OA17324A - Derivatives of azaindazole or diazaindazole type for treating pain. - Google Patents

Abstract

The present invention relates to a compound of following formula (I) : or a pharmaceutically acceptable salt or solvate of same, a tautomer of same, or a stereoisomer or mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture; for use in the treatment of pain.

Description

DERIVATIVES OF AZAINDAZOLE OR DIAZAINDAZOLE TYPE FOR TREATING PAIN

The présent invention relates to azaindazole and diazaindazole fused bicyclic dérivatives for use in the treatment or prévention of pain, in particular pain associated with at least one Trk protein.

Pain is a term used to describe an abnormal sensation and painful received by a living being and perceived by the brain. This îs an unpleasant sensory and emotiona! expérience associated with tissue damage, or described présent or potential in terms of 10 such damage. Pain can be acute or chronic and is associated with various pathologies.

Several mechanisms at the origin of pain hâve been described:

- Nociceptive pain: this is an alarm signal in response to an aggression against the body, for example, pain caused by bums, trauma, contusion, shingles, surgery or tooth extraction. A message is sent to the brain to alert him of the attack.

- Inflammatory pain is associated with acute or chronic inflammation, as it can be found in infections, arthritis or Crohn’s disease.

- Neuropathie pain: it is a pain following nerve injury. This lésion causes a malfunction of the peripheral or central nervous system. It may be a neuropathie pain of central origin, such as following brain lésion or infract, or a peripheral neuropathie pain such as sciatica duc to dise hemiation.

- Idiopathic pain: it is a pain syndrome whose causes are poorly explained. The tests are normal, but the pain is there. Such pain is présent in patients presenting with, for exemple, functional syndromes such as fîbromyalgia or irritable bowcl syndrome.

- Psychogenic pain: it is a pain of psychological origin (bereavement, dépréssion, trauma, etc.). It is notably chronic pain found in dépréssion.

Pain is sometimes of mixed origin: nociceptive and inflammatory, as for example in cancers.

Analgésies or painkillers are drugs used to relieve pain. They were classified 30 into three levels by the World Health Organization (WHO):

- Level 1 consists of non-opioid analgésies (paracétamol, anti-inflammatory drugs). They are used for mild to moderate pain;

VL

V* «

- Level 2 includes weak opioids (eg codeine). They are used for moderate to severe pain, or when level 1 painkillers were not effective for pain relief;

- Level 3 consists of strong opioids (eg morphine). These drugs are used for acute pain, or when the level 2 analgésies were not effective for pain relief.

Other classes of drugs are also used to treat certain pain, such as neuroleptics or antidepressants for neuropathie pain, or triptans for migraine headaches.

The need to find new treatments for pain is unavoidable given the limited effectiveness or side effects of current treatments, whatever the level of the WHO analgésie, the type or origin of pain. For example, Level I analgésies according to WHO, which include among other paracétamol, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygcnasc inhibitors arc generally incfïcctivc against intense pain, but are well tolerated, although adverse gastric effects may occur. Nevertheless, sélective inhibitors of type 2 cyclo-oxygcnasc, as rofecoxib (Vioxx ®) hâve shown serious cardiovascular risks. Opiates such as morphine and dérivatives are effective on certain acute pains or severe chronic pain, but can cause drowsiness, nausea and vomiting at initiation of treatment, and then constipation, or respiratory dépression in overdose. Repeated or chronic use of opioids can lead to tolérance to the analgésie effect, which requires higher doses, doser to toxic doses, dependence and withdrawal syndrome on discontinuation of treatment. Opiates and dérivatives are not very effective on neuropathie pain and chronic pain in the low to moderate intensity.

Protein kinases are enzymes that play a key rôle in cell signal transduction. They are involved in physiological processes such as cell prolifération, mitosis, différentiation, ccll invasion and mobility, and apoptosis, for example.

Dcrcgulation of the physiological mechanisms controlled by protein kinases is central to the appearance and development of many pathologies, notably including cancers and pain.

Of particuiar interest in the context of the invention, tyrosine receptor kinases of the tropomyosine-related kinases (Trks) hâve been associated with acute or chronic pain. Trks are receptor tyrosine kinases involved in the development of nervous system. The Trk receptor family is composed of three members TrkA, Trk B and TrkC activated by spécifie ligands called neurotrophins. Trk proteins and their associated ligands hâve *

« been described to play a rôle in the development of pain (Sah et al. 2003 Nat Rev Drug Discovery, 2:460-472).

For instance, mutations in the TrkA receptor gene hâve been described in patients with congénital insensitivity to pain (Indo et al., 1996, Nat Genet. 13:485-488; Indo et al., 2001, Hum Mutations, 18: 308-318). TrkA is expressed in nociceptive neurons, the neurons that convey pain messages, and influences electrophysîological properties of sodium channels involved in pain message transmission (Fang et al., J. Neurosci. 25: 4868-4878). Several review articles highlight the role of TrkA and its ligand Nerve growth Factor (NGF) in the initiation of pain at the level of nociceptive neurons, particulariy in inflammatory pain states, for instance rheumatic diseases such as ostcoarthritis, lower back pain, lumbar dise hemiation and nerve root compression (Hefti et al., 2006; Trends Pharmacol Sci. 27:85-91; Pczet and McMahon, 2006, Ann Rev Neurosci. 29:507-538; Cheng and Ji, 2008, Neurochem Res. 33:1970-1978; Seidel et al. 2010, Semin Arthritis Rheum. 40:109-126).

TrkB and its ligand Brain-Derived Neurotrophic factor (BDNF) hâve also been implicated în chronic pain. BDNF is synthesized in primary sensory neurons and anterogradely transported to the central terminais of the primary afferents in the spinal chord (Obata et al., 2006, Neurosci Res. 55: 1-10). BDNF synthesised by microglia in the spinal chord causes the shift in neuronal anion gradient, leading to disinhibition of pain transmission after nerve injury (Coull étal., 2005, Nature, 438: 1017-1021). This resuit indicates that blocking BDNF/TrkB pathway will be usefut to treat neuropathie pain. Supraspina! BDNF also plays a rôle in pain facilitation (Guo et al., 2006, J Neurosci. 26: 126-137). Increased BDNF sérum concentration has also been reported in fibromyalgia (Laskc et al., 2006, J Psychiatrie Res, 41: 600-605). The rôle of the BDNF/TrkB signalling in pain modulation has been reviewed (Merighi et al., 2008 85: 297-317).

Blocking the TrkA or TrkB pathway can be achieved by soluble Trk receptors or neutralizing antibodies. Such strategies has been validated for the NGF/TrkA pathway in animais, where it reduced pain associated with bone cancer (Sevcik et al., 2005, Pain 115: 128-141) or non-inflammatory joint pain (McNamce et al., 2010 Pain 149:386392). Tanezumab, a recombinant humanized monoclonal antibody against NGF is currently being tested as a treatment in humans for acute and chronic pain associated with several conditions (Cattaneo, 2010, Curr Opin Mol Ther 12: 94-106). However, such therapy must be administered via repeated intraveinous infusions. Other forms of treatment, such as small Trk inhibitor molécules with oral bioavailability are highly désirable.

The number of Trk inhibitors reported in the literature is limited and until yet none is used as a drug against pain, although Trk inhibitors hâve already demonstrated analgésie efficacy in experimental preclinical models, notably models of bone cancer pain (Ghilardi et al. 2010, Mol Pain 6: 87) and chronic inflammatory pain (Winckler et al. 2009, 8^m International Association for the Study of Pain Research Symposium, 10 Poster #348).

There is thus a need for compounds capable of inhibiting Trk.

The article of Wang et al. (Expert Opin. Ther. Patents 2009, 19(3), 305-319) is a review of patent applications since 2002 relative to Trk inhibitors and their use in the treatment of cancer and pain. None of the compounds described corresponds to an 15 azaîndazo le or d iazaindazo le co mpound.

WO 2008/112695 describes compounds of type 5-azaindazo!e or 5,7diazaindazole substituted in position 6 as inhibitors of protein kinases such as Trk. However, no biological resuit is présent in this application proving the inhibition of any protein kinases and in particular of the protein kinase Trk. Moreover, it is never 20 specified in this application that the compounds can treat or prevent pain.

WO 2004/113303 describes notably compounds of type 5-azaindazole substituted in position 6 as inhibitors of the protein kinase JNK. It is never mentioned that such compounds could also inhibit the protein kinase Trk.

WO 2007/023110 describes notably compounds of type azaindazole or 25 diazaindazole as inhibitors of the protein kinase p38. It is never mentioned that such compounds could also inhibit the protein kinase Trk.

WO 2008/089307 describes compounds of type azaindazole or diazaindazole as inhibitors of the A5-desaturase activity. It is never mentioned that such compounds could also inhibit the protein kinase Trk.

The compounds of the présent invention hâve the property of inhibiting or modulating the enzymatic activity of Trk proteins. Consequently, said compounds can be used as drugs in the treatment or prévention of pain, in particular pain associated with at least one Trk protein.

Furthermore, the compounds according to the invention are particularly interesting insofar as the inventors were able to show that they inhibit or modulate the activity of more than one Trk protein. They thus allow treating at the same time pains of several origins (for example, the association of inflammatory and nociceptive pains as is observed in case of cancer).

More particularly, the présent invention thus has as an object a compound of following general formula (I):

or a pharmaceutically acceptable sait or solvaté of same, a tautomer of same, a stereoisomer or a mixture of stcrcoisomcrs of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture, wherein:

- Y| and Y₄ each represent, independently of each other, a CH group or a nitrogen atom,

- Yi represents a nitrogen atom or a CH or C-X-Ar group,

- Y₃ represents a nitrogen atom or a C-X-Ar or C-W group, on the condition that:

at least one and at most two Yj, Yj, Y₃, and Y₄ groups represent a nitrogen atom,

Yi and Y₄ cannot represent a nitrogen atom at the same time, when Yf=C-X-Ar, then Y₃ represents a nitrogen atom or a C-W group, and when Yï=CH or N, then Y₃ represents a C-X-Ar group,

- Ar represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, (Ci-Cé)alkyl, (Cj-Celhaloalkyl, (CjCe)haloalkoxy, (Ci-Ce)halothioalkoxy, CN, NO2, ORn, SR12, NR13R14, CO2R15, CONRisRn. SO2R18, SO2NR19R20, COR21, NR22COR23, NR24SO2R25, and R26NR27R28 and/or optionally fused to a heterocycle,

- X represents a divalent group selected from O, S, S(O), S(Oh, NR4, SfNRj), S(O)(NR4), S(O)₂(NR,), NR4S, NR4S(O), NR4S(O)₂, CH₂, CH₂S, CH₂S(O), CH₂S(O>2, SCH_2i S(O)CH₂, S(O)₂CH2, CH2CH2, CH=CH, OC, CH₂O, OCH₂, NR4CH2, and CH2NR4,

- W represents an Rs, SR5, OR5 or NRsR$ group,

- U represents a CH2 or NH group, one or more hydrogen atoms which may be replaced by a (CrC«)a[ky[ group,

- V represents C(O), C(S) or CH₂,

- n represents 0 or 1,

- Rj represents a hydrogen atom, or an OR7 or NR7R8 group,

- Ri represents a hydrogen atom, an optionally substituted heterocycle, NO2, OR9 or NRgRjo,

- Rj, R», Ru to R» and R27 to Ri» each represent, independently of each other, a hydrogen atom or a (Ci-Celalkyl group,

- Rs and R< each represent, independently of each other, a hydrogen atom or a (CiCe)alkyl, optionally substituted aiyl or optionally substituted benzyl group,

- R7, R«, R» and Rio each represent, independently of each other, a hydrogen atom or an optionally substituted (Ci-Ce)alkyl or (C3-C uïcycloalkyl group or an optionally substituted heterocycle, and

- R26 represents (Ci-Cô)alkyl, for use in the treatment or prévention of pain, in particular pain associated with at least onTrk protein.

In the preceding définitions, ail the combinations of substituents or variables are possible insofar as they Icad to stable compounds.

It should be noted moreover that at least one but only one of Yi and Y3 represents a C-X-Ar group.

If)^v

In a preferred embodiment the présent invention has as an object a compound of following general formula (I):

or a pharmaceutically acceptable sait or solvaté of same, a tautomer of same, or a stereoisomer or mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture, wherein:

- Yi and Y₄ each represent, independently of each other, a CH group or a nitrogen atom on the condition that at least one of Yi and Y< represent a nitrogen atom,

- Yi represents a C-X-Ar group,

- Yj represents a C-W group,

- Ar represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, (CrCelalkyl, (Ct-C<5)ha!oalkyt, (CiCejhaloalkoxy, (Ci-Cejhalothioalkoxy, CN, NO₂, ORn, SRj₂, NRbRh, CO₂Ru, CONRisRn» SO₂Ris, SO2NR19R20, COR21, NR22COR23, NR24SO2R25, and R26NR27R28 and/or optionally fused to a heterocycle,

- X represents a divalent group selected from O, S, S(O), S(O>2, NR4, S(NR»), S(O)(NRA S(O)₂(NR4), NR4S, NR4S(O), NR4S(O)₂, CH2, CH₂S, CH₂S(O), CH₂S(O)2, SCH₂, S(O)CH₂, S(O)₂CH2, CH2CH2, CH=CH, OC, CH₂O, OCH₂, NR4CH2, and CH₂NR«,

- W represents an Rj, SR5, OR5 or NRjR^ group,

- U represents a CH2 or NH group, one or more hydrogen atoms which may be replaced by a (Ci-Q^alkyl group,

- V represents C(O), C(S) or CH2,

Ex.**	ArX	*4	W	Ri	Compound names	Yield	Mass MH*
8-1	hn F	CH	H	H	N-(2,5-difluorophcny 1)-1Hpyrazolo[43-b]pyridine-3,5-diamme	4% 4 steps	262.0
8-2	HN* “'Φ a	CH	H	H	N-(2,5-dichlorophenyl)-l Hpyrazolo[43-b]pyridine-3,5-diaminc	9% 4 steps	294.0
** 'H NMR: ÔF	ppm (401	) MHz, DMSO): 8-1: 11.46 (1 H, s, NH), 8.75-8.82 (2H, m,

CHarom), 7.65 (IH, dd, CHarom, J=9.2Hz), 7.19-7.31 (2H, m, CHarom), 6.67-6.63 (IH, s!, CHarom), 5.06 (2H, s, NH₂). 8-2: 11.58 (IH, si, NH), 8.65 (IH, s, CHarom),

8.35 (IH, s, CHarom), 7.69 (IH, d, CHarom, J=12.0Hz), 7.45 (IH, d, CHarom, J=11.6Hz), 7.24 (IH, d, CHarom, J=12.0Hz), 6.96 (IH, dd, CHarom, J=11.2Hz), 5.03 (2H, si, NHi).

Example of method B3

Exampie 9:5-(3,5-dinuorobenzyI)-lII-pyrazoIo[4,3-b]pyrldÎn-3-amlne

This compound can be prepared from the following intermediates, according to method B3.

Exampie 9a: 2-(3,5-dinuorobenzyI)-4,4,5,5-tetramethyH,3,2-dioxaborolane Example 9b: 6-(3^-difluorobeiuyl)-3-nitroplcolinonitriIe

Example 9c: 3-amlno-6-(3,5-diflaorobenzyl)picoIÎnonitrile

Example of method B4

7-6	A	N	H	H	5-(3,5-difluorophenylthio)-1Hpyrazolo[3,4-b]pyrazin-3-arnnie	6% 7 steps	279,9
7-7	ι^τα a	N	H	H	5-(2,4-dich)orophenyïthio)-l Hpyrazolo[3,4-b]pyrazîn-3-ainine	4% 7 steps	311,9
7-8	c F S'	N	H	H	5-(2-(trifluoromcthyl)phcnylthÎo)-l Hpyrazolo[3,4-b]pyrazin-3-amine	6% 7 steps	311.9
7-9	♦ fjÔlf	CH	H	H	5-(3,5-di fluorobenzy loxy)-1Hpyrazolo[4J-b]pyridin-3 -amine	6% 3 steps	277.0
7-10	F	CH	H	H	5-(2^-difluorobcnzyloxy)-l Hpyrazolo[43-b]pyridin-3-amÎne	3% 3 steps	277.0
7-11	a	CH	H	H	5-(2,5-dichlorobenzylûxy)-1Hpyrazolo[43-b]pyridin-3-amine	32% 3 steps	309.0
7-12	& a	CH	H	H	5-(5-chIon>-2(trifluoromcthyl)benzyloxy)-l Hpyrazolo[43-b]pyridin-3-amine	8% 3 steps	343.1
7-13	à	CH	H	H	5-(pyridÎn-3-y Imcthoxy)-1Hpyrazolo[43-b]pyridin-3-amine	6% 3 steps	342.1

·* ’H NMR: 5H ppm (400 MHz, DMSO): 7-1: 11.61 (IH, s large, NH), 7.73 (IH, d,

CHarom), 7.24 (2H, m, CHarom), 7.18 (1 H, m, CHarom), 6.86 (IH, d, CHarom). 7-2: 11.95 (1 H, s), NH), 7.78 ( 1 H, d, CHarom, J= 11.6Hz), 7.33 (1 H, d, CHarom, J=11.6Hz),

7.19 (IH, t, CHarom), 7.04 (2H, 2d, CHarom, J=8.8Hz), 5.51 (2H, s, NH₂). 7-3: 11.80 (IH, si, NH), 7.70 (IH, d, CHarom, J=8.8Hz), 7.60 (IH, t, CHarom), 7.49 (IH, q,

CHarom), 7.27-7.33 (IH, m, CHarom), 7.11 (IH, d, CHarom, J=8.8Hz), 5.41 (2H, s,

NH₂). 7-4:11.93 (IH, si, NH), 7.80 (IH, d, CHarom, J=11.6Hz), 7.62 (IH, d, CHarom, J=11.6Hz), 7.40 (IH, dd, CHarom, J=11.2Hz), 729 (IH, d, CHarom, J=11.6Hz), 7.1 (IH, s, CHarom), 5.51 (2H, s, NH₂). 7-5: 11.86 (IH, si, NH), 7.87 (IH, d, CHarom, J=9.6Hz), 7.73 (IH, d, CHarom, J=11.6), 7.50-7.68 (2H, m, CHarom), 7.44 (IH, d, CHarom, J=10.4Hz), 7.11 (IH, d, CHarom, J=11.6Hz), 5.46 (2H, s, NH₂). 7-6: 12.66 (IH, si, NH), 8.52 (IH, s, CHarom), 7.12-720 (IH, m, CHarom), 7.02-7.10 (2H, m, CHarom), 5.90 (2H, s, NH₂). 7-7: 12.70 (IH, s, NH), 8.52 (IH, s, CHarom), 7.60 (IH, d, CHarom, J=8.8Hz), 7.38 (IH, dd, CHarom, J=8.4Hz), 7.12 (IH, s, CHarom), 5.92 (2H, s, NH₂). 7-8: 12.66 (IH, s, NH), 8.39 (IH, s, CHarom), 7.84 (IH, d, CHarom, J=7.6Hz), 7.58 (IH, t, CHarom), 7.50 (IH, t, CHarom), 7.34 (IH, d, CHarom, J=7.6Hz), 5.87 (2H, s, NH₂). 7-9: 11.57 (IH, s, NH), 7.74 (IH, d, Charom, J=9Hz), 7.25 (3H, m, CHarom), 6.88 (IH, d, Charom, J=9Hz), 5.44 (2H, s), 5.08 (2H, s). 7-10: 11.58 (IH, s, NH), 7.73 (IH, d, CHarom, J=12.0Hz), 7.48-7.58 (IH, m, CHarom), 7.21-7.37 (2H, m, CHarom), 6.85 (IH, d, CHarom, J=12.0Hz), 5.44 (2H, s, CH), 5.10 (2H, si, NH₂). 7-11: 11.60 (IH, si, NH), 7.70-7.77 (2H, m, CHarom), 7.57 (1H, d, CHarom, J=112Hz), 7.40-7.50 (IH, m, CHarom), 6.89 (IH, d, CHarom, J=12.0Hz), 5.48 (2H, s, CH), 5.06 (2H, si, NH₂). 7-12: 11.60 (IH, si, NH), 7.91 (IH, s, CHarom), 7.83 (IH, d, CHarom, J=11.2Hz), 7.75 (IH, d, CHarom, J=12.0Hz), 7.66 (IH, d, CHarom, J=9.6Hz), 6.88 (IH, d, CHarom, J=12.0Hz), 5.58 (2H, s, CH), 5.01 (2H, si, NH₂). 7-13: 11.56 (IH, si, NH), 8.77 (IH, s, CHarom), 8.55 (IH, s, CHarom), 7.96 (IH, d, CHarom, J=10.4Hz), 7.72 (IH, d, CHarom, J=12.0Hz), 7.42 (IH, dd, CHarom, J=10.0Hz), 6.83 (IH, d, CHarom, J=11.6Hz), 5.45 (2H, s, CH), 5.15 (2H, si, NH₂).

Example 8: N5-(3,5-dinuorophenyl)-lH-pyrazolo[4,3-b]pyrldine-3,5-dÎamine

NH

F

Example 8a: 6-(3^-dlflaorophenylamino)-3-nitropicolinonitrlle

A mixture of 6.5 g of 6-chk>ro-3-nitropicolinonitrile (0.065 mol) and 6.2 g of 3,5difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70°C for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using saturated NaCI solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid.

Exampie 8b: 3-amIno-6-(3^-dîfluorophenylamino)pIcoIinonitriIe ml of concentrated HCl is added to a solution of 6-(3,5-dichlorophenylthio)-35 nitropicolinonitrile (3.9 g, 0.0141 mol) in 150 ml of éthanol under stirring. The reaction medium is refluxed, added together with 2.4 g of iron (0.0423 mol) and stirred at 80°C for 1 hour. After retuming to 0°C the pH is adjusted to 8 using 1 N soda solution and the réaction medium is filtered on Celite. The reaction mixture is added together with 100 ml of ethyl acetate and 50 ml of methanol. The organic phase is extracted and the 10 aqueous phase is extracted several times by ethyl acetate fractions. The organic phases arc combined and then dried on anhydrous sodium sulfate before being concentrated to yield, after concentration, 2.3 g (66%) of a brown solid.

Exampie 8: 5-(3,5-dinuorophenyIamino)-lH-pyrazolo[43-b]pyridin-3-amine

A solution of 713 mg of NaNO? (10.3 mmol) in water (5 ml) is added, drop by drop, to a stirring solution of 2.3 g of 3-amino-6-(3,5-difluorophenylamino)picolinonitriIe (9.4 mmol) in 100 ml of 6 N hydrochloric acid at 0°C. The mixture is stirred for 20 minutes at 0-5°C. A solution of 5.3 g of SnC12‘2H2O (23.5 mmol, 2.5 eq) in hydrochloric acid (12 N solution, 30 m!) is then added drop by drop and the solution is stirred for 1 hour at room température. The reaction medium is then cooled at 0°C and 20 basified to pH 8 using 30% soda solution. The mixture is extracted with ethyl acetate and washed using saturated NaCI solution and the organic phase is dried on anhydrous sodium sulfate before being concentrated under vacuum. The residue is purified by silica column chromatography (AcOEt). A light yellow solid is obtained (530 mg, 22%).

LCMS: m/z 262 (M+H*).

’H NMR: 6H ppm (400 MHz, DMSO): 11.47 (s, IH), 9.45 (s, IH), 7.65 (m, 3H), 6.87 (d, IH, J=7.8 Hz), 6.60(m, IH), 5.09(s, 2H).

The following compounds are obtained by a similar method:

CIL· ’H NMR: ÔH ppm (400 MHz, DMSO): 12.18 (IH, s, NH), 8.38 (IH, d, CH_mn), 8.37 (IH, d, CHuwn), 5.66 (2H, s, NH).

Examples of method A2

Example 3:5-iodo-l H-pyrazoIo[3,4-b] pyrazine-3-amine

NH

Example 3a: methyl 3-amino-6-lodopyrazine-2-carboxy!ate

1.5 équivalents of N-îodosuccinimide are added at room température to 5 g (32.7 mmol) of a methyl 3-aminopyrazîne-2-carboxylate solution in 25 ml of dimethylformamide. The reaction medium is heated at 65°C for 1 hour, added together with 0.5 équivalents of N-iodosuccinimide and maintained at 65°C for 24 hours. After retuming to room température, the solvent is evaporated and then the product is extracted several times with dichloromethane. The organic phases are combined, washed with 10% sodium bisulfite solution, dried on magnésium sulfate and concentrated to yield 8 g (88%) of methyl 3-amino-6-iodopyrazine-2-carboxylate in the form of a yellow solid.

LCMS (El, m/z): (M+1) 280 ’H NMR: 6H ppm (400 MHz, DMSO): 8.50 (IH, s, CH™), 7.50 (2H, bs, NH₂), 3.20 (3H, s, CH₃).

Example 3b: 3-amlno-6-iodopyrazine-2-carboxamide ml of ammonia in water is added under magnetic stirring to 15 g (53.8 mmol) of a solution of methyl 3-amino-6-iodopyrazine-2-carboxylate in 150 ml of methanol The reaction medium is stirred at 25°C for 48 hours. After évaporation of the solvents, the precipitate obtained is fîltered, rinsed with water and then dried at 50°C to yield 12.50 g of 3-amino-6-iodopyrazinc-2-carboxamidc (88%) in the form of a beige solid.

LCMS (El, m/z): (M+1) 265.02 ’H NMR: 6H ppm (400 MHz, DMSO): 8.35 (IH, s, CH™), 7.85 (IH, bs, NH), 7.60 (3H, bs, NH), 3.25 (3H, s, CH₃).

Example 3c: N*-(3-cyano-5-iodopyrazine-2-yI>-N,N-dimethylformimldamide

13.59 ml (146 mmol) of phosphorus oxychloride is added drop by drop at 0°C to 11 g (41.7 mmol) of a solution of 3-amino-6-iodopyrazine-2-carboxamide in 80 ml of dimethytformamide. The reaction mixture is stirred at room température ovemight and then poured in a beaker containing ice and a little water. The pH is adjusted to 8 with 1 N soda solution; a precipitate is formed. The mixture is allowed to gradually retum to room température and then the solid formed is filtered, rinsed with water and dried at 50°C to yield 10.50 g of N*-(3-cyano-5-iodopyrazine-2-yl)-N,N-dimethyl formimidamide (84%) in the form of a beige solid.

LCMS (El, m/z): (M+1) 302.07 ’H NMR: δΗ ppm (400 MHz, DMSO): 8.69 (IH, s, ClU_ra), 8.67 (IH, s, CH^), 3.20 (3H, s, CHj), 3.11 (3H, s, CH₃).

Example 3d: 3-amino-6-iodopyrazlne-2-carbonitriIe ml (77 mmol) of 1 M hydrochloric acid solution is added to 7.7 g (25.6 mmol) of N’(3-cyano-5-iodopyrazin-2-yl)-N,N-dimethylformimidamide. The reaction medium is heated at 50°C for 4 hours and then stirred at room température ovemight. The precipitate formed is filtered, rinsed with water and dried at 50°C to yield 6 g (95%) of 3-amino-6-iodopyrazine-2-carbonitrilc in the form of a beige solid.

LCMS (El, m/z): (M+I) 247.0 ^lH NMR: δΗ ppm (400 MHz, DMSO): 8.49 (IH, s, CH™.), 7.53 (2H, bs, NH₂).

Example 3e: 3-chIoro-6-lod opyrazln e-2-ear bo n itrile

64.3 ml of hydrochloric acid is added at -5°C to 7.7 g (31.3 mmol) of 3-amino-6iodopyrazine-2-carbonitrile. At this température, a sodium nitrite solution (4.32 g, 62.6 mmol) dissolved in 9 ml of water is added to the reaction mixture and is stirred for 4 hours at -50°C and then at room température ovemight. Another équivalent of sodium nitrite is added to the reaction mixture and the precipitate formed is filtered, rinsed with water and dried at 50°C to yield 3.65 g (44%) of 3-chloro-6-iodopyrazinc-2-carbonitrilc in the form of a beige solid.

LCMS (El, m/z): (M+1) 266.49 ’H NMR: δΗ ppm(400 MHz, DMSO): 9.13 (IH, s, CH™.)

Exampie 3; 5-lodo-l H-pyrazolo [3,4-b]pyrazin e-3-ami n e

0.74 ml (9.8 mmol) of hydrazine is added to 2.6 g (9.80 mmol) of a solution of 3chloro-6-iodopyrazine-2-carbonitrile in 15 ml of butanoL The reaction mixture is heated at l l0°C for 5 hours and then left at room température ovemight. The suspended solid is filtered, rinsed with butanol and then dried in an oven at 50°C to yield 2.2 g (86%) of

5-iodo-lH-pyrazoIo[3,4-b]pyrazine-3-amine in the form of a brown solid.

LCMS (El, m/z): (M+l) 262.02 ’H NMR: δΗ ppm (400 MHz, DMSO): 12.59 (IH, bs, NH), 8.60 (IH, d, 5.83 (2H, bs,NH₂).

Examples of method A3

Example 4: 5-lodo-6-methoxy-lH-pyrazoIo[3,4-b]pyridln-3-amine

NHa

Example 4a: ethyl 5-cyano-2-hydroxy-6-(methylthio)nicotinate

Ethyl 5-cyano-2-hydroxy-6-(mcthylthio)nicotinatc is obtained by following the procedure of Ya. Yu. Yakunin et al., Russian Chemical Bulletin, 1999, 48(1), 195-6 with a total yield of 34%.

LCMS (El, m/z): (M-l) 237.22 ‘H NMR: δΗ ppm (400 MHz, DMSO): 12.72 (IH, bs, OH), 8.40 (IH, s, ClUm), 4.29 (2H, q, CH₂), 2.64 (3H, s, CHj), 1.30 (3H, t, CHj).

Exemple 4b: 5-cyano-2-hydroxy-6-(methylthio)nlcotinlc acid

4.16 g (2eq) of lithium hydroxide monohydrate is added at room température to a solution of 11.8 g (49.5 mmol) of ethyl 5-cyano-2-hydroxy-6-(mcthylthio)nicotinatc in 100 ml of éthanol and 100 ml of water. The reaction mixture is stirred at 60°C for 2 hours. The éthanol is evaporated and 1 N aqueous soda is added. The aqueous phase is washed with ethyl acetate and then re-acidified by adding 1 N aqueous hydrogen chloride (pH=l). The precipitate formed is filtered, rinsed with water and with diethyl ether and then dried under vacuum to yield 9.9 g (95%) of 5-cyano-2-hydroxy-6(methylthio)nicotinic acid in the form of a brown powder.

EL·.

LCMS (El, m/z): (M-l) 209.09 'H NMR: SH ppm (400 MHz, DMSO): 8.32 (IH, s, CH.™), 2.61 (3H, s, CH₃).

Example 4c: 6-hydroxy-2-(methyIthio)nicotinonitrile

A solution of 6 g (28.5 mmol) of 5-cyano-2-hydroxy-6-(methylthio)nicotinic acid in 35 ml of diphenyl ether is stirred at 250°C for 4 hours. After retuming to room température, 100 ml of cyclohexane is added and the réaction medium is triturated for 30 minutes. The solid formed is filtered, rinsed thoroughly with cyclohexane and then dried under vacuum to yield 2.87 g (60%) of 6-hydroxy-2-(methyIthio)nicotinonitri!e in the form of a brown powder.

LCMS (El, m/z): (M+1) 167.12 ’H NMR: SH ppm (400 MHz, DMSO): 12.16 (IH, bs, OH), 7.92 (IH, d, CH.™), 6.46 (IH, d, CH»™), 2.59 (3H, s, CH₃).

Example 4d: 6-hydroxy-5-iodo-2-(methylthIo)nlcotînonitrile g (1.6 eq) of silver sulfate and 4.58 g (1.5 eq) of iodine are added successively to a solution of 2 g (12 mmol) of 6-hydroxy-2-(mcthylthio)nicotinonitri!c in 200 ml of éthanol The reaction medium is stirred at room température for 2 hours. The solid is filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and then taken up în ethyl acetate. The organic phase is washed with water three times, dried on magnésium sulfate and evaporated to yield 3.18 g (90%) of 6-hydroxy-5-iodo-2(methylthio)nicotinonitrile in the form of a yellow powder.

LCMS (El, m/z): (M+1) 292.93 ’H NMR: SH ppm (400 MHz, DMSO): 12.96 (IH, bs, OH), 8.38 (IH, s, CH,™), 2.62 (3H, s, CHj).

Example 4e: 5-lodo-6-methoxy-2-(methylthlo)nlcotInonitrile

905 μΐ (2eq) of methyl iodide and 2.1 g (1.05 eq) of silver carbonate are added successively to a solution of 2.12 g (7.26 mmol) of 6-hydroxy-5-iodo-2(methylthio)nicotinonitrile in 20 ml of 1,4-dioxane. The reaction medium is stirred at 60°C for 5 hours. The solid is filtered and the residue rinsed thoroughly with methanoL The filtrate is evaporated and the residue purified by silica column chromatography (4:6 dichloromethane/cyclohexane as eluent) to yield 1.52 g (68%) of 5-iodo-6-methoxy-2(methylthio)nicotinonitrile in the form of a white powder.

LCMS (El, m/z): (M+1) 306.95 ’H NMR: δΗρρτη (400 MHz, DMSO): 8.50 (IH, s, CH.™,), 4.04 (3H, s, CH₃), 2.63 (3H, s, CHj).

Exampie 4f: 5-iodo-6-methoxy-2-(methylsulfiny!)nîcotïnonitrile

1.42 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.6 g (5.23 mmol) of 5-iodo-6-methoxy-2-(methylthio)nicotinonitrile in 20 ml of dichloromethane. The reaction medium is stirred at room température for 1 hour. Ethyl acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnésium sulfate, filtered and evaporated to yield 1.63 g (97%) of 5-îodo-6-methoxy-2-(methylsulfinyl)nicotinonitrile in the form of a white powder which may also contain 5-iodo-6-methoxy-2-(methylsulfonyl)n!COtinonitrile in small proportions (<20%). If necessary, the mixture is used as-is in the following steps. LCMS (El, m/z): (M+l) 322.95 *H NMR: δΗ ppm (400 MHz, DMSO): 8.86 (IH, s, CH.™,), 4.05 (3H, s, CHj), 2.95 (3H, s, CH₃).

