WO2004113303A1 - INDAZOLE/PYRZOLO[4,3-c]PYRIDIN DERIVATIVES AS JNK INHIBITORS, COMPOSITIONS AND METHODS RELATED THERETO AS WELL AS INTERMEDIATE THEREOF - Google Patents

Abstract

The present invention relates to new compounds of formula (I) in which:X is CR4 or N; R1 is -OR5, -NHCOR6 or -NR6R7; R2 is hydrogen, Oar1 or -NHAr1 wherein Ar1 is aryl optionally substituted with one or more of R8, -OR8, -NR8R9, -CONR8R9, -COOR8, -NR8COR9, -SR8, -SO2NR8R9, -NR8SO2 R9, halogen, cyano, or nitro; R3 is hydrogen or -NHAr2 wherein Ar2 is benzene optionally substituted with one or more of R8, -OR8, -NR8R9, halogen or nitro, wherein R2 and R3 is not simultaneously hydrogen; a process for their preparation and new intermediates used therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.

Description

lndazole/pyrzolo[4,3-.c]p τidin derivatives as JNK inhibitors, compositions and methods related thereto as well as intermediate thereof.

TECHNICAL FIELD

The present invention relates to novel indazole derivatives, useful for treatment of various disorders. The invention relates to methods for producing these compounds. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of utilizing these compositions in the treatment of various disorders.

BACKGROUND TO THE INVENTION

Protein kinases are important components of intracellular signalling pathways and kinases are involved in the regulation of a variety of cellular functions. The MAP kinase signalling pathways are activated by engagement of a number of cell surface receptors. One of these pathways, the JNK pathway is activated specifically by stress or pro-inflammatory cytokines. Activators include LPS, the cytokines tumor necrosis factor (TNF-α) and Interleukin-1 (IL-1), osmotic shock, chemical stress and UV radiation (Cohen, P. Trends in Cell Biol. 7:353-361 1997). Targets of the JNK pathway include a number of transcription factors, such as but not exclusively c-jun and ATF-2 (Whitmarsh, A. and Davis, R. J. Mol. Med. 74:589-607 1998).

Three different genes: JNK1 , JNK2 and JNK3; encode the JNK family of enzymes.

Alternatively spliced forms of these genes can give rise to 10 distinct isoforms: four for JNK1, four for JNK2 and two for JNK3. (Gupta, S. et al EMBO J. 15:2760-2770 1996). JNK1 and JNK2 are ubiquitously expressed in human tissues whereas JNK3 is selectively expressed in the brain, heart and testis (Dong, C. et al. Science 270:1-4 1998).

JNKs 1, 2 and 3 have been selectively knocked out in mice both singularly and in combination by both gene deletion and/or transgenic expression of dominant negative forms of the kinases (Dong, C. et al Science 282:2092-2095, 1998; Yang, D. et al Immunity 9:575-585 1998; Dong, C, et al Nature 405:91-94 2000; Yang, D. et al Nature 389:865-870 1997). Mice with targeted disruption of the JNK3 gene develop normally and are protected from excitotoxin-induced apoptosis of neurons. This finding suggests that specific inhibitors of JNK 3 could be effective in the treatment of neurological disorders characterized by cell death such as Alzheimer's disease and stroke. Mice disrupted in either JNK 1 or 2 also develop normally. Peripheral T cells from either type of mice can be activated to make JL2, but in both cases, there is a defect in Thl cell development. In the case of JNK1 -/- mice, this is due to an inability to make gamma interferon (a key cytokine essential for the differentiation of Thl cells). In contrast, JNK2 -/- mice produce interferon gamma but are unable to respond to the cytokine. Similar defects in T cell biology (normal IL2 production but a block in Thl cell differentiation) are seen in T cells disaφted in the MKK7 gene confirming this role for the JNK pathway in T cell differentiation (Dong, C, et al Nature 405:91-94 2000).

JNK also plays a major role in apoptosis of cells (Davis RJ. Cell. 103:239-252, 2000). JNK is essential for UV induced apoptosis through the cytochrome C mediated pathway (Tournier, C. et al Science 288:870-874 2000). Ischemia and ischemia coupled with re- perfusion as well as restricted blood flow itself have been shown to be accompanied by activation of JNK. Cell death can be prevented with dominant negative forms of JNK transfected into cells demonstrating a potential utility for JNK in conditions characterized by stress-induced apoptosis.

Activation of the JNK pathway has been observed in a number of human tumors and transformed cell lines (Davis RJ. Cell. 103:239-252, 2000). Indeed, one of the major targets of JNK, c-jun, was originally identified as an oncogene indicating the potential of this pathway to participate in unregulated cell growth. JNK also regulates phosphorylation of p53 and thus modulates cell cycle progression (Chen T. et al Mol. Carcinogenesis 15:215-226, 1996). Inhibition of JNK may therefore be beneficial in some human cancers.

Based on current knowledge JNK signalling, especially JNK3, has been implicated in areas of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, traumatic brain injury, as well as ischemic and haemorrhaging stroke. Thus there is a high unmet medical need for JNK specific inhibitors useful in treating the various conditions associated with JNK activation.

DISCLOSURE OF THE INVENTION

It has been found that compounds of the Formula I, which are substituted indazole compounds, are particularly effective and thereby suitable in the treatment of the various conditions.

In one aspect, the invention relates to compounds of the general Formula I:

in which: X is CR⁴ or N;

R¹ is -OR⁵, -NHCOR⁶ or -NR⁶R⁷;

R² is hydrogen, -OAr¹ or -NHAr¹ wherein Ar¹ is aryl optionally substituted with one or more of R⁸, -OR⁸, -NR⁸R⁹, -CONR⁸R⁹, -COOR⁸, -NR⁸COR⁹, -SR⁸, -SO₂R⁸,

-SO₂NR⁸R⁹, -NR⁸SO₂R⁹, halogen, cyano, or nitro; R³ is hydrogen or -NHAr² wherein Ar² is benzene optionally substituted with one or more of R⁸, -OR⁸, -NR⁸R⁹, halogen or nitro; wherein R² and R³ is not simultaneously hydrogen;

R⁴ is hydrogen, NO₂, CN, C_1-3 alkyl or halogen;

R⁵is -CH^r¹ wherein Ar¹ is aryl optionally substituted with one or more of R⁸, -OR⁸, - NR⁸R⁹, -CONR⁸R⁹, -COOR⁸, -NR⁸COR⁹, -SR⁸, -SO₂R⁸, -SO₂NR⁸R⁹, -NR⁸SO₂R⁹, halogen, cyano, or nitro;

R⁶ and R⁷ are each independently hydrogen, C_1-6alkyl, C_2-6alkenyl, (C _-8cycloalkyl)C_0-

₆alkyl, Cι_-6fluoroalkyl, arylCo_-6alkyl, heteroarylC_0-6alkyl or heterocycleC_0-6alkyl; and said Cι_-6alkyl, C_2-6alkenyl, (C_3-8cycloalkyl)C₀-₆alkyl, -efluoroalkyl, arylC_0-6alkyl, heteroarylC₀-₆alkyl or heterocycleC_0-6alkyl, may be substituted with one or more B; or R and R form together a 4-, 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S, and said ring may be substituted with one or more B;

B is R⁸, -COOR⁸, -COR⁸, -NHCOR⁸, -NR⁸R⁹, -CONR⁸R⁹, -OR⁸, -SO₂NR⁸R⁹, CN, oxo or halogen;

R⁸ and R⁹ each independently are hydrogen, Ci-βalkyl, -βfluoroalkyl, or hydroxy .

₆alkyl, or; o q R and R form together a 4-, 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S, and said ring may be substituted with one or more B; as a free base or salt thereof.

Listed below are definitions of various terms used in the specification and claims to describe the present invention.

For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined' or 'defined hereinbefore' the said group encompasses the first occurring and broadest definition as well as each and all of the preferred definitions for that group.

For the avoidance of doubt it is to be understood that in this specification 'C_1-6' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.

For the avoidance of doubt it is to be understood that in this specification 'Co-e' means a carbon group having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.

In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups. Cι_-6alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-buty], t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, and hexyl. In this specification, unless stated otherwise, the term "C_3-8 cycloalkyl" includes a non- aromatic, completely saturated cyclic aliphatic hydrocarbon group containing 3 to 8 atoms. Examples of said cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In this specification, unless stated otherwise, the term "alkenyl" includes both straight and branched chain alkenyl groups but references to individual alkenyl groups such as 2-butenyl is specific for the straight chain version only. Unless otherwise stated, the term "alkenyl" advantageously refers to chains with 2 to 5 carbon atoms, preferably 3 to 4 carbon atoms. C₂-₆alkenyl may be ethenyl, propenyl, 2-methylpropenyl, butenyl and 2- butenyl.

In this specification, unless stated otherwise, the term "heterocycle" includes a 3- tolO- membered non-aromatic partially or completely saturated hydrocarbon group, which contains one or two rings and at least one heteroatom. Examples of said heterocycle include, but are not limited to pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, oxazolyl, 2-oxazolidonyl, tetrahydrofuranyl, 4H-l,3-benzodioxinyl, tetrahydropyranyl or 4-oxo-l,4-dihydroquinolinyl.

In this specification, unless stated otherwise, the expressions "R⁸ and R⁹ form together a 4-

5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S" and "R⁶ and R⁷ form together a 4-, 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S" include, but are not limited to piperidinyl, piperazinyl and morpholinyl.

In this specification, unless stated otherwise, the term "aryl" may be a C,- C₁ aromatic hydrocarbon and includes, but is not limited to, benzene, naphthalene, indene, anthracene, phenanthrene.

In this specification, unless stated otherwise, the term "heteroaryl" may be a monocyclic heteroaromatic, or a bicyclic fused-ring heteroaromatic group. Examples of said heteroaryl include, but are not limited to, pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, benzofuryl, indolyl, isoindolyl, benzimidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl or triazolyl.

In this specification, unless stated otherwise, the term halogeno may be fluor, chlorine, bromine or iodine.

In this specification, unless stated otherwise, the term "Cι.₆ fluoroalkyl" may be an alkyl substituted with one or more fluorine atoms. Examples of said fluoroalkyl include, but are not limited to, monofluoromethyl, trifluoromethyl, difluoromethyl and trifluoroethyl.

In one aspect of the invention there is provided compounds of formula I wherein wherein

X is CR⁴ or N;

R¹ is -OR⁵, -NHCOR⁶ or -NR⁶R⁷; R² is hydrogen, or -OAr¹, wherein Ar¹ is aryl optionally substituted with -SO₂R⁸ or one or more halogen;

R³ is hydrogen or -NHAr² wherein Ar² is benzene substituted one or more halogen;

R⁴ is hydrogen or NO₂;

R⁵ is -CH₂Ar¹ wherein Ar¹ is aryl substituted with one or more halogen; R and R are each independently hydrogen, C_1-6alkyl, (C _-8cycloalkyl)C_0-6alkyl, arylCo-

₆alkyl, heteroarylCo-₆alkyl or heterocycleC_0-6alkyl; and said Cι_-6alkyl, arylCo-βalkyl, heteroarylCo-₆alkyl or heterocycleC₀-₆alkyl, may be substituted with one or more B;

B is -COR⁸, -NHCOR⁸, -OR⁸, or halogen;

R⁸ is hydrogen or Cι_-6alkyl.

In another aspect of the present invention there is provided compounds of formula I wherein R³ is hydrogen.

In another aspect of the present invention there is provided compounds of formula I wherein R² is -OAr¹ and Ar¹ is phenyl. In one embodiment of the present aspect there is provided compounds of formula I wherein Ar¹ is is phenyl, said phenyl being substituted with one or more halogen. In another embodiment of the present aspect there is provided compounds of formula I wherein said phenyl is substituted with one fluoro.

In another aspect of the present invention there is provided compounds of formula I wherein R² is -OAr¹ and Ar¹ is phenyl. In one embodiment of the present aspect there is provided compounds of formula I wherein said Ar¹ is phenyl substituted with with -SO₂R^s, and R⁸ is Cι_-6alkyl.

