol-2-yl]-4,5,6, 7 -tetrahydro-1HpyrazoloF4,3-c pyridine

H

N

0 -N N NI~

N

HN

By proceeding in a manner similar to Example 251I(a) above, but using 3-[5-(2-morpholin-4-yl-ethoxy)- I H-benzoi mi dazol1-2 1 ,4,6,7-tetrahydro-pyrazo lo [4,3 pyri dine -5 -carboxyl ic acid tert-butyl ester [Example 252(e)] there was prepared 3-r5-(2-morpholin-4-yl-ethoxV)- I H-benzoimidazol-2-yl]-4,5 .6,7- WO 031035065 PCT/GB02/04763 -435tetrahydro-IH-pyrazoloF4,3-clpyridine (200mg) as an off-white solid. LC-MS (METHOD RT 2.55 minutes, 369.19 3'-(5-trifluorom-ethvl- I I-benzoim-id-azol-2-yl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-clpyrid'ne

H-

N

F

F

F N N N NH

H

By proceeding in a manner similar to Example 25 1(a) above but using 3-(5-trifluorometh-yl-1benzoimidazol-2-yl)- I ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester [Example 252(g)] there was prepared 3-(5-trifluoromethyl- I H-benzoimiidazol-2-yl)-4,5,6,7-tetrahydiro- Ilipyrazolo[4,3-c pyridine (500mg) as an off-white solid, LC-N4S (METHOD RT 3.21 minutes, 308.17 (MaH)+.

EXAMPLE 252 3-(5,6-Dimethyl- 1H-benzoinmidazol-2-ylP-1I 4,6.7-tetrahydro-oyrazolo[4.3-cloyridine-5carboxylic acid tert-butvl ester

O

t Bu CH

N

CH- a N>N 3H A suspension of l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid, 3-(2-amino-4,5dimethylphenyl)amide, 5-tert-butyl ester 1.091 g, Reference Example 39(a)] in acetic acid (5mI) was heated to 100'C for 12 minutes in a Smith Creator Microwave. The mixture was neutralised with care by addition of solid sodium hydrogen carbonate and then extracted twice with ethyl acetate. The combined extracts were evaporated to yield 3-(5,6-dimethyl- IH-henzoimidazol 1,4,6,7tetrahydro-pyrazolo[4,3-clpyridinie-5 -carboxylic acid tert-butyl ester LC-MS (METHOD RT 2.79 minutes; 368 -Methoxy-2-(4-nitro- 1H-pvyrazol-3-yl)- IH-benzoi midazole WO 031035065 PCT/GB02/04763 -43 6-

NH

3

N-N

H

By proceeding in a manner similar to Example 252(a) above but using 4-nitro- 1H-pyrazole-3carboxylic acid (2-amino-4-methoxy-phenyl)-amide [4 10mg, Reference Example 36(d)] and heating at 120'C for 5 minutes, (ii) pouring the reaction mixture into water, adjusting to pH14 with 2N sodiumn hydroxide and filtering, and (iii) adjusting the p1-I of the filtrate to 6 with 2N hydrochloric acid and collecting the precipitate by filtration, there was prepared 5-methoxv-2-(4-nitro-1 H-pyrazol-3 I Hbenzoli-ida7ole (3271-g) as, a yellow powder. LC-MS (Method RT= 1.61 minutes, 260-25 2-58.26 5-Fthoxy-2-(4-nitro- I vrazol-3-yl)- IH-henzoim-idazole O 2N CH1 3 CH 2 0 N -C N N~N

H-

By proceeding in a manner similar to Example 252(b) above but using 4-nitro- I H-pyrazole-3carboxyl ic acid (2-aimino-4-ethoxy-phenyl)-arnide [824mg, Reference Example 36(e)] there was prepared 5 -ethoxy-2-(4-nitro- 1H-pyvrazol-3-yl)l H-heinzoim idazole (407mg) as a light brown powder.

LC-MS (Method RT 1.82 minutes, 274.26 272.30 3-(5-Chloro-6-methyl-l1H-benzoimidazol-2-yl)- 1,4,6,7-tetrahydro-pyrazoloF4,3-cl carboxylic acid tert-butyl ester

O

t Bu 0

N

Cl- XT..~ WO 031035065 PCT/GB02/04763 -43 7- By proceeding in a manner similar to Example 252(b) above, but using 3-(2-amino-4-chloro-5-methylphenylcarbam-oyl)-1I,4,6,7-tetraihydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester [Reference Example 39(c)] and heating- at 1 I0 0 C for 15 minutes, there was prepared 3-(5-chloro-6mnethiyl-I H-benizolimidazol-2-yl)-1 ,4,6,7-tetrahvro-pyrazolo[423-clpyridine-5-carboxylic acid tert-butyl ester (391mg) as a brown solid. LC-MS (METHOD RT 3.53 minutes, 388 3-[5-(2-Morpholin-4-yl-ethoxy)- IH-benzoimidazol-2-yll-1I,4,6.7-tetrahydro-pyrazolor4,3acid tert-butyl ester 0OtBu

N

-0N j N N

H

By proceeding in a manner similar to Example 252(b) above, but using 3-[2-amino-4-(2-mor-pholin-4yl-ethoxy)-phenylcarbamoyl]-l ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester [Reference Example 39(d)] there was prepared 3 -[5-(2-morphol in-4-yl-ethoxy)- 11benzoimidazol-2-yll -1 .4,6,7-tetrahydro-pyrazolo[4,3 -clpyridine-5-carboxylic acid tert-butyl ester (350mg) as a brown solid. LC-MS (METHOD RT -3.53 minutes, 469.24 (M±H) 3-(5 .6-Dimethyl- IH-benzoimidazol-2-yl)- 1,4,6,7 -tetra hydro-pyra no I4.3-clovrazole 0 CH 3 Dl N

CH

3 H N N By proceeding in a manner similar to Example 252(a) above but using 1,4,6,7-tetrahydro-pyrano[4,3c]pyrazole-3-carhoxylic acid (2-amino-4,5-dimnethiyl-phenyl)-amide [Reference Example 39(e)] and heating at 120'C for 3 minutes there was prepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yi)-1L4,6,7tetrahydro-pyranor4,3-clpvyrazole (49mg) as a pale brown solid. MS: 269 HPLC (METHOD C RT 19.68 minutes.

3-(5-trifluoromethyl- IH-benzoimidazol-2-yt)- I 4,6,7-tetrahydro-pyrazolo[4,3-clpyridi carboxylic acid tert-hutyl ester WO 031035065 PCT/GB02/04763 -438- 0'1 Bu

N

F V-F

N-N

~N N~N

H

By proceeding in a mnanner similar to Example 2 52(a) above but using 3-(2-aino-4-trifluoromlethylphenylcarbamnoyl)- 1,4,6,7-tetrahydro-pyrazolo[4,3 -c jpyridine-5-carboxyl ic acid tert-butyl ester [Reference Example 39(f)] there was prepared 3-(5-trifluoromethyl-IH-benzoimidazol-2-yfl-1,4,6,7tetrahydro-pyrazolo[4,3-clpyridine-5-carboxylic acid tert-butyl ester (950mng) was preparedl as a brown solid, LC-MS (METHOD RT -3.90 minutes, 408 EXAMPLE 253 6-Dirnethyl-LH-benzoimidazol-2-vi) -IH-pvrazol-4-yi] -2-morn~holin-4-yl-acetamidel- 0 C 0

NJ

HN

CH

3 N CHN

N~F

3

H

A stirred solution of 3-(S,6-dimethyl- I H-benzoimidazol-2-yl)- I H-pyrazol-4-ylamine [1I00mg, Example 233(c)] and di isop ropy]lethyl amine (307i t) In dichioromethane (l0mi) was treated with chioroacetyl chloride (105 tl). The reaction mixture was stirred for 30 minutes at room temperature, then treated with morpholine (575ii1), then kept at room temperature overnight and then evaporated. The oiiy residue was partitioned between ethyl acetate and water and the organic phase was washed with water, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate to give the N-f 3-(5,6-dimethyl-IH-benzoimidazol- 2-yl)-I V-pyrazol-4-yll-2-mornholin-4-yl-acetamidc (49.9mg) as an off-white solid. MS: 355.68 HPLC (METHOD BI1): RT =8.28 minutes.

2-Dimethvlamino-N-[ 3-(5 .6-dimethvl- I H-benzoimidazol-2-vfl- I H-nvrazol-4-vll -acetamide WO 031035065 WO 03/35065PCT/GB02/04763 -439- H C

CH

3

N

C: N

-NNH

3

H

By proceeding in a manner similar to Example 253(a) above but using dimethylamnine hydrochloride there was prepared 2-dimethylamino-N-r3-(5,6-dimethyl-lH-benzoimidazol-2-yvr- 1H-pyrazol-4-yl]acetamide (52mg) as a white solid. LC-MS (METH-OD RT 8.28 minutes, 355.68 N-r3-(5,6-Dimethyl-lIH-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin- 1 -y-acetamide

N~N

Cl-I 3' By proceeding in a manner similar to Example 253(a) above but using piperidine there was prepared N-r3-(5,6-dimethyl-1H-benzoim-idazol-2-yl)-1 H-pyrazol-4-yl]-2-12iperidin- 1 -y-acetamide (4mg) as a white solid. LC-MS (METH-OD RT =7.69 minutes, 353.68 EXAMPLE 254 N-r3-(5.6-Dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yll- 2-(lH-l ,2.3,4-tetraazol- 1-yi)acetamide N 0

N

RIN

CHN

N

C

3

H

Astirred solution of 1 -dimethylaminop ropyl)-3 -ethyl carbodi imi de hydrochloride (295.7 mg) and di isopropylethylamine (269g1) in dimethylformamide (1 Cml) were treated with 3-(5,6-dimethyl- 1Hbenzoimidazol-2-yl)- 1H-pyrazol-4-ylamine [100mg, Example 233(c)] and IH-i ,2,3,4-tetraazol- l-yl) WO 031035065 PCT/GB02/04763 -440acetic acid (1I97.8mg). The reaction mixture was stirred for 72 hours then treated further with I -(3-dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (295.7mg), di isopropylethylami ne (269ji1) and 2-(IH-1,2,3,4-tetraazol-1-yI) acetic acid (197.8mg). Stirring wvas continued for a further 48 hours then the reaction mixture was partitioned between ethyl acetate and water. The organic phase was evaporated and the residue was treated with IN potassium hydroxide in a mixture of methanol and tetrahydrofuran 8 ml). After I hour this mixture was extracted with ethyl acetate. The extract was washed with brine, then dried over magnesium sulfate and then evaporated to dryness. The residue was subjected to preparative HPLC to give N-F3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4l- 2- 11-1-1 2,3,4-tetraazol-t- I -acetamnide (13.7mg) as an off-white solid. MS: 338.14 HPLC (METHOD B RT 7.26 minutes.

N- 6-Dimeth l-1H-benzoimidazol-2-yl) -lH-py razol-4-vfl -isonicotinamide 0 HN

N

CH 3 H N N By proceeding in a manner similar to Example 254(a) above but using isonicotinic acid there was prepared ,6-dimethyl- IH-benzoimidazol-2-yl)- 1H-pyrazol-4-yll-isonicotinam-ide (9mg) as a white solid. LC-MS (METHOD RT =8.71 minutes, 331.21 2-Cyclopropyl-N-[3-(5,6-dimethl- I H-benzoimidazol-2-yl)- I H-pyrazol-4-yl] -acetamide 0

HN

CH 3 N N WN

CH

3 H By proceeding in a manner similar to Example 254(a) above but using cyclIopropyl acetic acid there was prepared 2-cyc lopropyl-N-[3-(5,6-dimethyl- 1H-benzoimidazol-2-yll- 1H-pyrazo1-4-yl -acetamide (98mg) as a light pink solid. LC-MS (METHOD RT 11.04 minutes, MS: 310 EXAMPLE 255 1 -F3-(5,6-DimethVl-1 H-benzoimidazol-2-yl)- 1H-pyrazol-4-yl]-3-methyl-urea WO 03/035065 PCT/GB02/04763 -441- 0 NHCH 3 CH 3 :f

N

CHN

N--NH

CH~ H A solution of 3-(5,6-diinethyl-IH-benzoimidazol-2-yl)- IH-pyrazol-4-ylamine [0.500g, Example 233(c)] in tetrahydrofuran (5m1) was treated with methyl isocyanate (0.502m1) and the mixture stirred at ambient temperature for 16 hours. The mixture was then concentrated in vacuo and the residue was redissolved in IN potassium hydroxide in a mixture of methanol and tetra hyd ro furan 5m1). The mixture was stirred for a further I hour, then concentrated and then partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate and the combined organic extracts were washed with brine, then dried over magnesium sulfate, and then evaporated. The residue was subjected to flash column chromatography on silica eluting initially with a mixture of ethyl acetate and hexane t, vAv) and then with ethyl acetate to afford 1-[3-(5,6-dimethvl-1H-benzoimidazol-2-yl)- IH-pyrazol-4-yll-3-mnethyl-urea (230mg) as a white solid. MS: 269 HPLC (METHOD Dl): RT 597 minutes- 14-3-(5,6-Diniethyl-l i benzoimidazol-2-yl)-1 H-pyrazol-4-vll-3-isopropyl-urea 0

NUCH(CH

3

HN

CH

3 N N

N--NH

CH 3

H

By proceeding in a manner similar to Example 255(a) above but using isopropyl isocyanate there was prepared I -[3-(5,6-dimethyl- 1H-benzoimidazol-2-yl)- I 1-pyrazol-4-vI -3-isopropyl-urea as a white solid. MS: 313 HPLC (METHOD DI): RT 10.94 minutes.

1 -[3-(5,6-Dimethyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-l]1-3-phenvl-urea WO 03/035065 WO 03/35065PCT/GB02/04763 -442- By proceeding in a manner similar to Example 255(a) above but using phenyl isocyanate there was prepared L-[3-(5,6-dimethyl- IH-benzoimidazol-2-yl)- I I--pyrazol-4-ylI-3-phenyl-urea as a white solid.

MS: 3 47 HPLC (METHOD BI1): RT =16.16 minutes.

I -Benzyl-3-[3-(5,6-dimethyl- I H-benizoimidaz.ol-2-yl)-1H-pyraizol-4-yi]-urea By proceeding in a manner similar to Example 255(a) above but using benzyl isocyanate there was prepared 1-bcnzyl-3-r3-(5,6-dimethyl-IH-bcnzoimidazol-2-yl)-1H-pyrazol-4-yll-urea as a white solid.

M4S: HPLC (METHOD DI): RT 7.78 minutes.

3-(5 ,6-Dimcthyl- IH-bcnzoimidazol-2-yl)- 1,4,6, 7-tctrahydro-pyrazoloF4,3-clpyridine-5carboxylic acid isopropylarnide f1 NHCH(CH 3 2 CH(3-

I-

By proceeding in a manner similar to Example 255(a) above but using 3-(5,6-dimethyl-1Hbenzoimidazol-2-yl)-4,5,6, 7-tetrahydro- IH-pyrazoloL4,3-c]pyridine [Example 25 and isopropylisocyanate, and subJecting the reaction product to flash column chromatography eluting with ethyl acetate/methanol (19: 1, there was prepared 3 -(5.6-dimethyl- IH-benzoimidazol-2-yl)- 1,4,6,7- WO 03/035065 PCT/GB02/04763 -443tetrahvdro-pyraizoloF4,3-clpyridine-5-carboxylic acid isopropylamide (93.3mg) as an off-white solid.

LC-MS (METHOD RT 10. 15 minutes, 353 EXAMPLE 256 Cyc lopropanecarboxyl ic acid[3-(5 -ethoxy-6-ethyl- I H-benzoimidazol-2-yl)- I H-pyrazol-4vi] amide Iz:0

HN

CH3CHO2

N

CH 3

CH

2 N N -NH 2 H A solution of cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-IH-benizoimidazol-2-yI)- 1- (tetrahydropyran-2 I H-pyrazol-4-yl-lamid e ro.3 g, Reference Example 48(a)] and p-toluenesulfon ic acid hydrate (1.2g) in ethanol (25mL) was heated in an 80'C in an oil bath for 1 hour, then cooled, and then poured into aqueous sodium bicarbonate solution. The aqueous mixture was extracted twice with ethyl acetate (75mL). The combined extracts were evaporated and thc residue was redissolvcd in a mixture of mnethylene chloride (1 O0mi) and methanol (I OnL). This solution was washed with aqueous sodium bicarbonate, to remove some residual p-toluenesulfonic acid, then evaporated to give eye lopropanearboxylic acidl3 -(5-ethoxy-6-ethyl- IH-benzoimidazol-2-yi)- I H-pyrazol-4-ijainide (I 20mg) as a white solid. LC-MS (Method RT 2.36 minutes, 340 341( .5,6,7-Tetrahydro- 1 3-diaza-s-indacen-2-yI1H-pvrazot-4-ylamine H 2

N

N

N N-NH

H

By proceeding in a similar manner to Example 256(a) but using 3-(1,5,6,7-tetrahydro-l,3-diaza-sindacen-2-yl)- 1 -(tetrahydropyran-2-yl)- 1 H-pyrazol-4-ylamine [0.9g, Reference Example 49(d)] and p-toluenesulfonic acid (1.0g) in ethanol (100 mL) and carrying out the reaction at 55'C for 2 hours, there was prepared 3-(1I,5 .6,7-tetrahydro- 1.3-diaza-s-indacen-2-yl)- 1 H-pyrazol-4-ylamine (800 mg) as a brown solid. LC-MS (Method RT 2.68 minutes, 240 WO 031035065 PCT/GB02/04763 -444- 4-MethyIpiperazine- I-carboxyl ic acid 1 .5,67-tetrahydro-1I 3-diaza-s-indacen-2-yl)-IH pyrazol-4-vilamide 0

-N

H

By proceeding in a similar manner to Example 256(a) but using 4-methylpiperazine-l-carboxylic acid 1,5,6,7-tetrahiydro- 1,3-diaza-s-inidacen-2-yl)- I-(tetrahydropyran-2-yl)- IH-pyrazol-4-yllam-ide [171mg, Reference Example (ii) carrying out the reaction at 55 0 C for 1.5 hours, then at for 1 hour, and (iii) subjecting the reaction product to chromatography on silica gel (ethyl acetate! Dgradient 0 to 20% methanol), there was prepared 4-methylpiperazine-t-carboxylic acid tetrallydro-1,3-diaza-s-inidacen-2-yl)-1H-pyfazol-4-yllaiide (55 mig) as a white solid. LC-M4S (Method RT 1.53 minutes, 366 1, 1 -Dimethiyl-3-[3-(1I,5,6,7-tetralhydro-s-inidaceni-2-y)-1 H-pyrazol-4-yl urea 0 /CH 3

NN

CH 3 N N NH

H

By proceeding in a si milar manner to Example 2 56(c) but using 1, 1-di methyl-3 -f3-(1,5,6,7-tetrahydro- 151 s-indacen-2-yl)- I -(tetrahydropyrarn-2-yl)- I 1--pyrazol-4-yl]urea (230m-g) and p-toluenesulfonlic acid hydrate [40 mg, Reference Exam pie 48(c)] there was prepared 1, 1 -dimethy 1-3- 13-(1,5,6. 7-tetrahydro-sindacen-2-yl)-11--pvrazol-4-yllurea (106 mi-g) as a tan solid. LC-MS (Method R-~ 1 1.97 minutes, 311 EXAMPLE 257 Cyc lop~ropanecarboxylic acid [3-(6-ethoxy-5-fluoro- IH-benzimidazol-2-yl)- 1H-pyrazol-4yllamide WO 031035065 WO 03/35065PCT/GB02/04763 -445- CH 3 CH 2 0' A solution of cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro- 1H-benzimidazol-2-yl)-lI- (tetrahydropyran-2-yl)-lI H-pyrazol-4-yl]arnide [90mg, Reference Example 48(d)] in a 1/1 mixture of trifluoroacetic acid and dichloromethane (3OinL) was stirred for 5 hours and then evaporated. The residue was mixed with ethyl acetate (3OmL) and aqueous sodium bicarbonate (30m1n). The organic layer was evaporated to give cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro- IH-benzimidazol-2yl)- IH-pyrazol-4-yllamide (44 mg), LC-MvS (Method RT =2.34 minutes, 330 (b) 4-yllam Tetrahvd1ronvrnn-4-ca.,rhmxvl ic c-id R4--thoxv-5-fl]Ar-1 I-hi-niMidqayn1 -Xv-V1 H-nvrq-/cniide

F)CN

CH 3 CH 2 0 N

N

By proceeding in a similar manner to Example 257(a) but using tetrahydropyran-4-carboxylic acid [3- IH-benzimidazol-2-yl)- I-(tetrahydropyran-2-yl)- 1H-pyrazole-4-yl]amide [120 mg, Reference Example 48(e)] there was prepared tetrahydropyran-4-carboxylic acid f3 -(6-ethoxy-5 -fluoro- IH-be-nzimidazol-2-yl)-1H-pyrazole-4-yllamide (65mg). LC-MS (Method E) RT =2.17 minutes, 374 Morpholine-4-carboxylic acid[3-(6-ethoxy-5-fluoro- IH-benzimidazol-2-yl)- IH-pyrazol-4y1 amide WO 031035065 WO 03/35065PCT/GB02/04763 -446- 0

N

0_-

F,

CH

3 ,CH, 0 By proceeding in a similar manner to Example 257(a) but using morpholine-4-carboxylic acid[3-(6- I H-benzimidazol-2-yI)- t -(tetrahydropyran-2-yl)-l H--pyrazol-4-yl Jaride 140mg, Reference Example 48(f)] there was prepared morpholine-4-carboxylic acid[3-(6-ethoxy-5-tluoro-1Hbenzimidazol-2-yl)-1H-pyrazol-4-vl] amidle (65mgy). LC-MS (Method RT 2.62 minutes, 375 Piperidine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-IH-benzirnidazol-2-yl)- 1H-pyrazol-4lamide

F

CH

3

CH

2 0) By proceeding in a similar mnanner to Example 257(a) but using p~iperidine-4-carboxytic acid[3-(6- IH-benzimidazol-2-yl)- I-(tetrahydropyran-2-yl)- 1H-pyrazol-4-yljamide [127mg, Reference Example 48(g)] there was prepared p2iperidine-4-carboxylic acid[3-(6-ethoxy-5-fluoro- 1 benzimiclazol-2-vl)-IH-pyrazol-4-yIlamide 6 5mg). LC-MS (Method RT 3.15 minutes. MS 373 3-r6-Ethoxy'-5 -fluoro- I H-benzimiclazol-2-yi)- I H-pvyrazol-4-vll- 1.1 -diethvlurea WO 031035065 PCT/GB02/04763 -44 7-

CH

3 CH2I>..

-HC

HN

CH3CHO H

NN

By proceeding in a similar manner to Example 257(a) but using 3-[6-ethoxy-5-fluoro- IH-benzimidazol- 2-yl)-lI -(tetrahydropyran-2-yI)-1H-pyrazol-4-yl]- 1, 1-diethylurea (110 mg, Reference Example 48(h)] there was prepared 3-[6-ethoxy-5-fluoro-IH-benizimnidazol-2-vl)-1H-pVrazol-4-yll-1J -diethylurea LC-MS (Method RT 3.13 minutes, 361 5 -Methoxy-2-(4-nitro- 1H-pyrazol-3-v- I HIf-benzo imidazole

O.N

CH 3 0 ,C N N

N-NH

H

By proceeding in a similar manner to Example 257(a) but using 5-methoxy-2-[4-nitro-1-(tctrahydropyrani-2-yl)- IH-pyrazol-3-yl]- IH-benzoirnidazole (282mg, Reference Examnple 50(d) there was prepared 5 -merhoxy-2-(4-nitro-lIH-pyrazol-3-yl)- IH-benzoimidazole (373mg) as a red powder. LC-MS (Method RT- 1.60 minutes, 260.22 (M+H) m 258.23 Morpholine-4-carboxyl ic acid [3-(5,6-dimethyl- I H-benzoimidazol-2-yl)- I H-pyrazol-4imethyI -amide WO 031035065 PCT/GB02/04763 -448- By proceeding in a similar manner to Example 257(a) but using morpholine-4-carboxylic acid (2,4dit-ethoxy-benzyl)-[3 -(5,6-dimethyl- I H-benzoimidazol-2-yl)- 1-(tetrahydro-pyran-2-yl)- I H--pyrazol-4ylmethyl]-amide (Reference Example 59), subjecting the reaction product to flash chromatography on si'lica [elluting with dichlorornethane to dichloroniethane/methanol and recrystallising from water/acetonitrile followed by trituration with diethyl ether there was prepared morpholine-4carboxylic acid [3-(5,6-dimethvl- IH-benzoimidazol-2-yl)- IH-pyrazol-4-ylmethyll-amide (16.5mg) as a white solid. LC-MS (Method RT= 6.97 minutes, MS: 355.36 (M+1 Ifl, 353.39 Nh 3-[3-(5-Difluoromethoxy- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-vl]- 1,1 -diethyl-urea 0 FF

N

YF

HN

N1 N N~N

H

By proceeding in a manner similar to Example 25 7(a) above but using 3-[3-(5-difluoromethoxy-IHbenzoim idazol-2 1 -(tetrahydro-pyran-2 1 H-pyrazol 1, 1 -di ethyl -u rca [Reference Example 480j)] there was prepared 3 -[3-(5-difluoromiethoxv- IH-ben-zolimiidazol -2-yl)-lIH-pyrazol-4-vll-1,1 diethyl-urea (60mg) as a white solid. LC-MS (METHOD RT =10.61 minutes.

1I-i NMR(CD 3 0D): 5 1.24 614), 3.43 4H), 6.72 (bt, 1H), 6.99 IH), 7.26 IH), 7.47 IH), 7.91 I H).

Pip eridine-1-carboxylie acid [3-(5-difluoromethoxv-l-IH-benzoimidazol-2-yl) nrazol-4-yllamide 0 Fy F H N 0- CN> \NNH

H-

By proceeding in a manner similar to Example 257(a) above but using piperidine-l-carboxylic acid [3- -difluorometlhoxy- IH-benzoimidazol-2-yl)- 1-(tetrahydro-pyran-2-yl)- 1H-pyrazol-4-yl] -amide [Reference Example there was prepared piperidine-l-carboxylic acid IH-benzoimidazol-2-yI)-1H-pyrazol-4-yll-amide (52mg) as a white solid. HPLC (METHOD El): RT WO 03/035065 PCT/GB02/04763 -449- -10.78 minutes. IH NMR(CD 3 OD): 8 1.69 (bin, 6H), 3.64 (bin, 4H), 6.82 (bt, IH), 7.09 (bin, 7.39 (bin, IH), 7.61 (bin, II-D,8.05 (bin, IH).

EXAMPLE 258 Cyclopropanecarboxylic acid [3-(6-chloro-5-methoxv- IH-benzoimidazol-2-vl)- 11--px'razol-4- Yl-de 0 CH 3 0N N N NH Cl H A so luti on of 3 -(6-ch Io ro-5 -meth oxy- I H-l-benzoi iidazol1-2 I H-pyrazolI-4-yl amine [50Omg, Example 233(e)] and diisopropylethylainine (40 .tL) in dichioromerhane (2OrmL), stirred at room temperature, was treated with cyclopropanecarbonyl chloride (51l, 3 eq). After stirring for a further 20 hours the reaction mixture was evaporated and the residue was subjected to chromatography on silica gel (ethyl acetate/heptane 1/1) to give the bis-acylated product (60mg) as an orange solid. MS 400 The bis-acylated product was dissolved in methanol (5 mE), then treated with potassium hydroxide solution 5N), then stirred at 60'C for 1 hour, then cooled and then evaporated. The residue was treated with water (I5inL) and the pH of the aqueous mixture was adjusted to 5 and then extracted twice with ethyl acetate (25niL). The combined extracts were dried with magnesium sulfate, then evaporated and the residue was triturated with diisopropyl ether, filtered and the precipitate was vacuum dried at to give cycj<p opanecarboxylic; acid 6-chloro-5-methoxy- 1 H-benzoimidaznl-2-yl)-1 H-pyrazol-4vil-amide (I I mng) as an off-white solid, mnp 225-226'C. LC-MS (Method RT =2.92 minutes, 332 Cyclopropanecarboxyl ic acid 1 .5.67-tetrahydro-1I 3-diaza-s-indacen-2-ll- IH-pyrazol-4ytlamide 0 WO 03/035065 PCT/GB02/04763 -4 By proceeding in a similar manner to Example 258(a) above but treating a solution of 3-(l,5,6,7tetrahydro-1I,3-di-aza-s-indaceni-2-yl)- I H-pyrazol-4-ylamine [3 10 mng, Example 256(b)] and triethylamnine (4 eq) in tetrahydrofuran (15 rnL) with cyclopropanecarbonyl chloride (4 eq), (i i) stirring the reaction mixture at 60'C for 2 hours, (i ii) treating thc resulting bis-acylated product with methanolic potassium hydroxide (20 mL, 1.05g KOH) at 40 0 C for I hour followed by treatment with aqueous ammonium chloride (200 mE), (iii) extracting this mixture three times with ethyl acetate (I00mL), (iv) evaporating the comrbined extracts and chromatographing the residue on silica gel (ethyl acetate gradient of 50-0% heptane) there was prepared cyclopropanecarboxylic acid [3- (I ,5,6,7-tetrahydro-1 ,3-diaza-s-indacen-2-yl)- IH-pyrazol-4-yllam-ide (50mg) as a yellow solid. LC-MS (Method E) RT =2.05 minutes, 308 Morpholine-4-carboxylic acid[3- 1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yD)- IH-pyrazol-4yl]-amide 0 HN 0

_N

NN

H

By proceeding in a similar manner to Example 258(b) above but using morpholine-4-carbonyl chloride there was prepared t-norplioline-4-ca rboxylic acid .5,6,7-tetra hydro-1I,3-diaza-,-Iidacen-2-yIV1-l" pyrazol-4-yl] -amide as an orange solid. LC-MS (Method E) RT =2,45 minutes, 353 (M-v Piperidine- I -carboxyl ic acid F3-(5-rnethoxy- I H-benzoimida7ol-2-l)- 1 H-pyrazol-4-yll-amide 0 N N 1

H

By proceeding in a similar manner to Example 258(a) above treating 3-(5-methoxy- IH-benzoimidazol- 2-yl)-1H-pyra'zol-4-ylamine [257mg, Example 233(f)] with I -piperidiine-carbonyl chloride in the presence of diisopropylethylamine and using tetrahydrofuran as the solvent there was prepared WO 03/035065 PCT/GB02/04763 1p2ineridine- 1 -carboxylic acid r3-(5-methoxy- I H-benzoimidazol-2-yl)- 1H-Ipvrazol-4-vll-amide (46.1Img) as a white solid. LC-MS (Method L) R' 1 6.43 minutes, 341.28 3J143-5-klethoxy- I H-henizoimidazol-2-yfl- I N-pyrazol-4-yfl-l 1I -dimethvl-urea 0 C3

N

FIN

CH 3 0_C C NCH3 N>

N-NH

H

By proceeding in a manner similar to Example 25 8(d) above but using dimethylcarbamyl chloride there was prepared 3-[3-(5-niethoxy- I H-benzoimnidazol-2-yl)- I H-pyrazol-4-yl]- 1.1-dimethyl-urea as a white solid. LC-MS (Method RT 7.64 minutes, 301.35 (J Piperidine- 1-carboxylic acid 3 45-ethyl -6-methyl- 1 H-benzoim idazol-2 I H-pyrazol-4-yllam ide 0 HN

N

CH 3 CH 2

NX

CH1 3 H

NNH

By proceeding in a manner similar to Example 258(d) above but using 3 -ethyl -6-methyl- IHbenzoimidazol-2-yl)- I I--pyrazol-4-ylamine [400mg, Example 233(d)], 1 -piperi din ecarbonyl chloride (1.25m1) and diisopropylethylamine (1.74m1) with tetrahydrofuran (20m1) as the solvent and, stirring the reaction mixture at ambient temperature for 48 hours, then at 50 0 C for 24 hours, (ii) treating the bis-acylated product with IM potassium hydroxide in methanol/tetrahydrofu ran 20m1) at room temperature, and (iii) subjecting the product to flash column chromatography on silica [eluting with ethyl acetate/hexane 1 v/v) to ethyl acetate/hexane 1 there was prepared piperid ine-1Icarboxylic acid [3-(5-ethyl-6-methyl- 1H-benzoimidazol-2-vl)- IH-pyrazol-4-yl] -amide (425mg) as a white solid. LC-MS (METHOD RT 7.55 minutes, 353.34 3-[3-(5-Fluoro-6-methyl-lH-benzoimidazol-2-yl)-1H-p2yrazol-4-yll-1. I -dimethyl-urea WO 031035065 PCT/GB02/04763 -452- 0

CH

V 3N

NN

F CH 3 CHN

N'N

C

3

H-

By proceeding in a manner similar to Example 258(f) above but using 3-(5-fluoro-6-i-nthyl- 1 Hbenzoi midazol-2-yl)- 1H-pyrazol-4-ylamine [Example 233(h)] and NN '-dimethylcarbamylchloride there was prepared 3-[3-(5-fluoro-6-methyl- 1H-benzoimidazol-2-yl)- 1H-pyrazol-4-yll- 1,1-dimiethylurea (32mg) as a white solid. LC-[VS (METHOD RT -10.40 minutes, 303.34 Morohol ine-4-carboxylic acid [3-(5-trifluoromethyl- IH-benzoimidazol-2-yl)- 1H-pyrazol-4-ytlarnide 0 HN 0 CF 3

N

By proceeding- in a manner similar to Example 258(1) above but using benzoimidazol-2-yl)- I I-pyrazol-4-ylamine [Example 2330j)] and morphol ine-i -carbonyl chloride there was prepared m-orpholine-4-carboxyl ic acid [3-(5-trifluoromethyl- IH-benzoirnidazol-2-yl)-1 H-pyrazol- 4-yll-amide (131mg) was prepared as a white solid. MS: 379.08 HPLC (METHOD El): RT 10.61 minutes.

3-(5.6-Dimethvl-IH-benzoimidazol-2-y)- 1,4,6,7-tetrahydro-pyrazolo[4,3-clpyridine-5carboxylic acid diethylamide WO 031035065 PCT/GB02/04763 -453- By proceeding in a manner similar to Example 258(f) above, but using 3-(5,6-dimethyl- IHbenlzoimidazol-2-yl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-clpyridine [Example 251(a)] and diethylcarbamyl chloride, and subjectinQ the reaction product to flash column chromatography eluiting with ethyl acetate to ethyl acetate/methanol (49: 1, there was prepared 3-(5,6-dimethyl-IHbenzoimidazol-2-yl)-1I,4,6,7-tetrahydro-pyrazolo[4,3-eipyridine-5-carboxylic acid diethylamide (20.9mg) as an off-white solid. LC-MS (METHOD RT 3.44 minutes, 367 [3-(5,6-Dimethyl-1I-1-benzoimidazol-2-yl)-1I,4,6,7-tetrahydro-pyrazolo[4,3-clpyridin-5-tLpyrrolidin-1I-yi-methanone

NO

N

CH 3 CHN

N--NH

3H By proceeding in a manner similar to Example 25 8(i) above, but using I -pyrollidincarbonyl chloride and triturating the reaction product with ethyl acetate, methanol and dichioromethane, there was prepared I 5,6-dimethyl- I Fl-benzoimidazol-2-yl)-lI.4,6,7-tetrahydro-pvrazolo[4,3-clpyridin-5-yl]pvyrrolidin-1-yl-methanone (68mg) as an off-white solid. MS: 365 HPLC (METHOD El): RT 10.32 minutes.

F3-(5,6-Dimethyl-lH-benzoiimidazol-2-yl)- I .4,6,7-tetrahydro-pyrazolor4,3-clpyridin-5-vLpioecridin-l -vI-methanone

CHJ

By proceeding in a manner similar to Example 258(f) above, but using 3-(5,6-dimnethyl-1Hbenzoimidazol-2-yI)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridine [Example 251(a)] and subpecting WO 031035065 PCT/GB02/04763 -454the reaction product to flash column chromatography eluting with ethyl acetate/petrol 1, v/v) to 100% ethyl acetate to ethyl acetate/methanol (19: 1, there was prepared r3-(5,6-diimethyl- IHbenzoimidazol-2-yvP- I ,4.6,7-tetrahydro-pyrazolo[4,3-c] pyridin-5-yl]-piperidin- 1 -yl-methanone (93.3mg-) as an off-white solid. LC-MS (METHOD R-T 6.77 minutes, 379 [3-(5,6-Dimethyl- I 11-benzoimidazol-2-l-1I 4,6,7-tetrahydro-pvrazolor4,3-clpyridin-5-yl]morphol in-4-yl-methanone cl-If~ N~i- By proceeding in a manner similar to Example 25 8(k) above, but using I -morpholinecarbonyl chloride and azeotroping the reaction product with toluene and dichloromethane, there was prepared dimcthyl-1 H-bcnzoimidazol-2-yl)-1 .4,6,7-tetrahydro-pyrazolo[4,3-c Ipyrdin-5-yI -mompholin-4-ylmnethanone (32mg) as an off-white solid. MS: 381 HPLC (METHOD El): RT 9.39 minutes.

(mn) 3 -Chloro-6-methyl- 11--benzoimidazol-2-vl)-1 .4.6,7-tetrahydro-pyrazolo[4,3-clpyridine-5carboxylic acid diethylamide

N

-NH

ClI

N

C

3 H N H By proceeding in a manner similar to Example 258(a) above but using 3-(5-chloro-6-methyl-1Hbenzoimidazol-2-yl)-4,5,6,7-tetrahydro- 1 H-pyrazolo[4,3-c]pyridine [Example 25 and diethylcarbamyl chloride, and (ii) subjecting the reaction product to flash column chromatography, eluting with ethyl acetate to ethyl acetate/methanol (47:3, v/v) followed by trituration with ethanol, WO 031035065 PCT/GB02/04763 there was prepared 3(5 -chloro-6-methyl- 1H-benzoimidazol-2-yl- 1 ,4,6,7-tetrahydro-pyrazolo[4,3acid diethylainide (35.6mg) as a pale yellow solid. MS: 387/389 HPLC (METh OD El1): RT 11.07 minutes.

Morpholine-4 carboxylic acid [3-(5,6-dimethyl- 1H-benzoimidazol-2-vl)-1--pyrazol-4-yllarnide 0 -Nl CHI-IN 0 CH 3 N By proceeding in a manner similar to Example 258(p) above but using 3-(5,6-dimethyl-1Hbenzoirnidazol-2-yli-1J--pyrazol-4-ylainine [Example 233(c)] and 1-morpholinecarbonyl chloride there was prepared moQ2phol ine-4-carboxylic acid r3-(5,6-dimethvl- 1H-benzoimidazol-2-yl)-1 H-pyrazol-4yil-amide (206mg) as a white solid. LC-MS (METHOD RT 7.36 minutes, 341 Pineridine- I -carboxvlic acid 1 34-( 6-dirnethivl- I H-benizoimidizol-2-vl- I H--nvrazol-4-vil-amnide By proceeding in a manner similar to Example 2 58(p) above but using I1-piperidinecarbonyl chloride there was prepared piperidine-lI-carboxylic acid I 5,6-dimethyl- IH-benzoimidazol-2-yl)- I-pyrazol- 4-yll-amide (185mg) as a white solid. LC-MS (METHOD RT 10.79 minutes, 339 3-[5-(2-Morpholin-4-yl-ethoxy)-1 H-benzoimidazol-2-yl]-1 ,4,6,7-tetrahydro-pyrazolo[4,3clpyridine-5 -carboxyl ic acid diethylamnide WO 031035065 PCT/GB02/04763 -4 56-

N

N

N

0 -C N NH

H

By proceeding in a manner similar to Example 258(a) above but using 3-[5-(2-morpholin-4-yl-ethoxy)- IH-benzoimidazol-2-ylJ-4,5,6,7-tetrahydru- I Hi-pyrazolo[4,3-clpyridine [Example 25 and diethylcarbamyl chloride there was prepared 3-[5-(2-morpholin-4-yI-ethoxv)- I H-benzoimidazol-2-yl- 1,4,6,7-tetrahydro-pyrazolo[4.3-clpyridine-5-carboxylic acid diethylarnide (28mg) as a white solid.

MS: 468.30 HPLC (METHOD ElI): RT 9.47 minutes.

3-(5-tri fluoromethyl-l1H-benzoimidazol-2-yl)-1I,4,6,7-tetrahydro-pyrazoloF4,3-cl nyridine-5 carboxylic acid diethylamide 0

N

N

IFFF

F N N

N-NH

H

By proceeding in a manner simlar to Example 258(a) above but using 3-(5-trifluoromethyl- I benzoimidazol-2 -yl)-4,5,6,7-tetrahydro- 1 H-pyrazo lo [4,3 pyri dine [Example 251 and diethylcarbamy I chloride there was prepared 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6 7tetrahydro-pyrazoloF4,3-clpyridine-5-carboxylic acid diethylamide (103mg) as a white solid. MS: 407.17 HPLC (METHOD El): RT [0.81 minutes.

3-[3-(5,6-Dimcrhyl- IH-bcnzoimidazol-2-yl)- IH-pyrazol-4-yl]- 1.1-dimethyl-urca WO 03/035065 WO 03/35065PCTIGBO2I04 763 0 N (CH 3 2 By proceeding in a manner similar to Example 2 5 8 above but using dimethiylcarbamyl chloride there was prepared 3-1l3-(5,6-dimcthyl- IH-benzoimidazol-2-yfl)-IH-pyrazol-4-yll-l .1-dimethyl-urea. MS: 299 I-I PLC (Method El): RT 8.24 minutes.

EXAMPLE 259 2-41 H-Indazol-3-,yl)- I H-benzoimidazole-5-carboxylic acid [2-(2H-tetrazol-5-yl)-ethyl]-amide A stirred solution of 1H-indazol-3-yl)- I H-benzoiniidazolc-5-carboxylic acid (2-cyano-ethyl)-amide [150mg, Example 246(s)] and azidotributyltin (2m1) was heated at 95TC for 24 hours. The reaction was cooled to ambient temperature and stirred for 2 hours with acetonitrile (20rm1), tetrahydroffiran (l1inI) and acetic acid (20m1). The reaction mixture was washed with iso-hexane (6 x 80ml) and concentrated in vacuo. The residue was subjected to preparative I-PLC to give 2-(0 H-indazol-3-yl)-IHacid [2-(2H-tetrazol-5-yi)-ethyll-amide (35.9mg) as a brown solid.