Example 4: 5-iodo-6-methoxy-lH-pyrazolol3,4-b]pyridln-3-amine

294 μΐ (1.2 eq) of hydrazine monohydrate is added to a solution of 1.63 g (5.05 mmol) of 5-rodo-6-methoxy-2-(methylsu!fïnyl)nicotinonitrile in 30 ml of 2-propanol. The reaction medium is stirred at 80°C for 9 hours. After rctuming to room température, the solid formed is filtered and rinsed with 2-propanol to yield 1.14 g (78%) of 5-iodo-6methoxy-1 //-pyrazolo[3,4-b]pyridin-3-amine in the form of a white powder.

LCMS (El, m/z): (M+l) 291.00 ’H NMR: δΗρρτη (400 MHz, DMSO): 11.87 (IH, s, NH), 8.49 (IH, s, CH.™,), 5.49 (2H, bs, NH₂), 3.90 (3H, s, CHj).

Exampie 5: 5-iodo-lH-pyrazolo[3,4-bIpyridine-3,6-diamlne nh₂

Example 5a; 4-methylmorpholinium (2,4)-ethyl-5-amino-2,4-dicyano-5mercaptopenta-2,4-dienoate

4-methyImorpho linium (2,4)-cthyl-5-amino-2,4-dicyano-5-mercaptopenta-2,4-dîenoate is prepared according to the procedure described by V.D. Dyachcnko et al., Chemistry of Hetcrocyclic Compounds, 2005, 41(4). 503-10 with a yield of 50 %.

*H NMR: 8H ppm (400 MHz, DMSO): 9.60 (IH, bs, NH), 8.66 (IH, s, CH), 8.33 (IH, bs, NH), 7.43 (IH, bs, NH), 4.08 (2H, q, CH₂), 3.82-4.02 (2H, m, CH₂), 3.55-3.78 (2H, m, CH₂), 3.24-3.42 (2H, m, CH₂), 3.98-3.17 (2H, m, CH₂), 2.81 (3H, s, CH₃), 1.19 (3H, t, CH₃).

Example 5b: ethyl 2-amino-5-cyan&-6-(methylthIo)nicotinate

2.73 ml (1 eq) of methyl iodide is added to a solution of 14.2 g (43.8 mmol) of 4methylmorpholinium (2,4)-ethyl-5-amino-2,4-dicyano-5-mercaptopcnta-2,4-dienoate in 78 ml of MN-dimethylformamidc. The reaction mixture is stirred at room température for 1 hour and then at 75°C for 20 hours. After retuming to room température, water is 10 added and the solid formed is filtered and dried under vacuum to yield 10.31 g (100 %) of ethyl 2-amino-5-cyano-6-(methyIthio)nicotinate in the form of a beige powder.

LCMS (El, m/z): (M+1) 238.20 *H NMR: δΗ ppm (400 MHz, DMSO): 825 (IH, s, CH_mra), 8.19 (IH, bs, NH), 7.99 (IH, bs, NH), 4.27 (2H, q, CH₂), 2.58 (3H, s, CH₃), 1.31 (3H, t, CH₃).

Example 5c: 2-amino-5-cyano-6-(methylthio)nkotinic acid

3.08 g (2 eq) of lithium hydroxide monohydrate is added at room température to a solution of 8.7 g (36.7 mmol) of ethyl 2-amino-5-cyano-6-(methylthio)nicotinate in 87 ml of éthanol and 87 ml of water. The reaction mixture is stirred at 60°C for 2 hours.

The éthanol is evaporated and 1 N aqueous soda is added. The aqueous phase is washed 20 with ethyl acetate and then re-acidified by adding 1 N aqueous hydrogen chloride (pH=l). The precipitate formed is filtered, rinsed with water and with diethyl ether and then dried under vacuum to yield 7.67 g (quantitative) of 2-amino-5-cyano-6(methylthio)nîcotinic acid in the form of a brown powder.

LCMS (El, m/z): (M+1) 210.16 *H NMR: δΗ ppm (400 MHz, DMSO): 13.28 (IH, bs, CO₂H), 8.21 (IH, s, CH_aronl),

8.13 (2H, bs, NH₂), 2.57 (3H, s, CH₃).

Example 5d: 6-amIno-2-(methylthîo)nicotinonitrile

A solution of 3 g (14.3 mmol) of 2-amino-5-cyano-6-(methylthio)nicotinic acid in 30 ml of diphenyl ether is stirred at 255°C for 60 hours. After retuming to room température, 30 60 ml of cyclohexane is added and the reaction medium is triturated for 30 minutes. The solid formed is filtered and then rinsed thoroughly with cyclohexane. The solid is redissolved in ethyl acetate and then the organic phase is washed with water, dried on

6l magnésium sulfate, fïltered and then evaporated to yield 1.32 g (55%) of 6-amino-2(methylthio)mcotinonitrile in the form of a brown powder.

LCMS (El, m/z): (M+l) 166.13 'H NMR: 5H ppm (400 MHz, DMSO): 7.58 (IH, d, CH^J, 7.12 (2H, bs, NH₂), 6.20 (IH, d, CH.™,). 2.51 (3H, s, CHj).

Example 5e: 6-amino-5-îodo-2-(methylthio)nicotinonitrile

3.75 g (1.5 eq) of silver sulfate and 2.85 g (1.4 eq) of iodine are added successivety to a solution of 1.32 g (8.02 mmol) of 6-amino-2-(methyIthio)nicotinonitrile in 65 ml of éthanol. The reaction medium is stirred at room température for 3 hours. The solid is fïltered and the residue rinscd thoroughly with methanol. The filtrate is evaporated and redissolved in ethyl acetate. The organic phase is washed with water three times, dried on magnésium sulfate and evaporated to yield 1.89 g (81%) of 6-amino-5-iodo-2(methylthio)nicotinonîtrile in the form of a brown powder.

LCMS (El, m/z): (M+l) 291.99 ’H NMR: δΗ ppm (400 MHz, DMSO): 8.13 (IH, s, CH_amm), 7.19 (IH, broad fiat singlet, NH₂), 2.51 (3H, s, CH₃).

Example 5f: 6-amino-5-iodo-2-(methylsulfiny])nicotinonitrile

1.77 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.89 g (6.51 mmol) of 6-amino-5-iodo-2-(methyIthio)nicotinonitrile in 60 ml of dichloromethane. The reaction medium is stirred at room température for 1 hour. Ethyl acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnésium sulfate, fïltered and evaporated to yield 1.5 g (75%) of 6amino-5-iodo-2-(methylsulfïnyl)nicotinonitrile in the form of a white powder which may also contain 6-amino-5-îodo-2-(mcthylsulfonyl)nicotinomtrile in small proportions (<20%). If necessary, the mixture is used as-is in the following steps.

LCMS (El, m/z): (M+l) 307.98 ’H NMR: δΗ ppm (400 MHz, DMSO): 8.45 (IH, s, CIU_m), 7.70 (2H, broad fiat singlet, NH₂), 2.84 (3H, s, CHj).

Example 5:5-lodo-lH-pyrazoIo[3,4-b]pyridlne-3,6-dianilne

275 μί (2 eq) of hydrazine monohydrate is added to a solution of872 mg (2.84 mmol) of 6-amino-5-iodo-2-(mcthylsuIfïnyl)nicotînonitrile in 11 ml of 2-propanol. The reaction medium is stirred at 80°C for 3 hours. Water is added and the product is extracted with *

ethyl acetate. The organic phase is dried on magnésium sulfate, filtered and evaporated. The residue is triturated in a minimum of diisopropyl ether. The solid is filtered to yield 523 mg (67%) of5’iodo-lH-pyrazoIo[3,4-b]pyridin-3,6-diamine in the form of a brown

LCMS (El, m/z): (M+1) 276.00 ’H NMR: δΗ ppm (400 MHz, DMSO): 11.23 (IH, s, NH), 8.26 (IH, s, CH^), 6.11 (2H, bs, NH₂), 5.25 (2H, bs, NH₂).

Examples of method B1

Exampie 6: 5-(33*difluorobenzyIthio)-lH-pyrazo!o[43-b]pyridiii-3-amine

F

Exampie 6a: 6-chloro-3-nîtropicolinonItrile

2,6-Dich!oro-3-nitropyridine (5.18 mmol, 1 g) is mixed with 5 ml of N-methyl-2pyrrolidinone in a microwave reactor. The reaction mixture is heated at 180°C for 15 minutes (6 bars). The crude reaction product is dissolved in ethyl acetate, filtered and washed several times using an aqueous phase. The organic phase is collected, dried on magnésium sulfate and dry concentrated. The crude product thus obtained is purified by silica gel chromatography (heptane/AcOEt) to yield, after concentration, 0.62g (65%) of a brown oil.

’H NMR: δΗ ppm (400 MHz, DMSO): 8.81 (IH, d, CH^_m), 8.18 (IH, d, CH_mm).

Example 6b: 3-ni tro-6-t hîoxo-1,6-d Ihyd ro pyridin e-2-carbonitr Ile

Onc équivalent of NaSH:H₂O is added to a solution of 6-chloro-3-nitropicolinonitriIc (5.45 mmol, 1 g) in 20 ml of EtOH. The color tums orange. The reaction medium is stirred at room température for 30 minutes. The crude reaction product is then concentrated, redissolved in ethyl acetate and extracted several times using an acidic aqueous phase (1 N HCI) and then a neutral phase. The organic phase is concentrated and the crude reaction product recrystallîzed in acetone to yield 0.64 g (79%) of yellow crystals.

‘H NMR: δΗ ppm (400 MHz, DMSO): 8.71 (IH, d, CH.™,), 8.27 (IH, d, CH.™,).

Example 6c: 6-(3^-difluorobenzylthlo)-3-nltropIcoIinonItrile

A mixture of 3-nitro-6-thioxo-l,6-dihydropyridin-2-carbonitrilc (4.42 mmol, 1.34g),

3,5-difluroben2ylbenzyîbromide (8.83 mmol, 1.828 g), and K₂CO₃ (11.04 mmol,

1.525 g) in 5 ml of acetone is heated at 70°C for 10 hours and then evaporated under reduced pressure. The residue is purified by silica gel chromatography (AcOEt/heptane) to yield 1.33 g (98%) of the expected product.

LCMS (ES-): m/z 306 (M-H+).

’H NMR: δΗ ppm (400 MHz, DMSO): 8.53 (IH, d, CH.™,), 7.91 (IH, d, CH.™,), 7.21 10 (2H, m), 7.17 (IH, m), 4.55 (2H, CH₂).

Example 6d: 3-amino-6-(3,5-(linuorobenzyIthio)picolinainide

A mixture of 6-(3,5-difluorobenzylthio)-3-nitropicolinonitrile (0.05 g, 0.163 mmol) and PtO₂ (0.739 mg, 3.25 gmol) in 10 ml of MeOH is placed under stirring at atmospheric pressure of hydrogen for 2 hours. The catalyst îs fîltered, the solution is concentrated 15 and the residue thus obtained is purified by silica gel chromatography (AcOEt/hcptanc) to yield, after concentration, 0.04 g (83%) of white crystals.

LCMS (ES+) m/z: 296 (MH+).

’H NMR: δΗ ppm (400 MHz, DMSO): 7.84 (IH, broad s, NH), 7.40 (IH, broad s, NH), 7.14 (IH, d, CH.™,), 7.08 (4H, m, CH^_m), 6.80 (2H, broad s, NH₂), 4.43 (2H, s, CH₂).

Example 6e: 3-amino-6-(3,5-difluorobenzyltlilo)picoIinonitrile

A mixture of 3-amino-6-(3,5-difluorobeiizylthio)picolinoamide (2.37 mmol, 0.7 g) and P₂Clj (9.48 mmoL 1.346 g), 20 ml of toluene and 1 m! of ionic solvent (l-butyl-3mcthylimidazolium tctrafluoroboratc) arc placed in a microwavc reactor and then heated at 140°C for 30 minutes. The crude reaction product is then concentrated under reduced 25 pressure and the orange crystals thus obtained arc rcdîssolved în ethyl acetate and washed using saturated aqueous NaHCOj solution. The organic phase is dried on magnésium sulfate and then concentrated to yield 0.7 g of a brown oil. This crude reaction product is purified by silica gel chromatography (AcOEfheptane + 0.1% of NEtj) to yield, after concentration, 0.15 g (23%) of orange crystals.

’H NMR: δΗ ppm (400 MHz, DMSO): 7.73 (1 H, d, CH^), 7.25 (2H, m, CH^_m), 7.18 (IH, m), 6.85 (IH, d), 5.43 (2H, CH₂).

V'17324

Exampie 6: 5-(3,5-difluorobenzyIthio)-IH-pyrazoIo[4,3-b]pyridin-3-aniine

A solution cooled to 0°C of NaNO₂ in 3 ml of water is added drop by drop to a solution at 0°C of 3-amino-6-(3,5-difluorobenzy!thio)picolinonitrile (1.587 mmol, 0.44g) in ml of 6 N HCl solution. After 15 minutes, a solution cooled to 0°C of SnCl₂2H₂O diluted in 4 ml of 12 N HCl is added drop by drop. The reaction medium is then stirred at 25°C for 1 hour. The solution is extracted with ethyl acetate and then washed using saturated NaHCOj solution and then saturated NaCI solution. The organic phase is collected, dried on magnésium sulfate and then concentrated under reduced pressure. The residue is purified by silica gel chromatography (AcOEt/heptane) to yield, after concentration of the organic phases, 0.07 g (15%) of black crystals.

’H NMR: 5H ppm (400 MHz, DMSO): 11.64 (IH, s, NH), 7.63 (IH, d, CH.™), 7.21 (2H, m, CH^_m), 7.13 (IH, d, CH.™), 7.04 (IH, m, CH.™), 5.38 (2H, s, NH₂), 4.51 (2H, s, CH₂).

The following compounds are obtained by a similar method:

Ex**	ArX	w	Y4	Ri	Compound names	Yield	Mass MH+
6-2		H	CH	H	5-(2,5-difluorobenzy Ithio)-1Hpyra2olo[43-b]pyridin-3-aminc	5% 4 steps	293.0
6-3		H	CH	H	5-(2,5-dichIorobcnzy Ithio)-1Hpyrazolo[43-b]pyridin-3-amine	3% 4 steps	324.9

** ’H NMR: 5H ppm (400 MHz, DMSO): 6-2: 11.65 (IH, s, NH), 7.64 (IH, dd,

CHarom, >8.8Hz), 7.42-7.51 (IH, m, CHarom), 7.20-7.25 (IH, m, CHarom), 7.14 (IH, dd, CHarom, J=8.8Hz), 7.01-7.11 (IH, m, CHarom), 5.37-5.41 (2H, m,NH2), 4.49 (2H,

s). 6-3: 11.65 (IH, s, NH), 7.83 (IH, m, CHarom), 7.61 (IH, dd, CHarom, J=8.8Hz),

7.50 (IH, m, CHarom), 7.28-7.32 (IH, m, CHarom), 7.10 (IH, dd, CHarom, J=8.8Hz), 7.01-7.11 (IH, m, CHarom), 5.42 (2H, s, NH2), 4.47 (2H, s).

Examples of method B2

Example 7: 5-(3^-dichlorophenylthio)-lH-pyrazolo[43-b]pyridin-3-amine nh₂

Cl

Cl

Example 7a: 6-(3,5-dichlorophenylthlo)-3-nitropicolinonitriIe

A mixture of 6-chloro-3-nitropicolinonitrile (3.70g, 0.02 mol), 3,5-dichlorobenzenethiol (3.60 g, 0.02 mol) and K2CO3 (5.6 g, 0.04 mol) in 100 ml of acetonitrile is carried at 70°C for 16 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using an aqueous phase. The organic phase ts dried with sodium sulfate and the residue is purified by silica gel chromatography (AcOEt/petroleum ether) to yield 5.4 g (80%) of a yellow solid.

Example 7b: 3-amlno-6-(3^-dichlorophenylthio)picolinonitriIe ml of concentrated HCl is added to a solution of 6-(3,5-dichlorophenylthio)-3nitropicolinonitrilc (3.4 g, 0.01 mol) in 50 ml of methanol under stirring, The réaction medium is refluxed, added together with 1.68 g (0.03 mol) of iron and stirred for 10 minutes. After retuming to room température, the reaction mixture is added together with 100 ml of ethyl acetate and 50 ml of water. The pH is adjusted to 10 using 30% soda solution and the organic phase is extracted and then dried on anhydrous sodium sulfate before being concentrated. The residue is purified by silica gel chromatography (ethyl acetate/petroleum ether) to yield, after concentration of the fractions, 2.82 g (91%) of a yellow solid.

LCMS (m/e): 296(M+H+). %.

Example 7: 5-(3^-dlchloroph eny Ithio)-1 H-pyrazolo[43-b]pyridin-3-amine

A solution of 350 mg of NaNO₂ (5.07 mmol) in water (2 ml) is added to a stirring solution of 1.5 g of 3-amino-6-(3,5-dichlorophenylthio)picolinonitrile (5.07 mmol) in 100 ml of 50% sulfuric acid at 0°C. The mixture is stirred for 20 minutes at 0-5°C. A solution of 2.9 g of SnCI₂-2H₂O (12.7 mmol, 2.5 eq) in hydrochloric acid (12 N solution, 10 ml) is then added and the solution is stirred for 1 hour at room température.

The solid formed is filtered and then washed twice with 20 ml of water. The solid is suspended in 100 ml and the pH is adjusted to 10 by adding 30% soda solution. The organic phase is separated and then dried on anhydrous sodium sulfate before being 5 concentrated under vacuum. A light yellow solid is obtained after recrystallization in ethyl acetate (470 mg, 34%).

LCMS m/z 311 (M+H⁴).

’H NMR: δΗ ppm (400 MHz, DMSO): 11.91 (IH, bs, NH), 7.79 (IH, d, CH.™), 7.55 (IH, s, CfUn,). 7.36 (2H, s, CH.™), 7.33 (IH, m, CH.™), 5.42 (2H, s, NH₂).

The following compounds arc obtained by a similar method:

NH₂

Ex**	ArX	Yl	W	K	Compound names	Yield	Mass MH*
7-1	♦ i.	CH	H	H	5-(3,5-<lifluorobenzyloxy)-l Hpyrazolo[43-b]pyridin-3-amine	28%	277
7-2	Â.	CH	H	H	5-(33-difluoropheny lthio)-1Hpyrazolo[4,3-b]pyridin-3-ainine	33% 3 steps	278,9
7-3	b F	CH	H	H	5-(2,4-difluorophcnyIthio)-l Hpyrazo!o[4,3-b]pyridin-3-amine	24% 3 steps	279,0
7-4	·> Cl	CH	H	H	5-(2,4-dichlorophcny lthio)-1Hpyrazolo[43-b]pyridin-3-amine	24% 3 steps	311,0
7-5	F S*	CH	H	H	5-(2-(trifluoromethyl)phenylthio)-l Hpyrazolo[43-b]pyridin-3-aminc	17% 3 steps	311,0

The 6-hydroxy-4-(methylthio)nicotinonitrilc or 6-hydroxy-4-(mcthylthio) pyridazin-3-carbonitrile dérivatives are oxidized, typicalîy by the use of m-CPBA or oxone to form the corresponding methyl sulfoxides or methyl sulfones. These compounds, sometimes obtained as mixtures, are used as-is in the aminopyrazole ring formation réaction by use of an optionally substituted hydrazine in a polar solvent such as éthanol at températures varying between 25°C and 150°C.

The pyrazolopyridines and pyrazolopyridazines thus obtained are subjected to a dehydrochlorination reaction, typicalîy in the presence of phosphores oxychloride, with or without solvent, at températures varying between 70°C and 180°C. If a solvent is used, a high boiling-point non-polar solvent such as toluene or xylene will be preferred. The optionally substituted 6-chforo-pyrazo!o[4,3-c]pyridin-3-aminc and 6-chloropyrazo!o[4,3-c]pyridazin-3-amine respectively obtained are then reacted with a nucleophile such as a phénol, an aniline or a thiophenol in the context of aromatic nucleophilic substitution. In this case, the reaction is carried out in a polar solvent such as DMSO, DMF, acetone, THF or acetonitrile, in the présence of a base such as potassium ierf-butylate or NaH. If necessary, these reactions may be catalyzed by the action of copper and may also be carried out without solvent. Typicalîy, the preferred protocol involves températures ranging between 20°C and 150°C.

Altematively, the use of organic bases such as pyridine, diisopropylamine, triethylamine or DBU, or inorganic bases such as sodium or potassium carbonate is also possible.

Altematively, the compounds of formula (XlVa) may give rise to a catalytic coupling reaction such as a Suzuki réaction. In this case, thèse compounds arc brought together with an optionally substituted 2-benzyl-4,4,5,5-tetramethyl-l,3,2dioxaborolane described above in preceding method B3, a palladium catalyst such as Pd(dppf)Ct2 or Pd(PPhj)4, an organic base such as triethylamine or an alcoholate, or an inorganic base such as sodium, potassium or césium carbonate in a solvent such as toluene, benzene, THF or dioxane. The preferred reaction températures are between 20°Cand 100°C.

Method C3:

Method C3, presented in diagram 12a below, is a variant of method Cl based on the regioselective functionalization of 2,6-dichloronicotinonitrile either by an anionic nucleophile such as a phenate or a thiophenate, or by an organometallic such as a benzylzinc chloride. In the latter case, the réaction is catalyzed for example with a palladium(II) complex. The transformation of the chloronicotinonitrile thus obtained in the corresponding pyrazolopyridine, in the case where Y] = CH, is carried out as

Diagram 12a

Method D:

These methods hâve as an object the synthesis of compounds of general formula (I) or (Vil) by the use of various catalytic coupling methods.

Method Dit

Method Dl, presented in diagram 13 below, makes use of the coupling reaction as described in J.A.C.S., 1984,106, 158 between an organozinc compound prepared in situ and an aryl bromide catalyzed by palladium complexes.

[RH

Diagram 13

The optionally substituted 3-amino-diazaindazoles or 3-amino-azaindazoles are brought together with a zinc benzyl chloride, optionally substituted, in an aprotic polar solvent such as THF or dioxane, in the presence of a catalytic quantity of a palladium complex such as (dppOzPdCtCHiCb. The coupling reaction is carried out at températures ranging between 25°C and 100°C.

Method D2:

Method D2, presented in diagram 14 below, makes use of the coupling reaction as described by Gueifïïer A. et al., Tetrahedron, 2006, 62, 6042-6049, between a thiol, in particular a thiophenol or a benzylthiol, and an aryl iodide catalyzed by copper complexes.

Br

N

Rf

Rf

Rj=H or N-protecting group R₂

Ru» H or n = 0 or 1

Diagram 14

This reaction is typically carried out in a high boiling-point polar solvent such as 2-propanol in the présence of a catalytic quantity of polyethylene glycol, a métal sait such as copper iodide (Cul) and an excess of an inorganic base such as potassium carbonate, calcium carbonate or sodium carbonate. The reaction températures typically vary between 50°C and 100°C.

Method D3:

Method D3, presented in diagram 15 below, makes use of the coupling reaction as described by Sonogashira, K. et al. in Tetrahedron Lett., 1975, 16, 4467-4470 between an acetylene dérivative and an aryl halide catalyzed by copper and palladium complexes.

ei/

ÎPd*J

Rj=H or N-protecting group

Ri

R*»H or n » O or I

Diagram 15

Such a réaction is typicaliy carried out by the reaction under an inert atmosphère of a heteroaryl halide with a stoichiometric quantity of an optionally substituted ethynylbenzene in the presence of a catalytic quantity of a palladium complex, for example PdCl2(PPhi)2 or Pd(PPhj)₄, a catalytic quantity of a copper sait, for example Cul, and an organic base such as tricthylaminc or DIPEA, or an inorganic base such as potassium or césium carbonate. The protocol generally involves reaction températures ranging between 20°C and 45°C in solvents including DMF, THF, dioxane or diethyl ether.

Method E:

The protocols of method E aim at functionalizing the exocyclic amine of aminopyrazole rings by their reaction with an intermediate featuring an electrophile function, optionally generated in situ, such as acid chloride, an isocyanate, a isothiocyanate or an aldéhyde.

Method El:

Method El, presented in diagram 16 below, aims at the transformation of the primary exocyclic amine function of aminopyrazole compounds into an amidc fonction.

Diagram 16

These compounds arc synthesized via the corresponding 3-aminopyrazole by the addition of adéquate acid chloride prepared beforehand by the use of oxalyl chloride and a catalytic quantity of DMF in a solvent such as tetrahydrofuran. These acid chlorides may be obtained by the use of alternative methods, such as those based on the use of thionyl chloride or phosphorus oxychloridc, well known to the person skilled in the art. The condensation of acid chlorides on aminopyrazoles is typically carried out in 10 an aprotic solvent such as tetrahydrofùran, toluene or dichloromethane in the presence of a base such as DIPEA, pyridine or triethylamine.

Altematively, the use of a base as a solvent, in particular pyridine, is a possibility.

Altematively, this type of reaction may be conducted in a biphasic system 15 according to the well-known Schotten-Baumann method.

Altematively, formation of the amide bond may be carried out from the corresponding 3-aminopyrazole and the acid of interest by the use of peptide coupling conditions using rcagents such as HOBt (hydroxybenzotriazole), TBTU (O(bcnzotriazol-l-yl)-N,N,N’,N’-tctramethyluiOnium tetrafluoroboratc), HATU (2-(lH-720 azabenzotriazol-l-yl)-l,l,3,3-tetramethyturonium hexafluorophosphate), EDCI (1ethyl-3-(3-dimethylaminopropyl)carbodiimide) or carbonyldiimîdazole at a température ranging between -20°C and 100°C in an aprotic solvent such as tetrahydrofùran, dioxane, dichloromethane or any solvent with similar properties.

Method E2:

Dérivatives characterized by the presence of a secondary amine in position 3 of the aminopyrazole ring are synthesized by a reducing amination reaction according to diagram 17 below.

Rk <

NH

[Red]

Rj=H or N-protectîng group

R₂

Ta

Diagram 17

Reducing amination reactions are typically carried out by mixing adéquate stoichiometric quantifies of aminopyrazole and aldéhyde in a solvent such as DCE 10 (dichloroethane), THF or acetonitrile, optionally in the presence of a quantity of water, TFA (trifluoroacetic acid) or acetic acid, by adding successive fractions of a reducing agent such as NaBHi, NaBH(0Ac)3 or NaBHjCN. These réactions are typically carried out at room température.

Method E3:

Dérivatives carrying a 3-ureido or 3-thioureido function are obtained by the reaction, presented in diagram 18 below, of an aminopyrazole with an isocyanate or isothiocyanate obtained according to methods well known to the person skilled in the art.

Rj=H or N-protecting group Z=Oor S »

Diagram 18

In a typical reaction, the reaction mixture is prepared in a polar or non-polar aprotic solvent such as dichloromethane, acetone, DMF, DMA, acetonitrile, THF or dioxane carried at températures varying between 20°C and the boiling point of the chosen solvent. If necessary, recourse to a weakly nucleophilic organic or inorganic base may prove to be necessary. In this case, sodium hydride is a possible option.

Method F: post-synthetic deprotections and modifications

Method Fl: deprotections

The trifluoroacetate protecting groups are removed by the action of an organic base such as tricthylaminc or pyridinc in a polar solvent such as methanol, éthanol or THF at the reflux températures of the solvents used.

The /eri-butyl or trityl protecting groups carried by the pyrazole rings are displaced by the action of a strong acid, typically TFA, in a non-polar solvent such as dichloromethane or DCE.

Method F2: alkyne réductions

(RedJ

Rj=H or N-protecting group «2

R*“H or

Diagram 19

Reactions for reducing diaryl alkynes into diaryl alkanes are typically carried out by catalytic hydrogénation, under hydrogen pressure, in the presence of catalysts such as PtOj, Pt, Pd/C, Ni or Rh. Aitematively, the use of DIBAL-H (diisobutylaluminum hydride) in the presence or the absence of a catalyst such as CpîTiCh is conceivable.

Method F3: oxidation of sulfides into sulfones and sulfoxides

R R _N.Rj

J

Rj=H or N-protecting group Rj

R* = H or

Diagram 20

Oxidation reactions of sulfides into sulfoxides are typically carried out via the use of oxone in a mixture of polar solvents such as THF/MeOH or DMF/watcr. The optimal reaction températures are typically between 25°C and 50°C.

Many alternative methods are available, and some give the possibility of producing semi-oxidized dérivatives, namely sulfoxides. Such alternative methods include the use of m-CPBA, KMnGi/MnCh in dichioromethane, H2O2 (30%) in a biphasic medium and the presence of a phase transfer catalyst or a catalyst in the form of a urea complex (UHP).

The combined use of H2O2 and métal complexes such as Sc(OTf)3 promûtes partial oxidation dérivatives.

Other known methods include, for example, the use of CAN/NaBrCh (CAN=ceric ammonium nitrate).

The cxamplcs and figures which follow illustratc the invention without limiting its scope in any way.

FIGURES

Figure IA represents a histogram ofthe inhibition effect on NGF-induced hyperaigesia (time latency) of Compound 30 administered to a mouse at various doses by intraperitoneal route.

Figure IB represents a histogram of the inhibition effect on NGF-induced hyperaigesia (time latency) of Compound 30 administered to a mouse at various doses by oral route.

Figure 2A represents a graph relative to the number of spontaneous flinches after administration to a rat by intraperitoneal route of Compound 30 at various doses.

Figure 2B represents a graph relative to the mcasurc of mechanical allodynia after oral administration to a rat of Compound 30 at various doses.

Figure 3A represents a histogram of the limb use score as a function of time after administration of a saline solution or of Compound 30 at the dose of 2.5 mg/kg.

Figure 3B represents a histogram of the light touch-evoked flinching as a function of time after administration of a saline solution or of Compound 30 at the dose of

2.5 mg/kg.

EXAMPLES

The following abbreviations are used:

DMSO Dimethylsulfoxide

El Electron impact

ES Electrospray

LCMS Liquid chromatography - mass spectrometry mg milligram mL milliliter

NMR Nuclear magnetic résonance

I. Synthesis of the compounds according to the Invention

Examples of method Al

Example 1: 5-iodo-lII-pyrazoIo[3,4-b]pyridine-3-aniine

Example la: 2-hydroxy-5-iodoiilcotInonltrile g (0.5 eq) of N-iodosuccinimide at room température is added to a solution of 10 g (83 mmol) of 2-hydroxynicotinonitrile in 150 ml of anhydrous dimethylformamide. The reaction mixture is stirred at 60°C. After 30 minutes of stirring, 9 g (0.5 eq) of Niodosuccinimide îs added and then the reaction mixture is stirred at 60°C for 5 hours. The solvent is evaporated and the precipitate formed is filtered, rinscd with water and with diethyl ether and then dried under vacuum to yield 18.5 g (90%) of 2-hydroxy-5iodonicotinonitrile in the form of a beige powder.

LCMS (El, m/z): (M+1) 246.93 ’H NMR: δΗ ppm (400 MHz, DMSO): 12.79 (IH, s, OH), 8.36 (IH, d, CH_wra), 8.04 (IH, d, CHuot,).

Example lb: 2-chloro-S-iodonlcotinonitriIe

30.7 ml (329 mmol) of phosphorus oxychloride at 0°C and 6 drops of sulfuric acid are added to 9 g (6.6 mmol) of 2-hydroxy-5-iodonicotinonitri!e. The reaction mixture is heated at 110°C for 5 hours and then at room température ovemight. The reaction 5 mixture is poured in a bcaker containing ice and a little water, and a precipitate is formed. The mixture is allowed to gradually retum to room température and then is filtered and rinsed with water. The solid is dried to yield 6.8 g (70%) of 2-ch!oro-5iodonicotinonitrile.

LCMS (El, m/z): (M+1) 265.45 ’H NMR: SH ppm (400 MHz, DMSO): 9.61 (IH, d, CH™,), 9.14 (IH, d, CH^). Example 1: 5-lodo-lH-pyrazolo[3,4-b]pyrldlne-3-amlne

Hydrazine (3.86 ml, 79 mmol) is added at room température to 7 g (26.5 mmol) of a solution of 2-ch!oro-5-iodonicotinonitrile in 25 ml of propan-2-oL The reaction mixture îs heated at 85°C for 7 hours and then at room température ovemight. The suspended 15 solid is filtered, rinsed with isopropanol and then with ether and dried in an oven at 50°C to give 6 g (87%) of 5-iodo-lH-pyrazolo[3,4-b]pyridine-3-amine.

LCMS (El, m/z): (M+1) 260.95 ‘H NMR: SH ppm (400 MHz, DMSO): 12.12 (IH, bs, NH), 8.51(1H, d, CH™,), 8.45 (IH, d, CH™,), 5.64 (2H, bs, NH₂).

The following compounds were obtained according to the same method.

NH₂

Ex**	W	Rj	Compound name	Yield	Mass MH+
1-2	H	t-butyi	1 -iert-butyl-5-iodo-1 H-pyrazolo[3,4-b]pyridin3-amine	68%	317.05
1-3	Me	H	5-iodo-6-methy 1-1 H-pyrazolo [3,4-b]pyridin-3amine	93%	275.02
♦♦ Ή1	*4MR,DM	SO-de, Ex. 1-2: 8.55 (IH, bs, CH™,), 8.42 (IH, bs, CH™,), 6.33 (IH,

bs, CH„_om), 1.57 (9H, s, CH); 1-3: 11.92 (IH, s, NH), 8.55 (IH, s, CH™,), 5.59 (2H, bs, NH₂), 2.66 (3H, s, CH₃).

SL

Exampie 2: 5-bromo-lH-pyrazolo[3,4-b]pyrldîne-3-amîne

NHj

Example 2a: 2-metboxy-nlcotinonitriIe

4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room température for 10 minutes and then 10 g (72.2 mmol) of 2chloronicotinonitrile is added at 0°C. The reaction medium is stirred at 25°C for 16 hours. The reaction is hydrolyzed by slowly adding water at 0°C. After retuming to room température, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 7.85 g (81%) of 2-methoxy-nicotinonitrilc in the form of a yellow solid. LCMS (El, m/z): (M+1) 135.04 *H NMR: 5H ppm (400 MHz, DMSO): 8.46-8.48 (IH, dd, CH,_rom), 8.25-8.27 (IH, dd, CIL™), 7.17-7.20 (IH, dd, CH,™), 3.99 (3H, s, CHj).