In another aspect of the present invention there is provided compounds of formula I wherein R¹ is NR⁶R⁷. In one embodiment of the present aspect there is provided compounds of formula I wherein R andR is selected from C_1-6alkyl, arylC_0-6alkyl, heteroaryl Co-₆alkyl and heterocycleCo_-6alkyl and said C_1-6alkyl, arylC_0-6alkyl, heteroarylCo_-6alkyl, heterocycleCo_-6alkyl may be substituted with one or more B. In another embodiment of the present aspect there is provided compounds of formula I wherein said B is selected from -NHCOR⁸, -OR⁸, and halogen. In yet another embodiment of the present aspect there is provided compounds of formula I wherein wherein said R⁸ is methyl.

In another aspect of the present invention there is provided compounds of formula I wherein R¹ is -OR⁵ and R⁵ is CH₂Ar^! and said Ar¹ is aryl substituted with one or more halogen.

In another aspect of the present invention there is provided compounds of formula I wherein X is CR⁴ and R⁴is hydrogen.

In another aspect of the present invention there is provided compounds of formula I wherein X is N.

In another aspect of the present invention there is provided compounds of formula I wherein R² is hydrogen. In one embodiment of the present aspect there is provided compounds of formula I wherein R³ is -NHAr² and Ar² is benzene substituted with one or more halogen. In another embodiment of the present aspect there is provided compounds of formula I wherein said benzene is substituted with one chloro.

In another aspect of the present invention there is provided compounds of formula I wherein R¹ is -NHCOR⁶, and R⁶ is selected from (C_3-8cycloalkyl)C_0-6alkyl, heteroarylC_{0- 6}alkyl and heterocycleC₀.₆alkyl.

In another aspect of the present invention there is provided compounds of formula I wherein R¹ is -NR⁶R⁷ and R⁶ and R⁷ are each independently selected from hydrogen, . ₆alkyl, (C_3-8cycloalkyl)C_0-6alkyl, and heteroarylCo_-6alkyl.

The present invention relates to the use of compounds of formula I as hereinbefore defined as well as to the salts thereof. Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I. Such salts are possible, includes both pharmaceutically acceptable acid and base addition salts. A suitable pharmaceutically acceptable salt of a compound of Formula I is, for example, an acid-addition salt of a compound of Formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric; or, for example a salt of a compound of Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt, or a salt with an organic base.

Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.

Certain compounds of the present invention may exist as tautomers. It is to be understood that the present invention encompasses all such tautomers.

Specific compounds of Formula I are:

N-(2,5-Dimethoxybenzyl)-4-phenoxy-lH-pyrazolo[4,3-c]pyridin-3-amine; N-(2,5-Dimethoxybenzyl)-4-ρhenoxy-lH-indazol-3-amine trifluoroacetate; N-(4-{ [(4-Phenoxy-lH-pyrazolo[4,3-c]pyridin-3-yl)amino]methyl}phenyl)acetamide trifluoroacetate;

N-[(6-Fluoro-4H-l ,3-benzodioxin-8-yl)methyl]-4-phenoxy-lH-indazol-3-amine;

(+/-)-N-[ 1 -(2-Methoxyphenyl)ethyl]-4-phenoxy-lH-indazol-3-amine trifluoroacetate; N-(2,5-Dichlorobenzyl)-4-phenoxy- lH-indazol-3-amine;

N-(2,5-Dimethoxybenzyl)-5-nitro-4-phenoxy-lH-indazol-3-amine hydrochloride;

N-(4-{ [(5-Νitro-4-phenoxy-lH-indazol-3-yl)amino]methyl}phenyl)acetamide;

N-(4- { [(4-Phenoxy- lH-indazol-3-yl)amino]methyl }phenyl)acetamide;

3-[(2-Chlorobenzyl)oxy]-4-phenoxy-lH-indazole; 8-{[(4-Phenoxy-lH-indazol-3-yl)amino]methyl}quinolin-4(lH)-one;

N-[4-({ [4-(4-FluoLOphenoxy)-lH-indazol-3-yl]amino}methyl)phenyl]acetamide;

N- { 4- [( { 4- [4-(Methylsulfonyl)phenoxy] - lH-indazol-3-yl } amino)methyl]phenyl } acetamide;

N-(2,5-Dimethoxybenzyl)-4-[4-fluoro-phenoxy]-lH-indazol-3-amine; N-(2,5-Dimethoxybenzyl)-4-[4-(methylsulfonyl)phenoxy]-lH-indazol-3-amine;

(+/-)-N-[ 1 -(2,5-Dimethoxyphenyl)ethyl]-4-phenoxy-lH-indazol-3-amine trifluoroacetate;

4-Phenoxy-N-(l,3-thiazol-2-ylmethyl)-lH-indazol-3-amine;

N6-(2-chlorophenyl)-lH-indazole-3,6-di amine;

N6-(2-ch]orophenyl)-N3-isopropyl-lH-indazole-3,6-diamine; N-{6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}-2-furamide;

N6-(2-chloiOphenyl)-N3-(2-furylmethyl)-lH-indazole-3,6-diamine;

N-{6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}cyclopropanecarboxamide;

N-{6-[(2-ch]orophenyl)amino]-lH-indazol-3-yl}-3-furamide;

N6-(2-chlorophenyl)-N3-(cyclopropylmethyl)-lH-indazole-3,6-diamine; N-{6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}piperidine-3-carboxamide;

(3S)-N- { 6-[(2-chloroρhenyl)amino]- lH-indazol-3-yl }tetrahydrofuran-3-carboxamide;

Methyl 3-[({6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}amino)carbonyl]benzoate;

3-[({6-[(2-chloroρhenyl)amino]-lH-indazol-3-yl}amino)carbonyl]benzoic acid;

N-{6-[(2-chloiOphenyl)amino]-lH-indazol-3-yl}tetrahydro-2H-pyran-4-carboxamide; as a free base or a salt thereof. The present invention relates to novel pyridine derivatives, which are inhibitors of c-Jun N- terminal kinases (JNKs). JNKs have been implicated in mediating a number of disorders. The invention relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention, uses of the inhibitors of the invention in the manufacture of medicaments and methods of utilizing the compositions in the treatment of various disorders.

Pharmaceutical compositions

According to one aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula I, as a free base or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, for use in the prevention and/or treatment of conditions associated with c-Jun N-terminal kinases (JNKs).

The composition may be in a form suitable for oral administration, for example as a tablet, for parenteral injection as a sterile solution or suspension. In general the above compositions may be prepared in a conventional manner using pharmaceutically carriers or diluents. Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man, are approximately 0.01 to 250 mg kg bodyweight at peroral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration. The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.

A compound of formula I, or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, can be used on its own but will usually be administered in the form of a pharmaceutical composition in which the formula I compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable diluent or carrier. Dependent on the mode of administration, the pharmaceutical composition may comprise from 0.05 to 99 %w (per cent by weight), for example from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

A diluent or carrier includes water, aqueous polyethylene glycol, magnesium carbonate, magnesium stearate, talc, a sugar (such as lactose), pectin, dextrin, starch, tragacanth, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose or cocoa butter.

A composition of the invention can be in tablet or injectable form. The tablet may additionally comprise a disintegrant and/or may be coated (for example with an enteric coating or coated with a coating agentsuch as hydroxypropyl methylcellulose).

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula I, or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, a hereinbefore defined, with a pharmaceutically acceptable diluent or carrier.

An example of a pharmaceuticall composition of the invention is an injectable solution containing a compound of the invention, or a a pharmaceutically acceptable salt, solvate or solvate of salt thereof, as hereinbefore defined, and sterile water, and, if necessary, either sodium hydroxide or hydrochloric acid to bring the pH of the final composition to about pH 5, and optionally a surfactant to aid dissolution.

Liquid solution comprising a compound of formula I, or a salt thereof, dissolved in water.

Medical use The compounds of Formula I have activity as medicaments. In particular the compounds of formula I are potent JNK inhibitors and preferred compounds are selective JNK inhibitors. The present invention provides a compound of Formula I for use as a medicament. In particular the present invention provides a compound of Formula I for use in the prevention or treatment of conditions associated with JNK activation. The present invention provides a method of treating or preventing conditions associated with JNK activation comprising the administration of a therapeutically effective amount of a compound of Formula I to a mammal (particularly a human including a patient) in need thereof.

In a further aspect the present invention provides the use of a compound of Formula I in the manufacture of a medicament for the treatment of conditions associated with JNK activation.

Conditions that may be treated by the compounds of this invention, according to Formula I, or a pharmaceutical composition containing the same, include any condition associated with JNK activation. Conditions associated with JNK activation include but are not limited to: central or peripheral neurological degenerative disorders including Alzheimer's disease, cognitive disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Gaum, HIV dementia, corticobasal degeneration, dementia pugilistica, Down's syndrome, postencephelatic parkinsonism, progressive supranuclear palsy, Pick's Disease, Niemann- Pick's Disease, epilepsy, a peripheral neuropathy, spinal cord injury, head trauma; autoimmune diseases including Multiple Sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, asthma, septic shock, transplant rejection; cardiovascular diseases including stroke, arterosclerosis, myocardial infarction, myocardial reperfusion injury; cancer including breast-, colorectal, pancreatic, prostate cancer.

In addition, JNK inhibitors of the instant invention may be capable of inhibiting the expression of inducible pro-inflammatory proteins. Therefore other conditions, which may be treated by the compounds of this invention, include edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritis pain. In the context of the present specification, the term "therapy" also includes "prevention" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

The term "condition", unless stated otherwise, means any disorder and disease associated with JNK activity.

Non-medical use

In addition to their use in therapeutic medicine, the compounds of formula I or salt thereof, are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of JNK inhibitor related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.

Methods of preparation

According to the invention there is provided a process for the preparation of compounds of formula (I) which comprises:

(a) reaction of a compound of formula (JJ):

in which X, R² and R³ are as defined in formula (I) or are protected derivatives thereof, Pg is an amino protecting group or hydrogen and A is NH₂ , with a compound of formula (III):

(HI)

in which R⁶ is as defined in formula (I) or is protected derivatives thereof, ' or, optionally after reaction (a) reduction of the formed amide bond to yield a compound of formula (I) or,

(b) reaction of a compound of formula (JJ) with a compound of formula (TV):

(IV) in which R and R are as defined in formula (I) or are protected derivatives thereof, or, (c) reaction of a compound of formula (U) where A is NH₂ or OH with a compound of formula (V):

(V)

in which n, R⁶ and R⁷ are as defined in formula (I) or are protected derivatives thereof and

Lg represents a leaving group, and optionally thereafter in any of the reaction: • removing any protecting groups present • forming a pharmaceutically acceptable salt. A representative compound of Formula (JJ) is tert-butyl 3-amino-6-[(2- chlorophenyl)amino]-lH-indazole-l-carboxylate.

The reaction of compounds (II) and (III) can be carried out using standard chemistry, for example, acylation of amine groups. These acylations can be performed by reacting the amine group with the corresponding acid in an inert solvent such as DMF in the presence of coupling reagents such as 1,3-dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, ΗATU or TBTU.

The reaction of compounds (II) and (III) can also be carried out under amine acylation conditions such as reacting the amine group with the corresponding acid chloride in an inert solvent, such as toluene in the presence of an amine, or in pyridine.

After the reaction of compound (II) and (III) the formed amide bond can optionally be reduced to the corresponding amine derivatives with a reducing agent such as lithium aluminiumhydride or diborane in an inert solvent such as tetrahydrofuran.

The reaction of compounds (II) and (IV) can be carried out under reductive amination conditions, for example using acid/sodium cyanoborohydride, sodium triacetoxyborohydride or sodium borohydride. The reaction may be carried out in a solvent such as methanol at ambient temperature.

The reaction of compounds (JJ) and (V) can be carried out under standard alkylation conditions. Suitable leaving groups Lg include halogen, in particular bromine and chlorine, or a p-toluenesulphonate or mesylate group.

Compounds of formula (II) in which A is NΗ₂ can be prepared from the corresponding compounds of formula (VI):

in which X, R" and R are as defined above or protected derivatives thereof and L is a leaving group, using hydrazine displacement and cyclisation.