LC-MS (Method RT =9.80 minutes, 374.21 EXAMPLE 260 I -Cyclopropyl-3-r3-(5-ethyl-6-r-nethyl-l1H-benzoimidazol-2-yI)- 1H-nvrazol-4-yll -urea 0

N

FIN H WO 03/035065 WO 03/35065PCT/GB02/04763 To a stirred solution of 3-(5-ethyl-6-methyl- IH-benzoimidazol-2-yl)- 1H-pyrazol-4-ylamine Example 233(d)] in tetra hydroftiran (20m1) was added 1,I-carbonyldlimidazole (740mg) and the reaction heated at reflux for 60 hours. The reaction mixture was cooled to ambient temperature and the solvent removed in vacuo. The residue was added 2M cyclopropylamnine in tetrahydrofuran The reaction Mixture was transferred to a pressure tube and heated at reflux for 48 hours. The reaction mixture wvas cooled to ambient temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate and the combined organic extracts washed with brine, dried over magnesium sulfate, and concentrated. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate/hexane 1 v/v) to 100% ethyl acetate to afford I -cyclopropyl-3-[3-(5-ethyl-6-methyl-lH-benzoimidazol-2-y)- IH-pyrazol-4-yll-urea (95mng) as a white solid. LC-MS (METHOD RT 9.40 minutes, 325.32 1 -f 3-(5-Ethyl-6-imethyl- 1 H-bcnzoimidazol-2-yl)- 1H-nvrazol-4-yll-3-methvl-Lirea 0 HN NHCH 3

CHCH,

CH

3 H By proceeding in a manner similar to Example 260(a) above but using 2M methylamine in tetrahydrofuran there was prepared I -[3-(5-ethyl-6-methyl-_IHf-benzoimidazol-2-yl)-1 H-pyrazol-4-yfl-3methyl-urea (36mg) as a white solid. LC-MS (METHOD RT 7.08 minutes, 299.34 4-Methiyl-piperazine-l1-carboxylic acid [3-(5-ethyl-6-methyl- 1H-benzoimidazol-2-yl)- 1Hpyrazol-4-yll-amide 0 TIN N-HC3 CH 3 CH 2 N CHO N N N H

C

3

H

By proceeding in a manner similar to Example 260(a) above but using 2M 1-rnethylpiperazine in tetrahydrofuran there was prepared 4-methyl pipeazin- I-carboxylic acid L3-(5-ethyl-6-methyl-lIHbenizoimidazol-2-vl)-1H-pyrazol-4-yl]-amide (247mg) pared as a white solid. LC-MS (METHOD M): RT 5.21 minutes, 368.32 WO 03/035065 PCT/GB02/04763 9- Piperidine-lI-carboxyl ic acid [3-(5-fluoro-6-methyl- 1H-benzoliidazol-yl)-1 H-12vrazol-4-yllam ide 0 No F NN N

-NI

C

3 HN <N By proceeding in a manner similar to Example 260(a) above but using 3-(5-fluoro-6-mrethyl- I Hbenzoimidazol-2-yl)-lII1-pyrazol-4-ylamine [Example 233(h)] and 2M piperidine in tetrahydroftiran there was prepared piperidine- 1 -carboxylic acid [3-(5-tluoro-6-mnethyl- 1 H-benzoimidazol-2-yl)-1Hpyrazol-4-yl]-ai-nide (140mg) as a white solid. LC-MS (METHOD RT 8.29 minutes, 343.26 I -r3-(5-Fluoro-6-methyl- I H-benzoim idazol-2-yl)- I H--pyrazol-4-yll -3-miethyl-urea 0 HN NHCH3 F

N

N N NH CH

H

By proceeding in a manner similar to Example 260(d) above but using 2M methylamine in tetrahydrofuiran there was prepared 1 -[3-(5-flluoro-6-methyl-l1H-benzoimidazol-2-yl)- I l-pyrazol-4-yl] 3-methyl-urea (6 1mg) as a white solid. LC-MS (METHOD RT 4.85 minutes, 289.26 Morpholinc-4-carboxylic acid [3-(5-fluoro-6-mnethyl-1H-benzoimidazol-2-y) -1H-pv razol-4-yll amide 0 HN 0 F N N1 CH 3 H By proceeding in a manner similar to Example 260(d) above but using 2M morpholine in tetrahydrofuran there was prepared morpholine-4-carboxylic acid [3-(5-fluoro-6-methyl-1H- WO 03/035065 PCT/GB02/04763 -460beinzoimidazol-2-yl)-IH-pyrazol-4-yll-amide (49mng) as a white solid. LC-MS (METHOD RT 6.26 minutes, 345.33 4-Methyl-piperazine- I-carboxylic acid F3-(5-fluoro-6-miethyl-1 H-benzoim-idazol-2-yl)- IHpyrazol-4-yl]-amide 0 HN N-CH 3 F:0

N

N N~N Cl'] 3 H By proceeding in a manner similar to Example 3 1(d) above but using 2M 1-methylpiperazine in tetrahydrofuran there was prepared 4-methyl-piperazine-l-carboxylic acid [3-(5-fluoro-6-methyl-IHbenzoirnidazol-2-yl)-lH-pyrazol-4-yl]-amide (58mg) as a white solid. LC-MS (METHOD RT 7.72 minutes, 358.19 I -Methyl-3-F3-(5-trifluoromethyl- I I-benzoimidazol-2-yl)- 1H-prwrazo1-4-yll -urea 0 NHCH 3

HN

CF

3

N

N

NNH

H

By proceeding in a manner similar to Example 260(a) above but using 3-(5-trifluoromethyl-1Hbenzoimidazol-2-yl)- I H-pyrazol-4-ylamine [Example 2330j)] and 2M methylarnine in tetrahydrofuran there was prepared I -methyl-3-F3-(5-trifluorornethyl-l H-benizoimidazol-2-vl)- IH-pyrazol-4-yl]-urea (99mg) as a white solid. LC-MS (METHOD RT 6.51t minutes, 325 (MTH) 0i) 1 -(5-Chloro-6-methyl- 1H-benzoimidazol-2-yl)- IH-pyrazol-4-yll -3-methyl-urea 0 HN NHCH 3 CHN N -NHI

H

3

H-

WO 031035065 PCT/GB02/04763 -46 1- By proceeding in a manner similar to Example 260(a) above but using 3-(5-chloro-6-methyl-1Hbenzoimidazol-2-yl)- 1H-pyrazol-4-ylatmine [Example 261] and 2M methylamine in retrahydrofuran there was prepared I -F3-(5-chloro-6-m-ethyl- IH-benzoirnidazol-2-vl)- IH-pyrazol-4-yl]-3-methyl-urea as a white solid. LC-MS (METHOD RT 5.85 minutes, 305/307 4-Methyl-piperazine-1 -carboxylic acid [3-(5-chloro-6-rnethyl- 1 H-benzoimidazol-2-yl)- 1Hpyrazol-4-yl] -amidc 0 HN N-CH Cl

N

~NH

CH

3 N N 3 H By proceeding in a manner similar to Example 260(i) above hut using 2M 1-methylpiperaxine in tetraliydrofuran there was prepared 4-niethyl-piperazine-l -carboxylic acid [3-(5-chloro-6-rnethyl-I H- .benzoimidazol-2-yl)-lH-pyrazol-4-yl]-amide (60mg) as a pale yellow solid. LC-MS (ME'IHOD M): RT 6.35 minutes, 374 Nk 1-tert-Buty 1-3- 6-dimeth vl-I H-benzoimidazol-2-yl) -lI--pyrazol-4-yll -urea 0

N

HN H-

CH

3

CN

CH

3 H

NN

By proceeding in a manner similar to Example 260(a) above but using 3-(5,6-dimethyl-IHbenzoimidazol-2-yI)- I H-pyrazol-4-ylamine [Example 233(c)] and ter/-butylamine there was prepared I -tert-butyl-3-[3-(5,6-dimethyl- I H--benzoimidazol-2-yl)-lI pyrazol-4-yll-urea (21mg) as a white sol id.

LC-MS (METHOD RT 5.38 minutes, 327 t-r3 -(5,6-Dimethyl- IH-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-3-ethyl-urea WO 031035065 WO 03/35065PCT/GB02/04763 -4 62- 0

N'

j H By proceeding in a manner similar to Example 260(k) above but using 2M ethylamine in tetrahydrofliran there was prepared 1 -f3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)- IH-pyrazol-4-yl]-3ethyl-urea (39mg) as a white solid. LC-MS (METHOD R, 1 3.95 minutes, 299 (N4-iH)+.

(in) 4-Methyl-piperazine-l-carboxylic acid 6-dimethy l-IH-benzoirniidazol-2-yfl -1IH-pyraizol-4yl]-amide 0 N HN N-=CH3 NH N'N CH 3 NH By proceeding in a manner similar to Example 260(k) above but using 2M 1-methylpiperazine in tetrahydrofuran there was prepared 4-iniethiyl-niperazline-l-carboxylic acid r3-(5,6-dirnethyl-1Hbenzoimnidazol-2-yvB-1H-pyrazol-4-yl]-amide (1 13mg) as a white solid. MS: 354 HPLC (METHOD El): RT 10.21 minutes.

I-Cyclopropy 1-3-f 6-dimethyl-1H-benzoimidazol-2-yl)-IH-pyrazol-4-yl] -urea 0

N

HN H CH 3 N CHN N NH

C

3

H

By proceeding in a manner similar to Example 260(k) above but using cyclopropylarnine there was prepared 1 -cyclopropyl-3-[3-(5 ,6-dimethyl- 1H-benzoimidazol-2-yl)-l1H-pyrazo1-4-yll -urea (80mg) as a white solid. MS: 311 HPLC (METHOD El): RT 10.36 minutes- 3-[3-(5,6-Dimethvl-1 H-benzoimidazol-2-yfl)-lH-pyrazol-4-yi]- 1,1 -diethyl-urea WO 031035065 WO 03/35065PCT/GB02/04763 -463- 0

N

CH3; By proceeding in a manner similar to Example 260(k) above but using 2M diethylamine in tetrahydrofuran there was prepared 3-[3-(5,6-dimethyl-lH-benzoimidazol-2-yl)-IH-pyrazol-4-vl- 1,1 diethyl-urea (61mg) as a white solid. MS: 327 HPLC (METHOD El): RT 11.36 minutes.

I -[3-(5.6-Dimethvl- 1 H-benzoirnidazol-2-vl)- 1 H-nvrazol-4-vll-3-isobutvl-urea 0

N/

HN H

CH

3

N

3 H N H By proceeding in a manner similar to Example 2601 above but using 2M isobutylamine in tetrahydrofuran, there was prepared 1 -[3-(5,6-dimethiyl- I H -benzoiniidazol-2-yl)- I H-pyrazol-4-yl]-3isobutyl-urea (58mg) as a white solid. MS: 327 HPLC (METHOD El): R 1 10.95 minutes.

I -Cyclopropylmethyl-3-r3-(5 .6-dimethyl- I l-benzoimidazol-2-yl)- IH-pyrazol-4-y1 -urea 0

N/

HN H

CH

3 N

NH

CH

3

N

3 H By proceeding in a manner similar to Example 260(k) above but using 2M (aminomethyl)cyclopropane in tetrahiydrofuran, there was prepared 1 -cyclopropyliinetlhvl-3-[3-(5 .6-di miethiyl-l1H-benzoimnidazol-2vl)-1H-pyrazol-4-yll-urea (29mg) as a white solid. MS: 325 HPLC (METHOD El): RT 10.63 minutes.

EXAMPLE 261 3-(5 -Chloro-6-methyl- 1H-benzoimidazol-2-yl)-1 H-pyrazol-4-ylamine WO 03/035065 PCT/GB02/04763 -464-

HN

Cl

N

CH, N NNH

H

A stirred solution of 5-chloro-6-methyl-2-(4-nitro- 1H-pyrazol-3-yl)- IH-benzoimidazole [0.320g, Example 249(g)] and tin chloride (1.10g) in ethanol (5 ml) was heated in a Smith Creator microwave at 140 0 C for 10 minutes. The reaction mixture was basified using saturated sodium hydrogen carbonate solution to pH 8 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-vlamine as a pale brown solid. LC-MS (METHOD RI 2.28 minutes, 248.13 (M+H) EXAMPLE 262 3-(5-Ethyl-6-methyl-lH-benzoimidazol-2-yl)- H-indazole-5-carboxylic acid amide dihydrochloride

NH,

CH

3

CH

2 N

CH

3

H

.2HC1 A stirred suspension of 3-(5-ethyl-6-methyl- [100mg, Example 235(an)] in acetic acid (Iml) and concentrated hydrochloric acid (Iml) was heated at 0 C for 30 minutes and then at 100°C for 4 hours. The reaction was cooled to ambient temperature and stirred for 16 hours. The reaction was then heated at 80"C for 2.5 hours and then at 100 0 C for 2 hours. The reaction mixture was cooled to ambient temperature and neutralized with aqueous sodium carbonate solution. The resulting white precipitate was collected by filtration and the aqueous layer was extracted with ethyl acetate, combined with the precipitate and concentrated in vacuo. The residue was taken up in methanol, transferred to a solid phase cartridge containing MP-carbonate resin (100mg) and shaken for 16 hours. The reaction was then filtered, the resin washed with methanol and the combined organic layers concentrated in vacuo. The residue was triturated with diethyl ether, taken up in methanol and acidified with 4M hydrogen chloride in 1,4-dioxane The solvent was removed in vacuo to give 3-(5-ethyl-6-methvl- H-benzoimidazol-2-yl)- H-indazole-5-carboxylic acid amide dihydrochloride (58mg) as a pale brown solid. LC-MS (METHOD RT 9.40 minutes, 320(M+H) WO 03/035065 PCT/GB02/04763 -465- EXAMPLE 263 3-(5,6-Dimethyl-I H--benzoiinidazol-2-yl)- I Fl-indazole-5-carboxylic acid

OH-

0 CH] N N-N

C

3 14 A stirred suspension of 3-(5,6-dimethyl- I H--benzoimidazol-2-yl)- I H-indazole-5 -carbon itrile dihaydrochloride [200mg, Reference Example 6(aq)] in acetic acid/concentrated hydrochloric acid (4ml, 1: 1 v/v) was heated at 1 00 0 C for 16 hours. The reaction mixture was cooled to ambient temperature and filtered. The precipitate was washed with water and dried in vacuo to give 3-(5,6-dimethyl-IHbenzoimidazol-2-yl)-l I-l-indazole-5-carboxylic acid (195mg) as a white solid. LC-MS (METHOD B): RT 2.52 minutes, 307 EXAMPLE 264 2-(4-Isobutyrylamino-lIH-pyrazol-3-yli- I H-benzoimidazole-5-carboxylic acid 0 0

HN

110 N

N

_a N> N'N

H

To a stirred solution of 2-(4-amino-1H-pyrazol-3-yl)-I-benzoimidazole-5-carboxylic acid methyl ester [200mg, Example 233(k)] in tetrahydrofuran (5mi) was added diisopropylethylamine (54541l) and isobutyryl chloride (327j tl) dropwise and the reaction stirred for 30 minutes. The reaction mixture was concentrated in vcicuo and the residue was taken up in 1M potassium hydroxide in tetrahydroffiran/methanol v/v) (5mI) and stirred for 1 hour. The reaction mixture was concentrated in vcicuo and the residue was taken up in 1M sodium hydroxide in water/methanol (5m1) and stirred for 1 hour. The solvent was removed in vacuo and the residue was partitioned hetween ethyl acetate and water and the layers separated. The aqueous layer was acidified to p1-I 3-4 with citric acid solution, extracted with ethyl acetate and the organic layer washed with brine. The organic layer was then dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 2- (4-isobutyvlamino-H-pyrazol-3-yl)-lH-benzoimidazole-5-carboxylic acid (140mg) as a white solid.

LC-MS (METHOD RT 2.87 minutes, 313.33 WO 03/035065 PCT/GB02/04763 -466- EXAMPLE 265 2-(1 H-Indazol-3-vl)-3H-benzoimidazol-5-amine H 2 N

N

H2H

-N

N J

H

A stirred solution of 3-(5-nitro-1H-benzoimidazol-2-yl)-H-indazole [90.8 mg, Reference Example 233(as)] in methanol (1 ml) was treated with tin chloride (616mg). The reaction was heated at reflux for 16 hours and then cooled to ambient temperature. The pH of the reaction mixture was adjusted to pH 8 by addition of aqueous sodium bicarbonate and then this mixture was extracted with ethyl acetate.

The organic extracts were dried over magnesium sulfate and then evaporated to yield an oil. The crude product was subjected to flash column chromatography on silica eluting with ethyl acetate and triethylamine to give 2-(1 H-indazol- 3 -vl)- 3 H-henzoimidazol-5-amine (826mg). MS: 250 31 248.3 I HPLC (Method RT 2.03 minutes.

REFERENCE EXAMPLE 1 5,6-Dimethyl-2-(5-methlsulfanyvl-I H-pyrazol-3-vl)-1-(2-trimethylsilanl-ethoxymethyl)-1Hbenzoimidazole CH0 N SCH

CH

3

N

N N~N C 3

CHOCH

2

CH

2 Si(CH 3 3 A mixture of 1-[5,6-dimethyl- I -(2-trimethylsilanyl-ethoxymethyl)- I H-benzoimidazol-2-yl]-3,3-bismethylsulfanyl-propenone [318mg, Reference Example hydrazine (2mL) and ethanol (l2mL) was heated at reflux temperature for 1 hour. The reaction mixture was then cooled to room temperature, then stirred at room temperature overnight, then heated at 60 0 C for 2 hours, then heated at reflux temperature for 3 hours, then stood at room temperature for 3 days and then evaporated. The residue was dissolved in dichloromethane and this solution was washed with water plus a little brine to facilitate separation and the aqueous phase was washed with dichloromethane and then with ethyl acetate. The combined organics were dried over magnesium sulfate and then evaporated to give 5,6-dimethyl-2-(5-methvlsulfanyl-IH-pyrazol-3-yl)- I-(2-trimethylsilanyl-ethoxymethyl)-1Hbenzoimidazole (90mg) as a colourless solid.

WO 03/035065 PCT/GB02/04763 -46 7- By proceeding in a similar manner to Reference Example 1(a) above but using m-ethyl-i -(2-trim-ethylsi lanyl-ethoxymerhyl)- I I-I-benzoinmidazol-2-yl] -3,3-hi s-rnethylsulfanyl-propennne [Reference Example there was prepared 6-ehloro-5-methyl-2-(5-methylsulfanyl- 1H-pyrazol-3-yl)- I -(2-trinmethylsilanyl-ethoxym-ethyl)- I H-benizoimidazole.

By proceeding in a similar manner to Reference Example 1(a) above but using 1-[6-chloro-5methyl- I -(2-tni methylsilIany]l-ethoxymethyl)- I H-benzo imidazol1-2-yl] -3 ,3 -bi s-ethylsulfanyl-propenone [Reference Example 2 there was prepared 6-c hlo ro-5 -methyl -eth yl sulfanyl- IH-pyrazol-3-yl)-If2-trimethyl silanyl-ethoxymethyl)- I I--benzoimidazole By proceeding in a similar mnanner to Reference Example 1(a) above but using 3,3-bismethylsulfanyl- I -[5-trifluoromethyl-l1-(2-trimethylsilanyl-ethoxymethyl)- IH-benzoimidazol-2-yl]propcnone [Reference Example there was prepared 2 -(5-mcthylsulfanyl- .trifluorometlwyl-l1-(2-tri methiylsilanyl-ethioxymethyl)- 1H-benzoi midazole By proceeding in a similar manner to Reference Example 1(a) above but: using 3,3-hiscyclopropylmerhyl sulfanyl- 1 -1 5,6-dimethyl-l1-(2-trimethylsilanyl-cthoxymethyl)- 1H-benzoimidazol-2yl] -propenone [Reference Example there was prepared 2-(5-cyclopropyl methylsulfanyl- 1Hpyra70l--3-yl)-5,~6-dimetiiyl-]I-(2-trit-netliylsilanyl-etlioxyi-ethyl)-I1 H-henzonicliazole.

By proceeding in a similar manner to Reference Example 1(a) above but using 1-[5,6-ditmethyl- 1 -(2-trimethylsi lanyl-ethoxymethyl)- 1 1--benzoimidazol-2-yt]-3,3 -bi s-ethylsul fanyl propcnone [Reference Example there was prepared 5,6-d i methyl -2 -(5-ethyl su Ifan yl- I H-pyrazol -3 -yll- 1 trimethylsi lanvl-ethoxymethyl)- 11--benzoiinidazole.

By proceeding in a similar manner to Reference Example 1 above but using 1-[5,6-dimethyl- 1 -(2-trimethylsilanyl-ethoxymethyl)-l1H-benzoimidazol-2-yl]-3,3-bis-(pyridin-3-ylmethylsulfanyl)propenone [Reference Example there was prepared 5 .6-dimethyl-2-(5-(pyridin-3ylmethylsulfanyl- IH-pyrazol-3-yI)- 1-(2-trimethylsilanyl-ethoxymethyl)- IH-benzoimidazole.

By proceeding in a simnilar manner to Reference Example 1(a) above but using 1-[5-fluoro-1- (2-trimethylsi lanyl-ethoxymethyl)- IH-benzoimidazol-2-yI]-3,3-bis-methylsulfanyl-propenone [Reference Example there was prepared 5-fluorco-2-(5-methyl sulfanyl- IH-pyrazol-3 1-(2trimethylsilanyl-ethoxymethyl)- 1H-benzoimidazole.

WO 031035065 PCT/GB02/04763 -468- By proceeding in a similar manner to Reference Example 1(a) above but using 1-[5,6-dimethyl- I -(2-trimerhylsilanyl-ethoxymethyl)- IH-benzoimidazol-2-yI]- 3,3-bis-phenethylsulfanyl-propenone [Reference Example there was prepared 5,6-dimethyl-2-(5-phenethylsul fanyl- IH-pyrazol-3-yl)- I- (2-trimnethylsilaniyl-ethoxymethyl)- I I-l-benzoimidazole.

By proceeding in a similar manner to Reference Example 1(a) above but using 3,3-bismethylsulfanyl-l1-[4-methyl-I -(2-tn m-ethiylsilanyl-ethioxymethiyl)- 1 -benzoim-idazol-2-yl]-propenone [Reference Example 2(k) I there was prepared 4-methyl-2-(5-methvlsul fanvl-1 -I-ovrazol-3 1-f2trimethylsilanyl-ethoxymethyl)-1 H-benzoimidazole.

By proceeding in a similar manner to Reference Example 1(a) above but using 3,3-bisbenzylsulfanyl- I -[5,6-dimethyl-l1-(2-trimethylsilanyl-ethoxymethyl)- IH-benzoimidazol-2-yI]propenione [Reference Example there was prepared 2-(5-benzylsulfanyl I H-pyrazol-3-yi)-5,6dimelivl-I -(2-trimeithiylsilaniyl-ethioxyinethiyfl-l benizoinidazole.

By proceeding in a similar manner to Reference Example 1(a) above but using methyl-I -(2-trimethylsilanyl-ethoxymethyl)- 1H-benzoi midazol-2-ylJ- 3-methylstilfanyl-3-morphol in-iyl-propenone [Reference Example 13] there was prepared 6-chloro-5-methyl-2-(5 -morpholin-4-yl- 1Hpyrazol-3-yI)- 1-(2-trimethylsilanyl-ethoxymethyl)- I 1--benzoimidazole.

(in) By proceeding in a similar mianner to Reference Example 1(a) above but using 1-[5,6-dirnethyl- I -(2-trimethylsilanyl-ethoxymethyl)- IH-benzoimidazol-2-yI] -3,3-bis-(thiophen-2-ylmethylsulfanyl)propenone [Reference Example there was prepared 5,6-dimethyl-2-F5-(thiophen-2ylmethylsulfainyl)- 1H-pvrazol-3-yl] -lI-(2-trir-nethylsilanyl-ethoxyrnethyl)- 1H-benzoimidazole.

REFERENCE EXAMPLE 2 1 -[5,6-Dimethyl- l-(2-trimethylsilanyl-ethoxymethyl)-lH-benzoimida2ol-2-y1lI-3,3-bis methylsulfanyl-p2ropenione SCH 3

SCH

3

CH

3 N 0

CH

2

OCH

2

CH

2 Si(CH,) 3 A stirred suspension of sodium tert-butoxide (350mg) in bcnzene (6mL), at -5 0 C, was treated with a solution of I -[5,6-dimethyl- t-(2-trimethylsi lanyl-ethoxymethyl)- 1H-benzoimidazol-2-vl]-ethanone [240mg, Reference Example in benzene (5mL) followed by carbon disulfide (2304iL). The WO 03/035065 PCT/GB02/04763 -46 9resulting orange solution was stirred for 1 hour at then treated with methyl Iodide (1 80jAL), then allowed to warm to room temperature and then stirred at room temperature overnight. An orange precipitate was formed. The reaction mixture was poured into ice-water and this mixture was then extracted with dichioromnethane. The combined organic extracts were washed with water, then dried over sodium sulfate and then evaporated to give 1-[5,6-dimethyl-l-(2-trimethylsilany-ethoxymethvl)- I H-benzoim-idazol-2-yll-3,3-bis-inetlhvlsulfaniyl-propenone (318mg) as an orange oil which was used without further purification.

By proceeding in a similar manner to Reference Exam-ple 2(a) above but using methyl-I -(2-trimethylsilanyl-ethoxymethyl)-IH-benzoimidazol-2-y]-ethanone [Reference Example there was prepared I -[6-chloro-5-methvl-lI-(2-trimethylsilanyl-etho~xymethyl)- IH-benzoimidazol- 2-yl1-3,3-b is-methylsulfanyl-propenone.

By proceeding in a similar manner to Reference Example 2(a) above but using 1-[6-chloro-5methyl-i -(2-tn methylsilanyl-ethoxymethyl)-1I-l-benzoimidazol-2-y] -ethianone [Reference Example and ethyl iodide there was prepared 1 -[6-chloro-5-methvl-l1-(2-trimethylsilanyl -ethoxymethyl)- IH-benzoimidaizol-2-yfl-3,3-bis-ethylsilfainl-propenone.

By proceeding in a similar manner to Reference Example 2(a) above but using I -L5-trifluoromnethyl-l1-(2-trimnethylsi lanyl -ethoxymethiyl)- IH-benzoim idazol-2-yl] -ethanone [Reference Example there was prepared 3 ,3-bis-methylsulfan1-1 5 -trifluoromethyl-l1-(2-trimethylsi lanylethoxymethyl)- 1H-benzoimnidazol-2-yll-prope none.

By proceeding in a similar manner to Reference Example 2(a) above but using bromomethylcyclopropane there was prepared 3,3-bis-cyclopropylmethylsulfanvl- 1-r5,6-dimethvl-l1-(2trimethylsi lanyl-ethoxymethyl)- I -benzoimidazol-2-yll-propenone.

By proceeding in a similar manner to Reference Example 2(a) above but using ethyl iodide there was prepared 14-5 .6-dimethyl- I -(2-trimethylsi lanyl-ethoxymethyl)- 1H-bcnzoimidazol-2-yl]- 3,3-bis-ethylsulfanyl-propenone.

By proceeding in a similar manner to Reference Example 2(a) above but using 3-picolyl chloride there was prepared 1 -f5,6-dim-ethyl-1 -(2-trimethylsi lanyl-ethoxymethyl)- IH-benzoimidazol-2- VI] -3,3-bis-(pyridin-3-ylmethylsulfanyl)-propenone.

WO 031035065 PCT/GB02/04763 -4 By proceeding in a similar manner to Reference Example 2(a) above but using 1-[5-fluoro-1- (2 -trimethylsilanyl-ethoxymethyl)- IH-benzoimidazol-2-ylj-ethanone [Reference Example there was prepared I -F5-fluoro- I-(2-trimethvlsilanyl-ethoxymethyl)-IH-benzoi midazol-2-yl]-3,3-bismethylsulfanyl-propenone.

Wi By proceeding in a similar manner to Reference Example 2(a) above but using phenethyl bromide there was prepared I -F5,6-dimethyl- I-(2-trimethylsi lanyl-ethoxymiethyl)- I]H-benzoimidazol-2yl]- 3,3-bis-phenethylsulfanyl-propenone.

By proceeding in a similar manner to Reference Example 2(a) above but using 1-[5-methoxy-1- (2-trimethyls ilaniyl-ethoxymietlyl I H-benlzoimidazol-2-yl]-ethianione [Reference Example 4 (g)I and ethyl bromide there was prepared 3.3-bis-cthylsulfanyl-1H[5-methoxy-2- (trimethylsilanyl)ethoxyrnethyl)- 1H-benzoimidazol-2-yl]-properione.

By proceeding in a similar manner to Reference Example 2(a) above but using 1-[4-methyl- I (2-trimethylsi lanyl-ethoxymethyl)- IH-benzoimidazol-2-yl] -ethanone [Reference Example there was prepared 3,3 -bis-methylsu Ifanyl-lI-[4-methyl-i- 2-trimethvlsilanyl-ethoxymethyl 1Hbenzolimidazol-2-yll-propenone.

By proceeding in a similar manner to Reference Example 2(a) above but using I -[5-methyl- I (2 -trimethylsi lanyl-ethoxymethyl)- I H-benzoi midazol-2-yl] -pentan- 1-one [Reference Example 3(f)] there was prepared 2-(bis-mcthylsulfianvl-methylene)- 5-m-ethyl- I1--benzoimidazol-2-yl)-pcntan- 1one.

(in) By proceeding in a similar manner to Reference Example 2(a) above but using l-[5-methyl -I- (2-trimethylsi lanyl-ethoxymethiyl)- I J--benzoimidazol-2-yl]-pentan- 1-one [Reference Example and 4-methoxybenzyl chloride there was prepared 2-[bis-(4-methoxy-benzylsulfanyl)-methylenel- mnethyl -1 H-benzoimnida7ol-2-yl)-p2entai-I I-one.

By proceeding in a similar manner to Reference Example 2(a) above but using 3-methyl-1-[5methyl -I -(2-trimethylsilanyl-ethoxymethyl)- I H-benzoimidazol-2-yl]-butan- 1-one [Reference Example and henzyl chloride there was prepared 2-(bis-benzvlsulfanyl-imethiylene)-3 -methyl-i I -(2-trimethylsilanyl-ethoxymethyl)- 1 H-benzoimidazol-2-yll-butan- 1 -one.

WO 03/035065 PCT/GB02/04763 -471- By proceeding in a similar manner to Reference Example 2(a) above but using benzyl chloride there was prepared 3,3-bis-benzvl sulfanyl- I -[5,6-dir-nethiyl-l1-(2-trimethylsilanyl-ethoxyvmethyl)- I Hbenzoimidazol-2-yi]-propenone.

By proceeding in a simiilar manner to Reference Example 2(a) above but using I -LI-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-cthanone [Reference Example 4(h)] with tetrahydrofuran as the solvent and carrying out the reaction at room temperature and then subjecting the reaction product to flash chromatography on silica under gradient elution conditions to 33% ethyl acetate in pentane) there was prepared 3,3-bis-mnethanesulfanyl -1-[1-(2-trimethylsilanyleth oxy methyl)- IH-be nzoinidaz.o 1-2 -v 11-propen one as an oil which slowly solidified on standing at room temperature.

By proceeding in a similar manner to Reference Example 2(a) above but using methyl- I -(2-trimethylsi ]anyl -ethoxymethyl)- 1 H-beiizoimidazol-2-yl] -ethanione [Reference Example and methyl iodide there was prepared I -[6-chloro-5-methyl- 1 -(2-trimethylsilanyl-ethoxymethyl)- IH-benzoimidazol-2-yl]-3,3-bis-methylsuI fanyl-propenone.

By proceeding in a similar manner to Reference Example 2(a) above but using 1-[5-methoxy-1- (2-trimethylsilanyl-ethoxymethyl)- I H-henzoi mida7ol-2-yl]-propan-I -one [Re Ference Example antI methyl iodide there was prepared I -[5-methoxy- I -(2-trimethylsi lanyl-ethoxymethyl)-I Ilbenzoimidazol-2-yl]- 2-rnerchyl-3-(bis-methanesulfanyl)- I -propenone.

By proceeding in a similar manner to Reference Example 2(a) above but using of 1 -[5,6-dimethyl-l1-(2-trimethylsilanyl-ethoxymethyl)- 1H-benzoim-idazol-2-yl] -ethanone [Reference Example and 2-chloromethylthiophene [Reference Example 14]) there was prepared 1-[5.6dimethyl-lI-(2-trimethylsilanyl-ethoxymethyl)- IH-benzoimidazol-2-yl]-3 ,3-bis-(thiophen-2ylmethylsulfanyl)-propenone.

By proceeding in a similar manner to Reference Example 2(a) above but using 1-f (2-trimethylsilanyl-ethoxymethyl)- 1 H-benzoimidazol-2-yl]-propan- I -one [Reference Example 3(h)] there was prepared 1 -[5-methyl-i -(2-trimethylsilanyl-ethoxymethyl)- 1I--benzoimidazol-2-yll- 2methyl-3-(bis-methanesulfanyl)-1 -propenone.

REFERENCE EXAMPLE 3 I -[5.6-Dimethyl-lI-(2-trimethylsilanyl-ethoxymethyl)- IH-benzoimidazol-2-yll -ethanone WO 031035065 WO 03/35065PCT/GB02/04763

CHI

2 OCHCH,Si(CHf,).

A solution of 5,6-dimethyl- I-(2-triinethylsilanyl-ethoxyrmethyl)-I1H-benzoimidazole [5.01 g, Reference Example in dry tetrahydrofuran (55mL), at -78'C, was treated with a solution of lithium diisopropylamide in a mixture of tetrahydrofuran and heptane (1 1.9mL, 2M) over 10 minutes. The mixture was stirred for 15 minutes then treated dropwise with dimethylacetamide (2.l5miL) over minutes. After stirring at -78'C for a further 30 minutes the reaction mixture was poured into ice and then left until all thc ice had melted. This mixture was extracted with dichlorornethanc and thle extracts were washed with brine, then with water, then dried over magnesium sulfate and then evaporated. The residual orange oil (5.91Ig) was subjected to column chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate v/v) to give ]-r5,6-dimethyl-I-(2trim-ethylsilaniyt-ethoxvrnethyl)- IH-benzoimidazol-2-yll-ethanone (3 .93g) as a yellow crystalline solid.

By proceeding in a similar manner to Reference Example 3(a) above but using methyl-l-(2-trim-ethylsilanyl-ethoxymethyt)-IH-benzomidazole [Reference Example there was prepared I -F6-chloro-5-methyl-lI-(2-trimethylsilanyl-ethoxymethy IH-benzoimnidazol-2- ll-ethanone.

By proceeding in a similar manner to Reference Example 3(a) above hut using 5-trifluoromethyl-lI-(2-trimethyl silanyl-ethoxymethyl)- IH-benzoi midazole [Refcrence Example 4(c)] there was prepared t-[5-trifluorornethyl-lI-(2-trimethylsi lanyl-ethoxymethyl)- IH-benzoimidazol-2-yllI ethanone.

By proceeding in a similar manner to Reference Example 3(a) above hut using 5-fluoro-lI-(2trimethylsilanyl-ethoxymethyl)- I Il-henzoimidazole [Reference Example there was prepared I -[5-fluoro-l1-(2-trimethylsilanvl-ethoxymethyl)- 1H-benzoimidazol 2 -vll -ethanone.

By proceeding in a similar manner to Reference Example 3(a) above but using 4-m~ethyl-l-(2tinmethylsilanyl-ethoxymethyl)- 1 H-benzoimidazole [Reference Example there was prepared 1 methyl-I -(2-trimethylsilanyl-ethoxymethyl)- IH-benzoimidazol-2-yll -ethanone.

By proceeding in a similar manner to Reference Example 3(a) above but using 5-methyl-l-(2tri methylsilanyl-ethoxymethyl)- 1 H-benzoimidazole [Reference Example and dimethylvaleramide [Reference Example there was prepared 14-5-methyl. I -(2-trimethylsi lanyl-ethoxymethyl 1H1benzoimidazol-2-yll-pcntan- 1 -one.

WO 031035065 PCT/GB02/04763 -473- By proceeding in a similar manner to Reference Example 3(a) above but using 5-methyl-I trimethiylsi lanyl-ethioxymiethiyl)- 1H-benizoi idazole [Reference Example and dimethylisovalerylamide [Reference Example there was prepared 3-methyl-1-F5-niethyl-l-(2tri methylsi lanyl-ethoxymethyl)- 1 H-benzoimidazol -2-yll-butan- 1-one.

By proceeding in a similar manner to Reference Example 3(a) above but using 5-m-ethyl- 1 trimethylsilanyl-ethoxymethyl)- 1H-benzoimidazo le [Reference Example and dimethylpropionamide there was prepared I -[5-methyl- I-(2-trimethvlsi lanyl-ethoxymethyl)- 1Hbenzoimidazol-2-yll-propan- I-one.

REFERENCE EXAMPLE 4 5,6-Dimethyl-1 -(2-trimiethylsilanyl-ethoxymethyl)-1 H-benzoimidazole

CH

3

CH

3

N

CH

2 OCH 2

CH

2 SI(CH 3 )1 A stirred mixture of sodium hydride (l.O9g) in dimethylformamide (?XOmL) was treated with a solution of 5,6-dimethyl- IH-benzoimidazole (4.

9 5gc i dimethyl formamide (5Oml-) at room temperature over minutes. After stirring for a further 1 hour the mixture was then treated with 2-(trimethylsilanyl)ethoxymethyl) chloride (6.4mL) over 15 minutes and then stirring was continued for18 hours. The reaction mixture was treated with methanol (l5mL) and water (Ilin) and then evaporated. The residue was treated with water (50mL) and this mixture was then extracted twice with diethyl ether (8OmL then 50mE). The combined extracts were washed three times with water then dried over magnesium sulfate and then evaporated. The residual brown oil (10.3g) was purified by Flashmaster using mixtures of ethyl acetate in hexane (20% to 80%) at 40m1/minute to give 5.6-dimnethyl-l -(2-trim-ethylsilanyl-ethoxymethyl)- IH-benzoi midazole 7 .54g) as an orange oil.

By proceeding in a similar manner to Reference Example 4(a) above but using methyl- I I1-benzoimidazole [Reference Example there was prepared 6-chloro-5-methyl-l-(2trimethylsilanyl-ethoxymethyl)- 1 H-benzoimidazole.

By proceeding in a similar manner to Reference Example 4(a) above but using IH-benzoimidazole [Reference Example there was prepared I -(2-trimethyisilanyl-ethoxymethyl)- I H-benzoimidazole.

WO 031035065 PCT/GB02/04763 -474- By proceeding in a similar manner to Reference Example 4(a) above but using benzoimidazole [Reference Example there was prepared 5-fluoro- I-(2-tri rethylsilanylethoxymethyl)-lI H-benzoirnidazole.

By proceeding in a similar manner to Reference Example 4(a) above but using 4-methyl-IHbenzoimidazole [Reference Example there was prepared 4-methyl-l-(2-trimethylsitanylethoxymethyl)- I H-benzoimnidazole.

By proceeding in a similar manner to Reference Example 4(a) above but using benzoimidazole there was prepared 5-methyl- I -(2-tni methyl si I anylI-ethoxymethyl)- I H-benzoimridazole.

By proceeding in a similar manner to Reference Example 4(a) above but using IH-benzoimidazol-2-yl)-ethanone [Reference Example there was prepared 45-methoxy- 1 trin-iethiylsilanyl-erhoxymethiyl)- I H--benizoi idazol-2-yI] -ethianonie.

By proceeding in a similar manner to Reference Example 4(a) above but using (IH-benizoimidazol-2-yl)-t-ethanone and carrying out the reaction in tetrahydrofuran there was prepared i-ri -(2-trimethylsilanyl-ethioxymethyl)- 1H-benzoimidazol-2-yll-ethanone as a colourless oil.

By proceeding in a similar manner to Reference Example 4(a) above but using I1H-benzoimidazol-2-yl)-propan-lI-one [Reference Example there was prepared I- 5-metlioxy--1- (2-trimethylsilanyl-ethoxymethyl)- I H-benzo imidazol-2-yi]-propan- I-one REFERENCE EXAMPLE CH 3 N ci N

H

A solution of 5-chloro-4-methyl- I 2-phenylenediamine (7.8g) in a mixture of formic acid (35mL) and hydrochloric acid (300mL) was heated at 50'C for 3 hours then treated with ammonium hydroxide solution until the solution was basic. The reaction mixture was then extracted with dichloromethane.

The extracts were evaporated to give 6-chloro-5 -m-ethyl-li i-benzoi midazole (7g).

By proceeding in a similar manner to Reference Example 5(a) above but using 4-trifluoromethyl- 1,2-phenylenediamine there was prepared 5-trilluoromethyl- 1H-benzoimidazole.

WO 03/035065 WO 03/35065PCT/GB02/04763 By proceeding in a similar manner to Reference Example 5(a) above but using 4-fluoro-ophenylenedianiine there was prepared By proceeding in a similar manner to Reference Example 5(a) above but using 2,3-diaminotoluene there was prepared 4-methiyl-IH-benizoiriidazole.

REFERENCE EXAMPLE 6 1 -(5-Metlhoxy- 1H-benzoimidazol-2 -yfl-ethanonie

CH

3 0 N CH 3 N 0

H

A stirred mixture of 1-(5-mnethoxy-lI-benzoimidazole)-lI-ethanol [5.14g, Reference Example and manganese dioxide (9a) in chloroform (8OmL) was heated at 60'C for 18 hours, then cooled to roomn temperature and then filtered. The filtrate was evaporated to give 1-(5-methoxy- IH-benzoimidazol-2yi)-ethanone (4.2 8g).

I -(5-Methoxy-1H-benzoimidazol-2-yl)-propan- 1-one

CH

3 N CH,CH 3 N 0

H

By proceeding in a similar manner to Reference Example 6(a) above but using 1-(5-methoxy-1benzoimidazole)-I-propanol [Reference Example there was prepared 1- 1H-benzoimidazol-2-yl)-propan-I -one.

5-Fluoro- IH-indazole-3-carbaldcliyde

CHO

\N

H

By proceeding in a similar manner to Reference Example 6(a) above but using (5-fluoro- I H-indazol-3yl)-methanol [Reference Example 25(a)] with acetone as the solvent, a reaction temperature of and subjecting the reaction product to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate 1 v/v) there was prepared.5-fluoro- I H-indazole-3-carbaldehyde as a light brown solid. LC-MS (METHOD RT =2.74 minutes, 165 WO 03/035065 PCT/GB02/04763 6-Fluoro-1H-indazole-3-carbaldehyde By proceeding in a manner similar to Reference Example 6(a) above but using (6-fluoro-lH-indazol-3yl)-methanol [Reference Example 25(b)] with acetone as the solvent, a reaction temperature of 55 0

C

and subjecting the reaction product to flash column chromatography on silica cluting with a mixture of 40/60 petrol and ethyl acetate (1:1 v/v) there was prepared 6-fluoro- H-indazole-3-carbaldehyde as a light brown solid. LC-MS (METHOD RT= 2.74 minutes, 165 (M+H) H-indazole-3-carbaldehyde

CH,-

By proceeding in a manner similar to Reference Example 6(a) above but using (5-methyl-IH-indazol-3yl)-methanol [Reference Example 25(c)] with dichloromethane as solvent, a reaction temperature of 0 C and subjecting the reaction product to flash column chromatography on silica eluting with a mixture of hexane and ethyl acetate v/v) there was prepared 5-methyl-lH-indazole-3carbaldehyde as a pale brown solid. LC-MS (METHOD R T 2.79 minutes, 161 (M+H) 6-Methoxy-1H-indazole-3-carbaldehyde

CHO

f

N

CH

3 0 O

H

By proceeding in a manner similar to Reference Example 6(a) above but using (6-methoxy-lH-indazol- 3-yl)-methanol [Reference Example 25(e)] with acetone as the solvent, a reaction temperature of and subjecting the reaction product to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate (1:1 v/v) there was prepared 6-methoxy-1H-indazole-3-carbaldehvde as a light brown solid. LC-MS (METHOD RT= 2.76 minutes, 177 (M+H) WO 03/035065 PCT/GB02/04763 -477- 4-Phenvl-1H-pvrazole-3-carbaldehyde

N

By proceeding in a similar manner to Reference Example 6(a) above but using (4-phenyl-1H--pyrazol-3yl)-methanol [Reference Example 25(f)] with acetone as the solvent, a reaction temperature of 60 0 C for 2 hours, and subjecting the reaction product to flash column chromatography on silica eluting with a mixture of dichloromethane and methanol (49:1, v/v) there was prepared 4-phenyl-lH-pyrazole-3carbaldehyde as a white solid. LC-MS (METHOD RT 2.76 minutes; 213 (M+H) 5-Chloro-lH-indazole-3-carbaldehyde

CHO

Cl

N

H

By proceeding in a similar manner to Reference Example 6(a) above but using (5-chloro-1-l-indazol-3yl)-methanol [Reference Example 25(d)] with a mixture ofdichloromethane and tetrahydrofuran as solvent, heating at reflux temperature and subjecting the reaction product to flash column chromatography on silica eluting with a mixture ofhexane and ethyl acetate v/v) there was prepared 5-chloro-lH-indazole-3-carbaldehyde as a pale brown solid. LC-MS (METHOD RT 2.89 minutes, 181 3-Formyl-pyrazole-4-carboxylic acid ethyl ester 0 O SOLEt OHC

NN

H

By proceeding in a manner similar to Reference Example 6(a) above but using 3-hydroxymethyl-1 Hpyrazole-4-carboxylic acid ethyl ester [Reference Example 41(a)] there was prepared 3-formvlpyrazole-4-carboxylic acid ethyl ester as a brown solid. LC-MS (METHOD RT= 2.65 minutes; 169 (M+H) WO 031035065 PCT/GB02/04763 -478- 3-Formyl-pyrazole-4-carboxyl ic acid isopropylamide 0

NHCH(CH-I

3 2

OHC

N.~

H

By proceeding in a manner similar to Reference Example 6(a) above but using 3-hydroxymethyl-1Ipyrazole-4-carboxylic acid isopropylamide [Reference Example 4 there was prepared 3-formylpyrazole-4-carboxylic acid isopropylamide as a waxy orange solid. LC-MS (METHOD RT= 2.73 minutes; 182 3-Fon-nyl-5-methyl-pyrazole-4-carboxylic acid ethyl ester 0 -O~t

OHC

-CH3

NN

H

By proceeding in a manner similar to Reference Example 6(a) above but using r-nethyl-LH-pyrazole-4-carboxylic acid ethyl ester [Reference Example 4 1 there was prepared 3formyl-5-rnethyl-pyrazole-4-carboxylic acid ethyl ester as a white solid. LC-MS (METHOD RT= 2.80 minutes; 183 IH-indazole-3-carbaldehyde

CHO

N.