Example 2b: 5-bromo-2-methoxy-nicotinonitrile

12.23 g (149 mmol) of sodium acetate and then 7.66 ml (149 mmol) of bromine at 0°C are added to 10 g (74.6 mmol) of a solution of 2-methoxy-nicotinonitrile in 29 ml of acetic acid. The reaction mixture is heated at 70°C ovemight. After retuming to room température, the réaction medium is added to an ice bath and the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 11.6 g (73%) of 5-bromo-2methoxy-nicotinonitrile in the form of a white solid.

LCMS (El, m/z): (M+1) 214.95 ’H NMR: δΗ ppm (400 MHz, DMSO): 8.61 (IH, d, CIL™), 8.60 (IH, d, CH™,), 3.98 (3H, s, CH₃)

Example 2: 5-bromο-1 H-pyrazolo[3,4-b]pyrIdine-3-amine ml (23.47 mmol) of hydrazine is added at room température to 5 g (23.47 mmol) of

5-bromo-2-methoxynicotinonitrile. The reaction medium is carried at 100°C for 3 hours. After retuming to room température, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 3.6 g (72%) of 5-bromo-lH-pyrazolo[3,4b]pyridine-3-amine in the form of a yellow solid.

LCMS (El, m/z): (M+1) 214.05 diagram 6. The following référencés illustrate the method used: Gueiffïcr et al.

Hcterocycles, 1999,51(7), 1661-1667; Gui-Dong Zhu et al. Bioorg. Med. Chem., 2007,

15.2441-2452.

(IVb) (Ve)

Diagram 6

The compounds of general formula (Ilia), acetylated beforehand by one or another of the methods well known to the person skilled in the art, are subjected to the action of isoamyl nitrite, sodium nitrite or any other équivalent organic or inorganic nitrite, in water or acetic acid, for periods typically varying from 1 to 3 days at températures varying between 0°C and 40°C. The compounds of general formula (IVa) thus obtained are deprotected in acidic conditions, for example by the use of hydrochlonc acid, beiorc being subjected to the action ot nitration agents suen as concentrated nitric acid or potassium nitrate in sulfuric acid at températures varying between 0°C and 25°C.

It should be noted that the direct conversion of compounds of general formula (Ilia) into deprotected compounds (TVb) is possible in general.

The nitropyrazolcs thus obtained arc typically reduced into aminopyrazolcs of general formula (Ve) by the use of SnCl₂ in hydrochloric acid. Alternative methods include the use of iron, zinc or tin in acidic conditions and methods of catalytic hydrogénation in the presence of complexes of platinum, nickel or Pd/C under an atmosphère of hydrogen or in the presence of équivalent agents such as cyclohexadiene, cyclohexene, sodium borohydride or hydrazine.

Vl L·

Method B:

According to method B, the compounds of formula (I) are obtained by the pretiminary syntnesis ot compounds ot general tormuta (VI) cnaractenzed Dy a functionalized heterobicyclic ring possessing an exocyclic amine. These compounds are obtained via the synthesis of intermediates of general formula (VI).

Method Bit

Method B1 is represented in diagram 7 below, with W notably representing H, (Ci-CejalkyL, aryl or benzyl.

[CN1

W Y< no₂ w y,no?

Diagram 7

The 3-nitro-6-thioxo-l,6-dihydropyridin-2-carbonitriIe and 3-nitro-6-thioxo-l,6dihydropyrazine-2-carbonîtrile dérivatives, optionally functionalized in position 5, are typicaliy obtained from the corresponding 2,6-dichloro-3-nitropyridincs or 2,6-dichloro-

3-nitropyrazincs by the successive réactions of a cyanidc sait, such as copper cyanidc, in a high boiling-point polar solvent such as N-methylpyrroiidone at températures ranging between 100°C and 200°C; followed by the reaction of aqueous sodium hydrosulfite in a polar solvent, these compounds are then alkylated, tor example Dy the use ot a substituted benzyl bromide, in basic medium, according to methods well known to the person skilled in the art. The preferred protocol includes the use of an aprotic and anhydrous polar solvent such as acetone carrid at its boiling point and an organic base such as pyridine, triethylamine or DIPEA, or an inorganic base such as sodium, potassium or calcium carbonate. Reactions for reducing the nitro function in amine are preferentially carried out by the use of SnCfe in hydrochloric acid. Alternative methods inciude the use of iron, zinc or tin in acidic conditions and methods of catalytic hydrogénation in the presence of complexes of platinum, nickel or Pd/C under an atmosphère of hydrogen or in the presence of équivalent agents such as cyclohexadiene, 5 cyclohexene, sodium borohydride or hydrazine.

In certain cases, the product of the réduction reaction, in addition to having a primary amine, has a carboxamide function resulting from hydrolysis of the nitrile function. In this case, isolation of the corresponding 3-aminopicolinonitriles or 3aminopyrazine-2-carbonitriles may be carried out by déhydration of the carboxamide 10 into nitrile via the use of phosphores oxychloride in the presence of DMF or any other method well known to the person skilled in the art. Lastly, formation of the aminopyrazole ring is carried out preferentially by the formation of a diazonium, obtained by the successive reaction at low température of isoamyl nitrite, sodium nitrite or any other équivalent organic or inorganic nitrite, in water, hydrochloric acid, acetic 13 aciO or suitunc acid, at températures varytng between (FU and zinc, toliowed by rts réduction into hydrazine and intramolecular cyclization activated by heating of the reaction medium. The réduction reaction is preferentially carried out with tin chloride in acidic conditions but may also be carried out by catalytic hydrogénation or any other method well known to the person skilled in the art. In an alternative to this last step, it is 20 conceivable that the intermediate diazonium undergoes a Sandmeyer reaction during which this functional group is substîtuted by a halogen atom, such as iodine, by the reaction of an adéquate sait, such as Nal. If this option is preferred, formation of the aminopyrazole ring is carried out by the use of a hydrazine, functionalized or not, in a polar solvent such as éthanol at températures varying between 25 °C and 150°C.

Method B2:

Alternatively, it is possible to take advantage of an aromatic nucleophiïic substitution reaction to fùnctionalize the pyridine or pyrazine ring in position 6. In this case the nucleophiles used are phénols, thiophenols, benzyl alcohols or thiobenzyl alcohols as well as anilines or benzylamines, functionalized or not. The general reaction 30 diagram 8a rs presented below, notably with W=H, (Ci-C6)alkyl, aryl or benzyl.

[Red]

N

W Y₄ nh₂

(VI tb)

Diagram 8a (Vld)

In the case in which X=0 or S, the 6-chIoro-3-nitropicolinonitriles and 6-chloro5 3-nitropyrazine-2-carbonitri!es, optionally substituted in position 5, are reacted in the presence of the suitable nucleophile, alcohol or thiol, in a polar solvent such as acetonitrile in the presence of an inorganic base such as potassium or sodium carbonate. Solvents such as DMSO (dîmethylsulfoxide), DMF (dimethylformamide), acetone, THF (tetrahydrofuran) or pyridine may also be considered. If necessary, these reactions may 10 bc catalyzed by the action of copper and may also bc carried out without solvent.

Typically, the preferred protocol in volves températures ranging between 20°C and 150°C.

Altematively, the use of bases such as pyridine, DIPEA, diisopropylamine, triethylamine, DBU, potassium ierr-butylate, NEtj or NaH is also possible.

In the case in which X=N, toluene is a preferred solvent and triethylamine (NEt3) the base of choice.

The following steps, up to the compounds of general formula (Vllb), are identical to those documented in method B1 above.

Method B3:

2U Method B3, presented in diagram 8b below, is a variant ot method B2 characterized by a first step resulting from a catalytic coupling reaction between a benzyl boronatc, in acid or ester form, and a 6-chloro-3-nitropicolinonitrilc or 6-chloro-

3-nitropyrazine-2-carbonitrilc dérivative. It is also well known to the person skilled in the art that catalytic coupling reactions using alternative catalysts and benzyl dérivatives are also possible. Among these, the Stille reaction, based on tin complexes, or those based on organozinc compounds may be considered.

Cl

CN

[Red]

N

U NHj 2. [Red] (Vig)

(Vile)

Diagram 8b

An optionally substituted 2-benzyl-4,4,5,5-tetramethyH,3,2-dioxaboroIane is obtained beforehand, for example from the corresponding benzyl chloride and octamethyl-bi-dioxaborolane in dioxane in the presence of potassium acetate and Pt(dppf)Cl₂ (dppf=l,l’-bis(diphenylphosphino)fcrrocene). This compound is brought together with a 6-chIoro-3-nitropico!inonitriIe, a 6-chloro-3-nitropyrazine-2-carbonitrile optionally substituted in position 5 or a 5-chloro-2-nitronicotinonitrile optionally substituted in position 6 and a palladium catalyst such as Pd(dppf)C12 or Pd(PPhi)4, an organic base such as triethylamine or an alcoholate, or an inorganic base such as sodium, potassium or césium carbonate in a solvent such as toluene, benzene, THF or dioxane. The preferred reaction températures are between 20°C and 100°C. The products of these reactions correspond to substituted 6-bcnzyl-3-nitropicolinonitrile, 6benzyl-3-nitropyrazine-2-carbonitrile or 5-benzyl-2-nitronicotinonitrile dérivatives for which the following transformation steps are reproduced from method B1 above.

Method B4:

Method B4, presented in diagram 9 below, gives access to pyrazolopyridine and pyrazolopyrazines bicycles featuring optionally functionalized aryl sulfonamide fonctions, with Rr^CrCéjalkyl and notably W=H, (C)-C6)alkyt, aryl or benzyl.

BU

Diagram 9

The ethyl 2<hloro-5-(chIorosulfbnyl)nicotinate dérivatives required for this réaction sequence may bc obtained according to the methods described by Lcvctt P.C. et a!., Org. Proc. Res. Dev., 2002,6(6), 767-772; WO 01/98284 and WO 2008/010964.

The formation of sulfonamides is typically carried out by mixing the 2-chk>ro-5(chlorosulfonyl)nicotinate of interest with a primary or secondary aniline, optionally functionalized, in an aprotic solvent such as dichloromethane, THF, acetone or acetonitrile in the presence of an organic base such as triethylamine (NEtj), pyridine or DIPEA. The use of an inorganic base such as sodium or potassium carbonate may also be considered. The optimal réaction températures are between 0°C and 70°C.

The saponification reaction of the product thus obtained, notably by the use of lithium hydroxide m a 1 Ht-/water mixture, gives access to the corresponding 2-chloro-

5-(N-phenyIsulfamoyl)nicotinic acids.

The corresponding acid chloridcs arc prepared by treatment with thionyl chloride in toluene under reflux or by any other dehydrochlorination method well known to the person skilled in the art. The reaction of these intermediates with aqueous ammonia makes it possible to form optionally functionalized 2-chloro-5-(Nphenylsulfamoyl)nîcotinamides which are then engaged in a déhydration reaction, notably by the use of POCI3, at a température ranging between 75°C and 150°C. The alternative use of agents such as P2O5 or trifluoroacetic anhydride and pyridine may also bc considcrcd.

Lastly, these dérivatives of general formula (Vlh) are reacted in the presence of a hydrazine, functionalized or not, in a polar solvent such as éthanol at températures

Sx___ varying between 25°C and 150°C to form the corresponding dérivatives of general formula (Vlld).

Method B5:

Method B5, presented in diagram 10 below, gives access to pyrazolopyridine bicycles featuring optionally functionalized benzyl ether fonctions, notably with W=H, (Ci-Cejalkyl, aryl or benzyL

NHj

Diagram 10

The method described below is inspired by the work of J. Baldwin et al., J. Heterocyclic. Chem., 1980, 17(3), 445-448. The 5-hydroxynicotinonitrile dérivatives, optionally functionalized in position 6, are alkylated, typically by the use of an optionally functionalized benzyl halide in the presence of a base. The preferred method rcquircs the use of an aprotic polar solvent such as DMF and a base such as NaH. The optimal reaction températures are between 20°C and 100°C. Altematively, the solvents which may bc used include, for example, THF, DMSO, dioxane, acetonitrile, dichloromethane or acétone and bases such as ‘BuOK, DIPEA, pyridine, triethylaminc, DBU or sodium, potassium or césium carbonate.

Oxidation of the pyridine ring into pyridine-N-oxîde is typically carried out by use of m-CPBA in dichloromethane at room température. Nevertheless, many alternative methods are conceivable, notably those based on the use of sodium percarbonate in the presence of a rhénium catalyst, sodium perborate in the presence of acetic acid or the urea-hydrogen peroxide complex.

Treatment of these pyridine-N-oxide dérivatives with phosphorus oxychloride leads to the formation of the corresponding 2-chloronicotinonitriles (VI).

Their réaction under heat with a hydrazine, fiinctionalized or not, in a polar solvent such as isopropanol or éthanol leads to the formation of the pyrazolopyridine bicycles (Vile) sought.

Method B6:

Method B6, presented in diagram 10a below, gives access to optionally functionalized pyrazolopyridine and pyrazolopyrazine bicycles featuring with reversed sulfonamide fonctions, notably with W=H, (Cj-CeJatkyl, aryl or benzyl.

Ar Ar

O=S=0 O=S=O _Nh₂

H2N.___.Y, .CN riCUS-Ar HN..Y, .CN ΗΝ,.Υ,__(

T Y ^CIO;SAf. T X » X Γ»

W^N^CI P»se] W N^CI (Vi) (Vllf) ^Rj

Diagram 10a

Le method described below consists in forming a sulfonamide fonction from an aromatic amine and an aiytsulfonyl halide, or any other équivalent reagent, in the presence of a base, which can optionally be introduced as solvent or co-solvent. Altematively, the arylsulfonyl halide or its équivalent can be generated in situ.

Their reaction under heat with a hydrazine, functionalized or not, in a polar solvent such as isopropanol or éthanol leads to the formation the desired pyrazolopyridine and pyrazolopyrazine bicycles (Vllf).

Method C:

Method C aims at the préparation of compounds of general formula (XI) as described in diagram 1.

Method Cl:

Method Cl, presented in diagram 11 below, is intended for the préparation of pyrazofopyridines and pyrazolopyrazines fiinctionalized at position 6 with R_a=ha!ogen, mesylate, tosylate or triflate, X=O, S, NH, N-(Ci-C.)alkyl, and optionally CH₂ for (Xc) and (Xd), and R,=H or N-protecting group.

This method can also be used to carry out the synthesis of molécules comprising a diatomîc X group corresponding notably to an ArX group represcnting: -ArCH₂NH-, -Ar€H₂N(R4)-, -A1CH2O-, -ArCH₂S-, -ArCH₂CH₂-, -ArCHCH-, or-ArCC-.

PL·

Diagrim 11

The 6-hydroxy-2-(methylthio)mcotinonitriles or 5-hydroxy-3-(mcthylthio) pyrazine-2-carbonitriles are subjected to a dehydrochlorination réaction, typically in the presence of phosphores oxychloride, with or without solvent, at températures varying between 70°C and 180°C. If a solvent is used, a high boiling-point non-polar solvent such as toluene or xylene will be preferred. Altematively, it is possible to activaie the

6-hydroxy-2-(methy lthio)nicotinonitriles and 5 -hydroxy-3 -(methy lthio)pyrazine-2carbonitriles by their dérivation into sulfonic esters via the formation of the corresponding tosylates, mesylates or triflates. If this option is preferred, the use of tosyl, mcsyl or triflyl chlorides in a solvent such as toluene, dichloromethane, THF, acetonitrile, acetone or dioxane in the presence of an organic or inorganic base gives access to these dérivatives.

The 6-chloro-2(methylthio)nicotinonitrilcs and 5-chloro-3-(methylthio)pyrazine2-carbonitriles respectively obtained, or their sulfonic ester analogues if this option is preferred, are then reacted with a nucleophile such as a phénol, an aniline or a thiophenol in the context of aromatic nucleophilic substitution. In this case, the reaction is carried out in a polar solvent such as DMSO, DMF, acetone, THF or acetonitrile, in the presence of a base such as potassium rert-butylate or NaH. If necessary, these reactions may be catalyzed by the action of copper and may also be carried out without solvent. Typically, the preferred protocol involves températures ranging between 20°C and 150°C.

Vilz

Altematively, the use of organic bases such as pyridine, diisopropylamine, triethylamine or DBU, or Înorganîc bases such as sodium or potassium carbonate is also possible.

Altematively, the compounds of formula (IXb) may give rise to a catalytic coupling reaction such as a Suzuki reaction. In this case, these compounds are brought together with an optionally substituted 2-bcnzyl-4,4,5,5-tetramethyl-l,3,2dioxaborolane already described in preceding method B3, a palladium catalyst such as Pd(dppf)Cl₂ or PdfPPhj).», an organic base such as triethylamine or an alcoholate, or an inorganic base such as sodium, potassium or césium carbonate in a solvent such as toluène, benzene, THF or dioxane. The preferred reaction températures are between 20°C and 100°C.

The dérivatives obtained by one or another of these methods are then oxidized, typically by the use of m-CPBA or oxone to form the corresponding methyl sulfoxides or methyl sulfones. These compounds, sometimes obtained as mixtures, are used as-is in the aminopyrazole ring formation réaction by use of an optionally substituted hydrazine in a polar solvent such as éthanol at températures vaiying between 25°C and 150°C.

Altematively, it is possible to modify the reaction sequence, notably by reversing the synthesis steps.

Method C2:

Method C2, presented in diagram 12 below, is intended for the préparation of pyrazolopyridines and pyrazolopyridazines functionalized at position 6 with X=O, S, NH, N-(Ci-C.)alkyl, or CH₂ and Rj=H or N-protecting group.

	1.[Ox]	NH2 Ή'υ,τΛ	NH2
	2. R,NHNH2	ηΛΑ	CI^An
(XJla)		(Xllla)	(XJVa)^

NHï

(Xlb) «i

Diagram 12

30-72	Ο J HN-\J ΎΎ ° VXz Q ψ N B p> F Χ-Νχ	27-5	? HN-O ÇTirW V, F
30-13	V W* p> F v\	30-14	JL ο ΓΛ> A ηνΑΪ·<^ rAJ\A,N,J fA F >1 Xv ff Ί H Q
30-15		30-16	A «Ατθ f Uy -
30-17		30-18	ï O A hnA 7^ Α^ΟγΝ y q Q H O
30-19	A >J ηνΌ	30-20	A j ™O Γ il ηνΎ-Λ ΥΧ/ΟγΝΥ j/ / A JX Χ-Νχ
30-21	a r^o JJ HN-X__! \ li hn-\j — ΥύΑ q FTF ζ>	30-22	N P HN-Z^J0 Γ Ί1 hnAj γΝΑ Q \ί^Ν N-X H < '

30-23	_N.	HNί	£ HN-θ’ Y X	30-24	Fy	S___N. Xi	HN-*1 A N H	O Y'0 Q o
		HN-	o γ^ο				HN-
	F^. ___N.					-Ν„		T^X
30-25	YY Y t	*N	v?	30-26	YY		Yn	M
	F	h	X^N X			kx	tf	Q
		HN-	£_ηνΌ				MM—	o -Y^°
30-27		<5	30-28	°v	Ύ	0*	Q
	r	fl	Q		a		n	O V- Νχ
		HN	o J *b / HN-\_J				HN	° _Y^°
			Υ^'χ			.S.___N
30-29	YY T	Γ ,N		30-30	Y^	Γ ΊΤ	ï>	A4
	^Ssx* ‘^ϋχ α	H	<Νχ			Y Y		Q X
		HN-	?hn-Go		fAf		HN-*	o Γλ> HN-V_J
30-31	1Ί T	Tx	C)	30-32	nr	TI	XN	M
		*N H	γΝχ				'N H	O
	φ T	C HN—Λ	_Λ^ο HN^_y				HN-*	0 J V) ‘'AJ
30-33	Â.S___N__ ΓΎ T T	A	Q?	30-34		Yl	^N	O
		N H	ΥΝχ		fAx	ï F	N H	Y? X-Nx

«C

30-35	A ΗΝ-ζτΟ X—Νχ	30-36	O Λ^° Λ HN\/ HN\ / .s.n___( c i T Pn U Q X
30-37	C(	30-38	S HN-Ç^ X
30-39	A? K QX	30-40	J hnO V ^H'N p) F M.
30-41	ο /^O JJ HN-\? H η,νΑ-λ FvÇfR'0^N Q.	30-42	F -A HN*^C/0 F H KN-\j Λγύ va y w X
30-43	f .A hn-C3° 1 H H/N V-< !ί\Μγ4 FS Y la/	30-44	ο Jl hnAJ h αχζτχ,Ν Νχν ΓΑ II II Ç / LAa LA/ h o X-\
30-45	o Λ^Ο rl Jt HN-\J ? H HN -\7 ZFXx	30-46	J WÇJ ΗΝ\ / — ργγγΝΰ (S T H* f Q X

30-47	o Ji hn-xj HN-\ / — Il ίΓ^ Il l'' Ç 7 y W Nx	30-48	F jô _J HN-^J* ^iAfj N Ax N 1
30-19	F A o L IL n hn-\/ ^V-x N H l / \	30-50	o J *b HN--V wY T « N— /
30-51	° -Ζ^Ίρ <3 n ψΜ- qq	30-52	Y hn-îtO qYxvq H X-N X
30-53	J HN'^J> O P ην-\ J °ts' N YÀ f^q	30-54	P HN-O Λ¥Ό f-Q /> F X-\
30-55	[As n Jt HN-Ç^ vSCnJc )A ί /γ r% O Xi-x H Q	30-56	(Aj| J? HNÇ3O Wd X
30-57	|A| ? HN-O° Jl 1 p hn-\Jj α oWq ^An p	30-58	A * hn<tO H M.

VJ C

30-59	n	30-60	ΐΤΥίΑ ΗΝΧΧ •W Χ-Νχ
30-61	«Λτ'θ ï n	30-62	Z nN'Æj0 HiN V<
30-63	f J HN-O Q7rN A Q Y Άι p	30-64	θ _/ ° „ Λ HN-\J XX F°* XX>
30-65	o J ^'Çj HN A-=< c rY A Q XX c>	30-66	o J \> „ Jl HN-\J WXI> M h o \_N X
30-67	Ο ηνΑ Τθ X	30-68	o Jî hn-XX 9 hn-Vù a xYA Q r>
31-1	î θ Z^° A «Λτν fAa^Mn Q F'')

The présent invention also relates to the use of a compound of formula (1) such as defined above, for the manufacture of a drug, notably intended for the treatment or prévention of pain, in particular pain associated with at least one Trie protein.

The présent invention also relates to a method for the treatment or prévention of pain, in particular pain associated with at least one Trk protein comprising the administration to a person in need thereof of an effective dose of a compound of tormuia (1) sucn as detined above.

The présent invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) such as defined above, and at least one pharmaceutically acceptable excipient for use in the treatment or prévention of pain, in particular pain associated with at least one Trk protein.

The pharmaceutical compositions for use in the treatment or prévention of pain, in particular pain associated with at least one Trk protein according to the invention may be formulated notably for oral administration or for injection, wherein said compositions are intended for mammals, including humans.

The active ingrédient may be administered in unit dosage forms of administration, in mixture with standard pharmaceutical carriers, to animais or to humans. The compounds of the invention as active ingrédients may bc used in doses ranging between 0.01 mg and 1000 mg per day, given in a single dose once per day or administered in several doses throughout the day, for example twice a day in equal doses. The dose administered per day advantageously is between 5 mg and 500 mg, even more advantageously between 10 mg and 200 mg. It may be necessary to use doses outside these ranges as determined by the person skilled in the art.

The pharmaceutical compositions for use in the treatment or prévention of pain, in particular pain associated with at least one Trk protein according to the invention may further comprise at least one other active ingrédient, such as example an anticancer agent.

The présent invention also has as an object a pharmaceutical composition for use in the treatment or prévention of pain, in particular pain associated with at least one Trk protein, comprising:

(i) at least one compound of formula (I) such as defined above, and (ii) at least one other active ingrédient, such as an anticancer agent, as a com tu nation product tor simuitaneous, separate or séquentiel use.

In the context of the invention, the term “treatment” means reversing or alleviating pain.

The term “pain” according to the invention means any kind of pain and in particular nociceptive pain, inflammatory pain, neuropathie pain, idiopathic pain or psychogenic pain, preferably inflammatory or neuropathie pain. The pain according to the invention can also be a combination of two or more of this kind of pains, for example a combination between an inflammatory and a nociceptive pain.

The pain according to the invention can be from any origin. In an embodiment the pain according to the invention is due to cancer, for exemple bone cancer. In another embodiment the pain according to the invention is duc to a nerve injury, as occurs for example in neuropathie pain. In another embodiment, the pain according to the invention is due to an inflammatory state, as occurs for example in rheumatic diseases such as osteoarthritis, lower back pain, lumbar dise hemiation and nerve root compression. In another embodiement, the pain according to the invention is associated with functional disorders such as, for instance, fïbromyalgia.

According to the invention, “Trk protein” means any member of the Ttrk family, for example TrkA (in particular described in GenBank under the number ABOI9488), TrkB (in particular described in GenBank under the number AAB33109.1) and TrkC (in particular described in GenBank under the number CAA 12029.1), preferentially TrkA.

ne 1 rk protein accoramg to tne invention may De in its native torm or m a modified form. By “a modified form” is intended a mutated form of the wild-type protein. The mutation may bc a point mutation, it may also bc a dclction or an insertion of one or more amino acids in the sequence of the Trk protein. Altematively, the modified Trk protein according to the invention may be a fusion protein, for exampie obtained after a chromosomal re-arrangement. The modified Trk protein can also resuit from an alternative splicing.

By the expression “associated with at least one Trk protein” according to the invention, is intended to mean that the pain to be treated is relayed by signaling pathways going through one or more Trk proteins. In particular, the pain will be considered as associated with a Trk protein when it is an inflammatory or a neuropatic pain.The Trk signaling pathways are well known of the skilled person.

VC

The compounds according to the invention hâve the property of inhibiting or modulating the enzymatic activity of one or more Trk proteine, preferably more than one Trk protein.

By inhibiting or modulating the activity of one or more Trk protein according to 5 the invention, is intended to mean that the compound according to the invention is capable of modulating the activation of at least one Trk protein, which results in a decrease, possibly an inactivation of a Trk signal pathway, itself resulting in a decrease in the feeling of pain. The compounds according to the invention allow for example a réduction in Trk protein activity of more or about 5%, notably more or about 10%, in 10 particular more or about 50%.

The compounds of formula (I) according to the présent invention can be prepared by various methods notably summarized in diagrams la and lb below.

Method A precursors

Hal <') (t;

Rj=H or N-protecting group Rm HX OMe, S02Me

Method fi precursors

NH_?

Method f

Method D (VI)_____________________(Vil)_______

Ri = NOj. halogen, OH, OMe, SMe, S(O)Me, SO-Me, OMs, OTf or OTs Rj = H or N-protecting group

Diagram la

Method £

Method £

Method

Ί* (w

Method p R J

I Method F R2 ’

Ri = NO2, halogen, OH, OMe, SMe, S(O)Me, SO₂Me, OMs, OTT or OTs Rj = H or N-protecting group κη = Haï, ums, u 1 s or u it (Tf represents an -SO2CF3 group and Ts represents a tosyl group)

Diagram lb

Method A:

According to method A, compounds of formula (I) are obtained by the preliminary synthesis of compounds of general formula (V) characterized by a halogenated heterobicyclic ring having an exocyclîc primary amine. These compounds are obtained via the synthesis of intermediates of general formula (II) or (III).

Method Al:

Method Al, presented in diagram2 (iodized compounds) or 3 (brominated compounds) below, describes the general process giving access to compounds of general formula (V) with W defined as in the description of general formula (I), and notably H, (C]-C$)alkyl or aryl, and Rj=H or N-protecting group.

.CN .CN

NHj

W N OH

W N OH

W N a

Cia)

Diagram 2 in tne context ot diagram Z, tne optionally substituted Z-chloro-3iodonicotinonitrile (Ha) is obtained from the corresponding hydroxynicotinonitrile by the successive use of an îodination agent such as N-iodosuccinimîde (NIS), or molecular iodine with an inorganic base such as, for example, K2CO3 or NaiCOa, notably in a polar solvent such as hot DMF, followed by treatment with phosphores oxychloride, pure or diluted in a high boiling-point non-polar solvent, or any other équivalent chlorination agent well known to the person skilled in the art. Reaction températures are between -20°C and 200°C. The compound (lia) thus obtained is then transformed into optionally substituted 5-iodo-pyrazolo[3,4-b]pyridinc-3-aminc (Va) by its reaction, preferably under heat, in the presence of a hydrazine optionally carrying an N-protecting group such as trityL iert-butyl or BOC.

The brominated analogues of general formula (V) as described in diagram la may be obtained by the use of the method described in the following references: Witherington étal, Bioorg. Med. Chem. Lett., 2003,13, 1577-1580 and Lijuan Chen et al., Bioorg. Med. Chem. Lett., 2010,20,4273-4278. For reasons of convenîence, these molécules were obtained by the use of the reaction sequence presented in following diagram 3.

ci

W‘ .CN ‘OMe

Diagram 3

The optionally fonctionalized 2-methoxy-nicotinotrile is obtained, for example, by reaction of sodium methanoiate in methanol at a température between -20°C and the boiling point of the mixture. Altematively, this compound may be obtained by méthylation of2-hydroxynicotinonitrile or other methods described above. Bromination of 2-methoxy-nicotinonitrile is typically carried out with dibromine in acetic acid at a température varying between 20°C and llO°C. Formation of the pyrazole is typically carried out by reaction of an excess of hydrazine, functionalized or not, at a température varying between 20°C and 100°C in the presence of a polar solvent such as water, éthanol, tetrahydrofùran (THF) or any other solvent with comparable properties. Altematively, the use of hydrazine in a saline or hydrated form, without solvent, is also possible.

Method A2:

Method A2 relates to the synthesis of the fonctionalized pyrazolopyrazines presented in diagram 4 below with Rj=H or N-protecting group, Hal=halogen and in particular W=H, (Cj-Ce)alkyl or aryl.

w .CN

Haï W N Hal (c) (Ve) ^Rj

Diagram 4

The optionally functionalized 3-amino-6-iodopyrazine-2-carboxamides are typically obtained in two steps from the corresponding methyl 3-aminopyrazine-2carboxylates by iodination in the presence of N-iodosuccinimide or molecular iodine optionally in the presence of a cofactor such as KIOj, AgCC^CFj, AR2SO.4, AIClj, CuClî or HgO, followed by a conversion reaction of the methyl ester fonction into carboxamide, notably by the use of ammonia in a polar solvent such as water, methanol or THF at températures varying between 0°C and 100°C. The carboxamide fonction of the optionally functionalized 3-amino-6-iodopyrazine-2-carboxamide is then converted into nitrile by the use of déhydration agents such as, in particular, CCLj/PPhj, SOCh, PhSC^CI, P2O5, TsCl, COCI2, DCC/py (Ν,Ν’-dicyclohexylcaibodiimide/pyridine) or (COCI)2 used as the case may bc in the présence of an organic base such as pyridine. The preferred method involves the use of phosphorus oxychloride in dimetnyitormamide (UMt*). Deprotection ot tne dimetnyitormimidamide tunction is carried out by treatment with acid such as aqueous hydrochloric acid or any other reagent with équivalent properties. Formation of the pyrazole ring is carried out by a Sandmeyer reaction, well known to the person skilled in the art, followed by a reaction in the presence of a hydrazine, functionalized or not, under conditions as described in the methods above. Altematively, the diazonium sait, an intermediate of the Sandmeyer reaction, may be reduced by the use, for example, of tin chloride in an acid medium or any other équivalent agent, in order to form a hydrazine fonction that can undergo intramolecular cyclization under the effect of heat.

Method A3:

Method A3 aims at obtaining dérivatives of general formula (V) featuring a variable fonction in position 6 of the pyrazolopyridine bicycle, it is detailed in diagram 5 below.

RjNHNHj

W=OH. OMk. NH^ NW*. Ak. Ar. CHjAr

R)=H cr N-protectng group (Alk=(Ci-C6)alkyl, Ar=aryl, CfhAr^benzyL, H=halogen)

Diagram 5

Reaction of the cyanothioacetamide with ethyl 3-ethoxyacrilates variously substituted according to methods described notably by Litrivnor et al. in Russ. Chem.

Bull., 1999,48(1), 195-196 and Tsann-Long Su et al. in J. Med. Chem., 1988,31, 12091215 makc it possible to yield acccss, in two steps, to ethyl 5-cyano-6(methylthio)nicotinates canying a variable functionality in position 2. These synthèses 10 are typically carried out, for the first step, in an anhydrous polar solvent such as, for example, éthanol at a température ranging between ü“U and /U“C in the presence ot an organic base such as methylmorpholine, triethylamine, DIPEA (N,Ndiisopropylethylamine) or DBU (l,8-diazabicyclo[5,4,0]undcc-7-cnc). The second step of intramolecular cyclization and of alkylation is typically carried out by the heating to a 15 température ranging between 20°C and 100°C of a solution of the intermediate

P thioamidate in a polar solvent, for example éthanol in the presence of a suitable alkylating agent such as alkyl halide or dialkyl sulfate.

The 5-cyano-6-(methy!thio)nicotinic acids substituted in position 2 are typicaliy obtained by saponification of the corresponding ethyl esters according to methods well known to the person skilled in the art, notably by the use of hot lithium hydroxide. Décarboxylation of these compounds is carried out by heat treatment in a high boilingpotnt soivent suen as diphenylether at a température ranging between ntru and Z2>U^WC.

Halogénation reactions principally aim at obtaining iodinated, brominated or chlorinated dérivatives, more particularly iodinated dérivatives. The latter are typicaliy obtained by a molecular iodine treatment in the presence of a silver sait such as, for example, Ag2SO₄ in a polar solvent such as éthanol at a température ranging between 0°C and 70°C. Alternative methods, notably those based on other salts such as KIOj, AgCOîCFj, AIClj, CuCh or HgO, or other iodination agents such as Niodosuccinimide, are also considered. The conceivable bromination methods typicaliy rely on agents such as N-bromosuccinimide or dibromine according to methods well known to the person skilled in the art.

In the case in which W=OH (typicaliy resulting from the use of diethyl 2(ethoxymethylenc)malonatc'), the corresponding compounds are protected by an alkylation reaction. This réaction is notably carried out by the use of methyl iodide or bromomethane, and silver carbonate in dioxane, THF, acetonitrile or acetone, or any other équivalent agent such as dimethylsulfate. The 5-ha!o-2-(methylthio) nicotinonitriles obtained are subjected to oxidation of their thiomethoxy fonction, typicaliy by the use of m-CPBA (m-ch!oropcrbcnzoic acid), oxonc or any other équivalent agent, to lead to the formation of the corresponding sulfoxide. These compounds, which may contain variable quantifies of the corresponding sulfone, are engaged in a réaction in the presence of an optionally substituted hydrazine to form the corresponding 5-halogeno-pyrazolo[3,4-b]pyndin-3-amine carrying a variable fùnctionality in position 6.