The reaction may be carried out in a suitable solvent, for example an alcohol solvent such as butanol, at elevated temperature such as reflux. Suitable leaving groups L include halogen such as fluoro or a methoxy group.

Compounds of formula (VI) can be prepared by reacting compounds of formula (VU):

in which X and L are as defined above and L' is a leaving group, with compounds of formula (VIII):

HO-Ar or NH₂-Ar or NH₂-Ar

(VTJJ)

in which Ar¹ and Ar² is as defined above. The reaction of compounds (VJJ) and (VIH) can be carried out in the presence of a base in a solvent such as dimethylformamide at elevated temperature, for example at 60°C. The reaction of compounds (VJJ) and (VIU) can also be carried using a palladium catalyst such as Pd(dba) and BINAP in an inert solvent such as toluene in the presence of a base at elevated temperature as described in JACS 1996, 118, 7215-7216.

Suitable leaving groups L' include halogen, triflate or methoxy.

Compounds of formula (II) in which A is OH can be prepared from reaction of a compound of formula (IX) wherein R² and R³ are as defined above and X is C-R* where R*is an alkyl group, such as methyl or ethyl, L represents a leaving group such as fluorine:

(LX) with hydrazine hydrate in a solvent, such as ethanol or butanol, at an elevated temperature, such as 40- 100°C, ideally 80°C, followed by protection of the N-1 amino functionality with a suitable protecting group, such as ethyl carbamate.

Compounds of formula (LX) can be prepared by reaction of a compound of formula (X), where L' represents a leaving group such as a halogen atom or an ether and R* is as defined above:

(X)

with a compound of formula (VLTJ) in a suitable solvent, such as dimethylformamide, at an elevated temperature, such as 40-100°C, ideally at 80°C, with a suitable base, such as caesium carbonate. Compounds of formula (HI), (IV), (V) and (VH) are either commercially available or can be prepared using standard chemistry.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.

The protection and deprotection of functional groups is fully described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 2nd edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1991).

Working Examples

The invention will now be described in more detail with the following examples that are not to be construed as limiting the invention.

All chemicals and reagents were used as received from suppliers. 1H and ¹³C nuclear magnetic resonance (NMR) spectra were recorded on a BRUKER DPX 400 (400 MHz) spectrometer using the following solvents and references.

CDC1₃ : 1H NMR TMS (0.0 ppm) and ¹³C the central peak of CDC1₃ (77.0).

CD₃OD : 1H NMR 3.31 ppm (central peak) and ¹³C 49.0 ppm (central peak).

OMSO-d₆: Η NMR 2.50 ppm (central peak) and ¹³C 39.51 ppm (central peak).

Mass spectra (TSP) were recorded on a Finigan MAT SSQ 7000 spectrometer.

Mass spectra (El) were recorded on a Finigan MAT SSQ 710 spectrometer. LC-MS were recorded on a Waters Alliance 2790 + ZMD spectrometer equipped with software Mass Lynx 3.5.

Flash column chromatography was carried out on silica gel 60 (230-400 mesh). List of abbreviations

DMAP Dimethylamino pyridine

DMF NN-dimethylformamide

BINAP 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl

Pd(dba) tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct

EtOAc Ethyl acetate THF Tetrahydrofuran

MeOH ^' Methanol

DIPEA Diisopropylethylamine

HATU 0-(7- Azabenzotriazol- 1 -yl)-NNN',N'-tetramethyluronium hexafluorophosphate

TBTU 0-{ 1 H-Benzotriazol- 1 -yl)-NNN',N'-tetramethyluronium tetrafluoroborate

ΗOBt 1-Ηydroxybenzotriazole hydrate

Example 1

N-(2,5-DimethoxybenzyI)-4-phenoxy-lH-pyrazolo[4,3-c]pyridin-3-amine a) 4-Phenoxy- 1 H-pyrazolo[4,3-c] pyridin-3-amine

To 2-chloro-4-methoxy-3-pyridinecarbonitrile (168 mg) in DMF (3 mL) was added phenol

(97 mg) and caesium carbonate (338 mg). The mixture was warmed to 60°C and stirred for 2 h after which it was allowed to cool to room temperature. Hydrazine hydrate (1 mL) and ethanol (2 mL) were then added and the mixture heated to 100°C for 18 h. After cooling to room temperature the solution was poured into water and extracted with dichloromethane. The combined organic extracts were evaporated in vacuo, treated with concentrated hydrochloric acid and the mixture diluted with water. Neutralisation with saturated sodium hydrogen carbonate solution yielded a suspension which was filtered to give the titled compound (75 mg) as an off white solid.

1H NMR (400 MHz, d₆-DMSO) 57.59 (1H, d), 7.40-7.45 (2H, m), 7.21-7.26 (3H, m), 6.90 (1H, d), 5.38 (2H, s).

b) N-(2,5-Dimethoxybenzyl)-4-phenoxy-lH-pyrazolo[4,3-c]pyridin-3-amine

To 4-phenoxy-lH-pyrazolo[4,3-c]pyridin-3-amine (176 mg) in methanol (0.4 mL) and acetonitrile (2 mL) was added 2,5-dimethoxybenzaldehyde (130 mg). Acetic acid (30 μL) was added and the mixture stirred at room temperature for 2 h. Sodium cyanoborohydride (60 mg) was added and the mixture stirred for a further 18 h. The resulting mixture was poured into a saturated solution of sodium hydrogen carbonate in water (5 mL) and then ethyl acetate (10 mL) was added. The organic layer was separated and the aqueous layer further extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried (magnesium sulphate), concentrated in vacuo and purified by column chromatography (Silica : ethyl acetate / isohexane 1:1) to yield the titled compound (95 mg) as an off-white solid. MS (APCI) +ve ^m/z = 377 [(M+H)⁺]. 1H NMR (400 MHz, d₆-DMSO) δ 12.03 (1H, s), 7.63 (1H, d), 7.40-7.48 (2H, m), 7.21-7.28 (3H, m), 6.86-6.94 (3H, m), 6.75 (1H, dd), 5.92 (1H, t), 4.44 (2H, d), 3.75 (3H, s), 3.64 (3H, s).

Example 2

N-(2,5-Dimethoxybenzyl)-4-phenoxy-lH-indazol-3-amine trifluoroacetate a) 4-Phenoxy- 1 H-indazol-3 -amine

To 2-fluoro-6-phenoxy-benzonitrile (5 g) in n-butanol (60 mL) was added hydrazine hydrate (1.1 mL) and the mixture heated to 110°C for 24 h. After cooling to room temperature the solution was poured into water and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), evaporated in vacuo and purified by column chromatography (Silica : ethyl acetate / isohexane 1:1) to yield the titled compound (3 g) as a white solid. 1H NMR (300 MHz, d₆-DMSO) δ 11.59 (1H, s), 7.43 (2H, t), 7.06-7.24 (4H, m); 6.95 (1H, d), 6.14 (lH, d), 4.94 (2H, m).

b) N-(2,5-Dimethoxybenzyl)-4-phenoxy-lH-indazol-3-amine trifluoroacetate 4-Phenoxy-lH-indazol-3-amine (200 mg) and 2,5-dimethoxybenzaldehyde (146 mg) in toluene (5 mL) and methanol (40 μL) were azeotroped to give a colourless oil. The residue was then re-dissolved in acetonitrile (3 mL) and acetic acid (200 μL) added.

(Polystyrylmethyl)trimethylammonium cyanoborohydride (600 mg) was added to the mixture which was then stirred at room temperature for 2 h. The suspension was filtered and the filtrant treated with saturated sodium hydrogen carbonate solution (5 mL). The solution was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers dried (magnesium sulphate), concentrated in vacuo and purified by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1% aqueous trifluoroactetic acid) to yield the titled compound (184 mg) as its solid trifluoroacetate salt. MS (APCI) +ve ^m/z = 376 [(M+H)⁺].

1H NMR (300 MHz, d₆-DMSO) δ 11.8 (1H, br s), 7.41-7.48 (2H, m); 7.11-7.27 (4H, m), 6.97 (1H, d), 6.82-6.90 (2H, m), 6.74 (1H, dd); 6.14 (1H, d), 4.40 (2H, s), 3.70 (3H, s), 3.62 (3H, s).

Example 3

N-(4-{[(4-Phenoxy-lH-pyrazolo[4,3-c]pyridin-3-yl)amino]methyl}phenyl)acetamide trifluoroacetate

To 4-phenoxy-lH-ρyrazolo[4,3-c]pyridin-3-amine (188 mg) in methanol (3 mL) was added 4-acetamidobenzaldehyde (135 mg). The mixture was stirred at room temperature for 0.5 h and then acetic acid (30 μL) was added. Sodium cyanoborohydride (52 mg) was added and the mixture stirred for a further 18 h. The resulting solution was poured into saturated sodium hydrogen carbonate solution (5 mL) and then dichloromethane (10 mL) was added. The organic layer was separated and the aqueous layer further extracted with dichloromethane (2 x 5 mL). The combined organic layers were dried (magnesium sulphate), concentrated in vacuo and purified by preparative reversed phase column chromatography (Symmetry C8, methanol 10.1% aqueous trifluoroacetic acid) to yield the titled compound (135 mg) as its solid trifluoroacetate salt. MS (APCI) +ve ^m/z = 374 [(M+H)⁺].

1H NMR (300 MHz, d₆-DMSO) δ 9.85 (1H, s), 7.61 (1H, d), 7.39-7.52 (4H, m), 7.21-7.36 (5H, m), 6.92 (1H, d), 4.43 (2H, d), 2.01 (3H, s).

Example 4 N (6-FIuoro-4H-l,3-benzodioxin-8-yl)methyl]-4-phenoxy-lH ndazol-3-amine a) 6-Fluoro-4H- l,3-benzodioxine-8-carbaldehyde Anhydrous sodium carbonate (400 mg) was added to 8-(chloromethyl)-6-fluoro-4H-l,3- benzodioxine (260 mg) in dimethylsulphoxide (2 mL). The mixture was heated to 130°C for 24 h after which it was cooled and added to water (10 mL). The mixture was extracted with dichloromethane (3 x 5 mL), the combined organic layers dried (magnesium sulphate) and evaporated in vacuo to yield the title compound as a colourless oil (203 mg).

1H NMR (300 MHz, d₆-DMSO) δ 10.2 (1H, d), 7.35-7.41 (2H, m), 5.41 (2H, s), 4.96 (2H, s). _,

b) N-[(6-Fluoro-4H-l,3-benzodioxin-8-yl)methyl]-4-phenoxy-lH-indazol-3-amine 4-Phenoxy- 1 H-indazol-3-amine (300 mg) and 6-fluoro-4iϊ-l,3-benzodioxine-8- carbaldehyde (200 mg) in toluene (5 mL) and methanol (300 μL) were azeotroped to give a colourless oil. The residue was then re-dissolved in a mixture of acetonitrile (4 mL) and methanol (300 μL) and acetic acid (100 μL) added. (Polystyrylmethyl)trimethylammonium cyanoborohydride (1 g) was added to the mixture which was then stirred at room temperature for 18 h. The suspension was filtered and the filtrant treated with saturated sodium hydrogen carbonate solution (5 mL). The solution was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers dried (magnesium sulphate), concentrated in vacuo and purified by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1 % aqueous trifluoroactetic acid) to yield the titled compound as an off white solid (104 mg).

MS (APCI) +ve ^m/z = 392 [(M+Η)⁺j.

1H NMR (300 MHz, d₆-DMSO) δ 11.68 (1H, s), 7.45 (2H, m), 7.09-7.25 (4H, m), 6.96

(1H, dd), 6.88 (1H, dd), 6.79 (1H, dd), 6.14 (1H, d), 5.25 (2H, s), 4.86 (2H, s), 4.40 (2H, s).

Example 5

(+/-)-N-[l-(2-Methoxyphenyl)ethyl]-4-phenoxy-l£T-indazoI-3-amine trifluoroacetate

4-Phenoxy-lH-indazol-3-amine (250 mg) and 2-methoxy-acetophenone (164 mg) in toluene (5 mL) and methanol (300 μL) were azeotroped to give a colourless oil. The residue was then re-dissolved in a mixture of acetonitrile (3 mL) and methanol (500 μL) and acetic acid (10 μL) added. (Polystyrylmethyl) trimethylammonium cyanoborohydride (700 mg) was added to the mixture which was then stirred at room temperature for 48 h.