H

By proceeding in a manner similar to Reference Example 6(a) above but using (1H-indazol-3-yl)methanol [Reference Example 25(g)] with acetone as the solvent and carrying out the reaction at reflux temperature for 16 hours there was prepared I H-indazole-3-carbaidehyde as a yellow solid.

LC-MS [METHOD RT 2.63 minutes; 147.26 145.26 (in) 4-Nitro- 1 -(tetrahydro-pyran-2-yl)- IH-pyrazole-3-carbaldehvde WO 031035065 PCT/GB02/04763 -4 79- OHC\

NO

2 0

N

N

0 By proceeding in a manner similar to Reference Example 6(a) above but using [4-nitfo-1- (tetrahydro-pyran-2-yI)-l1H-pyrazol-3-yl]-methanol (6631ng, Reference Example 53) and manganese (IV) oxide (2.54g) with acetone as the solvent, (ii) carrying out the reaction at 65'C for 2 hours and (iii) subjecting the reaction product to flash silica chromatography eluting with a mixture of pentane and ethyl acetate (70:30, there was prepared 4-nitro- I -(tetra hydro-pyran-2-yl)- I H-pyrazo le-3 carbaldehyde (19 1mg) as a pale yellow oil. LC-MS (Method RT= 2.19 minutes, 248.24 3-Formyl I F--prazole-4-carboxylic acid (2-methoxy-ethyl)-amide

H

OHC

N

N

OCH

N3 By p roceeding i n a manner s imi lar to Reference Examp le 6(a) above but usi ng 3 -hydroxymerhyl-lIHpyrazole-4-carboxyl ic acid (2-methoxy-ethyl)-amide [Reference Example 41(d)] there was prepared 3 -formyl- 1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide (325mg) as a yellow oil. LC-MS (METHOD B3): RT 2.13 minutes, 198 3-Formyl- 1 H-pyrazole-4-carboxylic acid propylarnide 0

H

OHC N

N

H

By proceeding in a manner similar to Reference Example 6(a) above but using 3-hydroxymethyl-l Hpyrazole-4-carboxylic acid propylamide [Reference Example 4 there was prepared 3-formyl-IHpvrazole-4-carboxylic acid propylamide (414mg) as an orange oil. LC-MS (METHOD B3): RT 2.42 minutes, 182 (M+4H)-i.

WO 031035065 WO 03/35065PCT/GB02/04763 3-Formyl- I H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-vl)-amide 0

OHCN

N

H 0 By proceeding, in a manner similar to Referencc Example 6(a) above but using 3-hydroxymethyl- IHpyrazole-4-carboxylic acid (tetrahydro-pyran-4-yi)-amide [Reference Example 4 1 there was prepared 3-formyl -11H-pyrazole-4-carboxylic acid (tetra hvdro-pV ra n-4-yl) -am ide (400mg) as a brown oil. LC-MS (METHOD RT 2.34 minutes, 224.31 3-Forinyl- I H-pyrazole-4-carboxvlic acid cyclopropylamide 0

H

OFIC N

N

H

By proceeding in a manner similar to Reference Example 6(a) above but using 3-hydroxymethyl-1pyrazole-4-carboxylic acid cyclopropylamide [Reference Example 41(f)] there was prepared 3-formnyl- Ili--pyrazole-4-carboxylic acid cyclopropylamide (125mg) as a yellow oil. LC-JMS (METHOD 1

RT

=1.87 minutes, 178.31 REFERENCE EXAMPLE 7 1 -Methoxy-lIH--benzoimidazol-2-yl)-ethanoI A mixture of 4-methoxy-phenylenediamine dihydrochioride (l0g), sodium L-lactate (10g) and hydrochloric acid (60mL, 4M) was heated at 70'C for 48 hours. The reaction mixture was cooled to room temperature, then treated with ammonium hydroxide. The resulting precipitate was filtered and dried to give 1-(5-methoxy-lH-benzoimidazol-2-yl)-ethanoI (5.14g).

I -(5-Methoxy- I -benzoimidazole)- I -propanol WO 03/035065 PCT/GB02/04763 -481- CH O 0N

CHCH,

N OH

H

By proceeding in a similar manner to Reference Example 7(a) above but using 2-hydroxybutyric acid there was prepared 1-(5-methoxy-l-benzoimidazole)- I-propanol.

REFERENCE EXAMPLE 8 Dimethylvaleramide A solution ofdimethylamine hydrochloride (6.76g) and triethylamine (30mL) in dichloromethane (1O00mL), under nitrogen and at 0°C was treated dropwise with valeryl chloride (10g). After stirring at room temperature overnight the reaction mixture was treated with hydrochloric acid (2N) and dichloromethane. The organic phase was separated, dried over magnesium sulfate and then evaporated to give dimethylvaleramide as a clear oil.

By proceeding in a similar manner to Reference Example 8(a) above but using isovaleryl chloride there was prepared dimethylisovalerylamide.

REFERENCE EXAMPLE 9 2,3-Diaminopyrazine Liquid ammonia (50mL) was introduced into a pressure reaction vessel containing a small lump of ice.

To this was added copper bronze (1.17g), copper (II) iodide (0.224g) and 2,3-dichloropyrazine (4g).

The sealed reaction vessel was heated at 170 0 C for 48 hours, then cooled to ambient temperature and then vented. The reaction mixture was treated with water (75mL) and this mixture was extracted four times with diethyl ether (400mL). The combined extracts were evaporated to give 2,3-diaminopvrazine as a white solid The aqueous layer was continuously extracted with diethyl ether for 18 hours to yield a further quantity of 2,3-diaminopyrazine (1.24g). 1 H-NMR [(CD 3 )2SO]: 8 5.87 4H), 7.15 (s, 21-1).

REFERENCE EXAMPLE 1H-Pyrazole-3-carbaldehyde Dry dimethylformamide (77.6mL) was stirred at 80 0 C while cyanuric chloride (26.6g) was added in portions, whilst keeping the reaction temperature between 80 and 110 0 C. The reaction mixture was stirred at 100"C for another 30 minutes then cooled and then allowed to stand at room temperature overnight. The reaction mixture was filtered to give dimethylvinylamine.

WO 03/035065 PCT/GB02/04763 -482- (ii) The dimethylvinylamine from was added to dry methanol (260mL) and the mixture was then treated with pyruvic aldehyde dimethylacetal (51mrL), followed by a solution of sodium methoxide in methanol 81mL), then stirred for 2 hours at ambient temperature, then heated at reflux temperature for another hour, then cooled and then filtered. The filtrate was evaporated to give 1,1-dimethoxy-but-3-en-2-one as a brown oil (96.8g).

(iii) A stirred solution of 1,l-dimethoxy-but-3-en-2-one in water (300mL) was treated dropwise with hydrazine hydrate (21 mL). After standing at room temperature overnight the reaction mixture was treated with sodium chloride (108g) and the mixture was then extracted with methyl-t-butylether (200mL then 100mL). The combined extracts were dried with magnesium sulfate and then evaporated to give 1H-pyrazol-3-carbaldehyde dimethyl acetal as a light brown oil (18.47g).

(iv) A solution of 1H-pyrazol-3-carbaldehyde dimethyl acetal in water (85mL) was treated with glacial acetic acid (3.7mL). After two days the mixture was filtered to give IH-pyrazole-3-carbaldehyde (1.3g) as a light brown solid.

REFERENCE EXAMPLE 11 H-pyrazol-3-yl)- -(2-trimethylsilanyl-ethoxymethyl)- 1H-benzoimidazole N OCH CH, N

NNH

N

CH

2 OCH CH 2 Si(CH 3 3 Sodium hydride (0.1 g) was added to ethanol (5mL) and the mixture was stirred for ten minutes, then treated with 3,3-bis- methanesulfanyl-l-[1-(2-trimethylsilanyl-ethoxymethyl)- H-benzoimidazol-2-yl]propenone [0.5g, Reference Example and then heated at reflux temperature for six hours. The reaction mixture was cooled, then treated with hydrazine hydrate (1 27mmol) and then heated at reflux temperature for four hours. The mixture was then evaporated and the residue was triturated with water and filtered. The solid was subjected to chromatography on silica gel eluting with ethyl acetate to give H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole as a yellow oil.

REFERENCE EXAMPLE 12 2-(5-Methylsulfanyl-isoxazol-3-yl)- -(trimethylsilanyl-ethoxymethyl) 1 H-benzoimidazole N

SCH,

CH

2

OCH

2

CH

2 Si(CH,) 3 Hydroxylamine hydrochloride (168mg) was added to a solution of sodium methoxide in methanol [prepared by the addition of sodium hydride (122mg) to methanol The mixture was stirred for WO 03/035065 PCT/GB02/04763 -48 3ten minutes, then treated with 3,3-bis-methanesulfanyl- I J[ 1-(2-trimethylsilanyl-ethoxymethyl)- 1 Hhenzoirnidazol -2-yl] -prope none [500mg, Reference Example then heated at reflux for six hours, then cooled and then evaporated. The residue was taken up in water and the aqueous mixture was extracted with ethyl acetate. The extracts were dried and evaporated. The residue was subjected to chromatography on silica eluting with methylene chloride to give 2-(5-methylsulfanyl-isoxazol-3-yl)- I- (tritmethylsilanyl-ethoxyrnethyl)1H-benizoimidazole (0.16 g) as a colourless oil.

REFERENCE EXAMPLE 13 1-r6-Chiloro-5-methyl-1 -(2-trimnethylsilanyl-ethoxymethyl)- IH-benzoimidazol-2-yl]- 3-methylsulfanyl- 3-morp~holin-I-yl-propenone C0

N-

CH

3 N

SCH

3 Cl1 N 0

CHOCH-

2

CH

2 Si(CH) 3 A solution of t-[6-chloro-5-methyl- I -(2-trimethylsilanyl-ethoxymethyl)-1I--benzoimidazol-2-yl]- 3,3bis-methanesulfanyl-propenone [800mg, Reference Example 2 in morpholine (3mL) wvas heated at for 2 hours and then evaporated to give 14r6-chloro-5-methyl- I -(2-trimcthylsilanylethoxymethyl)- IH-benzoimidazol-2-yll- 3-methylsulfanyl-3-i-norphol in-i -yl-propenone.

REFERENCE EXAMPLE 14 2-Chloromethyl-thiophene S

CH

2

CI

To a three-necked flask fitted with stirrer bar, pressure equalizing dropping funnel and inlet/outlet adapter was added thiophene (1inmL) and aqueous hydrochloric acid (5.5irnL). Hydrogen chloride gas [generated by dropping sulfuric acid (3OmL) onto dry sodium chloride (50 was bubbled through the reaction mixture with vigorous stirring at 0 0 C. This mixture was then treated dropwise with formaldehyde solution 12.5mL) and stirring was continued for 45 minutes. The phases were separated and the aqueous phase was extracted three times with diethyl ether (l0mL). The organic phases were then washed twice with water (lOmL), then twice with saturated sodium hydrogen carbonate (l0rmE), then dried over magnesium sulfate and then evaporated. The residue was distilled at mml-g using a heat gun to give 2-chloromethyl-thiophene which was used immediately without further purification.

WO 03/035065 PCT/GB02/04763 -484- REFERENCE EXAMPLE Bis(methvlthio)-3,3-(benzoimidazol-2-yl)- -prop-2-en-2-one

SCH

3

SCH,

N 0

H

A mixture of sodium hydride (19.2g) and toluene (400mL), at 80 0 C, was treated portionwise with tertiary-butanol 3 0 After 2 hours the reaction mixture was cooled to room temperature and treated dropwise with a mixture of dimethylformamide (40mL), carbon disulfide (12mL) and 2-acetyl- 1-(tetrahydropyran-2-yl)-benzoimidazole (5 Ig, Reference Example 16) over 90 minutes. After addition the red reaction mixture was stirred at 80 0 C for 30 minutes, then cooled to room temperature and then treated with methyl iodide (50nL). This mixture was stirred at 80°C for 30 minutes when a precipitate started to form. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated to give a viscous red oil, which was dissolved in methanol (300mL). This solution was treated with p-toluenesulfonic acid (2g) and water (4mL), then heated at reflux temperature for 13 hours and then cooled in an ice-bath. The resulting solid was filtered and then washed with isopropyl ether to give bis(methylthio)-3.3-(benzoimidazol-2-vl)-l-prop-2-en-2-one (11.2g), m.p. 2240C.

REFERENCE EXAMPLE 16 2-Acetyl-l-(tetrahydropyran-2-yl)-benzoimidazole N CH 3 N 0 Dihydropyran (20.5mL) as added dropwise to a solution of 2-acetylbenzoimidazole (32g) and p-toluenesulfonic acid (2g) in dichloromethane (280mL) at reflux. The reaction mixture was stirred at this temperature for 24 hours, then cooled and the insoluble materials were filtered off. The filtrate was concentrated to give 2-acetyl-1-(tetrahydropvran-2-vl)-benzoimidazole as an amber oil (51.8g).

TLC: (dichloromethane:methanol, 97:3) RF 0.80.

REFERENCE EXAMPLE 17 4,5,6,7-Tetrahydro-lH-indazole-3-carboxvlic acid WO 03/035065 PCT/GB02/04763

N

A solution of 4,5,6,7-tetrahydro- IH-indazole-3-carboxylic acid ethyl ester [0.606g, Reference Example 18(a)] in methanol (50m1) was treated with sodium hydroxide (0.500g). The mixture was refluxed for 16 hours, then cooled and then evaporated. The residual white solid was treated with hydrochloric acid (30m1, 2N) and the resulting solution was extracted three times with ethyl acetate (50ml). The combined organic extracts were dried over sodium sulfate and then evaporated to yield tetrahydro-IFI-indazole-3-carboxylic acid (0.

4 24g) as a white solid. LC-MS (METHOD RT=2.44 minutes; 167 5-Isopropyl- I H-pyrazole-3-carboxylic acid CH(CH 3 )2

HO

0 By proceeding to a manner similar to Example 1 7(a) above but using 5-isopropyl-1 H-pyrazole-3carboxylic acid ethyl ester [Reference Example there was prepared 5-isopropyl-lH-pyrazole-3carboxylic acid as a white solid (0.973g) which was used without further purification.

bC-MS (METHOD RT-2.43 minutes; 155 5 -Ethyl- I H-pyrazo le-3 -carboxyl i c acid CH CH, HO

'NH

N-

0 By proceeding in a manner similar to Reference Example 17(a) above, but using 5 -ethyl-1IH-pyrazo le- 3-carboxylic acid ethyl ester [Reference Example 1 there was prepared 5 -ethyl-1IH-pyrazole-3 carboxylic acid as a white solid. LC-MS (METHOD RT=2.34 minutes; 141 3-tert-Butvloxvmethvl-1H-Dvrazole-4-carboxvlic acid WO 031035065 PCT/GB02/04763 -486- 0

OH

'BuOCH 2

H

By proceeding in a manner similar to Reference Example 17(a) above, but using 3-tenlbutyloxymethyl- 11--pyrazole-4-carboxylic acid ethyl ester [Reference Example 42], there was prepared 3-teri-butyloxymethyl-1IH-pyrazole-4-carboxylic acid as a white solid which was used without further purification. LC-MS (METHOD RT=2.75 minutes; 199 I 4,7 -Tetra hyd ro-pyrano[143 3-c]I pyrazo le-3 -c arbo xylic acid 0 HO 9 NII

N

0 By proceeding in a manner similar to Reference Example 17(a) above but using I ,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylic acid ethyl ester [Reference Example 18(e)] there was prepared 1,4,6.7-tetrahydro-pyrano[4,3-clpyrazole-3-carboxylic acid (261 mg) as a white solid. LC-MS (METHOD R 1 I 1.98 minutes, 169 1.4,5. 6-Tetrah ydro-c vclopentapyrazole-3-carboxy lie acid

N

N

0 By proceeding in a manner similar to Reference Example 17(a) above but using 1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylic acid ethyl ester [Reference Example 18S(f)] there was prepared 1,4,5.6-tetrabydro-cyclopentapyrazole-3-carboxylic acid (0.641ig) as a white solid. LC-MS (METH-OD B3): RT 2 .13 minutes, 153.22 REFERENCE EXA-MPLE 18 4.5 .6,7-Tetrahydro- I H-indazole-3-carboxylic acid ethyl ester WO 03/035065 PCT/GB02/04763 -487-

N

0 A solution of oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester [7.5g, Reference Example 19(a)] in acetic acid (150ml) was treated dropwise with hydrazine monohydrate (1.65ml). The mixture was refluxed for 8 hours, then cooled and then evaporated. The residue was partitioned between ethyl acetate (200ml) and saturated sodium bicarbonate solution (200ml) and the organic layer was dried over sodium sulfate and then evaporated. The residual orange oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane v/v) to give 4,5, 67tetrahydro-lH-indazole-3-carboxylic acid ethyl ester (606mg) as an orange oil which solidified on standing. LC-MS (METHOD RT =2.79 minutes; 195 (M+H) 5-Isopropyl-lH-pyrazole-3-carboxylic acid ethyl ester

CH(CH,)

2

N

0 By proceeding to a manner similar to Reference Example 18(a) above but using 5-methyl-2,4-dioxohexanoic acid ethyl ester [2.00g, Reference Example 19(b)] there was prepared pyrazole-3-carboxylic acid ethyl ester as a light yellow oil which was used without further purification.

LC-MS (METHOD RT=2.79 minutes; 183 (M+H) 5-Ethyl- H-pyrazole-3-carboxylic acid ethyl ester

CH

2

CH

3

N

O

0 By proceeding in a manner similar to Reference Example 18(a) above, but using 2,4-dioxo-hexanoic acid ethyl ester [Reference Example and subjecting the reaction product, an orange oil, to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane there was prepared 5-ethyl-lH-pyrazole-3-carboxvlic acid ethyl ester as a yellow oil. LC-MS (METHOD B): RT=2.64 minutes; 169 (M+H) WO 03/035065 PCT/GB02/04763 -488- I ,4,6,7-Tetrahydro-pyrazolo['4,3-clpyridine-3,5-dicarboxytic acid 5-tert-butyl ester 3-ethyl ester 0 0 -GEt tBuG J Na

N

N

H

By proceeding in a manner similar to Reference Example 18(a) above, but using 3-ethoxyoxalyl-4-oxopiperidine-lI-carboxylic acid tert-butyl ester [Reference Example there was prepared 1,4,6,7 tetrahydro-pyrazolof4,3-clpyridine-3,5-dicarboxylic acid 5-tei-t-butyl ester 3-ethyl ester as a yellow oil.

LC-MS (METHOD RT-2.73 minutes; 296 1,4,6,7-Tetrahydro-pyraniol4.3-clpvrazole-3-carboxylic acid ethyl ester 0 0 N 0 By proceeding in a manner similar to Reference Example 18(a) above but using tetrahydro-4H-pyran- 4-one there was prepared 1,4,6. 7-tetrahydro-pyranoF4,3-clpyrazole-3 -carbo~xylic acid ethyl ester (385mg) as a white solid. LC-MS (METHOD RT 2.43 minutes, 197 I ,4,5,6-Tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester 0 By proceeding in a manner similar to Reference Example 18(a) above but using oxo-(2-oxocyclIopentyl) -acetic acid ethyl ester [Reference Example 19(e)] there was prepared 1,4.5,6-tetrahydrocyclopentapyrazole-3-carboxylic acid ethyl ester (2.06g) as a yellow solid. LC-MS (METHOD RT 2.56 minutes, 185 (Ma-H) m REFERENCE EXAMPLE 19 WO 031035065 PCT/GB02/04763 -489- Oxo-(2-oxo-cyclohex yI)-acetic acid ethyl ester 0 0 A solution of sodium (1.75g) in ethanol (IlO0mI) was treated with a mixture of diethyl oxalate (9.41m1) and cyclohexanone 1 Sml). The mixture was heated to 60'C for 5 hours then cooled and then evaporated to yield oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester as a brown foam (Il 6 6 35g). LC-MS (METHOD RT 3. 10 minutes; 197 5-Methyl-2,4-dioxo-hexanoic acid ethyl ester 0 W 0 0 0 By proceeding to a manner similar to Example 19(a) above but using 3-m-ethyl-2-butanone there was prepared 5-methyl-2,4-dioxo-hexanoic acid ethyl ester as a white solid. L.C-MS (METHOD RT 3.47 minutes; 187 2,4-Dioxo-hcxanoic acid ethyl ester 0 0 0 By proceeding in a manner similar to Reference Example 19(a) above, but using 2-butanone, there was prepared 2,4-dioxo-hexanoic acid ethyl ester as a brown oil which was used without further purification. LC-MS (METH-OD RI, 3.28 minutes;, 173 3-Ethoxyoxalyl-4-oxo-1piperidine-l1-carboxylic acid tert-bLityl ester 0 0 H OUt 0 WO 03/035065 PCT/GB02/04763 -490- By proceeding in a manner similar to Reference Example 19(a) above, but using N-Boc piperidone, there was prepared 3-ethoxvoxalvl-4-oxo-piperidine-1-carboxvlic acid tert-butvyl ester as a brown oil which was used without further purification. LC-MS (METHOD RT3.

4 3 minutes; 244 (M-tBu) Oxo-(2-oxo-cyclopentyl)-acetic acid ethyl ester 0 o 6r 0 0 By proceeding in a manner similar to Reference Example 19(a) above but using cyclopentanone there was prepared oxo-(2-oxo-cvclopentvl-acetic acid ethyl ester (9.99g) as a yellow solid. LC-MS (METHOD RT 3.12 minutes, 185 REFERENCE EXAMPLE 3-Formyl-5-methoxy-inda7zole-1-carboxvlic acid rert-butvl ester

CHO

CH O

N

0 A solution of 5-methoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester [282mg, Reference Example 21(a)] in tetrahydrofuran (4ml) and water (1.5ml) was treated with a solution of osmium tetroxide in water (54 tL, 4wt%) and sodium periodate (400mg). The reaction mixture was stirred at ambient temperature for 16 hours and then filtered. The filtrate was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petrol v/v) to yield indazole-1-carboxvlic acid tert-butvl ester (162mg) as a white solid. LC-MS (METHOD RT= 2.97 minutes; 277 4-Fluoro-1H-indazole-3-carbaldehyde WO 031035065 PCT/GB02/04763 -491- F

CHO

N

N

H

By proceeding in a manner similar to Reference Example 20(a) but using 4-fluoro-3-(2methoxycarbonyl-vinyl)-indazole-lI -carboxylic acid terlf-butyl ester [Reference Example 21 there was prepared 4-fluoro-iHl-iindazole-3-carbaldehyde as a light brown solid. LC-MS (METHOD RT 2.63 mninutes; 1 65 4-Chiloro-3-formiyl-inidazole-l1-carboxyl ic acid tert-butyl ester Cl

CHO

/N

N

0 0 By proceeding in a manner similar to Reference Example 20(a) but using 4-chloro-3-(2methoxycarbonyl-vinyl)-indazole-l1-carboxylic acid tert-butyl ester [Reference Example 21(c)] there was prepared 4-chloro-3-fornwl-indazole-I -carboxylic acid tet-t-butyl ester (0.2 17g) as a brown oil.

LC-MS (METHOD RT 3.49 minutes; 283 5-Ethoxy-3 -formyl-indazole-l1-carboxyl ic acid tert-butyl ester

CHO

EtO 0 By proceeding in a manner similar to Reference Example 20(a) but using 5-ethoxy-3-(2methoxycarbonyl-vinyl)-indazole- I -carboxylic acid tert-butyl ester [Reference Example 2 there was prepared 5-ethoxy-3-formvl-indazole-l-carboxylic acid /ert-butyl ester as a brown oil. TLC(ethyl acetate:hexane, 1:9, RF= 0.25. IH NMR (400MHz, CDCI 3 8 1.38(3H, 1.67(9H, 4.05(2H-, 7.12(]H, 7.60(IH, 7.98(1H, 10.20(1H, s).

WO 031035065 PCT/GB02/04763 -492- REFERENCE EXAMPLE 21.

5-Methoxy-3-(2-methoxycarbonyl-vinyl ndazole-l1-carboxyl ic acid tert-butvl ester 0

OCH

3

CH

3 0

/N

N

OC(CI)

3 0 A solution of 3-iodo-5-methoxy-indazole-l1-carboxyl ic acid fert-butyl ester [0.

5 0 0 g, Reference Example 22(a)] in dioxane (I15m1) and under an atmosphere of nitrogen was treated with triethylamine (l.86m1) followed by methyl acrylate triphenyiphosphine 1 05g), and palladium (11) acetate The resulting mixture was heated at 50'C for 16 hours, then cooled to ambient temperature and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and 40/60 petrol v/v) to yield 5-methoxy-3-(2-methoxycarbonvyl-vinyl)-inidazole- I -caiboxyl ic acid terf-butyl ester (282mg). LC-MS (METHOD RT=3.33 minutes; 333 By proceeding in a manner similar to Reference Example 21 1(a) but using 4-fluoro-3-iodoindazole-l-carboxylic acid tert-butyl ester [Reference Example 22(b)] there was prepared 4-fluoro-3- (2-methoxycarbonyl-vinyl)-indazole-l-carboxylic acid tert-butvl ester as a light brown solid.

LC-MS (METHOD R-13.39 minutes; 321 By proceeding in a manner similar to Reference Example 2 1(a) but using 4-chloro-3-iodoindazole-lI-carboxylic acid tert-butyl ester [Reference Example 22(c)] there was prepared 4-chloro-3- (2-methoxycarbonyl -vinyl) -indazole-lI-carboxyl Jc acid tert-hutyl ester as a brown solid.

LC-MS (METHOD RT=3.48 minutes; 339 By proceeding in a manner similar to Reference Example 21(a) but using 5-ethoxy-3-iodoindazole-lI-carboxylic acid tert-butyl ester [Reference Example 22(d)] there was prepared 5-ethoxy-3- (2-methoxycarbonyl-vinyl)-indazole-l-carboxylic acid tert-butyl ester as an off-white solid. LC-MS (METHOD RT =3.41 minutes; 347 WO 03/035065 PCT/GB02/04763 -493- REFERENCE EXAMPLE 22 3 -lodo-5-mnetlioxy-indazole- I-carboxyl ic acid tei-t-butyl ester C H 3 0

N

3 3

I

A solution of 3-iodo-5-methoxy- I H-indazole [1.48g, Reference Example 23(a)] in acetonitrile (6m1) was treated with triethylainine (O.98m1) and N,N-dimethylaminopyridine 132g). The mixture was cooled to 0 0 C then treated with a solution of di-ter-t-butyl dicarbonate (1.4 1ig) in acetonitrile (6m1).

After stirring for I hour at ambient temperature the reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The pH was adj- usted to 2 and the organic layer was dried over magnesium sulfate and then evaporated. The residual orange oil was subjected to flash column chromatography on silica cluting with a mixture of ethyl acetate and pctrol v/v) to yield 3iodo-5-niethoxy-indazole-l1-carboxylic acid tert-hutyl ester 72g) as a yellow solid.

LC-MS (METHOD B3): RT =3.45 minutes 3 75 4-Fluoro-3-iodo-indazole-t-carboxylic acid tert-butyl ester F

I

X/

0 OC(CH 3 3 By proceeding in a manner sim-ilar to Reference Example 22(a) above but using 4-fluoro-3-iodo- IHindazole [Reference Example 23(b)] there was prepared 4-fluoro-3-iodo-indazole- I-carboxylic acid tert-butyl ester as a light brown solid. LC-MS (METH-OD RT 3.48 minutes; 363 4-Chloro-3-iodo-indazole-1 -carboxyl ic acid tert-butyl ester C1

/N

N

0 "OC(CH 3 3 WO 03/035065 PCT/GB02/04763 -494- By proceeding in a manner similar to Reference Example 22(a) above but using 4-chloro-3-iodo-lHindazole [Reference Example 23(c)] there was prepared 4-chloro-3-iodo-indazole-1-carboxvlic acid te-rt-butyl ester as a brown solid. LC-MS (METHOD RT= 3.39 minutes; 381 (M+H) 5-Ethoxy-3-iodo-indazole-l-carboxylic acid tert-butyl ester EtO

N

O OC(CH 3 By proceeding in a manner similar to Reference Example 22(a) above but using 5-ethoxy-3-iodo- Hindazole [Reference Example 23(d)] there was prepared 5-ethoxv-3-iodo-indazole- I-carboxylic acid tert-butyl ester as an off-white solid. LC-MS (METHOD RT 3.49 minutes; 389 (M+H) REFERENCE EXAMPLE 23 3-Iodo-5-methoxy- H-indazole

I

CHO

N

H

A solution of 5-methoxy-1H-indazole [0.815g, Reference Example 24(a)] in dimethyl formamide (8ml) was treated with iodine (2.80g) and potassium hydroxide (1.16g). The mixture was stirred at ambient temperature for I hour then poured into 10% aqueous sodium bisulfite solution (200ml) and then extracted three times with ethyl acetate. The combined organic extracts were washed with water, then with brine, then dried over magnesium sulfate and then evaporated to yield indazole (1.48g) as a yellow solid. LC-MS (METHOD RT 2.96 minutes; 275 (M+H) 4-Fluoro-3-iodo-1H-indazole

F

N

H

By proceeding in a manner similar to Reference Example 23(a) above but using 4-fluoro-IH-indazole [Reference Example 24(b)] there was prepared 4-fluoro-3-iodo-lH-indazole as a red solid.

WO 03/035065 PCT/GB02/04763 -495- LC-MS (METHOD RT 3.06 minutes; 281 4-Chloro-3-iodo-1H-indazole Cl

I

N

H

By proceeding in a manner similar to Reference Example 23(a) above but using 4-chloro-lH-indazole [Reference Example 24(c)] there was prepared 4-chloro-3-iodo-lH-indazole as a light brown solid.

LC-MS (METHOD RT= 2.97 minutes; 263 (M+H) 5-Ethoxy-3-iodo-1H-indazole EtO

N

H

By proceeding in a manner similar to Reference Example 23(a) above but using [Reference Example 37] there was prepared 5-ethoxy-3-iodo-lH-indazole as a light brown solid.

LC-MS (METHOD RT= 2.97 minutes; 263 (M+H) REFERENCE EXAMPLE 24 5-Methoxy- H-i ndazole

CH

3

O

N

H

A solution of4-methoxy-2-methylaniline (2ml) in dichloromethane (10ml) was treated with triethylamine (3.27ml). The mixture was cooled to 0°C then treated with acetic anhydride (2.38ml), then stirred at ambient temperature for Ihour, then cooled to 0 C when a pink solid precipitated. This solid was filtered, then washed with cold dichloromethane and then dissolved in acetic acid (55ml) and concentrated hydrochloric acid (20ml). This solution was cooled to then treated with a solution of sodium nitrite (2.68g) in water (20ml), then stirred at that temperature for 1 hour and then treated with water (100ml). This mixture was stirred vigorously at 0°C for 10 minutes after which a yellow solid precipitated. This solid was filtered, then washed with water and then dissolved in toluene (13ml). This solution was heated to 80 0 C for 1.5 hours, then cooled and then washed with aqueous 1N WO 03/035065 PCT/GB02/04763 -496sodium carbonate solution. The organic phase was extracted three times with aqueous 2N hydrochloric acid and the acid extracts chilled and then made alkaline by addition of aqueous 5N sodium hydroxide solution. The aqueous layers were extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate and then evaporated to yield 5-methoxy- H-indazole (0.410g) as a yellow solid. LC-MS (METHOD R T 1.32 minutes; 149 4-Fluoro-I H-indazole

F

N

H

To tetrafluoroboric acid (8.2ml, 48 wt in water) was added 3-fluoro-2-methylaniline (2.27ml). The mixture was cooled to 0°C when a precipitate formed which was redissolved by the addition of water (8ml). A solution of sodium nitrite (1.38g) in water (2.7ml) was then added dropwise and the mixture was then allowed to warm to ambient temperature and then stirred for a further 1 hour. The precipitated solid was filtered, then washed with diethyl ether, and then dried under suction for minutes. The resulting tetrafluoroborate salt was added to a suspension of potassium acetate 3 92 g) and 18-crown-6 (0.264g) in chloroform (45ml). After stirring for 3 hours at ambient temperature the bright orange mixture was filtered and the insoluble material was washed with dichloromethane, then subjected to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate (3:1 v/v) to give 4-fluoro-1H-indazole (0.675g) as an off-white solid. LC-MS (METHOD B): RT= 2.70 minutes; 137 4-Chloro- -H-indazole Cl f N

H

By proceeding to a manner similar to Reference Example 24(a) above but using 3-chloro-2methylaniline, there was prepared 4-chloro-lH-indazole as a red solid (0.807g) which was used without further purification. LC-MS (METHOD RT= 2.90 minutes; 155 (M+H) REFERENCE EXAMPLE (5-fluoro- IH-indazol-3-vl-methanol WO 03/035065 PCT/GB02/04763 -497-

CH

2

OH

F

N

H

A solution of 5-fluoro-H-indazole-3-carboxylic acid [0.680g, Reference Example 26(a)] in anhydrous tetrahydrofuran (15ml), at 0°C, was treated portionwise with lithium aluminium hydride (0.716g), then stirred for 2 hours at ambient temperature and then treated with saturated aqueous sodium sulfate. The reaction mixture was acidified by addition of hydrochloric acid (IN) and then extracted three times with ethyl acetate (30ml). The combined organic extracts were dried over magnesium sulfate and then evaporated. The residual dark brown oil was subjected to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate (1:1 to 1:3 v/v) to yield (5-fluoro-lH-indazol-3yl)-methanol (0.1 4 4 g) as a brown solid. LC-MS (METHOD R T 2.40 minutes; 167 (M+H) (6-Fluoro- IH-indazol-3-yl)-methanol f N F H By proceeding in a manner similar to Reference Example 25(a) above but using 6-fluoro-1H-indazole- 3-carboxylic acid [Reference Example 26(b)] there was prepared (6-fluoro-lH-indazol-3-yl)-methanol (0.265g) as a dark grey solid. LC-MS (METHOD RT 2.40 minutes, 165 (5-Methyl-I H-indazol-3-yl)-methanol

CH

2 0H

CHCH

N

H

By proceeding in a manner similar to Reference Example 25(a) above but using 3-carboxylic acid [Reference Example 26(c)] there was prepared (5-methyl-lH-indazol-3-yl)-methanol 11g) as a brown oil. LC-MS (METHOD RT= 2.45 minutes; 163 (M+H) (5-Chloro-lH-indazol-3-vl)-methanol WO 031035065 PCT/GB02/04763 -498-

CH

2

O

Cl

N~

H

By proceeding in a manner similar to Reference Example 25(a) above but using 3-carboxylic acid [Reference Example 26(d)] there was prepared (5-chioro- 1I-indazol-3 -yl )-methanol as a dark brown oil which solidified on standing. LC-MS (METHOD RT 2.5 1 minutes; 185 (6-Methoxy- IH-inidazol-3 -yi)-methanoI

CH

2

O

N

CH 3

H

By proceeding in a manner similar to Reference Example 25(a) above but using 6-methoxy-1indazole-3-carboxyl ic acid [Reference Example 26(e)] there was prepared (6-methoxy- I H-indazol-3yl)-methanol (0.265g) as a brown solid. LC-MS (METHOD RT 2.37 minutes; 179 (4-Phenyl-IH-pyrazol-3-yll-methanioI

HOCH

HN\

N

By proceeding in a manner similar to Reference Example 25(a) above but using 4-phenyl-tH-pyrazole- 3-carboxylic acid [Reference Example 47] and subjecting the reaction product to flash column chromatography on silica eluting with a mixture of dichloromethane and methanol 1, v/v) there was prepared (4-phenyl-IH-pyrazol-3-yl)-methanol. LC-MS (METHOD RT= 2.51 minutes; 175 (11--indazol-3-yI)-methanol WO 03/035065 PCT/GB02/04763 -499- By proceeding in a manner similar to Reference Example 25(a) above but using indazole-3-carboxylic acid and subjecting the reaction product to column chromatography on silica eluting with a mixture of a mixture of n-hexane and ethyl acetate to ethyl acetate there was prepared (1H-indazol-3-yl)methanol as a pale yellow solid. LC-MS (METHOD RT 3.17 minutes; 149.2 REFERENCE EXAMPLE 26 5-Fluoro-1H-indazole-3-carboxylic acid

CO,H

N

N

H

A solution of 5-fluoroisatin 2 g) and sodium hydroxide (0.509g) in water (20ml) was heated to 50 0

C

for 30 minutes, then cooled and then treated with sodium nitrite (0.836g). This mixture was added over 10 minutes to a solution of concentrated sulfuric acid (2.26g) in water (200ml), at 0°C, whilst maintaining the temperature below 5 0 C. After a further 15 minutes a solution of tin (11) chloride (5.51g) in concentrated hydrochloric acid (10.5ml) was added and the resulting mixture maintained at 0 C for a further 30 minutes. The mixture was then stirred for a further 1 hour whilst warming to ambient temperature then filtered. The light brown paste was dissolved in ethyl acetate and the solution was dried over magnesium sulfate and then evaporated to yield 5-fluoro-1H-indazole-3carboxylic acid (0.863g) as a light brown solid which was used without further purification.

LC-MS (METHOD RT= 2.51 minutes; 181 (M+H) 6-Fluoro-lH-indazole-3-carboxvlic acid CO2H

N

F H By proceeding in a manner similar to Reference Example 26(a) above but using 6-fluoro-1H-indole- 2,3-dione [Reference Example 27(a)] there was prepared 6-fluoro-lH-indazole-3-carboxylic acid (1.962g) as a light brown solid. LC-MS (METHOD RT= 2.50 minutes; 181 (M+H) 5-Methvl-1H-indazole-3-carboxvlic acid WO 03/035065 PCT/GB02/04763 -500- C O,H By proceeding in a manner similar to Reference Example 26(a) above but using 5-methyl isatin there was prepared 5-methyl-H-indazole-3-carboxvlic acid as a light brown solid. LC-MS (METHOD B): RT 2.53 minutes; 177 5-Chloro-1H-indazole-3-carboxylic acid C By proceeding in a manner similar to Reference Example 26(a) above but using 5-chloro isatin there was prepared 5-chloro-1H-indazole-3-carboxylic acid as a light brown solid. LC-MS (METHOD B): RT= 2.58 minutes; 171 6-Methnxv-1 H-i nda7ole-3-carhoxvl ic acid By proceeding in a manner similar to Reference Example 26(a) above but using 6-methoxy-IH-indole- 2,3-dione [2.50g, Reference Example 27(b)] there was prepared 6-methoxy-IH-indazole-3-carboxylic acid as a light brown solid. LC-MS (METHOD RT 2.45 minutes; 193 REFERENCE EXAMPLE 27 6-Fluoro-1H-indole-2,3-dione To vigorously stirring polyphosphoric acid (100g) at 75C was added N-(3-fluoro-phenyl)-2hydroxyimino-acetamide [10.304g, Reference Example 28(a)] portionwise over 30 minutes. The resulting mixture was stirred at 80'C for 15 minutes, then poured into ice, then left to stand for 16 WO 03/035065 PCT/GB02/04763 -501hours and then filtered to give a brown paste. The filtrate was extracted four times with ethyl acetate.

The combined organic fractions were dried over magnesium sulfate and then evaporated. The residue and the brown paste from the filtration above were combined and treated with aqueous sodium hydroxide The mixture was filtered and the filtrate was acidified by addition of aqueous hydrochloric acid The resulting brown solid was filtered and then treated with aqueous sodium hydroxide This mixture was filtered and the filtrate was acidified by addition of aqueous hydrochloric acid (2N) and then filtered. The combined acidic aqueous filtrates were extracted four times with ethyl acetate, then dried over magnesium sulfate, and then evaporated to give 6-fluoro-IHindole-2,3-dione (1.861g) as a pale orange solid. LC-MS (METHOD RT= 2.49 minutes; 166

(M+H)

6-Methoxy-1H-indole-2,3-dione

O

c-H N O"

N

CH3O H By proceeding in a manner similar to Reference Example 27(a) above but using 2-hydroxyimino-N-(3methoxy-phenyl)-acetamide [7.20g, Reference Example 28(b)] there was prepared 6-methoxy-lHindole-2,3-dione as a brown solid. LC-MS (METHOD R T 2.49 minutes; 178 (M+H) REFERENCE EXAMPLE 28 N-(3-Fluoro-phenyl)-2-hydroxvimino-acetamide

N

F

A mixture of chloral hydrate (0.819g) in water (25ml) was treated with sodium sulfate (5.10g), 3-fluoroaniline (0.43ml), concentrated hydrochloric acid (0.3ml), and hydroxylamine hydrochloride (0.938g). The mixture was warmed to 80 0 C for 2 hours then allowed to cool and then filtered. The solid was washed with water and then dried in air for 16 hours to afford N-(3-fluoro-phenvl)-2hydroxyimino-acetamide (0.756g) as a buff solid. LC-MS (METHOD RT= 2 .51 minutes; 181

(M+H)

2-Hvdroxyimino-N-(3-methoxy-phenvl)-acetamide WO 03/035065 WO 03135065PCTGB02O4 763 CH 3 N OH

N

By proceeding in a manner similar to Reference Example 28(a) above but using m-anisidine there was prepared 2-hydroxyimino-N-(3-methoxy-phenyl)-acetamide as a brown solid. LC-MS (METHOD RT 2.44 minutes; 195 REFERENCE EXAMPLE 29 4-Ethyl-phenylene diamine

C

3

CH-

2

NH,

NH 2 A stirred solution of 5-ethyl-2-nitro-aniline [200 mg, Reference Example 30(a)] and tin chloride (2.75 g) in ethanol (5 ml) was heated in a Smith Creator microwave at 140'C for 10 minutes. The reaction mixture was basified to pH 8 by addition of saturated sodium hydrogen carbonate solution and then extractedI with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to give 4-ethyl-p2henytene diamine (140 mg) as a pale orange solid, which was used without future purification. MS: 137.2 1-PLC (METHOD RT 2.91 minutes.