Method A4:

Method A4 aims at obtaining dérivatives of general formula (V) from the compounds of general formula (III) via intermediate formation of compounds of formula (IV). These compounds are typicaliy obtained by the pathway presented in

- n represents 0 or l,

- Rj represents a hydrogen atom, or an OR7 or NR₂Rg group,

- Rj represents a hydrogen atom, an optionally substituted heterocycle, NO₂, OR$ or NRgRjQ,

- Rj, Ri, Ru to Rm and Rn to R» each represent, independently of each other, a hydrogen atom or a (Ci-Ce)alkyl group,

- Rj and Ri each represent, independently of each other, a hydrogen atom or a (CiCe)alkyl, optionally substituted aryl or optionally substituted benzyl group,

- R7, R», R» and R₍₀ each represent, independently of each other, a hydrogen atom or an optionally substituted (Ci-Ce)alkyl or (C3-Ci₂)cycbalkyl group or an optionally substituted heterocycle, and

- Rie represents a (Ci-C₆)alkyl group, for use in the treatment or prévention of pain.

The term “halogen” refers to fluorine, chlorine, bromine or iodine.

The term “(CrQ) alkyl” refers to saturated linear or branched hydrocarbon chains comprising 1 to 6 carbon atoms. It may be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ierï-butyl, pentyl or hexyl group.

The term “(Ci-Ceialkoxy” refers to a (Ci-Ce) alkyl chain linked to the rest of the molécule via an oxygen atom. As an example, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy groups.

The term “(Ci-Cô)thioalkoxy” refers to a (Ci-Ce) alkyl chain linked to the rest of the molécule via a sulfiir atom. As an example, mention may be made of thiomethoxy, thioethoxy, thiopropoxy, thioisopropoxy, thiobutoxy or thio-teri-butoxy groups.

The term “(Ci-C6)haloalkyl” refers to a (C|-Cé) alkyl chain such as defined above wherein one or more hydrogen atoms are replaced by a halogen atom such as defined above. It may be in particular a trifluoromethyl group.

The term “(Ci-QOhaloalkoxy” refers to a (Ci-Ce)alkoxy chain such as defined above wherein one or more hydrogen atoms are replaced by a halogen atom such as defined above. It may be in particular a trifluoromethoxy group.

BL·

The term “(Ci-Cejhalothioalkoxy” refers to a (Ci-Ce)thioalkoxy chain such as defined above wherein one or more hydrogen atoms are replaced by a halogen atom such as defined above. It may be in particular a trifluorothiomethoxy group.

The term “(Ci-CnJcycloalkyl” refers to cyclic hydrocarbon Systems comprising from 3 to 12 carbon atoms and comprising one or more rings, in particular fused rings.

As an example, mention may be made of an adamantyl or cyclohexyl group.

The term “aryl” refers to an aromatic hydrocarbon group preferably comprising from 6 to 14 carbon atoms and comprising one or more fused rings, such as, for example, a phenyl or naphthyl group. Advantageously, it is a phenyl group.

The term “heteroaryl” refers to a cyclic aromatic group comprising 5 to 7 atoms includcd in the ring or a bicyclîc aromatic group comprising 8 to 11 atoms includcd in the rings, wherein 1 to 4 of the atoms included in the rings are a heteroatom selected independently from sulfur, nitrogen and oxygen atoms, and wherein the other atoms included in the rings are carbon atoms. Examples of heteroaryl groups include fiiryt, 15 thienyl, pyridinyl, and benzothienyl groups.

The term “heterocycle” refers either to a stable monocycle containing from 4 to cyclic atoms, or to a stable bicycle containing from 8 to 11 cyclic atoms, which may be either saturated or unsaturated, wherein 1 to 4 of the cyclic atoms are a heteroatom selected independently from sulfur, nitrogen and oxygen atoms, and wherein the other 20 cyclic atoms are carbon atoms. As an example, mention may be made of furan, pyrrolc, thiophene, thiazole, isothiazole, oxadiazole, tmïdazole, oxazole, isoxazole, pyridine, piperidine, pyrazine, piperazine, tetrahydropyran, pyrimidine, quinazoline, quînoline, quinoxaline, benzofuran, bcnzothiophcnc, indolinc, indolizinc, bcnzothiazolc, benzothienyl, benzopyran, benzoxazole, benzo[l,3]dioxole, benzisoxazole, 25 benzimidazole, chromanc, chromcnc, dihydrobenzofuran, dihydrobenzothicnyl, dihydroisoxazole, isoquinoline, dihydrobenzo[l,4]dioxane, imidazo[l,2-a]pyridine, furo[2,3-c]pyridine, 2.3-dihydro-lH-indene, [l,3]dioxolo[4,5-c]pyridîne, pyrrolo[l,2cjpyrimidine, pyrrolo[l,2-a]pyrimidine, tetrahydronaphthalene, benzo[b][l,4]oxazin.

In the context of the présent invention, “optionally substituted” means that the 30 group in question is optionally substituted by one or more substituents which may be selected in particular from a halogen atom, (Ci-Ce)alkyl, (C|-Ce)haloalkyl, (CjCejhaloalkoxy, (Ci-Ce)halothioalkoxy, CN, NO₂, ORn, SR|₂, NRijRh, CO₂Ris, ίο

CONR|₆R|7, SO2R1Î, SO2NR19R20, COR21, NR22COR23, NR24SO2R25» and R26NR27R28, wherein Ru to R» are such as defined above.

In the présent invention, “pharmaceutically acceptable” refers to that which is useful in the préparation of a pharmaceutical composition that is generally safe, 5 nontoxic and neither biofogically nor otherwise undesirable and that is acceptable for vcterinary and human pharmaceutical use.

“Pharmaceutically acceptable sait or solvaté” of a compound refers to salts and solvatés which are pharmaceutically acceptable, as defined herein, and which has the desired pharmacological activity of the parent compound.

Acceptable salts for the therapeutic use of the compounds of the présent invention include the conventional nontoxic salts of the compounds of the invention such as those formed from pharmaceutically acceptable organic or inorganic acids or from pharmaceutically acceptable organic or inorganic bases. As an example, mention may be made of salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and those derived from organic acids such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fiimaric acid, malic acid, tartane acid, citric acid, ascorbic acid, maleic acid, giutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, methanesulfonte acid, stearic acid and lactic acid. As an example, mention may be made of salts derived from inorganic bases 20 such as soda, potash or calcium hydroxide and salts derived from organic bases such as lysine or arginine.

These salts may be synthesized from the compounds of the invention containing a basic or acidic part and the corresponding acids or bases according to conventional chemical methods well known to the person skilled in the art.

Acceptable solvatés for the therapeutic use of the compounds of the présent invention include conventional solvatés such as those formed during the last step of the préparation of the compounds of the invention due to the presence of solvents. As an example, mention may be made of solvatés due to the presence of water or éthanol.

In the context of the présent invention, “stereoisomer” refers to a géométrie 30 isomer or an optical isomer.

Géométrie isomers resuit from the different position of substituents on a double bond which can then hâve a Z or E configuration.

tjL n

Optical isomers resuit notably from the different position in space of substituents on a carbon atom comprising four different substituents. This carbon atom thus constitutes a chiral or asymmetrical center. Optical isomers include diastereoisomers and enantiomers. Optical isomers that are mirror images of each other but are nonsuperimposable are enantiomers. Optical isomers that are not mirror images of each other are diastereoisomers.

In the context of the présent invention, “tautomer” refers to a constitutional isomer of the compound obtained by prototropy, i.e., by migration of a hydrogen atom and a change in location of a double bond. The different tautomers of a compound are generally interconvertible and are in equilibrium in solution in proportions which may vary according to the solvent used, the température or the pH.

According to a first embodiment, Y₄=N.

Advantageously, Yi=C-X-Ar and Yj preferably represents a C-W group.

In particular:

- Yj=CH or N, and advantageously CH,

- Yï=C-X-Ar,

- Y₃=C-W, and

- y₄=n.

According to a second embodiment, Yj and/or Y₄ represent a nitrogen atom.

In this case, Y₂ and Yj preferably do not represent a nitrogen atom.

In particular:

- Yi and/or Y₄ = N,

- Yj=CH or C-X-Ar, and

- Y₃=C-W or C-X-Ar.

In particular:

- Yi represents a CH group,

- Y₄ represents a nitrogen atom,

- Yj represents a CH or a C-X-Ar group, and

- Y₃ represents a C-X-Ar or a C-W group, on the condition that:

• when Yi=C-X-Ar, then Yj represents a C-W group, and • when Y₂=CH, then Y₂ represents a C-X-Ar group.

Advantageously, X represents a divalent group selected from O, S, S(O), S(O)₂,

NR4, CH₂, CH₂S, CH₂S(O), CH₂S(O)₂, NHS(O)₂, SCH₂, S(O)CH₂, S(O)zCH₂,

S(O)₂NH, CH₂CH₂, CH=CH, OC, CH₂O, OCH₂, NR4CH₂, and CH₂NR4.

In particular, X represents a divalent group selected from S, S(O), S(O)2, NR», CH₂, CH₂S, CH₂S(O), CH₂S(O)_2i NHS(O)₂, SCH₂, S(O)CH₂, S(O)₂CH₂, S(O)₂NH, CH₂CH₂, C=C, CH₂O, OCH₂, NR₄CH₂, and CH₂NR|.

More particularly, X may be selected from S, S(O), S(O)2, CH₂, CH₂S, CH₂S(O), CH₂S(O)₂, NHS(O)2, SCH₂, S(O)CH₂, S(O>2CH₂, S(O)₂NH, ch₂ch₂, CH=CH, and C=C.

In particular, X may bc selected from S, S(O)₂, CH₂, SCH₂, S(O)2CH₂, S(O)₂NH, CH₂S, CH₂S(O)₂, NHS(O)₂, CH₂CH₂, and OC.

X may notably be selected from S, S(O), S(O)2, NR», CH₂, SCH₂, S(O)CH₂, S(O)₂CH₂, SÎOJiNH, CH₂CH₂, OC, OCHi, and NR|CH₂; notably from S, S(O)₂, CH₂, SCH₂, S(O)₂CH₂, S(O)₂NH, CH₂CH₂, and OC, wherein the first atom of these groups is bound to atom C of the Ç-X-Ar chain.

X may be in particular S, S(O)₂, SCH₂, S(O)2CH₂, S(O)₂NH, CH₂S, CH₂S(O)₂, or NHS(O)2_; and notably S, S(O)2, SCH₂, S(OhCH₂, or S(O)₂NH, wherein the first atom of these groups is bound to atom C of the Ç-X-Ar chain.

Advantageously, Ar represents a heteroaryl group, such as pyridine, or an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Cj-QOalkyl, (Ci-Cô)haloalkyl, (C]-C₆)haloalkoxy, (CjCe)halothioalkoxy, CN, NO₂, ORn, SR]₂, NRijRh, CO₂Ris, CONRieRn, SO₂R|8» SO₂NR|gR₂₀, COR₂), NR₂₂COR₂3, and NR₂₄SO₂R₂s; and/or optionally fused to a heterocycle.

More particularly, Ar may represent an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Ci-Ce)alkyl, (CjCeihaloalkyl, (Ci-Cejhaloalkoxy, (Ci-Cejhalothioalkoxy, CN, NO₂, ORn, SRj₂, NRjjRu, CO₂Rh, CONRifiRp, SO₂Rig, S0₂NR]gR₂o, COR₂i, NR₂₂COR₂₃, and NR₂₄SO₂R25.

Ar may notably represent an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Cj-C^alkyl, (Ci-Ci)haloalkyl, (5C and CONRteRp, and in particular from a halogen atom such as fluorine, (Ci-Gs)a!ky1 such as methyl, and CONRieRn such as CONH₂.

Ar can also represent a pyridine group.

Ar may notably be selected from the following groups:

J » » » »

notably from the following groups:

I > * « t t

in particular, from the fo llowing groups:

Ar may advantageously represent the group:

W may advantagcously represent an Rs, SRs, OR5 or NRsR« group, and preferably R5, OR5 or NRjRî, with R5 and R« representing, independently of each other, a hydrogen atom or a (C]-Ce)alkyl group.

W may represent in particular H, OMe, Me, OH or NH₂, and notably H.

Advantageously, Rj represents a hydrogen atom.

U may represent more particularly a CH₂ or NH group.

Advantagcously, n may represent 0.

V may represent more particularly a C(O) or C(S) group, and advantageously a C(O) group.

According to a particular embodiment ofthe invention:

- Rj=H,

- U=CH₂orNH,

- V=C(O) or C(S), and notably C(O), and

- n=0 or 1, and notably 0.

According to another particular embodiment of the invention:

- V=C(O) or C(S), and notably C(O), and

- n=0.

According to still another particular embodiment of the invention:

- R3=H,

- V=C(O) or C(S), and notably C(O), and

- n=0.

Ri may represent more particularly a hydrogen atom or an NR7R8 group, with R7 notably representing a hydrogen atom and R« notably representing an optionally substituted (C3-Ci₂)cycloalkyl group or an optionally substituted heterocyclc.

The (C3-Ci₂)cycloalkyl group may be in particular a cyclohexyl. It may be substituted by one or more halogen atoms. It may be in particular the group:

The heterocyclic group may be in particular a tetrahydropyran, notably unsubstituted. It may thus be the following group:

Ri may thus represent more particularly one ofthe following groups:

Ri may represent more particularly an optionally substituted heterocycle (notably substituted by (Ci-Cô)alkyl or NH₂), NO₂ or NR9R10, with notably R9=Rjo=H or elsc R9 and Rio each represent H or an optionally substituted (Ci-GOalkyL

Rz may represent in particular an optionally substituted heterocycle, notably substituted by (Ci-C6)alkyl or NH₂. The heterocycle may be in particular a heterocycle with 5 or 6 members comprising at least one nitrogen atom, and in particular one or two. The heterocycle may thus bc sclcctcd from pipcrazinc, pipcridinc and pynolidinc.

Rï may notably represent one of the following groups:

NH₂, NH(CH₂)iNMe2, NMe(CH₂)jNMe₂, NO₂,

“K”^- '----f , and ; and notably NH₂, NO₂,

particular

; and more particularly

The compounds of the présent invention may be selected from the compounds cited in the following table:

14-2	o Γ'ο * HN-\7 HNy-i T N h (X X-N X	14-10	o / vo „ Λ HN-\J C* HN-XJ T «H α <4 X
14-11	O -O F s T”*N 1 N<V F \-N X	15	F Δ ? ™-C° HN-XgJ % V {->
26-4	FYVsYçr^-O'N02 F	26-8
27	ΗΝ-ζϊ'θ f	27-1	ΑνΛ5° N H X-N X
28	F <Νχ	29	V V? F
29-a	m-t FS-X-j1 VSïXH F	30	y 'q

30-1	P HN-Cj° ΝΛ ^χ—n X	30-3	W ° hh-c° °-sn>u N B V-N X
30-1	T V-[jN 'P) F kJx	30-5	Pm-O ΎΥΤΊΑ F
30-0	.UrO N « ^<ΝΛ	30-9	τ kAN F <-Ns
30-10	F ΗΝΑΤθ1 Yï4-U H O ^NX	30-11	Ο /*% Λ HN-\7 HN-\J \
30-12	F iÀ y A ηνΗλ X-N x	30-«	o ° F S ΗΝΎ\, H ΝΛ F k/’NH;,
31	F J^jL j? HN-Z^J° F [ HN-XJ \XN	32	Λ% HN HN-\> ρΊΓΎδΥ?ΊΑ ζχ Y SA» F V^'N\

Fc

32-1	F	33	·Λθ* VOÎ- F
35	J* HN~C° f s HN — hct' rr N n -x F	26-12	O nN-^s* f'tTTs'AT4h ζ-Λ y (*-> F Χ-Νχ
30-69	0 Jt HN-\j HN-\ J FYYsTTS Q F r	27-2	ο I «rO ° xÀ il \ Il ίΓιι c / Ύ NH r> F
27-3	ΗΝ-ζΤθ σΥ V*n \=< N [( \	27-4	F HrÎT^ jrS α5Γμ. X-N^
30-73	JyO FyyF	14bb	?».ο H HNV( FyyRγγ£Ν Ψ >όΓ F X\
30-70	J HN-O hn AJ XKhjÇx> Q V-N X	30-71	»° HN-Q F,VPVF #7 ^r-nf '-C v\

« %

Example 10:3-amino-N-(3^-difluorophenyl)-l H-pyrazolo[3,4-b|pyridîne-5sulfonamide

Exampie 10a: 5-(N-(3,5-difluorophenyl)suIfainoyl)nicotinic acid

2.74 g (9.64 mmol) of ethyl 2-chloro-5-(chlorosulfonyl)nicotinate in solution in 20 ml of anhydrous dichloromethane is added, drop by drop at 0°C, to a mixture of 623 mg (4.82 mmol) of3,5-difluoroanitine and 1.68 ml (12.05 mmol) of triethylamine diluted in 10 ml of anhydrous dichloromethane. The solution is stirred at room température for 3 hours. The solvent is evaporated to yield a light brown solid. The solid is triturated in 20 ml of methanol, filtered and then rinsed with 3 ml of methanol to yield 2.85 g of a white solid.

This solid is redissolved in 25 ml of tetrahydrofuran and is added together with a solution of 0.421 g (10.04 mmol) of lithium monohydrate hydroxide in 10 ml of water. The réaction mixture is left under stirring for 3 hours at 35°C and then diluted in water, acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is collected, dried on sodium sulfate, filtered and concentrated to yield 1.12 g of 5-(N(3,5-difluorophenyl)sulfamoyI)nicotinic acid in the form of an orange solid (yietd-67%).

’H NMR: 5H ppm (400 MHz, DMSO): 8.91 (IH, s, CH^_ra), 8.51 (IH, s, CfUJ, 7.02 (IH, dd, CfW), 6.83 (2H, d, CH._rom).

Exampie 10b: 2-chloro-5-(N-(3,5-difluorophenyl)suIfamoyl)nicotinamide

0.288 ml (3.87 mmol) of thionyl chloride and a drop of DMF arc added successively to 0.450 g (1.29 mmol) of 2-chloro-5-(N-(3^-difluorophenyl)sulfamoyl)nicotinic acid in 5 ml of anhydrous toluene. The mixture is placed under stirring, at reflux of toluene, for 2 hours. The acid chloride reaction mixture is then added drop by drop to an iced solution, under stirring, of 4.5 ml of 25% ammonium hydroxide. A release of gas is observed. The reaction medium is left under stirring at room température for 30 minutes. The reaction medium is extracted several times with ethyl acetate. The combined organic phases are dried on anhydrous sodium sulfate and then concentrated.

0.315 g of 2-chloro-5-(N-(3,5-difluorophcnyl)sulfamoy])nicotinamide in the form of a light brown solid is obtained (yield=72%).

’H NMR: ÔH ppm (400 MHz, DMSO): 11.18 (IH, bs, NH), 8.86 (IH, s, CH_mra), 8.22 (IH, s, CH.™), 8.21 (IH, bs, NH), 7.98 (IH, bs, NH), 6.96 (IH, dd, CHaæm), 6.79 (2H, d, CHanxn).

Example 10c: 6-chloro-5-cyano-N-(3,5-dinuorophenyl)pyridine-3-sulfonamide

3.4 ml (36.2 mmol) of phosphoryl chloride and a drop of concentrated sulfuric acid are added to 0.315 g (0.906 mmol) of 2-chloro-5-(N-(3,5-difluorophenyl) sulfamoyl)nicotinamidc. The reaction mixture is stirred for 2 hours at 90°C and then added drop by drop to ice. The brown solid is filtered, rinscd with water and then dried under vacuum. 0.217 g of 6-chloro-5-cyano-N-(3,5-difluorophenyl)pyridine-3sulfonamide is obtained in the form of a light brown solid (yield=72%).

’H NMR: 6H ppm (400 MHz, DMSO): 11.34 (IH, bs, NH), 9.04 (IH, s, CH^), 8.92 (IH, s, CHU 7.03 (IH, dd, CH.™), 6.85 (2H, d, CH.™).

Example 10:3-amlno-N-(3,5-difluorophenyl)-l H-pyrazolo[3,4-b]pyridine-5sulfonamide

0.377 ml (2.63 mmol) of 35% hydrazine is added to 0.217 g (0.658 mmol) of 6-ch!oro5-cyano-N-(3,5-difluorophenyl)pyridine-3-sulfonamide diluted in 6 ml of isopropanoL The solution is heated at 75°C for 2 hours. The solvent is evaporated to yield 0.214 g of 3-amino-N-(3,5-difluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5-sulfonamide in the form of a yellow solid (yield=100%).

’H NMR: δΗ ppm (400 MHz, DMSO): 8.74 (IH, d, CH.™), 8.68 (IH, d, CH.™), 6.88 (IH, dd, CH.™), 6.80 (2H, d, CH.™), 6.04 (2H, bs, NH).

Examples of method B5

Example 11:5-(3,5-difluorobenzyloxy)-lH-pyrazoloI3,4-b]pyridin-3-amine

F

This compound can bc prepared from the following intermediates, according to method

B5.

Exampie lia: 5-hydroxynicotinonitrile

A mixture of lg of 5-methoxynicotinonitrilc (7.46 mmol) and 8.62 g of pyridine hydrochloride is heated at 200°C for 2 hours. The crude reaction product is diluted in a water fraction several times with diethyl ether. The aqueous phase is basified by adding sodium bicarbonate and then extracted again with diethyl ether. The organic phase is dried and then concentrated to yield 850 mg of 5-hydroxynicotinonitrile (95%) in the form of a beige solid.

LCMS: m/z 120.94 (M+H⁴).

*H NMR: SH ppm (400 MHz, DMSO): 10.79 (s, IH), 8.46 (s, IH, CHarom.), 8.42 (s,

IH, CHarom.), 7.60 (s, IH, CHarom.).

Example 11b: 5-(3^-difluorobenzyloxy)nicotlnon1trile

876 mg (2 eq) of sodium hydride is added gradually at 0°C under nitrogen to a solution 15 of 865 mg of 5-hydroxynicotinonitrile (7.2 mmol) in 15 mL of dimethylacetamide. The mixture is stirred 10 min at 0°C before adding 2.24 g (1.5 aq) of 3,5-difluorobenzyl bromide. The mixture is placed under stirring for 25 additional hours before being diluted in an ethyl acetate fraction and being washed with aqueous fractions. The organic phases are isolated, dried and concentrated. The solid residue obtained is 20 recrystallized in methanol to yield 1.1 g (68 % of 5-(3,5-difluorobenzyloxy) nicotinonitrile in the form of a beige powder.

LCMS: m/z 247.11 (M+H⁴).

'H NMR: SH ppm (400 MHz, DMSO): 8.69 (s, IH, CH), 8.65 (s, IH, CH), 8.08 (s, IH, CH), 7.26 (m, 3H, CH), 5.28 (d, 2H, CH₂).

Exampie 11c: 3-cyano-5-(3,5-dinuorobenzyloxy)pyridine 1-oxlde

224 mg of m-CPBA is added at 0°c to a solution in acetonitrile of 250 mg of 5-(3,5difluorobcnzyloxy)nicotinonitrilc. The réaction medium is stirred for 20 hours while a precipitate is formed progressivelt. this solid is then filtered and washed to yield 200 mg (75%) of 3-cyano-5-(3,5-difluorobenzyloxy)pyridine 1-oxide in the form of a white 30 powder.

LCMS: m/z 263.06 (M+H⁴).

Exampie lld: 2-chloro-5-(3,5-dinuorobeiizyloxy)nicotinonîtrile

A mixture of 650 mg of 3-cyano-5-(3,5-difluorobenzyloxy)pyridine l-oxide in 2.3 mL of POCb added with few drops of H2SO4 is heated at llO°C for lh30. The crude reaction medium is then poured in ice and the precipitate thus formed is isolated filtration and dried under vacuum to yield 600 mg of a beige solid in the form of a mixture of regioisomers comprising mainly the desired 2-chloro-5-(3,5difluorobenzyloxy)nicotinonitrile which is used without further purification.

LCMS: m/z 281.02 (M+H⁴).

Example 11; 5-(3,5-diflaorobenzyloxy)-l H-pyrazoIo[3,4-b]pyridin-3-amtne

313 mg of hydrazine hydrate (5 eq) is added to a solution of 1.6 g of 2-chloro-5-(3,5difluorobenzyloxy)nicotinonitrile (450 μπτοί) in 10 mL of propan-2-oL The reaction mixture is heated at 100°C for 6 hours. After rctum to room température lcading to a précipitation, the crude reaction medium is filtered, the solid is removed and the filtrate is dry evaporated. It is then purified by chromatography on a silica column eluted with a gradient of ethyl acetate and methanol, whcrcas the more polar fraction is isolated, concentrated and suspended again in a small fraction of methanol under stirring. The solid thus obtained is isolated and dried to yield 221 mg of 5-(3,5-difluorobenzy!oxy)lH-pyrazolo[3,4-b]pyridin-3-amine in the form of a beige solid wich is used without further purification.

LCMS: m/z 277.07 (M+H⁴).

Example of method B6

Example 11 bis: N-(3-amlno-lH-pyrazolol3,4-b]pyridin-5-yl)-3^-difluorobenzenesulfonamide

F

Example_____llbîs-a: N-(6-chIoro-5-cyanopyridln-3-yl)-3,5-difluorobenzenesulfonamlde

1.132 g (5.32 mmol) of 3,5-difluorobenzene-l-sulfonyle chloride is added under argon to a solution of 545 mg (3.55 mmol) of 5-amino-2-chloronicotinotrile in 20 mL of an anhydrous 1:1 mixture ofTHF and pyridine. The reaction medium is heated to 70°C for 3 hours and let 12 additional hours under stirring at room température. The solvent is dry evaporated and the crude reaction product is redissol ved in ethyl acetate and washed with several aqueous fractions. The organic phase is dried on magnésium sulfate, filtered, concentrated and then purified by silica gel chromatography to yield 784 mg (67%)ofN-(6-chloiO-5-cyanopyridin-3-yI)-3,5-difluorobenzene-sulfonamide.

‘H NMR: 5H ppm (400 MHz, DMSO): 1139 (IH, si NH), 8.34 (IH, m, CHarom), 8.10 (IH, m, CHarom), 7.67 (IH, m, CHarom), 7.59 (2H, m, CHarom).

Example 11 bis: N-(3-amino-lH-pyrazoIol3,4-bIpyridin-5-yl)-3,5-diniiorobenzenesulfonamide

1.786 g (35.7 mmol) of hydrazine hydrate is added under argon to a solution of784 mg (2.38 mmol) of N-(6-chloro-5-cyanopyridin-3-yl)-3,5-difluorobenzene-sulfonamide in 6 mL of éthanol The solution is heated to 100°C for 20 hours and then cooled to room température. The solvent is evaporated to yield 810 mg ofN-(3-amino-lH-pyrazolo[3,4b]pyridin-5-yl)-3,5-difluorobenzcne-sulfonamide (100%) which is used without further purification in the following steps.

LCMS: m/z 326.07 (M+H*).

Example of method Cl

Example 12: N6-(2,4-diflnorophenyI)-l II-pyrazolo[3,4-b]pyridine-3,6-diamine

This compound can bc prepared from the following intermediates, according to method Cl.

Example 12-a: 5-cyano-6-(methylthlo)pyridin-2-yl trlfluoromethanesulfonate

15.26 mL (1.2 eq) of potassium 2-methylpropan-2-olate and then 9.03 g (1.2 eq) of

1,1,1 -trifluoro-jV-phcnyl-A^r-(trifluoromcthylsulfony!)methancsulfonamidc are added dropwise to a solution of 3.5 g (21.06 mmol) of 6-hydroxy-2-(methylthio)nicotinonitrile in 180 mL of tetrahydrofùrane under nitrogen. The reaction mixture is stirred at room température for 2h45. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on anhydrous magnésium sulfate, filtered and evaporated to yield an orange solid. The product is purified on a silica gel column (eluent: cyclohexane/dichloromethane 5:5) to yield 5.31 g (85%) of 5-cyano-6(methylthio)pyridin-2-yl trifluoromethanesulfonate in the form of a yellow solid.

’H NMR: δΗ ppm (400 MHz, DMSO): 8.57 (IH, d, CH), 7.52 (IH, d, CH), 2.59 (3H, s, CH₃).

Exampie 12-b: 6-(2,4-difluorophenylamino)-2-(methylthlo)nlcotinonîtriIe

0.81 mL (1.2 eq) of ,4-difluoroaniline and 1.53 g (1.4 eq) of cesium(I) carbonate are added under nitrogen to a solution of 2 g (6.71 mmol) of 5-cyano-6(mcthylthio)pyridin-2-yl trifluoromethanesulfonate in 30 mL of 1,4-dioxane. The medium is degased for 5 minutes under argon before adding 0.25 g (0.06 eq) of de 2,2*bis(diphenylphosphino)-l,r-binaphthyl and 0.08 g (0.04 eq) of (1E,4E)-1,5diphenylpenta-l,4-dien-3-one, palladium(ll) complex. Thereaction medium is stirred at 100°C for 2 hours. After retum to room température, ethyl acetate and brine are added. The organic phase is dried on anhydrous magnésium sulfate, fitered and evaporated. The residue obtained is purified on silica gel chromatography (eluent: cyclohexane/ethyl acetate 8:2 then 7:3) to yield 1.52 g (82%) of 6-(2,4-difluorophenylamino)-2(methylthio)nicotinonitri!e in the form of a white solid.

LCMS (IE, m/z): (M+l) 278.06.

’H NMR: 6H ppm (400 MHz, DMSO): 9.57 (IH, s, NH), 7.73-7.86 (2H, m, CH), 7.287.44 (IH, m, CH), 7.02-7.18 (IH, m, CH), 6.60 (IH, d, CH), 2.41 (3H, s, CH₃).

Example 12: N6-(2,4-dMluorophenyl)-lH-pyrazolo[3,4-b]pyridine-3,6-dlamlne

769 mg (3.12 mmol) of m-chloroperbenzoic acid (mCPBA) is added under argon to a stiring solution of 786 mg (2.83 mmol) of 6-(2,4-difluorophenyIamino)-2(methylthio)nicotinonitrile in 25 mL of dichloromethane. The reaction medium is stirred 1 hour at room température before adding a fraction of ethyl acetate and washed this organic phase with a NaHCOj saturated solution. The combined organic phases are dried on magnésium sulfate and dry evaporated. The crude réaction product is dissolved again in 10 mL of propanol and 2 équivalents of hydrazine hydrochloride in water are added. The mixture is heated at 90°C for 6 hours before being diluted in water and extracted with ethyl acetate. The organic phase is dried on magnésium sulfate and dry evaporated before being purified by silica gel chromatography to yield 495 mg of N617324 (2,4-difluorophenyl)-lH-pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yelloworange solid (67%).

LCMS (IE, m/z): (M+1) 262.14.

^lH NMR: δΗ ppm (400 MHz, DMSO): 11.40 (IH, s, NH), 8.76 (IH, s, NH), 8.15 (IH, m, CH), 7.81 (IH, d, CH), 7.28 (IH, m, CH), 7.06 (IH, m, CH), 6.55 (IH, d, CH), 5.24 (2H, s, NH₂).

The following compound is obtained by a similar method:

NH₂

Λ⁴» ArX^N^fj

Ex.**	ArX	Y.	Compound names	Yield	Masse MH*
12-1	F	CH	N6-(3,5-dif!uoro benzyl)-1 H- pyrazo1o[3,4-b]pyridine-3,6-diamine	70%	276,15
**'HN	MR, dmso-de,	Ex.:	2-1:11.17 (IH, s, NH), 7.66 (IH, d, CH), 7.37 (IH, s, NH),

7.04 (3H, m, CH), 6.24 (I H, d, CH), 5.11 (2H, s, NH₂), 4.52 (2H, s, CH₂).

Example 12bis: N6-(2,4-difluorophenyI>-N6-methyl-lH-pyrazolo[3,4-bIpyridÎne-

3,6-diamine

Example 12bis-a: 6-((3^-difIuorophenylXmethyl)amIno)-2-(methylthio) nicotinonitrile

3.05 mL (5.04 mmol) of potassium 2-methyl propan-2-o la te and then 286 pL (1.8 eq) of iodomethane are added dropwîse under nitrogen to a solution of700 mg (2.52 mmol) of

6-(2,4-difIuorophenylamino)-2-(methylthio)nicotinonitrile in 20 mL of N,N-dimethyl formamide. The reaction medium is stirred at room température for 24 hours and then 126 pL (0.8 eq, 2.02 mmol) of iodomethane is added. The reaction medium is stirred at room température for 2 additional hours. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on anhydrous magnésium sulfate, fîltered, fi L and evaporated to yield 660 mg (90%) of 6-((2,4-difluorophenyl)(methyl)amino)-2(methylthio)nicotinonitrile in the form of a brown solid.

LCMS (IE, m/z): (M+1) 292.09.

’H NMR: δΗ ppm (400 MHz, DMSO): 7.74-7.80 (IH, m, CH), 7.55-7.63 (IH, m, CH), 5 7.43-7.52 (IH, m, CH), 7.18-7.27 (IH, m, CH), 6.16-6.30 (IH, m, CH), 3.43 (3H, s,

CH₃), 2.42 (3H, s, CHj).

Example 12bis: N6-(2,4-difluorophenyI)-N6-methyHII-pyrazo!o|3,4-b]pyridine-

3,6-diamlne

452 mg (1.84 mmol) of mCPBA is added under argon to a stirring solution of486 mg 10 (1.67 mmol) of 6-((2,4-difluorophenylXmethyl)amino)-2-(mcthylthio)nicotmonitrilc in mL of dichloromethane. The reaction medium is stirred 30 min at room température before adding an ethyl acetate fraction. The organic phase is washed with a NaHCOj saturated solution, dried on magnésium sulfate and dry evaporated. The crude reaction product is dissolved again in 6 mL of propanol and 164 pL (3.38 mmol) of hydrazine 15 hydrochloride in water is added. The mixture is heated at 90°C for 6 hours before being diluted in water and extracted with ethyl acetate. the organic phase is dried on magnésium sulfate and dry evaporated before being purified by silica gel chromatography to yield 328 mg of N6-(2,4-difluorophenyl)-N6-methyl-lHpyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yellow-orange solid (70%).