The suspension was filtered and the filtrant treated with saturated sodium hydrogen carbonate solution (5 mL). The solution was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers dried (magnesium sulphate), concentrated in vacuo and purified by preparative reversed phase column chromatography (Symmetry C8, methanol /

0.1% aqueous trifluoroactetic acid) to yield the titled compound (12 mg) as its trifluoroacetate salt.

MS (APCI) ^m/z = 360 [(M+H)⁺].

1H NMR (400 MHz, d₆-DMSO) δ 11.67 (IH, br s), 7.46 (2H, m), 7.10-7.27 (6H, m), 6.95 (IH, d), 6.93 (IH, d), 6.81 (IH, dt), 6.18 (IH, d), 5.07 (IH, q), 3.74 (3H, s), 1.38 (3H, d).

Example 6 N-(2,5-Dichlorobenzyl)-4-phenoxy-lH-indazol-3-amine

4-Phenoxy-lH-indazol-3-amine (200 mg) and 2,5-dimethoxy-benzaldehyde (152 mg) in toluene (5 mL) and methanol (300 μL) were azeotroped to give a colourless oil. The residue was then re-dissolved in a mixture of acetonitrile (3 mL) and methanol (1 mL) and acetic acid (300 μL) added. Sodium cyanoborohydride (60 mg) was added to the mixture which was then stirred at room temperature for 24 h. Sodium hydrogen carbonate solution (5 mL) was added and the solution extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried (magnesium sulphate), concentrated in vacuo and purified by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1% aqueous trifluoroacetic acid) to yield the titled compound as an off white solid (30 mg). MS (APCI) +ve ^m/z = 384 [(M+H)⁺].

1H NMR (400 MHz, d₆-DMSO) δ 11.64 (IH, s), 7.24-7.49 (3H, m), 7.36 (IH, d), 7.31 (IH, dd), 7.11-7.26 (4H, m), 6.96 (IH, d), 6.15 (IH, d), 6.02 (IH, t), 4.50 (2H, d).

Example 7 N-(2,5-Dimethoxybenzyl)-5-nitro-4-phenoxy-lfir-indazol-3-amine hydrochIoride a) 6-Fluoro-3-nitro-2-phenoxybenzonitrile and 2-fluoro-3-nitro-6-phenoxybenzonitrile 2,6-Difluoro-3-nitro-benzonitrile (10 g) and phenol (5.1 g) were dissolved in dimethylformamide (80 mL). Sodium hydride (60% in mineral oil) (2.2 g) was added and the mixture stirred for 10 h at room temperature under nitrogen. Both regioisomers were formed in a 2: 1 ratio in favour of the 2-phenoxy substituted desired product. Isopropyl alcohol was cautiously added followed by dilute hydrochloric acid (2M). The resulting solution was extracted with dichloromethane and the combined organic extracts washed with water. The organic phase was washed with brine, dried (magnesium sulphate), filtered and concentrated in vacuo. The residue obtained (9.7 g) was used in subsequent reaction without further purification. GCMS ^m/z = 258 [(M^+*)].

b) N-(l-Methylethylidene)-5-nitro-4-phenoxy-lH-indazol-3-amine A 2: 1 mixture of 6-fluoro-3-nitro-2-phenoxybenzonitrile and 2-fluoro-3-nitro-6- phenoxybenzonitrile (15.2 g) respectively was dissolved in n-butanol and hydrazine monohydrate (11.4 mL) was slowly added. The solution was stirred for 48 h. The solvent was evaporated in vacuo to leave a solid residue that was triturated with acetone, sonicated and then filtered. The filtrate was purified by column chromatography (Silica : dichloromethane) to afford the titled compound as a yellow solid (2 g). Identification of the required isomer was achieved by NMR experiments.

1H NMR (400 MHz, d₆-DMSO) δ 10.03 (IH, s), 8.26 (IH, d), 7.36 (2H, ddt), 7.27 (IH, d), 7.10 (IH, tt), 6.93 (2H, d), 2.00 (3H, s), 1.81 (3H, s).

c) 5-Nitro-4-phenoxy-lH-indazol-3-amine

N-(l-Methylethylidene)-5-nitro-4-phenoxy-lH-indazol-3-amine (2 g) was dissolved in methanol (20 mL) and 2M aqueous hydrochloric acid (20 mL) was added. The reaction mixture was stirred at room temperature for 2 h. After evaporation of the methanol, the resulting suspension was filtered to give an off-white solid (1.5 g). 1H ΝMR (400 MHz, d₆-DMSO) δ 8.00 (IH, d), 7.34 (2H, ddt), 7.30 (IH, d), 7.09 (IH, tt), 6.92 (2H, d).

d) N-(2, 5-Dimethoxybenzyl)-5-nitro-4-phenoxy-lH-indazol-3-amine hydrochloride A suspension of 5-nitro-4-phenoxy-lH-indazol-3-amine (200 mg) and 2,5- dimethoxybenzaldehyde (123 mg) in acetonitrile (3 mL) and methanol (1 mL) was stirred at room temperature under nitrogen. After 1 h, sodium borohydride (56 mg) was added and the suspension was stirred for 12 h. Isopropyl alcohol (3 mL) was added then 2M aqueous hydrochloric acid (3 mL). The reaction mixture was evaporated to dryness and the residue partitioned between dichloromethane and water. The aqueous layer was further extracted with dichloromethane and the combined organic layers were washed with brine, dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was purified by column chromatography (Silica : dichloromethane — > 1% methanol in dichloromethane).

The residue was dissolved in ether and the solid hydrochloride salt (10 mg) precipitated by addition of hydrochloric acid (1M in ether).

MS (APCI) +ve ^m/z = 421.1 [(M+H)]⁺. 1H NMR (400 MHz, d₆-DMSO) δ 8.01 (IH, d), 7.32 (2H, ddt), 7.28 (IH, d), 7.08 (IH, tt),

6.91 (2H, d), 6.83 (IH, d), 6.71 (IH, dd), 6.63 (IH, d), 4.32 (2H, s), 3.62 (3H, s), 3.56 (3H, s).

Example 8 N-(4-{[(5-Nitro-4-phenoxy-lH-indazol-3-yl)amino]methyl}phenyl)acetamide

A mixture of 5-nitro-4-phenoxy-lH-indazol-3-amine (300 mg) and 4- acetamidobenzaldehyde (181 mg ) in toluene (20 mL) and methanol (5 mL) were heated to reflux for 12 h in a round bottom flask equipped with a Dean and Stark condenser. The reaction mixture was allowed to cool to 40°C and sodium borohydride (84 mg) was added under nitrogen. The mixture was stirred for 1 h after which isopropyl alcohol (3 mL) and then 2M aqueous hydrochloric acid (3 mL) were added. The reaction mixture was evaporated to dryness and the residue partitioned between dichloromethane and water. The aqueous layer was further extracted with dichloromethane and the combined organic layers were washed with brine, dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was purified by preparative reversed phase column chromatography

(Symmetry C8, methanol / 0.1 % aqueous trifluoroactetic acid) to yield the titled compound as a yellow solid (35 mg).

MS (APCI) +ve ^m/z = 418.1 [(M+H)⁺J. 1H NMR (400 MHz, d₆-DMSO) δ 12.44 (IH, s), 9.82 (IH, s), 8.00 (IH, d), 7.38 (2H, d), 7.33 (2H, ddt), 7.27 (IH, d), 7.10 (IH, tt), 6.97 (2H, d), 6.91 (2H, d), 5.65 (IH, t), 4.30 (2H, d), 2.00 (3H, s).

Example 9

N-(4-{[(4-Phenoxy-lH-indazoI-3-yl)arnino]methyI}phenyl)acetamide

4-Phenoxy-3-amino-lH-indazole (225 mg) and 4-acetamidobenzaldehyde (163 mg) were dissolved in methanol (10 mL) and toluene (10 mL) to give a solution which was then evaporated to dryness. The operation was repeated another two times and once completed the residue re-dissolved in methanol (10 mL) and acetic acid (50 μL) added. The reaction mixture was stirred for 20 minutes after which sodium cyanoborohydride (126 mg) was added in one portion and the mixture stirred for 48 h. The precipitated product was isolated by filtration of the reaction mixture and recrystallised from methanol and dichloromethane to yield the required solid (82 mg). MS (APCI) +ve ^m/z = 373.1 [(M+H)⁺] .

1H NMR (400 MHz, d₆-DMSO) δ 11.59 (IH, s), 9.84 (IH, s), 7.46 - 7.41 (4H, m), 7.22 (3H, d), 7.14 (2H, d), 7.10 (IH, t), 6.94 (IH, d), 6.11 (IH, d), 5.52 (IH, t), 4.37 (2H, d), 2.01 (3H, s).

Example 10 3-[(2-Chlorobenzyl)oxy]-4-phenoxy-lH-indazole

a) Methyl 2-fluoro-6-phenoxybenzoate

Methyl 2,6-difluorobenzoate (2 g), phenol (1.09 g), caesium carbonate (3.79 g), and dimethylformamide (10 mL) were loaded in a 100 mL round bottom flask and the resulting suspension heated to 80°C for 6 h. After cooling the reaction to room temperature, water (30 mL) was added and the mixture extracted with dichloromethane (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was purified by column chromatography (Silica : dichloromethane / hexane 5:2) to give the titled compound as a clear oil (1.7 g). GCMS ^m/z = 246 [(M^+*)].

b) 4-Phenoxy- 1 ,2-dihydro-3H-indazol-3-one

To methyl 2-fluoro-6-ρhenoxybenzoate (1 g) in n-butanol (5 mL) was added hydrazine monohydrate, and the solution heated to 100°C for 6 h. After cooling to room temperature, the reaction mixture was diluted in water and extracted with dichloromethane. The combined organic layers were washed with brine, dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was treated with dichloromethane and the insoluble material filtered to afford the titled compound (0.4 g). 1H NMR (300 MHz, d₆-DMSO) δ 11.58 (IH, s), 10.38 (IH, s), 7.37 (2H, ddt), 7.20 (IH, d), 7.12 (IH, tt), 7.01 (3H, d), 6.28 (IH, d).

c) Ethyl 3-oxo-4-phenoxy-2,3-dihydro-lH-indazole-l-carboxylate

To a chilled suspension of 4-phenoxy-l,2-dihydro-3H-indazol-3-one (180 mg) in pyridine (20 mL) at 0°C was slowly added ethyl chloroformate (91μL). The suspension was stirred at 0°C for 1 h and then allowed to warm up slowly to room temperature. After stirring for 48 h, the reaction mixture was evaporated in vacuo, diluted with water and extracted with dichloromethane. The aqueous was further extracted with dichloromethane and the combined organic phases washed with aqueous 1M hydrochloric acid and brine. The combined organic phases were dried (magnesium sulphate), filtered and evaporated in vacuo. Trituration with ether afforded the titled compound (103 mg).

1H NMR (300 MHz, d₆-DMSO) δ 11.98 (IH, s), 7.79 (IH, d), 7.51 (IH, t), 7.42 (2H, ddt), 7.18 (IH, tt), 7.06 (2H, d), 6.64 (IH, d), 4.42 (2H, q), 1.37 (3H, t).

d) Ethyl 3-[(2-chlorobenzyl)oxy]-4-phenoxy-lH-indazole-l-carboxylate

A mixture of 2-chlorobenzylchloride (84 mg, 66 μL), ethyl 3-oxo-4-phenoxy-2,3-dihydro- lH-indazole- 1 -carboxylate (155 mg), caesium carbonate (169 mg) and potassium iodide (5 mg) were suspended in dimethylformamide (2 mL) and the reaction mixture heated to 80°C for 2 h. The mixture was then allowed to cool and the suspension diluted with water (10 mL) and extracted with dichloromethane (2 x 10 mL). The resulting combined organic phases were washed with brine, dried (sodium carbonate), filtered, and evaporated in vacuo. Both O and N alkylated products were present in a 1:1 ratio and were separated by column chromatography (Silica : dichloromethane / hexane 1:3 — » dichloromethane). The less polar N-alkylated product was isolated (103 mg) and identified by ¹³C and 1H NMR experiments.