4-Methoxy-5-methyl-benzene- 1 .2-diamine CH 0O NH, CH 3

NH)

By proceedingc in a manner similar to Reference Example 29(a) above but using 4-methoxy-5-methyl-2nitro-phonylamine [582mg, Reference Example 3 there was prepared benzene- 1,2-diamine (454mg) as a light brown solid. LC-MS (Method RT 2.39 minutes, 153.20 4-(2-Moruholin-4-yl-ethoxy)-benzenie- 1,2-diamiine 0 j -NH2 By proceeding in a manner similar to Reference Example 29(a) above but using 4-[2-(3,4-dinitrophenoxy)-ethyl]-morpholine [Reference Example 67] there was prepared 4-(2-mornholin-4-yI-ethoxy)- WO 03/035065 PCT/GB02/04763 03benzene- 12-diamnine (170mg) as a pale brown oil. LC-MS (METHIOD RT 2.2 minutes, 238.21 REFERENCE EXAMPLE 4-Ethyl-5-imethlyl-phenvyleie diarnine CH 3 CH 2 NH 2 CH 3

:N

A stirred solution of 4-ethyl-5-methyl-2-nitro-anil ine [484 mg, Reference Example 31 (b)1 in methanol ml) was treated with tin chloride (5.09 then heated at refhix for 16 hours and then cooled to ambient temperature. The pH of the reaction mixture was adjusted to pH 8 by addition of aqueous sodium bicarbonate and then this mixture was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to give 4-ethyl-5-methyl-phenylene diamine (374 mg) as an off-white solid. LC-MS (METHOD RT 1.80 minutes; 151.25 4-lsopropyl-5-iethyl-phien yle fe diamine (CH 3 2 CH,

NIHI

2 CH 3

NH,

By proceeding in a manner similar to Reference Example 30(a) above but using 2-nitro-anilinc [Reference Example 3 1 there was prepared 4-isopropyl-5-methvl-phenylene diamine as a I ght brown solid. LC-MS (Method RT 3.30 minutes; 165.16 4-Bromo-5-i-ethyl-phenylere diamine Br

NH-

2 CH 3 N By proceeding in a manner similar to Reference Example 30(a) above but using 4-bromo-5-methyl-2nitro-aniline [Reference Example 31(d)] there was prepared 4-brormo-5-methyl-phenvlene diamine as an off-white solid. LC-MS (METHOD RT 2.63 minutes; 203.22 4-n-propyl-phenylene diamine WO 03/035065 PCT/GB02/04763 -504-

CHI

3 CH 2 2II NF12 By proceeding in a manner similar to Reference Example 30(a) above but using 4-n-propyl-2-nitroaniline [Reference Example 3 1 there was prepared 4-n-propyl-phenylene diamine as an off-white solid. LC-MS (METHOD RT 2.07 minutes, 151.30 4--Bronio-phenvle ti diamine Br NH2 By proceeding in a manner similar to Reference Example 30(a) above but using 4-bromlo-2-nitroaniline there was prepared 4-bromo-p2henylene diamine as a yellow solid. LC-MS (METHOD RT 1.77 minutes; 187.22 3',4'-diaminobophenyl-3-carbonitrile

CN

NH 2 By proceeding in a manner similar to Reference Example 30(a) above but using 4'-amino-3'-nitrobiphenyl-3-carbonitrile [Reference Example 34(a)] there was prepared 3',4'-diaminobophenyl-3carbonitrile as an off-white solid. LC-MS (METHOD )RT 2.72 minutes; 210.3 44pVyridine-3-yl)benzene-1,2-diamine

N

NH2 By proceeding in a manner similar to Reference Example 30(a) above but using 2-nitro-4-pyridine-3yl-phenylamine [Reference Example 34(b)] there was prepared 4-(pyridine-3-yl)benzene- I .2-diamine as an off-white solid. LC-MS (METHOD RT 0.37 minutes; 186.3 WO 031035065 WO 03/35065PCT/GB02/04763 6-methvlhinhenvI-1-4-diamine By proceeding in a manner similar to Reference Examnple 30(a) above but using 2-methyl-5 -nitrobiphenyl-4-ylamine [Reference Example 34(c)] there was prepared 6-methylbiphenyl-3,4-diamine as an off-white solid. LC-MS (METHOD RT 2.36 minutes; 199.25 0i) bi phenyl-3,4-di aminte By proceeding in a manner similar to Reference Example 30(a) above but using 3-nitrobiphenyl-4ylamine [Reference Example 34(d)] there was prepared biphenyl-3,4-diamine as a yellow solid.

LC-MS (METHOD RT 2.25 m111ites; 185.3 2'-fluorobiphenyl-3,4-diamine By proceeding in a manner similar to Reference Example 30(a) above but using 2'-fluoro-3-nitrobiphenyl-4-ylamine [Reference Example 34(e)] there was prepared 2'-fluorobiphenyl-3,4-diamine as a white solid. LC-MS (METHOD RT =2.73 minutes; 203.3] (kc) 4-benzoF 1 ,3]dioxol-5-ylbenzene- 1,2-diamine WO 031035065 WO 03/35065PCT/GB02/04763 06- By proceeding in a manner similar to Reference Example 30(a) above but using 4-benzo[1,3]dioxo-5yl-2-nitrophenylamine [Reference Example 34(D] there was prepared 4-benzo[ 1 ,3 1dioxol-5 -yl benzene- 1.2-diamine as a white solid. LC-MS (METHOD RT =2.66 minutes; 229.3 2'-methoxybiphenyl-3 4-diamine ,OCH 3 'NH 2 By proceeding in a manner similar to Reference Example 30(a) above but using 2'-mnethoxy-3-nitrob iphenyl-4-yla mine [Reference Example 34(g)] there was prepared 2'-methoxybiphenx'I-3,4-diamine as a white solid. LC-MS (METHOD RT =2.74 minutes.; 215.33 4'-chlorob iphenyl-3,4-diamine By proceeding in a manner similar to Reference Example 30(a) above but using 4'-chloro-3-nitrobiphenyl-4-yl-amine [Reference Example 34(h)] there was prepared 4'-chlorobiphenyt-3,4-diamine diamine as a white solid. LC-MS (METHOD RT 2.85 minutes; 219.3 (M+H)7 4'-mcthylbiphcnyl-3,4-diaminc WO 031035065 PCT/GB02/04763 07- By proceeding in a manner similar to Reference Example 30(a) above but using 4'-methyl-3-nitrobiphenyl-4-yl-amine [Reference Example 34(i)] there was prepared 4'-methylbiphenyl-3,4-diamine as a white solid, LC-MS (METHOD R- 1 2.39 minutes, 199.25 (o) 4-beiizyloxybenzene- 1,2-diamine By proceeding in a manner similar to Reference Example 30(a) above but using 4-benzyloxy- 1,2dinitrobenzene [Reference Example 35(a)] there was prepared 4-benzyloxybenzene-1.2-diamine as a white solid. LC-MS (METHOD RT 2.34 minutes, 215.33 benzor 1, Yl dioxo le-5,6-di amine 0

NH

2 By proceeding in a manner similar to Reference Example 30(a) above but using 5,6-dinitrobenzo[ 1,3]dioxole rReference Example 56(b)] there was prepared benzo[l.,3]dioxole-56-diamne as an oily solid. LC-MS (METHOD RT 0.43 minutes, 153. 18 4.5-dimethoxvbenzene-1I.2-diamine By proceeding in a manner similar to Reference Example 30(a) above but using 4,5-dimnethoxy-2nitroaniline there was prepared 4,5-dimethoxybenzene- 1,2-diamine as an oily solid. LC-MS (METHOD RT 0.43 minutes, 169.24 4,5-diethylbenzetie-1 .2-diamine WO 03/035065 PCT/GB02/04763 -508-

CH

3

CH

2 NH 2

CH

3

CH

Ni- 2 By proceeding in a manner similar to Reference Example 30(a) above but using 4,5-diethyl-2nitroaniline [Reference Example 31I(f)] there was prepared 4,5-diethylbenzene-1,2-diamine which was used without future purification. LC-MS (METHOD RT 2.21 minutes, 165.24 4-ethoxy-5 -ethvl-benzene- 1,2-diamine CH 3

CH

2 O a NH 2

CH

3 CH 2

NI-,

By proceeding in a manner similar to Reference Example 30(a) above but using 4-ethoxy-5-ethyl-2nitrophenyla-ilne [Reference Example 3 1l(g)] there was prepared 4-ethoxy-5-cthyl-benzene-l1 2diami ne.

Wt 4-Ethoxy-3 -ethyl -p henyl lam ine

CH

3 CH2 CH3CH 2a

H

By proceeding in a manner similar to Reference Example 30(a) above but using I1-ethoxy-2-ethyl-4nitrobenzene [Reference Example 32(h)] and subjecting the reaction product to chromatography on silica gel (heptane, ethyl acetate gradient 25-35%) there was prepared 4-ethoxy-3-ethyl-phenylamine (0.6 g) as an oil. GS-MS one peak, RT 7.17 minutes. MS 165 4-Methoxy-3-methvl-phonylamine CH 3 0 CH 3 NI-1 2 By proceeding in a manner similar to Reference Example 30(a) above but using I-methoxy-2-methyl-4nitrobenzene 7 g, Reference Example 56(a)] there was prepared 4-rnethoxy-3 -methyl-phenylamine (2.07g). RF 0. 5 [ethyl acetate/n-pentane, 1: 1, v/Y].

4-Ethoxv-benzene-1 .2-diamine WO 03/035065 PCT/GB02/04763 -509- CH 3 CH 2 0,a H NH 2 By proceeding in a manner similar to Refecrence Example 30(a) above but using 4-ethoxy-2-nitroani line 4-ethoxy-benzene-1,2-diamnine (1.02g) as a brown oil. LC-MS (Method RT= 0.50 and 3.88 minutes, 153.30 4-Fluoro-5-methyl-benizene-1,2-diamine F a 2H CH 3 NH 2 By proceeding in a manner similar to Reference Example 30(a) above but using 4-fluoro-5-methyl-2nitro-phenylamnine [Reference Example 3 10)] there was prepared 4 -11uoro-5 -methyl -benzene- 1,2diamine (1.27g) as a yellow solid. LC-MS (METHOD RT 1.93 minutes, 141.25 (x 3,4-Diamino-N-benzyl -henzeniesul foniaide 0 0 S NH2 N 2 By proceeding in a manner similar to Reference Example 30(a) above but using 4-amino-N-benzyl-3nitro-benzenesulfonamide [Reference Example 61] there was prepared 3,4-diamino-N-benzylbenzenesulfonamide (0.

3 50g) as a yellow film. LC-MS (METHOD RT 2.87 minutes, 278.28 4-Difluoromethoxy-benzene-1, 2-dliamine FyF NH 2 By proceeding in a manner similar to Reference Example 30(a) above but using 4-difluoroi-ethoxy-2nitro-phenylamine [Reference Example 31I(k)] there was prepared 4-difluoromethoxy-benzene-1,2diamine (2.70g) as a pale brown solid LC-MS (METHOD RT 2.45 minutes, 175 WO 03/035065 PCT/GB02/04763 Wz 4-Ethvl-5-methoxy-benzene-1I 2-d jamine 1200 mg, Reference Example CH 3 CH 2 NH 2 By proceeding in a manner similar to Reference Example 30(a) but using 5 -ethyl -4-methoxy-2-nitrophenylamine [2A4 g, Reference Example 3 there was prepared 4-ethyl-5-methoxy-benzene-1,2- ,diamine (1.6 g) as a black solid. LC-MS (METHOD 1, AMMONIUM ACETATE, 5m-ni): RT 3.50 minutes, 167.17 (aa) 3 -Ethyl-4-rnethoxy-p he nyla mine

CH

3 0

CH

3

CH

2 NH 2 By proceeding in a manner similar to Reference Example 30(a) but using 5-ethyl-4-methoxy-2-nitrophenylamine [3.6g, Reference Example 31l(1)] and carrying out the reaction for 24 hours, there was prepared 3-ethyl-4-methoxy-phenylamine (2.5c, as a brown oil. LC-MS (METHOD RT 2.04 minutes, 1 52.2 REFERENCE EXAMPLE 31 5-Ethyl-2-nitro-ani line

CH

3

CH

2 a NO 2 A stirred solution of sodium methoxide (0.35 g) in methanol (15 ml) was treated with a solution of 4-ethyl-2-nitro-N-acetyl-aniline [1g, Reference Example 32(a)] in methanol (15 ml). The reaction mixture was stirred at room temperature for 24 hours and then poured onto ice-water. The resulting precipitate was filtered and then dricd to give 5-ethyl-2-nitro-aniline (650 mg). LC-MS (METHOD 1B): RT =3.11 minutes; 167.2 4-Ethyl-5-methyl-2-nitro-aniline WO 03/035065 PCT/GB02/04763 -511- CH 3 N2 By proceeding in a manner similar to Reference Example 3 1 above but using 4 -ethyl -5 -methyl-2nitro-N-aceryl-ani line [I g, Reference Example 32(b)] there was prepared 4-ethyl-5-methyl-2-nitroaniline as a orange solid. LC-MS (METHOD RT 3.16 minutcs.- 181.14 4-isopropyl-5-methyl-2-nitro-aniline 2 CH NO 2 CH3 NH2 By proceeding in a manner similar to Reference Example 3 1(a) above but using 2-nitro-N-acetyl-anilinc [Ig, Reference Example 32(c)] there was prepared 4-isopropyl-5-methyl-2nitro-aniline as an orange solid. LC-MS (METHOD RT 3.26 minutes;, 195.3 4-bromno-5-methyl-2-nitro-aniline Bra NO 2 CH3 NH2 By proceeding in a manner similar to Reference Example 31(a) above but using 4-bromo-5-inethyl-2nitro-N-acetyl-aniline [1g, Reference Example 32(d)] there was prepared 4-bromo-5 -methyl-2 -nitroaniline as a brown solid. LC-MS (METHOD RT 3.24 minutes; 231-2 (M+H) m 4-n-Propyl-2-nitro-aniline CH 3 CH 2 CH 2

-,NO

2

NH-I

2 By proceeding in a manner similar to Reference Example 3 1(a) above but using 2-nitro-4-propyl-Nacetyl-aniline there was prepared 4-n-propyl-2 -nitro-ani line as an orange solid.

LC-MS (Method RT =3.46 minutes; 18 1.2 4,5 -diethyl-2-n itro-ani line WO 031035065 PCT/GB02/04763 -512-

CH

3

CH

2 NO, CH 3 CH, NH 2 By proceeding in a manner similar to Reference Example 3 1(a) above but using 4,5-diethyl-2-nitro-Nacetyl-aniline [Reference Example 32(f)] there was prepared 4.5-diethyl -2-nitro-aniline.

LC-MS (METHOD RT 3.27 minutes; 195.22 (g 4-Ethoxy-5 -eth 1-2 -nitro phenylamine C113 CH2 0NO,

CH

3

CH-

2 a NH 2 N-(4-Ethoxy-5-ethyl-2-nitrophenyl)acetamide [0.2g, Reference Example 32(g)] was dissolved in ethanol (25 mE) and sodium hydride (100 mg, 50% dispersion in mineral oil, 2 rnmol) was added.

Mixture was stirred overnight at ambient temperature, aq ammonium chloride (3mL) was added and the mixture was evaporated. The residue was chromatographed on silica gel (heptane with gradient of 25-50% ethyl acetate) to give 4-ethoxy-5-ethyl-2-nitrophenylamine (0.1g) as a red solid. LC-MS (Method RT 3.4 minutes, 2 1 (11) 5-Cliloi-o-4-mietlhoxy-2-initropheinylarinie

CH

3 0

NO

2 ClNH 2 N-(5-Chloro-4-mnethioxy-2-nitrophenyl)acetarnide (8.0g, Reference Example 32(i) was added to a solution of sodium methoxide 0.037 mole) in methanol (150 mL) and the mixture was stirred at ambient temperature for 4 hours, The reaction mixture was added to ice water (750 mL), stirred for minutes and the aqueous mixture was filtered. The precipitate was washed with water and dried at under vacuum to give 5-chloro-4-miethoxy-2-nitrophenylamine (6.52 g) as an orange solid, mp 128-129" C.

4-Methoxy-5-methy 1-2-nitro-phenylamine

CH

3 O a NO 2 CH 3 +2 By proceeding in a manner similar to Reference Example 3 1(a) above but using WO 031035065 PCT/GB02/04763 methyl-2-nitro-phenyi)-acetamide [2.53g, Reference Example 320j)] there was prepared methyl-2-nitro-phenylamine 2 .05g) as a bright orange solid. LC-MNS (Method RT =3.46 minutes, 183.29 S 4-Fluoro-5-methiyl-2-nitro-plienylamine F N O 2 CH 3 NH 2 By proceeding in a manner similar to Reference Example 3 1 above but using 2-nitro-phenyl)-acetamide 2 5 3 Reference Example 32(k)] there was prepared 4-fluoro-5-methyl-2nitro-p2henylainine (2.25g) as an orange solid. LC-MS (METHOD RT 3.53 minutes, 171.28 4-difluoromethoxy-2-nitro-phenylamine

F

0- a NO, By p roce eding in a manine r s imi lar to Refere nce E xamp le 3 1(a) above bu t u s ing N-(4-di fl uoromethoxy- 2-nitro-phenyl)-acetamide [Reference Example 32(1)] there was prepared 4-difluoromethoxy-2-nitrophenylamine (l0g) as an orange solid. LC-MS (METHOD RT 3.86 minutes, 205 5-Fthyl-4-methoxy-2-n itro-phenylami ne

CH

3 O0 NO, CH 3 CH 2 NH 2 By proceeding in a manner similar to Reference Example 31I(a) but using N-(5-ethyl-4-methoxy-2nitro-phenyl)-acetamide [2.4 g, Reference Example 32(m)] there was prepared 5-ethyl-4-methoxv. -2nitro-phenylamine (1.9 g) as a brown solid. LC-MS (METHOD RT 4.14 minuites, 197.09 REFERENCE EXAMPLE 32 4-Ethyl-2-nitro-N-acetyl-aniline WO 031035065 PCT/GB02/04763 14-

CH

3 CH 2

,NO

NH-C(=0)CH 3 A stirred solution of 4-ethyl-N-acetyl-ani line [3g, Reference Example 33(a)] in acetic anhydride (8mL) and acetic acid at wvas treated dropwise with a mixture of acetic acid (I.7SmL) and concentrated nitric acid (1.22mL). The mixture was warmed to 0 0 C, then stirred at 0 0 C for 2 hours and then poured onto water. This mixture was evaporated and the resulting oil was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated.

The residual oil was subjected to flash colun chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether to give 4-ethyl-2-nitro-N-acetyl-aniline (1 .4g) as an orange solid.

LC-MS (METHOD RT 2.95 minutes; 209.2 4-Ethyl-5-m-ethyl-2-nitro-NV-acetyl-aniline CH 3 C1-1 2

NO,

CH 3 NH-C(=O)CH 3 By proceeding in a manner similar to Reference Example 32(a) above but using 3-methyl-4-ethyl-Nacetyl aniline there was prepared 4-ethyl-5-m-ethyl-2-nitro-AI-acetyl-aniline as a orange solid.

LC-MS (METHOD B3): RT 3.03 minutes; 223.25 4-isopropyl-5-miethvl-2-nitro-N-acetvl-aniline (CH 3 2 CH NO 2 CH 3 N~HC(=O)-CH 3 By proceeding in a manner similar to Reference Example 32(a) above but using 3-methyl-4-isepropyl- N-acetyl aniline [Reference Example 33(b) there was prepared 4-isopropyl-5-methyl-2-nitro-NacetyI-aniline as an orange solid. LC-MS (METHOD RT 3.15 minutes; 231.36 4-Bromo-5-methyl-2-nitro-N-acetyl-aniline Br, NO WO 03/035065 PCT/GB02/04763 -515- By proceeding in a manner similar to Reference Example 32(a) above but using 3-methyl-4-bromo-Nacetyl aniline [Reference Example 33(c)] there was prepared 4-bromo-5-methvl-2-nitro-N-acetylaniline as an orange solid. LC-MS (METHOD R T 3.06 minutes; 274.2 (M+H) 4.5-Diethvl-2-nitro-N-acetyl-aniline CHCH 2

NO

CFI

3 CH 2

NH-C(=O)CH

3 By proceeding in a manner similar to Reference Example 32(a) above but using 3,4-diethyl-N-acetyl aniline [Reference Example 33(d)] there was prepared 4,5-diethyl-2-nitro-N-acetyl-aniline as an orange solid. LC-MS (METHOD RT 3.18 minutes; 237.4 (M+H) N-(4-Ethoxy-5-ethyl-2-nitrophenyl)acetamide

CH-

3 CHO

NO

2

CH

3 CH 2 NH-C(=O)CH N- (4-Ethoxy-3-ethyl-phenyl) acetamide Ig, Reference Example 33(e)] was dissolved in acetic anhydride (5 mL), a solution of nitric acid in acetic acid (0.5mL of 95% nitric acid, in 4mL) was added and the mixture was stirred overnight at ambient temperature. The mixture was diluted with water (100mL) and the aqueous mixture was extracted twice with ethyl acetate (IOOmL). The combined extracts were evaporated and the residue was chromatographed on silica gel (heptane/ethyl acetate 9/1) to give N-(4-ethoxv-5-ethyl-2-nitrophenvl)acetamide (3.0 g) as a bright yellow solid. LC- MS (Method RT 3.27 minutes, 253 (M+H) 1 -Ethoxy-2-ethyl-4-nitrobenzene

CHCH

2 0

CH

3

CH

2

NO

2 A solution of 1-ethoxy-2-ethyl benzene (3.5g, Reference Example 51) in acetic anhydride (30 mL) was chilled in an ice-water bath. A solution of nitric acid (1.4 mL of 90% 30% excess) in acetic acid mL) was added dropwise and the mixture was stirred overnight at ambient temperature. The reaction mixture was poured into ice water (300 mL) and the aqueous mixture was extracted with ethyl acetate (2 X 200 mL). The combined extracts were evaporated and the residue was chromatographed on silica WO 031035065 PCT/GB02/04763 16gel (heptane with gradient of 5 to 10%'Y ethyl acetate) to give I -ethoxy-2-ethyl-4-nitrobenzene (1.4 g) as a clear liquid. LC-MS (Method E) RT -3.75 minutes, 196 N-(5-Chloro-4-methoxy-2-nitrophenvl)acetamide

CH

3 0 NO 2

NH-C(-O)CH-

3 A solution of N-(3-chloro-4-methoxyphenyl)acetamide (6.85g, Reference Example in a mixture of acetic acid (20 mL) and acetic anhydride (35 m-L) was cooled to 5 C and a solution of fumning nitric acid (3 mL) in acetic acid (4 niL) was added dropwise keeping the reaction temperature below 0 0

C.

The mixture was stirred at 0 0 C for 30 minutes at which point a yellow precipitate developed. After another 1.5 h at 0 0 C, the mixture Was pouired into water (100 m-L) and the aqueous mixture was vigorously stirred for 15 minutes and filtered. The yellow precipitate was washed with water and dried under vacuumn at 60'C to give the product (8.0g) as a yellow solid, mp 152-1530 C. MIS 245 C) N-(4-Methoxy-5-methyl-2-nitro-pheny'l)-acetamide

CH

3 0:a NO 2

CH

2 I NH-C(=O)CH 3 By proceeding in a manner similar to Reference Example 32(a) but using N-(4-methioxy-3-methylphenvl)-acetamide [2 .65g, Reference Example 33(f)] there was prepared N-(4-methoxy-5-methyl-2nitro-phenyl)-acetamide (2.53g) as a orange solid. LC-MS (Method RT =3.30 minutes, 225.29 223.29 N-(4-Fluoro-5-methvl-2-nitro-phenyl)-acetamide F aNO 2 Cl-I 3 NH--C(=O)C-1 3 By proceeding in a manner similar to Reference Example 32(a) above but using N-(4-fluoro-3-methylphenyl)-acetamide [2 .65g, Reference Example 33(g)] there was prepared N-(4-fluoro-5-methyl-2-nitrophen-yl)-acetamide (2.25g) as a yellow solid. LC-MS (METHOD RT 3.31 minutes, 211.26 (M- N-(4-Difluoromethoxy-2-nitro-phenyl)-acetamide WO 031035065 PCT/GB02/04763 -517-

F

0 aNO 2

NH-C(=O)CH

3 By proceeding in a manner similar to Reference Example 32(a) above but using N-(4-diflIloromethoxy-phenyl)-acetamide [Reference Example 33(h)] there was prepared N-(4-difluoromethoxy-2-nitro-phenyl)-acetamidc (450mg) as a yellow solid. LC-MS (METHOD K): RT 3.72 minutes, MS: 245 (in) N-(5-Ethyl-4-mnethoxy-2-nitro-phenyl)-acetamide

CH

3 0 NO, CH 3

CH

2

NH-C(=O)CH

3 By proceeding in a manner similar to Reference Example 32(a) but using N-(3-ethyl-4-methoxyphenyl)-acetainide [2.9 g, Reference Example 3 there was prepared N-(5 -Ethyl -4-methoxy-2 -nitrophenyl)-acetamide (2.4 g) as a yellow solid. LC-MS (METHOD RT =4.04 minutes, MS: 239.16 REFERENCE EXA-MPLE 33 4-Ethyl-N-acetyl -aniline CH3 C

NH-C(=O)CH

3 A stirred solution of 4-ethylaniline (2g) and triethylamine (13.91 mL) in dichloromethane (4OniL) at O'C under nitrogen was treated dropwise with acetic anhydri de (4.67m-L). The mixturc was warmed to ambient temperature, then stirred for 16 hours at room temperature, then washed with 10% citric acid (40mL), (ii) water (4OmL) and (iii) brine (40mL). The organic phase was dried over magnesium sulfate and then evaporated to give 4-ethyl-N-acetyl-aniliine (2.36g) as a pale orange solid which was used without further purification. LC-MS (METHOD RT =2.80 minutes; 164.2 3-Methyl-4-isopropyl-N-acetyl aniline WO 03/035065 PCT/GB02/04763 (CH1) 2

CH

CH 3 NI--C(=O)-CH 3 By proceeding in a manner similar to Reference Example 33(a) above but using 3-methyl-4isopropylaniline there was prepared 3-methyl-4-isopropyl-A-acetyl aniline as an orange solid.

LC-MS (METHOD RT 2.97 minutes; 192.3 3-Methyl-4-broino-N-acetyl aniline

CH

3 a

NH-C(=O)-H

By proceeding- in a manner similar to Reference Example 33(a) above but using 3-rnethyl-4bromoaniline there was prepared 3-methyl-4-bromo-N-acetyl aniline as a brown solid.

LC-MS (METHOD RT =2.88 minutes; 228.12 3,4-Diethyl-N-acetyl aniline CH 3

CH

2 NH--C(-O)-CH 3 By proceeding in a manner similar to Reference Example 33(a) above but using 3,4-diethylaniline there was prepared 3,4-diethyl-N-acetyl aniline which was used without further purification.

LC-MS (METH-OD RT 3.03 minutes; 192-30 N- (4-Ethoxy-3-ethyl-phenyfl acetamide CH 3CH 2 0 C14I 3

CH

2 aHQ=)

NHC=)C

3 To a solution of 4-ethoxy-3 -ethyl -phenylarmne [0.6 g, Reference Example 30(t)] in pyridine (5mL) was added acetic anhydride (I mL) and the mixture was stirred 18 hours at ambient temperature. The reaction mixture was diluted with water (I OOmL) and the aqueous mixture was extracted twice with ethyl acetate (I OOmL). The combined extracts were evaporated to give N- (4-ethoxy-3-ethyl-phenyl) acetarnide (0.6g) as a pink foam. Ge-MS one peak, RT =9.16 minutes, MS 207 WO 03/035065 PCT/GB02/04763 19- N-(4-Methoxy-3-methvl-phenyl)-acetamide

CH

3 NH-C(-O)-C-l 3 By proceeding in a manner similar to Reference Example 33(a) above but using 4-mnethoxy-3-methylphenylamine 2 0 7 g, Reference Example 30(u)) and subjecting the reaction product to flash chromatography on silica cluting with a mixture of ethyl acetate and n-pentane 1, vlv) there was prepared N-(4-miethoxy-3-metlwyl-pheinyl)-acetainide (2.65g) as a pale pink crystalline solid. LC-MS (Method RT 2,94 minutes, 180.30 N-(4-Fluoro-3 -methyl-plhenvl)-acetamide

F

C3NH-C(=O)-CH 3 By proceeding in a manner similar to Reference Example 33(a) above hut using 4-fluoro-3methylaniline there was prepared N-(4-fluoro-3-inethyl-phenyl)-acetai-ide (3.82 g) as an orange solid.

LC-MS (METHOD RT 3.08 minutes, 168.24 N-(4-Difl luoromethoxy-p2henyl)-acetamide F, F NH-C(=O)-CH 3 By proceeding in a manner similar to Reference Example 33(a) above but using 4-difluoromethoxyan iline there was prepared N-(4-diflluoromethoxy-phenyl)-acetarnidc (5.90 g) as an orange solid. LC-M4S (METHOD RT 3.62 minutes, 202 N-(3-Ethyl-4-methoxy-phenyl)-acetamide

CH

3 0 CH3CH 2NH-C(=O)-CH 3 By proceeding in a manner similar to Reference Example 33(a) but using 3-ethyl-4-methoxyphenylaniine 2 .5g, Reference Examiple 30(aa)] there was prepared N-(3-ethyl-4-methoxy-phenyll- WO 031035065 PCT/GB02/04763 -520acetamide 2.9 g) was prepared as a light brown solid. LC-MS (MET HOD RT =3.92 minutes, 194.16 REFERENCE EXAMPLE 34 4'-Am ino-3'-n itro-b iphenyl -3 -carboni1trile

CN

NO 2 6---aNH 2 A stirred soIlution of 3-cyanophenyl boronic acid (812mg) and tetrakis(triphenylphosphine) palladium (1 50mg) in tetrahydrofuran (4mL) under at atmosphere of nitrogen was treated with 4-bromo-2nitroaniline in tetrahydrofuran (ItUmL). 'I'he reaction mixture was heated at 85'C for 48 hours, then cooled to ambient temperature and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane to give 4'-amino-3'-nitro-biphenyl-3-carbonitrile (224mg) as a yellow solid. LC-MS (METHOD RT 3.21 minutes, 240.3 2-nitro-4-pyridine-3-yl-phenylamine

N

NO 2 By proceeding in a manner similar to Reference Example 34(a) above but using pyridine-3-boronic acid there was prepared 2-nitro-4-pvridine-3-yl-phenylamine as a yellow solid. bC-MS (MEIFHOD B): RT 2.09 minutes, 216.24 2-methyl-5-nitro-biphenyl-4-vl amine WO 03/035065 PCT/GB02/04763 -521- By proceeding in a manner similar to Reference Example 34(a) above but using phenyl boronic acid and 4-bromo-5-methyl-2-nitro-an 1line [Reference Example 3 there was prepared 2-methyl -5 -nitrobiphenyl-4-yl amine as an orange solid. LC-MS (METHOD RT 3.30 minutes, MS: 29923 3-nitrophenyl-4-ylamine By proceeding in a manner similar to Reference Example 34(a) above but using phenyl boronic acid there was prepared 3-nitrophenyl-4-ylamine as a red solid. LC-MS (METHIOD RT 3.43 minutes, 2'-fluoro-3-nitro-b iphenyl-4-vl amine By proceeding in a manner similar to Reference Example 34(a) above but using 2-fluorophenyl boronie acid there was prepared 2'-fluoro-3-nitro-biphenyl-4-ylamine as a red solid. LC-MS (METHOD B): RT =3.33 minutes, 233.3 4'-benzo[1,31dioxo-5-yI-2-nitrophenylamine By proceeding in a manner similar to Reference Example 34(a) above but using 3,4-methylenedioxyphenyl boronic acid there was prepared 4'-benzo[l1,3ldioxo-5 -vl-2nitrophenyiamine as a orange solid. LC-MS (METHOD RT 3.23 minutes, 259.3 WO 031035065 WO 03/35065PCT/GB02/04763 22- Wg 2'-methoxy-3-nitro-biphenyl-4-ylamine By proceeding in a manner similar to Reference Example 34(a) above but using 2-methoxyphenyl boronic acid there was prepared 2'-iretlioxy-3-nitro-biphenyl-4-ylamine as an orange solid. LC-MS (METH-OD RT 3.30 minutes, 245.3 4'-ch loro-3-n itro-b iphenYl-4-ylaminie By proceeding in a manner similar to Reference Example 34(a) above but using 4-chlorophenyl boronic acid there was prepared 4'-chloro-3-initro-biphlenivl-4-ylaniine as an orange solid. LC-MS (METHOD RT 3.45 minutes, 249.27 4'-methvl-3-nitro-bipheniyl-4-ylamine By proceeding in a manner similar to Reference Example 34(a) above but using 4-methylphenyl boronic acid there was prepared 4'mtil3iir-bpey--lmn as an orange solid. LC-MS (METHOD RT 3.3 3 minutes, 229.2 REFERENCE EXAMPLE 4-benzyloxy- 1,2-dinitrobenzene WO 03/035065 PCT/GB02/04763 -523- O

NO,

NO,

A stirred solution of 3,4-dinitrophenol (Ig) in dimethylformamide (30mL) was treated with benzyl bromide (723i.L) and potassium carbonate (1.

13 The reaction mixture was stirred at ambient temperature for 24 hours and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane v/v) to give 4-benzyloxy-1,2-dinitrobenzene (1.30g) as a yellow solid. LC-MS (METHOD RT 3.31 minutes. 1H NMR [(CD 3 2 CO, ppm): 5 5.28 2H), 7.26-7.42 6H), 7.57 1H), 8.12 1H).

1 -Ethyl-2-methoxy-benzene

CH

3

CH

2 By proceeding in a manner similar to Reference Example 35(a) above, but using 2-ethylphenol and iodomethane (2.6 ml) with acetone as solvent and heating at 70 0 C for 24 hours in a sealed pressure vessel, there was prepared 1-ethyl-2-methoxy-benzene (5.6 g) as a yellow oil which was used without future purification. LC-MS (METHOD RT 3.83 minutes. 1 H NMR (d 6 acetone): 8 6.95 (m 6.75 (d 1H), 6.68 IH), 3.67 3H), 2.44 2H) 0.95 3H).

REFERENCE EXAMPLE 36 4-Nitro-l H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl)amide

CH,

3 NH 2

CH

3 NH NO,

O

N-N

H

Method A A stirred solution of 4,5-dimethylphenylenediamine (4.32g) and diisopropylethylamine in dichloromethane (200ml) was treated with 4-nitropyrazole-3-carboxylic chloride portionwise at 0°C. The reaction mixture was warmed to ambient temperature and stirred for minutes. The solvent was removed in vacuo and the oily residue was partitioned between ethyl acetate WO 031035065 PCT/GB02/04763 24and water. The organic layer was dried over magnesium sulfate and concentrated. The residual oil was re-crystallised from ethyl acetate and methanol to give 4-nitro- IH-pyrazole-3-carboxylic acid (2-ainto-4,5-diimethvylphenvl)amlide (6.58g) as an orange solid. LC-MS (METHOD RT 2.36 minutes, 276.09 Method B Polyphosphoric acid (500g) was added to a 1 L flask equipped with an overhead stirrer and heated to 70'C under nitrogen. A blended mixture of 4-nitro-3-pyrazole carboxylic acid (50g) and 1,2-diamino-4,5-dimethylbenzene (43.4g) was added and the mixture was heated to 1 80'C. After 1 hour at this temperature the reaction mixture was cooled to 130'C and poured into ice water This mixture was stirred with an overhead stirrer and then treated with aqueous ammoniumn hydroxide (350mrl- 30%) until the pH was 2.1. After stirring, for a fuirther 15 minutes the mixture was filtered and the filtered solid was washed three times with water (200mL) then dried under vacuum to give 4-nitro- I H-pyrazole-3-carboxylic acid (2-am-ino-4,5-dimethylphenyl)amide as a brown solid.

4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-ethvl-5-methylphenl)amile CH 3

CH

2

NH,

CH

3 a NH NO,

H

By proceeding in a manner similar to Reference Example 36(a), Method A, above but using methyl-phenylene diamine [Reference Example 30(a)] there was prepared 4-nitro- 1H-pyrazole-3earboxylic acid (2-amino-4-ethyl-5-methylphenyl)amide as a dark red solid. LC-MS (METHOD B): RT 2.89 minutes, 290.24 4-Nitro- 1H-pyrazole-3 -carboxyl ic acid (2-amino-S -chloro-4-methoxyphenyl)amide CH 3 0

N

2 Cl NH N0 2

H

By proceeding in a manner similar to Reference Example 36(a), Method A, above but using methoxybenzene-1,2-diamine [Ig, Reference Example diisopropylethylamine (4.lmL, 4 eq), WO 031035065 PCT/GB02/04763 -525dichloromethane (50 rnL) and a solution of 4-nitropyrazole-3-carbonyl chloride (Ig, 5.8 mmol) in dichloromethane (25 mE) and stirring the reaction mixture at ambient temperature for 18 hours there was prepared a mixture of 4-nitro- IH-pyrazole-3-carbox ylic acid (2-amino-5-cliloro-4methoxypheny lamni de -and thc bis-acylated material, MS 3 10 and 449 This material was used without further purification in Example 4-Nitro- I I-pyrazole-3-carboxyl ic acid (2-amino-4-miethoxy-phenyl)-am-ide

CH

3 0 a NI- 2 NH

NO,

0 N-

N

H

By proceeding in a mnanner similar to Reference Example 36(a), Method A, above but usingy 4-methoxy- 1,2 -phenylenediami ne (880mg) and 4-nitropyrazole-3 -carboxylic chloride [prepared by treating a solution of 4-nitropyrazole-3-cairboxylic acid (1g) in dry dichloromethane (70m1l) under nitrogen with oxalyl chloride (1.1I ImI) and dimethylformamide and after stirring overnight evaporating the reaction mixture then azeotroping three times with toluene (l0ml)] there was prepared 4-nitro-1Hpyrazole-3-carboxyl ic acid (2 -amino-4-methoxy-phenyl)-amide (800mg). LC-MS (Method RT 2.67 minutes, 278.25 276.28 4-Nitro- IH-pyrazole-3-carboxy lie acid (2-amino-4-ethoxy-phenyl)-am-ide

CHICH

2 O 0a NH 2 NH

NO,

N

N

H

By proceeding in a manner similar to Reference Example 36(d) above but using 4-ethoxy-bcnzene-1,2diamine [1 .25g, Reference Example 30(v)] and subjecting the reaction product to flash chromatography on silica, eluting initially with ethyl acetate and then with a Mixture of ethyl acetate and methanol 1, there was prepared 4-nitro- I H-pyrazole-3-carboxylic acid (2-amino-4-ethoxy-phenyl)-amide 8 2 4mg) a black solid. LC-MS (Method RT =2.90 minutes, 292.27 290.30 (f) 25 4-Nitro- I H-pyvrazole-3-carboxvlic acid (2-amino-4-fluoro-5-methvl-ohenvfl-amide WO 03/035065 PCT/GB02/04763 26- F a NH 2 CH 3 NH NO 2 0 K

N-N

H

By proceeding in a manner similar to Reference Example 36(d) above but using benzene- 1,2 -di amine [Reference Example 30(w)] there was prepared 4-nitro-tH-prazole-3-carboxylic acid (2-amino-4-fluoro-5-methyl-phenyl)-amide 12g) as a red oil. LC-MS (METHOD RT 3.02 minutes, 280.25 ()4-Nitro-1 H-pvyrazole-3-carboxylic acid (2-aminio-4-tr-ifluor-omctlhoxy-phcnyl)-aiuide CEO 3,NH 2 NH N

O,

N-N

H]

By proceeding in a manner similar to Reference Example 36(d) above but using 4-trifluorornethoxybenzene- 1,2-diamine [Reference Example 30(x)] there was prepared 4-nitro-IH-pyrazole-3-carboxylic acid (2-amino-4-tritluoromethoxy-phcnyl)-amidc 850g) as a red solid. LC-MS (METHOD RT 3.34 minutes, 332.21 (11) 4-N itro- 1H-pyrazole-3-carboxylic acid (2-ainino-4-trifIl oromethyl-phenyl)-amide CF 3 2 NH NO

N-N

H

By proceeding in a manner similar to Reference Example 36(d) above but using 4-trifluoromethylbenzene- I ,2-diami ne [Reference Example 3 there was prepared 4-nitro- 1H-pyrazole-3-carboxylic acid (2-amino-4.-trifluoromethyl-phenyl)-amide (0.250g) as an red solid. LC-MS (METHOD R 1

I

3.35 minutes, 316.14 WO 03/035065 PCT/GB02/04763 -527- 4-Nitro-TH-pyrazole-3-carboxy lie acid (2-amino-4-chloro-5-methyl-p henyl)-am~ide Cl

NH,

CH 3 N-H NO 2

N-N

H

By proceeding in a manner similar to Reference Example 36(d) above but using benzene-l,2-dian-ine there was prepared 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-chloro-5methyl-phenyl)-amide (0.300g) as ayellow solid. LC-MS (MElTHOD B3): RT =2.72~ minutes, 296.l10 3-Amino-4-[(4-nitro- IH-pyrazole-3 -carbonyl)-aminol-benzoic acid methyl ester 0 CH 3 0OI:

NH

2 NH NO,

H

By proceeding in a manner similar to Reference Example 36(d) above but using methyl -3 ,4diamninobenzoate there wvas prepared 3-amino-4-[(4-nitro- 1H-pyrazole-3-carbonfl)-ami no] -benzoic acid methyl ester (2.5 1Ig) as a tan foamn solid. LC-MS (METHOD RT 2.83 minutes, 306.21 REFERENCE EXAMPLE 37 S-Ethoxy- 1H-indazole EtC

N"

H

A solution of5-hydroxy-IH-indazole[o.5g, Reference Example 38] in acetone (l0mi) was treated with potassium carbonate (2.56g) then with iodoethane (0.296m1). The mixture was refluxed for 4 hours then cooled and then evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer was further extracted twice with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and then evaporated to yield a brown residue which was subjected to WO 03/035065 PCT/GB02/04763 -528flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane v/v) to gCiv 5-ethoxy-IH-indazole (0.38g) as an off-white solid. LC-MS (METHOD B3): RT= 2 .68 mnts 163 REFERENCE EXA-MPLE 38 1 H-indazole

HO

A solution of 5-methoxy-lH-indazole [0.

4 10g, Reference Example 24(a)] in dichloromethane (7.Sml) was treated with a solution of boron tribromide in dichloromethane (7.5m1, IM). The mixture was then heated to reflux for 4 hours, then cooled to 0 0 C and then treated dropwise with water (2ml). The pH of this mixture was adjusted to 7-8 by addition of 10% aqueous sodium hydrogen carbonate. The mixture was then extracted three timnes with ethyl acetate. The combined extracts were dried over magnesiumn sulfate and then evaporated. The residual brown oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane 1, v/v) to give 5-hydroxy- IH-indazole (0.310~g) as a yellow solid. LC-MS (METHOD RT-1.96 minutes; 135 REFERENCE EXAMPLE 39 I .4,6,7-tetrahydro-p'vrazolo[4,3-clpyridine-3,5 -dicarboxylic acid, 3-(2-amino-4,5dimethylphenyl)amidc. 5-tert-butyl ester N0 O'Bu

H

3

H

N-N

H

To a solution of 4,5 -di methyl benzene- 1 ,2 -diami ne (0.841 g) and I ,4,6,7-tetrahydro-pyrazolo[4,3 acid 5-tert-butyl ester [1 .5g, Reference Example 40(a)] in dimethyl formamide (100mI) was added diisopropylethylamine (1.08m1) and 2-(1H-9-azabenzotriazole-1-yl)- 1, 1,3,3-tetramnethyluronium hexafluorophosphate (2.35g). The mixture was stirred for 1.5 hours and diluted with ethyl acetate then washed six times with brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield a pale brown solid. The solid was then triturated with methanol to yield 1 ,4,6,7-tetrahvdro-pvrazolor4,3-cloyridine-3,5-dicarboxylic acid. 3-(2-amino- 5-tert-butyl ester (0.

9 9 g) as an off-white solid.

WO 03/035065 PCT/GB02/04763 -529- LC-MS (METHOD 13): RT 2.94 minutes; 386 Morpholine-4-carboxylic acid f3-(2-amino-4,5-di methyl-phenylcarbamoyl)-I -(tetrahiydropyran-2-yI)- 1H-pyrazol-4-ylmethlyll-(2,4-diwrethoxy-benzyt)-amide rl 0 CHNH 2 0 N CH NIa N CH~ 3/ OMe MeG By proceeding in a manner similar to Reference Example 39(a) above but using 4-{[(2,4-dimethoxybenzyl)-(morpholinc-4-carbonyl)-amnino]-methyl -(tetrahydro-pyran-2-yl)- 1H-pyrazOle-3-carboxyl ic acid [534mng, Reference Example 40(b)] there was prepared morpholine-4-carboxylic acid [3-(2-aminomiethiyl-phenyl car-baniovi I-(tetrahydro-pyr-an-2-yI)- 11--pyrazol-4-yl methyl]-(2 .4-dimethoxybenzyl)-arnide (1.66g) as a yellow oil. LC-MS (METHOD B3): RT 2.81 minutes, 607.71 (M+Hj4.

3 -Amin o-4-chloro-5 -methyl-phenylcarbamoyl)- 1,46,7-tetrahydro-pyrazo lo[4,3 -clpyridineacid tert-butyl ester Cl a NI 2 0 O'Bu

CH

3 NI-I N

N-N

H

By proceeding in a manner similar to Reference Example 39(a) above but using 4-chloro-5-methyl-1,2phenylenediamine there was prepared 3-(2-amino-4-chloro-5-methyl-nheniylcarbamoyl)- 1,4,6,7tetrahydro-pyrazolo[4,3-clpyridine-5-carboxylic acid tert-butyl ester (411 mg) as a brown solid.