LCMS (IE, m/z): (M+1) 276.15.

’H NMR: δΗ ppm (400 MHz, DMSO): 11.41 (IH, s,NH), 7.75 (IH, d, CH), 7.51-7.55 (IH, m, CH), 7.40-7.43 (IH, m, CH), 7.17-7.22 (IH, m, CH), 6.03 (IH, d, CH), 5.23 (2H, s, NH₂), 3.28 (3H, s, CH₃).

Example of method C3

Example 12ter: 6-(2,4-difluorophenylthio)-lH-pyrazoIo[3,4-b|pyridin-3-amine nh₂

Example 12ter-a: 2-chloro-6-(2,4-difluoropbenyIthio)nicotinonitrile

A solution of 362 mg (1.05 eq) of potassium hydroxide in 10 mL of éthanol is added, under nitrogen, to a solution of 698 pL (6.16 mmol) of 2,4-difluorobenzenethiol in 30 mL of éthanol. The reaction medium is stirred at room température for 15 minutes and then cooled in ice before adding a solution of 1.015 g (0.95 eq) of 2,6dichloronicotinonitrile in 30 mL of ethanoL The reaction medium is stirred for 2 hours at 0-5°C. 63 mL of a 0.1N HCl solution is added to stop the reaction. Water is added and the producted is extracted with ethyl acetate. The organic phase is dried on anhydrous magnésium sulfate, fïltered and evaporated. The residue is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 94:6) to yield 1.09 g (66%) of 2chloro-6-(2,4-difluorophcnylthio)-nicotinonitrilc in the form of a white solid.

LCMS (1E. m/z): (M+l) 282.98.

’H NMR: SH ppm (400 MHz, DMSO): 8.24 (IH, d, CH), 7.77-7.85 (IH, m, CH), 7.52-

7.63 (IH, m, CH), 7.25-7.35 (2H, m, CH), 2.41 (3H, s, CH₃).

Example 12ter: 6-(2,4-dinaorophenylthio>-lH-pyrazolo[3,4-b]pyridin-3-amlne

0.561 mL (11.57 mmol) of hydrazine monohydrate is added under nitrogen to a stirring solution of 1.09 g (3.86 mmol) of 2-chloro-6-(2,4-difluoropheny!thio)nicotinonitrile in 15 mL of propanoL The reaction medium is heated at 80°C for 4 hours. A precipitate is obtained when the reaction medium is retumed to room température. This precipitate is fïltered and rinced with éthanol. The solid is dissolved in an ethyl acetate fraction and washed with a IN HCI solution. The organic phase is dried on magnésium sulfate and dry evaporated to yield 420 mg (39%) of 6-(2,4-difluorophenylthio)-lH-pyrazolo[3,4b]pyridin-3-amine in the form of a yellow solid.

’H NMR: δΗ ppm (400 MHz, DMSO): 12.10 (IH, s, NH), 8.11 (IH, d, CH), 7.827.89(1H, m, CH), 7.58-7.63 (IH, m, CH), 7.32-7.36 (IH, m, CH), 6.86 (IH, d, CH),

4.59 (2H, s, NH₂).

The following compound is obtained by a similar method:

NH₂

Ex.**	ArX	Yi	Ri	Compound names	Yield	Mass MH*
12ter-l	F	CH	H	6-(2,4-difluorophcnoxy)-1Hpyrazolo[3,4-b]pyridin-3-aminc	ND	263,06

Example 12ouaten 6-(3,5-dinuorobenzyI)-lH-pyrazoIo[3,4-b]pyridin-3-amine

17.35 mL of a 0.5M solution in THF of (3,5-difluorobcnzyl)zinc chloride (8.58 mmol) is added under argon to a solution of 416 mg of palladium(ll) chloride (510 mmol) and 883 mg of 2,6-dichloronicotinonitrile (5.1 mmol) in 2 mL of anhydrous THF. The reaction is refluxed for 7 hours, then cooied to room température. A IN soda aqueous solution is added and the product is extracted with several successive ethyl acetate fractions. The organic phases are dried on magnésium sulfate and dry evaporated before being purified by silica gel chromatography to yield 680 mg of a mixture of 2-ch!oro-6(3,5-dÎfluorobcnzyJ)-nicotinonitrile and by-products wich is used without further purification in the following step.

The previous mixture is dissolved in 10 mL of isopropanol under stirring and 750 pL of 35% hydrazine hydrate is added. The solution is heated at 80°C for 4 hours. The solvent is dry evaporated and the product is purified by silica gel chromatography (dichloromcthane/methanol 9:1) to yield 290 mg of 6-(3,5-difluorobenzyl)-lHpyrazolo[3,4-b]pyridin-3-aminc (64%).

LCMS CE, m/z): (M+1) 261.16.

‘H NMR: 6H ppm (400 MHz, DMSO): 11.82 (IH, s, NH), 8.01 (IH, d, CH), 6.99-7.04 (3H, m, CH), 6.91 (IH, d, CH), 5.49 (2H, s, NH₂), 4.12 (2H, s, CH₂).

Example of method Dl:

Exampie 13:5-f3^-dîfluorobenzyI)-l H-pyrazolo[3,4-b]pyridine-3-amine nh₂

F

0.575 g (0.704 mmol) of (dppfhPdCh-CHiCh and 28 ml (14.08 mmol) of 3,5difluorobenzyl zinc 01) chloride are added to 1.5 g (7.04 mmol) of a solution of 55 bromo-lH-pyrazolo[3,4-b]pyridin-3-amine in 10 ml of tetrahydrofuran. The reaction medium is heated at 90°C for 18 hours. After rctuming to room température, the réaction is hydrolyzed by slowly adding water at 0°C. After filtration of the precipitate formed, the solid is rinsed with tetrahydrofûran and the aqueous filtrate is extracted several times with ethyl acetate. The organic phases are combined, dried on magnésium 10 sulfate and concentrated. The residue is purified by silica chromatography (95:4.5:0.5 and then 95:4:1 dichloromethane/methanol/ammonium as eluent) to yield 1.7 g (93%) of 5-(3,5-difluorobcnzyl)-lH-pyrazolo[3,4-b]pyridine-3-amine in the form of a beige solid.

LCMS (El, m/z): (M+1) 261.41.

‘H NMR: 5H ppm (400 MHz, DMSO): 11.87 (IH, s, NH), 8.31 (IH, d, CIL™,), 7.92 (IH, d, CH_arora), 6.98-7.08 (3H, m, CH_wm), 5.47 (2H, s, NH), 4.04 (2H, s, CIL).

The following compounds arc obtained by a similar method:

NH2

Ex.**	ArX		W	Ri	Compound names	Yield	Mass Μ1Γ
13-1	A	CH	H	H	5-(3,5-difluorobcnzy 1)-1H pyrazolo[4 3-b]pyridin-3-aminc	8% 4 steps	261.1
13-2	A	N	H	H	5-(3,5-difluorobcnzyï)-1HpyrazoIo[3,4-b]pyrazin-3-amine	21% 3 steps	262.1

*♦ ’H NMR: δΗ ppm (400 MHz, DMSO): 13-1: 11.61 (IH, si, NH), 7.65 (1H, d,

CHarom, J=11.6Hz), 7.20 (IH, d, CHarom, J=11.2Hz), 6.95-7.10 (3H, m, CHarom),

5.32 (2H, si, NH₂), 4.18 (2H, s, CH₂). 13-2: 12.31 (IH, si, NH), 8.44 (IH, s, CHarom),

7.03-7.08 (3H, m, CHarom), 5.61 (2H, si, NH₂), 4.25 (2H, s, CH₂).

Examples of method D2

Exampie 14:5-(3,5-dinuorophenylthio)-l II-pyrazolo[3,4-b]pyrazin-3-amine

NH₂

F

0.7 g (2.68 mmol) of 5-iodo-lH-pyrazolo[3,4-b]pyridine-3-amine, 0.74 g (5.36 mmol) of anhydrous potassium carbonate and 0.10 g of copper iodide (0.536 mmol) are mixed in a 50 ml round-bottom flask. 15 ml of propan-2-οζ 0.01 g (0.2 mmol) of polyethylene glycol and 0.43 g (2.95 mmol) of 3,5-difluorothiophenol are then added. The reaction mixture is heated at 80°C for 2 hours. The solvent is evaporated and the solid formed is filtered, rinsed with water and then with pentane and dried in an oven at 50°C to yield 0.75 g (100%) of 5-(3,5-diflurophenylthio)-lH-pyrazolo[3,4-b]pyrazin-3-amine in the form of a brown solid.

LCMS (El, m/z): (M+1) 280.03.

’H NMR: 6H ppm (400 MHz, DMSO): 12.65 (IH, bs, NH), 8.52 (IH, s, CH™,), 7.18 (IH, t, CH™,), 7.05-7.18 (2H, m, CH,™), 5.89 (2H, s, NH).

The following dérivatives were obtained according to the same method:

Ex.**	Ar	R*	η	Yi,Yj.Y<	Rj	«i	Compound name	Yield	Mass MH+
14-1	ΟγΝΗΐ σ	Η	0	CH, CH, N	H	H	2-[3-amino-1 H-pyrazolo[3,4b]pyridin-5-ylthio)benzamidc	ND	ND
14-2	γ	σ·$ 0 Ν 1	0	CH, CH, N	H	H	N-(5-(3,5dimcthy Iphenylthîo)-1Hpyrazolo[3,4-b]pyridin-3-y1)4-(4-mcïhylpïpcrazîn-l -yl)2-{tctrahydro-2H-pyran-4ylamino)bcnzamidc	ND	ND
14-3	v F	Η	0	CH, CH,N	H	H	5-(3,5-difluorophenylthio)- 1 H-pyrazoïo[3,4-b]pyridin-3aminc	45%	(M+1) 27928
144	α Φ' α	Η	0	CH,C-OMe,N	H	H	5-(2.5-dichlorophcnylthÎo)-6methoxy-1 H-pyrazoIo[3,4b]pyridin-3-amine	80%	ND
14-5	α Çr α	Η	0	CH,C-NH2,N	H	H	5-(2.5-dichlorophenylthÎo)- I H-pyrazo!o[3,4-b]pyridine3,6-diaminc	35%	ND
14-6	,ά.	Η	0	CH, CH, N	H	’Bu	1 -iert-butyl-5-(3,5difluorobenzylthio)-l Hpyiazolo[3,4-b]pyridin-3aminc	ND	(M+1) 293.08
14-7	γ F	Η	0	CH, CMc, N	H	H	5-(3,5-difluorophenylthio)-6mcthyl-1 H-pyrazolo[3,4b]pyridin-3-amînc	ND	(M+1) 293.06
14-8	γ F	Η	0	CH,C-OMe,N	H	H	5-(3,5-difluorophenylthio)-6mcthoxy-1 H-pyrazo!o[3,4b]pyridin-3-amÎne	28%	(M+1) 610.30
14-9	v F	Η	0	CH,CH,N	H	*Bu	1 -ZfTi-butyl-5-(3,5dî fluorophenylthio)-1Hpyrazolo[3,4-b]pyridin-3aminc	79%	(M+1) 335.26
14-10	α φτ α	Ù Ν	0	CH, CH, N	H	H	N-(5-(2.5dichloropheny lthio}-1HpyTazolo[3,4-b]pyridin-3-yl)4-(4-mcthy lpiperazin-1 -y I)2-(tctrahydn>-2H-pyran-4ylamino)benzamide	31%	(M+1) 612.37

14-11	v F	C) N 1	0	CH,C-NHi, N	H	H	N-(6-amino-5-(3,5difhjorophenylthîo)-l Hpyrazolo(3,4-b]pyridin-3-yl)4-(4-methylpipcrazin-l -yl)2?tetrahydro-2H-pyran-4ylanûno)bcnzamîdc	68%	ND
·* 'H NMR, DMSO-de,	Ex.: 14-3: 12.65 (IL	, bs, NH), 8.52 (IH, s, CH.™), 7.18 (IH, t,

CH_W„), 7.05-7.18 (2H, m, CH_mm), 5.89 (2H, s, NH). 14-6: 8.21 (2H, bs, CH.™), 7.07 (IH, m, CH_wm), 6.90 (2H, m, CH_mra), 6.27 (2H, bs, NH), 4.03 (2H, s, CH), 1.63 (9H, s, CH). 14-7: 12.16 (IH, bs, NH), 8.39 (IH, s, CH^,_ra), 7.00-7.08 (IH, m, CH^_m), 6.645 6.72 (2H, m, CH^_m), 5.73 (2H, bs, NH₂), 2.54 (3H, s, CH,). 14-9: 8.51 (IH, bs,

CH_wra), 8.35 (IH, bs, CH„_om), 7.02 (IH, m, CH.™), 6.72 (2H, bs, C1U™), 6.52 (2H, bs, NH), 1.67 (9H, s, CH). (ND: not detennined).

Exampie 14bîs: N-(5-(3,5-difluorophenylamtao)-lH-pyrazolo[3,4-b]pyrIdin-3-y])-410 (4-methyïplperazin-l-yI)-2-(tetrahydrO’2H-pyran-4-yIamIno)benzamide.

A solution of 225 mg of N-(5-iodo-l-trityl-lH-pyrazolo[3,4-b]pyridin-3-yl)-

4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4-ylammo)benzamide (0.25 mmol), 36 mg of difluoroaniline (0.275 mmol), 19 mg of R-(+)-2,2’-bis(diphenylphosphino)-

Ι,Γ-binaphtyle (0.030 mmol), 11 mg (0.013 mmol) of tris(dibenzylideneacetone) dipaHadium(0) and 75 mg (0.75 mmol) of sodium tert-butoxide in 10 mL of THF is refluxed under argon ovemight. The crude reaction medium is cooled, extracted with ethyl acetate and washed with water. The organic phase is dried on magnésium sulfate and purified by silica gel chromatography to yield N-(5-(3,5-difluorophenylamïno)-l20 trityl-lH-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-mcthylpipcrazin-l-yl)-2-(tctrahydro-2Hpyran-4-ylamino)benzamide which is used in the following step without further purification.

The product thus obtained is dissolved in 10 mL of dichlorométhane at 0°C and 56 mg (0.5 mmol) of TFA is added. Tlie reaction medium is stirred for 4 hours. Water is added and the pH of the reaction medium is adjusted to 7 with a NaHCOj solution. The aqueous phase is collected, basified (pH 9-10) with a concentrated K₂COj solution and extracted with dichloromethane. The organic phase is collected, dried on magnésium sulfate and dry ccentrated to yield 40 mg of N-(5-(3,5-difIuorophenylammo)-lHpyrazo lo [3,4-b]pyridin-3-yl)-4-(4-methy lp iperazin-1 -yl)-2-(tetrahydro-2 H-pyran-4y!amino)bcnzamide.

LCMS (IE, m/z): (M+l) 562.12.

'H NMR: 5H ppm (400 MHz, DMSO): 13.45 (IH, si, NH), 10.47 (IH, si, NH), 8.65 (IH, s, ΟΗ,π,π,), 8.55 (IH, s, CH.™), 8.14 (IH, d, NH), 7.77 (IH, d, CH.™), 7.26 (2H, m, CHarom), 7.05 (IH, m, ClU_ra), 6.25 (IH, d, CH.™), 6.14 (IH, s, NH), 6.77 (IH, s, NH), 3.82-3.84 (2H, dt, CH), 3.72 (IH, m, CH), 3.47-3.52 (2H, m, CH), 3.28-3.34 (4H, m, CH), 2.43 (4H, m, CH), 2.23 (3H, s, CHj), 1.94 -1.97 (2H, m, CH), 1.37-1.39 (2H, m, CH).

Examples of method D3:

Example 15: N-(5-((3,5-dif]aorophenyl)ethynyI)-lH-pyrazolo[3,4-b]pyridin-3-yl)-4(4-met hylpi perazïn-1 -yI)-2-(tetrahyd ro-2H-pyr an-4-y lamin o)be nza mlde

0.94 mg (0.926 mmol) of triethylamine is added to 400 mg (0.712 mmol) of N-(5-iodo1 H-pyrazolo[3,4-b]pyridin-3-yI)-4-(4-mcthylpiperazin-1 -yl)-2-(tetrahydro-2H-pyran-4ylamino)benzamide, 67.8 mg (0.356 mmol) of Cul, and 50 mg (0.071 mmol) of Pd(PPh3)₂Cl₂ under argon in 12 ml of anhydrous dioxane under stirring. The reaction is heated for 3.5 hours at 100°C. The reaction mixture is diluted with 30 ml of water and extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated. The residue obtained is purified by silica gel chromatography (dichloromethane/methano!) to yield 152 mgofN-(5-((3,5-difluorophenyl)ethynyl)-lHpyrazo!o[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4ylamino)benzamïde in the form of a yellow solid (yield=37%).

LCMS (El, m/z): (M+1) 572.17.

‘H NMR: ÔHppm (400 MHz, DMSO): 13.57 (IH, bs, NH), 10.56 (IH, bs, NH), 8.68 (IH, s, CHarom), 8.43 (IH, s, CH^_m), 8.13 (IH, d, NH), 7.80 (IH, d, CH^J, 7.38 (2H, m, CHarom), 6.27 (IH, d, 6.15 (IH, d, CH^_m), 3.84-3.82 (2H, dt, CH), 3.70 (IH, m, CH), 3.45-3.50 (2H, m, CH), 3.21-3.33 (4H, m, CH), 2.42-2.46 (4H, m, CH),

2.28 (3H, s, CHj), 1.94-1.97 (2H, m, CH), 1.37-1.39 (2H, m, CH).

The following dérivative was obtained according to the same method:

NH₂

Ex.**	ArX	Υ1ΛΑΥ4	Compound name	Yield	Mass MH+
15-1		N.CH.N	5-((3,5-difluorophcnyI)cthynyl)-l Hpyrazolo[3,4-b]pyraziii-3-aminc	6% 6 steps	272.1
** Ή NMR, dmso-d	e. Ex.: 15-1: 12.71 (IH, si, NH), 8.66 (IH, s, CH	arom), 7.40-7.47

(3H, m, CHarom), 6.01 (2H, si, NH₂).

Exampies of method E

The protocols comprising method E aim at fùnctionalizing the cxocyclic amine of the aminopyrazole rings by their reaction with an intermediate featuring an electrophilic function, optionally generated in situ, such as acid chloride, isocyanate, isothiocyanate or aldéhyde.

Préparation of the reaction intermediates

Exampie 16: 2-(N-(4,4-difluorocyciohexyI)-2,2,2-trinuoroacetamido)-4-(4-methyl piperazln-l-yl)benzoic acid

Example 16a: tert-butyl 4-(4-methylpiperazin-l-yl)-2-nitrobenzoate

This compound was previously described in WO 2008/74749.

5.28 ml (47.6 mmol) of 1-methylpiperazine is added to 4.1 g (17 mmol) of tert-butyl 4fluoro-2-nitrobenzoate. The reaction mixture is stirred without solvent for 5 hours. 150 ml of water is added to the reaction mixture and it is stirred for 24 hours. The precipitate formed is filtered, rinsed with water and dried under vacuum to yield 4.9 g (90%) of tert-butyl 4-(4-methylpiperazin-l-yl)-2-nitrobenzoate in the form of a yellow solid.

LCMS (El, m/z): (M+l) 322.37.

'H NMR: 6H ppm (400 MHz, DMSO): 7.69 (IH. d, CU,™), 7.30 (IH, d, CH*™_m), 7.20 (IH, dd, CHuqoi), 3.38 (4H, m, CH), 2.40 (4H, m, CH), 2.22 (3H, s, CHj), 1.45 (9H, s, CHj).

Example 16b: tert-butyl 2-*mino-4-(4-methylplperazin-l-yl)benzoate

This compound was previously described in WO 2008/74749.

0.160 g (1.500 mmol) of palladium on carbon (10%) and 15.19 ml (150 mmol) of cycfohexene are added to a solution of 4.82 g (15 mmol) of tert-butyl 4-(4methyîpiperazin-l-yl)-2-nitrobenzoate in 100 ml of éthanol The reaction mixture is heated at a température of 80°C for 8 hours. The reaction mixture is filtered and then rinsed with éthanol to yield 4.2 g (yield=96%) of tert-butyl 2-amino-4-(4methylpipcrazin-l-yl)benzoate in the form of a yellow solid.

LCMS (El, m/z): (M+l) 292.39.

’H NMR: δΗ ppm (400 MHz, DMSO): 7.44 (IH, d, CH*™,), 6.40 (2H, bs, NH₂), 6.19 (IH, dd, CH*™,), 6.12 (IH, d, CH*™,), 3.17 (4H, m, CH), 2.40 (4H, m, CH), 2.22 (3H, s, CHj), 1.49 (9H, s, CHj).

Exampie 16c: tert-butyl 2-(4,4-dinuorocyclohexylamfno)-4-(4-methyIpIperazin-lyl)benzoate l .045 ml (13.57 mmol) of trifluoroacetic acid, lg (7.46 mmol) of 4,4difluorocyclohexanone and 2.158 g (8.20 mmol) of tétraméthylammonium triacetoxyborohydride are added to 1.521 g (5.22 mmol) of ieri-butyl 2-amino-4-(4methylpiperazin-l-yl)benzoate dissolved in 60 ml of dichloromethane. The reaction is left under stirring at room température for 24 hours. The solvent is evaporated and then the crude reaction product is redissolved in 30 ml of ethyl acetate. The solution is successivcly washed with 0.5 M HCl solution, 0.5 M soda solution and finally with saturated NaHCOj solution. The organic phase is dried on sodium sulfate, fîltered and concentrated to obtain 2.2 g of tert-butyl 2-(4,4-difluorocyclohcxylamino)-4-(4methylpiperazin-l-yl)benzoate in the form of a light brown gum (yield=72%).

LCMS (El, m/z): (M+1) 410.3.

’H NMR: 5H ppm (400 MHz, DMSO): 7.73 (IH, bs, NH), 7.58 (IH, m, CH™), 7.77 (IH, m, CH™), 6.09 (IH, bs, CH™), 3.37 (4H, m, CH), 3.27 (4H, m, CH), 2.47 (4H, m, CH), 2.25 (3H, s, CH), 1.99 (4H, s, CH), 1.40 (9H, s, CH).

Example 16d: tert-butyl 2-(N-(4,4-dliluorocy clohexyl)-2,2^-trifluoroacetamido)-4(4-met hylplperazin-1 -yI)benzoate

0.99 ml (6.98 mmol) of trifluoroacetic anhydride and 1.12 ml (8.06 mmol) of triethylamine are added to 2.2 g (5.3 mmol) of tert-butyl 2-(4,4difluorocyclohexylamino)-4-(4-methylpiperazin-l-yl)benzoate dissolved in 40 ml of dichloromethane. The réaction is left under stirring at room température for 3 hours. The solvent is evaporated and then the crude reaction product is taken up in 30 ml of ethyl acetate. The solution is washed with saturated NaHCO₃ solution. The organic phase is dried on sodium sulfate, fîltered and concentrated to obtain 2.5 g of rerf-butyl 2-(N-(4,4-difluorocyclohexyl)-2,2,2-trifluoroacetamido)-4-(4-methylpiperazm-l-yl) benzoate in the form of a light brown gum (yield=92%).

LCMS (El, m/z): (M+1) 506.26.

’H NMR: δΗ ppm(400 MHz, DMSO): 7.84 (IH, m, CH™), 7.09(lH, m, CH™), 6.89 (IH, bs, CH™), 3.45-3.39 (8H, m, CH), 2.83 (4H, m, CH), 2.20 (4H, m, CH), 2.05 (3H, s, CH), 1.46 (9H, s, CH).

Example 16: 2-(N-(4,4-difliiorocyclohexyI)-2,2,2-trifluoroacetainido)-4-(4-niethyI plperazin-l-yl)benzolc acid ftL·

7.62 ml (99 mmol) of trifluoroacetic acid is added to 2.5 g (4.95 mmol) of tert-butyl 2(N-(4,4-difluorocyclohexyl)-2,2,2-trifluoroacetamido)-4-(4-methylpiperazÎn-l-y!) benzoate dissolved in 30 ml of dichloromethane. The reaction is left under stirring at room température ovemight. The solvent is evaporated and then the crude reaction product is redissolved in 30 ml of ethyl acetate. The solvents are evaporated, the solid formed is redissolved in ethyl ether and the solvent is evaporated again. This operation is repeated three times until a light brown solid is obtained. 2.2 g of 2-(N-(4,4difluorocycIohexyl)-2,2,2-trifluoroacetamido)-4-(4-methylpiperazin-l-yI)benzoic acid in the form of a trifluoroacetic sait is obtained (yield=79%).

LCMS (El, m/z): (M+1) 450.1.

'HNMR: 6H ppm (400 MHz, DMSO): 10.01 (1 H, bs, OH), 7.92 (IH, m, CH.™), 7.13 (IH, m, CH.™), 7.01 (IH, bs, CH.™), 4.39 (IH, m, CH), 3.12-3.52 (8H, m, CH), 2.86 (3H, s, CH), 1.75-2.0 (8H, m, CH).

The following compounds are also obtained by this method:

4-(4-met hy Ipi perazin- l-yl)-2-(2,2,2-trlfl uoro-N-(tetrahyd r o-2 H-pyra n-4-yl) acetamido)benzoic acid.

This compound was previously described in WO 2008/74749, WO 2009/13126 and WO 2010/69966.

LCMS (El, m/z): (M+1) 416.40.

’H NMR: ÔH ppm (400 MHz, DMSO): 12.60 (IH, bs, OH), 10.08 (IH, bs, OH), 7.90 (IH, d, CH.™), 7.13 (IH, dd, CH.™), 6.90 (IH, d, CH.™), 4.40 (IH, m, CH), 4.10 (2H, m, CH), 3.70-3.90 (2H, m, CH), 3.59-3.62 (4H, m, CH), 3.30-3.32 (4H, m, CH), 2.87 (3H, s, CHj), 1.87-1.98 (IH, m, CH), 1.59-1.60 (IH, m, CH), 1.00-1.54 (2H, m, CH).

4-((3-(dimethylamino)propylXmethyl)amino)-2-(2^^-trinuoro-N-(tetrahydro-2Hpyran-4-yl)acetamido)benzoIc acid.

This compound was previously described in WO 2009/13126 and WO 2008/74749.

Example 17: (S)-2-(2,2,2-trifliioro-N-(tetrahydro-2H-pyran-4-yl)acetamido}-4-(3(2,2,2-trÎfluoroacetamido)pyrrolidin-l-yl)benzoîc acid

Example 17a: terf-butyl (S)-4-(3-(terf-butoxycarbonylamlno)pyrrolidin-l-yI)-2(tetrahydro-2//-pyran-4yIamino)benzoate

This compound was obtained by reproducing example 16d using tert-butyl (S)5 pyrrolidin-3-ylcarbamate.

Example 17b: (S)-4-(3-aminopyrrolidin-l-yl)-2-(tetrahydro-2H-pyran-4-yIamino) benzoic acid

19.7 ml (25 eq) of trifluoroacetic acid is added to a solution of 4.72 g (10.23 mmol) of tert-butyl (S)-4-(3-(tert-butoxycarbonylamino)pyrrol idin-1 -yl)-2-(tetrahydro-2//-pyran10 4-yIamino)benzoate in 100 ml of dichloromethane. The reaction medium is stirred at room température for 30 hours. The solvents arc evaporated and the residue is redissolved in diethyl ether and triturated until a solid is obtained. The solid formed is fïltered and dried under vacuum to yield 4.3 g (100%) of a yellow powder of (S)-4-(3aminopyrrolidin-l-yl)-2-(tetrahydro-2/7-pyran-4-ylamino)bcnzoic acid in the form of a 15 trifluoroacetic acid sait.

LCMS (El, m/z): (M+l) 306.22.

Example 17: (S)-2-(2,2^-trlfluoro-N-(tetrahydro-2H-pyran-4-yl)acetamldo)-4-(3(2,2,2-trinuoroacetamido)pyrrolidin-l-yl)benzoic add

1.74 ml (3.5 eq) of triethylamine and 1.6 ml (2.1 eq) of trifluoroacetic anhydride are 20 added to a solution of 1.5 g (3.58 mmol) of (S)-4-(3-aminopyrrolidin-l-yl)-2- (tetrahydro-277-pyran-4-ylamino)bcnzoic acid in the form of a trifluoroacetic acid sait in ml of dichloromethane at 0°C. The reaction medium is stirred at room température for 24 hours. Water (10 ml) is added drop by drop and then the organic phase is washed with saturated sodium chloride solution, dried on magnésium sulfate, fïltered and 25 evaporated. The residue is purified by silica get chromatography (96:4

9I dichloromethane/methanol as eluent) to yield 250 mg (14%) of (S)-2-(2,2,2-trinuoro-N(tctrahydro-2H-pyran-4-y])acctamido)-4-(3-(2,2,2-trifluoiOacetamido)pyTTolidin-l-yl) benzoic acid in the form of a yellow powder.

LCMS (El, m/z): (M+l) 498.07.

Example 18: 2-(2-fluoroethoxy)-4-(4-methylplperazin-l-yl)benzolc add

This compound can be prepared from the following intermediates.

Example 18a: tert-butyl 4-fluoro-2-(2-fluoroethoxy)benzoate

Example 18b: tert-butyl 2-(2-fluoroethoxy)-4-(4-methylpiperazin-l-y])benzoate

The following compound was also obtained by this method: 2-(2-fluoroethoxy)-4-(4-(l-methylpiperidin-4-yl)piperazin-l-yl)benzoic add.

Example 19: 4-(4-methylpipentzin-l-yl)-2-(2,2,2-trinuoro-N-(2-fluoroethyl)acetamido)-benzoic add

This compound can be prepared from the following intermediates.

Example 19a: tert-butyl 4-fluoro-2-(2-fluoroethylamino)benzoate

Example 19b: tert-butyl 4-fluoro-2-(2^^-trifIuoro-N-(2-fluoroethyl)acetaniido) benzoate

Example 19c: tert-butyl 4-(4-methylpiperazln-l-yI)-2-(2,2,2-trifluoro-N-(220 fluoroethyl)-acetamido)-benzoate

The following compound was also obtained by this method:

4-((3-(diinethyIamino)propylXmethyl)amîno)-2-(2,2,2-trinuoro-N-(2-nuoroethyl) acetamido)benzolc add.

Example 20: 4-(l-methylplperidln-4-yI)-2-(2,2,2-trifluoro-N-(tetrahydro-2Hpyran-4-y!)acetamido)benzolc add hydrotrifloroacetate

This compound can be prepared from the following intermediates.

Example 20a: tert-butyl 2-nitro-4-(pyridin-4-yl)benzoate

1.67 g of bis(triphenylphosphine)panadium(II)chloride (2.38 mmol) and 15.8 g of sodium carbonate (149 mmol) are added to a solution of 18 g of tert-butyl 4-bromo-2nitrobenzoate (59.6 mmol) and 10.98 g of pyridine-4-ylboronic acid (89 mmol) in a mixture of 200 ml of dimethoxyethane and 100 mL of water. The reaction medium is heated at 100°C for 24 hours and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (CHîCh/AcOEt: 100:0 to 70:30, 30 min). The product is isolated in the form of an oil which crystallizes to yield 14.64 g (82%) of crystals.

MS (m/z): (M+l) 301.0.

*H NMR: 6H ppm (400 MHz, DMSO): 8.73 (2H, d, CHarom, J=6.0Hz), 8.44 (IH, s, CHarom), 8.24 (IH, dd, CHarom, J=8.0Hz), 7.97 (IH, d, CHarom, J=8.0Hz), 7.85 (2H, dd, CHarom, J=4.4Hz), 1.54 (9H, s).

Example 20b: 4-(4-(tert-butoxycarbonyI)-3-nitrophenyl)-l-methylpyridinium iodide

7.55 mL od iodomethane (121 mmol) is added to a solution of 16.2 g of tert-butyl 2nitro-4-(pyridin-4-yl)benzoatc (60.6 mmol) in 20 mL of acetone. The réaction medium is heated at 60°C for 4 hours and then at room température ovemight. After dry concentration, 27 g of orange crystals are isolated (100%).

MS (m/z): (M+l) 315.0.

’H NMR: 6H ppm (400 MHz, DMSO): 9.14 (2H, d, CHarom, J=6.4Hz), 8.71 (IH, s, CHarom), 8.63 (2H, d, CHarom, J=6.4Hz), 8.47 (IH, dd, CHarom, J=8.0Hz), 8.08 (IH, d, CHarom, J=8.0Hz), 4.37 (3H, s, CH), 1.54 (9H, s).

Example 20c: tert-butyl 2-amino-4-(l-methylp!peridin-4-yl)benzoate

0.48 g of platine (TV) oxide (2.12 mmol) is added to a solution of 26.8 g of 4-(4-(tertbutoxycarbonyI)-3-nitrophcnyl)-l-mcthylpyridinium iodide (60.6 mmol) in 200 mL of methanol placed in a reactor made in stainless steel. The reaction medium is brought under 5 bar of hydrogen for 24h. The catalyst is filtered and the filtrate is concentrated under reduced pressure to yield 24.8 g (98%) of white crystals.

MS (m/z): (M+l) 291.1.

’H NMR: δΗ ppm (400 MHz, DMSO): 9.18 (IH, s, HI), 7.60 (IH, d, CHarom,

J=8.4Hz), 6.54-6.40 (3H, m, CHarom), 6.39 (IH, d, CHarom, J=8.0Hz), 3.48-3.53 (2H, m, CH), 3.06 (2H, t, CH), 2.81 (3H, s, CH), 2.60-2,70 (IH, m, CH), 1.89-1.97 (2H, m,

CH), 1.70-1.80 (2H, m, CH), 1.52 (9H, s).

Example 20d: terf-butyl 4-(l-methylplperidin-4-yI)-2-(tetraliydro-2H-pyran-4ylamlno)benzoate

7.18 mL of 2,2,2-trifluoroacetic acid (93 mmol). 4.11 mg of dihydro-2H-pyran-4(3H)one (44.5 mmol) and then 14.5 g of tétraméthylammonium triacetoxyborohydride (53.8 mmol) are successively added to a solution of 15 g of tert-butyl 2-amino-4-(lmethylpiperidin-4-yl)bcnzoate in 200 mL of dichloromethane under stirring. The reaction medium is stirred at room température for 2 h and then taklen up with a IN soda solution. The organic phase is isolated, dried on magnésium sulfate and then dried concentrated. The residue contained always HI. It is thus taken up in dichloromethane and washed with 100 mL of a IH soda solution. The organic phase is decanted, dried on magnésium sulfate and dry concentrated to yield 14.6 g of a yellow solid (quantitative yield).