MS (APCI) +ve ^m/z = 423.1 [(M+H)⁺].

1H NMR (400 MHz, d₅-DMSO) δ 7.86 (IH, d), 7.59 (IH, t), 7.48 (IH, d), 7.40 - 7.27 (5H, m), 7.16 (IH, t), 7.03 (2H, d), 6.78 (IH, d), 5.47 (2H, s), 4.48 (2H, q), 1.41 (3H, t).

e) 3-[(2-ChIorobenzyl)oxy]-4-phenoxy-lH-indazole

Ethyl 3-[(2-chlorobenzyl)oxy]-4-phenoxy-lH-indazole-l-carboxylate (85 mg) was treated with 0.1M ethanolic potassium hydroxide (2 mL) and the reaction mixture was stirred for 1 h. Addition of water produced a white precipitate that was filtered and dried to afford the titled compound (57.5 mg).

MS (APCI) -t-ve ^m/z = 351.0 [(M+Η)]⁺.

1H NMR (300 MHz, d₆-DMSO) δ 12.17 (IH, s), 7.44 (IH, d), 7.39 - 7.09 (8H, m), 7.00 (2H, d), 6.47 (IH, d), 5.36 (2H, s).

Example 11 8-{[(4-Phenoxy-lH-indazol-3-yl)amino]methyl}quinolin-4(liϊ)-one

a) 5-(Methoxymethylene)-2,2-dimethyl-l,3-dioxane-4,6-dione

2,2-Dimethyl-l,3-dioxane-4,6-dione (10 g) was dissolved in trimethyl-orthoformate and the solution was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and then the excess trimethylorthoformate was evaporated in vacuo. The residue was triturated with ether, filtered and the resulting solid washed with cold ether to give the titled compound (10.5 g).

1H NMR (400 MHz, CDC1₃) δ 8.14 (IH, s), 4.26 (3H, s), 1.71 (6H, s). b) 2-{[(2,2-Dimethyl-4, 6-dioxo-l, 3-dioxan-5-ylidene)methyl]amino}benzonitrile To a solution of 2-aminobenzonitrile (3 g) in acetonitrile (30 mL) was added 5- (methoxymethylene)-2,2-dimethyl-l,3-dioxane-4,6-dione (4.73 g) in acetonitrile (10 mL). After 2 minutes of stirring, a fine suspension developed which was filtered to afford the titled product (4.3 g).

1H NMR (400 MHz, d₆-DMSO) δ 11.60 (IH, d), 8.72 (IH, d), 7.93 (2H, t), 7.79 (IH, td), 7.44 (IH, td), 1.70 (6H, s).

c) 4-Oxo-l, 4-dihydroquinoline-8-carbonitrile

2-{[(2,2-Dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)methyl]amino}benzonitrile (4 g) was added portionwise to refluxing diphenylether (40 mL). The reaction was refluxed for a further 5 min and then cooled to room temperature. The reaction mixture was poured into isohexane (100 mL) with vigorous stirring. The resulting yellow supernatant and the isohexane layer were decanted from the brown oily residue which was allowed to solidify at room temperature to afford the titled compound (2.1 g).

1H NMR (400 MHz, d₆-DMSO) δ 11.79 (IH, s), 8.39 (IH, d), 8.22 (IH, d), 7.86 (IH, t), 7.46 (IH, t), 6.18 (lH, d).

d) 4-Oxo-l,4-dihydroquinoline-8-carbaldehyde

4-Oxo-l,4-dihydroquinoline-8-carbonitrile (700 mg) was dissolved in tetrahydrofuran (6 mL) and sodium hydride (60% in oil, 166 mg) was added. The reaction was stirred for 1 h under nitrogen and then cooled to 5°C whereupon lithium aluminium hydride (1M in tetrahydrofuran, 2.1 mL) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for a further 1 h. After quenching with water, the aqueous phase was further extracted with ethyl acetate and the combined organic phases were washed with brine, dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was purified by column chromatography (Silica : dichloromethane / methanol 5:1) to give 120 mg of the desired product. MS (APCI) +ve ^m/z = 174.0 [(M+H)]⁺.

e) 8-{[(4-Phenoxy-lH-indazol-3-yl)amino]methylJguinolin-4(lH)-one By the method outlined in example 12 (part b), 4-phenoxy-3-amino-lH-indazole (97 mg) and 4-oxo-l ,4-dihydro-8-quinoline carbaldehyde (75 mg) were combined to give after isolation and purification by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1 % aqueous trifluoroactetic acid) 25 mg of the titled compound as an off-white solid.

1H NMR (300 MHz, d₆-DMSO) δ 11.70 (IH, s), 8.12 (IH, d), 8.08 (IH, dd), 7.77 (IH, d), 7.45 (2H, t), 7.38 (IH, t), 7.23 (IH, t), 7.18 (2H, d), 7.12 (IH, t), 6.94 (IH, d), 6.41 (IH, d), 6.09 (IH, d), 4.78 (2H, s).

Example 12 N-[4-({[4-(4-FIuorophenoxy)-lH-indazol-3-yl]amino}methyl)phenyl]acetamide a) 4-(4-Fluυrophenoxy)-lH-indazol-3-amine

A mixture of 2-fluoro-6-(4-fluorophenoxy) benzonitrile (2.31 g) and hydrazine hydrate (2.5 g) in ethanol (30 mL) was heated to reflux for 18 h and was then cooled to room temperature. The resulting solution was poured into a 5% (w/v) solution of sodium hydrogen carbonate in water (150 mL) and the resulting solid filtered and dried to afford the titled compound (4.86 g) as an off-white solid.

MS (APCI) +ve ^m/z = 244 [(M+H)]⁺. 1H NMR (300 MHz, d₆-DMSO) δ 11.59 (IH, s), 7.30 - 7.16 (4H, m), 7.09 (IH, t), 6.93

(IH, d), 6.07 (IH, d), 4.99 (2H, s).

b) N-[4-({[4-(4-Fluorophenoxy)-lH-indazol-3-yl]amino}methyl)phenyl]acetamide A solution of 4-(4-fluoroρhenoxy)-lH-indazol-3-amine (0.243 g), 4-acetylanilino benzaldehyde (0.179 g) and acetic acid (0.2 mL) were stirred together in methanol (5 mL) at room temperature for 4 h. Sodium cyanoborohydride (0.081 g) was added in one portion and the resulting solution stirred at room temperature for 10 h. The reaction mixture was poured into water (25 mL) and the resulting suspension was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by column chromatography (Silica : dichloromethane : methanol 50:1 → 20:1). The resulting oil was triturated with diethyl ether (5 mL) to afford the titled compound as a white solid (0.061 g). mp 225-228°C.

MS (APCI) +ve ^m/z = 391 [(M+H)]⁺.

1H NMR (300 MHz, d₆-DMSO) δ 11.59 (IH, s), 9.84 (IH, s), 7.46 (2H, d), 7.30 - 7.17

(6H, m), 7.09 (IH, t), 6.92 (IH, d), 6.06 (IH, d), 5.60 (IH, t), 4.38 (2H, d), 2.01 (3H, s).

Example 13

N-{4-[({4-[4-(MethylsuIfonyl)phenoxy]-lH-indazoI-3-yl}amino)methyl]phenyl} acetamide a) 4-[4-(Methylsulfonyl)phenoxy]-lH-indazol-3-amine

To a stirred solution of 2-fluoro-6-[(4-methylthio)phenoxy]benzonitrile (2.59 g) in anhydrous dichloromethane (100 mL) was added, portionwise metα-chloroperoxy benzoic acid (70% purity, 5.42 g - CARE EXOTHERM) and the resulting suspension stirred at room temperature for 2 h. The resulting mixture was diluted with dichloromethane (100 mL) and was washed with a solution of saturated sodium hydrogen carbonate in water (3 x 50 mL) and water (1 x 50 mL). The dichloromethane solution was dried (magnesium sulphate), filtered and concentrated in vacuo. The crude product was dissolved in ethanol (50 mL) and hydrazine hydrate (5.0 g) was added. The mixture was heated to reflux for 18 h and was then cooled. The resulting solution was poured into a 5% (w/v) solution of sodium hydrogen carbonate in water (150 mL) and the resulting solid filtered and dried to afford the titled compound (2.80 g) as an off-white solid. MS (APCI) +ve ^ra/z = 304 [(M+H)]⁺.

1H NMR (300 MHz, d₆-DMSO) δ 11.72 (IH, s), 7.93 (2H, dd), 7.28 - 7.19 (3H, m), 7.10 (IH, d), 6.44 ( IH, d), 4.91 (2H, s), 3.20 (3H, s).

b) N-{4-[({4-[4-(Methylsulfonyl)phenoxy]-lH-indazol-3-yl}amino)methyl]phenyl} acetamide

By the method outlined in example 12 (part b), 4-[4-(methylsulfonyl)phenoxy]-lJ3^r- indazol-3-amine (0.303 g), 4-acetylanilino benzaldehyde (0.179 g), acetic acid (0.2 mL) and sodium cyanoborohydride (0.081 g) were reacted together in methanol (5 mL). The crude reaction mixture after work-up was purified by column chromatography (Silica : dichloromethane / methanol 50: 1 → 20: 1). The resulting oil was triturated with ether (5 mL) to afford the titled compound as a white solid (0.095 g). mp 216-217°C

MS (APCI) +ve ^m/z = 451 [(M+H)]⁺.

1H NMR (300 MHz, d₆-DMSO) δ 11.72 (IH, s), 9.83 (IH, s), 7.94 (2H, d), 7.42 (2H, d), 7.28 (2H, d). 7.22 (IH, t), 7.16 - 7.07 (3H, m), 6.41 (IH, d), 5.53 (IH, t), 4.33 (2H, d), 3.20 (3H, s), 2.00 (3H, s).

Example 14 N-(2,5-Dimethoxybenzyl)-4-[4-fluoro-phenoxy]-lH-indazol-3-amine

A solution of 4-(4-fluorophenoxy)-lH-indazol-3-amine (0.243 g), 2,5- dimethoxybenzaldehyde (0.183 g) and acetic acid (0.2 mL) were stirred together in methanol (5 mL) at room temperature for 4 h. Sodium cyanoborohydride (0.081 g) was added in one portion and the resulting solution stirred at room temperature for 10 h. The reaction mixture was poured into water (25 mL) and the resulting suspension was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (magnesium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (Silica : diethyl ether : isohexane 1:1 — > diethyl ether). The title compound was obtained as an oil (0.151 g). MS (APCI) +ve ⁿ7z = 394 [(M+H)]⁺.

*H NMR (400 MHz, CDC1₃) δ 7.27 (2H, s), 7.13-7.05 (3H, m), 7.00 (IH, d), 6.91 (IH, d), 6.79-6.72 (2H, m), 6.13 (IH, d), 5.33-5.29 (IH, m), 4.58 (2H, d), 3.74 (3H, s), 3.73 (3H, s).

Example 15 N-(2,5-Dimethoxybenzyl)-4-[4-(methylsulfonyl)phenoxy]-Lff-indazoI-3-amine

A solution of 4-(4-methanesulfonyl-phenoxy)-lH-indazol-3-amine (0.303 g), 2,5- dimethoxybenzaldehyde (0.183 g) and acetic acid (0.2 mL) were stirred together in methanol (5 mL) at room temperature for 4 h. Sodium cyanoborohydride (0.081 g) was added in one portion and the resulting solution stirred at room temperature for 10 h. The reaction mixture was poured into water (25 mL) and the resulting suspension was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (magnesium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (Silica : ethyl acetate : dichloromethane 1:4). The titled compound was obtained as an oil (0.107 g).

MS (APCI) +ve ^m/z = 454 [(M+H)]⁺.