LC-MS (METHOD RT 3.66 minutes, 406/408 3-[2-Amino-4-(2-morpholin-4-vyl-ethoxy)-p2henylcarbamoyll- 1 .4.67-tetrahydropyrazolo[4,3-clpyridine-5-carboxyl ic acid tert-butyl ester WO 031035065 PCT/GB02/04763 j "'oN NH2 0 O'Bu 00

NN

H

By proceeding in a manner similar to Reference Example 39(a) above but using 4-(2-morpholin-4-yIethoxy) -benzene- 1, 2-d iam ine [Reference Example 29(c)] there was prepared 3- 2-amino-4-(2miorpholin-4-yI-ethoxy)-phenylcarbai-ioylI -14.6,7-tetrahydro-pyrazolol 4.3-c I pyridine-S -carboxylic acid tert-butyl ester (400mg) as a brown solid. LC-MS (METHOD RT -3.33 minutes, 485.18 1A4.6 7-Tetra hyd ro-p yrano[K3 -cl pyrazoIe -3 -c arboxy i c acid (2-amino-4.5-dimethyl-phenvl)amide CH, NH 2 CHI a NI-I 0

H

By proceeding in a manner similar to Reference Example 39(a) above but using 1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylic acid [Reference Example 17(e)] there was prepared 1,46,7 tetrahydro-pyrano[4,3-clpyrazole-3-carboxylic acid (2-am-ino-4,5-di methyl-phenyl)-amide (1 16mg) as a cream solid. LC-MS (METHOD RT 2.32 minutes, 287 3-(2-Amino-4-trifluoromethyl-phenylcarbamoyl)-1I,4,6,7-tetrahydro-pyrazolo[4,3-clpyridine-5carboxvlic acid tert-butvl ester WO 031035065 PCT/GB02/04763 -53 1- F

F

F

N

2 o OBu NH N 0 By proceeding in a manner similar to Reference Example 39(a) above but using 4-trifluoromnethyl-1,2phenylenediamine there was prepared 3-(2-anmino-4-trifluioroi-nethyl-phenylcarbamoyl)- 1,4,6,7tetrahiydro-p2yrazolor4,3-clpyridine-5-carboxylic acid tert-butyl ester (1.00g) as a brown solid. LC-MS (METHOD RT 3.75 minutes, 424. 10 REFERENCE EXAMPLE I 7-Tetralwdro-pyrazolo[4,3-clpyridiine-3,5-dicarboxylic acid 5-tert-butyl ester 0 0 OH 'Buo J N

H

A solution of 1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridi ne-3 ,5 -dicarboxylic acid 5 -tert-butyl ester 3-ethyl ester 105g, Reference Examnple 1 and lithium hydroxide monohydrate (0.870g) in methanol (30m1) and water (10mI) was stirred at 55'C for 2.5 hours. The mixture was acidified with saturated aqueous potassium hydrogen sulfate solution and extracted three times with ethyl acetate. Tfhe organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to yield 1,4,6,7 tetrahydro-pyrazolol4,3-clpyridine-3,5-dicarboxylic acid 5-tert-butvl ester (4.442g) as a pale yellow solid, MS: 268 (M+H) m 1IPLC (METH-OD Cj): RT 2.86 minutes.

4- {r(2,4-dimethoxy-benzyl)-(moMholine-4-carbonyl)-aminol -methyl 1-1 -(tetrahydro-pyran-2- 1H-pyrazole-3-carboxvlic acid WO 031035065 PCT/GB02/04763 32- 0CH 3 0 CH 3 0 SN4 0

NNN-

0 By proceeding in a manner similar to Reference Example 40(a) abovc but using 4-{[(2,4-dimethoxybenzyl)-(morpholine-4-carbonyl)-amino]--methiyl -1-(tetraliydro-pyran-2-yl)- 1H-pyrazole-3-carboxylic acid ethyl ester [594mg, Reference Example 48(i)] there was prepared 4- f (2,4-dirnethoxy-benzyl)- (morphol ine-4-carbonyl)-aminol -rethyl} -1-(tetrahydro-pyran-2-yl)- IH-pyrazole-3-carboxylic acid (534mg) as a white fluffy solid. L-C-MS (Method RT 2.71 minutes, 489.21 REFERENCE EXAMPLE 41.

3-Hydroxyrnethyl- I H--pyrazole-4-carboxylic acid ethyl ester 0 HOCH 2

N

H

A solution of 3-ter-t-butyloxymethyl- 1I-pyrazole--4-carboxylic acid ethyl ester [3.46cg, Reference Example 42] in dicbloromethane (25ml) was treated with trifluoroacetic acid (25m1). The mixture was stirred for 1.5 hours and then concentrated. The residue was partitioned between saturated sodium carbonate solution and ethyl acetate. The organic layer was dried over magnesium sulfate and then evaporated to give 3-hydroxymnethyl-IH-pyrazole-4-carboxylic acid ethyl ester (2.49g) as a brown solid which was used without further purification. LC-MS (METHOD B3): RT 2.54 minutes; 171 3-Hydroxymethyl-l1H-pyrazole-4-carboxylic acid isopropylamide 0 NEH1(CH 3 2

I-OCH

2 By proceeding in a manner similar to Reference Example 4 1 above but using 3-ter-t-butyloxymethyl- IH-pyrazole-4-carboxylic acid isopropylamnide [Reference Example 44(a)] there was prepared WO 031035065 PCT/GB02/04763 33- 3-hydroxymethyl- I H-pyrazole-4-carboxylic acid isopropylamide as a pale yellow solid, which was used without further purification. LC-MS (METHOD RT 2.43 minutcs.- 184 3-HydIroxymietlhyl-5-m-ethiyl- I H-pyrazole-4-carboxylic acid ethyl ester 0 -OEt HO C1- 2

C

H

By proceeding in a manner simiilar to Reference Example 41 above but using 3-tet-butyloxymethyl- IH-pyrazole-4-carboxylic acid ethyl ester [Reference Example 43] there was prepared 3- IH-pyrazole-4-carboxylic acid ethyl ester as a orange solid which was used without further purification. LC-MS (METHOD RT 2.58 minutes; 185 3-Hydroxymethyl I H-pyrazole-4-carboxyl ic acid (2-methoxy-ethyl)-amide 0 H

N

HOCH

2

OCH

3 1 N

N

H

By proceeding in a manner similar to Reference Example 41 above but using 3-ter-t-butyloxymethyl- 1H-pyrazole-4-carboxylic acid (2-mcthoxy-ethyl)-amide [Reference Example 44(b)] there was prepared 3-hydroxymethyl- IH-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide (398mg) as an orange oil. LC-MS (METHOD B3): RT 1.66 minutes, 222 3-Hydroxyrnethyl- 1 H-p'vrazole-4-carboxyl ic acid propylamide 0 H

N

HOCH 2

NN

H

By proceeding i n a manner sim ilar to Reference Example 4 1 above but using 3 -tert-butyloxymethyllH-pyrazole-4-carboxylic acid propylamide [Reference Example 44(c)] there was prepared 3-hydroxymcthyl- I H-pyrazole-4-carboxylic acid propylamnide (73 1 mg) as an orange oil. LC-MVS (METHOD RT 2.09 minutes, 206 WO 03/035065 PCT/GB02/04763 -534- 3-Hydroxymethyl- I H-pyrazole-4-carboxyl ic acid (tetrahydro-pyran-4-fl)-an ide o H

N

HOCH 2 N

H

By proceeding in a manner similar to Reference Example 41 1(a) above but using 3-tert-butyloxymethyl- 1H-pyrazole-4-carboxylic acid (tetra hyd ro-pyran-4 -yl) -lam ide [Reference Example 44(d)] there was prepared 3-hydroxymethyl- IH-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4.1l0g) as an orange oil, LC-M S (METHOD RT 1.89 minutes, 226(M 11H)+.

3-1lydroxymethyl- I H-pvrazole-4-carboxylic acid cyclopropylamide O H

N

HOCH 2

NN

H

By proceeding in a manner simi lar to Reference Examp le 4 1 above but using 3 -ten-butyloxymeffiyl- 1H-pyrazole-4-carboxylic acid cyclopropylamide [Reference Example 44(e)] there was prepared 3-hydroxymethyl-lH-pyrazole-4-carboxylic acid cyclopropylamide (2.48g) as a white foam. LC-MS (METHOD RT =1.85 minutes, 180.15 REFERENCE EXAMPLE 42 3-tert-Butyloxymethyl- IH-pyrazole-4-carboxylic acid ethyl ester 0 OEt 'BuOCH 2

H

A solution of dimethyl formamide acetal (3.47m1) and 4-tert-butoxy-3-oxo-butyric acid ethyl ester [3.52g, Reference Example 43] in toluene (50ml) was heated at 65'C for 2 hours. The mixture was then concentrated and the residue redissolved in acetic acid (3m1). To the mixture was added hydrazine hydrate (0.93m1) and the whole allowed to stir at ambient temperature for 2 hours. The mixture was again concentrated in vacuo and the residue partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and WO 03/035065 PCT/GB02/04763 -535then concentrated to yield a brown oil which was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petrol v/v) to give 3-tert-butyloxvmethyl-1 H-pyrazole- 4-carboxylic acid ethyl ester 3 4 6 g) as a yellow solid. LC-MS (METHOD R

T

2.79 minutes; 227

(M+H)

REFERENCE EXAMPLE 43 4-terr-Butoxy-3-oxo-butyric acid ethyl ester O 0 tBuO OEt A suspension of sodium hydride (4.44g, 60% dispersion in mineral oil) in dimethyl formamide at 0°C, was treated dropwise with ethyl-4-chloroacetoacetate (5ml) and then with tert-butyl alcohol (7.08ml). This mixture was maintained at 0°C for 2 hours, then a further 2 hours at ambient temperature and then poured onto 2N hydrochloric acid/ice and then extracted four times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution, then with water, then with brine, then dried over magnesium sulfate and then evaporated. The resulting yellow oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petrol v/v) to give 4-tert-butoxy-3-oxo-butvric acid ethyl ester (5.20g) as a yellow oil. TLC (silica, 1:4, v/v ethyl acetate/petrol): RF= 0.51. NMR (400MHz, CDC13): 8 1.21(9H, 1.28(3H, 3.55(2H, 4.19(2H, q).

REFERENCE EXAMPLE 44 3-tert-Butyloxvmethyl-1H-pvrazole-4-carboxylic acid isopropvlamide 0

-NHCH(CH

3 2 'BuOCH 2

N

H

To a solution of 3-tert-butyloxymethyl-IH-pyrazole-4-carboxylic acid [1.520g, Reference Example hydroxybenzatriazole (3.110 g) and diisopropyl ethylamine (4.010ml) in dimethyl formamide (130ml) was added isopropylamine (1.960ml) followed by 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride 4 .420g). The mixture was heated at 70°C for 2.5 hours, then diluted with ethyl acetate, then washed with water, then with brine, then dried over magnesium sulfate and then evaporated. The residue was triturated with a mixture of ethyl acetate and petrol to yield 3-tertbutyloxvmethyl- H-pyrazole-4-carboxylic acid isopropylamide (652mg) as an off-white solid.

LC-MS (METHOD 2.99 minutes; 240 WO 03/035065 PCT/GB02/04763 36- Nb 3-tert-Butyloxymethyl- IH-pyrazole-4-carboxyl ic acid (2-methoxy-ethyfl-am-ide 0 NHCHCH,0CH 3 BuiOCH 2

NN

H

By proceeding in a manner similar to Reference Example 44(a) above but using 2-methoxyethylamnine, there was prepared 3-ter-t-but'yloxymethyl-]--pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide (8 11mg)- as an orange oil. LC-MS (METHOD RT 2.43 minutes, 278 (M+Na)t.

3-tet--Butyloxymethyl- I l--pyrazole-4-carboxyl ic acid propylamide 0 NHCH2CH 2

CH,

BuOCH 2 N

N

H

By proceeding in a manner similar to Reference Example 44(a) above but using n-propylamine there was prepared 3-rert-butyloxymethyl- I H-pyrazole-4-carboxyl ic acid propylamide (1.1t2g) as an orange oil. LC-MS (METHOD RT 2.65 minutes, 262 (M+Na)t.

3 -tert-Butyloxymethyl- I H-pyrazole-4-carboxyl ic acid (tetrahydro-pyran-4-yl )-lamidc 0 H

N

BuOC-1 N0

H

By proceeding in a manner similar to Reference Example 44(a) above but using tetrahydropyran-4ylani ne there was prepared 3-ter-t-butyloxymethyl-11 -oyrazole-4-carboxylic acid (tetrahydro-pyran-4- 1 )-lamide (5.50g) as an orange oil. LC-MS (METHOD RT 3.05 minutes, 282 3-tert-Butyloxymethyl- IH-pyrazole-4-carboxylic acid cyc lopropylamide WO 03/035065 PCT/GB02/04763 -537- C0 H

N

'BuOCH 2

N-/

H

By proceeding in a manner similar to Reference Example 44(a) above but using cyclopropylamine there was prepared 3 -ert-butyloxymethyl-lH-pvrazole-4-carboxylic acid cyclopropvlamide (3.27g) as an orange oil. LC-MS (METHOD RT 2.24 minutes, 238.38 REFERENCE EXAMPLE 3-tert-Butvloxvmethvl-5-methyl-lH-pyrazole-4-carboxylic acid ethyl ester O OEt 'BuOCH 2

NN

H

To a solution of 2-acetyl-4-tert-butoxy-3-oxo-butyric acid ethyl ester [0.

32 5g, Reference Example 46] in acetic acid (3ml) was added hydrazine hydrate (71pL). The mixture was stirred at ambient temperature for 16 hours and then evaporated to remove the acetic acid. The residue was dissolved in ethyl acetate and the solution was washed with 5% sodium hydrogen carbonate solution, then with water, then dried over magnesium sulfate, and then evaporated to yield methyl-lH-pyrazole-4-carboxvlic acid ethyl ester (0.258g) as a yellow oil which was used without further purification. LC-MS (METHOD R T 3.22 minutes; 241 REFERENCE EXAMPLE 46 2-Acetyl-4-tert-butoxy-3-oxo-butyric acid ethyl ester 0 OEt t B u O C H 2 C H 0 O CH A suspension of dry magnesium chloride (0.471g) in dichloromethane (6ml) was treated with 4-tertbutoxy-3-oxo-butyric acid ethyl ester [1.00g, Reference Example 43]. This mixture was cooled to 0°C, then treated with pyridine (0.80ml), then stirred for 15 minutes at 0°C and then treated with acetyl chloride (0.352ml). After stirring for a further 15 minutes at 0 C and then for 1 hour at ambient temperature the reaction mixture was treated with saturated aqueous ammonium chloride solution and WO 03/035065 PCT/GB02/04763 then extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated to yield 2-acetvl-4-tert-butoxy-3-oxo-butyric acid ethyl ester (1.15g) as a yellow oil which was used without further purification. LC-MS (METHOD RT 3.16 minutes; 243 REFERENCE EXAMPLE 47 4-Phenyl- H-pyrazole-3-carboxylic acid A solution of 3-methyl-4-phenylpyrazole (1.00g) in tert-butanol (15ml) and water (25ml), at 60°C, was treated portionwise potassium permanganate (5.47g). The temperature was then slowly elevated to 90 0 C and maintained at that temperature for 5 hours. The mixture was then cooled and filtered through a pad of celite. The filtrate was concentrated and the pH was adjusted to 10 to 14 by addition of aqueous sodium hydroxide solution. This mixture was washed twice with ethyl acetate. The aqueous layer was then acidified to pH 3 to 5 and then extracted four times with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated to yield 4-phenyl-1H--pyrazole-3carboxylic acid (0.512g) as a white solid, which was used without further purification. MS:189 (M+H) HPLC (METHOD RT 2.48 minutes.

REFERENCE EXAMPLE 48 Cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-lH-benzoimidazol-2-yl)-l- (tetrahydropyran-2-yl)- H-pyrazol-4-yllamide

O

CH

3 CH,

N

H

C H 3C H 2 N N 0 A solution of 3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)- -(tetrahydropyran-2-yl)-1H-pyrazol-4ylamine [0.3 g, Reference Example 49(a)] and triethylamine (0.8 mL, excess) in tetrahydrofuran 2 0 mL) was treated dropwise with cyclopropanecarbonyl chloride (0.3 g, 2.4 mmol). This mixture was WO 03/035065 PCT/GB02/04763 -539stirred for 48 hours then diluted with aqueous sodium bicarbonate solution (100 mE) and then extracted twice with ethyl acetate (I OOmnL). The comrhined extracts were evaporated and the residue was dissolved in tetrahydrofuran (5OmE). This solution was treated with a solution of potassiumn hydroxide (1.1 g) in ethanol (10 mL) and the mixture was stirred for 2 hours, then poured into water (1 00 ml) and then extracted twice with cthyl acetate (I OOfl. The comnbincd extracts were evaporated and the residue was chromatographed on silica gel eluting with a mixture of heptane and ethyl acetate (1I/1, v/v) to give eyeclopropanecarboxyl ic acid [3-(5-ethoxy-6-ethyl- I H-benzoimidazol-2-yi)- I1- (tetrahydropyrain-2-yll- 1H-pyrazol-4-yllamide (0.3g) as an off-white solid. LC-MS (Method RT= 2.99 minutes, 424 4-Methylpiperazine-l1-carboxylic acid l3-( 1,5,6,7-tetrahydro- 1,3-diaza-s-indacen-2-yl)- 1- (tetra hvdropyra n-2 1 H-pyrazol-4-yllamiide 0 HN N-CH3

_N

N

N

H

By proceeding in a similar manner to Reference Example 48(a) above but treating a solution of 1,5 ,6,7-tetrahydro- I ,3 -diaza-s-i ndacen-2-yl)- I -(tetrahydropyran-2-yl)- I H-pyrazol-4-ylamine [302mg, Refercnce Example 49(d)] and triethylamine (0.9 4 g, 10 cq) in tetrahyclrofuran (10 mnL) with 4-methylpiperazine-1-carbonyl chloride (930mg, 4.67 mmol), (ii) stirring the mixture at 45'C for 4 hours, then at 55'C for 1 hour, (iii) treating the cooled reaction mixture with aqueous sodium bicarbonate (200mL) and extracting this mixture three times with ethyl acetate (100~mb), and (iv) evaporating the combined extracts and chromatographing the residue on silica gel (ethyl acetate/garad ient 5-20%, methanol) there was prepared 4-methylpiperazine-l1-carboxyl ic acid 1,5,6,7tetrahydro- 1,3 -diaza-s-indacen-2-yl)- I-(tetrahydropyran-2-yl)-I1H-pyrazol-4-yllamide (189mg) as a purple solid. LC-MS (Method RT 2.28 minutes, 450 1.1 -Dimethyl-3 1.5 .67-tetrahydro-s-indacen-2-vl)- 1-(tetrahydropyran-2-yl)- 1H-pyrazol-4yljurea WO 031035065 PCT/GB02/04763 0 CH3

N

HN

N

H

By proceeding in a similar manner to Reference Example 48(b) above but using dimethylcarbamyl chloride (4 eq) there was prepared 1J1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-l- (tetirahiycropyrani-2-yl)-IH-pvr-azol-4-vllur-ea as a beige foam. LC-MS (Method RT 3.22 minutes, 395 Cyc lopropanecarboxylic acid F3 -(6-ethoxy-5-fluoro- 1H-benzimidazol -2 1-(tetrahydropyran- 2-yl)- 1H-pyrazol-4-yljatnide 0

HN

F aN C H 3

CH

2 0 N NN 0

H

By proceeding in a similar manner to Reference Example 48(a) above but using 6-ethoxy-5-fluoro-2[4amino-i -(tetrahydropyran-2-yl)-1 H-pyrazole-3-yl]- 1H-benzimidazole [0.45g, Reference Example 49(e)] and subjecting the reaction product to chromatography on silica gel (heptane/ethyl acetate, 7/3,v/v) there was prepared cyclopropanecarboxy lic acid 6-ethoxy-5-fluoro- IH-benzimidazol-2-yi)- I -(tetra hydropyran-2-yl)- IH-pyrazo 1-4-yll amide (90mg). LC-MS (Method RT 8.1 minutes, 414 Tetrahydropyran-4-carboxylic acid 13-(6-ethoxy-5-fluoro- 1H-benzimidazol-2-yl)- 1- (tetrahydropyran-2-yl)- 1H-pyrazole-4-yll am-ide WO 031035065 PCT/GB02/04763 -541- 0 0

HN

F: N XKh CH 3CH 2 0 N NN

H

By proceeding in a similar manner to Reference Example 48(a) above but using 6-ethoxy-5 -fluoro-2 [4amino- I -(tetrahydropyran-2-yl)- 1 H-pyrazole-3 -yIJ- I H-benzimidazole [0.45g, Reference Example 49(e)] and tetrahydropyran-4-carbonyl chloride (0.135g) and subjccting the reaction product to chromatography on silica gel (hieptane/ethyl acetate, 7/3,v/v) there was prepared tetrahiydropyran-4carboxylic acid r3-(6-ethoxy-5-fluoro- IH-benzi midazol-2Z-yl)-1I-(tetrahydropyran-2-yl)- 1H-pyrazole-4yllamide (120mg). L-C-MS (Method RT 8.05 minutes, 458 (N4-IH)+.

Morphol ine-4-carboxyl ic acid D -(6-ethoxy-5-fluo ro- 1 H-benzimi dazol-2 1 -(tetrahydropyra n- 2-yi)-tIH-pyrazol-4-yllamide 0

N

IN

F:I N

H

By proceeding in a similar manner to Reference Example 48(a) above but treating fluoro-2 [4-amino-I -(tetrahydropyran-2-yl)- 1H-pyrazole-3-yl]- 1H-benzimidazole [90mg, Reference Example 49(e)] and diisopropylethylamine (168mg) in tetrahydrofuran (4 rnL) with morpholine-4carbonyl chloride (194mg) for 2 days at ambient temperature, and (ii) subjecting the reaction product to chromatography on silica gel (heptane/ethyl acetate, there was prepared mornholine-4carboxylic acid F3 -(6-eth oxy-5-fluoro- I H-benzimidazol-2 I -(tetrahydropyran-2-yi)- 1 H-pyrazo 1-4yllamide (140 mg). LC-MS (Method RT 7.35 minutes, 459 WO 031035065 PCT/GB02/04763 -542- Piperidine-4-carboxyl ic acid[ 3-(6-ethoxy-5 -fluoro- I H -benzi midazol-2 I -(tetrahydropyran- 2-yi)- I H-pyrazol-4-yllamide

N

0 CH 3

CH,(

By proceeding in a similar manner to Reference Examplc 48(f) above but using piperidine-1 -carbonyl chloride (191mng) there was prepared piperidine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1Hbenzirnidazol-2-vfll-1-(tetrahydropyran-2-yl) -IH-pv razol-4-yli amide (127mg). LC-MS (Method RT 8.2 minutcs, 457 3-[6-Ethoxy-5-fluoro- 1H-benzimidazol-2-yI)-lI-(tetrahydropyran-2-yl)- 11--pyrazo1-4-y I- 1.1- [0 diethylurea CH 3CHl-IC By proceeding in a similar manner to Reference Example 48(f) above but using diethylcarbamnyl chloride (1 75mg) there was prepared 3-[6-ethoxy-5-fluoro- I H-benzimidazol-2-yi)- I -(tetrahydropyran- 2-yl)-1H4-pyrazol-4-vll-I. 1-diethyluirea (I110mg). LC-MS (Method G) RT =7.9 minutes, 445 4- f(24-Dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino1-methy [-1-(tetrahydro-pvran-2yl)-1I H-pyrazole-3-carboxylic acid WO 031035065 PCT/GB02/04763 -543- 0 OCH 3 0 CH 3 (0 0

CH

3 CH,O0

N"

0 By proceeding in a similar manner to Reference Example 48(a) above but using 4-[(2,4-dimnethoxybenzvlamino]-methyl -1 -(tetrahydro-pyran-2-yl)- 1H-pyrazole-3-carboxyl ic acid ethyl ester (829mg, Reference Example 60) and 4-norpholinecarbonyl chloride (0.96m1), and (ii) subjecting the reaction product to flash chromatography on silica eluting with ethyl acetate, there was prepared 4-f F(2,4dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino] -methyll -1-(tetrahydro-pyran-2-yl)- 1H-pyrazole-3carboxylic acid (595mg) as a colourless oil. LC-MS (Method RT -2.96 minutes, 517.30 3-[3-(5-Difluoroiniethoxy- I H-benizoimidazol-2-vl)- I-(tetraliydro-pyran-2-yl)-I1H-pyrazol-4-yll 1,1-diethyl-urea

\-N

F F 0

HN

0 N N NN 0

H

By proceeding in a manner similar to Reference Example 48(a) above but using I H-benzoimidazol-2-yl)- I-(tetrahydro-pyran-2-yl)-1 H-pyrazol-4-ylamine [Reference Example 4 9 and diethylcarbamyl chloride, there was prepared 3-r3 -(5-difluoromethoxy-l1H-benzoi midazol-2-yl)- 1- (tetrahydro-pyran-2-yl)-1Hl-pyrazol-4-yll-l,1-diethyl-urea (220mg) as a pale brown solid. LC-MS (METHOD RT 4.02 minutes, 447.27 Piperidine-l1-carboxyl ic acid r3 -difluoromethoxy- 1H-benzoimidazol-2-yl)- 1-(tetrahydrotivran-2-vl)- 1H-n~vrazol-4-vll-arnide WO 03/035065 PCT/GB02/04763 -544- FF FN 0

HN

H

By proceeding in a manner similar to Reference Example 48(j) above but using piperidine- I-carbonyl chloride there was prepared pipcridine- 1 -carboxylic acid [3-(5-difluloromethoxy- I H-benzoimidazol-2yl)- I-(tetra hydro- p vran -2 -y1) IH-pyrazol1-4-yl I-a mide (2 20mg) a s a pale brown so li d. LC -MS (METHOD RT 4.07 minutes, 459.28 REFERENCE EXAMPLE 49 3 -(5-Ethoxy-6-ethyl- IH-benzoimidazol-2-yl I -(tetrahydropyran-2-yl)- 1H-pyrazol-4-ytamine

H.,N

CH

3

,CH

2 O _N CH CH 2 N NN 0 A solution of 5-ethoxy-6-ethyl -2-[4-nitro-lI-(tetrahydropyran-2-yl)-I H-pyrazol-3-yl] I Hbenzoimidazole [0.8g, Reference Example 50(a)] in ethanol (IlOOmL) was treated with palladium on carbon 1Ig, 10%) anid mixture was hydrogenated at atmospheric pressure (balloon) for 4 days. The catalyst was filtered off, the filtrate was evaporated and the residue was chromatographed on silica gel (ethyl acetate with gradient of 0-10% methanol) to give 3-(5-ethoxy-6-ethyl- IH-benzoimidazol-2-yl)- 1- (tetrahvdropyran-2-yl)-IH-pyrazo1-4-ylamine (0.3g) as a solid. LC-MS (Method RT 2.15 minutes, 356 4-chloro-5-methoxybenzene- 1 2-diamine CH 3 0

NH

2 Cl

NH

2 WO 031035065 PCT/GB02/04763 -54 By proceeding in a similar manner to Reference Example 49 above, but using 5-chloro-4-methoxy- 2-nitrophenylamine [Reference Example 3 1 and subjecting the reaction product to chromatography osiiagel (ethyl acetate with gradient of 40% to 0% heptane)teewsppad4choomethoxybenzene-1,2-diarnine (1.0 g) as an orange solid. M4S: 173 4 -ethoxy-5 -ethyl -benzene- 1 ,2-diamine

CH

3

CH

2 O NH 2 CH 3 CH 2 NH I By proceeding in a similar manner to Reference Example 49(a) above, but using 4-ethoxy-5 -ethyl -2 nitrophenylamine [Reference Example 3l1(g)] and subjecting the reaction product to chromatography on silica gel eluting with ethyl acetate there was prepared 4 -ethoxy-5 -ethyl -benzene- 1, 2-d iami ne as a dark solid. LC-MS (Method RT 8.434 minutes, 1980 1,5,6,7-tetrahydro-1 ,3-diaza-s-indacen-2-yl)- 1 -detrahydropyran-2-yl)- I H-pyrazol-4-ylarnine

_N

N NN 0 By proceeding in a similar manner to Reference Example 49(a) above, but using a solution of 2-[4nitro- I -(tetrahydropyran-2-yi)- I H-pyrazol-3-yl]- I ,5,6,7-tetrahiydro-1 ,3-diaza-s-indacene 1 g, Reference Example 50(b)] in ethanol (120 rnL) and 5% palladium on carbon (320 mg), and (ii) using a Parr hydrogenation apparatus at 60 psi for 18 hours there was prepared 1.5,6,7-tetrahydro- 1,3-diazas-indaicen-2-yl)-l1-(tetrahydropyran-2-yl)- I H-pyrazol-4-ylamirie (368 mg) as a brown solid. LC (Method RT 3,079 minutes, 324 (M-rH)-l and 346 6-Ethoxy-5-fluoro-2[4-amino-l-(tetrahdropran-2-yl -1H-pyrazole-3-yl-IH-benzimidazole

H

2

N

F CH 3

CH

2 0 N N N o

H

By proceeding in a similar manner to Reference Example 49(a) above, but using 6-ethoxy-5-fluoro-2- [4-nitro- 1 -(tetrahydropyran-2-yI)- 1 1--benziniidazole 1.

2 g, Reference Example 50(c)] there was WO 03/035065 PCT/GB02/04763 -546prepared 6-ethoxv-5-fluoro-21 4-amino- I -(tetrahydropyran-2-yl)- 1 H-pyrazole-3-yiI- 1 H-benzimidazole LC-MS (Method RT 6.74 minutes, 346 4- ehnslfn l-ezn -12-imn 0

H

3 C 2 H C S-,-NH, By proceeding in a similar manner to Reference Example 49(a) above, but using N* I *-benzyl4 methanesulfonyl-henzene- 1,2-diamiine [Reference Example 65] there was prepared 4-methanesulfony1benzene- 1,2-diamine as a white solid. LC-N4S (METHOD J RT 0.98 minutes, 187.32 3-(5-Difluoromethoxy- 1H-benzoimidazol-2-yl)- 1-(tetrahydro-pyran-2-yl)- 1H-pyrazo1-4vi amine 0 a N

H

By proceeding in a manncr similar to Reference Example 49(a) above but using 5-difluoromethoxy-2- [4-niitro-l1-(tetrahydro-pyrani-2-yl)- IH-pyrazol-3 -yl] H-beinzoi midazole [Reference Example there was prepared 3 -difluoromethoxy- IH-benzoimnidazol-2-yl)- 1 4tetrahvdro-pyran-2-yl)- IHpyrazol-4-ylamine (730mg) as a pale brown solid. LC-MS (METHOD RT 3.27 minutes, 350.29 REFERENCE EXAMPLE 5-Ethoxy-6-ethyl -2-[4-nitro- 1-(tetrahydropyran-2-yI)- 1H-pyrazol-3-yll- IH-benzoimidazole

CH

3

CH

2

I

A mixture of 4-ethoxy-5-ethyl-benzene-1,2-diamine [0.18g, Reference Example 4-nitro-1- WO 031035065 PCT/GB02/04763 -547- (tetrahydro-pyran-2-yl)- 1H-pyrazole-3-carbaldehyde [0.225g, Reference Example and sodium bisulfite 12 g, 1.2 rnrol) in dim-ethylformamide (lOmL) was heated at 120'C for 1 hour. The mixture was cooled, water (100 ml) was added and the aqueous mixture was e xtracted with twice ethyl acetate (5OmL-). The combined extracts were evaporated and the residue was chromatographed on silica gel (ethyl acetate with gradient of 20-0% heptane) to give 5-ethoxy-6-ethyl -2-[4-nitro- 1 (tetrahvydropyran-2-yl)- IH-pyrazol-3-yll- 1H-benzoini dazole (200mg) as a solid. LC-MS (Method E) RT 2.85 minutes, 386 2-[4-nitro- I-(tetrahydropyrani-2-yl)- IH-Ipyrazol-3-yll- I 5,6.7-tetrahiydro- 1 3-diaza-s-indacene

N

N N N o

H

By proceeding in a similar manner to Reference Example 50(a) but using indane-5,6-diamine (1 prepared as described by Sui Xiong Cai et el., J.Med.Chenrn., 1997, 40, pages 730-738) and 4-nitro-1- (tetrahydro-pyran-2-yl)- 1I-pyrazole-3-carbaldehyde 5g, Reference Example there was prepared 2-[4-nitro-l1-(tetrahydropyran-2-yl)- IH-pyrazol-3-yl]- 1 5,6,7-tetrahydro-1 ,3-dliaza-s-indacene which was used without father purification.

6-Ethoxy-5-fluoro-2- f4-nitro-l-(tetrahydropyran-2-yl) -lH-benzimidazole F2 N CH 3

CH

2 O N NN o

H

By proceeding in a similar manner to Reference Example 50(a) but using 1,2-diamine (2.2 g, prepared according to the method of Uchida, et al, Chem. Pharm. Bull. 1989, volume 37, pages 1517 to 1523) there was prepared 6-ethoxy-5-fluoro-2-[4-nitro- I-(tetrahydropyran-2- H--benzimidazole. bC-MS (Method RT =8.1 minutes, 376 t 5-Methoxv-2-r4-nitro-l1-(tetrahvdro-pyran-2-yl)- I H-pyrazol-3-vll IH-benzoimidazole WO 031035065 PCT/GB02/04763 -548-

ON

CH 3 0 ,C N N N -N o

H

By proceeding in a similar manner to Reference Example 50(a) but using 4-methoxy-I,2phenylenediamine (117mg1) there was prepared 5-methoxy-2-[4-initro-1-(tetrahydro-pyratn-2-yfl-]Hpyrazol-3-yl I-I H-benzoimidazole (282mgn) as a deep red oil. LC-MS (Method RT =2.02 minutes, 344-2 1 342.24 5-Difloroniethoxv-2-F4-nitro-lI-(tetrahydro-pyran-2-yl)- I H-pyrazol-3-fl]- 1H-benzoiimidazole 0,N

N

H

By proceeding in a manner similar to Reference Example 50(a) above but using difluoromethoxybenzene- 1,2 -diamine [Reference Example 30(y)] and 4-nitro-lI-(tetrahydropyran-2-yl)-l1H-pyrazole-3earbaldehyde [ReferenceExample there was prepared 5-difluoromethoxy-2-F4-nitro-l (tetrahydro-pyran-2-vl)- 1H-pyrazol-3 -yii- IH-benzoimidazole (910mg) as a pale brown solid. LC-MS (METHOD RT 3.40 minutes, 380.22 REFERENCE EXAMPLE 51.

1 -Ethoxy-2-ethyl benzene To a solution of 2-ethylphenol (6.9g, 56.5 mm-ol), triphenylphosphine (15.7 g, 60 mmol) and ethanol (6 mL, excess) in tetrahydrofuran (lO0rniL) was added dropwise DIAD (12.lIg, 60 mmol). After stirring for 18 hours, mixture was evaporated and the residue was chromnatographied on silica gel (heptane/ethyl acetate 9/1) to give I -ethoxy-2-ethyl benzene (7.2g) as a clear liquid. GC-MS shows one peak, RT 5.6 minutes. MIS 150 REFERENCE EXAMPLE 52 N-(3-Chloro-4-methoxyphenvl)acetamide WO 03/035065 PCT/GB02/04763 -549- A solution of 3-chloro-4-methoxyphenylamine (6.3g) and triethylamine (4.04g) in dichloromethane (100 mL) was chilled in an ice bath, acetyl chloride (3.45g) was added dropwise and the mixture was stirred at ambient temperature overnight. The reaction mixture was extracted with water (2X30 mL) and brine (2X30 mL) and the organic layer was dried with magnesium sulfate. The drying agent was removed by filtration and the filtrate was evaporated to give N-(3-chloro-4-methoxyphenyl)acetamide (7.45g) as a dark oil, which solidified on standing. MS: 200 (M+H) REFERENCE EXAMPLE 53 [4-Nitro-l-(tetrahydro-pyran-2-vl)-1H-pyrazol-3-yl]-methanol A stirred solution of 4-nitro-l-(tetrahydro-pyran-2-yl)- H-pyrazole-3-carboxylic acid methyl ester [500mg, Reference Example 54(a)] in tetrahydrofuran (20ml) under nitrogen at -78 0 C was treated dropwise with a solution of diisobutylaluminium hydride in tetrahydrofuran (8.82ml, 1M). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was taken up in diethyl ether (100ml) and quenched with water (150ml). The resulting suspension was filtered through celite and the organic layer was collected from the filtrate, then dried over magnesium sulfate and then evaporated to yield [4-nitro-l-(tetrahydro-pyran-2-yl)- lH-pyrazol-3-yl]-methanol (349mg) as a peach oil. LC-MS (Method RT= 2.08 minutes, 250.29 (M+H+Na) REFERENCE EXAMPLE 54 4-Nitro-l-(tetrahydro-pyran-2-yl)-lH-pyrazole-3-carboxylic acid methyl ester A suspension of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.3g, Reference Example 55) and p-toluene sulfonic acid (144mg) in chloroform (30ml) at 0 C was treated with 3,4-dihydropyran WO 03/035065 PCT/GB02/04763 -550- (1.04m1) dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate (40ml) and water (3 x 40m1nl). The combined aqueous layers were extracted with dichloromethane (3 x 60ml). The organic layers were combined, dried over magnesium sulfate and concentrated to yield 4-nitro-l-(tetrahvdro-pvran-2-vl- IH-pyrazole-3-carboxlic acid methyl ester (2.23g) as a viscous brown oil. LC-MS (Method RT= 2.79 minutes, 278.21 4-Formyl- 1 -(tetrahydro-pyran-2-yl)-1 -I-pyrazole-3-carboxylic acid ethyl ester

O

CH

3

CH

2 O

CHO

N

N

O

0 By proceeding in a manner similar to Reference Example 54(a) above but using 4-formyl-lH-pyrazole- 3-carboxylic acid ethyl ester(100mg, Reference Example 57) there was prepared 4-formyl-1- (tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid ethyl cster (170mg) was prepared as a viscous yellow oil. LC-MS (Method RT 3.29 minutes, 275.30 REFERENCE EXAMPLE 4-Nitro-1H-pyrazole-3-carboxylic acid methyl ester

O

CHO NO 2

N

N

H

A stirred suspension of 4-nitro-3-pyrazolecarboxylic acid (1g) in dichloromethane under nitrogen at 0 0 C was treated with oxalyl chloride (1.11ml) followed by dimethylformamide (5drops). The reaction mixture was warmed to room temperature and stirred overnight. Methanol (lO0ml) was added and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure and azeotroped with toluene twice to yield 4-nitro-1H-pyrazole-3-carboxlic acid methyl ester (1.3g) as a pale green solid. LC-MS (Method RT= 1.94 minutes, 170.23 REFERENCE EXAMPLE 56 WO 03/035065 PCT/GB02/04763 -551- 1-Methoxy-2-methyl-4-nitrobenzene

CH

3 0

CH

3 NO 2 2-Methylanisole (2.5ml) in acetic acid (140ml) and dichloromethane (1 50ml) was cooled to 15 0

C.

Concentrated nitric acid (20ml) was added slowly keeping the temperature of the reaction below The reaction was stirred at ambient temperature for 30 minutes and cooled to 0°C before adding fuming nitric acid (50ml) dropwise. The reaction mixture was allowed to warm to ambient temperature slowly and stirred for a further 4 days. The reaction mixture was poured onto ice water (600ml) and the organic layer was washed with water (2 x 40ml) and saturated sodium hydrogencarbonate (2 x dried over magnesium sulfate and concentrated. The residual deep red solid was subjected to flash silica chromatography on silica eluting with isohexane/ethyl acetate to to yield 1-methoxy- 2-methyl-4-nitrobenzene (2.70g) as an off white solid. LC-MS (Method RT 3.74 minutes, 168.27

(M+H)

5,6-Dinitro-benzol[1,3]dioxole O- -NO, 0 NO, By proceeding in a manner similar to Reference Example 56(a) above but using 1,2-methylenedioxybenzene there was prepared 5,6-dinitro-benzo[1,3]dioxole as an orange solid.

HPLC (Method RT 2.99 minutes; 490.24 (2M+1).

REFERENCE EXAMPLE 57 4-Formvl-1H-pvrazole-3-carboxylic acid ethyl ester 0

CH

3 CH20

CHO

N

N

H

Phosphorus oxychloride (5.07ml) was added dropwise to dimethylformamide (8.4ml) at 0OC under nitrogen. Ethyl pyruvate semicarbazide (4.3g, Reference Example 58) was added portionwise to the stirring solution at o0C under a nitrogen positive pressure. The reaction mixture was heated at 60°C for hours and cooled to ambient temperature before pouring slowly onto ice (30g). The pH of the reaction mixture was adjusted to pH12 with 6.25M sodium hydroxide solution whilst maintaining the WO 03/035065 PCT/GB02/04763 -552temperature at O'C. The aqueous reaction mixture was heated at 60'C for 5 minutes and cooled to OTC.

The pH was re-adjusted to p1-16 with IM hydrochloric acid. The resulting precipitate which form-ed after 1 hour was collected by filtration to yield 4-formyl-IH-pyrazole-3-carboxylic acid ethyl ester (1.02g) as a pale yellow solid. LC-MS (M~ethod Rj- 2.55 inutes, 169.27 167.30 (M- REFERENCE EXAMvPLE 58 Ethyl pynivate semicarbazide 0 YNH 2 0 A stirred solution of semicarbazide hydrochloride (11. 1ig) and sodium acetate (8.2g) in water (250m1) was treated with ethyl pyruvate (10.9m1) in one portion. The resulting white precipitate was collected by filtration to yield ethyl pyruvate semicarbazide (16.59g) as a white powder. LC-MS (Method J): RT= 2.38 minutes, 174.31 172.32 REFERENCE EXAMPLE 59 Morpholine-4-carboxylic acid (2.4-dimethoxy-benzyl)-[3-(5,6-dimethyl- I H-benzoimidazol-2-vl)- I1- (tetrahydro-pyran-2-yl)- 1 H--pyrazol-4-ylmcthyll -amide r-0

NJ

CHR

3 N MeO

C

3 H A stirred solution of [332mg, Reference Example 39(b)] in acetic acid (5m1) was heated at 120'C for minutes in a Personal Chemistry Smith Creator microwave. The mixtures from five reactions were combined and the solvent removed in vacuo to yield morpholine-4-carboxylic acid (2,4-dimethoxy- WO 03/035065 PCT/GB02/04763 53benzyl)-3-(5,6-dimethyl- I H-benzoimidazol I -(tetra hydro-pyran-2 1 H-pyrazol-4-ylm-ethyllamide (1.22g) as a dark yellow oil. LC-MS (Method RT= 2.70 m-inutes, 589.63 REFERENCE EXAMPLE 4-f FY2,4-Dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino]-niethvl 1-1-(tetrahydro-pyran-2-yl)- 1Hpyrazole-3-carboxylic acid ethyl ester OCH 3 CH3 0

N

0 A stir-red solution of 4-[(2,4-dimethoxy-benzylam ino)-methylj- I -(tetrahydro-pyran-2-yl)- 1H-pyrazole- 3-carboxylic acid ethyl ester I g, Reference Example 54(b)] in tetrahydrofuran (25m1) was treated with 2,4-dlimethyoxybenzylamine (0.596m]). After stirring for 12 hours sodium triacetoxyborohydride (t.68g) was added to the reaction mixture and the reaction mixture was stirred for a further 1 hour before partitioning between ethyl acetate (200m1) and saturated sodium hydrogencarbonate (200m]).