MS (m/z): (M+1) 375.2.

’H NMR: δΗ ppm (400 MHz, DMSO): 7.69 (IH, d, CHarom, J=8.4Hz), 7.63 (IH, d, CHarom, J=7.6Hz), 6.65 (IH, s, CHarom), 6.44 (IH, dd, CHarom, J=8.4Hz), 3.74-3.86 (2H, m, CH), 3.66-3.71 (IH, m, CH), 3.51 (2H, t, CH), 3.05-3.12 (2H, m, CH), 2.6-2.5 (IH, m, CH), 2.42 (3H, s, CH), 2.30-2.40 (2H, m, CH), 1.89-1.97 (2H, m, CH), 1.641.77 (4H, m, CH), 1.52 (9H, s), 1.33-1.45 (2H, m, CH).

Example 20e: ferf-butyl 4-(l-methylplperldln-4-yl)-2-(2,2»2-trinuoro-N(tetrahydro-2H-pyran-4-yl)acetamido)benzoate

6.35 mL of triethylamine and 5.50 mL of 2,2,2-trifluoroacctic anhydride (39.6 mmol) are added at 0°C to a solution of 11.4 g of tert-butyl 4-(l-methylpiperidin-4-yI)-2(tctrahydro-2H-pyran-4-ylamino)benzoatc (30.4 mmol) in 240 mL of dichloromethane under stirring. The reaction medium is stirred at room température for lh and then 100 mL of water is added dropwise. The organic phase is decanted, dried on magnésium sulfate and dry concentrated. The residue is taken up in a mixture of ethanol/diethyl ether to yield a solid which is filtered on a fritted dise and 12.06 g of white crystals is isolated. The filtrate is concentrated (4.5g) and then purified by flach chromatography on silica (CILCb/meOH: 95:5 to 90:10,20 min). The product obtained is recrysltallized in dîethyl ether to yield 1.04 g of additional white crystals (global yield = 74%).

MS (m/z): (M+1) 471.1.

'H NMR: SH ppm (400 MHz, DMSO): 9.45 (IH, si, NH*), 7. 96 (IH, d, CHarom, J=8Hz), 7.51 (IH, d, CHarom, J=8Hz), 7.31 (IH, s, CHarom), 4.6-4.5 (IH, m, CH), 3. 90-3.75 (2H, m, CH), 3.5-335 (4H, m, CH), 3.1-2.85 (3H, m, CH), 2.79 (3H, s, CH₃), 2.1-1.95 (3H, 3, CH), 1.9-1.75 (2H,m,CH), 1.55-1.40 (llH.m), 1.0-0.85 (1 H, m, CH). Example 20: 4-(l-methylplperidln-4-yI)-2-(2,2,2-trifluoro-N-(tetrahydro-2Hpyran-4-yl)acetamIdo)benzoic acid hydrotrlfluoroacetate.

6.33 mL of 2,2,2-trifluoroacetic acid (82 mmol) is added under stirring to a solution of 3.2 g of tert-butyl 4-(l-methylpiperidin-4-yl)-2-(2,2,2-trinuoro-N-(tetrahydro-2Hpyran-4-yl)acetamido)benzoate (5.47 mmol) (in the form of a sait of trifluoroacetic acid) in 30 mL of dichloromethane. The reaction medium is stirred at room température for 16h, and then evaporated under reduced pressure. The residue is taken up in éthanol, and the white solid formed is filtered on a fritted dise to yield 1.61 g (53%) of white crystals.

MS (m/z): (M+1) 415.1.

’H NMR: SH ppm (400 MHz, DMSO): 13.39 (IH, si, COOH), 9.46 (IH, si, COOH du TFA), 7.99 (1H, d, CHarom, J=8.4Hz), 7.49 (IH, d, CHarom, J=8.4Hz), 7.30 (1H, s, CHarom), 4.53 (IH, m, CH), 3.74-3.86 (2H, m, CH), 335-3.45 (5H, m, CH), 2.90-3.01 (3H, m, CH), 2.76 (3H, s, CH), 1.65-2.04 (5H, m, CH), 1.44-1.54 (2H, m, CH).

Example 21: l-(4-lsothlocyanatophenyl)-4-methylpiperazlne

This compound was prepared by adapting the method described in EP1215208.

The following compound was also obtained by this method:

tert-butyl 2-isothiocyanato-5-(4-methylpiperazin-l-yI)phenylcarbamate.

Example 22: tert-butyl 2-isocyanato-5-(4-methylpïperazîn-l-yl)phenylcarbamate

This compound can be prepared from the following intermediates.

Example 22a: tert-butyl 5-{4-methylplperazin-l-yI)-2-nitrophenylcarbamate Example 22b: tert-butyl 2-amino-5-(4-methylpiperazin-l-yl)phenylcarbamate Example 22: tert-butyl 2-isocyanato-5-(4-methyIpiperazln-l-yl)phenylcarbamate &L·

Exampie 23:4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzaldehyde

O^H

Example 23a: (4-(4-methyIplperazin-l-yl)-2-(tetrahydro-2H-pyran-4-ylamIno) phenyl)methanol

500 mg (1.060 mmol) of 4-(4-methylpiperazine-l-yl)-2-(22.2-trinuoro-N-(tetrahydro2H-pyran-4-yl)acetamido)benzoic acid dissolved in 5 ml of tetrahydroforan is added at 0°C to a suspension of 201 mg (5.30 mmol) of L1AIH4 in 9 ml of tetrahydrofuran. The reaction mixture is stirred at 0°C for 1 hour and then at room température for 3 hours.

The reaction mixture is cooled at 0°C and then, drop by drop, 200 μΐ water, then 200 μΐ of soda solution (15% by weight) and finally 1 ml of water are added. The reaction mixture is stirred at room température for 2 hours and then filtered and rinsed with tctrahydroforan. The filtrate is concentrated to yield 250 mg (yield=77%) of (4-(4methyIpiperazine-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl)methanol in the form 15 of a white solid.

LCMS (El, m/z): (M+1) 306.14.

’H NMR: Snppm (400 MHz, DMSO): 6.85 (IH, d, CH™,), 6.20 (IH, d, CH.™), 6.10 (IH, d, CH.™), 4.95 (IH, bs, OH), 4.87 (IH, d, NH), 4.37 (2H, d, CH₂), 3.83-3.86 (2H, m, CH), 3.56 (IH, m, CH), 3.46-3.56 (3H, m, CH), 3.45 (IH, m, CH), 3.05-3.07 (4H, m, 20 CH), 2.41-2.44 (4H, m, CH), 2.21 (3H, s, CH₃), 1.89-1.92 (2H, m, CH).

Example 23:4-(4-methylplperazin-l-yI)-2-(tetrahydro-2H-pyran-4-ylamlno) benzaldehyde mg (0.982 mmol) of manganèse dioxide is added at room température to a solution 25 of (4-(4-methylpipcrazine-l -y!)-2-(tetrahydro-2H-pyran-4-ylamino)phenyI)methanol (100 mg, 0327 mmol) in a mixture of ethyl acetate (10 ml) and dichloromethane (9 ml). The réaction mixture is placed in an ultrasonic bath for 5 hours. The réaction mixture is filtered, the solvents are evaporated and the crude product is purified by chromatography to yield 50.0 mg (yield=50.3%) of (4-(4-methyIpiperazine-l-yl)-2 (tetrahydro-2H-pyran-4-ylamino)benzaldehyde in the form of a white solid.

LCMS (El, m/z): (M+1) 304.19.

’H NMR: Ôuppm (400 MHz, DMSO): 9.43 (IH, d, CH), 7.32 (IH, d, CH™), 6.36 (IH, d, CH™), 6.08 (IH, d, CH™), 3.94-3.99 (2H, m, CH), 3.77 (IH, m, CH), 3.61-3.63 (2H, m, CH), 3.42-3.45 (4H, m, CH), 2.57-2.60 (4H, m, CH), 2.36 (3H, s, CH₃), 2.042.08 (2H, m, CH), 1.51-1.60 (2H, m, CH).

Example 24:2-(4-(4-methylpiperazin-l-yI)phenyI)acetîc add

I

Example 24a: 2,2^-trlchloro-l-(4-(4-methyIpiperazin-l-yI)phenyl)ethanol

1.0 ml (10.00 mmol) of trichloroacetic acid and, in small portions, 1.854 g (10 mmol) of sodium 2,2,2-trichforoacetate are added at room température to a solution of 1.362 g (6.67 mmol) of 4-(4-methylpiperazme-l-yl)benzaldehyde in 13.5 ml of dimethylformamide. The reaction mixture is stirred for 3 hours at room température. The solvent is concentrated and the crude reaction product extracted with ethyl acetate. The organic phase is washed using saturated sodium bicarbonate solution. The organic phases are combined, dried on magnésium sulfate and then concentrated to yield 1.760 g (yicld=82%) of 2,2,2-trichloro-l-(4-(4-mcthylpipcrazinc-l-yl)phcnyl)cthanol in the form of a white solid.

LCMS (El, m/z): (M+1) 324.04.

’H NMR: 6» (400 MHz, DMSO): 7.41 (2H, d, CH™), 7.02 (IH, bs, OH), 6.90 (2H, d, CH™), 5.08 (IH, bs, CH), 3.14-3.16 (4H, m, CH), 2.42-2.47 (4H, m, CH), 2.21 (3H, s, CHj).

Example 24:2-(4-(4-methyIpiperazin-l-yl)phenyl)acetic acid

0.559 g (14.77 mmol) of sodium borohydride is added quickly to 2.294 g (7.35 mmol) of dîbenzyl diselenide in 28 ml of ethanoL The réaction mixture is stirred at room température for 1 hour. 2.266 g (7 mmol) of 2,2,2-trichIoro-l-(4-(4-mcthyIpiperazine-l17324 yl)phenyl)ethanol and 1.680 g (42.0 mmol) of sodium hydroxide are then added. The reaction mixture is stirred at 35°C for 24 hours. The solvent is concentrated and the crude product extracted with ethyl acetate after adding a pH 5 aqueous phase. The organic phases are combined, dried on magnésium sulfate and then concentrated to yield 2-(4-(4-methylpiperazme-l-yI)phenyl)acetic acid which is used without additional purification.

LCMS (El, m/z): (M+1) 235.294.

Example 25: 2-(4-(4-methylpiperazin-l-yI)-2-nitrophenyI) acetic add

This compound can be prepared from the following intermediates.

Example 25a: diethyl 2-(4-fluoro-2-nltrophenyI)malonate

Example 25b: diethyl 2-(4-(4-methylplperazln-l-y!)-2-nitrophenyl)malonate

Example of method El:

Example 26: N-(5-(3,5-dinuorophenylthlo)-lII-pyrazoloI3,4-b]pyridin-3-yl)-4-(4met hylpiperazin-1 -y 1)-2-(2,2,2-tr ifluor o-N-(tetrahyd ro-2H-pyra n-4-y 1) acetamld o)benzamlde

0.95 ml (11.21 mmol) of oxalyl chloride and 2 drops of anhydrous dimethylformamide are added to 2.97 g (5.61 mmol) of a solution of 4-(4-mcthylpipcrazin-l-yl)-2-(2^,2trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamÎdo)benzoic acid in 95 ml of dichloromethane. The reaction mixture is stirred for 2 hours at room température. The solvents are evaporated, the solid formed is taken up in toluène and the solvent evaporated. This operation is repeated three times until a white solid is obtained. The acid chloride is dissolved in 35 ml of anhydrous tetrahydrofuran at -20°C and then the solution formed is added to a solution containing 1.56 g (5.61 mmol) of 5-(3,5difluorophenylthio)-lH-pyrazoto[3,4-b]pyridin-3-amÎne and 3.71ml (21.30 mmol) of & L17324

N-ethyl-N-isopropylpropan-2-amine in 30 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 3 hours at -20°C and then ovemight at room température. The precipitate obtained is filtered and rinsed with tetrahydrofuran and water and then dried to yield 2 g (53%) of N-(5-(3,5-difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-35 yl)-4-(4-methylp!perazin-l-y])-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4yl)acetamido)benzamide.

LCMS (El, m/z): (M+1) 676.20.

'H NMR: 5H ppm (400 MHz, DMSO): 13.66 (IH, bs, NH), 11.08 (IH, bs, NH), 8.61 (IH, s, CHerom), 8.46 (IH, s, CH.™), 7.83 (IH, d, CH„,„), 7.05-7.10 (2H, m, CH.™), 10 6.83-6.89 (3H, m, CH_mm), 4.39-4.44 (IH, m, CH), 3.83-3.85 (IH, m, CH), 3.69-3.72 (IH, m, CH), 3.59-3.62 (IH, m, CH), 3.30-3.32 (4H, m, CH₂), 2.30-2.44 (4H, m, CH₂), 2.27 (3H, s, CHj), 1.87-1.90 (1 H, m, CH), 1.59-1.60 (1 H, m, CH), 1.49-1.50 (lH.m, CH), 1.20-1.40 (IH, m, CH).

The following dérivatives were obtained according to the same method:

Ex**	Y	Ri	Ri	n	w	Ri	YbY<	Compound names	Yield	MassMH+
26-1	Ο^,ΝΗϊ σ8'	0 ,ΝγΟ F'T'F	ό N 4	0	H	H	CH, N	N-(5-(2-carbamoytphenyIthîo)-1Hpyrazolo[3,4-b]pyridin-3-yI)-4-(4meÆytpiperazm-l-yt)-2-(2^,2trifluoro-N-(tetiahydro-2H-pyTan-4yt)acctamido)benzamidc	ND	ND
26-2	ov A	Q F'T'F	Λ N t	0	H	H	CH, N	N-(5-(3,5-difluarophcnylsulfbnyl)lH-pyra2olo{3,4-b]pyridin-3-yï}-4(4-methylpi peiazin-1 -yi)-2(tetrahydro-2H-pyran-4ylamino)benzamide	ND	ND
26*3	1	Q F^F	ô N »	0	H	H	CH, N	N-fS-iodo-1 H-pyrazolo{3,4b]pyridin-3-yt)-4-(4-incthytpipcrazinl-yî)-2-(2JL2-trifluoro-N(tetrahydro-2H-pyran-4yl)acctaniido)bcnzaniide	ND	ND
26-4	A	H	NOi	1	H	H	CH, N	N-(5-(3,5-dinuorophcnyhhio)-l Hpyrarolo[3,4-b]pyTidin-3-yI)-2-(4nitrophenyl)acctaniide	ND	442.21
26-5	oV F	0 ,ΝγΟ F^F	ô N »	0	H	H	CH, N	N-(5-(3,5-dinuarobenzyîsulfonyl)1 H-pyrazoIo[3,4-b]pyndin-3-yl)-4(4-methyîpiperazin-1 -yl)-2-(2 ^2trinuoro-N-(tctrahydn>2H-pyTan-4yi)acctaniido)benzamide	ND	ND
26-6	S'	$ ,ΝγΟ f'J'f	ό N 4	0	H	H	CH, N	2-(N-(4,4-di iluorocyc1ohcxyï)-2,2,2trinuoroacetamido)-N-(5-(3^diflüoropbenylsulfonyl)-l Hpyra2Dlo[3,4-blpyridm-3-yi)-4-(4methylpÎperazin-1 -yl)bcnzamide	ND	ND

PL

100

26-7	A	$ F^F	0. N t	H	H	CH, N	N-(5-(3>xlifluorobenzyI)-1Hpyra2olo[3,4-b]pyTidin-3-yl>-4-{4methylpÎperazin-l-yl)-2-(2,2,2trifluoro-N-(tetrahyiro-2H-pyran-4yl)acetamido)bcnzamide	22%	676.2
26-8	sx A	H	(l· N 1	H	H	CH, N	N-(5-(3^-difluarophenyhhio)-1Hpyrazok>[3,4-b]pyrkiin-3-y1)-2-(4-(4methylpiperazin-1yl)phcnyl)acctaniidc	ND	495.17
26-9	1	0 f'T'f	ù' N	OMc	H	ai, N	N-(5-iodo-6-methnxy-lHpyrazolo[3,4-b]pyridin-3-y1)-4-(4methylpiperazm-l-yl)-2-(2,2,2trifluon>N-(tetrahydrt>-2H-pyran-4yi)acctamido)benzainide	ND	688.18
26-10	I	Q ,ΗγΟ F^F	Λ· N *	nh3	H	CH, N	N-(6-aniino-5-iodo-1 H-pyrazolo[3,4b]pyridin-3-y1)-4-(4-inethylpiperazÎnl-yt)-2-(2,2,24riniioro-N(tetrahydro-2H-pyran-4yl)acctamido)benzamide	ND	673.06
26-11	sx A	0 ,ΝγΟ f+f	'ï- 0 i	II	II	CT, N	(S)-N-(5-(3^-dinuarophenyhhio)l H-pyrazolo[3,4-b]pyridin-3-yi)-2(2^^-trifiuoro-N-(tetrahydro-2Hpyran-4-yi)acetamïdo)-4-(3-(2,2,2trifluomacetamidojpyrrolidin-l yi)benzamidc	ND	ND
26-12	sx A	H	ό N ♦	D H	H	CH, N	N-(5-(3^-difluor(^henyhhio)-lHpyrazolo[3,4-b]pyridin-3-yl)-4-(4methylpiperazin-1 -yi)benzamidc	46%	481.38
26-13	A	Q χΝγΟ F*T*F	ù N *	0 H	II	N, CT	N-(5-(3^-dinuorobcnzyl)-l Hpyrazolo[4,3-b]pyridm-3-yl)-4-(4meüiylpiperazm-1 -yi)-2-(2 A2triiluoro-N-(tetrahydro-2H-pyran-4yl)acctamido)bcnzaniide	35%	658.1

ΙΟΙ

26-14	y F	Q F^F	ù N 1	0	H	H	N, CH	N-(5-(3^-diiluorobenzyloxy}-l Hpyrazolo[43-b]pyTTdin-3-yl)X-(4mcthylpiperazin-1 -yl)-2-(223trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)benzamide	63%	674.1
26-15	y F	ç> ,ΝγΟ F^F	Φ	0	H	H	N, CH	N-(5-(3^-difluorobenzyloxy)-1Hpyrazolo[43-b]pyridin-3-yl)-4-(l mcthylpÎperidin-4-yI)-2-(2,23trifluoro-N-(tctrahjdro-2H-pyran-4yi)acetamido)benzamide	ND	673.1
26-16		0 F'T'F	ό N 1	0	H	H	N, CH	N45-(2,5-difluOTobenzyloxy)-lHpyrazolo[43-b]pyridin-3-y1 )-4-(4methyïpiperazin-1 -yl)-2-(223trifluoro-N-(tctrahydro-2H-pyran-4yijacctamidojbcnzamidc	62%	6742
26-17	FO(f	Q F^F	Φ	0	H	H	N, CH	N-(5-(23-<iinuorobenzyloxy)-l Hpyrazolo[43-b]pyrklin-3-yi)-4-{ l mcthylpipcridin-4-yl)-2-(223trifluon>N^(tetrahydro-2H-pyran-4yt)acetamido)ben2amide	ND	6733
26-18	y a	Q ,Νγ,Ο F^F	Λ N ♦	0	H	H	N, CH	N-(5-(23-dichlcrobcnzylo!ty)-lH' pyra2olo[43-b]pyridni-3-yl)-4-(4methylpiperazin-l -yl)-2-(233trifluora-N-(tetrahytlro-2H-pyran-4y1)acctamido)benzamidc	ND	ND
26-19	y a	Q ,ΝγΟ F^F	Φ	0	H	II	N. CH	N-(5-(23-<iichlcrcbenzyIoxy}-l Hpyrazolo[43 -b]pyridîn-3 -yl)-4-( 1 methyîpiperidin-4-yî)-2-(233triflixno-N-(tctrahydn>-2H-pyTan-4yl)acetamido)benzainide	ND	ND

102

26-20	X σ	Q F^F	ù N •	0	H	H	N, CH	N-(5-(5-chloro-2(trifluonjmcthyl)benzyloxy)-1Hpyra7olo[43-b]pyridin-3-yi)-4-(4methylpiperazin-1 -yl )-2-(222trinuoro-N-(tctrahyriro-2H-pyran-4yt)acctamido)bcnzamkle	55%	7402
26-21	X α	Q ,ΝγΟ F^F	Φ	0	H	H	N, CH	N-(5-(5-diloro-2(trifluOTomethyl)bcnzyloxy)-l Hpyrazolo[4,3-b]pyridin-3-yl)-4-(l methylpipcridin-4-yl)-2-(222triÎluoro-N-(tctiahydro-2H-pyran-4y!)acctainido)bcnzamide	ND	739.3
26-22	X	Q ,ΝγΟ F^F	ό N t	0	H	H	N, CH	4-(4-mcthylpipCTazin-l -yl)-N-(5(pyridin-3-yimethoxy)-l Hpymulo[43-b]pyridin-3-yl)-2(222-tnfluort>-N-(tctrahydro-2Hpyran-4-yi)acetamido)benzaniÎde	90%	6392
26-23	A	Q ,ΝγΟ	Φ	0	H	H	N, CH	4-(l -methyIptperidin-4-yI)-N-(5(pyridin-3 -yimelhoxy)-1Hpyrazolo[4,3 -b]pyridin-3 -yl)-2(2^2,2-trifluoro-N-(tctrahydro-2Hpyran-4-yl)acetamido)benzaniide	ND	6382
26-24	Â	Q ,ΝγΟ F'T'F	ό N 1	0	H	H	N, CH	N-(5-(3 ^-diflutxnphenyllhio)-l Hpyrazo!o[43-b]pyridin-3-yl)-4-(4methylpipcraziii-1 -yi)-2-(222trifluon>N-(tetrahydro-2H-pyTan-4yi)acelainÎdo)benzamidc	ND	ND
26-25	,ώ.	Q ,ΝγΟ F-T-F	Φ	0	H	H	N, CH	N-(5-(3^-difIuorophcnylthio)-lHpyrazoîo[43-b]pyTÎdin-3-yI)-4-(lmethylpipcridin-4-yl )-2-(222triflucro-N-(tetrahydio-2H-pyi3n-4yi)acetami]o)benzamkle	50%	ND

103

26-26	Sx A	0 χΝγΟ fAf	ό N *	0	H	H	N, CH	N-( 5-{2^-diIluarophcnyIlhio)-1Hpyram]o[43-b]pyridin-3-yï>4-(4methyîpiperazin-1 -yî)-2-(2&2trifluoro-N-(tctrahytin>2H-pyran-4yl)acetamido)benzamxk	ND	ND
26-27	s' A	,ΝγΟ fAf	Φ	0	H	H	N, CH	N-{5-(2^-diiluorophenylthio)-1Hpyrazolo[43-b]pyridin-3-yI )-4-( 1 methy1piperidin-4-yI)-2-(233tnfluoro-N-(tctrahyJro-2H-pyran-4yl)acctamido)benzamidc	ND	ND
26-28	s*	Φ ,N„fO fAf	û N 1	0	H	H	N, CH	N-(5-(3^ichIorophcnyîlhio)-IHpyTa2Dlo[43-b]pyridin-3-yl)-4-(4methylpiperazin-l-yî}-2-(2,23trif!uoTO-N-(tctrahjxlrô-2H-pyran-4yl)acetamido)benzamklc	ND	ND
26-29	A	Q ,ΝγΟ F*T*F	Φ	0	H	H	N, CH	N-(5-(33-dichlorophcnyîthio)-1HpyTazok>[43-b]pyTidin-3 -yl)-4-( 1 methyîpipcridin-4-yl)-2-(233triÎlüoro-N-(tetrahydro-2H-pyTan-4yl)acctam idojbenzamide	ND	ND
26-30	'fi.	ç> fAf	Λ N I	0	H	H	N, CH	N-(5-(23-dÎchlorcphcnylthio)-l Hp yra2Dlo[43 -b]pyridin-3-yï)-4-(4methylpipcTazin-1 -yî)-2-{233trinuoro-N-(t€trahydro-2H-pyran-4yi)acetamido)benzamidc	ND	ND
26-31	A	0 ,ΝγΟ fAf	Ψ	0	H	H	N. CH	N-(5-(23-didilarophenylihio)-1HpyraÆ>lo[43 -b]pyridin-3-yl)-4-( l methylpiperidin-4-yl)-2-(233trifluOTO-N^tctrahjxlro-2H-pyran-4yi)acetamido)bcnzamidc	ND	ND

104

26-32	s' A	Q ρφρ	Λ N ♦	0	H	H	N, CH	4-(4-methyipïperazm-1 -)1)-2-(2^2trifli>oro-N-(tctrahydn>-2H-pyraii-4yI)acetainido)-N-(5-(2(trifluoromcthyl)phenyhhio)-l Hpyrazolo[434>lpyridin-3yi)benzamide	ND	ND
26-33	A	Q ,Νγ° F^F	Φ	0	H	H	N, CH	4-( 1 -methylpiperidin-4-yl )-2-(233trifluoro-N-(tetrahydn>-2H-pyTan-4yl)acetamido)-N-(5-(2(triiluoroniethyl)phenyIthio)-lHpyTazolo[4,3-b]pyridm-3yi)benzamide	ND	ND
26-34	Y F	Φ f't'f	Λ N ♦	0	H	H	N, CH	N-(5-(3,5-diflixrobenzyîthio)-lHpyTazolo(43-b]pyndin-3-yI>4-(4mcthyipipcrazœ-l-y1)-2-(233trifliioro-N-(tetrahydro-2H-pyran-4yt)aceteniido)bcnzaniide	ND	ND
26-35	v F	ç χΝγΟ F^F	Φ	0	H	H	N, CH	N-(5-(33-difluorobenzylthio)-1Hpyra2olo[43-b]pyndin-3-yI )-4-(1 · mcthy1pipcridin-4-yl)-2-(233trifIuoro-Nÿtetrahydn>-2H-pyran-4yl)acetainkJo)bcnzamide	73%	ND
26-36	oj'	Φ ,N^O F^F	Λ N *	0	H	H	N, CH	N-(5-(23-diilucirobcnzylthio)-l Hpyrazok>[4,3-b]pyridin-3-yl)-4-(4methylpiperazin-l -y!)-2-(233trifluoro-hÎ-(tctrahydi’o-2H-pyran-4yt)acctamido)bcnzainide	ND	ND
26-37	•uf	ç ,ΝγΟ f'J'f	Φ	0	H	H	N, CH	N-(5-(23-dinuorobciizylthio)-l Hpyrazolo[43-b]pyridin-3-yl)-4-( 1 methy1pipcridm-4-yl)-2-(233trifluoro-N-(tctrahydn>2H-pyran-4yi)acctainîdo)benzamidc	ND	ND

105

26*38		Q ,ΝγΟ fAf	ù N 1	0	H	H	N, CH	N-(5-(2^-dichl(Tobenzyîthio)-l Hpyrazolo[43-b]pyridin-3-yl)-4-(4mcthyipiperazin-l -yï>2-(2A2trifiuoro-N-(tctrahydro-2H-pyran-4yl)acctamk]o)benzamide	ND	ND
26-39	Y	Q >N^O F^F	Φ	0	H	H	N, CH	N-(5-(2,5-dichlarobeTizylthio}-1Hpyrarolo[43-b]pyridin-3-yl)-4-(l methylpiperidîn-4-yl}-2-(222trinuoro-N-(tetrahjdro-2 H-pyran-4yl)acetainido)benzamide	ND	ND
2640	HH-'	ç> fAf	Λ N 1	0	H	H	N, CH	N-(5-(3>ÆnuoTOplieiiylamÎno)-lHpyTazolo[43-b]pyridin-3-yl)-4-(4methylpiperazin-1 -yl)-2-(22A trifluoro-N-(tetrahydn>2H*pyian-4yi)acetamido)benzamidc	79%	6592
2641	HN* A	Q ,ΝγΟ	Φ	0	H	H	N, CH	N-(5-(3,5-dinuorophcny1ainino)-l Hpyiazolo[4,3-b]pyridin-3-yï)-4-(lmcthy1pipcridin-4-yi)-2-(22»2trifluoro*N-(tetrahydro-2H*pyTan-4yi)acetamido)benzamidc	ND	6582
2642	un'' A	Q ,ΝγΟ F'T'F	ô N 1	0	H	H	N, CH	N-(5-(2^-difluorophenylamino)-l Hpyrazolo[43-b]pyridin-3-y1 )-4-(4methyipiperazin-1 -yl )-2-(2,2,2trifluoro-N-(tctralijdro-2H-pyran-4yl)acctatnido)benzanikle	ND	6592
2643	hn' A	0 ,ΝγΟ F^F	Φ	0	H	H	N, CH	N-(5-(3^-dinuorophenylaninK>}-l Hpyrazolo[43-b]pyridin-3-yl )-4-( 1 methyipipcridin-4-yl)-2-(2A2trifluoro-N4tctrahydro-2H-pyran-4yi)acctamido)benzamide	ND	6582

106

26-44	hn'	Q F^F	ù N *	0	H	H	N, CH	N-(5-(2^-dichlorophenylamino)-l HpyTazo]o[43-b]pyridin-3 -yi)-4-(4methylpiperazin-l -yl)-2-(233trifluoro-N-(tetrahjrfro-2H-pyran-4yl)acctaniido)beiizamide	26%	6913
26-45	hn'' ‘A.	-η z-/~p n 0	Φ	0	H	H	N, CH	N-(5-(2^-<!ichlarophenylaniino)-1Hpyrazolo[43-b]pyridin-3-yl)-4-(lmcthy1pipcridm-4-yl}-2-(233trifluoro-N-(tetrahjdn>-2H-pyran-4yl)ac€tamido)beTizamide	98%	6923
2646	A	Ç ,ΝγΟ F^F	ù N 1	0	H	H	N, N	N-(5-(33-<tifluorobenzyï)-lHpyTazofo[3,4-b]nyrazin-3-y1)-4-(4mcthylpiperazin-l-yl )-2-(233trifIuoro-N-(tctrahydro-2H-pyTan-4yi)acetamido)bcnzamide	ND	ND
2647	À		,ΝγΟ F^F	Φ	0	H	H	N, N	N-(5-(3>dinuorobenzy1>-l Hpyrazok>[3,4-b]pyrazin-3-yl )-4-( 1mcthylpipcridin-4-yl)-2-(233triflixwo-N4tetrabj'fro-2H-pyran-4yQacetamidoJbenzsmide	ND	ND
2648	i	y I	Φ ,ΝγΟ F*T*F	ύ *	0	H	H	N, N	N-(5-((33-<iiflüorophcnyI)ethynyl)- 1 H-pyrazo1o[3,4-b]pyrazin-3-yl)-4(0(dimethylamino)propylXmethyl)anim o)-2-(233-tririuoro-N-(tetrahydro2H-pyran-4-y!)acetamido)benzamide	ND	ND
2649	I	r l	Q ,ΝγΟ F^F	Φ	0	H	H	N, N	N-(5-((33-dÎfluoropbcnyI)ethynyï)- 1 H-pyrazok»[3,4-b]pyrazin-3-yI)-4( 1 -methyîpipcTidin-4-yi)-2-(23!3trifiuoro-N-(tetrahylro-2H-pyran-4yl)acetamido)benzamide	ND	ND

107

26-50	Â,	Q ρφρ	*	0	Η	Η	Ν,Ν	Ν-(5-(3 A-dinuarophenylthio)-l Ηpyrazolo[3,4-b]pyrazin-3-yl)-4-((3(dimetliyîamino)piOpyJXniethyl)aniin o)-2-(233-trinuofx>N-(tctrahydn> 2H-pyran-4-yl)acetamido)bcnzamidc	43%	693.2
26-51		ç> ,ΝγΟ	φ	0	Η	Η	Ν,Ν	N-(5-(23-dichlarcphenyithio)-1Hpyrazolo[3,4-b]pyTazm-3-yl)-4-(4mcÜiylpiperazin-l-y!)-2-(233trifluon>N-(tctrahjdro-2H-pyran-4yi)acetamido)benzamide	ND	ND
26-52	s' A)	φ ,ΝγΟ	ό Ν *	0	Η	Η	Ν, CH	4-(4-niethylpipcrazin-l-y! )-2-(233triflüoro-N-(tetrahydro-2H-pyran-4yl)acctaniido)-N-(5-{2(trifluOTomcthyl)phenylthio)-l Hpyrazolo[3,4-b]pyrazin-3yijbenzamidc	66%	709.1
26-53	°V ,h.	ψ ,ΝγΟ F^F	Ù Ν ♦	0	Η	Η	N.CH	N-(5-(3,5-dinuoropheny1suIfony1)- 1 H-pyrazo1o[43-b]pyridtn-3-yl)-4(4-mcthylpipcrazin-1 -yi)-2-(233trifluort>-N-(tctrahydro-2H-pyran-4y!)acetamido)benzaniidc	28%	7083
26-54	°v ,h.	ζ> χΝγΟ ρφρ	φ	0	Η	Η	Ν, CH	N-(5-(33-difluorophcnylsulfonyi)1 H-pyrazok>[43*b]pyridin-3-yl)-4( 1 -methyîpiperidin-4-yl )-2-( 233trifluoro-N-(telrahydro-2H-pyTan-4yl)acetaniido)benzamidc	74%	7073
26-55		t? ,ΝγΟ F-T-p	ό Ν 1	0	Η	Η	N.CH	N-(5-(23-difluorophcnylsul fonyl)1 H-pyronlo[43’b Jpyridin-3 -yi)-4(4-methylpipCTazin-1 -yl)-2-(233trifluoro-N-(tetrahydro-2H^yran-4yî)acetamido)benzaniidc	ND	ND

bc

108

26-56	V .ù·	Q F^F	Φ	0	H	H	N. CH	N-(5-(2^-dinuorophenylsuIfony1)- 1 H-pyraTolo[43-b]pyridin-3-yl)-4(1 -methy!piperidÎn-4-yl}-2-(2^,2tnfluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)benzamide	ND	ND
26-57		Q ,NyO F^F	ό *	0	H	H	N, CH	N-(5-(3^-dicHcrophcnylsulfonyl)111-pyrazoIo(43-b]pyridin-3-yiy4(4-methytpiperazin-1 -yl)-2-{2,23triiluoro-N-(tctrahydn>-2H-pyTan-4yl)acelamido)benramide	ND	ND
26-58	V A	Q ,ΝγΟ fA	Φ	0	H	H	N, CH	N-(5-{3^-dich1oropbcnyl5ulfnnyl}1 H-pyrazolo[4,3-b]pyridin-3-yi)-4( 1 -mcthyipiperidin-4-yî)-2-(2Â2trifluoro-N-(tetrahylro-2H-pyran-4yi)accUmido)bcnzaaiidc	ND	ND
26-59	°v A	,ΝγΟ F'T'F	Λ N 1	0	H	H	N, CH	N-(5-(2^-<iichlarophcnylsulfonyl)l H-pyrazolo[43-b]pyridin-3-yl)-4(4-mcthylpipcrazin-1 -yî)-2-(2i2trifluoTD-N-(tetrahydro-2H-pyran-4yi)acetamido)bcn2amide	ND	ND
26-60	V A	Q xNyO Fj>	Φ	0	H	H	N. CH	N-(5-{23-dichlarophenylsulfonyl)- 1 H-pyrazoJo[43-blpyridjn-3-yî)-4( 1 -methy1pipcridin-4-yl)-2-(23,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamide	ND	ND
26-61	o o=s* v F	Q ,Νγ° F^F	0 1	0	H	H	N, ai	N-(5-(33-dïnûOTobCTizylsulfonyI)- 1 H-pyrazolo[4 J -b]pyrîdin-3-yl)-4(4-methylpipcrazin-1 -yl)-2-(2,23trinuoro-N-(tctrahydrt>-2H-pyran-4yi)acetamîdo)benæinide	94%	ND