*H NMR (300 MHz, CDC1₃) δ 7.96-7.89 (2H, m), 7.23-7.19 (3H, m), 7.07 (IH, d), 6.87

(IH, d), 6.77-6.70 (2H, m), 6.43 (IH, d), 4.95 (IH, t), 4.52 (2H, d), 3.72 (3H, s), 3.72 (3H, s), 3.05 (3H, s).

Example 16 (+/-)-N-[l-(2,5-Dimethoxyphenyl)ethyl]-4-phenoxy-lH-indazol-3-amine trifluoroacetate

To 4-phenoxy-lH-indazol-3-amine (100 mg) and 2,5-dimethoxy-acetophenone (78 mg) in dichloromethane (4 mL) at room temperature was added trimethylaluminium (2M in hexanes, 0.44 mL). The mixture was stirred under nitrogen for 90 min. Sodium borohydride (80 mg) was added to the mixture which was then stirred at room temperature for 18 h. The mixture was poured into 1M hydrochloric acid (5 mL) and the solution extracted with dichloromethane (3 x 10 mL). The combined organic phases were dried (magnesium sulphate), concentrated in vacuo and purified by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1% aqueous trifluoroactetic acid) to yield the titled compound (35 mg) as its trifluoroacetate salt. MS (APCI) z = 390 [(M+Η)⁺].

^!H NMR (400 MHz, d₆-DMSO) δ 11.65 (IH, s), 7.47 (2H, t), 7.08-7.28 (4H, m), 6.95 (IH, d), 6.87 (IH, d), 6.79-6.83 (IH, m), 6.71 (IH, dd), 6.17 (IH, d), 4.98-5.08 (IH, m), 3.70 (3H, s), 3.63 (3H, s), 1.37 (3H, d).

Example 17 4-Phenoxy-N-(l,3-thiazol-2-ylmethyI)-lH-indazoI-3-amine

A solution of 4-phenoxy-3-amino-lH-indazole (119 mg), l,3-thiazole-2-carbaldehyde (60 mg) and acetic acid (0.05 mL) were stirred together in methanol (10 mL) at room temperature for 30 minutes. Sodium cyanoborohydride (0.067 g) was added in one portion and the resulting solution stirred at room temperature for 12 h under nitrogen. To the reaction mixture was added a mixture of 1M aqueous hydrochloric acid (5 mL) and methanol (5 mL) and the resulting suspension was concentrated to 1/3 of the original volume. The residue was extracted with dichloromethane (2 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (magnesium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (Silica : dichloromethane : methanol 0% -» 0.5% — > 2%) to afford the titled compound as a brown solid (0.02 g). MS (APCI) +ve ' z = 323 [(M+H)]⁺. H NMR (400 MHz, d₆-DMSO) δ 11.93 (IH, s), 7.80 (IH, d), 7.63 (IH, d), 7.52 (2H, dd), 7.32-7.19 (4H, m), 7.02 (IH, d), 6.18 (IH, d), 4.83 (2H, s).

Example 18 N⁶-(2-chlorophenyl)-lH-indazoIe-3,6-diamine a) (2-chlorophenyl)amino]-2-fluorobenzonitrile

A Schlenk tube was charged with 4-bromo-2-fluorobenzonitrile (2 g), 2-chloroaniline (1.86 mL), sodium rert-butoxide (1.34 g), tris(dibenzylideneacetone)dipalladium(0) (20 mg),

BINAP (50 mg), and toluene (30 mL) under argon. The tube was heated to 80 °C with stirring until the starting material had been completely consumed as judged by LC analysis.

The solution was then allowed to cool to room temperature, taken up in ether (30 mL), filtered, concentrate in vacuo and purified by column chromatography (Silica : diethyl ether) to yield the titled compound (1.26 g) as a pale pink solid. (Ref. J. Am. Chem. Soc.

1996, 118, 1215-1216)

MS (APCI) m/z = 245 (M⁺), 247 [(M+2)⁺j.

1H NMR (400 MHz, CD₃OD) δ 7.43 (3H, m), 7.29 (IH, m), 7.09 (IH, m), 6.78 (2H, m), 6.33 (IH, br s). ¹³C NMR δ 166.0 (1C), 149.3, 149.2 (1C), 136.3 (1C), 134.4 (1C), 130.4 (1C), 127.7 (1C), 126.2 (1C), 125.1 (1C), 121.6 (1C), 114.8 (1C), 112.1 (1C), 102.5, 102.2 (1C), 91.7 (1C).

b) frr-(2-chlorophenyl)-lH-indazole-3, 6-diamine A solution of 4-[(2-chlorophenyl)amino]-2-fluorobenzonitrile (1.01 g) and hydrazine (10% solution in water) (8 mL) in 77-buthanol (20 mL) was heated to reflux for 72 h. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered, concentrate in vacuo and purified by column chromatography (Silica : ethyl acetate) to yield the titled compound (0.64 g) as a solid. MS (APCI) m/z = 259 (M⁺), 261 [(M+2)⁺J.

1H NMR (400 MHz, d₆-DMSO) δ 10.98 (IH, s), 7.63 (IH, s), 7.51 (IH, d, J = 8.6), 7.42 (IH, dd, J = 8.1, 1.5), 7.28 (IH, dd, J = 8.1, 1.5), 7.20 (IH, dt, J = 7.6, 1.5), 6.91 (IH, dt, J = 7.6, 1.5), 6.74 (IH, d, J = 1.5), 6.69 (IH, dd, J = 8.1, 1.5), 5.17 (IH, s).

Example 19 N⁶-(2-chlorophenyl)-N³-isopropyl-lH-indazole-3,6-diamine A solution of /V°-(2-chlorophenyl)-lH-indazole-3,6-diamine (52 mg), acetone (0.5 mL), borane (10M solution stabilized with dimethylsulfide) (0.03 mL) and acetic acid (0.02 mL) in dichloromethane (2 mL) under nitrogen atmosphere were stirred at room temperature for 48 h. To the reaction mixture was added amonium hydroxide 0.1 M (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered, concentrate in vacuo and purified by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1 % aqueous trifluoroactetic acid) to yield the titled compound ( 16 mg) as a white solid. (Ref. Tetrahedron Asymmetry 2002, 13, 137-144) MS (APCI) m/z = 301 (M⁺), 303 [(M+2)⁺j. 1H ΝMR (400 MHz, CD₃OD) δ 7.56 (IH, d, J = 8.6), 7.37 (IH, d, J = 8.1), 7.32 (IH, d, J = 7.6), 7.16 ( 1 H, m), 6.86 (2H, m), 6.77 (IH, dd, J = 8.6, 1.5), 3.87 (IH, m), 1.27 (3H, s), 1.26 (3H, s).

Example 20 N-{6-[(2-chlorophenyl)amino]-lH-indazoI-3-yl}-2-furamide A solution of N⁵-(2-chlorophenyl)-lH-indazole-3,6-diamine (129 mg) and 2-furoyl chloride (0.049 mL) in pyridine was stirred at 0-5°C for 17 h. To the reaction mixture was added water ( 10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered, concentrate in vacuo and purified by crystallization (dichloromethane / heptane) to yield the titled compound (43 mg) as a white solid. (Ref. Arch. Pharm, Med. Chem. 1999, 332, 317-320) MS (APCI) m/z = 353 (M⁺), 355 [(M+2)⁺j. 1H ΝMR (400 MHz, CD₃OD) δ 7.72 (IH, s), 7.64 (IH, d, J = 9.1), 7.34 (2H, m), 7.26 (IH, d, J = 3.5), 7.15 (IH, t, J = 7.8), 6.97 (IH, s), 6.88 (2H, m), 6.61 (IH, br s).

Example 21 N⁶-(2-chlorophenyl)-N³-(2-furyImethyl)-lH-indazole-3,6-diamine

A mixture of N-{6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}-2-furarnide (42 mg) and borane (10M solution stabilized with dimethylsulfide) (0.02 mL) in TΗF (5 mL) was heated to reflux for 20 h. To the reaction mixture was added amonium hydroxide 0.1 M (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered, concentrate in vacuo and purified by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1 % aqueous trifluoroactetic acid to yield the titled compound (14 mg) as a white solid. (Ref. Synthetic Communications 2001, 31, 685-695) MS (APCI) m/z = 339 (M⁺), 341 [(M+2)⁺J. 1H ΝMR (400 MHz, CD₃OD) δ 7.51 (IH, d, J = 8.6), 7.36 (IH, m), 7.32 (IH, dd, J = 8.1, 1.5), 7.28 (IH, dd, J = 8.1, 1.5), 7.11 (IH, m), 6.85 (IH, d, J = 1.5), 6.82 (IH, dt, J = 7.8, 1.5), 6.72 (IH, dd, J = 8.6, 2.0) 6.25 (2H, m), 4.43 (2H, s).

Example 22 N-{6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}cyclopropanecarboxamide

A solution of /V⁵-(2-chloroρhenyl)-lH-indazole-3,6-diamine (129 mg) and cyclopropanecarbonyl chloride (0.045 mL) in pyridine was stirred at 0-5°C for 21 h. To the reaction mixture was added water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered, concentrate in vacuo and purified by crystallization in methanol to yield the titled compound (98 mg) as a white solid. (Ref. Arch. Pharm, Med. Chem. 1999, 332, 317-320) MS (APCI) m/z = 327 (M⁺), 329 [(M+2)⁺J.

1H NMR (400 MHz, d₆-DMSO) δ 12.14 (IH, s), 10.53 (IH, s), 7.81 (IH, s), 7.62 (IH d, J = 8.6,), 7.45 ( IH, d, J = 8.1), 7.33 (IH, d, J = 7.6), 7.24 (IH, d, J = 7.6), 6.96 (IH, t, J = 7.6), 6.82 (2H, m), 1.91 (IH, m), 0.8 (4H, m).

Example 23 N-{6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}-3-furamide

A solution of /V^δ-(2-chlorophenyl)-lH-indazole-3,6-diamine (129 mg) and 3-furoyl chloride (prepared in situ following the procedure described in Phytochemistry 1995, 39, 1219-1222) (65 mg) in pyridine was stirred at 0-5°C for 17 h. To the reaction mixture was added water ( 10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered, concentrate in vacuo and purified by crystallization (dichloromethane / heptane) to yield the titled compound (30 mg) as a white solid. (Ref. Arch. Pharm, Med. Chem. 1999, 332, 317-320)

MS (APCI) m/z = 353 (M⁺), 355 [(M+2)⁺].

1H NMR (400 MHz, CD₃OD) δ 7.72 (IH, s), 7.64 (IH, d, J = 9.1), 7.34 (2H, m), 7.26 (IH, d, J = 3.5), 7. 15 (IH, t, J = 7.8), 6.97 (IH, s), 6.88 (2H, m), 6.61 (IH, br s).

Example 24

N⁶-(2-chlorophenyl)-N³-(cyclopropylmethyl)-lH-indazole-3,6-diamine

A mixture of N- { 6-[(2-chlorophenyl)amino]- lH-indazol-3-yl }cyclopropanecarboxamide

(67 mg) and borane (10M solution stabilized with dimethylsulfide) (0.02 mL) in TΗF (5 mL) was heated to reflux for 6 h. To the reaction mixture was added amonium hydroxide 0.1 M (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered, concentrate in vacuo and purified by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1% aqueous trifluoroactetic acid) to yield the titled compound (12 mg) as a white solid. (Ref. Synthetic Communications 2001, 31, 685-695)

MS (APCI) m/z = 313 (M⁺), 315 [(M+2)⁺]. 1H NMR (400 MHz, d₆-DMSO) δ 7.59 (IH, d, J = 8.6), 7.37 (IH, d, J = 8.1), 7.33 (IH, d, J = 8.1), 7.16 ( IH, t, J = 7.8), 6.87 (2H, m), 6.78 (IH, d, J = 9.1), 3.18 (2H, d, J = 6.6), 1.18 (IH, m), 0.53 (2H, m), 0.28 (2H, q, J = 5.1)

Example 25 tert-butyl 3-amino-6-[(2-chlorophenyl)amino]-lH-indazoIe-l-carboxylate

A solution of N⁶-(2-chlorophenyl)-lH-indazole-3,6-diamine (129 mg) in dioxane (3 mL) and ΝaOΗ solution (1M, 0.62 mL) was stirred for 5 h, with the addition of the di-tert- butyl-dicarbonate (1 14 mg). To the reaction mixture was added water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered, concentrate in vacuo and purified by column chromatography (Silica : ethyl acetate) to yield the titled compound (0.158 g) as a white solid. MS (APCI) m/z = 359 (M⁺), 361 [(M+2)⁺]. 1H ΝMR (400 MHz, d₆-DMSO) δ 8.09 (IH, s), 7.60 (IH, d, J = 8.6), 7.49 (IH, dd, J = 8.0, 1.6 ), 7.4 (2H, m), 7.29 (IH, dt, J = 8.0, 1.4), 7.05 (IH, dt, 7.6, 1.6), 6.91 (IH, dd, J = 8.6, 2.0), 6.10 (2H, s) 1.48 (9H, s).