The aqueous layer was extracted twice with ethyl acetate (I 00ml) and the combined organic layers were dried over magnesium sulfate and then concentrated in vacuto to yield 4-f[(2,4-dimcthoxybenlzyl )-(morpholine-4-carbonyl)-aminol-methyl 1-1-(tetrahydro-pyran-2-yl)-l1H-pyrazole-3-carboxylic acid ethyl ester (1.66g) as a yellow oil. LC-MS (Method B3): RT= 2.27 minutes, 404.17 REFERENCE EXAMPLE 6 1 4-Amino-N-benzyl-3-nitro-benzenesulfonamide N N2 H N_2 To a stirred suspension of (4-Benzylsulfamoyl-2-nitro-phenyl)-carbamic acid ethyl ester (1 Reference Example 62) in ethanol (3Oinl) was added 2M sodium hydroxide solution (5.93m1) and the reaction heated at 75'C for 2 hours. The reaction mixture was cooled to ambient temperature, poured onto ice-water and acidified to p113 with 2M hydrochloric acid (30m1). The resultant precipitate was WO 03/035065 PCT/GB02/04763 -554collected by filtration and dried in vacuo to give 4-amino-N-benzvl-3-nitro-benzenesulfonamide (1.01g) as a yellow solid. LC-MS (METHOD R T 3.41 minutes, 308.22 (M+H) REFERENCE EXAMPLE 62 (4-Benzylsulfamoyl-2-nitro-phenyl)-carbamic acid ethyl ester oS N2 N 2°

H

NI-

O0 OCH 2

CH

3 To a stirred solution of (4-chlorosulfonyl-2-nitro-phenyl)-carbamic acid ethyl ester (2g, Reference Example 63) in dichloromethane (50ml) at 0°C, under a nitrogen atmosphere, was added diisopropylethylamine (2.71ml) and benzylamine (0.850ml). The reaction was warmed to ambient temperature and stirred for 12 hours. The reaction mixture was then washed with water (2x20ml) and brine (2x20ml), dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the title compound 2 .29g) as a brown solid. LC-MS (METHOD R T 3.83 minutes, 380.12 (M+H) REFERENCE EXAMPLE 63 (4-Chlorosulfonyl-2-nitro-phenyl)-carbamic acid ethyl ester 0/ O S

NO

2 Cl

NH

S0'OCH 2

CH,

To a stirred suspension of (4-chlorosulfonyl-phenyl)-carbamic acid ethyl ester (5g, Reference Example 64) in concentrated sulfuric acid (25ml) at 0°C, was added dropwise a suspension of sodium nitrate (1.61g) in concentrated sulfuric acid and the reaction stirred for 3 hours. The reaction mixture was then poured onto ice, the resultant precipitate collected by filtration and dried in vacuo to give (4-chlorosulfonyl-2-nitro-phenyl)-carbamic acid ethyl ester (4.80g) as a yellow solid. LC-MS (METHOD RT 3.32 minutes, 307.08 REFERENCE EXAMPLE 64 WO 031035065 PCT/GB02/04763 (4-Chlorosulfonyl-phenyl)-carbamic acid ethyl ester 0 Cl 0 )a N 'kOCH 2 C1 3

H

To a stirred solution of chiorosulfonic acid (20m1) at OTC, was added N-phenyl urethane (9.90g) at such a rate that the temperature did not exceed 20'C. The reaction was then heated at 60'C for 3 hours, cooled to ambient temperature and poured carefully onto ice. The resultant precipitate was collected by filtration and dried in vacuio to glive (4-chlorosulfonyl-phenyl)-carbamic acid ethyl ester (Il 4 .50g) as an off-white solid. LC-MS (METHOD RT 3.11I minutes, 284.23 REFERENCE EXAMPLE N* I*-Be1izyl-4metlianesulfonyl -benizene-1I 2-diam-ine 0O\ /0 H 3C S,,NH 2

N

H-

A stirred solution of benzyl-(4-methanesulfonyl-2-nitro-phenyl)-amine (0.300g, Reference Example 66) and tin chloride (1.86g) in ethanol (5 ml) was heated in a Smith Creator microwave at NOT 0 for minutes. The reaction mixture was basified using saturated sodium hydrogen carbonate solution to pHT 8 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give N* I *..benzyl-4methanesulfonyl..benzene-1,2.diamine (0.255g) as a pale brown solid. LC-MS (METHOD RT 2.74 minutes, 275.20 REFERENCE EXAMPLE 66 Benzyl-(4-methanesulfonyl-2-nitro-phenyl)-amine 0 0 NO2 H 3 C 1 a2

H

To a stirred suspension of (4-fluoro-2-nitrophenyl)methylsulfone (0.50g) and sodium hydrogen carbonate (0.575g) in ethanol and water (30ml) was added benzylamine (O.374ml) and the WO 03/035065 PCT/GB02/04763 -556reaction stirred for 16 hours. The reaction mixture was then poured onto ice water, the resultant precipitate collected by filtration and dried in vacuo to give benzvl-(4-methanesulfonvl-2-nitrophenyl)-amine (0.660g) as a yellow solid. LC-MS (METHOD RT 2.97 minutes, 307.04 (M+H) REFERENCE EXAMPLE 67 4-[2-(3,4-Dinitro-phenoxy)-ethyl]-morpholine 00 N

NO

NN2 A mixture of 3,4-dinitrophenol (250mg), 4-(2-chloroethyl)morpholine hydrochloride (252mg) and potassium carbonate (375mg) in dimethylformamide (3ml) was heated at 120 0 C for 20 minutes in a Personal Chemistry Smith Creator microwave. The reaction mixture was partitioned between ethyl acetate and water and the organic layer dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 4-[2-(3,4-dinitro-phenoxy)-ethyl]-morpholine (319mg) as a yellow oil.

LC-MS (METHOD RT 2.13 minutes, 298 (M+H) REFERENCE EXAMPLE 68 3-Formyl-1

N

OHC

/T

H

To a suspension of 5-cyanoindole (3.93g) and sodium nitrite (19.07g) in water was added 6M hydrochloric acid slowly until the pH was less than 2. The suspension was then stirred for 3 hours at ambient temperature. The mixture was then extracted with ethyl acetate, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 4 .5g) as a pale brown solid. LC-MS (METHOD RT 2.47 minutes, 172.29 (M+H) IN VITRO TEST PROCEDURES A. IN VITRO TEST PROCEDURES FOR SYK WO 03/035065 PCT/GB02/04763 -557- 1. Inhibitory effects of compounds on SYK kinase Inhibitory effects of compounds on SYK kinase were determined using a time-resolved fluorescent assay.

The catalytic domain of SYK kinase (residues A340-N635 was expressed as a fusion protein in yeast cells and purified to homogeneity. Kinase activity was determined in 50mM Tris-HCI buffer pH containing 50mM NaC1, 5mM MgC12, 5mM MnC12, 1 .M adenosine triphosphate and 10lM synthetic peptide Biotin-( P-Alanine) 3

-DEEDYEIPP-NH

2 Enzyme reactions were terminated by the addition of buffer containing 0.4M KF, 133rmM EDTA, pH 7.0, containing a streptavidin-XL665 conjugate and a monoclonal phosphospecfic antibody conjugated to a europium cryptate Features of the two fluorophores, XL-665 and Eu-K are given in G.Mathis et al., Anticancer Research, 1997, 17, pages 3011-3014. The specific long time signal of XL-665, produced only when the synthetic peptide is phosphorylated by SYK, was measured on a Packard Discovery Microplate analyzer or on an LJL Biosystems Analyst AD microplate reader, Inhibition of SYK activity with compounds of the invention was expressed as percentage inhibition of control activity exhibited in the absence of test compounds. Particular compounds of the invention inhibit SYK activity with IC 5 0 's in the range 100 micromolar to 0.1 nanomolar. Preferred compounds of the invention inhibit SYK activity with IC 50 's in the range 5000 nanomolar to 0. 1 nanomolar. Particularly preferred compounds of the invention inhibit SYK activity with IC 5 0 's in the range 1000 nanomolar to 0.1 nanomolar. Especially preferred compounds of the invention inhibit SYK activity with IC 50 's in the range 100 nanomolar to 0.1 nanomolar. More especially preferred compounds of the invention inhibit SYK activity with IC 50 's in the range 10 nanomolar to 0. I nanomolar.

2. Antigen-induced degranulation of Rat Bosophilic leukemia (RBL) cells as measured by [3H] 5-hydoxytryptamine (serotonin) release 2.1 Cell culture, labelling of RBL-2H3 cells and performance of assay.

Method A: For each 24-well culture plate to be set up, 6 x 106 cells RBL-2H3 cells were washed and resuspended in 15 mL DMEM-10 containing 25p of ImCi/ mL 3 H]-serotonin (0.5gCi/ mL final concentration) and lpg/ mL (15mL) of anti-DNP IgE. 0.5 mL of cell suspension was added into each well of a 24-well plate. Cells were incubated for 2 days at 37 0 C, until they have reached confluence.

The medium was gently aspirated from each well and the cells were then washed with assay buffer. A WO 03/035065 PCT/GB02/04763 -558final volume of 200mL of assay buffer or the test compounds at the appropriate concentrations) was then added to each of three replicate wells. 100ng/ mL of DNP (antigen) was then added to all wells (excluding negative control wells i.e. to measure spontaneous 3 H]-serotonin release in the absence of receptor cross-linking). The cells were incubated for 30 minutes at 37 0 C and the reaction was stopped by transferring 100tl of the supernatant from each sample into a liquid scintillation microtitre plate kept on ice. 200gl of scintillant-40 was then added to each well of the microtitre plate and the plate was read on a Topcount Liquid Scintillation Counter.

Method B: RBL-2-H3 cells are maintained in T75 flasks at 37 0 C and 5%CO2, and passaged every 3-4 days. To harvest cells, 5 ml trypsin-EDTA is used to rinse the flask once, then 5 ml trypsin is added to each flask, and incubated at room temperature for 2 minutes. Cells are transferred to a tube with 14ml medium, spun down at 1100 rpm RT for 5 minutes and resuspended at 2x10 5 /ml. Cells are sensitized by adding 1pl of DNP-specific IgE (1 mg/ml stock solution) to every 10 ml of cells. 200)t1 of cells are added to each well of a flat-bottom 96 well plate (40,000 cells/well), and the plate incubated overnight at 37C and 5%C0 2 The next day compounds are prepared in 100% DMSO at 10mM. Each compound is then diluted 1:100 in assay buffer and then diluted further in 1% DMSO-assay buffer to obtain final concentrations of0.03-30pM. 80tl assay buffer (Hank's Balanced Salt Solution with Ca 2 mg/ml glucose, 0.03% BSA) is added to each well, followed by 10tl of diluted compound. Incubation follows for 5 minutes. 1Opl of DNP-HSA (100ng/ml) is added to each well and incubated at 37 0 C (no CO2) for 30 minutes. As one control, 1% DMSO alone (no compound) is added to a set of wells to determine total release. As another control, buffer is added instead of DNP- HSA to another set of wells to determine the assay background. After 30 minutes incubation, the supernatants are transferred to a new 96-well plate. Add 50tl supernatant to each well of an assay plate. Add 100ptl of substrate solution (5 mM PNAG in 0.4M citric acid, 0.2M NaZHJP0 4 to each well and incubate at 37 0 C for 90 minutes. Add 50pil of 0.4 M glycine solution to stop the reaction and the plate is read at 405 nm on a Molecular Devices SpectraMax 250 plate reader.

2.2 Calculation of results Method A The mean s.e.m. of each set of triplicate wells was calculated.

(ii) Maximum response was the positive control wells containing antigen (10ng/mL) but no compound.

(iii) Minimum response was the control wells containing no antigen and no compound.

(iv) Using these values as the maximum (100%) and minimum values respectively, the data was normalised to give a percentage of the maximum response.

WO 03/035065 PCT/GB02/04763 -559- A dose response curve was plotted and the IC 5 0 of the compound was calculated.

Method B The mean SD of each set of triplicate wells was calculated.

(ii) Maximum response was the positive control wells containing antigen (100ng/mL) but no compound.

(iii) Minimum response was the control wells containing buffer (no antigen) and no compound.

(iv) Using these values as the maximum (100%) and minimum values respectively, the experimental data was calculated to yield a percentage of the maximum response (designated control).

A dose response curve was plotted and the IC 5 0 of the compound was calculated using Prism GraphPad software and nonlinear least squares regression analysis.

B. IN VITRO TEST PROCEDURES FOR KDR 1. Inhibitory effects of compounds on KDR The inhibitory effect of the compounds is determined in a test of phosphorylation of a substrate by the enzyme KDR in vitro by the flasplate technique (96-well plate, NEN).

The cytoplasmic domain of human KDR enzyme is cloned in the form of a GST fusion into the baculovirus expression vector pFastBac. The protein is expressed in the SF21 cells and purified to about 60% homogeneity.

The kinase activity of KDR is measured in 20mM MOPS, 10mM MgCI2, I mM MnC12, ImM DTT, EGTA, 10mM (3glycerophosphate, pH 7.2 in the presence of 10mM MgC12, 100pM Na3VO4, 1 mM NaF. 10pl of the compound are added to 70pl of kinase buffer containing 100ng of KDR enzyme at 4 0 C. The reaction is initiated by adding 20pl of solution containing 2.g of substrate (fragment SH2-SH3 of PLCy expressed in the form of a GST fusion protein), 2pCi y33P[ATP] and 2pM cold ATP. After incubating for 1 hour at 37 0 C, the reaction is quenched by adding 1 volume (1001g) of 200mM EDTA. The incubation buffer is removed and the wells are washed three times with 300l of PBS. The radioactivity is measured in each well using a Top Count NXT instrument (Packard).

Background noise is determined by measuring the radioactivity in wells in quadruplet containing radioactive ATP and the substrate alone.

An activity control is measured in wells in quadruplet containing all the reagents (y33P-[ATP], KDR and the substrate PLCy) and in the absence of compound.

WO 03/035065 PCT/GB02/04763 -560- The inhibition of the KDR activity with the compound of the invention is expressed as a percentage of inhibition of the control activity determined in the absence of compound.

The compound SU5614 (Calbiochem) (1pM) is included in each plate as inhibition control.

The IC 5 0 values for the compounds are calculated by plotting the dose-response curves. The IC 5 0 corresponds to the concentration of compound that induces a 50% inhibition of the kinase activity.

Particular compounds of the invention inhibit KDR activity with IC 5 0 's in the range 100 micromolar to nanomolar. Preferred compounds of the invention inhibit KDR activity with IC 5 0 's in the range 3000 nanomolar to 10 nanomolar. Particular preferred compounds of the invention inhibit KDR activity with IC 5 0's in the range 300 nanomolar to 10 nanomolar.

II) Cellular activity on endothelial cells 1) Inhibition of the VEGF-dependent proliferation of HDMECs The anti-KDR activity of the molecules is assessed by incorporating [14C]-thymidine into HDMECs (Human Dermal Microvascular Endothelial Cells) in response to VEGF.

HDMECs (Promocell, passage 5 to 7) are inoculated in 100l at 5000 cells per well in Cytostar (Amersham) 96-well plates precoated with attachment factor (AF, Cascad Biologics) at 37 0 C, 5% C02, on day 1. On day 2, the complete medium (basal medium supplemented with 5% FCS and a mixture of growth factors) is replaced with minimum medium (basal medium supplemented with 5% FCS) and the cells are incubated for 24 hours. On day 3, the medium is replaced with 200gl of fresh medium that has or has not been supplemented with 100ng/ml of VEGF (R&D System) and containing or not containing the compound of the invention and 0.1tCi [14C]-thymidine. The cells are incubated at 37'C under C02 for 4 days. The incorporation of [14C]-thymidine is then quantified by counting the radioactivity.

'he tests are performed in 3 wells. The final concentration of DMSO in the test is The of inhibition is calculated as follows: [cpm(+VEGF) cpm (+VEGF cpd) cpm(+VEGF) cpm (BM5%FCS)]x100.

2) Inhibition of the production of TF (Tissue factor) by endothelial cells in response to VEGF The endothelial cells are inoculated at 20 000 cells per well in a 96-well plate precoated with attachment factor. After culturing for 8 hours, the medium is changed and the cells are preincubated with the compounds (0.1 DMSO final) in basal medium for 16 hours. The synthesis of the TF (tissue factor) is induced by adding VEGF (100ng/ml final). After incubating for 6 hours, the cells are rinsed and lysed. The tissue factor is then detected by means of the Imubind ELISA test.

WO 03/035065 PCT/GB02/04763 -561- 3) Effect of the molecules on the VEGF-independent growth of HDMECs The IIDMECs (5000 cells per well) are inoculated in complete medium in Cytostar (Amersham) 96-well plates precoated with attachment factor (AF, Cascad Biologics) at 37 0 C, 5% C02, on day 1.

The whole medium is then removed and the cells are incubated in 200l of complete medium containing the molecules of the invention and [14C]-thymidine (0.1 The incorporation of the [14C]-thymidine is measured using a Wallac counter after incubating for 3 days. The of inhibition is calculated as follows: [cpm(CM) cpm (CM cpd) cpm(CM)]xl00.

Table 5below gives the results obtained in the above tests for the products indicated as examples in the present patent application.

TABLE

IC

5 0 (IM) on of inhibition of the Example inhibition of the phosphorylation of PLCy by No. phosphorylation of KDR (product tested at a PLCy by KDR concentration of 14 1.2 0.8 16 2 3.4 21 1 0.47 2 0.45 3 -91.8 4 0.45 91.9 6 0.33 7 0.72 8 0.67 9 0.35 WO 031035065 PCT/GB02104 763 -562- 0.34 11 0.26 12 0.16 13 0.61 18 -91.2 23 2 WO 03/035065 PCT/GB02/04763 563- The pharmacological results obtained in the above tests for products indicated in examples in the present application are given in the table 6 below, the degrees of activities of the products being indicated by signs according to the ranges of activity indicated in the table, iLe.: for an activity of greater than 3 micromolar 5-1-v for an activity of between 0.3 and 3 micromolar for an activity of less than 0.3 micromolar TABLE 6 Activity Example No. Molecular formula Molecular IC 5 0 3 pjiM weight M<IC 50 3 IM 28 C221118N603S 446.49..

29 C20H21N502 363.42 C221-I6BrN5O 446.31 31 C231-119N503S 445.50 32 C26H19N50 417.47 33 C23Hl6F3N50 435.41 i--i 34 C20H I5N5OS 373.44 C24H22N60 410. 49 36 C26H-30N603 474.56 37 C22H16N603 412.41 38 C21HI6N60 368.40 39 C22Hl68rN5O 446.31 C23H419N502 397.44 41 C23H-17N503 411.42 42 C24Hl7N50S 423.50 43 C21H-19N70 385.43 44 C23H16F3N502 451.41 WO 03/035065 PCT/GB02/04763 -564- C23Hl9N50 381.44 46 C2lHl7N5OS 387.46 47 C23H16F3N50 435.41 48 C28H21N502 459.51 49 C23H16F3N502 451.41 C21H-23N502 377.45 51 C20Hl7N70 371.40 52 C25H23N50 409.49 53 C22H19N502 385.43 ±4 54 C24H1ITh50S 423.50 C26H24N603 468.52 56 C2IH15C1N6O 402.84 57 C24H17N50S2 455.56 ±4 58 C24Hl9N502 409.45 59 C23U-16N60 392.42 C24H16CINSOS 457.94 61f C23H16F3N50 435.41+ 62 C23H19N50S 413.50 63 C24H17N50S 423.50..

64 C21H21N502 375.43 C24H19N503 425.45 66 C20H15N502 357.37 67 C22H16N603 412.41 68 C20HISN50S 373-44 -H- 69 C24H2lN50 395.47 C24Hl9N70 421.46 71 C23H19N50 381.44 72 C22H16C1N50 401.86 WO 031035065 WO 03/35065PCT/GB02/04763 73 C22H I8N603S 446.49 74 C20H2lN502 363.42 C22Hl6BrN5O 446.31 76 C26H19N50 417.47 77 C2OH15N5OS 373.44 78 C24H22N60 410.48 79 C22H16N603 412.41 C21H16N60 368.40 ±4 81 C22Hl6BrN5O 446.31 82 C231-19N502 397.44 83 C24H17N50S 423.50 84 C281-21N502 459.51 C23H16F3N502 451.41 +F 86 C211-15C1N60 402.84 87 C24H19N502 409.45 88 C23H16F3N50 435.41 89 C23H19N50S 413.50 C20H-15N502 35 7.3 7 91 C22H16N603 412.41 92 C24H21N50 395.47 93 C221-116CIN50 401,86 94 C21H15N50 353.38 +1- C22H17N50 367.41 96 C23Hl9N50 381.44 97 C201-11N4 310.36 98 C20Ht2Cl2N4 379.25+ 99 C24H16N4 360.42 100 C2OHl3FN4 328.35 101 C2OH13CIN4 344.80 102 C21H16N40 340.39 103 C2OHI2CIFN4 362.79 104 C20Hl2C12N4 379.25 105 C26H16N4S2 448.57 WO 03/035065 WO 03/35065PCT/GB02/04763 66- 106 C26HI18N4 386.46+ 107 C21HI6N4 324.39+ 108 C21Hl6N4 324.39 109 C'2 1H1I6N4 324.39 110 CI8Hl2N4S 316.39 111 C21H13F3N4 378.36+ 112 C211-13F3N4 378.36+ 113 C201-13C1N4 344.80 114 C21H16N40 340.39 115 C22H-18N4 338.41 116 C22HI8N4 338.41+ 117 C21H14N402 354.37 118 C24H-22N4 366.47+ 119 C20H20N4 316.41 120 C22H18N402 370.41 121 C20Hl4N40 326.36 122 C20H-114N40 326.36 123 C20HI2CI2N4 379.25 124 C21HI3F3N40 3 94. 36 125 C22H16N40 352.40 126 C22H14N4S 366.45 127 C23H-20N403 400.44 128 C2OHI4N40S 358.42 129 C22H16N40 352.40 130 C27H201'.40 416.48 131 C26H17FN4 404.45 132 G22H14N4S 366.45 133 C21Hl6N40 340.39 WO 031035065 WO 03/35065PCT/GB02/04763 67- 370.48 134 C22HlI8N4S 135 C20H]2F2N4 346.34 136 C211113F3N40 394.361 137 C2IHI5FN4 34 2.3 8 138 C22Hl5FN4 354.39 139 C22H1I5C1N4 370.84 140 C231-118N402 382.42 141 C21H16N40 340.39 142 C18Hl2N40 300.32 -H- 143 C27H20N40 416.48 144 C231120N4 352.44 1 145 C21H16N402S 388.45 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 WO 031035065 WO 03/35065PCT/GB02/04763 68- 162 163 164 165 166 4-4 167 168..

169 170 171 172 173 174 175 4-4 176..

177 178 179 180..

181 182 183 184 185 186 187 188 189 WO 031035065 WO 03/35065PCT/GB02/04763 190 I_ _I 192 +4 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 WO 03/035065 PCT/GB02/04763 -570- 218 219 220 221 222 223 224 225 226 227 228 C. IN VITRO TEST PROCEDURES FOR ITK 1. Inhibitory effects of compounds on ITK kinase Inhibitory effects of compounds on ITK kinase were determined using a Fluorescence Polarization assay.

ITK kinase was produced with Baculovirus expression system.

1.1 Assay Technology The assay measures the autophosphorylation of the ITK kinase. The assay is configured based on Fluorescence Polarization method. The enzyme is incubated with ATP and compound. After incubation, a mixture containing fluorescence labeled phospho-peptide tracer and anti-phosphotyrosine antibody (CoreHTS tyrosine kinase assay kit, P2837, Panvera) is added in order to generate the specific signal that is reversely proportional to the phosphorylation of the enzyme. The phosphorylated ITK generated from the kinase reaction will compete specifically for the antibody and release the fluorescence labeled tracer. Inhibition of ITK kinase activity will result in increased FP value.

1.2 Assay Conditions The assay is run in BD black 384-shallow well plate. For enzyme reaction, the final reagent concentration/well: 16.5nM ITK enzyme, 501.M ATP, 20 mM Hepes (pH 0.15M NaCI, 3mM WO 03/035065 PCT/GB02/04763 -571- MgCl2, ImM MnCl 2 0.01% Triton X-100, ImM DTT, 5% glycerol and 0.1% y-globulin. Incubation time: 45 minutes. Temperature: 25°C. Reaction volume: 10pL. For immuno-reaction, add 10pL of Stop-Detection mixture containing 10mM EDTA, 1:2 dilution of antibody and 1:4 dilution of tracer in lx dilution buffer (Panvera). Incubation time: 90 minutes at 37 0 C followed by room temperature minutes.

1.3 Assay Procedure: 1. Add 5.0pL ATP solution to each well of the black 384-shallow well plate.

2. Add 1.0pL compounds or 1% DMSO in TBS buffer.

3. Start Reaction by adding 5.0plL enzyme solution.

4. Incubate at 25 0 C for 45 minutes.

Add 10ltL of stop-detection solution.

6. Incubate for 90 minutes at 37°C followed by incubation at room temperature for 60 minutes.

7. Read by LJL Acquest at FP mode using a fluorescence filter set 485 nm, 535 nm) with FL dichroic mirror. Integration Time: 200.000 ps. G factor instrument dependent [G factor (Slrllr ll Se'B /r) Inhibition of ITK activity with compounds of the invention was expressed as percentage inhibition of control activity determined in the absence of test compounds.

The IC 50 values for the compounds are calculated by plotting the dose-response curves. The IC 5 0 corresponds to the concentration of compound that induces a 50% inhibition of the kinase activity.

Particular compounds of the invention inhibit ITK activity with IC 50 's in the range 100 micromolar to 1 micromolar.

IN VIVO TEST PROCEDURES A. IN VIVO TEST PROCEDURES FOR SYK 1. Inhibition of antigen-dependent passive cutaneous anaphylaxis.

Compounds of the invention were assessed in the Balb/c mouse passive cutaneous anaphylaxis (PCA) model. The model used in these in vivo studies mimics relevant features of mast cell-driven antigendependent activation and functional responses. These studies demonstrated that compounds of the invention inhibit the increase in edema observed in the sensitized mouse ear following antigen exposure.

WO 03/035065 PCT/GB02/04763 -572- Protocol for sensitization and challenge Balb/c mice were sensitized in the right ear on day 0 with monoclonal anti-DNP IgE 2 administered intradermally in the ear pinnae. The left ear was injected with PBS to serve as a control.

Sixteen to twenty hours after sensitization, mice were antigen challenged with 150 pg DNP-albumin administered i.v.

Protocol for dosing and calculation of results Test drug was administered orally 15-60 minutes before DNP-albumin antigen challenge. Doses of compound were administered at half log divisions between 3 and 100 mg/kg. A control set of mice was administered vehicle alone, and thereafter treated identically. Ear thickness was measured at t 0, 30 or 60 minutes after DNP-albumin antigen challenge, in both ears, by digital calipers and expressed in units of mm x 0.01. Ear thickness at t-0 was recorded to serve as a baseline. The net increase in both the right and left ear was calculated by subtracting the values at t=0 from those at t=15, 30 or 60 minutes. Percent inhibition of ear edema was then calculated as [ear thickness of control-(ear thickness of right ear-ear thickness of left ear)]/ear thickness of control x 100 for each time point measured.

Results The compound demonstrated dose-dependent inhibition of ear edema following oral administration of 3-100 mg/kg. Inhibition of ear edema was observed at t= 15, 30 and 60 minutes after antigen challenge.

These results indicate that compounds of the invention inhibit mast cell activation and functional responses when given orally in a mouse model of passive cutaneous anaphylaxis.

2. Antigen-induced degranulation of Rat Bosophilic leukemia (RBL) cells as measured by [3H] 5-hydoxytryptamine (serotonin) release 2.1 Cell culture, labelling of RBL-2H3 cells and performance of assay.

Method A: For each 24-well culture plate to be set up, 6 x 106 cells RBL-2H3 cells were washed and resuspended in 15 mL DMEM-10 containing 25Il of ImCi/ mL 3 H1-serotonin (0.5ltCi/ mL final concentration) and lyg/mL (15mL) of anti-DNP IgE. 0.5 mL of cell suspension was added into each well of a 24-well plate. Cells were incubated for 2 days at 37 0 C, until they have reached confluence.

The medium was gently aspirated from each well and the cells were then washed with assay buffer. A WO 03/035065 PCT/GB02/04763 -573final volume of 200mL of assay buffer or the test compounds at the appropriate concentrations) was then added to each of three replicate wells. 100ng/ mL of DNP (antigen) was then added to all wells (excluding negative control wells i.e. to measure spontaneous 3 H]-serotonin release in the absence of receptor cross-linking). The cells were incubated for 30 minutes at 37 0 C and the reaction was stopped by transferring 100l of the supernatant from each sample into a liquid scintillation microtitre plate kept on ice. 200.Il of scintillant-40 was then added to each well of the microtitre plate and the plate was read on a Topcount Liquid Scintillation Counter.

Method B: RBL-2H3 cells are maintained in T75 flasks at 37°C and 5%C0 2 and passaged every 3-4 days. To harvest cells, 5 ml trypsin-EDTA is used to rinse the flask once, then 5 ml trypsin is added to each flask, and incubated at room temperature for 2 minutes. Cells are transferred to a tube with 14ml medium, spun down at 1100 rpm RT for 5 minutes and resuspended at 2x10 5 /ml. Cells arc sensitized by adding l1l of DNP-specific IgE (1 mg/ml stock solution) to every 10 ml of cells. 2001l of cells are added to each well of a flat-bottom 96 well plate (40,000 cells/well), and the plate incubated overnight at 37 0 C and 5%C0 2 The next day compounds are prepared in 100% DMSO at 10mM. Each compound is then diluted 1:100 in assay buffer and then diluted further in 1% DMSO-assay buffer to obtain final concentrations of0.03-30iM. 80pl assay buffer (Hank's Balanced Salt Solution with Ca-/Mg", 2 mg/ml glucose, 0.03% BSA) is added to each well, followed by 10lO1 of diluted compound. Incubation follows for 5 minutes. 10l 1 of DNP-HSA (100ng/ml) is added to each well and incubated at 37 0 C (no C0 2 for 30 minutes. As one control, 1% DMSO alone (no compound) is added to a set of wells to determine total release. As another control, buffer is added instead of DNP- HSA to another set of wells to determine the assay background. After 30 minutes incubation, the supernatants are transferred to a new 96-well plate. Add 50[l supernatant to each well of an assay plate. Add 100l of substrate solution (5 mM PNAG in 0.4M citric acid, 0.2M Na 2

HPO

4 to each well and incubate at 37 0 C for 90 minutes. Add 5 0ltl of 0.4 M glycine solution to stop the reaction and the plate is read at 405 nm on a Molecular Devices SpectraMax 250 plate reader.

2.2 Calculation of results Method A The mean s.e.m. of each set of triplicate wells was calculated.

(ii) Maximum response was the positive control wells containing antigen (Ong/mL) but no compound.

(iii) Minimum response was the control wells containing no antigen and no compound.

(iv) Using these values as the maximum (100%) and minimum values respectively, the data was normalised to give a percentage of the maximum response.

574 o00 A dose response curve was plotted and the IC 50 of the compound was Scalculated.

;Z

Method B The mean SD of each set of triplicate wells was calculated.

(ii) Maximum response was the positive control wells containing antigen (100ng/mL) but no compound.

(iii) Minimum response was the control wells containing buffer (no antigen) and no compound.

(iv) Using these values as the maximum (100%) and minimum values respectively, the experimental data was calculated to yield a percentage of the maximum response (designated control).

A dose response curve was plotted and the IC 5 0 of the compound was calculated using Prism GraphPad software and nonlinear least squares regression analysis.

Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

Claims (32)