109

26-62	9X ’p5 F	Q ,ΝγΟ F^F	Φ-	H	H	N, CH	N-(5-(35-difiuorobcnzylsulfonyl}- 1 H-pyrazolo[4,3-b]pyridin-3 -y1)-4( 1 -methylpiperidin-4-y1)-2-(222· triiluoro-N-(tetrahydro-2H-pyran-4yl)acctamido)benzainidc	99%	ND
26-63	Y	0 >NyO F^F	ô. N 1	H	H	N, CH	N-(5-(25-<linuorobcnzylsuIfonyI)1 H-pyrazolo[43-b]pyridin-3-y1)-4(4-τπ ethyl piperazni-l-yl)-2-(2Î2trifluoro-N-(tetrahyjro-2H-pyraii-4yl)acctamido)benzaniide	60%	ND
26-64	Y	Q >NyO F^F	9'	H	H	N, CH	N-(5-{25-difluorobcnzy1sulfonyl)1 H-pyrazolo{43-blpyridin-3-y1)-4( 1 -nicthylpiperidin-4-yl)-2-(233trifIuoro-N-(tetrah>dro-2H-pyran-4yl)acetainido)benzamide	36%	ND
26-65		Q ^NyO f'J'f	Φ·	) H	H	N. CH	N-(5-(25-dinuorobenzylsulfinyI)lH-pyrazolo{43-b]pyridin-3-yl)-4( 1 -mcthylpipcridin-4-yl )-2-(233 trifluoro-N-(tctrahydro-2H-pyran-4y1)acetamido)bcnzaniÎde	ND	ND
26-66	O o=s Xç	Q ,ΝγΟ f'J'f	Φ	9 H	H	N, CH	N-(5-(25-dÎchlorobcnzyîsuIfonyi)1 H-pyraznlo[43-b]pyridjn-3-yl)-4(4-methylpipcrazin-l-yl)-2-(233“ trifli>ort>N-(tetrahydro-2H-pyran-4yj)acctainido)ben2amide	52%	ND
26-67	9, o=s xi	Φ „ΝγΟ f'T'f	Φ	0 H	H	N, CH	N-(5-{23-dichlorobenzylsu1fonyl)- 1 H-pyrazo1o[4,3-b]pyridin-3-yl)-4(1 -melhylpipcridÎn-4-yl)-2-(233trifluoro-N-(tetrahydro-2H-pyTan-4yl)acetainido)benzamidc	90%	ND

no

26-68		F^F	Φ	0	H	H	N, CH	N-(542,5-dichl(Tobcnzylsulfiny!}1 H-pyra2Dlo[43-b]pyridin-3-yl)-4( 1 -methylpipcridîn-4-yl)-2-(233trifliKjro-N-(tctrahylro-2H-pyran-4yi)acctamïdo)benzamide	50%	ND
26-69	I	F'T'F	Λ N t	0	H	C(P hh	CH. N	N-(5-iodo-l -trityi-1 H-pyrazok>[3,4b]pyndin-3-yi)-4-(4-me!hylp!perazinl-ji)-2-(tetrahydro-2H-pyran-4yiamino)benzamide	67%	900.23
26-70	F	Q F^F	Λ N ♦	0	H	H	CH, N	N-(5-(33difluorophenylsulfonamido)-1Hpyrazo1o[3,4-b]pyridin-3-yi)-4-(4methylpiperazin-l -yt)-24233trifluoro-N-(lrtrahydro-2H-pyran-4yt)acctamido)benzaiiiidc	11%	ND

«♦ ’H NMR, dmso-de, Ex.: 26^1: 13,64 (IH, si. NH), 11,26 (IH, si NH), 8,68 (IH, d, CH™,), 8,58 (IH, d, CH™,), 8,20 (2H, d, CH™,), 7,64 (2H, d, CH™,), 7,03 (IH, m, CH™,), 6,78 (2H, m, CH™,), 3,95 (2H, m, CH₂). 26-8: 13,59 (IH, si NH), 11,05 (IH, si, NH), 8,68 (IH, d, CH™), 8,57 (IH, d, CH™,), 7,19 (2H, d, CH™,), 6,99-7,08 (IH, 5 m, CH_mm), 6,88 (2H, d, CH™,), 6,75-6,79 (2H, m, CH_wm), 3,61 (2H, m, CH₂), 3,073,09 (4H, m, CH), 2,41-2,44 (4H, m, CH),2,20 (3H, s, CH₃). 26-9: 13,17 (IH, si,NH),

10,90 (IH, si NH), 8,55 (IH, s, CHarom), 7,79 (1H, d, CHarom), 7,07 (1H, dd, CHarom), 6,90 (IH, d, CHarom), 4,40-4,50 (IH, m, CH), 3,96 (3H, s, CH₃), 3,82-3,89 (IH, m, CH), 3,74-3,80 (IH, m, CH), 3,34-3,41 (2H, m, CH), 3,28-3,33 (4H, m, 10 2*CH₂), 2,43-2,47 (4H, m, 2*CH₂), 2,23 (3H, s, CHj), 1,85-1,92 (IH, m, CH), 1,58-

1,63 (IH, m, CH), 1,45-1,53 (IH, m, CH), 1,22-1,33 (IH, m, CH). 26-10: 12,48 (IH, si, NH), 10,72 (IH, si, NH), 8,30 (IH, s, CHarom), 7,77 (IH, d, CHarom), 7,06 (IH, dd, CHarom), 6,88 (IH, d, CHarom), 6,40 (2H, si NH₂), 4,40-4,50 (IH, m, CH), 3,82-3,89 (IH, m, CH), 3,74-3,80 (IH, m, CH), 3,34-3,41 (2H, m, CH), 3,28-3,33 (4H, m, 15 2*CH₂), 2,43-2,47 (4H, m, 2*CH₂), 2,23 (3H, s, CHj), 1,85-1,92 (IH, m, CH), 1,58-

1,65 (IH, m, CH), 1,45-1,55 (IH, m, CH), 1,22-1,34 (IH, m, CH). (ND: not determined). 26-14: 12.99 (IH, si, NH), 10.25 (IH, s, NH), 7.96 (IH, d, CHarom, lll

J=9.2Hz), 7.90-7.80 (IH, m, CHarom), 723-7.16 (3H, m, CHarom), 7.12-7.08 (IH, m, CHarom), 6.96 (IH, d, CHarom, J=8.8Hz), 6.87 (IH, s, CHarom), 5.31 (2H, s), 4.49-

4.42 (IH ,m), 3.86-3.75 (2H, m), 3.45 (IH, m), 3.37 (lH,m), 3.35 (4H, s), 2.42 (4H, s), 2.22 (3H, s), 1.90-1.75 (2H, m), 1.53-1.49 (IH, m), 1.31-1.25 (IH, m). 26-16: 13.00 (IH, s, NH), 1027 (IH, s, NH), 7.95 (IH, d, CHarom, J=8.8Hz), 7.89-7.84 (IH, m, CHarom), 7.50-7.40 (IH, m, CHarom), 7.35-720 (2H, m, CHarom), 7.12-7.09 (IH, m, CHarom), 6.94 (IH, d, CHarom, J=8.8Hz), 6.87 (IH, s, CHarom), 5.30 (2H, s), 4.52-

4.43 (IH, m), 3.85-3.75 (2H, m), 3.46-3.43 (IH, m), 3.36 (5H, s), 2.45 (4H, s), 222 (3H, s), 1.92-1.82 (2H, m), 1.60-1.52 (IH, m), 1.33-126 (IH, m). 26-20: 13.01 (IH, s, NH), 1022 (IH, s, NH), 7.97 (IH, d, CHarom, J=8.8Hz), 7.90-7.78 (3H, m, CHarom), 7.68-7.64 (IH, m, CHarom), 7.12-7.08 (IH, m, CHarom), 6.97 (IH, d, CHarom, J=8.8Hz), 6.85 (IH, s, CHarom), 5.43 (2H, s), 4.45-4.40 (IH, m), 3.86-3.70 (2H, m), 3.46-3.42 (IH, m), 3.30-328 (5H, m), 2.46 (4H, s), 2.23 (3H, s), 1.90 (IH, d, J=112Hz), 1.77 (IH, d,J=11.2Hz), 1.58-1.50 (1 H, m), 1.30-120(1H, m).

In certain cases, the major product of these reactions corresponds to the disubstituted product characterized by the additional fimctionalization of the pyrazolc ring. In these cases, this product is isolated and transformed into a monosubstituted product by treatment with a base as described below.

Example 27: N-(5-(3,5-dinuorophenylthio)-l-H-pyrazolo[3,4-b]pyrazine-3-yl)-4-(4methylplperazine-l-yI)-2-(tetrahydro-2H-pyran-4-y!amlno)benzamlde

Example 27a: N-(5-(3»5-difl«iorophenylthlo>-l-(4-(4-methyIpiperazine-l-yI)-2(2,2,2-trinuoro-N-(tetrahydro-2H-pyTan-4-yl)acetamldo)benzoyl)-lH-pyrazolo(3,4 b]pyrazine-3-yI)-4-(4-methyIpîperazIne-l-yI)-2-(2,22-trinuoro-N-(tetrahydro-2Hpyran-4-yl)acetamido)benzamide

112

1.51 ml (17.90 mmol) of oxalyl chloride and 2 drops of anhydrous dimethylformamidc are added to 4.74 g (8.95 mmol) of a solution of 4-(4-methylpiperazine-l-yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoic acid in 60 ml of dichlorométhane. The reaction mixture is stirred for 2 hours at room température. The solvents are evaporated, the solid formed is taken up in toluene and the solvent is evaporated; this operation is repeated three times until a white solid is obtained.

The acid chloride is added at 0°C in small fractions to 1 g (3.58 mmol) of 5-(3,5difluorophenylthio)-lH-pyrazolo[3,4-b]pyrazine-3-amine dissolved in 15 ml of pyridine. The reaction mixture is stirred at 25°C ovemight at room température. After évaporation of the solvent, the residue is purified by silica gel chromatography (90:10 dichloromcthanc/mcthanol and then 90:9:1 and then 90:5:5 dichlorométhane/ methanol/ammonium as eluent) to yield N-(5-(3,5-difluorophenylthio)-l-(4-(4methylpiperazine-1 -yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido) benzoyl)-1 H-pyrazolo[3,4-b]pyrazine-3-yl)-4-(4-methylpiperazine-1 -yI)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4-y[)acetamido)benzamide.

LCMS (El, m/z): (M+1) 1074.64.

Example 27: N-(5-(3,5-dlfluorophenylthIo)-l-H-pyrazolo[3/l-b]pyrazine-3-yI)-4(4-methylplperazlne-l-yl)-2-(tetrahydro-2H-pyran-4-ylamlno)benzamide.

0.27 ml (1.95 mmol) of triethylamine is added to 0.21 g (0.19 mmol) of a solution ofN(5-(3,5-difluorophenylthio)-l-(4-(4-methylpiperazine-l-yl)-2-(2,2,2-trifluoro-N(tetrahydro-2H-pyran-4-yl)acetamido)benzoyI)-1 H-pyrazolo[3,4-b]pyrazine-3-y!)-4-(4methylpipcrazine-1 -yl)-2-(2,2,2-trifluoro-N*(tctrahydro-2H'pyran-4-yl)acetamido) benzamide in 5 ml of methanol. The réaction medium is heated at 65°C for 4 hours, and then ovemight at room température. After évaporation of the solvent, the product is extracted several times with ethyl acetate. The organic phases are combined, washed with saturated sodium bicarbonate solution, dried on magnésium sulfate and concentrated. The residue is purified by silica gel chromatography (95:4:1 dichloromethane/methanol/ammonium as eluent) to yield 0.065 g (57%) of N-(5-(3,5difluorophenylthio)-1 -H-pyrazolo[3,4-b]pyrazine-3-yI)-4-(4-methylpiperazine-1 -yl>2(tctrahydro-2H-pyran-4-ylamino)benzamide in the form of a yellow solid.

LCMS (El, m/z): (M-l) 579.21.

113 ’H NMR: δΗ ppm (400 MHz, DMSO): 13.95 (IH, bs, NH), 10.25 (IH, bs, NH), 8.62 (IH, s, CH™), 8.27 (IH, d, NH), 7.80 (IH, d, CH™), 7.17-7.27 (3H, m, CH™), 6.27 (IH, d, CH™), 6.12 (IH, d, CH™), 3.79-3.82 (2H, m, CH), 3.67 (IH, m, CH), 3.453.50 (2H, m, CH), 3.26-3.29 (4H, m, CH), 2.42-2.44 (4H, m, CH), 2.22 (3H, s, CH₃),

1.90-1.93 (2H, m, CH), 1.31-1.36 (2H, m, CH).

The following compounds were obtained by the same method:

R*

Ex.**	Y	Ri	Rî	Y.	n	w	R*	Compound naines	Yield	Mass
27-1	O O-s	Q ^.NH	ό N «	CH	0	H	H	N-(5-(3> difiuorophenylsulfonyï)-1Hpyraz»lo[3,4-b]pyridîn-3jij-i-f+methylpipeTazin-1 yl)-2-(tetrahydrô-2H-pyTan4-yiamino)benzarnîdc	18,6%	(M+H) 612.13
27-2	A,	,NH	ό N ♦	N	0	H	H	N-(5-(33difluorophenylsulfïnyl)-1Hpyrazok>[3,4-b]pyTazin-3y1)-4-(4-methylpiperazin-1 yi)-2-(tetrahydro-2H-pyran4-ylamino)benzaniide	ND	(M+Na) 619.6
27-3	A	Q ,NH	ό N «	N	0	H	H	N-Î5O3difluorophenylsulfonyl)-! Hpyrarolo[3,4-b]pyTazin-3yl)-4-(4-nicthyipipcTazin-1 yl)-2-(tctrahydrô-2H-pyTan4-ylamino)betizaniÎde	ND	(M+H) 6133
27-4	H	Q ,NH	ό N *	CH	0	A	H	N-(643,5-difluorobcnzyl)- 1 H-pyrazolo[3,4-b]pyridin- 3-yl)-4-(4-inethyîpipCTazin- 1 -yl)-2-(tetrahydrô-2Hpyran-4-ylainino)bcnzamide	24%	(M+H) 562.00
27-5	H	Q ,NH	ό N t	CH	0	HN F	H	N-(6-(3> difluorobenzylammo)-! Hpyrazolo[3,4-b]pyridin-3yJ)-4-(4-methy1piperazin-l yl)-2-(tctTahydrô-2H-pyran4-ylamino)benzamidc	ND	(M-H) 275.1

114

Reactions carried out in pyridine often make it possible to modify the regioisomer distribution of the products. The following example is characteristic of a reaction of this type.

Example 27-bIs: N-(5-(N-(3^-dinuoropheny])su!famoyl)-lH-pyrazolo[3,4bIpyridin-3-yI)-4-(4-methyIpiperazIn-l-yI)-2-(2,24-trinuoro-N-(tetrahydro-2Hpyran-4-yI)acetamldo)benzamide

0.224 ml (2.63 mmol) of oxalyl chloride and 2 drops of anhydrous dimethylformamide are added to 0.697 g (1.316 mmol) of a solution of 4-(4-methylpiperazin-l-yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetainido)benzoic acid in 20 ml of dichloromethane. The reaction mixture is stirred for 2 hours at room température. The solvents are evaporated, the solid formed is redissolved in toluene and the solvent is evaporated. This operation is repeated three times until a white solid is obtained.

The acid chloride is dissolved in 5 ml of anhydrous pyridine and then the solution formed is added to a solution of 0.214 g (0.658 mmol) of 3-amino-N-(3,5difluorophcnyl)-lH-pyrazoîo[3,4-b]pyridinc-5-su!fonamidc in 5 m! of pyridine at 0°C. The reaction mixture is stirred for 3 hours at 0°C, and then ovemight at room température. The pyridine is evaporated and the crude reaction product is redissolved in toluene and then dry concentrated. The reaction mixture is diluted with saturated NaHCOi solution and extracted with ethyl acetate. The organic phase is dried on MgSO^, filtered and concentrated and the crude product is used directly in the deprotection reaction with no purification or characterization.

ht

115

The following compounds were obtained by the same method:

Rj

Ex.**	Y	Ri	Rî	Y.	n	w	Ri	Compound names	Yield	Mass
27bls-l	H		û N 4	CH	0	F	H	N-(6-(2,4-di fluoropheny Ithio)-1Hpyrazolo[3,4-b]pyridin-3-yl)-4-(4methylpipçrazin-1 -yl)-2-(2,2,2trifluoro-N-(tetrahydn>-2H-pyran4-yl)acctamido)benzamidc	ND	676.18 (M+H)
27bfc-2	H		ô N I	CH	0	HNX F	H	N-(6-(2,4-difluorophenylamino)- 1 H-pyi3zolo[3,4-b]pyridin-3-yl)4-(4-mcthylpipcrazin-1 -y I)-2(2J2,2-trifluoro-N-(tctrahydro-2HpyTaiF4-yl)acetanûdo)benzamidc	28%	657.13 (M-H)
27biS“3	H	Q ,ΝγΟ	ό N ♦	CH	0	''n F	H	N-(64(2,4difluorophenylXmcthyl) amino)1 H-pyrazo1o[3,4-b]pyridin-3-yI)4-(4-mcthylpiperazin-1 -y l)-2(2,2,2-trifluoro-N-(tctTahydro-2Hpyran-4-yl)acctamido)bcnzamidc	ND	671.05 (M-H)

Exampie of method E2:

Exampie 28: 5-(3^-difluorophenylthlo)-N-(4-(4-methylpiperazin-l-yl)benzyl)-lH’ pyrazolo[3,4-b]pyridin-3-amine

41.5 μΐ of trifluoroacetic acid (0.539 mmol) and, in small fractions, 129 mg 10 (0.611 mmol) of sodium triacetoxyborohydride are added to a solution of 100 mg (0.35 mmol) of 5-(3,5-difluoropheny!thio)-lH-pyrazolo[3,4-b]pyridin-3-amine and mg (0.395 mmol) of 4-(4-methylpiperazin-l-yI)benzaldehyde in 20 ml of a 1:1

U

116 mixture of dichloromethane and tetrahydrofuran. The reaction medium is stirred for hours at room température. An additional fraction of 125 μΐ of trifluoroacetic acid and 388 mg of sodium triacetoxyborohydride are added and the reaction medium is stirred for an additional 24 hours. The solvent is then concentrated and the reaction 5 medium extracted with ethyl acetate and washed using saturated sodium bicarbonate solution. The organic phases are combined, dried on magnésium sulfate and then concentrated to yield a yellow oil. A trituration of this oil in methanol leads to the isolation of 135 mg of a yellow solid.

LCMS (El, m/z): (M+1) 467.57.

‘H NMR: SH ppm (400 MHz, DMSO): 12.43 (IH, bs, NH), 8.49 (IH, d, CH™,), 8.47 (IH, d, CH.™), 7.25 (2H, d, CH™,), 7.03-7.08 (IH, m, CH.™), 6.89 (2H, d, CH™,), 6.76-6.77 (3H, m, NH and CH.™), 4.34 (2H, d, CH), 3.08 (4H, m, CH), 2.44 (4H, m, CH), 2.21 (3H, s, CHj).

The following dérivative was obtained according to the same method:

Rj

Ex.**	ArX	Ri	Ri	n	W	Rj	Compound name	Yield	Mass MH1
28-1		NO2	c5 N »	0	H	H	5-(3,5-difluorophenylthio)-N-(4(4-methylpiperazin-1 -y l>-2nitrobenzy 1)-1 H-pyrazo lo [3,4b]pyridin-3-aminc	91%	512.16

•♦‘H NMR, DMSO-de, Ex.: 23-1: 12.43 (IH, bs, NH), 8.49 (IH, d, CH™,), 8.47 (IH, d, CH.™), 7.51 (IH, d, CH™,), 7.45 (IH, m, CH.™), 7.27 (IH, m, CH™>), 7.03-7.08 (IH, m, CH.™), 7.00 (IH, t, NH), 6.77-6.80 (2H, m, CH™,), 4.63 (2H, d, CH), 3.19-

3.21 (4H, m, CH), 2.42-2.45 (4H, m, CH), 2.21 (3H, s, CHj).

Example of method E3 ll7

Example 29: l-(5-(3,5-dînuorophenyIthio)-lH-pyrazolo[3,4-b|pyridin-3-yI)-3-(4-(4methylpiperazin-l-yl)phenyl)thiourea

0.507 g (2.17 mmol) of l-(4-isothïocyanatophenyl)-4-methylpiperazine is added at 25°C to 0.540 g (2.17 mmol) of 3,5-difluorophcny!thio-lH-pyrazo!o[3,4-b]pyridin-3-amine dissolved in 12 m! of anhydrous dimethylacetamide. The mixture is left under stirring for 15 hours at 85°C. The reaction is treated by adding 20 ml of water and then is extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated. The product is purified by silica chromatography (15:1 dichloromethane/methanol as eluent) to yield 0.156 g (yield=15%) of 1 -( 1 -tert-buty 1-5(3,5-difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-niethylpiperazin-lyl)phenyl)thiourea in the form of a light brown solid.

LCMS (El, m/z): (M+1) 512.08.

’H NMR: δΗ ppm (400 MHz, DMSO): 13.69 (IH, bs, NH), 11.50 (IH, bs, NH), 11.19 (IH, bs, NH), 8.96 (IH, d, CH™,), 8.66 (IH, d, CH_arom), 7.41 (2H, d, CH™,), 7.10 (IH, ddd, CH™,), 6.95 (2H, d, CH™,), 6.89 (2H, bd, CH™,), 3.13-3.16 (4H, m, CH), 2.45-2.47 (4H, m, CH), 223 (3H, s, CH).

Example 29-bIs: l-(5-(3,5-dlfIuorophenylthio)-lH-pyrazolo[3,4-bIpyridÎn-3-yI)-3(4-(4-methylpiperazln-l-yl)phenyl)urea

0.048 g (1.19 mmol) of sodium hydride is added at 0°C to 0.200 g (0.598 mmol) of 1rert-buty!-5-(3,5-dîfluorophenylthio)-1 H-pyrazo!o[3,4-b]pyridin-3-amine dissolved in 10 ml of anhydrous dimethylacetamide. The reaction is left under stirring for 10 minutes. 0.130 g (0.598 mmol) of l-(4-isocyanatophenyI)-4-methylpÎperazine is then added at 0°C. The mixture is left under stirring for 3 hours at room température. The

ML

I18 reaction is treated by adding 20 ml of water drop by drop at 0°C and then is extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated. The product is purified by silica chromatography to yield 0.150 g (yield=45%) of l-(l-terr-buty!-5-(3,5-difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3yï)-3-(4-(4-methylpiperazm-l-yl)phenyl)urea in the formofa light brown solid.

LCMS (El, m/z): (M+1) 552.21.

'H NMR: 5H ppm (400 MHz, DMSO): 8.92 (IH, bs, NH), 8.58 (IH, bs, NH), 8.51 (IH, bs, CH.™), 8.30 (IH, bs, CH.™), 7.31 (2H, d, CH^), 7.05 (IH, m, CH.™), 6.83-6.85 (2H, m, CH™,), 3.03-3.08 (4H, m, CH), 2.45-2.48 (4H, m, CH), 2.21 (3H, s, CH), 1.76 (9H, s, CH).

A solution of 0.150 g (0.272 mmol) of l-(l-rert-butyl-5-(3,5-difluorophenylthîo)-lHpyrazolo[3,4-b]pyridin-3-y!)-3-(4-(4-methylpiperazin-l-yl)phenyl)urea dissolved in 20 ml of TFA (trifluoroacetic acid) is refluxed for 3 hours. The solvent is evaporated and the crude réaction product is diluted with saturated NaHCOj solution and extracted with ethyl acetate. The organic phase is dried on MgSO₄, filtered and concentrated. The solid obtained is triturated in methanol, filtered and dried. 110 mg (82%) of 1-(5-(3,5difluorophenylthio)-1 H-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-methyIpiperazin-1 -yl) phenyl)urea in the form of a beige solid is obtained.

LCMS (El, m/z): (M+1): 496.06.

’H NMR: 5Hppm (400 MHz, DMSO): 10.85 (IH, bs, NH), 9.57 (IH, bs, NH), 8.57 (IH, bs, CH™,), 8.30 (IH, bs, CH.™), 7.39 (2H, d, CH™,), 6.99 (IH, m, CH.™), 6.89 (2H, d, CH™,), 6.70 (2H, bd, CH™,), 3.03-3.08 (4H, m, CH), 2.45-2.48 (4H, m, CH), 2.21 (3H,s, CH).

Examples of method F

Examples of method Fl: deprotectlon

Example 30: N-(5-(3,5-dlfluorophenylthlo)-l-H-pyrazoloI3,4-b]pyridine-3-yl)-4(4-methylpiperazine-l-yI)-2-(tetrahydro-2H-pyran-4-ylamino)benzamIde

119

9.08 ml (65.1 mmol) oftriethylamine is added to 2 g (2.96 mmol) ofa solution ofN-(5(3,5-dîfluorophenyIthio)-lH-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpipcrazin-l-yl)-2(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acctanudo)benzamide in 65 ml of 5 methanoL The reaction medium is heated at 65°C for 2 hours, and then ovemight at room température. The precipïtate formed is filtered, rinsed with pentane, with water and then with diethyl ether, and then is dried under vacuum to yield 0.73 g (43%) of (N(5-(3,5-difluorophenylthio)-l-H-pyrazolo[3,4-b]pyridine-3-yl)-4-(4-methylpiperazine-lyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a white solid.

LCMS (El, m/z): (M+1) 580.23.

’H NMR: 6H ppm (400 MHz, DMSO): 13.59 (IH, bs, NH), 10.56 (IH, bs, NH), 8.61 (IH, s, CiU_ra), 8.50 (IH, s, CH.™), 8.17 (IH, d, NH), 7.80 (IH, d, CIU_ra), 7.07 (IH, m, CH.™), 6.86 (2H, m, CH.™), 6.23 (IH, d, CH.™), 6.13 (IH, d, CHU, 3.79-3.82 (2H, dt, CH), 3.60 (IH, m, CH), 3.45-3.50 (2H, m, CH), 3.21-3.33 (4H, m, CH), 2.4215 2.46 (4H, m, CH), 2.22 (3H, s, CH₃), 1.91-1.94 (2H, m, CH), 1.35-1.38 (2H, m, CH).

'et17324

120

The following dérivatives were obtained according to the same method:

M M «t S	ND	ND	(M+1) 626.14	ND	610.20	592.12	(M-l) 574.87
2	Q	Q	Q	Q	Q	Q	2
	Z	Z	Z	Z	Z	Z
	ά -y?	m T·* • >· o 111 m	ώ , K 01-8 Oil	• . m ♦ m ïâ-s ïal	X JL K 4 X 1 · A lx.â « E <i ϊ'Λ ΐ	1 't'?· m ” i ·	« 44 â.|^
o E	tii!	o S ·=· s S.-P*	-A.*** Ë 8 .2 .é « 8	E y G u
Compound na	6 .E yJj 0.7^-0 x g a*· e g «V .S s As Έ f-Γ S	U- OÂ 2 iii 10 i^g	~ έ O U fel δ ·? ~ Z! aâlî Ύ ο E r	l£s| szf | Λ .5 i C itï< m-	a § ç- s 6 AÇ.e Ί·4 i c <4 c x lïh	x ’S. 9· s X -5 X § Î?E aI ^ts ΕλΈ g	x I ô E àl 2 4 -S Έ o h B E Y* S x
	CJ. 8 .Ê-l <A g A2 Z E	— x x m •«M , ' ’ •A 2, Ύ ' Z^	*1 P.& t 2-p Ύ 0.5 * 1	s 3jh 4Ό A *—* Λ t	Y s .s- g S ε -s •Λ X « ε	US il J?	J1S tl x>
s?	S	X	S	Œ	x	X	X
					z	z	X
>	δ		5	Z rf	4> S	<J s	•
>· A >	4 Q	ô		?	8	8
	S	nf	rf	X*	U rf	O	CJ jf
		V		w	tj	U	U
	o	o	o	o	o	o	p
	o	U	o	Q	U	U	U
£	î	?	o 1	î	?	o 1	o 1
-W	c	G	c	C	G	C	c
	/X		/X	/~A	/-^	/X	Λ~Λ
Si	X__/	\S	\—/	V_7	\—f	X__f	X—/
	0-¾	0¾	0-¾	:0-¾	0¾	0¾	0-¾
ArX	/ « (f) rt>		A-	U.	'-0 IL.
« *.	W t O	M ô	f*» 1 e	Σ	«n	e	e
M M	<*)	f*ï		ΓΊ	r>	r>	ri

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(M+1) 627.20	(M+1) 562.42	(M+1) 594.11	(M+1) 579.11	(M+1) 579.11	r<S Ό «n	578.27	577.27
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130 ♦♦ ^lH NMR, DMSO-de, Ex.: 30-3: 13.86 (IH, bs, NH), I0.70 (IH, bs, NH), 8.67 (2H, bs, CH™), 8.10 (IH, d, NH), 7.77 (IH, d, CH™), 7.22 (IH, m, CH™), 6.95 (2H, d, CH™), 6.26 (IH, d, CH™), 6.16 (IH, bs, CH™), 4.85 (2H, bs, CH), 3.82-3.86 (2H, dt, CH), 3.70 (IH, m, CH), 3.47-3.53 (2H, m, CH), 3.28-3.32 (4H, m, CH), 2.42-2.46 (4H, m, CH), 2.20 (3H, s, CH₃), 1.94-1.98 (2H, m, CH), 1.34-1.41 (2H, m, CH).; 30-5: 13.25 (IH, bs, NH), 10.48 (IH, bs, NH), 8.42 (IH, s, CH™), 8.11 (IH, d, NH), 7.76 (IH, d, CH™), 7.00-7.10 (IH, m, CH™), 6.79-6.87 (2H, m, CH™), 6.23 (IH, dd, CH™), 6.12 (IH, d, CH™), 3.94 (3H, s, CH₃), 3.75-3.83 (2H, m, CH), 3.63-3.71 (IH, m, CH), 3.42-3.52 (2H, m, CH), 3.22-3.32 (4H, m, 2*CH₂), 2.36-2.48 (4H, m, 2*CH₂),

2.22 (3H, s, CH₃), 1.88-1.97 (2H, m, CH), 1.32-1.42 (2H, m, CH). 30-6: 13.10 (IH, bs, NH), 10.38 (IH, bs, NH), 8.56 (IH, s, CH™), 8.12 (IH, d, NH), 7.75 (IH, d, CH™),

6.23 (IH, dd, CH™), 6.14 (IH, d, CH™), 3.97 (3H, s, CHj), 3.80-3.86 (2H, m, CH), 3.62-3.74 (IH, m, CH), 3.40-3.55 (2H, m, CH), 3.22-3.32 (4H, m, 2*CH₂), 2.36-2.48 (4H, m, 2*CH₂), 2.23 (3H, s, CH₃), 1.90-1.99 (2H, m, CH), 1.32-1.45 (2H, m, CH). 307: 12.43 (IH, bs, NH), 10.22 (IH, bs, NH), 8.32(1H, s, CH™), 8.13(1H, d, NH), 7.73 (IH, d, CH™), 6.37 (2H, bs, NH₂), 6.22 (IH, dd, CH™), 6.13 (IH, d, CH™), 3.78-

3.86 (2H, m, CH), 3.65-3.74 (IH, m, CH), 3.44-3.54 (2H, m, CH), 3.22-3.32 (4H, m, 2*CH₂), 2.36-2.48 (4H, m, 2*CH₂), 2.23 (3H, s, CH₃), 1.90-1.99 (2H, m, CH), 1.32-

l. 45 (2H, m, CH). 30-8: 13.79 (IH, bs, NH), 10.91 (IH, bs, NH), 10.69 (IH, bs, NH), 8.83 (IH, s, CH™), 8.76 (IH, s, CH™), 8.18 (IH, d, NH), 7.80 (IH, d, CH™), 6.82-

6.75 (3H, m, CH™), 6.26 (IH, d, CH™), 6.15 (IH, d, CH™), 3.87-3.82 (2H, dt, CH), 3.72 (IH, m, CH), 3.54-3.47 (2H, m, CH), 3.32-3.29 (4H, m, CH), 2.42-2.46 (4H, m, CH), 2.28 (3H, s, CH₃), 1.97-1.95 (2H, m, CH), 1.43-1.36 (2H, m, CH). 30-13:12.99 (IH, s, NH), 9.92 (IH, s, NH), 8.38 (IH, d, NH, J=7.6Hz), 7.92 (IH, d, CHarom, J=8.4Hz), 7.84 (IH, d, CHarom, J=9.2Hz), 7.32 (IH, d, CHarom, J=8.4Hz), 7.07-7.00 (3H, m, CHarom), 6.26 (IH, d, CHarom, J=8.8Hz), 6.14 (IH, s, CHarom), 4.21 (2H, s), 3.82-3.76 (2H, m), 3.69-3.63 (IH, m), 3.48 (2H, t), 3.28 (4H, s), 2.46 (4H, s), 2.25 (3H, s), 2.00-1.90 (2H, m), 1.37-1.26 (2H, m). 30-14: 12.96 (IH, si, NH), 9.84 (IH, s, NH),