Example 26 N-{6-[(2-chlorophenyI)aminoJ-lH-indazol-3-yl}piperidine-3-carboxamide

A solution of fert-butyl 3-amino-6-[(2-chlorophenyl)amino]-lH-indazole-l-carboxylate (129 mg) and tert-butyl 3-(chlorocarbonyl)piperidine-l-carboxylate (prepared in situ from the carboxylic acid following the procedure described in Phytochemistry 1995, 39, 1219-1222) (37 mg) in pyridine was stirred at 0-5°C for 21 h. To the reaction mixture was added water ( 10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered and concentrate in vacuo. Trifluoroacetic acid (excess) and dichloromethane (3 mL) were added to the crude and stirred at room temperature for 15h. The reaction mixture was evaporated and purified by preparative reversed phase column chromatography (Symmetry C8, methanol 10.1% aqueous trifluoroactetic acid) to yield the titled compound (21 mg) as a white solid. MS (APCI) m/z = 370 (M⁺), 372 [(M+2)⁺].

^!H NMR (400 MHz, d₆-DMSO) δ 10.30 (IH, s), 7.81 (IH, s), 7.60 (IH, d, J = 9.1), 7.45 (IH, dd, J = 8.1 , 1.5), 7.32 (IH, dd, J = 8.1, 1.5), 7.23 (IH, m), 6.96 (IH, m), 6.83 (2H, m), 3.03 (IH, m), 2.85 (IH, m), 2.69 (IH, m), 2.54 (2H, m), 1.90 (IH, m), 1.62 (2H, m), 1.42 (lH, m).

Example 27 (3S)-N-{6-[(2-chIorophenyl)amino]-lH-indazol-3-yl}tetrahydrofuran-3-carboxarrιide

A solution of tert-butyl 3-amino-6-[(2-chlorophenyl)amino]-lH-indazole-l-carboxylate (90 mg) and tetrahydrofuran-3-carbonyl chloride (prepared in situ from the carboxylic acid following the procedure described in Phytochemistry 1995, 39, 1219-1222) (67 mg) in pyridine was stirred at 0-5°C for 17 h. To the reaction mixture was added water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered and concentrate in vacuo. Trifluoroacetic acid (excess) and dichloromethane (3 mL) were added to the crude and stirred at room temperature for 15 h. The reaction mixture was evaporated and purified by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1 % aqueous trifluoroactetic acid) to yield the titled compound (14 mg) as a white solid. MS (APCI) m/z = 357 (M⁺), 359 [(M+2)⁺j. 1H ΝMR (400 MHz, d₆-DMSO) δ 12.19 (IH, s), 10.38 (IH, s), 7.84 (IH, s), 7.63 (IH, m), 7.45 (IH, d, J = 7.0), 7.33 (IH, m), 7.24 (IH, t, J = 7.4), 6.96 (IH, m), 6.83 (2H, m), 5.74 (IH, s), 3.96 ( IH, m), 3.75 (3H, m), 3.25 (IH, m), 2.10 (2H, m).

Example 28

Methyl 3-[({6-[(2-chlorophenyI)amino]-lH-indazol-3-yl}amino)carbonyl]benzoate A solution of N^δ-(2-chlorophenyl)-lH-indazole-3,6-diamine (100 mg) and 3- (methoxycarbonyl)benzoyl chloride (prepared in situ following the procedure described in Phytochemistrv 1995, 39, 1219- 1222) (77 mg) in pyridine was stirred at room temperature for 48 h. To the reaction mixture was added water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered, concentrated in vacuo and purified by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1 % aqueous trifluoroacetic acid) to yield the titled compound (18 mg) as a white solid. (Ref. Arch. Pharm, Med. Chem. 1999, 332, 317-320) MS (APCI) m/z = 419 [(M-l)⁺], 421 [(M+l)⁺]

1H ΝMR (400 MHz, CD₃OD): δ 8.73 (s, 1 H), 8.20 (d, 7=7.8 Hz, IH), 8.11 (d, 7=7.8 Hz, IH), 7.82 (d, 7=8.6 Hz, IH), 7.51 (t, 7=7.8 Hz, IH), 7.27 - 7.34 (m, 2H), 7.04 - 7.11 (m, IH), 7.01 (d, 7=1.3 Hz, IH), 6 85 (dd, 7=8.8, 1.8 Hz, IH), 6.78 (td, 7=7.6, 1.4 Hz, IH), 6.17 (s, IH), 3.94 (s, 3H) ¹³C ΝMR: δ 170.0, 169.1, 149.3, 147.2, 144.5, 139.2, 135.1, 133.2, 130.7, 130.6, 130.3, 130.1, 129.2, 127.6, 122.0, 1 19.3, 113.15, 112.8, 108.35, 107.8, 91.75, 51.95.

Example 29 3-[({6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}amino)carbonyl]benzoic acid LiOΗ (1 M, 0.2 ml) was added to a solution of methyl 3-[({6-[(2-chlorophenyl)amino]-lH- indazol-3-yl}amino)carbonyl]benzoate (18 mg) in TΗF (3ml), after stirring at room temperature overnight the mixture was concentrated under vacuum and the residue purified by preparative reversed phase column chromatography (Symmetry C8, methanol / 0.1% aqueous trifluoroacetic acid) to yield the titled compound (9 mg) as a white solid. MS (APCI) m/z = 407 (M⁺), 409 [(M+2)⁺]

Example 30 N-{6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}tetrahydro-2^T-pyran-4-carboxamide

A solution of tert-butyl 3-amino-6-[(2-chlorophenyl)amino]-lH-indazole-l-carboxylate (170 mg) and tetrahydro-2H-pyran-4-carbonyl chloride (prepared in situ from the carboxylic acid following the procedure described in J. Med. Chem. 1994, 37, 4538-4554) (65 mg) in triethylamine was stirred at 25°C for 24 h. To the reaction mixture was added water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (sodium sulphate), filtered and concentrated in vacuo. Trifluoroacetic acid (excess) and dichloromethane (3 mL) were added to the crude and stirred at room temperature for 17 h. The reaction mixture was evaporated and purified by preparative reversed phase column chromatography (Symmetry

C8, methanol / 0.1 % aqueous trifluoroacetic acid) to yield the titled compound (24 mg) as a white solid.

MS (APCI) m/z = 369 [(M-l f], 371 [(M+l)⁺].

1H NMR (400 MHz, d₆-DMSO):δ 12.17 (IH, s), 10.19 (IH, s), 7.82 (IH, s), 7.60 (IH, m),

7.45 (IH, m), 7.33 (IH, m), 7.24 (IH, t, J = 7.4), 6.96 (IH, m), 6.84 (2H, m), 3.91 (2H, m), 2.68 (2H, m), 1.73 (5H, m).

List of abbreviations

SPA scintillation proximity assay

ATP adenosine triphosphate

ATF Activating transcription factor

MOPS 3-[N-Morpholino]-propanesuIfonic acid

EGTA Ethylene glycoI-bis(β-aminoethyIether)-N,iV,N^,,iV^',-tetraacetic acid

DTT dithiothreitol

JNK c-Jun N-terminal kinases

MAP mitogen-activated protein

Biological evaluation The compounds of this invention may be assayed for their activity according to the following procedure:

A scintillation proximity assay (SPA) based on the inhibition of JNK3 catalyzed transfer of the γ-phosphate group of [γ- ^~ P] ATP to biotinylated ATF2, has been set up to identify inhibitory compounds. The resulting 33 P-labeled biotinylated ATF2 is trapped on SPA beads surface coated with streptavidin.

The assay is performed in 96-well plates. Test compounds made up at 10 mM in DMSO and 1:3 serial dilutions are made in 100% DMSO. These serial dilutions are then diluted 1:10 in assay buffer (50 mM MOPS pH 7.2, 150 mM, NaCl, 0.1 mM EGTA, 1 mM DTT, 6.25 mM β-glycerolphosphate) and 10 μl are transferred to assay plates (results in 2% DMSO final concentration in assay). To each well with test compound a 2.4 μl JNK3/ATP enzyme solution (1.18 U/ml JNK3, 20 μM ATP, 2 mM Mg(Ac)2, 0.01 % Brfj-35 in assay buffer) was added. The mixtuie was pre-incubated for 10 minutes at ambient temperature. After this, 3.6 μl of a [γ-³³PJ ATP-solution (0.20 μCi/μl [γ-³³P]ATP, 66.6 mM Mg(Ac)₂, 1 mM DTT, 50 mM MOPS pH 7.2, 150 mM NaCl, 0.1 mM EGTA) was added to each well followed by 10 μl a ATF2 solution (60 μg/ml biotinylated ATF2 in assay buffer) to start the reaction. The reaction was allowed to proceed for 10 minutes at ambient temperature. After this, the reaction was terminated by the addition of 200 μl per well of stop buffer/bead mix (0.4 mg/ml streptavidin coated SPA-beads in 50 mM EDTA, pH 7.6). Plates were sealed with a plastic cover and centrifuged (2000 rpm, 5 minutes) to settle the beads followed by counting in a Wallac 1450 microbeta™.

The IC₅₀ values were calculated as the concentration of test compound at which the ATF2 phosphorylation is reduced to 50% of the control value.

Results Typical K, values for the compounds of the present invention are in the range of about 0.001 to about 10,000 nM. Other values for K, are in the range of about 0.001 to about 1000 nM. Further values for K, are in the range of about 0.001 nM to about 300 nM.

Claims

1. A compound of the general Formula I

in which:

X is CR⁴ or N; R¹ is -OR⁵, -NHCOR⁶ or -NR⁶R⁷;

R² is hydrogen, -OAr¹ or -NHAr¹ wherein Ar¹ is aryl optionally substituted with one or more of R⁸, -OR⁸, -NR⁸R⁹, -CONR⁸R⁹, -COOR⁸, -NR⁸COR⁹, -SR⁸, -SO₂R⁸,

-S0₂NR⁸R⁹, -NR⁸SO₂R^y, halogen, cyano, or nitro;

R³ is hydrogen or -NHAr² wherein Ar² is benzene optionally substituted with one or more of R⁸, -OR⁸, -NR^SR⁹, halogen or nitro; wherein R² and R³ is not simultaneously hydrogen;

R⁴ is hydrogen, NO₂, CN, C_1-3 alkyl or halogen;

R⁵ is -CH₂Aι^-1 wherein Ar¹ is aryl optionally substituted with one or more of R⁸,

-OR⁸, -NR⁸R⁹, -CONR⁸R⁹, -COOR⁸, -NR⁸COR⁹, -SR⁸, -SO₂R⁸, -SO₂NR⁸R⁹, -NR⁸S0₂R⁹, halogen, cyano, or nitro;

R⁶ and R⁷ are each independently hydrogen, C|_-6alkyl, C_2-6alkenyl, (C_{3- 8}cycloal kyl)C(_)-6alkyl, C ι .₆fluoroalkyl, arylCo_-6alkyl, heteroarylC_0-6alkyl or heterocycleCo.galkyl; and said Cι_-6alkyl, C₂.₆alkenyl, (C₃.₈cycloalkyl)Co-6alkyl, C_\.