1. 2. A pharmaceutical composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier or excipient.
2. 3. A compound according to claim 1 of formula (Ixa) R R N R SW M N R (Ixa) wherein R 7 is hydrogen or alkyl; R 8 and R 9 are independently selected from hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 14 -C(=O)R 4 -C(=O)NY 1 y 2 -C(=O)OR 4 579 00 8 N(R 6 )C(=O)R 4 -N(R 6 )C(=O)NY1Y 2 -N(R 6 )C(=O)OR 4 -N(R 6 )S0 2 R 4 -NY 1 y 2 -OR 4 -OC(=O)R 4 -OC(=O)NY1y 2 -S(O)nR 4 and r -S(0) 2 NY1Y 2 where X, Y, Z, W, R 4 R 6 Y 1 Y 2 and n are defined in claim 1; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or o solvate.
3. 4. A compound according to claim 3 wherein R 2 and R 3 are independently alkyl; aryl; CN; NO 2 halo; haloalkyl; heteroaryl; OR 4 C(=O)R 4 C(=O)NY1Y2 C(=0)OR 4 NHC(=O)R 4 CH(OH)aryl; S(0) 2 NY1Y 2 or S(O)nR 4 where R 4 R 6 Y' and Y 2 and n are defined in claim 1. A compound according to claim 3 wherein R 2 is attached to X and R 3 is attached to Y; X-R 2 is C-CH 3 C-CH 2 CH 3 C-CH(CH 3 2 C-OCH 3 C-OCH 2 CH 3 C-Br or C-CI; Y-R 3 is C-CH 3 C-CH 2 CH 3 C-OCH 3 C-Br, C-CI, C-F, C or C-C(=O)-NH-CH-
4. 6. A compound according to claim 3 wherein R 2 is CH 3 and is attached to Y and R 3 is CH 3 and is attached to Z.
5. 7. A compound according to claim 3 wherein CR 2 is attached to X; and CR 3 is attached to Y and R 2 and R 3 form the group -CH 2 -O-CH 2 580 00
6. 8. A compound according to claim 3 wherein CR 2 is attached to X; CR 3 is attached to Y, and R 2 and R 3 form the group -CH 2 -CH 2 -CH 2
7. 9. A compound according to claim 3 wherein R 7 represents hydrogen. A compound according to claim 3 wherein R 8 represents hydrogen, C 1 9 4 alkyl, -SR 4 S-NY 1 y 2 or -OR 5
8. 11. A compound according to claim 3 wherein R 9 represents hydrogen, C 1 7alkyl, aryl, -C(=O)NY 1 Y 2 -N(R 6 )C(=O)R 4 where R 4 is alkyl optionally substituted by aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or where R 4 is NY 1 y 2 or -OR 5 or where R 4 is aryl or where R 4 is cycloalkyl, or where R 4 is heteroaryl, or where R 4 is heterocycloalkyl; or R 9 represents -N(R 6 )C(=O)NYY 2 -NY 1 y 2 or alkyl substituted by -N(R 6 )C(=O)NY 1 Y 2
9. 12. A compound according to claim 3 wherein R 2 is H; or R 3 is CH 3 and is attached to Z; R 7 represents hydrogen; R 8 represents hydrogen, C 2 4 alkyl, -SR 4 -NY 1 y 2 and R 9 represents hydrogen, C2-7alkyl, aryl -C(=O)NY'Y 2 -N(R6)C(=O)R 4 particularly -NHC(=O)R 4 -N(R 6 )C(=O)NYY 2 -NY 1 y 2 or alkyl substituted by N(R 6 )C(=O)NY1Y 2
10. 13. A compound according to claim 3 wherein 581 00233 C R 2 is H; R 3 is attached to Y and Y-R 3 represents C-Cl 1 4 alkyI, C-aryl, 0N C-CN, C-NO 2 C-halo, C-haloalkyl, 0-heteroaryl, C-OR 4 C-C(=O)R 4 C- C=O)NY y 2 C-C(=O)0R 4 or C-CH(OH)aryl; R 8 represents hydrogen, C2-4alkyl -SR 4 -NY 1 y 2 or -OR 5 and R 9 represents hydrogen, C2-7alkyl, aryl -C(=O)NY'Y -N(R 6 y 2 -NY 1 y 2 or alkyl substituted by -N(R 6 )C(=O)NY1 y 2
11. 14. A compound according to claim 3 wherein R 2 is attached to X and X-R 2 represents C-CH 3 C-CH 2 CH 3 C-CH(CH 3 2 C-OCH 3 C-OCH 2 CH 3 C- Br or C-Cl; R 3 is attached to Y and Y-R 3 represents C-CH 3 C-CH 2 CH 3 C-OCH 3 C-Br, C- Cl, C-F, c or c-c(=o)-NII-CHj R 7 represents hydrogen; R 8 represents hydrogen, C 2 4 alkyl -SR 4 -NY 1 y 2 or -OR 5 and R 9 represents hydrogen, C 2 7 alkyl, aryl y 2 -(6C=)4 -N(R 6 y 2 -NY 1 y 2 or alkyl substituted by -N(R 6 )C(=O)NY1 y 2 A compound according to claim 3 wherein R 2 and R 3 are CH 3 and attached to Y and Z respectively; R 7 represents hydrogen; 582 00 R 8 represents hydrogen, C 2 4 alkyl, -SR 4 -NY 1 y 2 or -OR 5 and c^ R 9 represents hydrogen, C27alkyl, aryl, -C(=)NY1Y 2 -N(R6)C(=O)R 4 S-N(R 6 )C(=O)NY1Y 2 -NY 1 y 2 or alkyl substituted by -N(R 6 )C(=O)NY1Y2
12. 16. A compound according to claim 3 wherein n CR 2 is attached to X and CR 3 is attached to Y where R 2 and R 3 form the group -CH 2 -O-CH 2 R 7 represents hydrogen; R 8 represents hydrogen, C 2 4 alkyl -SR 4 -NY 1 y 2 or -OR 5 and R 9 represents hydrogen, C 2 7 alkyl aryl -C(=O)NY1y 2 ;-N(R6)C(=O)R 4 -N(R 6 )C(=O)NY1y 2 -NY 1 y 2 or alkyl substituted by -N(R 6 )C(=O)NY 1 Y 2
13. 17. A compound according to claim 3 wherein CR 2 is attached to X and CR 3 is attached to Y where R 2 and R 3 form the group -CH 2 -CH 2 -CH 2 R 7 represents hydrogen; R 8 represents hydrogen, C 2 4 alkyl, -SR 4 -NY 1 2 or-OR 5 and R 9 represents hydrogen, C 2 7 alkyl, aryl, -C(=O)NYY 2 -N(R6)C(=O)R 4 -N(R 6 )C(=O)NY1y 2 -NY 1 y 2 or alkyl substituted by -N(R 6 )C(=O)NY1Y2
14. 18. A compound according to claim 3 wherein R 8 is hydrogen or -CH 3 and 583 R 9 is -CH 2 -CH(CH 3 2 -C(=O)-NH-CH 2 GH 3 3 3 -C(=0)-NH-CH 2 CH 2 CH 3 -C(=O)-NH-H(H 3 2 3 2 CH 2 OH, 2 GH 3 -C(=O)-NH-CH 2 CHI- 2 0CH 3 0, -NI-C(=O)-CH(CH 3 2 -NH-C(=0)-CH 3 3 3 ,9 -NH-C(=O)-CH(H 3 )CH 2 CH 3 -NH-C(=O)-CHi-/ -N -NH-C(=O)-CH 2-o 2 2 CH 3 ,I 2 H(GH 3 2 2 C(CH 3 3 -NH-C(=O)-GH 3 2 -NI-(=O)-CH 2 -N 0, -NH-C(=)-CH2OCH 3 /C -NH-C(=0)/I -NH /0 HG3 N H 3 C -NI-C(=0)-NHCH 3 b I -NH-C(=)-NCH 2 CH 3 -NH-C(=)-NHCH(H 3 2 -NH-C(=)-NHG(CH 3 3 -HC=)NC 3 -NH-C(=O)-N(CH 3)21 584 -NH-C(=O)-N(CH 2 CH 3 2 -NH-C(=O)-NH-CH 3 -CH 2 -NH-C(=O)-CH(CH 3 2 or -NH-C(=O)-NH--CH 2 0/ -CH 2NH-C(=O) 0
15. 19. A compound according to claim 3 wherein R 9 represents hydrogen and R 8 represents -CH(CH 3 2 -S-CH 3 1 S-CH 2 CH 3 or SC2 A compound according to claim 3 wherein R 2 is attached to Y and Y-R 2 is CH, C-CH 2 CH 3 C-CH 2 CH 2 CH 3 C-0 CN C6 F C-b N C 0 C C: 0 C-CN, C-Br, C-CF 3 C N, C-OCH 3 C-OCH 2 CH 3 1 C-OCHF 2 1 C-OCF 3 C-O-CH 2 C-C(=O)-NH-CH3' C--C 2 3 C-C(=0)-NH-CH 2 3 1 585 C-C(=O)-NH-CH(CH A C-C(=O)-NI-CtH 2 C 2 CN, CH 3 C-C(=O)-NH-CH1 2 6 C-C(=O)-NII-(CH 2 /0\ C-C(=O)-NII-(CH 2 N1 C-C(=O)-NH--CH 2 C-C(=O)-NH-C(CH 3 2 -CH 2 OH, C-C(=O)-NI-CH 2 CH 2 OCH 3 CH 3 C-C(=O)-NII-(CH 2 0 C-C(=0)-NH-(CH 2 )-N C-C(=0)-NE--CH 2 C-C(=O)-NH-(CH 2 )jN~ C-C(=0)-NH0 I C-C(=O)OCH 3 C-C(=O)OH. C-CH(OH)o I SO 2 CH 3 or C-SO 2-NH-CH 2 an and Z is CH.
16. 21. A compound according to claim 3 wherein R 2 is attached to X and X-R 2 is C-CH 3 or C-CH 2 CH 3 R 3 is attached to Y and Y-R 3 is 586 C-OH 3 C-CH 2 CH 3 C-CH(CH 3 2 C-Br C-Cl, C-F, C or C-C(=O)-NH-CH
17. 22. A compound according to claim 3 wherein R 2 is attached to X and X-R 2 is C-OCH 3 R 3 is attached to Y and Y-R 3 is OH, C-OH 3 C-CH 2 CH 3 C-Cl or C-OCH 3
18. 23. A compound according to claim 3 wherein R 2 is attached to X and X-R 2 is C-OCH 2 CH 3 R 3 is attached to Y and Y-R 3 is C-F.
19. 24. A compound according to claim 3 wherein R 2 is attached to X and R 3 is attached to Y where R 2 and R 3 atoms form the group -CH 2 -CH 2 -CH 2 A compound according to claim 3 wherein R 2 is attached to X and R 3 is attached to Y where R 2 and R 3 form the group -CH 2 -O-CH 2
20. 26. A compound according to claim 3 wherein R 8 is hydrogen. and -C(=O)-NI-CH 2 CH 3 -C(=O)-NH-CH 2 CH 2 CH 3 -C(=O)-NH-CH(CH 3 2 -C(=O)-NH-CH 2 CH (CH 3 2 -C(=O)-NI-C(CH 3 3 ,1 -C(=O)-NH-C(CH 3 2 CH 2 OH, 2 CH 3 2 -C(=O)-NH-CH 2 CH20CH 3 -NI-C(=O)-CH(CH 3 2 ,1 -C(=O)-NHCH 2 -C(=O)-NH-C -NH-C(=O)C oI -NH-C(=O)-(CH 2 )CH 3 -NH-C(=O)-C(CH A -NI-C(=O)-CH 2 CH(CH A 2 587 -NH-C(=O)-CH(CH 3 )CH 2 CH 3 N -NH-C(=O)-CH 2 C(CH 3 3 -NH-C(=O)-C-1 2 0 -NH-C(=O)-CH 2 OCH 3 -N}I-C(=0)cI -NH-C(=0)/I -NH-C(=O)c -NH-C(=O)-NHCH 2 CH 3 -NH-C(=O)-NHC(CH 3 3 -NE-C(=O)-N(CH 3 2 -NHi-C(=O)-NH--CH 2 0/' -NH-C(=O)-NHCH 3 -NH-C(=O)-NICH(CH 3 2 -NH-C(=O)-N(CH 2 CH 3 2 -NH-C(=O>-NHCH -NH--C(=O)-NH-0 N-CH 3 or 0
21. 27. A compound according to claim 3 wherein R 2 is H and is attached to X; and R 3 is attached to Y and Y-R 3 is 588 00 COH 3 C-00H 2 0H 3 O-OOHF 2 C-CF 3 C-C(=O)-NH-CHi-- or C-C(=O)-N1-CH~ and Z is OH. ci28. A compound according to claim 3 wherein R 2 is OH 3 or CH 2 0H 3 and is attached to X; and R 3 is attached to Y and Y-R 3 is C-OH 3 or O-0H 2 0H 3 0-Cl or 0-F.
22. 29. A compound according to claim 3 wherein R 2 is attached to X and X-R 2 is O-OCH 3 R 3 is attached to Y and Y-R 3 is C-OH 3 C-0H 2 0H 3 0-Cl, 0-F, or 0- 00H 3 A compound according to claim 3 wherein R 2 is attached to X and X-R 2 is C-OCH 2 CH 3 R 3 is attached to Y and Y-R 3 is 0-Cl or 0-F.
23. 31. A compound according to claim 3 wherein R 2 is attached to X and R 3 is attached to YT, where R 2 and R 3 form the group -0H 2 -CH 2 -CH 2
24. 32. A compound according to claim 3 wherein R 2 is attached to X and R 3 is attached to Yt, where R 2 and R 3 form the group -0H 2 -O-0H 2
25. 33. A compound according to claim 1 selected from the group consisting of 2-(1I H-indazol-3-yl)-1 H-benzim idazole-5-carboxylic acid benzylamide; 2-(1I H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-methylam ide; 2-(1I H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-ethylamide; 1 H-indazol-3-yl)-1 H-benzim idazole-5-carboxylic acid N-isopropylamide; 589 00 2-(1 H-indazol-3-y)-1 H-benzimidazole-5-carboxylic acid N-phenylam ide; 1 H-indazol-3-y)-1 H-benzimidazole-5-carboxylic acid N-phenethylam ide; ,6-dimethyl-2-(5-methylsulfanyl-1 H-pyrazol-3-yl)-1 H-benzoimidazole; 6O-chloro-5-methyl-2-(5-methylsulfanyl-1 H-pyrazol-3-yl)-1 H-benzoim idazole; 6-chloro-2-(5-ethylsulfanyl-1 H -pyrazol-3-yI)-5-m ethyl- 1 H-benzoimidazole; 2-(5-methylsulfanyl-1 H-pyrazol1-3-yI)-5-trifl uo ro methyl- 1 H-benzoim idazole; pro pyl methyl sulfa nyl- 1 H-pyrazol-3-yI)-5,6-d im ethyl- 1 H-benzoimidazole; 2-(5-ethylsulfanyl-1 H-pyrazol1-3-y im ethyl -1 H-benzoim idazole; ,6-d imethyl-2-[5-(pyrid in-3-ylmethylsulfanyl)-1 H-pyrazol-3-y]-1 H- benzoimidazole; 5-fluoro-2-[5-methylsulfanyl)-1 H-pyrazol-3-y]-1 H-benzoimidazole; 5,6-d imethyl-2-(5-phenethylsulfanyl-1 H-pyrazol-3-yI)-1 H-benzoimidazole; 4-m ethyl-2-(5-m ethyl sulfa nyl- 1 H-pyrazol-3-yI H-benzoim idazole; ,6-d imethyl-2-(5-benzylsulfanyl-1 H-pyrazol-3-yl)-1 H-benzoim idazole; 6-chloro-5-methyl-2-(5-morpholin-4-yl-1 H-pyrazol-3-y)-1 H-benzoimidazole; ,6-d i methyl-2-[5-(th ioph en-2-yl methyl sulfa nyl)- 1 H-pyrazol-3-y]-1 H- benzoimidazole; 2-(5-ethylsulfanyl-1 H-pyrazol-3-yl)-5-methoxy-1 H-benzoim idazole hydrochloride; 5-methyl-2-(5-methylsulfanyl-4-propyl-1 H-pyrazol-3-yI)-1 H-benzoimidazole; 590 2-(5-(4-methoxy-benzylsulfanyl)-4-propyl-l H-pyrazol-3-yl)- 5-methyl-i H- benzoim idazole; 2-(5-benzylsulfanyl-4-isopropyl-1 H -pyrazol1-3-yI)-5-m ethyl- 1 H-benzoimidazole; sulfa nyl-4-m ethyl- 1 H-pyrazol-3-yl)-5-methoxy-1 H-benzoim idazole; ethylsulIfa nyl-4- methyl- 1 H-pyrazol1-3-yI)-5-m ethyl- 1 H-benzoimidazole; 3-(5-chloro-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-ylamine; 3-(5,6-dichloro-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-ylamime; 3-(5,6-dimethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-ylamine; 3-(5-ethyl-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-ylamine; 3-(6-chloro-5-methoxy-1 H-benzoim idazol-2-yI H-pyrazol-4-ylamine; 3-(5-methoxy-1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-ylamine; 3-(5-ethoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-ylamine; uo ro-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-ylamime; 3-(5-trifluoromethoxy-1 H-benzoim idazol-2-y)-1 H-pyrazol-4-ylamime; uoro methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-ylamime; 2-(4-amino-I H-pyrazol-3-yI H-benzoimidazole-5-carboxylic acid methyl ester; 3-(1 H-benzoimidazol-2-y)-1 H-indazole; 3-(5-methoxy-1 H-benzoim idazol-2-yi)-1 H-indazole; [2-(indazol-3-yl)-1 H-benzoim idazol-5-yI]-phenyl-metha none; 591 00 2-(lI H-indazol-3-yI)-3H-benzoimidazol-4-o; 2-phenyl-1 H-im 3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-indazole; 2-(l1 H-indazol-3-yI)-3H-imidazo[4,5-c]pyridine; 2-(l1 H-indazole-3-yI)-3H-imidazo[4, 2-(l1 H-pyrazol-3y1)-1 H-benzoimidazole; 3-(5,6-d imethyl-1 H-benzoim idazol-2-yI)-5-methoxy-1 H-indazole; 3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-yI)-5-methoxy-1 H-indazole; 3-(5,6-dimethyl-1 H-benzoimidazol-2-yi)-5-fluoro-1 H-indazole; 3-(5,6-d imethyl-1 H-benzoimidazol-2-y)-6-fluoro-1 H-indazole; 3-(5,6-d imethyl-1 H-benzoim idazol-2-yI)-5-methyl-1 H-indazole; 3-(5,6-dimethyl-1 H-benzoimidazol-2-yI)-6-methoxy-1 H-indazole; 5,6-d imethyl-2-(4-phenyl-1 H-pyrazol-3-yI)-1 H-benzoim idazole; 3-(5-ethyl-1 H-benzoim idazol-2-yI)-1 H-indazole; 3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 H-indazole; pro pyl-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 H-indazole; 3-(5-bromo-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 H-indazole; 3-(5-bromo-1 H-benzoim idazol-2-y)-1 H-indazole; 3-(5-(3-cyano)phenyl-1 H-benzoimidazol-2-y)-1 H-indazole; 592 00 3-(5-(pyrid-3-y)-1 H-benzoimidazol-2-y)-1 H-indazole; 3-(6-methyl-5-phenyl-1 H-benzoim idazol-2-yi)-1 H-indazole; 3-(5-phenyl-1 H-benzoimidazol-2-y)-1 H-indazole; 3-(5-(2-fluoro)phenyl-1 H-benzoimidazol-2-yl)- 1 H-indazole; ,6-methylenedioxy)phenyl-1 H-benzoimidazol-2-y)-1 H-indazole; 3-(5-(2-methoxy)phenyl-1 H-benzoim idazol-2-yl)-1 H-indazole; 3-(5-(4-chloro)phenyl-1 H-benzoim idazol-2-yl)-1 H-indazole; ethyl) phe nyl- 1 H-benzoim idazol-2-yI H-indazole; 3-(5-benzyloxy-1 H-benzoimidazol-2-y)-1 H-indazole; ,6-methylenedioxy-1 H-benzoim idazol-2-yI)-1 H-indazole; 3-(5,6-dimethoxy-1 H-benzoimidazol-2-y)-1 H-indazole; 3-(5,6-d iethyl- 1 H-benzoimidazol-2-yl)-1 H-indazole; 5-d imethyl-1 H-benzoimidazol-2-yl)-1 H-indazole; 1 H-indazol-3-yl)-1 3-(5-methoxycarbonyl-1 H-benzoim idazol-2-yI)-1 H-indazole; 3-(5,6-d imethyl-1 H-benzoim idazol-2-yl)-5-ethoxy-1 H-indazole; ,6-dimethyl-1 H-benzoimidazol-2-yl)-pyrazole-4-carboxylic acid ethyl ester; 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-yl)-1 H-benzoim idazole-5-carboxylic acid methyl ester; 593 00 0 3-(5 ,6-dimethyl-1 H-benzoimidazol-2-yI)-5-methyl-pyrazole-4-carboxylic acid ethyl CI ester; 3-(1 ,5,6,7-tetra hyd ro-1, ,3-d iaza-s-i nd ace 1 H-pyrazole-4-carboxylic acid cyclopropylamide; ethoxy-6-m ethyl- 1 H-benzoim idazol-2-yl)-1 H-pyrazole-4-carboxylic acid isopropylamide; 0 3-[5-(2-morpholin-4-yI-ethoxy)-1 H-benzoim idazol-2-y]-1 H-indazole; 3-(5,6-d imethyl-1 H-benzoim idazol-2-yi)-1 H-pyrazole-4-carboxylic acid (2- methoxy-ethyl)-am ide; 3-(5,6-d imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid pro pyla mid e; ,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid (tetrahyd ro- pyran-4-yl)-amide; 3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 3-(5-difluoromethoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid isopro pylam ide; 3-(5-difluoromethoxy-1 H-benzoim idazol-2-yI)- 1 H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(6-ethyl-5-methoxy-1 H-benzoimidazol-2-yI H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-d imethyl-1 H-benzoim idazol-2-yI)-1 2-(5-methyl-1 H-pyrazol-3-y)-1 H-benzoim idazole; 2-(5-ethoxy-1 H-pyrazol-3-yI)-1 H-benzoimidazole; 594 00 2-(5-methylsulfanyl-isoxazol-3-y)-1 H-benzoimidazole; 5-chloro-2-(4-nitro-1 H-pyrazol-3-y)-1 H-benzoimidazole; 5,6-d ichloro-2-(4-nitro-1 H-pyrazol-3-y)-1 H-benzoim idazole; (benzoimidazol-2-yI)-5-methylthio-3-pyrazole; ,6-d imethyl-1 H-benzoim idazol-2-yI)-4,5 7-tetrahyd ro-1 H-indazole; 2-(5-isopropyl-1 H-pyrazol1-3-yI)-5,6-d im ethyl- 1 H-benzoimidazole; 2-(5-ethyl-1 H-pyrazol-3-yI)-5 ,6-d imethyl-1 H-benzoimidazole; 5,6-dimethyl-2-( 1,4,5 ,6-tetrahydro-cyclopentapyrazol-3-y)-1 H-benzoimidazole; 3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-4-fluoro-1 H-indazole; 4-ch lo ro-3-(5 ,6-d im ethyl- 1 H-benzoimidazol-2-y)-1 H-indazole; ,6-dimethyl-1 H-benzoimidazol-2-yI)-5-chloro-1 H-indazole; 3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-1 3-(5-n-propyl-1 H-benzoim idazol-2-y)-1 H-indazole; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-sulfonic acid benzylam ide; 3-(5-methanesulfonyl-1 H-benzoim idazol-2-y)-1 H-indazole; [2-(indazol-3-yl)-1 H-benzoim [2-(indazol-3-y)-1 H-benzoim idazol-5-yI]-carboxylic acid; [2-(indazol-3-yI H-benzoimidazol-5-yI]-carboxylic acid, methylamide; [2-(indazol-3-y)-1 H-benzoimidazol-5-yI]-carboxylic acid, d imethylamide; 595 00 0 [2-(indazol-3-y)-1 H-benzoim idazol-5-yI]-carboxylic acid, isopropylamide; 1 -eziiao(5y]croyi aibnyaie 12(nao-l- H-benzoim idazol-5-y]-carboxylic acid, benzamide; 3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid (2-hyd roxy- 1 ,1 -dimethyl-ethyl)-amide; 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-yI)- 1 H-benzoimidazole-5-carboxylic acid (pyrid in-3-ylm ethyl )-am ide; 3-(5,6-dimethyl-1 H-benzo imid azo1-2-yI)-5- methyl- 1 H-pyrazole-4-carboxylic acid cyclopropylamide; 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-y)-1 H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (pyrid in-2-ylmethyl)-amide; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (pyrid i n-3-yl methyl)- amide; 2-(lI H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 3-methyl-benzylam ide; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 4-methyl-benzylam ide; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid [3-(2-oxo-pyrrolid in-i -yI)- propyl]-amide; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yI-ethyl)- amide; 596 00 2-(lI H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)- CI amide; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl)-am ide; 2-(l1H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (2-hyd roxy-1 ,1 -d imethyl- ethyl)-amide; 2-(l1H-I ndazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (3-imidazol-1 -yI-propyl)- amide; 6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid isobutyl- amide; 3-(5,6-dimethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1 H-benzoimidazol-2-yi)-1 H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3-(5,6-dimethyl-1 H-be nzo imid azo 1-2-yI)-5-m ethyl- 1 H-pyrazole-4-carboxylic acid tert-butylamide; 3-(5,6-d imethyl-1 H-benzoimidazol-2-y)-1 H-indazole-5-carboxylic acid dimethylamide; 2-(4-isobutyrylamino-1 H-pyrazol-3-yI H-benzoimidazole-5-carboxylic acid benzylamide; [2-(indazol-3-y)-1 H-benzoimidazol-5-yI]-carboxylic acid; ,6-dimethyl-1 H-benzoim idazol-5-yI)-pyrazole-4-carboxylic acid; 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-y)-1 H-benzoimidazole-5-carboxylic acid; ,6-d imethyl-1 H-benzoimidazol-2-yI)-5-methyl-pyrazole-4-carboxylic acid; 597 00 ,6-d im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-isobutyramide; N-[3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-1 H -pyrazol1-4-yI]-3- methyl- butyra mid e; imethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yI]-2-phenyl-acetamide; cyclopropanecarboxylic acid im ethyl- 1H-benzoimidazol-2-y)-1 H-pyrazol- 4-yII-amide; methoxyacetic acid [3-(5,6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- amide; cyclopentanecarboxylic acid ,6-d imethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazol- 4-yII-am ide; trimethylacetic acid im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]- amide; tert-butylacetic acid ,6-d i methyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yI]- amide; butanoic acid imnethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yi]-amide; acid ,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazol-4- yI]-am ide; ethyl buta no ic acid i methyl- 1 H-benzoimidazol-2-yI H-pyrazol-4- yI]-amide; cyclopropanecarboxylic acid [3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 H- pyrazo I-4-yI]-am ide; piperidine-1 -carboxylic acid [3-(6-chloro-5-methoxy-1 H-benzoim idazol-2-yI)-1 H- pyrazol-4-yi]-am ide; 598 00 0 ~3-[3-(6-chloro-5-methoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]-1 1 CI dimethylurea; cyclopropanecarboxylic acid [3-(5-methoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4- yI]-amide; cyclopropanecarboxylic acid [3-(5-ethoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4- yI]-amide; cyclopropanecarboxylic acid [3-(5-fl uo ro-6-m ethyl- 1 H-benzo im id azol1-2-yI)- 1 H- c-i pyrazol-4-yi]-amide; cyclopropanecarboxylic acid [3-(5-trifluoromethoxy-1 H-benzoim idazol-2-yI)-1 H- pyrazol-4-yI]-am ide; cyclopropanecarboxylic acid [3-(5-trifl uo ro methyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yi]-am ide; uorom ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-isobutyramide; cyclopropanecarboxylic acid [3-(5-chloro-6-methyl-1 H-benzoim idazol-2-yI)-1 H- pyrazol-4-yI]-am ide; 3,5-dimethyl-isoxazole-4-carboxylic acid [3-(5,6-dimethyl-1 H-benzoimidazol-2-yI)- 1 H-pyrazol-4-yI]-amide; i methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-acetamide; furan-3-carboxylic acid [3-(5-ch lo ro-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol- 4-yI]-amide; i methyl- 1 H-benzoim idazol-2-y)-1 H -pyrazol1-4-yI]-4-m ethyl -be nza mid e; 5,6-dimethyl-2-(4-nitro- I H-pyrazol-3-y)-1 H-benzoim idazole; 5-ethyl-6-methyl-2-(4-nitro-1 H-pyrazol-3-y)-1 H-benzoimidazole; 599 00 6-chloro-5-methoxy-2-(4-nitro-1 H-pyrazol-3-yI)-1 H-benzoim idazole; 5-fluoro-6-methyl-2-(4-nitro-1 H-pyrazol-3-y)-1 H-benzoim idazole; 2-(4-nitro-1 H-pyrazol-3-yI)-5-trifluoromethoxy-1 H-benzoimidazole; __2-(4-nitro-1 H- pyrazol1-3-yI)-5-trifl uo ro methyl- 1 H-benzoimidazole; 5-chloro-6-methyl-2-(4-nitro-1 H-pyrazol-3-y)-1 H-benzoim idazole; 2-(4-nitro-1 H-pyrazol-3-y)-1 H-benzoim idazole-5-carboxylic acid methyl ester; 3-(5,6-d imethyl-1 H-benzoimidazol-2-y)-1 ,4,6 ,7-tetrahydro-pyrazolo[4,3-c]pyridine- acid isopropylamide; cyclopropyl-[3-(5,6-dimethyl-1 H-benzoim idazol-2-yI)-1 ,4,6,7-tetrahydro- pyrazolo[4,3-c] pyrid in-5-yl]-metha none; iso pro pyl-[3-(5,6-d i methyl- 1 H-benzoim idazol-2-yI)-1 ,4,6 ,7-tetrahyd ro-pyrazolo[4,3- 1 ,6-d im ethyl- 1 H-benzoim idazol-2-yI)-1 ,4,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-5-yI]-2 ,2-d imethyl-propan-1 -one; ,6-d imethyl-1 H-benzoim idazol-2-y)-1 ,4,6 ,7-tetrahyd ro-pyrazolo[4,3-c]pyridine- acid methyl ester; ,6-d imethyl-1 H-benzoimidazol-2-yI)-4,5 7-tetrahyd ro-1 H-pyrazolo[4,3- cipyridine; lo ro-6-m ethyl- 1 H-benzoimidazol-2-yI)-4, 5,6, 7-tetrahyd ro- 1 H-pyrazolo[4,3- cipyridine; 3-[5-(2-morpholin-4-yl-ethoxy)-1 H-benzoimidazol-2-yl]-4, 5,6, 7-tetrahydro-1 H- pyrazolo[4,3-c]pyridine; 600 ro methyl- 1 H-benzoim idazol-2-yI)-4,5 ,6,7-tetrahydro-1 H-pyrazolo[4,3- cipyridine; ,6-dimethyl-1 H-benzoim idazol-2-yI)-1 ,4,6,7-tetrahyd ro-pyrazolo[4,3-c]pyridine- rboxyl ic acid tert-butyl ester; 5-methoxy-2-(4-nitro-1 H-pyrazol-3-yl)-1 H-benzoim idazole; 5-ethoxy-2-(4-nitro-1 H-pyrazol-3-y)-1 H-benzoimidazole; ro-6-m ethyl- 1 H-benzoimidazol-2-yI)-l ,4,6,7-tetrahydro-pyrazolo[4,3- c]pyrid ine-5-carboxylic acid tert-butyl ester; 3-[5-(2-morpholin-4-yI-ethoxy)-1 H-benzoim idazol-2-y]-1 7-tetrahyd ro- pyrazolo[4,3-c]pyrid ine-5-carboxylic acid tert-butyl ester; 3-(5,6-d imethyl-l H-benzoimidazol-2-yI)-I ,4,6 ,7-tetrahydro-pyranol4,3-c]pyrazole; uo ro methyl-l1 H-benzoimidazol-2-yI)-I ,4,6 ,7-tetrahyd ro-pyrazolo[4,3- acid tert-butyl ester; im ethyl-l1 H-benzoim idazol-2-yI)-I H-pyrazol-4-yI]-2-morpholin-4-yI- acetamide; 2-dimethylam ino-N-[3-(5,6-d imethyl-l H-benzoim idazol-2-yI)-l H-pyrazol-4-y]- acetamide; im ethyl-I1 H-benzoim idazol-2-yi)-I H-pyrazol-4-y]- 2-(1I H-I ,2,3,4- tetraazol-1 -yI)-acetamide; im ethyl- 1 H-benzoimidazol-2-yl)-l H-pyrazol-4-yI]-isonicotinamide; 2-cyclopro pyl- im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]- acetamide; 1 -[3-(5,6-dimethyl-l H-benzoim idazol-2-yI)-l H-pyrazol1-4-yI]-3-m ethyl- urea; 601 00 0~1 i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-3-isopropyl-urea; 1 -[3-(5,6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-3-phenyl-urea; 1 -benzyl-3-[3-(5,6-d im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-urea; 3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-1 7-tetrahyd ro-pyrazolo[4,3-c]pyridine- acid isopropylamide; cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]amide; 1,5,6, 7-tetra hyd ro- 1 3-d iaza-s-i nd ace 1 H-pyrazol-4-ylamime; 4-methylpiperazine-1 -carboxyl ic acid 1, 5,6,7-tetrahyd ro-1 ,3-diaza-s-indacen- 2-yI)-1 H-pyrazol-4-yI]amide; 1,1 -d i methyl-3-[3-( 1,5,6,7-tetra hyd ro-s-i nd ace 1 H-pyrazol-4-yI]urea; cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1 H-benzim idazol-2-y)-1 H- pyrazol-4-yIlamide; tetra hyd ropyran-4-carboxyl ic acid [3-(6-ethoxy-5-fluoro-1 H-benzimidazol-2-y)-1 H- pyrazole-4-yI]am ide; morpholine-4-carboxylic acid [3-(6-ethoxy-5-fluoro- 1 H-benzimidazol-2-y)-1 H- pyrazol-4-yI]am ide; piperid ine-4-carboxyl ic acid [3-(6-ethoxy-5-fluoro-1 H-benzim idazol-2-y)-1 H- pyrazol-4-yI]am ide; 3-[6-ethoxy-5-fluoro-1 H-benzim idazol-2-y)-1 H-pyrazol-4-y]-1 ,1 -d iethylurea; 5-methoxy-2-(4-nitro-1 H-pyrazol-3-y)-1 H-benzoim idazole; morpholine-4-carboxylic acid im ethyl- 1 H-benzoimidazol-2-yi)-1 H-pyrazol- 4-ylmethyl]-amide; 602 00 03-[3-(5-d ifluoromethoxy-1 H-benzoim idazol-2-yi)-1 H-pyrazol-4-y]-1 ,1 -diethyl-urea; piperidine-1 -carboxylic acid [3-(5-difluoromethoxy-1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yl]-am ide; cyclopropanecarboxylic acid [3-(6-chloro-5-methoxy-1 H-benzoim idazol-2-yI)-l1H- pyrazol-4-yl]-am ide; cyclopropanecarboxylic acid 1,5,6, 7-tetra hyd ro- 1 3-d iaza-s-i nd ace 1 H- pyrazol-4-yl]amide; morpholine-4-carboxylic acid 1,5 ,6,7-tetra hyd ro- 1 3-d iaza-s-i nd ace 1 H- pyrazol-4-yI]-amide; piperidine-1 -carboxylic acid 13-(5-methoxy-1 H-benzoimidazol-2-y H-pyrazol-4- yI]-amide; 3-[3-(5-methoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-y]-1 ,1I-d imethyl-urea; piperidine-1 -carboxylic acid [3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-yi)-1 H- pyrazol-4-yI]-am ide; 3-13-(5-fl uo ro-6-m ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]-1 ,1 -dimethyl- urea; morpholine-4-carboxylic acid [3-(5-trifluorom ethyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-am ide; 3-(5,6-d imethyl-1 H-benzoimidazol-2-y)-1 7-tetrahyd ro-pyrazolo[4,3-c]pyridine- acid diethylamide; i methyl- 1 H-benzoimidazol-2-yI)-I ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin- 5-yI]-pyrrolidin-1 -yI-methanone; ,6-d im ethyl- 1 H-benzoim idazol-2-yI)-1 7-tetrahydro-pyrazolo[4, 3-cipyrid in- in-I -yI-methanone; 603 00 ,6-dim ethyl- 1 H-benzoimidazol-2-yI)-1 7-tetrahydro-pyrazolo[4,3-c]pyridin- Cl 5-yi]-morpholin-4-yI-methanone; lo ro-6-m ethyl- 1 H-benzoimidazol-2-y)-1 7-tetrahydro-pyrazolo[4,3- acid d jethylamide; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1 H-benzoimidazol-2-yi)-1 H-pyrazol- 4-yI]-amide; piperidime-i -carboxyl ic acid [3-(5,6-dimethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazol- N- 4-yI]-amide; 3-[5-(2-morpholin-4-yI-ethoxy)-1 H-benzoim idazol-2-y]-1 7-tetrahydro- pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylam ide; uo rom ethyl- 1 H-benzoim idazol-2-yI)-1 ,4,6,7-tetrahydro-pyrazolo[4,3- c]pyrid ine-5-carboxylic acid d iethylamide; 2-(l1H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid [2-(2H-tetrazol-5-yI)- ethyl]-amide; 1 -cyclo pro pyl-3-[3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- urea; 1 -[3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-yI H-pyrazol-4-yI]-3-methyl-urea; 4-methyl-piperazine-1 -carboxylic acid [3-(5-ethyl-6-m ethyl- 1 H -be nzo imid azol1-2- yI)-l H-pyrazol-4-yI]-am ide; piperidime-i -carboxylic acid [3-(5-fluoro-6-methyl-1 H-benzoim idazol-2-yi)-1 H- pyrazol-4-yI]-amide; 1 -I3-(5-fluoro-6-methyl-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yI]-3-methyl-urea; morpholine-4-carboxyl ic acid [3-(5-fl uo ro-6- methyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-amide; 604 00 0 4-methyl-piperazine-1 -carboxylic acid [3-(5-fluoro-6-methyl-1 H-benzoimidazol-2- Cl yI)-1 H-pyrazol-4-yII-amide; 1 -methyl-3-113-(5-trifluorom ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-urea; 1 lo ro-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yl]-3-methyl-urea; 4-methyl-piperazine-1 -carboxylic acid [3-(5-ch lo ro-6-m ethyl- 1 H-benzo im id azol1-2- yl)-l H-pyrazol-4-yII-amide; 1 -tert-b utyl-3- ,6-d im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-urea; 1 im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-3-ethyl-urea; 4-methyl-piperazine-1 -carboxylic acid ,6-d imethyl-1 H-benzoim idazol-2-yl)- 1 H-pyrazol-4-yi]-amide; 1 -cyclo pro pyl-3-[3-(5,6-d im ethyl- 1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yI]-urea; im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]-1 1 -d iethyl-urea; 1 -[3-(5,6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-3-isobutyl-urea; 1 -cyclo pro pyl methyl-3-[3-(5,6-d im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yi]- urea; lo ro-6- methyl- 1 H-benzoim idazol-2-yI H-pyrazol-4-ylamine; 3-(5-ethyl-6-m ethyl- 1 H-benzo im id azol1-2-yI)- 1 H-i nd azo le-5-ca rboxyl ic acid amide di hydrochloride; 3-(5,6-dimethyl-1 H-benzoimidazol-2-yl)-1 H-indazole-5-carboxylic acid; 2-(4-isobutyrylamino-1 H-pyrazol-3-y)-1 H-benzoimidazole-5-carboxylic acid; imethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-1 1 -d imethyl-urea; 605 00 3-(5-nitro-1 H-benzoimidazol-2-yl)-1 H-indazole; 2-(l1H-I ndazol-3-y)-1 H-benzoimidazole-5-carboxyl ic acid (2-piperidin-1 -yI-ethyl)- amide; 1 H-I ndazol-3-yI H-benzoimidazole-5-carboxylic acid (pyrid in-2-yl methyl)- amide; 1 H-I ndazol-3-y)-1 H-benzoimidazole-5-carboxylic acid [3-(4-methyl-piperazin-1 yI)-propyl]-am ide; N-[2-(lIH-I ndazol-3-y)-1 H-benzoimidazol-5-yI]-isobutyram ide; N-[3-(5,6-Dimethyl-1 H-benzoim idazol-2-yi)-1 H-pyrazol-4-yI]-2-piperid in-i -yI- acetamide; 2-(l1H-indazol-3-yI)-3H-benzoim idazol-5-amime; or piperidine-I -carboxylic acid [3-(5,6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazol- 4-yl]-amide.
26. 34. A compound according to claim 1 selected from the group consisting of 1 H-indazol-3-y)-1 H-benzim idazole-5-carboxylic acid benzylam ide; 2-(1I H-indazol-3-yl)-1 H-benzim idazole-5-carboxylic acid N-methylam ide; 1 H-indazol-3-yl H-benzimidazole-5-carboxylic acid N-ethylam ide; 1 H-indazol-3-yl H-benzimidazole-5-carboxylic acid N-isopropylam ide; 1 H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-phenylam ide; 2-(1I H-indazol-3-yl)-1 H-benzim idazole-5-carboxylic acid N-phenethylam ide; 5,6-d imethyl-2-(5-methylsulfanyl-1 H-pyrazol-3-yl)-1 H-benzoim idazole; 6-ch lo ro-5-m ethyl-2-(5- methyl su Ifa nyl- 1 H-pyrazol-3-yl)-1 H-benzoimidazole; 606 00 0 6-chloro-2-(5-ethylsulfanyl-1 H-pyrazol1-3-yI)-5-m ethyl- 1 H-benzoimidazole; 2-(5-methylsulfanyl-1 H-pyrazol-3-yI)-5-trifluoromethyl-1 H-benzoimidazole; 2-(5-cyclopropylmethylsulfanyl-1 H-pyrazol1-3-y i methyl- 1 H-benzoimidazole; __2-(5-ethylsulfanyl-1 H -pyrazol1-3-yI im ethyl- 1 H-benzoim idazole; 5,6-d imethyl-2-[5-(pyrid in-3-ylmethylsulfanyl)-1 H-pyrazol-3-y]-1 H- N ~benzoimnidazole; 5-fluoro-2-[5-methylsulfanyl)-1 H-pyrazol-3-yi]- 1 H-benzoim idazole; ,6-dimethyl-2-(5-phenethylsulfanyl-1 H-pyrazol-3-yI H-benzoimidazole; 4-methyl-2-(5-methylsulfanyl-1 H-pyrazol-3-y)-1 H-benzoim idazole; 5,6-dimethyl-2-(5-benzylsulfanyl-1 H-pyrazol-3-y)-1 H-benzoim idazole; 5,6-dimethyl-2-[5-(thiophen-2-ylmethylsulfanyl H-pyrazol-3-yl]-1 H- benzoim idazole; 1 H-pyrazol-3-yl)-5-methoxy-1 H-benzoimidazole hydrochloride; methyl-2-(5-m ethyl suIfanyl-4-p ropyl- 1 H-pyrazol-3-y)-1 H-benzoimidazole; 2-(5-(4-methoxy-benzylsulfanyl)-4-propyl-1 H-pyrazol-3-yI)- 5-methyl-i H- benzoimnidazole; 2-(5-benzylsulfanyl-4-isopropyl-1 H-pyrazol1-3-yl)-5-m ethyl- 1 H-benzoimidazole; ethyl sulfa nyl-4- methyl- 1 H-pyrazol-3-yI)-5-methoxy-1 H-benzoim idazole; 2-(5-methylsulfanyl-4-methyl-1 H-pyrazol1-3-y ethyl- 1 H-benzoim idazole; 3-(5-chloro-1 H-benzoim idazol-2-y)-1 H-pyrazol-4-ylamine; 607 00 0 3-(5,6-dichloro-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-ylamine; ,6-dimethyl-2-(4-phenyl-1 H-pyrazol-3-y)-1 H-benzoim idazole; 1,5 7-tetrahyd ro-1 ,3-d iaza-s-indacen-2-yI)-1 H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(5-methoxy-6-m ethyl- 1 H-benzoim idazol-2-yi)-1 H-pyrazole-4-carboxylic acid isopropylamide; ,6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazole-4-carboxylic acid (2- methoxy-ethyl)-amide; 3-(5,6-d imethyl-1 H-benzoimidazol-2-yi)-1 H-pyrazole-4-carboxylic acid pro pylam ide; 3-(5,6-d imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid (tetrahydro- pyran-4-yI)-am ide; ifluoromethoxy-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid isopropylamide; ifluoromethoxy-1 H-benzoim idazol-2-y)-1 H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(6-ethyl-5-methoxy-1 H-benzoim idazol-2-y)-1 H-pyrazole-4-carboxylic acid isopropylamide; 2-(5-ethoxy-1 H-pyrazol-3-y)-1 H-benzoim idazole; (benzoimidazol-2-yI)-5-methylthio-3-pyrazole; 2-(5-isopropyl-1 H- pyrazol1-3-yI)-5,6-d i methyl- 1 H-benzoimidazole; 2-(5-ethyl-1 H -pyrazolI-3-yI)-5,6-d im ethyl- 1 H-benzoim idazole; 608 00 3-(5,6-dimethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid NI isopropylamide; ,6-d imethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid (2-hyd roxy- 1 ,1 -dimethyl-ethyl)-amide; 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; ,6-d imethyl-1 H-be nzo imid azo1-2-yI)-5-m ethyl- 1 H-pyrazole-4-carboxylic acid c-i cyclopropylamide; 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-yi)-1 H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazole-4-carboxylic acid isobutyl- amide; 3-(5,6-d imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-i H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid cyclopropylmethyl-am ide; ,6-d imethyl-1 H-benzoimidazol-2-yl)-5-methyl-1 H-pyrazole-4-carboxylic acid tert-butylamide; 2-(4-isobutyrylamino-1 H-pyrazol-3-yI H-benzoimidazole-5-carboxylic acid benzylamide; im ethyl- 1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yiI-isobutyramide; i methyl- 1 H-benzoim idazol-2-yi)-1 H-pyrazol-4-yl]-3-methyl-butyram ide; imethyl-1 H-benzoimidazol-2-yi)-1 H-pyrazol-4-yI]-2-phenyl-acetamide; 609 00 cyclopropanecarboxylic acid [3-(5,6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazol- Cl 4-yI]-amide; methoxyacetic acid i methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]- amide; cyclopentanecarboxylic acid i methyl- 1 H-benzo im id azol1-2-y)- 1 H-pyrazolI- 4-yI]-amide; trimethylacetic acid i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- amide; tert-butylacetic acid ,6-d im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- am ide; butanoic acid i methyl- 1 H-benzoimidazol-2-yI H-pyrazol-4-yI]-am ide; acid im ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4- yI]-amide; ethyl buta noic acid ,6-d i methyl- 1 H-benzoimidazol-2-y H-pyrazol-4- yI]-amide; cyclopropanecarboxylic acid [3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]-amide; piperidine-1 -carboxylic acid [3-(6-ch loro-5-methoxy- 1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]-amide; 3-[3-(6-chloro-5-methoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]-1 1 dimethylurea; cyclopropanecarboxylic acid [3-(5-methoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4- yI]-amide; 610 cyclopropanecarboxylic acid [3-(5-ethoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4- yI]-amide; cyclopropanecarboxylic acid [3-(5-fl uo ro-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-am ide; cyclopropanecarboxylic acid [3-(5-trifluoromethoxy-1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yi]-am ide; cyclopropanecarboxylic acid [3-(5-trifl uo rom ethyl- 1 H-benzoimidazol-2-yi)-1 H- pyrazol-4-yI]-am ide; N -[3-(5-trifl uo rom ethyl- 1 H-benzoimidazol-2-yi)-1 H-pyrazol-4-yiI-isobutyramide; cyclopropanecarboxylic acid [3-(5-ch lo ro-6-m ethyl- 1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]-am ide; 3, 5-dimethyl-isoxazole-4-carboxylic acid ,6-d imethyl-1 H-benzoim idazol-2-yi)- 1 H-pyrazol-4-yI]-amide; ,6-d im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-acetamide; furan-3-carboxylic acid [3-(5-ch lo ro-6-m ethyl- 1 H-benzo im id azol1-2-y)- 1 H-pyrazolI- 4-yI]-amide; i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-4-methyl-benzam ide; N-[3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-2-morpholin-4-yI- acetamide; 2-d imethyla m ino-N-[3-(5,6-d im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]- acetamide; ,6-d im ethyl-l1 H-benzoim idazol-2-yI)-l H-pyrazol-4-y]- 1 H-i ,2 ,3,4- tetraazol-1 -yI)-acetamide; 611 00 N-t3-(5,6-d i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yl]-isonicotinamide; 2-cyclo pro pyl- i methyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yI]- acetamide; 1 imethyl-1 H-benzoim idazol-2-yi)-1 H- pyrazol1-4-yIJ-3-m ethyl -u rea; 1 ,6-d im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yIJ-3-isopropyl-urea; 1 ,6-d im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yl-3-phenyl-urea; 1 -be nzyl-3-[3-(5,6-d im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-urea; cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]am ide; 4-methylpiperazine-1 -carboxylic acid 1,5,6, 7-tetrahydro-1 ,3-d iaza-s-indacen- 2-yI)-1 H-pyrazol-4-yI]amide; 1,1 -d imethyl-3-[3-( 1,5,6, 7-tetrahyd ro-s-indacen-2-y)-1 H-pyrazol-4-yI]urea; cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1 H-benzim idazol-2-y)-1 H- pyrazol-4-yI]am ide; tetra hyd ro pyra n-4-ca rboxyl ic acid [3-(6-ethoxy-5-fluoro-1 H-benzim idazol-2-yI)-1 H- pyrazole-4-yI]am ide; morpholine-4-carboxylic acid [3-(6-ethoxy-5-fluoro- 1 H-benzimidazol-2-y)-1 H- pyrazol-4-yI]am ide; piperidine-4-carboxylic acid [3-(6-ethoxy-5-fluoro- 1 H-benzim idazol-2-y)-1 H- pyrazol-4-yllam ide; 3-[6-ethoxy-5-fluoro-1 H-benzim idazol-2-y)-1 H-pyrazol-4-y]-1 -diethylurea; morpholine-4-carboxylic acid i methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol- 4-ylmethyl]-am ide; 612 00 ifluoromethoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-y]-1 1 -d iethyl-urea; piperidine-i -carboxylic acid [3-(5-difluoromethoxy-1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-amide; cyclopropanecarboxylic acid [3-(6-chloro-5-methoxy-1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]-amide; cyclopropanecarboxylic acid 1,5,6,7-tetra hyd ro-1, ,3-d iaza-s-i nd ace 1 H- pyrazol-4-yI]amide; morpholine-4-carboxylic acid 1,5,6, 7-tetrahydro-1 ,3-d iaza-s-indacen-2-y)-1 H- pyrazol-4-yI]-am ide; piperidine-1 -carboxylic acid [3-(5-methoxy-1 H-benzoim idazol-2-yI)-l1H-pyrazol-4- yI]-amide; 3-[3-(5-methoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]-1 ,1 -d imethyl-urea; piperidine-1 -carboxylic acid [3-(5-ethyl-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-amide; 3-[3-(5-fl uo ro-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-y]-1, 1 -d imethyl- urea; morpholine-4-carboxylic acid [3-(5-trifluo ro methyl- 1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]-am ide; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazol- 4-yI]-am ide; piperidime-i -carboxylic acid [3-(5,6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazol- 4-yI]-am ide; 1 -cyclop ro pyl-3-[3-(5-ethyl-6- methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- urea; 613 00 1 -[3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-3-methyl-urea; 4-methyl-piperazine-1 -carboxyl ic acid [3-(5-ethyl-6- methyl- 1 H-benzo im id azol1-2- yI)-l H-pyrazol-4-yI]-amide; piperidime-i -carboxylic acid [3-(5-fl uo ro-6-m ethyl- 1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]-amide; 1 -13-(5-fl uo ro-6- methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yi]-3-methyl-urea; morpholine-4-carboxylic acid [3-(5-fl uo ro-6-m ethyl- 1 H-benzoi m idazol-2-y)- 1 H- pyrazol-4-yl]-am ide; 4-methyl-piperazine-1 -carboxylic acid [3-(5-fluoro-6-methyl-1 H-benzoimidazol-2- yI)-1 H-pyrazol-4-yI]-am ide; 1 -m ethyl-3-[3-(5-trifl uo ro methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-urea; 1 lo ro-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-3-methyl-urea; 4-methyl-piperazine-1 -carboxylic acid [3-(5-ch lo ro-6-m ethyl- 1 H-benzo im id azol1-2- yI)-1 H-pyrazol-4-yI]-amide; 1 -tert-butyl-3-[3-(5,6-d im ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yi]-urea; 1 imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-3-ethyl-urea; 4-methyl-piperazine-1 -carboxylic acid i methyl- 1 H-benzo imid azo1-2-y 1 H-pyrazol-4-yI]-amide; 1 -cyclo pro pyl-3-[3-(5,6-d i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-urea; im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]-1 ,1 -d iethyl-urea; I -[3-(5,6-dimethyl-I H-benzoimidazol-2-yI)-I H-pyrazol-4-yI]-3-isobutyl-urea; 614 00 1 -cyclopropyl methyl-3-[3-(5,6-d im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- CI urea; im ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-y]-1 1 -d imethyl-urea; 2-(l1H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (2-piperid in-i -yI-ethyl)- amide; 2-(l1 H-indazol-3-yi)-1 H-benzoimidazole-5-carboxylic acid (pyrid i n-2-yl methyl)- 0 amide; 1 H-indazol-3-yI)- 1 i methyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yII-2-piperidin-1 -yl- acetamide; 2-(lI H-indazol-3-y)-1 H-benzimidazole-5-carboxylic acid N-morpholinoam ide; 2-(l1 H-indazol-3-y)-1 H-benzim idazole-5-carboxylic acid N'- methylpiperazino)amide; 2-(l1 H-indazol-3-yl H-benzim idazole-5-carboxylic acid N-pyrrolid inoamide; 2-(l1 H-indazol-3-yl)-1 H-benzim idazole-5-carboxylic acid N-(isobutyl)amide; 2-(lI H-indazol-3-yl)-1 H-benzim idazole-5-carboxylic acid N- (cyclohexylmethyl)amide; 2-(l1 H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-(2-furfuryl)amide; 2-(l1 H-indazol-3-y)-1 H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide; methyl 2-(l1 H-indazol-3-yI)-3H-benzim idazole-5- carboxylate; 5,6-dimethyl-2-( I H-indazol-3-y)-1 H-benzim idazole; 2-(l1 H-indazol-3-yl)-3H-benzimidazole-4-carboxylic acid; I 615 00 2-(5-ethoxy-2H-pyrazol-3-y)-1 H-benzimidazole-4-carboxylic acid; 5,6-d imethyl-2-(5-methyl-2H-pyrazol-3-y)-1 H-benzim idazole; 5,6-d imethyl-2-(5-thiophen-2-yl-2H-pyrazol-3-y)-1 H-benzim idazole; bro mo-2 H-pyrazo1-3-yl)-5,6-d i methyl- 1 H-benzim idazole; 2-(5-ethyl-2H-pyrazol-3-y)-5 ,6-d imethyl-1 H-benzim idazole; 2-(5-ethyl-2 H-pyrazol-3-yI)-4, 5-ethylenedioxy-1 H-benzimidazole; 2-(5-ethyl-2 H-pyrazol-3-yI)-5-methoxy-1 H-benzim idazole; 2-(5-ethyl-2H-pyrazol-3-yI)-4-hyd roxy-1 H-benzimidazole; and 2-(5-ethyl-2H-pyrazol-3-yI)-5-bromo-1 H-benzimidazole A compound according to claim 1 selected from the group consisting of 1 H-indazol-3-y)-1 H-benzim idazole-5-carboxylic acid benzylamide; 1 H-indazol-3-y)-1 H-benzim idazole-5-carboxylic acid N-methylamide; 1 H-indazol-3-y)-1 H-benzim idazole-5-carboxylic acid N-ethylamide; 1 H-indazol-3-y)-1 H-benzim idazole-5-carboxylic acid N-isopropylam ide; 1 H-indazol-3-yI H-benzimidazole-5-carboxylic acid N-phenylam ide; 1 H-indazol-3-y)-1 H-benzim idazole-5-carboxylic acid N-phenethylam ide; 5,6-d imethyl-2-(5-methylsulfanyl-1 H-pyrazol-3-y)-1 H-benzoim idazole; 6-chloro-2-(5-methylsulfanyl-1 H -pyrazol1-3-yI)-5-m ethyl- 1 H-benzoim idazole; 6-chloro-2-(5-ethylsulfanyl-1 H-pyrazol1-3-yI)-5- methyl- 1 H-benzoimidazole; 616 00 0 ~2-(5-methylsulfanyl-1 H -pyrazol1-3-yi)-5-trifl uo ro methyl- 1 H-benzoimidazole; 2-(5-cyclopropylmethylsulfanyl-1 H- pyrazol1-3-yI ,6-d i methyl- 1 H-benzoim idazole; 2-(5-ethylsulfanyl-1 H-pyrazol1-3-yI)-5,6-d i methyl- 1 H-benzoimidazole; 1,5,6,7-tetrahyd ro-1 ,3-diaza-s-indacen-2-y)-1 H-pyrazole-4-carboxylic acid cyclopropylamide; ethoxy-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-d imethyl-1 H-benzoim idazol-2-y)-1 H-pyrazole-4-carboxylic acid (2- methoxy-ethyl)-amide; ,6-dimethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid propylam ide; ,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid (tetrahyd ro- pyran-4-yI)-am ide; 3-(5-difluoromethoxy-1 H-benzoim idazol-2-yI H-pyrazole-4-carboxylic acid isopropylamide; 3-(5-difluoromethoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(6-ethyl-5-methoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid isopropylamide; 2-(5-isopropyl-1 H-pyrazol1-3-yI)-5,6-d im ethyl- 1 H-benzoim idazole; ,6-dimethyl-1 H-benzoim idazol-2-yi)-1 H-pyrazole-4-carboxylic acid isopropylamide; 617 00 0 3-(5,6-dimethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid (2-hyd roxy- CI 1 ,1 -dimethyl-ethyl)-amide; 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-yI)-1 H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 3-(5,6-dimethyl-1 H-benzoi mid azol1-2-yI)-5-m ethyl- 1 H-pyrazole-4-carboxylic acid cyclopropylamide; 0 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-yI)-1 H-benzoimidazole-5-carboxylic acid c-i phenylmethyl-amide, (compound denoted as A17-B106); 6-d imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid isobutyl- amide; ,6-dimethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid isopropyla mid e; 3-(5,6-dimethyl-1 H-benzoim idazol-2-yi)-1 H-pyrazole-4-carboxylic acid cyclopropylmethyl-am ide; ,6-dimethyl-1 H-benzo im id azol1-2-yI)-5- methyl- 1 H-pyrazole-4-carboxylic acid tert-butylamide; 2-(4-isobutyrylamino-1 H-pyrazol-3-y)-1 H-benzoimidazole-5-carboxylic acid benzylamide; N-[3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-isobutyram ide; i methyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yI]-3-methyl-butyramide; i methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-2-phenyl-acetamide; cyclopropanecarboxylic acid ,6-d imnethyl- 1H-benzoim idazol-2-yI)-1 H-pyrazol- 4-yI]-amide; 618 00 methoxyacetic acid im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- CI amide; cyclopentanecarboxylic acid im ethyl- 1 H-benzoimidazol-2-yI H-pyrazol- 4-yI]-amide; trimethylacetic acid ,6-d i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yi]- amide; tert-butylacetic acid ,6-d im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- c-i amide; butanoic acid i methyl- 1 H-benzoim idazol-2-yi)-1 H-pyrazol-4-yI]-amide; acid i methyl- 1 H-benzoim idazol-2-yi)- 1 H-pyrazol-4- yI]-amide; S(+)-2-methylbutanoic acid im ethyl- 1 H-benzoim idazol-2-yi)-1 H-pyrazol-4- yI]-amide; cyclopropanecarboxylic acid [3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 H- pyrazol-4-yI]-am ide; piperidime-i -carboxylic acid [3-(6-ch lo ro-5-methoxy- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-am ide; 3-[3-(6-chloro-5-methoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]-1 1 dimethylurea; cyclopropanecarboxylic acid [3-(5-methoxy-1 H-benzoimidazol-2-yI )-lIH-pyrazol-4- yI]-amide; cyclopropanecarboxylic acid [3-(5-ethoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4- yI]-amide; 619 00 cyclopropanecarboxylic acid [3-(5-fl uo ro-6- methyl- 1 H-benzoimidazol-2-y)-1 H- CI pyrazol-4-yI]-amide; cyclopropanecarboxylic acid [3-(5-trifluoromethoxy-1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]-amide; cyclopropanecarboxylic acid [3-(5-trifl uoro methyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yi]-amide; 0 ~N-[3-(5-trifl uorom ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yI]-isobutyramide; c-i cyclopropanecarboxylic acid [3-(5-chloro-6-methyl-1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yi]-am ide; 3, 5-d imethyl-isoxazole-4-carboxylic acid i methyl- 1 H-benzo imid azo1-2-y)- 1 H-pyrazol-4-yI]-amide; imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-acetamide; furan-3-carboxylic acid [3-(5-ch lo ro-6-m ethyl- 1 H-benzoimidazol-2-yi)-1 H-pyrazol- 4-yI]-amide; i methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-4-methyl-benzamide; i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-2-morpholin-4-yI- acetamide; imethyl-1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]- 2-(l1 H-i ,2 ,3,4- tetraazol-1 -yI)-acetamide; im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-isonicotinam ide; 2-cyclo pro pyl- i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]- acetamide; 1 ,6-dimethyl-i H-benzoimidazol-2-y)-1 H -pyrazol1-4-yl]-3-m ethyl- urea; 620 00 0 imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-3-isopropyl-urea; 1 ,6-d im ethyl- 1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yi]-3-phenyl-urea; 1 -benzyl-3-[3-(5,6-d im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yi]-urea; __cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]amide; 4-methylpiperazine-1 -carboxylic acid 1,5,6 ,7-tetra hyd ro- 1 3-d iaza-s-i nd ace n- 2-yI)-1 H-pyrazol-4-yI]amide; 1,1 Ad i methyl-3- 1,5 ,6,7-tetra hyd ro-s-i nd ace 1 H-pyrazol-4-yllurea; cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1 H-benzimidazol-2-y)-1 H- pyrazol-4-yI]amide; tetrahyd ropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1 H-benzim idazol-2-y)-1 H- pyrazole-4-yI]am ide; morpholine-4-carboxylic acid [3-(6-ethoxy-5-fl uoro- 1 H-benzim idazol-2-yi)-1 H- pyrazol-4-yl]am ide; piperid ine-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1 H-benzim idazol-2-yi)-1 H- pyrazol-4-yI]am ide; 3-[6-ethoxy-5-fluoro-1 H-benzimidazol-2-y)-1 H-pyrazol-4-y]-1 1 -d iethylurea; morpholine-4-carboxylic acid i methyl- 1 H-benzoimidazol-2-yI)-1 H-pyrazol- 4-ylmethyl]-amide; 3-[3-(5-difluoromethoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]-1 1 -d iethyl-urea; piperidime-i -carboxylic acid [3-(5-difluoromethoxy-1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yi]-amide; 621 00 cyclopropanecarboxylic acid [3-(6-chloro-5-methoxy-1 H-benzoim idazol-2-y)-1 H- CI pyrazol-4-yI]-am ide; cyclopropanecarboxylic acid 1,5,6, 7-tetrahyd ro-1 ,3-diaza-s-indacen-2-y)-1 H- pyrazol-4-yI]amide; morpholine-4-carboxylic acid [3-(1I,5 ,6,7-tetra hyd ro- 1, 3-d iaza-s- ind ace 1 H- pyrazol-4-yI]-amide; piperidine-1 -carboxylic acid [3-(5-methoxy-1 H-benzoimidazol-2-y)-1 H-pyrazol-4- c-i yI]-amide; 3-[3-(5-methoxy-1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]-1 ,1 -dimethyl-urea; piperidine-i -carboxylic acid [3-(5-ethyl-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-amide; 3- [3-(5-fl uo ro-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-y]-1 1 -d imethyl- urea; morpholine-4-carboxylic acid [3-(5-trifluoromethyl-1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-am ide; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazol- 4-yI]-amide; piperidine-1 -carboxylic acid imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazol- 4-yI]-am ide; 1 -cyclopropyl-3-[3-(5-ethyl-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yi]- urea; 1 -[3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-3-methyl-urea; 4-methyl-piperazine-1 -carboxyl ic acid [3-(5-ethyl-6-m ethyl- 1 H-benzo im id azol1-2- yI)-1 H-pyrazol-4-yI]-amide; 622 00 piperidine-I -carboxylic acid [3-(5-fl uo ro-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H- CI pyrazol-4-yI]-amide; 1 uo ro-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yI]-3-methyl-urea; morpholine-4-carboxylic acid [3-(5-fl uo ro-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yi]-amide; 4-methyl-piperazine-1 -carboxylic acid [3-(5-fluoro-6-methyl-1 H-benzoimidazol-2- yI)-1 H-pyrazol-4-yI]-amide; 1 -methyl-3-[3-(5-trifluoromethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yI]-urea; 1 lo ro-6-m ethyl- 1 H-benzoim idazol-2-yi)-1 H-pyrazol-4-yiI-3-methyl-urea; 4-methyl-piperazine-1 -carboxylic acid [3-(5-chloro-6-methyl-1 H-benzoim idazol-2- yI)-l H-pyrazol-4-yI]-amide; 1 -te rt-b utyl-3-[3-(5,6-d i methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-urea; 1 ,6-d im ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yiI-3-ethyl-urea; 4-methyl-piperazine-1 -carboxylic acid ,6-d im ethyl-i1 H-benzo im idazo1-2-yI)- 1 H-pyrazol-4-yI]-amide; 1 -cyclo pro pyl-3-[3-(5,6-d i methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-urea; im ethyl- 1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yl]-1, 1 -diethyl-urea; 1 ,6-dimethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yI]-3-isobutyl-urea; 1 -cyclo pro pyl methyl-3- im ethyl- 1 H-benzoim idazol-2-yI H-pyrazol-4-yl]- urea; im ethyl- 1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yl]-1 ,1 -d imethyl-urea; 623 00 02-(lIH-I ndazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (2-piperddin-i -yI-ethyl)- CI amide; 2-(l1H-I ndazol-3-yI H-benzoim idazole-5-carboxylic acid (pyrid in-2-yl methyl)- amide; and Dim ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yi]-2-piperidin-1 -yI- acetamide.
27. 36. A compound according to claim 1 selected from the group consisting of; 1,5,6, 7-tetrahyd ro-1, ,3-d i aza-s-i nd ace 1 H-pyrazole-4-carboxylic acid cyclopropylamide; ethoxy-6-m ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid isopropyla mide; 3-(5,6-d imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid (2- methoxy-ethyl)-am ide; ,6-dimethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid propylamide; 3-(5,6-d imethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid (tetrahydro- pyran-4-yI)-amide; 3-(5-difluoromethoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid isopropylam ide; 3-(5-difluoromethoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid cyclopropylam ide; 3-(6-ethyl-5-methoxy-1 H-benzoim idazol-2-yI H-pyrazole-4-carboxylic acid isopropylamide; 624 00 03-(5,6-d imethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1 H-benzoimidazol-2-yI)-1 H-pyrazole-4-carboxylic acid (2-hyd roxy- 1 ,1 -dimethyl-ethyl)-amide; 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-yi)-1 H-benzoim idazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 0 3-(5 ,6-d imethyl-1 H-benzoim idazol-2-yI)-5-methyl-1 H-pyrazole-4-carboxylic acid cl cyclopropylamide; 2-(4-isopropylcarbamoyl-1 H-pyrazol-3-yI)-1 H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 6-d imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid isobutyl- amide; 3-(5,6-d imethyl-1 H-benzoim idazol-2-yI)-1 H-pyrazole-4-carboxylic acid iso propylam ide; 3-(5,6-d imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3-(5,6-dimethyl-1 H-benzoim idazol-2-yI)-5-m ethyl- 1 H-pyrazole-4-carboxylic acid tert-butylamide; 2-(4-isobutyrylamino-1 H-pyrazol-3-yI)-1 H-benzoim idazole-5-carboxylic acid benzylamide; i methyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yI]-isobutyramide; ,6-dimethyl-1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yI]-3-methyl-butyram ide; cyclopropanecarboxylic acid i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol- 4-yI]-am ide; 625 00 methoxyacetic acid ,6-d i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- CI amide; cyclopentanecarboxylic acid ,6-d im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol- 4-yI]-amide; trimethylacetic acid im ethyl- 1 H-benzoimidazol-2-yi)-1 H-pyrazol-4-y]- amide; tert-butylacetic acid ,6-d i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- N- amide; butanoic acid im ethyl- 1 H-benzoimidazol-2-y H-pyrazol-4-yI]-am ide; acid i methyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4- yI]-amide; ethyl buta noic acid im ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4- yII-amide; cyclopropanecarboxylic acid [3-(5-ethyl-6- methyl- 1 H-benzoim idazol-2-yI)-1 H- pyrazol-4-yI]-am ide; piperidine-i -carboxylic acid [3-(6-chloro-5-methoxy-1 H-benzoim idazol-2-yi)-1 H- pyrazol-4-yI]-amide; 3-[3-(6-chloro-5-methoxy-1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-1, 1- dimethylurea; cyclopropanecarboxylic acid [3-(5-methoxy-1 H-benzoimidazol-2-yi)-1 H-pyrazol-4- yI]-amide; cyclopropanecarboxylic acid [3-(5-ethoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4- yI]-amide; 626 00 0 ~cyclopropanecarboxylic acid [3-(5-fl uo ro-6-m ethyl- 1 H-benzo im id azol-2-y)- 1 H- CI pyrazol-4-yI]-amide; cyclopropanecarboxylic acid [3-(5-trifl uo ro methyl- 1 H-benzoim idazol-2-yi)-1 H- pyrazol-4-yI]-amide; N -[3-(5-trifl uo ro methyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yi]-isobutyramide; cyclopropanecarboxylic acid [3-(5-chloro-6-methyl-1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-am ide; Ni 3, 5-d imethyl-isoxazole-4-carboxylic acid imethyl-1 H-benzoimidazol-2-y 1 H-pyrazol-4-yI]-amide; furan-3-carboxylic acid [3-(5-ch lo ro-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol- 4-yI]-amide; i methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-yI]-2-morpholin-4-yI- acetamide; i methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]- 1 H-i ,2 ,3,4- tetraazol-1 -yI)-acetamide; N-[3-(5,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-isonicotinam ide; 2-cyclopropyl- im ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-yII- acetamide; 1 im ethyl- 1 H-benzoim idazol-2-yI)-1 H-pyrazol1-4-yI]-3-m ethyl -u rea; 1 imethyl-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-3-isopropyl-urea; 1 -[3-(5,6-dimethyl-1 H-benzoim idazol-2-yi)-1 H-pyrazol-4-yi]-3-phenyl-urea; 1 -be nzyl-3-13-(5,6-d i methyl- 1 H-benzoim idazol-2-yi)-1 H-pyrazol-4-yI]-urea; 627 00 cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1 H-benzoimidazol-2-y)-1 H- CI pyrazol-4-yI]amide; 4-methylpiperazine-1 -carboxylic acid 1,5,6, 7-tetrahyd ro-1 ,3-diaza-s-indacen- 2-yI)-l H-pyrazol-4-yI]amide; 1,1 Adi methyl-3-[3-( 1,5,6, 7-tetra hyd ro-s-i nd ace 1 H-pyrazol-4-yI]urea; cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1 H-benzim idazol-2-yi)-1 H- pyrazol-4-yI]amide; tetrahyd ropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1 H-benzim idazol-2-yI)-1 H- pyrazole-4-yI]amide; morpholine-4-carboxylic acid [3-(6-ethoxy-5-fluoro- 1 H-benzimidazol-2-yi)-1 H- pyrazol-4-yI]am ide; piperid ine-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1 H-benzimidazol-2-yi)-1 H- pyrazol-4-yI]amide; 3-[6-ethoxy-5-fluoro-1 H-benzimidazol-2-y)-1 H-pyrazol-4-y]-1 1 -d iethylurea; ifluoromethoxy-1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]-1 1 -d iethyl-urea; piperidine-1 -carboxylic acid ifluoromethoxy-1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yi]-am ide; cyclopropanecarboxylic acid [3-(6-chloro-5-methoxy-1 H-benzoimidazol-2-yI)-1 H- pyrazol-4-yi]-am ide; cyclopropanecarboxylic acid 1,5,6,7-tetra hyd ro-1, ,3-d i aza-s- ind ace 1 H pyrazol-4-yI]am ide; mompholine-4-carboxylic acid 1,5,6, 7-tetra hyd ro-1, ,3-d iaza-s-i nd ace 1 H- pyrazol-4-yI]-am ide; 628 00 0piperidine-i -carboxylic acid [3-(5-methoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4- CI yI]-amide; 3-[3-(5-methoxy-1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]-1 ,1 -d imethyl-urea; piperidine-1 -carboxyl ic acid [3-(5-ethyl-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-amide; 3- [3-(5-fl uo ro-6-m ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-y]-1 ,1 -dimethyl- urea; morpholine-4-carboxylic acid [3-(5-trifluorom ethyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-am ide; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazol- 4-yI]-am ide; piperidime-i -carboxylic acid ,6-dimethyl-1 H-benzoim idazol-2-y)-1 H-pyrazol- 4-yI]-amide; 1 -cyclo pro pyl-3-[3-(5-ethyl-6-m ethyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- urea; 1 -[3-(5-ethyl-6-methyl-1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yI]-3-methyl-urea; 4-methyl-piperazine-1 -carboxylic acid [3-(5-ethyl-6-m ethyl- 1 H-be nzo im id azo l-2- yI)-1 H-pyrazol-4-yI]-amide; piperidine-1 -carboxyl ic acid [3-(5-fl uo ro-6-m ethyl- 1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]-am ide; 1 uo ro-6-m ethyl- 1 H-benzoim idazol-2-y)-1 H- pyrazol1-4-yI]-3-m ethyl- urea; morpholine-4-carboxylic acid [3-(5-fl uo ro-6- methyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]-am ide; 629 00 1 -m ethyl-3-[3-(5-trifl uorom ethyl- 1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yi]-urea; 1 lo ro-6-m ethyl- 1 H-benzoim idazol-2-yi)-1 H-pyrazol-4-yl]-3-methyl-urea; 4-methyl-piperazine-1 -carboxylic acid [3-(5-ch lo ro-6-m ethyl- 1 H-benzo im idazol-2- yl)-1 H-pyrazol-4-yl]-amide; 1 -tert-butyl-3-[3-(5,6-d im ethyl- 1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yl]-urea; N 1-[3-(5,6-dimethyl-1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yl]-3-ethyl-urea; 4-methyl-piperazine-1 -carboxylic acid ,6-d imethyl-1 H-benzoim idazol-2-yl)- 1 H-pyrazol-4-yl]-am ide; 1 -cyclo pro pyl-3-[3-(5,6-d i methyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yl]-urea; im ethyl- 1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yl]-1 -diethyl-urea; 1 im ethyl- 1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yl]-3-isobutyl-urea; 1 -cyclopropylmethyl-3-[3-(5,6-dimethyl-1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yl]- urea; or im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yl]-1 ,1 -d imethyl-urea; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
28. 37. A compound according to claim 1 selected from the group consisting of ethoxy-6-m ethyl- 1 H-benzoimidazol-2-yl)-1 H-pyrazole-4-carboxylic acid isopropylamide; 1,5,6, 7-tetra hyd ro-1, ,3-d iaza-s-i nd ace n-2-yl)- 1 H-pyrazole-4-carboxylic acid cyclopropylamide; 630 00 ,6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid (tetrahydro- Cl pyran-4-yI)-amide; 6-dimethyl-1 H-benzoimidazol-2-y)-1 H-pyrazole-4-carboxylic acid isobutyl- amide; cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl- 1 H-benzoimidazol-2-y)-1 H- pyrazol-4-yI]amide; 1,1 -d imethyl-3-[3-( 1,5,6, 7-tetrahyd ro-s-indacen-2-y)-1 H-pyrazol-4-yI]urea; piperidine-4-carboxylic acid [3-(6-ethoxy-5-fluoro- 1 H-benzimidazol-2-y)-1 H- pyrazol-4-yI]am ide; 3-[6-ethoxy-5-fluoro-1 H-benzimidazol-2-y)-1 H-pyrazol-4-y]-1 1 -diethylurea; 3-[3-(5-difluoromethoxy-1 H-benzoim idazol-2-yI)-1 H-pyrazol-4-y]-1 1 -diethyl-urea; piperidime-i -carboxylic acid [3-(5-difluoromethoxy-1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]-amide; cyclopropanecarboxylic acid 1,5,6,7-tetra hyd ro- 1, 3-d iaza-s-i nd ace 1 H- pyrazol-4-yI]am ide; piperidine-1 -carboxylic acid [3-(5-methoxy-1 H-benzoim idazol-2-yI H-pyrazol-4- yI]-amide; piperidime-I -carboxylic acid [3-(5-ethyl-6- methyl- 1 H-benzoim idazol-2-y)-1 H- pyrazol-4-yI]-am ide; piperidime-I -carboxylic acid ,6-dimethyl-1 H-benzoim idazol-2-yl)-1 H-pyrazol- 4-yl]-amide; I -cyclop ro pyl-3-[3-(5-ethyl-6- methyl- 1 H-benzoim idazol-2-y)-1 H-pyrazol-4-y]- urea; 631 00 0 piperidine-1 -carboxyl ic acid [3-(5-fl uo ro-6-m ethyl- 1 H-benzoimidazol-2-yl)-1 H- NI pyrazol-4-yI]-amide; 1 -tert- butyl-3- im ethyl- 1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yI]-urea; 1 -cyclo pro pyl-3-[3-(5,6-d im ethyl- 1 H-benzoim idazol-2-yl)-1 H-pyrazol-4-yl]-urea; N im ethyl- 1 H-benzoimidazol-2-y)-1 H-pyrazol-4-yll-1, 1 -d iethyl-urea; 1 -cyclo pro pyl methyl-3- im ethyl- 1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yI]- urea; or ,6-d im ethyl- 1 H-benzoi m idazol-2-yl)-1 H-pyrazol-4-yl]-1, 1 Ad i methyl-urea.
29. 38. A compound according to claim 1 selected from the group consisting of: 1 H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid benzylamide; 2-(1 H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-methylam ide; 1 H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-ethylamide; 2-(1 H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-isopropylam ide; 2-(1 H-indazol-3-yl)-1 H-benzim idazole-5-carboxylic acid N-phenylam ide; 1 H-indazol-3-yl)-1 H-benzim idazole-5-carboxylic acid N-phenethylam ide; 1 H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-morpholinoam ide; 2-(1I H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N(' methylpiperazino)amide; 2-(1I H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-pyrrolid inoam ide; 1 H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-(isobutyl)amide; 632 00 2-(l H-indazol-3-y)-1 H-benzimidazole-5-carboxylic acid N- Cl (cyclohexylmethyl)amide; 2-(l1 H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-(2-furfuryl)am ide; 2-(l1 H-indazol-3-yl)-1 H-benzimidazole-5-carboxylic acid N-benzyl-N-methylam ide; methyl 2-(l1 H-indazol-3-yI)-3H-benzim idazole-5- carboxylate; 5,6-dimethyl-2-(1 H-indazol-3-y)-1 H-benzimidazole; 5-methoxy-2-( 1 H-indazol-3-y)-1 H-benzimidazole; 2-(lI H-indazol-3-yI)-3H-benzimidazole-4-carboxylic acid; 2-(l1 H-indazol-3-yI )-3H-benzimidazole; 2-(5-ethoxy-2H-pyrazol-3-y H-benzimidazole-4-carboxylic acid; 5,6-d imethyl-2-(5-methyl-2H-pyrazol-3-yl)-1 H-benzim idazole; 5,6-d imethyl-2-(5-thiophen-2-y-2H-pyrazol-3-y H-benzimidazole; 2-(4-bro mo-2 H-pyrazol1-3-yl)-5 ,6-d i methyl- 1 H-benzimidazole; 2-(5-ethyl-2 H- pyrazol1-3-yl)-5,6-d i methyl- 1 H-benzimidazole; 2-(5-ethyl-2 H-pyrazol-3-yl)-4,5-ethylenedioxy-1 H-benzim idazole; 2-(5-ethyl-2H-pyrazol-3-yI)-5-methoxy-1 H-benzim idazole; 2-(5-ethyl-2H-pyrazol-3-yI)-4-hyd roxy-1 H-benzim idazole 2-(5-ethyl-2H-pyrazol-3-yI)-5-bromo-1 H-benzimidazole; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 2 ,4-d ichioro- benzylamide; 633 0 2-(l H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (3-ethoxy-propyl)- CI amide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 4-bromo-benzylamide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 4-methanesulfonyl- benzylamide; 2-(l H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (naphthalen-1 ylmethyl)-amide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 4-trifl uo ro methyl- benzylamide; 2-(lIH-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (th io phen-2-yl methyl)- am ide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 4-d imethylamino- benzylamide; H-indazol-3-y)-1 H-benzoimidazole-5-carbonyl]-am ino}-methyl)- piperidine-1 -carboxylic acid tert-butyl ester; 2-(l H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 4-nitro-benzylam ide; 2-(lIH-indazol-3-yI H-benzoim idazole-5-carboxyl ic acid (pyrid in-3-yl methyl)- amide; 2-(l H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid 3-bromo-benzylamide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 3-methoxy- benzylamide; 2-(l1H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (benzo[1 ,31d ylmethyl)-amide; 634 00 2-(1 H-indazol-3-yI)-1 H-benzoim idazole-5-carboxylic acid (benzo[b]thiophen-3- CI ylmethyl)-amide; 2-(lI H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (1 ,3-d imethyl-1 H- pyrazol-4-ylmethyl)-amide; 2-(l1 H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid 2-trifluoromethoxy- benzylamide; 2-(l1 H-indazol-3-yI)-1 H-benzoim idazole-5-carboxylic acid 2-methyl-benzylamide; 2-(1 H-indazol-3-yl H-benzoimidazole-5-carboxyl ic acid (3-methyl-thiophen-2- ylmethyl)-amide; 2-(l H-indazol-3-yI)-1 H-benzoim idazole-5-carboxylic acid 2-trifl uo rom ethyl- benzylamide; 2-(lI H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid 4-phenoxy- benzylam ide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 3-trifluoromethoxy- benzylamide; 2-(l1H-indazol-3-yl)-1 H-benzoimidazole-5-carboxylic acid (3-isopropoxy-propyl)- amide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (1 -methyl-i H-pyrazol-4- ylmethyl)-amide; 2-(lI H-indazol-3-y)-1 H-benzoimidazole-5-carboxyl ic acid 4-isopropyl- benzylamide; 2-(l1H-indazol-3-yl)-1 H-benzoim idazole-5-carboxylic acid (2 ,5-d imethyl-furan-3- ylmethyl)-amide; 635 00 2-(1 H-indazol-3-yl)-1 H-benzoim idazole-5-carboxylic acid (benzollb]thiophen-2- CI ylmethyl)-amide; 2-(lI H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid [3-(3-acetylamino- phenoxy)-propyl]-amide; 2-(l H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (6-chioro-pyrid in-3- ylmethyl)-amide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (12 c-i ylmethyl)-amide; 2-(l H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (2,3-d ihyd ro- ide; 2-(l H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 4-cyano-benzylamide; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxyl ic acid benzollb]thiophen-3-ylmethyl)-am ide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxyl ic acid 3-trifl uo ro methyl- benzylamide; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 2-methylsulfanyl- benzylamide; 2-(l1H-indazol-3-y)-1 H-benzoim idazole-5-carboxyl ic acid (benzo[b]thiophen-3- ylmethyl)-amide; 2-(l1H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (tetra hyd ro-pyra n-4- ylmethyl)-amide; 2-(l1 H-indazol-3-yi)-1 H-benzoimidazole-5-carboxylic acid (2 ,3-d ihydro- benzo[1 ,4]dioxin-2-ylmethyl)-am ide; 636 00 0 2-(l1 H-indazol-3-yi)-1 H-benzoimidazole-5-carboxylic acid (fu ra n-3-yl methyl)- CI amide; 2-(lI H-indazol-3-yI)-1 H-benzoim idazole-5-carboxylic acid 2-nitro-benzylam ide; 2-(1 H-indazol-3-yI)-1 H-benzoimidazole-5-carboxyl ic acid (th io phen-3-yl methyl)- amide; 2-(l H-indazol-3-yI)-1 H-benzoim idazole-5-carboxylic acid 3, benzylamide; 2-(l1 H-indazol-3-yi)-1 H-benzoimidazole-5-carboxylic acid (1 -methyl-i H- benzoimidazol-2-ylmethyl)-amide; 2-(l H-indazol-3-yI)-1 H-benzoimidazole-5-carboxyl ic acid 3-methyl-benzylam ide; 2-(lI H-indazol-3-yl)-1 H-benzoim idazole-5-carboxylic acid 3-chloro-benzylamide; 2-(l H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid 4-sulfamoyl- benzylamide; 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid (3-ethoxy-propyl)- amide; 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid 4-bromo-benzylamide; 2-(l1 H-indazol-3-yI)-3H-benzoim idazole-4-carboxylic acid (naphthalen-1 ylmethyl)-amide; 2-(l1H-indazol-3-yl)-3H-benzoim idazole-4-carboxylic acid (th io phen-2-yl methyl)- amide; 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid 4-d imethylamino- benzylamide; 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid 4-nitro-benzylamide; 637 00 0 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid (pyrid in-3-yl methyl)- CI amide; 2-(lI H-indazol-3-yI)-3H-benzoim idazole-4-carboxylic acid 3-bromo-benzylam ide; 2-(l1 H-indazol-3-yI)-3H-benzoim idazole-4-carboxylic acid 3-methoxy- benzylamide; 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid (benzo[b]thiophen-3- N ylmethyl)-amide; 2-(l1 H-indazol-3-yI)-3H-benzoim idazole-4-carboxylic acid 4-phenoxy- benzylamide; 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid 3-trifluoromethoxy- benzylamide; 2-(l1 H-indazol-3-yI)-3H-benzoim idazole-4-carboxylic acid (6-chloro-pyridin-3- ylmethyl)-amide; 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid (2,3-d ihyd ro- 2-(l1 H-indazol-3-yI)-3H-benzoim idazole-4-carboxylic acid 3-trifl uo ro methyl- benzylamide; 2-(l1 H-indazol-3-yI)-3H-benzoim idazole-4-carboxylic acid 2-methylsulfanyl- benzylamide; 2-(l1 H-indazol-3-yI)-3H-benzoim idazole-4-carboxylic acid (fu ra n-3-yl methyl)- amide; 2-(l1 H-indazol-3-yI)-3H-benzoim idazole-4-carboxylic acid 2-nitro-benzylam ide; 2-(l1 H-indazol-3-yI)-3H-benzoim idazole-4-carboxyl ic acid 3, benzylam ide; 638 00 0 2-(lI H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid 3-chloro-benzylam ide; 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid phenylam ide; 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid benzylam ide; 2-(l1 H-indazol-3-yI)-3H-benzoimidazole-4-carboxylic acid phenethyl-am ide; 3-(6-phenyl-1 H-benzoimidazol-2-yI)-2H-indazole; ichloro-phenyl)-1 H-benzoim idazol-2-yI]-2H-indazole; 3-(6-naphthalen-1 -yI-1 H-benzoimidazol-2-yI)-2H-indazole; 3-[6-(4-fluoro-phenyl)-1 H-benzoim idazol-2-yI]-2H-indazole; 3-[6-(4-chloro-phenyl)-1 H-benzoimidazol-2-yI]-2H-indazole; 3-[6-(4-methoxy-phenyl)-1 H-benzoimidazol-2-y]-2 H-indazole; 3-[6-(3-chloro-4-fluoro-phenyl)-1 H-benzoimidazol-2-yI]-2H-indazole; ichloro-phenyl)-1 H-benzoimidazol-2-yI]-2H-indazole; 3-(6-thianthren-1 -yI-1 H-benzoimidazol-2-yI)-2H-indazole; 3-(6-biphenyl-4-y-1 H-benzoim idazol-2-yI)-2 H-indazole; 3-(6-p-tolyl-1 H-benzoim idazol-2-yI)-2H-indazole; 3-(6-m-tolyl-1 H-benzoim idazol-2-yI)-2H-indazole; 3-(6-o-tolyl-1 H-benzoimidazol-2-yI)-2H-indazole; 3-(6-thiophen-3-y-1 H-benzoimidazol-2-yI)-2H-indazole; 3-[6-(3-trifl uo ro methyl- phenyl)- 1 H-benzoim idazol-2-yI]-2H-indazole; 639 00 3-[6-(4-trifl uo ro methyl- phenyl)- 1 H-benzoimidazol-2-yI]-2H-indazole; 3-[6-(3-chloro-phenyl)- 1 H-benzoimidazol-2-y]-2 H-indazole; 3-[6-(3-methoxy-phenyl)-1 H-benzoimidazol-2-y]-2 H-indazole; 3-[6-(3,5-dimethyl-phenyl)-1 H-benzoimidazol-2-y]-2 H-indazole; imethyl-phenyl)-1 H-benzoimidazol-2-yI]-2 H-indazole; 3-(6-benzo[1 ,3ldioxol-5-yI-1 H-benzoimidazol-2-yI)-2H-indazole; 3-[6-(4-tert-butyl-phenyl)-1 H-benzoimidazol-2-yI]-2H-indazole; 3-(6-hex-1 -enyl-1 H-benzoimidazol-2-yI)-2H-indazole; 3-[6-(3,4-dimethoxy-phenyl)-1 H-benzoimidazol-2-yI]-2H-indazole; 3-[2-(2H-indazol-3-yI H-indazol-3-yI 3-[6-(3,4-dichloro-pheny)-1 H-benzoim idazol-2-yI]-2H-indazole; 3-[6-(4-trifluoromethoxy-phenyl)-1 H-benzoim idazol-2-yI]-2H-indazole; 1 -{4-[2-(2H-indazol-3-yI)-3H-benzoimidazol-5-yI]-phenyl}-ethanone; 3-(6-benzo[b]thiophen-2-yi-1 H-benzoimidazol-2-yI)-2H-indazole; 5-trimethoxy-phenyl)-1 H-benzoimidazol-2-yl]-2H-indazole; 1 H-i ndazol-3-yI)-3 H-benzo im idazol-5-yI]-thiophen-2-yI}-etha none; 1 -{3-[2-(2HWind azol-3-yI )-3H-benzoi m idazol-5-yI]-phenyl}-etha none; 3-[6-(4-benzyloxy-phenyl)-1 H-benzoimidazol-2-yII-2H-indazole; 00 640 3-[6-(2-fluoro-biphenyl-4-y)-1 H-benzoim idazol-2-yI]-2H-indazole; 3-(6-benzo[b]thiophen-3-y-1 H-benzoimidazol-2-yI)-2H-indazole; {3-[2-(2H-indazol-3-yI)-3H-benzoim 3-[6-(4-ethylsulfanyl-phenyl)-1 H-benzoimidazol-2-y]-2 H-indazole; ifluoro-phenyl)-1 H-benzoimidazol-2-y]-2 H-indazole; 3-[6-(3-trifluoromethoxy-phenyl)-1 H-benzoimidazol-2-yI]-2H-indazole; 3-[6-(4-fluoro-2-methyl-phenyl)-1 H-benzoimidazol-2-yI]-2H-indazole; 3-{6-[2-(4-fluoro-phenyl )-vinyl]-1 H-benzoimidazol-2-yI}-2H-indazole; 3-{6-[2-(4-chloro-phenyl )-vinyl]-1 H-benzoimidazol-2-yI}-2H-indazole; H-indazol-3-yI)-3H-benzoim id azol-5-y]-phenyl}-pro pion ic acid; {4-[2-(2H-indazol-3-yI)-3H-benzoimidazol-5-yI]-phenyl}-methanol; 3-(6-furan-2-y-1 H-benzoim idazol-2-yI)-2H-indazole; 3-[6-(3-benzyloxy-phenyl)-1 H-benzoimidazol-2-yI-2 H-indazole; 3-[6-(4-isopropyl-phenyl)-1 H-benzoim idazol-2-yI]-2H-indazole; 3-[6-(4-methanesulfony-phenyl)-1 H-benzoim idazol-2-yI]-2H-indazole; 2-(l1H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (tetra hyd ro-pyra n-4- ylmethyl)-amide; 2-(l H-indazol-3-yl)-1 H-benzoim idazole-5-carboxylic acid 4-acetylamino- benzylamide; 2-(l H-indazol-3-yI H-benzoim idazole-5-carboxylic acid methylam ide; 641 00 0 2-(l1 H-indazol-3-yi)-1 H-benzoim idazole-5-carboxylic acid isopropylam ide; [2-(l1 H-indazol-3-y)-1 H-benzoimidazol-5-yI]-morpholin-4-yI-methanone; [2-(l1 H-indazol-3-y)-1 H-benzoimidazol-5-yI]-(4-methyl-piperazin-1 -yI)-methanone; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid benzyl-methyl-amide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 3-nitro-benzylamide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 2-fluoro-benzylam ide; 2-(lI H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 2,4-d ifluoro- benzylamide; 2-(lI H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 2 ,6-d ifluoro- benzylamide; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro- benzylamide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 4-chloro-2-fluoro- benzylamide; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxyl ic acid 4-bromo-2-fluoro- benzylam ide; 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 3,4-d ifluoro- benzylamide; 2-(lI H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 3,4,5-trifluoro- benzylamide; 2-(l1 H-indazol-3-yi)-1 H-benzoimidazole-5-carboxylic acid (4'-chloro-biphenyl-4- ylmethyl)-amide; 642 00 02-(l1H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 5'-d ichioro-biphenyl- Cl 4-ylmethyl)-amide; 2-(1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxyl ic acid (4'-fluoro-biphenyl-4- ylmethyl)-amide; 2-(l H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 2-fluoro-benzylam ide; 2-(l H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 2 ,6-d ifluoro-3-m ethyl- benzylamide; 2-(l H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 2,4-d ichioro- benzylam ide; 2-(l H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 4-chloro-benzylam ide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid 4-ch lo ro-2- methyl- benzylamide; 2-(lI H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid 4-fluoro-benzylam ide; 2-(l1 H-indazol-3-yi)-1 H-benzoimidazole-5-carboxylic acid (2'-chloro-biphenyl-4- ylmethyl)-amide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (6-trifl uo ro methyl- pyridin-3-ylmethyl)-amide; 2-(lI H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (5-pyrid in-2-yI-thiophen- 2-ylmethyl)-amide; 2-(l1H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (3-im idazol-1 -yi-propyl)- amide; 4-[2-(l1 H-indazol-3-yI H-benzoim idazole-5-carbonyl]-piperazine-1 -carboxylic acid tert-butyl ester; 643 00 0 2-(l1 H-indazol-3-y)-1 H-benzoimidazole-5-carboxylic acid (2 ,6-difluoro-4-chloro- Ni benzyl)amide; 2-(l1H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (2 ,4-d ichloro-6-fluoro- benzyl)amide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (3-fluoro-4-chloro- benzyl)amide; 2-(l1 H-indazol-3-y)-1 H-benzoim idazole-5-carboxyl ic acid (2-fluoro-4-chloro-6- methyl-benzyl)amide; 2-(lIH-indazol-3-y)-1 H-benzoim idazole-5-carboxylic acid (6-methoxy-pyridin-3- ylmethyl)-amide; 2-[5-(benzyloxy)-2H-pyrazol-3-y]-1 H-benzoimidazole; 2-[5-(3-phenyl-allyloxy)2H-pyrazol-3-y]-1 H-benzoimidazole; 2-[5-(2-methyl-aI Iyloxy)2H-pyrazol-3-yI]-1 H-benzoim idazole; imethyl-octa-2 ,6-dienyloxy)-2H-pyrazol-3-y]-1 H-benzoimidazole; 2-[5-(3-bromo-benzyloxy)-2H-pyrazol-3-y]-1 H-benzoimidazole; 3-[5-(l1 H-benzoim idazol-2-yI)- 1 H-pyrazol-3-yloxymethyl]-benzonitrile; 2-[5-(4-trifluoromethyl-benzyloxy)-2 H-pyrazol-3-y]-1 H-benzoim idazole; 2-[5-(3,4-dichloro-benzyloxy)-2H-pyrazol-3-yI]-1 H-benzoimidazole; 2-[5-pentafluorophenylmethoxy)-2H-pyrazol-3-y]-1 H-benzoimidazole; 2-[5-(4-tert-butyl-benzyloxy)-2 H-pyrazol-3-y]-1 H-benzoim idazo le; 2-[5-(2-benzenesulfonylmethyl-benzyloxy)-2H-pyrazol-3-yI-1 H-benzoimidazole; 644 00 4-[5-(l1 H-benzoimidazol-2-y)-1 H-pyrazol-3-yloxymethyl]-benzonitile; 2-[5-(biphenyl-4-ylmethoxy)-2H-pyrazol-3-y]-1 H-benzoimidazole; 2,3-dichioro-benzenesulfonic acid 5-(l H-benzoimidazol-2-yi)-1 H-pyrazol-3-yI ester; 2-[5-(2-morpholin-4-yI-ethoxy)-2H-pyrazol-3-y]-1 H-benzoimidazole; 2-[5-(2-piperid in-i -yI-ethoxy)-2 H-pyrazo I-3-yI]-1 H-benzoimidazole; 2-[5-(3-methoxy-benzyloxy)-2 H-pyrazol-3-y]-1 H-benzoimidazole; 2-[5-(l1 H-benzoi midazol-2-yi)- 1 H-pyrazo I-3-yloxy]-1 -p-to lyl-etha none; H-benzoimidazol-2-y)-1 H-pyrazol-3-yloxy]-3,3,4,4,4-pentafluoro-butan-2- one; H-benzoimidazol-2-y)-1 H-pyrazol-3-yloxy]-1 -biphenyl-4-yI-ethanone; 1 H-benzoim idazol-2-y)-1 H-pyrazol-3-yloxy]-buta n-2-one; H-benzoimidazol-2-y)-1 H-pyrazol-3-yloxy]-1 -(4-dimethylamino-phenyl)- ethanone; 2-[5-(l1 H-benzoim id azol-2-y)-1 H-pyrazol-3-yloxy]-1 ethanone; H-benzoim idazol-2-yi)-1 H-pyrazol-3-yloxy]-N-phenyl-acetamide; 1 H-benzoimidazol-2-y)-1 H-pyrazol-3-yloxy-3,3-dimethyl-butan-2-one; 1 -adamanta n-I I H-benzoim idazol-2-yI)-I H-pyrazol-3-yloxy]-etha none; 2-[5-(l1 H-benzoimidazol-2-y)-1 H-pyrazol-3-yloxy]-1 -naphtha len-2-yI-ethanone; H-benzoim idazol-2-yI H-pyrazol-3-yloxy]-acetyl}-benzon itrile; 645 00 0 H-benzoimidazol-2-y)-1 H-pyrazol-3-yloxy]-acetyl}-3,4-dihydro-1 H- NI quinolin-2-one; 2-[5-(l1 H-benzoim idazol-2-yI)- I H-pyrazol-3-yloxy]- I -(4-trifluoromethoxy-phenyl ethanone; H-benzoimidazol-2-y)-1 H-pyrazol-3-yloxy]-acetyl}-2-chlo ro- benzenesulfonamide; 0 H-benzoimidazol-2-y)-1 H-pyrazol-3-yloxy]-1 -(4-methoxy-phenyl)-ethanone; H-benzoim idazol-2-y)-1 H-pyrazol-3-yloxy]- 1 -cyclopropyl-ethanone; isonicotinic acid 5-(l1 H-benzoimidazol-2-y)-1 H-pyrazol-3-yI ester; 2,2-dimethyl-propionic acid 5-(1 H-benzoimidazol-2-y)-1 H-pyrazol-3-yI ester; benzyloxy-acetic acid 5-(l H-benzoim idazol-2-y)-1 H-pyrazol-3-yI ester; benzoic acid 5-(1 H-benzoimidazol-2-y)-1 H-pyrazo I- 3 -yI ester; 4-methoxy-benzoic acid 5-(l1 H-benzoi midazol-2-y)-1 H-pyrazol-3-y ester; phenyl-acetic acid 5-(l1 H-benzoim idazol-2-y)-1 H-pyrazo I-3-yI ester; 2,3,4, 5,6-Pentafluoro-benzoic acid 5-(l1 H-benzoimidazol-2-y)-1 H-pyrazol-3-y ester; cyclopropanecarboxylic acid 5-(1 H-benzoimidazol-2-y)-1 H-pyrazol-3-yI ester; 2,2 ,3,3,4,4,4-heptafluoro-butyric acid 5-(l H-benzoimidazol-2-y)-1 H-pyrazol-3-yI ester; cyclopentanecarboxylic acid 54(1 H-benzoimidazol-2-y)-1 H-pyrazol-3-y ester; 3-phenyl-propionic acid 5-(l H-benzoimidazol-2-y)-1 H-pyrazol-3-yI ester; biphenyl-4-carboxylic acid 5-(1 H-benzoimidazol-2-y)-1 H-pyrazol-3-y ester; 646 00 O 3,5-bis-trifluoromethyl-benzoic acid 5-(1 H-benzoimidazol-2-yl)-1 H-pyrazol-3-yl ester; 14-trifluoromethyl-benzoic acid 5-(1 H-benzoimidazol-2-yl)-1 H-pyrazol-3-yl ester; thiophene-2-carboxylic acid 5-(1 H-benzoimidazol-2-yl)-1 H-pyrazol-3-yl ester;
30. 39. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of the preceding claims, together t' with one or more pharmaceutically acceptable carriers or excipients. A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of a kinase protein comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 38.
31. 41. Use of a compound according to any one of claims 1 to 38 in the preparation of a medicinal product intended for inhibiting the activity of a kinase protein.
32. 42. A compound substantially as hereinbefore described with reference to the examples. AVENTIS PHARMACEUTICALS INC WATERMARK PATENT TRADEMARK ATTORNEYS P23926AU00