₆fluoroalkyl, arylCo_-6alkyl, heteroarylC₀,₆alkyl or heterocycleCo_-6alkyl, may be substituted with one or more B; or R⁶ and R⁷ form togetlier a 4-, 5- or 6-membered heterocyclic ring containing 1 or

2 heteroatoms independently selected from N, O and S, and said ring may be substituted with one or more B; B is R⁸, -COOR⁸, -COR^s, -NHCOR⁸, -NR⁸R⁹, -CONR⁸R⁹, -OR⁸, -SO₂NR⁸R⁹, CN, oxo or halogen;

R⁸ and R⁹ each independently are hydrogen, C|.₆alkyl, Cι_-6fluoroalkyl, or hydroxyC|_-6alkyl , or; o n R and R form together a 4-, 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S, and said ring may be substituted with one or more B; as a free base or salt thereof.

. A compound according to claim 1, wherein;

X is CR⁴ or N;

R¹ is -OR⁵, -NHCOR⁶ or -NR⁶R⁷;

R² is hydrogen, or -OAr¹ , wherein Ar¹ is aryl optionally substituted with -SO₂R⁸ or one or more halogen; R is hydrogen or -NHAr wherein Ar is benzene substituted one or more halogen;

R⁴ is hydrogen or NO₂;

R⁵ is -CH₂Ar^J wherein Ar¹ is aryl substituted with one or more halogen;

R⁶ and R⁷ are each independently hydrogen, Cι_-6alkyl, (C_3-8cycloalkyl)Co_-6alkyl, ary]Co-₆alkyl, heteroaryl Co_-6alkyl or heterocycleCo-₆alkyl; and said C_1-6alkyl, arylCo- ₆alkyl, heteroarylCo-βalkyl or heterocycleCo-βalkyl, may be substituted with one or more B ;

B is -COR⁸, -NHCOR⁸, -OR⁸, or halogen;

R⁸ is hydrogen or C_halky!.

3. A compound according lo claim 1 or 2, wherein R³ is hydrogen.

4. A compound according to claim 3, wherein R² is -OAr¹ and Ar¹ is phenyl.

5. A compound according to claim 4, wherein Ar¹ is is phenyl, said phenyl being substituted with one or more halogen.

6. A compound according to claim 5, wherein said phenyl is substituted with one fluoro.

7. A compound according to claim 4, wherein Ar¹ is phenyl said phenyl being substituted with with -SO R⁸, and R^h is C[.₆alkyl.

1 fi 7 8. A compound according to any one of claims 1 to 7, wherein R is NR R .

9. A compound according to claim 8, wherein R andR is selected from C_1-6alkyl, aryl Co-₆ lkyl, heteroaryl Co-₆alkyl and heteiOcycleC_0-6alkyl and said C_1-6alkyl, arylCo- ₆alkyl, heteroarylCo_-6alkyl, heterocycleCo-ealkyl may be substituted with one or more B.

10. A compound according to claim 9, wherein said B is selected from -NHCOR⁸, -OR⁸, and halogen.

11. A compound according to claim 10, wherein said R⁸ is methyl.

12. A compound according to any one of claims 1 to 1 1, wherein R¹ is -OR⁵ and R⁵ is CH₂Ar' and said Ar¹ is aryl substituted with one or more halogen.

13. A compound according to any one of claims 1 to 12, wherein X is CR⁴ and R⁴ is hydrogen.

14. A compound according to any one of claims 1 to 12, wherein X is N.

15. A compound according lo claim 1 or 2, wherein R² is hydrogen.

16. A compound according to claim 14, wherein R³ is -NHAr² and Ar² is benzene substituted with one or more halogen.

17. A compound according to claim 15, wherein said benzene is substituted with one chloro.

18. A compound according to any one of claims 14 to 16, wherein R¹ is -NHCOR⁶, and R⁶ is selected from (C_3-8cycloalkyl)C₀-₆alkyl, heteroarylC_0-6alkyl and heterocycleCo-

₆alkyl.

19. A compound according to any one of claims 14 to 16, wherein R¹ is -NR⁶R⁷ and R⁶ and R⁷ are each independently selected from hydrogen, C_1-6alkyl, (C_3-8cycloalkyl)C_{0- 6}alkyl, and heteroarylCo-₆alkyl.

20. A compound which is: N-(2,5-Dimethoxybenzyl)-4-phenoxy-lH-pyrazolo[4,3-c]pyridin-3-amine;

N-(2,5-Dimethoxybenzyl)-4-phenoxy-lH-indazol-3-amine trifluoroacetate;

N-(4-{ [(4-Phenoxy-lΗ-pyrazolo[4,3-c]pyridin-3-yl)amino]methyl}phenyl)acetamide trifluoroacetate;

N-[(6-Fluoro-4H-l,3-benzodioxin-8-yl)methyl]-4-phenoxy-lH-indazol-3-amine; (+/-)-N-[ 1 -(2-Methoxyphenyl)ethyl]-4-phenoxy- 1 H-indazol-3-amine trifluoroacetate;

N-(2,5-Dichlorobenzyl)-4-phenoxy-lH-indazol-3-amine;

N-(2,5-Dimethoxybenzyl)-5-nitro-4-phenoxy-lH-indazol-3-amine hydrochloride;

N-(4-{ [(5-Νitro-4-phenoxy-lH-indazol-3-yl)amino]methyl}phenyl)acetamide;

N-(4-{ [(4-Phenoxy-lH-indazol-3-yl)amino]methyl}phenyl)acetamide; 3-[(2-Chlorobenzyl)oxy]-4-phenoxy-lH-indazole;

8-{[(4-Phenoxy-lH-indazol-3-yl)amino]methyl}quinolin-4(lH)-one;

N-[4-({ [4-(4-Fluorophenoxy)-lH-indazol-3-yl]amino}methyl)phenyl]acetamide;

N-{4-[({4-[4-(Methylsulfonyl)phenoxy]-lH-indazol-3-yl}amino)methyl]phenyl} acetamide; N-(2,5-Dimethoxybenzyl)-4-[4-fluoro-phenoxy]- 1 H-indazol-3 -amine;

N-(2,5-Dimethoxybenzyl)-4-[4-(methylsulfonyl)phenoxy]-lH-indazol-3-amine;

(+/-)-N-[l-(2,5-Dimethoxyphenyl)ethyl]-4-phenoxy-lH-indazol-3-amine trifluoroacetate;

4-Phenoxy-N-( 1 ,3-thiazol-2-ylmethyl)-lH-indazol-3-amine; N6-(2-chlorophenyl)-lH-indazole-3,6-diamine;

N6-(2-chloiOphenyl)-N3-isopropyl-lH-indazole-3,6-diamine;

N-{6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}-2-furamide; N6-(2-chlorophenyl)-N3-(2-furylmethyl)-lH-indazole-3,6-di amine;

N-{ 6-[(2-chlorophenyl)amino]-lH-indazol-3-yl } cyclopropanecarboxamide;

N-{6-[(2-chloiOphenyl)amino]-lH-indazol-3-yl}-3-furamide;

N6-(2-ch]orophenyl)-N3-(cyclopropylmethyl)-lH-indazole-3,6-di amine; N-{6-[(2-chloiOphenyl)amino]-lH-indazol-3-yl}piperidine-3-carboxamide;

(3S)-N-{ 6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}tetrahydrofuran-3-carboxamide;

Methyl 3-[({6-[(2-chlorophenyl)amino]-lH-indazol-3-yl}amino)carbonyl]benzoate;

3-[({6-[(2-chlorophenyl)amino]-lH-indazol-3-yl }amino)carbonyl]benzoic acid;

N-{6-[(2-chloiOphenyl)amino]-lH-indazol-3-yl}tetrahydro-2H-pyran-4-carboxamide; as a free base or a salt thereof.

21. A compound according to any one of claims 1 to 20, as a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of any one of claims 1 to 21 in association with pharmaceutically acceptable carriers or diluents.

23. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of any one of claims 1 to 21 for use in the prevention and/or treatment of conditions associated with JΝK activation.

24. A compound according to any one of claims 1 to 21 for use in therapy.

25. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for the prevention and/or treatment of conditions associated with JΝK activation.

26. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for the prevention and/or treatment of conditions selected from: central or peripheral neurological degenerative disorders including Alzheimer's disease, cognitive disorders, Parkinson's disease, Ηuntinglon's disease, amyotrophic lateral sclerosis, Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Gaum, HIV dementia, corticobasal degeneration, dementia pugilistica, Down's syndrome, poslencephelatic parkinsonism, progressive supranuclear palsy, Pick's Disease. Nieinann-Pick' s Disease, epilepsy, a peripheral neuropathy, spinal cord injury, head trauma; autoimmune diseases includi ng Multiple Sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, asthma, septic shock, transplant rejection; cardiovascular diseases including stroke, arterosclerosis, myocardial infarction, myocardial reperfusion injury; cancer including breast-, colorectal, pancreatic, prostate cancer.

27. The use according to claim 26 wherein said condition is Alzheimer's disease.

28. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for the prevention and/or treatment of conditions associated with inhibiting the expression of inducible pro-inflammatory proteins.

29. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for the prevention and/or treatment of conditions selected from edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.

30. A method of treating or preventing conditions associated with JNK activation comprising the administration of a therapeutically effective amount of a compound of Formula I according to any one of claims 1 to 21 to a mammal in need thereof.

31. A method of treating or preventing conditions selected from central or peripheral neurological degenerative disorders including Alzheimer's disease, cognitive disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Gaum, HIV dementia, corticobasal degeneration, dementia pugilistica, Down's syndrome, postencephelatic parkinsonism, progressive supranuclear palsy, Pick's Disease, Niemann-Pick's Disease, epilepsy, a peripheral neuropathy, spinal cord injury, head trauma; autoimmune diseases including Multiple Sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, asthma, septic shock, transplant rejection; cardiovascular diseases including stroke, arterosclerosis, myocardial infarction, myocardial reperfusion injury; cancer including breast-, colorectal, pancreatic, prostate cancer comprising the administration of a therapeutically effective amount of a compound of Formula I according to any one of claims 1 to 21 to a mammal in need thereof.

32. The method according to claim 31, wherein said condition is Alzheimer's disease.

33. A method of treating or preventing associated with inhibiting the expression of inducible pro-inflammatory proteins comprising the administration of a therapeutically effective amount of a compound of Formula I according to any one of claims 1 to 21 to a mammal in need thereof.

34. The method according to claim 33, wherein the condition is selected from edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.

35. A compound of formula (II):

in which X, R² and R³ are as defined claim 1 , or are protected derivatives thereof, Pg is an amino protecting group or hydrogen, and A is NH₂.

36. A compound according to claim 35 said compound being tert-butyl 3-amino-6-[(2- chlorophenyl)amino]-lH-indazole-l-carboxylate.

37. A process for the preparation of compounds of formula (I) according to claim 1, comprising reacting of a compound of formula (II):

in which X, R² and R³ are as defined claim 1, or are protected derivatives thereof, Pg is an amino protecting group or hydrogen and A is NH₂; with a compound of formula (III):

(III)

in which R^fi is as defined in claim 1, or is protected derivatives thereof; optionally thereafter reduction of the formed amide bond to yield a compound of formula (I); and optionally thereafter removing any protecting groups present and thereafter forming a pharmaceutically acceptable salt.

38. A process for the preparation of compounds of formula (I) according to claim 1, comprising reacting of a compound of formula (II):

(II) in which X, R^" and R are as defined claim 1 , or are protected derivatives thereof, Pg is ah amino protecting group or hydrogen and A is NH₂; with a compound of formula (IV):

(IV) in which R^ft and R⁷ are as defined in claim 1 , or are protected derivatives thereof; and optionally thereafter removing any protecting groups present and thereafter forming a pharmaceutically acceptable salt.

39. A process for the preparation of compounds of formula (I) according to claim 1, comprising reacting of a compound of formula (II)

(π) in which X, R" and R³ are as defined claim 1, or are protected derivatives thereof, Pg is an amino protecting group or hydrogen and wherein A is NH₂ or OH; with a compound of formula (V);

(V) in which R⁶ and R⁷ are as defined in claim 1, or are protected derivatives thereof; and

Lg represents a leaving group; and optionally thereafter removing any protecting groups present and thereafter forming a pharmaceutically acceptable salt.