8.34 (IH, d, NH, J=7.6Hz), 7.96 (IH, d, CHarom, J=9.2Hz), 7.81 (IH, d, CHarom, J=8.8Hz), 7.25 (IH, s, CHarom), 7.23 (IH, s, CHarom), 7.17 (IH, t, CHarom), 6.96 (IH, d, CHarom, J=9.2Hz), 6.25 (IH, d, CHarom, >7.6Hz), 6.14 (IH, s, CHarom), 5.35 (2H, s), 3.82-3.77 (2H, m), 3.67 (IH, si), 3.46 (2H, t), 3.29 (4H, s), 2.50 (4H, s), 2.29 'S¹17324

I3l (3H,s), 1.93-1.88 (2H,m), 1.35-1.25 (2H,m). 30-15:13.01 (ΙΗ,δζΝΗ), 10.11 (IH, sL. NH), 7.99 (IH, si, NH), 7.97 (IH, d, CHarom, J=92Hz), 7.84 (IH, d, CHarom, J=8.4Hz), 7.25-7.14 (3H, m, CHarom), 6.97 (IH, d, CHarom, J=8.8Hz), 6.67 (IH, si, CHarom), 6.51 (IH, d, CHarom, J=8.0Hz), 5.35 (2H, s, CHarom), 3.83-3.78 (2H, m), 3.68-3.63 (IH, m), 3.47 (2H, t), 2.87 (2H, d, J=112Hz), 2.45-2.40 (IH, m), 2.19 (3H, s), 2.00-1.87 (4H, m), 1.75-1.65 (4H, m), 134-1.28 (2H, m). 30-16:12.95 (IH, si, NH),

9.85 (IH, s, NH), 8.33 (IH, d, NH, J=7.6Hz), 7.95 (IH, d, CHarom, J=8.8Hz), 7.81 (IH, d, CHarom, J=8.8Hz), 7.48 (IH, q, CHarom), 7.31-7.20 (2H, m, CHarom), 6.93 (IH, d, CHarom, J=92Hz), 6.25 (IH, d, CHarom, J=9.2Hz), 6.14 (IH, s, CHarom), 5.35 (2H, s), 3.81-3.76 (2H, m), 3.68 (IH, si), 3.47 (2H, t), 3.26 (4H, s), 2.44 (4H, s), 229 (3H, s), 1.94-1.88 (2H, m), 1.36-1.27 (2H, m). 30-17: 13.06 (IH, si, NH), 10.12 (IH, si, NH), 7.93 (IH, si, NH), 7.86 (2H, d, CHarom, J=8.4Hz), 7.51-7.44 (IH, m, CHarom), 7.307.20 (2H, m, CHarom), 6.90 (IH, si, CHarom), 6.64 (IH, si, CHarom), 6.49 (IH, si, CHarom), 537 (2H, s, CHarom), 3.83-3.76 (2H, m), 3.68-3.63 (IH, m), 3.46 (2H, t),

2.86 (2H, d, J=I0,4Hz), 2.44-238 (IH, m), 2.19 (3H, s), 1.99-1.90 (4H, m), 1.75-1.65 (4H, m), 1.40-130 (2H, m). 30-18: 12.94 (IH, si, NH), 9.81 (IH, s, NH), 832 (IH, d, CHarom, J=7.7Hz), 7.96 (IH, d, CHarom, J=9Hz), 7.81 (lH,d, CHarom, J=9Hz), 7.71 (IH, d, NH), 7.51 (IH, d, CHarom, J=8.6Hz), 7.43 (IH, dd, CHarom, J=8.6Hz), 6.97 (IH, d, CHarom, J=8.6Hz), 6.24 (IH, d, CHarom, J=8.9Hz), 6.13 (IH, s, CHarom), 5.39 (2H, s), 3.82-3.74 (2H, m), 3.72-3.62 (IH, m), 3.46 (2H, t), 3.28-3.22 (4H, m), 2.46-

2.40 (4H, m), 2.22 (3H, s), 1.95-1.87 (2H, m), 137-1.26 (2H, m). 30-19: 13.01 (IH, si, NH), 10.09 (IH, s, NH), 7.97 (2H, d, CHarom, J=9Hz), 7.83 (lH,d, CHarom, J=82Hz), 7.71 (IH, dd, NH), 7.50 (IH, d, CHarom, J=7.4Hz), 7.43 (IH, dd, CHarom, J=8.6Hz),

6.98 (IH, d, CHarom, J=9Hz), 6.67 (IH, s, CHarom), 6.51 (IH, d, CHarom, J=82Hz), 538 ( 2H, s), 3.84-3.75 (2H, m), 3.72-3.62 (IH, m), 3.46 (2H, t), 2.86 (2H, d), 2.43 (IH, m), 2.19 (3H, s), 1.99-1.88 (4H, m), 1.74-1.64 (4H, m), 138-1.26 (2H, m). 30-20: 12.97 (IH, si, NH), 9.82 (IH, s, NH), 832 (IH, d, NH, J=8.0Hz), 7.97 (IH, d, CHarom, J=8.8Hz), 7.87 (IH, s, CHarom), 7.80-7.76 (2H, m, CHarom), 7.64 (1H, d, CHarom, J=8.4Hz), 6.96 (IH, d, CHarom, J=8.8Hz), 624 (IH, d, CHarom, J=8.8Hz), 6.13 (IH, s, CHarom), 5.47 (2H, s), 3.81-3.76 (2H, m), 3.66 (IH, si), 3.46 (2H, t), 3.26 (4H, s), 2.43 (4H, s), 2.29 (3H, s), 1.93-1.88 (2H, m), 135-125 (2H, m). 30-21: 13.03 (IH, s, NH), 10.08 (IH, s, NH), 8.00-7.95 (2H, m, CHarom), 7.87-7.75 (3H, m, CHarom), 7.63 (IH,

132 d, CHarom,J=8.4Hz),6.97 (IH, d, CHarom,>8.8Hz), 6.67 (IH,s, CHarom), 6.51 (IH, d, CHarom, >8.0Hz), 5.47 (2H, s, CHarom), 3.83-3.76 (2H, m), 3.68-3.64 (IH, m),

3.47 (2H, t), 2.87 ( 2H, d, J=10.4Hz), 2.45-2.40 (IH, m), 2.20 (3H, s), 2.00-1.87 (4H, m), 1.74-1.65 (4H, m), 1.36-1.25 (2H, m). 30-22: 12.93 (IH, s, NH), 9.86 (IH, s, NH), 8.70 (IH, s, CHarom), 8.51 (IH, dd, CHarom, J=5.2Hz), 8.38 (IH, d, NH, J=8.0Hz), 7.96-7.90 (2H, m, CHarom), 7.84 (IH, d, CHarom, J=8.8Hz), 7.73-733 (IH, m, CHarom), 6.91 (IH, d, CHarom, J=8.8Hz), 637 (IH, d, CHarom, J=8.8Hz), 6.15 (IH, s, CHarom), 5.35 (2H, s), 3.83-3.77 (2H, m), 3.70-3.64 (IH, m), 3.47 (2H, t). 3.59 (4H, s),

2.59 (4H, s), 234 (3H, s), 1.95-1.88 (2H, m), 1.40-1.28 (2H, m). 30-23: 13.03 (IH, s, NH), 10.17 (IH, s, NH), 8.70 (IH, s, CHarom), 8.52 (IH, dd, CHarom, J=4.8Hz), 8.06 (IH, d, NH, J=7.6Hz), 7.96 (IH, d, CHarom, J=8.8Hz), 7.94-7.88 (2H, m, CHarom), 7.37-734 (IH, m, CHarom), 6.93 (IH, d, CHarom, J=9.2Hz), 6.69 (IH, s, CHarom), 6.52 (IH, d, CHarom, J=8.0Hz), 536 (2H, s, CHarom), 3.83-3.79 (2H, m), 3.68-3.64 (IH, m), 3.46 (2H, t), 3.25-3.15 (2H, m), 2.65-2.55 (3H, m), 2.54 (3H, s), 2.00-1.85 (6H, m), 1.41-1.28 (2H, m). 30-24: 13.21 (IH, s, NH), 10.00 (IH, s, NH), 830 (IH, d, NH, J=7.6Hz), 8.00 (IH, d, CHarom, J=8.8Hz), 7.79 (IH, d, CHarom, J=93Hz), 733 (IH, d, CHarom, J=8.8Hz), 7.26-7.16 (3H, m, CHarom), 6.24 (IH, d, CHarom, J=8.8Hz), 6.13 (IH, s, CHarom), 4.06-3.99 (2H, m), 3.67 (IH, si), 3.47 (2H, t), 3.28 (4H, s), 2.47 (4H, s), 2.25 (3H, s), 1.94-1.88 (2H, m), 137-1.26 (2H, m). 30-25: 13.26 (IH, s, NH), 10.28 (IH, s, NH), 8.02 (IH, d, CHarom, J=8.8Hz), 7.97 (IH, d, NH, >7.6Hz), 7.83 (IH, d, CHarom, J=8.0Hz), 734 (IH, d, CHarom, J=8.8Hz), 7.27-7.17 (3H, m, CHarom), 6.68 (IH, s, CHarom), 6.51 (IH, d, CHarom, J=8.0Hz), 3.85-3.78 (2H, m), 3.71-3.65 (IH, m), 3.47 (2H, t), 2.87 (2H, d, J=113Hz), 2.48-2.40 (IH, m),

2.19 (3H, s), 1.98-1.88 (4H, m), 1.74-1.66 (4H, m), 136-1.27 (2H, m). 30-26: 13.12 (IH, s, NH), 9.95 (IH, s, NH), 832 (IH, d, NH, J=7.6Hz), 7.93 (IH, d, CHarom, J=8.8Hz), 7.79 (IH, d, CHarom, J=8.8Hz), 7.73 (IH, t, CHarom), 7.52-7.40 (2H, m, CHarom), 7.12 (IH, d, CHarom, J=8.8Hz), 635 (IH, d, CHarom, J=8.8Hz), 6.13 (IH, s, CHarom), 3.83-3.77 (2H, m), 3.69 (IH, si), 3.48 (2H, t), 3.28 (4H, s), 2.44 (4H, s), 2.27 (3H, s), 1.96-1.89 (2H, m), 137-137 (2H, m). 30-27: 13.17 (IH, s, NH), 10.21 (IH, s, NH), 7.99-7.92 (2H, m, CHarom et NH), 7.81 (IH, d, CHarom, J=8.4Hz), 7.77-7.70 (IH, m, CHarom), 7.51-7.40 (2H, m, CHarom), 7.13 (IH, dd, CHarom, J=8.8Hz), 6.69 (IH, s, CHarom), 6.51 (IH, d, CHarom, J=8.4 Hz), 3.85-3.78 (2H, m), 3.72-3.67 (IH,

VL

133

m), 3.48 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.47-2.40 (IH, m), 2.20 (3H, s), 1.96-1.87 (4H, m), 1.75-1.65 (4H, m), 138-1.28 (2H, m). 30-28:1331 (IH, si, NH), 9.95 (IH, si, NH), 831 (1H, d, NH, >7.6Hz), 7.99 (1H, d, CHarom, J=7.6Hz), 7.78 (IH, d, CHarom, J=92Hz), 7.58-7.49 (3H, m, CHarom), 731 (IH, d, CHarom, J=8.8Hz), 6.24 (IH, d, CHarom, J=8.8Hz), 6.10 (IH, s, CHarom), 3.83-3.76 (2H, m), 3.70-3.60 (IH, m), 3.45 (2H, t), 3.21 (4H, s), 2.43 (4H, s), 2.22 (3H, s), 1.94-1.86 (2H, m), 138-1.28 (2H, m). 30-29; 13.26 (IH, s, NH), 10.25 (IH, s, NH), 8.01 (IH, d, CHarom, J=8.8Hz), 7.94 (IH, d, NH, J=7.6Hz), 7.82 (IH, d, CHarom, J=8.4Hz), 7.59-7.54 (3H, m, CHarom), 732 (IH, d, CHarom, J=8.8Hz), 6.67 (IH, s, CHarom), 6.54 (IH, d, CHarom, J=7.6Hz), 3.84-3.78 (2H, m), 3.71-3.62 (IH, m), 3.47 (2H, t), 2.87 (2H, d, J=112Hz), 2.45-2.41 (IH, m), 2.19 (3H, s), 1.96-1.90 (4H, m), 1.74-1.68 (4H, m), 1.34-127 (2H, m). 30-30: 1323 (IH, s, NH), 9.98 (IH, s, NH), 829 (IH, d,NH, J=7.6Hz), 8.01 (IH, d, CHarom, J=8.8Hz), 7.79 (IH, d, CHarom, J=8.8Hz), 7.62 (IH, d, CHarom, J=8.4Hz), 7.52 (IH, s, CHarom), 7.44 (IH, d, CHarom, J=7.6Hz), 724 (IH, d, CHarom, J=8.4Hz), 625 (IH, d, CHarom, J=8.0Hz), 6.12 (IH, s, CHarom), 3.82-3.75 (2H, m), 3.73-3.67 (IH, m), 3.47 (2H, t), 327 (4H, s), 2.43 (4H, s), 222 (3H, s), 1.95-1.87 (2H, m), 135-128 (2H, m). 30-31:1328 (IH, s, NH), 1025 (IH, s, NH), 8.02 (IH, d, CHarom, J=8.8Hz), 7.95 (IH, d, NH, J=7.6Hz), 7.81 (IH, d, CHarom, J=8.0Hz), 7.61 (1 H, d, CHarom, J=8.4Hz), 7.56 (IH, s, CHarom), 7.43 (IH, dd, CHarom, J=8.4Hz), 725 (IH, d, CHarom, J=8.8Hz), 6.68 (IH, s, CHarom), 6.51 (IH, d, CHarom, J=7.2 Hz), 3.84-3.78 (2H, m), 3.69-3.61 (IH, m), 3.47 (2H, t), 2.87 (2H, d, J=112Hz), 2.47-2.41 (IH, m), 220 (3H, s), 2.00-1.90 (4H, m), 1.76-1.69 (4H, m), 1.40-130 (2H, m). 30-32: 13.16 (IH, s, NH), 9.95 (IH, s, NH), 8.33 (IH, d, NH, J=8.0Hz), 7.93 (IH, d, CHarom, J=8.8Hz), 7.89 (IH, d, CHarom, J=9.2Hz), 7.79 (IH, d, CHarom, J=92Hz), 7.70-7.63 (2H, m, CHarom), 7.60 (IH, t, CHarom), 6.97 (IH, d, CHarom, J=8.8Hz), 625 (IH, d, CHarom, J=9.2Hz), 6.14 (IH, s, CHarom), 3.83-3.78 (2H, m), 3.68 (IH, si), 3.48 (2H, t), 3.28 (4H, s), 2.44 (4H, s), 223 (3H, s), 1.95-1.90 (2H, m), 1.38-128 (2H, m). 30-33: 1321 (IH, s, NH), 1022 (1H, s, NH), 7.99 (IH, d, NH, >7.6Hz), 7.94 (IH, d, CHarom, J=9.2Hz), 7.89 (IH, d, CHarom, J=72Hz), 7.82 (IH, d, CHarom, J=8.4Hz), 7.71-7.57 (3H, m, CHarom), 6.98 (IH, d, CHarom, J=8.8Hz), 6.69 (IH, s, CHarom), 6.52 (IH, d, CHarom, J=8.0 Hz), 3.85-3.79 (2H, m), 3.72-3.62 (IH, m), 3.48 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.47-2.41 (IH, m), 2.19 (3H, s), 2.00-1.90 (4H, m), 1.76-1.69 (4H, m), 1.4017324

134

1.30(2H,m). 30-34:13.07(IH,s,NH), ÎO.11 (IH,s,NH), 8.32 (IH, d, NH, J=7.6Hz),

7.90-7.85 (2H, m, CHarom), 7.22 (IH, d, CHarom, J=8.8Hz), 7.19 (IH, s, CHarom),

7.17 (IH, s, CHarom), 7.03 (IH, t, CHarom), 6.30 (IH, d, CHarom, J=8.4Hz), 6.19 (IH, s, CHarom), 4.43 (2H, s), 4.02 (2H, si), 3.80-3.74 (2H, m), 3.67 (IH, si), 3.44 (2H, t),

3.10 (4H, s), 2.84 (3H, s), 1.89-1.84 (2H, m), 1.30-1.14 (4H, m). 30-35: 13.08 (IH, s,

NH), 10.28 (IH, s, NH), 7.96 (IH, d, NH, J=7.6Hz), 7.88 (IH, d, CHarom, J=8.8Hz),

7.86 (1 H, d, CHarom, J=6.8Hz), 7.22 (IH, d, CHarom, J=8.8Hz), 7.18 (IH, s, CHarom),

7.17 (IH, s, CHarom), 7.02 (IH, t, CHarom), 6.66 (IH, s, CHarom), 6.51 (IH, d, CHarom, J=8.4Hz), 4.43 (2H, s), 3.80-3.74 (2H, m), 3.64 (IH, si), 3.44 (2H, t), 2.8910 2.84 (2H, m), 2.43 (IH, si), 2.20 (3H, s), 1.98-1.95 (2H, m), 1.89-1.84 (2H, m), 1.72-

l. 69 (4H, m), 1.29-1.20 (2H, m). 30-36: 13.10 (IH, si, NH), 10.11 (IH, s, NH), 9.73 (IH, si, COOH), 8.34 (IH, si, NH), 7.92-7.86 (2H, m, CHarom), 7.47-7.40 (1H, m, CHarom),7.23 (IH,d, CHarom, J=8.8Hz), 7.20-7.13 ( IH,m, CHarom), 7.11-7.05(IH, m, CHarom), 6.31 (IH, dd, CHarom, J=92Hz), 6.20 (IH, s, CHarom), 4.41 (2H, s),

4.04 (2H, d, >8.8Hz), 3.81-3.75 (2H, m), 3.70-3.66 (IH, m), 3.51 (2H, d, J=112Hz),

3.44 (2H, t), 3.16-2.97 ( 4H, m), 2.87 (3H, s), 1.91-1.84 (2H, m), 1.34-122 (2H, m). 3037:13.09 (IH, s, NH), 10.29 (IH, s, NH), 7.97 (IH, d, NH, J=7.6Hz), 7.90-7.86 (2H, m,

CHarom), 7.47-7.41 (IH, m, CHarom), 7.23 (IH, d, CHarom, J=8.8Hz), 7.19-7.13 ( IH, m, CHarom), 7.11-7.05 ( IH, m, CHarom), 6.67 (IH, s, CHarom), 6.52 (IH, d, 20 CHarom, J=8.0Hz), 4.41 (2H, s), 3.79-3.74 (2H, m), 3.66-3.62 (IH, m), 3.44 (2H, t),

2.86 ( 2H, d, >112Hz), 2.45-2.40 (IH, m), 2.19 (3H, s), 2.00-1.85 (4H, m), 1.74-1.65 (4H, m), 1.33-123 (2H, m). 30-38: 13.02 (IH, s, NH), 10.04 (IH, s, NH), 828 (IH, d,

NH, J=8.0Hz), 7.88-7.84 (2H, m, CHarom), 7.74 (IH, s, CHarom), 7.43 (IH, d, CHarom, J=8.8Hz), 729 (IH, dd, CHarom, J=8.4Hz), 7.22 (IH, d, CHarom, >8.8Hz),

625 (IH, dd, CHarom, J=9.2Hz), 6.12 (IH, s, CHarom), 4.50 (2H, s), 3.78-3.74 (2H,

m), 3.66-3.62 (IH, m), 3.44 (2H, t), 326 (4H, s), 2.43 ( 4H, s), 222 (3H, s), 1.91-1.84 (2H, m), 1.35-1.23 (2H, m). 30-39: 13.09 (IH, s, NH), 10.32 (IH, s, NH), 8.28 (IH, d,

NH, J=8.0Hz), 7.90 (2H, D, CHarom), 7.74 (IH, s, CHarom), 7.43 (IH, d, CHarom, J=8.4Hz), 729 (IH, dd, CHarom, J=8.4Hz), 725 (IH, d, CHarom, J=8.8Hz), 6.67 (IH, 30 s, CHarom), 6.54 (IH, dd, CHarom, J=8,4Hz), 4.51 (2H, s), 3.79-3.76 (2H, m), 3.70-

3.64 (IH, m), 3.44 (2H, t), 2.95-2.92 (2H, m), 2,52-2,51 (IH, m), 2.27 (3H, s), 2.13-

2,01 (2H, m), 1,90-1,87 (2H, m) 1.77-1.69 (4H, m), 1.32-124 (2H, m). 30-40: 12.77

135 (IH, s, NH), 9.86 (IH, s, NH), 9.60 (IH, s, NH), 8.40 (IH, d, NH, J=7.6Hz), 7.86 (IH, d, CHarom, J=8.8Hz), 7.83 (IH, d, CHarom, J=92Hz), 7.56 (2H, d, CHarom, J=8.8Hz), 6.93 (IH, d, CHarom, J=92Hz), 6.55 (IH, t, CHarom), 6.23 (IH, dd, CHarom, J=92Hz), 6.13 (IH, s, CHarom), 3.82-3.75 (2H, m), 3.69-3.61 (IH, m), 3.46 (2H, t), 3.27 (4H, s), 2.44 (4H, s), 2.29 (3H, s), 1.96-1.88 (2H, m), 1.38-1.26 (2H, m). 30-41: 12.85 (IH, si, NH), 10.13 (IH, s, NH), 9.62 (IH, s, NH), 8.03 (IH, d, NH, J=72Hz), 7.90-7.84 (2H, m, CHarom), 7.57 (2H, dd, CHarom, J=10.4Hz), 6.95 (IH, d, CHarom, J=8.8Hz), 6.68 (IH, s, CHarom), 6.60-6.50 (2H, m, CHarom), 3.83-3.78 (2H, m), 3.683.63 (IH, m), 3.46 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.45-2.40 (IH, m), 2.20 (3H, s), 2.00-1.92 (4H, m), 1.75-1.65 (4H, m), 1.37-127 (2H, m). 30-42: 12.77 (IH, s, NH),

9.87 (IH, s, NH), 9.02 (IH, s, NH), 8.80-8.72 (IH, m, CHarom), 8.41(1H, d, NH, J=7.6Hz), 7.86 (IH, d, CHarom, J=8.8Hz), 7.83 (IH, d, CHarom, J=92Hz), 7.28 (IH, d, CHarom, J=9.2Hz), 7.22-7.15 (IH, m, CHarom), 6.63-6.57 (IH, m, CHarom), 6.23 (IH, d, CHarom, J=8.8Hz), 6.13 (IH, s, CHarom), 3.83-3.75 (2H, m), 3.70-3.64 (IH, m),

3.46 (2H, t), 327 (4H, s), 2.44 (4H, s), 223 (3H, s), 1.95-1.88 (2H, m), 1.39-126 (2H, m). 30-43: 12.84 (IH, s, NH), 10.13 (IH, s, NH), 9.05 (IH, si, NH), 8.81-8.74 (IH, m, CHarom), 8.05 (IH, d, NH, J=7.2Hz ), 7.89-7.84 (2H, m, CHarom), 7.30 (IH, d, CHarom, J=8.8Hz), 723-7.15 (IH, m, CHarom), 6.67 (IH, s, CHarom), 6.64-6.58 (IH, m, CHarom), 6.51 (IH, d, CHarom, J=8.4Hz), 3.83-3.76 (2H, m), 3.68-3.64 (IH, m),

3.47 (2H, t), 2.89 ( 2H, d, J=10.8Hz), 2.45-2.40 (IH, m), 221 (3H, s), 2.01-1.91 (4H, m), 1.74-1.66 (4H, m), 1.38-1.27 (2H, m). 30-44: 12.80 (IH, s, NH), 10.16 (IH, s, NH), 8.89 (IH, s, CHarom), 8.52 (IH, s, NH), 8.34 (IH, d, NH, J=7.6Hz), 7.89 (IH, d, CHarom, J=9.2Hz), 7.81 (IH, d, CHarom, J=9.2Hz), 7.41 (IH, d, CHarom, J=8.8Hz), 7.35 (IH, d, CHarom, J=9.2Hz), 6.89 (IH, dd, CHarom, J=8.4Hz), 621 (IH, d, CHarom, J=92Hz), 6.11 (1 H, s, CHarom), 3.83-3.75 (2H, m), 3.66-3.60 (IH, m), 3.46 (2H, t), 325 (4H, s), 2.44 (4H, s), 2.23 (3H, s), 1.95-1.87 (2H, m), 1.37-126 (2H, m). 30-45: 12.86 (IH, s, NH), 10.10 (IH, s, NH), 8.91 (IH, s, CHarom), 8.54 (IH, s, NH), 8.00 (IH, d, NH, J=7.6Hz ), 7.90 (IH, d, CHarom, >9.2Hz), 7.85 (IH, d, CHarom, J=8.0Hz), 7.41 (IH, d, CHarom, J=8.4Hz), 7.37 (IH, d, CHarom, J=92Hz), 6.88 (IH, dd, CHarom, >8.4 Hz), 6.64 (IH, s, CHarom), 6.48 (IH, d, CHarom, J=8.4Hz), 3.833.77 (2H, m), 3.67-3.60 (IH, m), 3.47 (2H, t), 2.88 (2H, d, J=11.2Hz), 2.45-2.38 (IH, m), 221 (3H, s), 2.00-1.87 (4H, m), 1.75-1.65 (4H, m), 1.37-126 (2H, m). 30-46:13.74

136 (IH, si, NH), 10.14 (IH, s,NH), 8.62 (IH, s, CHarom), 8.33 (IH, d,NH), 7.81 (IH, d, CHarom, J=8.7Hz), 7.12-7.03 (3H, m, CHarom), 6.26 (IH, d, CHarom, J=8.8Hz), 6.13 (IH, s, CHarom), 4.31 (2H, s), 4.14-4.07 (4H, m), 3.68 (IH, si), 3.28 (4H, s), 2.43 (4H, s), 2.23 (3H, s), 1.92 (2H, d, J=12.4Hz), 1.38-1.26 (2H, m). 30-47; 13.80 (IH, si, NH), 10.41 (IH, s, NH), 8.64 (IH, s, CHarom), 8.02 (IH, d, NH), 7.85 (IH, d, CHarom, J=8.1Hz), 7.12-7.03 (3H, m, CHarom), 6.69 (IH, s, CHarom), 6.52 (IH, d, CHarom, J=8.1Hz), 4.30 (2H, s), 3.81 (2H, d, J=ll.lHz), 3.68 (IH, si), 3.48 (2H, t), 2.87 (2H, d, J=10.5Hz), 2.47-2.39 (IH, si), 2.19 (3H, s), 2-1.88 (4H, m), 1.76-1.66 (4H, m), 139-

1.27 (2H, m). 30-48:13.99 (IH, si, NH), 10.17 (IH, s, NH), 8.34 (IH, s, CHarom), 8.29 (IH, dl, NH), 7.78 (IH, d, CHarom, J=8.9Hz), 7.54-7.41 (3H, m, CHarom), 6.07 (IH, d, CHarom, J=8.9Hz), 5.87 (IH, s, CHarom), 3.82 (2H, dl), 3.62 (IH, si), 3.51-3.37 (4H, m), 2.97 (3H, s), 2.28-2.19 (2H, m), 2.15 (6H, s), 2-1.90 (2H, m), 1.71-1.61 (2H, m), 1.42-1.28 (2H, m). 30-49:14.06 (IH, si, NH), 10.56 (IH, s, NH), 8.85 (IH, s, CHarom),

7.97 (IH, si, NH), 7.85 (IH, d, CHarom, J=8.1Hz), 7.50-7.40 (3H, m, CHarom), 6.71 (IH, s, CHarom), 6.54 (IH, d, CHarom, J=8.1Hz), 3.83-3.76 (2H, m), 3.70 (IH, si),

3.48 (2H, t), 2.88 (2H, d, J=10.6Hz), 2.48-2.40 (IH, m), 2.20 (3H, s), 2.01-1.89 (4H, m), 1.76-1.66 (4H, m), 1.40-128 (2H, m). 30-50: 13.94 (IH, si, NH), 10.11 (IH, si, NH), 8.59 (IH, s, CHarom), 830 (1H, si, NH), 7.76 (1H, d, CHarom, J=92Hz), 7.27-

7.13 (3H, m, CHarom), 6.04 (IH, dd, CHarom, J=92Hz), 5.85 (IH, s, CHarom), 3.87-

3.76 (2H, m), 3.66-3.55 (IH, m), 3.49-3.26 (4H, m), 2.96 (3H, s), 2.22 (2H, t), 2.14 (6H,

s) , 1.97-1.89 (2H, m), 1.69-1.60 (2H, q), 1.40-128 (2H, m). 30-51: 13.95 (IH, si, NH),

10.17 (IH, si, NH), 8.54 (IH, s, CHarom), 8.28 (1H, si, NH), 7.78 (IH, d, CHarom, J=8.8Hz), 7.59 (IH, d, CHarom, J=92Hz), 7.42-7.38 (2H, m, CHarom), 6.23 (IH, d, CHarom, J=8.0Hz), 6.11 (IH, s, CHarom), 3.82-3.77 (2H, m), 3.66 (IH, si), 3.46 (2H,

t) , 3.26 (4H, s), 2.43 (4H, s), 2.22 (3H, s), 1.92-1.88 (2H, m), 134-1.24 (2H, m). 30-52:

13.97 (IH, si, NH), 10.20 (IH, s, NH), 838 (IH, s, CHarom), 8.27 (IH, d, NH), 7.88 (1H, d, CHarom, J=72Hz), 7.78 (IH, d, CHarom, J=9.2Hz), 7.66-7.55 (3H, m, CHarom), 6.26 (IH, dd, CHarom, J-9.2Hz), 6.13 (IH, s, CHarom), 3.85-3.76 (2H, m), 3.75-3.63 (IH, m), 3.48 (2H, t), 337-326 (4H, m), 2.61-2.52 (4H, m), 232 (3H, si), 1.96-1.88 (2H, m), 139-126 (2H, m). 30-53: 13.64 (IH, s, NH), 1020 (IH, s, NH), 830 (IH, d, CHarom, J=8.8Hz), 823 (IH, d, CHarom, J=8.0Hz), 8.19 (IH, d, CHarom, J=8.8Hz), 7.81 (IH, d, CHarom, J=9.2Hz), 7.75-7.65 (3H, m, CHarom), 628 (IH. dd,

137

CHarom, >8.8Hz), 6.14 (IH, s, CHarom), 3.83-3.77 (2H, m), 3.70-3.64 (IH, m), 3.48 (2H, t), 3.29 (4H, s), 2.44 (4H, s), 2.23 (3H, s), 1.95-1.89 (2H, m), 1.38-1.26 (2H, m).

30-54: 13.64 (IH, si, NH), 10.48 (IH, si, NH), 8.32 (IH, d, CHarom, >8.8Hz), 8.19 (IH, d, CHarom, >8.8Hz), 7.91 (IH, si, NH), 7.85 (IH, d, CHarom, >8.4Hz), 7.775 7.65 (3H, m, CHarom), 6.71 (IH, s, CHarom), 6.54 (IH, d, CHarom, J=8.4Hz), 3.86-

3.80 (2H, m), 3.71-3.64 (IH, m), 3.48 (2H, t), 2.89 (2H, d, J=112Hz), 2.45-2.40 (IH, m), 221 (3H, s), 2.00-1.90 (4H, m), 1.75-1.65 (4H, m), 1.38-1.27 (2H, m). 30-55: 13.64 (IH, s, NH), 10.16 (IH, s, NH), 8.29 (IH, d, CHarom, J=8.8Hz), 8.24 (IH, d, NH, J=7.6Hz), 8.17 (IH, d, CHarom, J=8.8Hz), 8.09 (IH, t, CHarom), 7.88-7.85 (IH, m,

CHarom), 7.81 (IH, d, CHarom, >9.2Hz), 7.67 (IH, q, CHarom), 6.28 (IH, d,

CHarom, >8.8Hz), 6.14 (IH, s, CHarom), 3.83-3.75 (2H, m), 3.72-3.67 (IH, m), 3.48 (2H, t), 3.29 (4H, s), 2.44 (4H, s), 2.23 (3H, s), 1.96-1.89 (2H, m), 1.35-1.28 (2H, m).

30-56:13.67(1H, s,NH), 10.43 (IH, s,NH), 8.31 (IH, d, CHarom, J=8.8Hz), 8.18(1 H, d, CHarom, >8.8Hz), 8.13-8.05 (IH, m, CHarom), 7.92 (IH, d, NH, >7.6Hz), 7.9015 7.82 (2H, m, CHarom), 7.66 (IH, q, CHarom), 6.71 (IH, s, CHarom), 6.54 (IH, d,

CHarom, >8.4Hz), 3.85-3.80 (2H, m), 3.73-3.65 (IH, m), 3.49 (2H, t), 2.89 (2H, d, J=11.2Hz), 2.48-2.42 (IH, m), 2.21 (3H, s), 1.99-1.90 (4H, m), 1.76-1.68 (4H, m), 1.37-

1.27 (2H, m). 30-57: 13.66 (IH, s, NH), 10.17 (IH, s, NH), 830 (IH, d, CHarom,

J=8.8Hz), 8.24-8.16 (2H, m, CHarom etNH), 8.03-7.97 ( 3H, m, CHarom), 7.81 (IH, d,

CHarom, J=9.2Hz), 6.28 (IH, d, CHarom, J=7.2Hz), 6.14 (IH, s, CHarom), 3.83-3.77 (2H, m), 3.71-3.67 (IH, m), 3.48 (2H, t), 3.29 (4H, s), 2.44 (4H, s), 2.23 (3H, s), 1.961.89 (2H, m), 1.34-1.28 (2H, m). 30-58: 13.71 (IH, s, NH), 10.45 (IH, s, NH), 832 (IH, d, CHarom, J=9.2Hz), 8.22 (IH, d, CHarom, >8.8Hz), 8.02-7.96 (3H, m,

CHarom), 7.86-7.81 (IH, m, NH), 7.83 (IH, d, Charom), 6.71 (IH, s, CHarom), 6.54 25 (IH, d, CHarom, >7.6Hz), 3.85-3.78 (2H, m), 3.72-3.65 (IH, m), 3.48 (2H, t), 2.88 (2H, d, J=11.2Hz), 2.48-2.44 (IH, m), 2.21 (3H, s), 1.97-1.87 (4H, m), 1.76-1.70 (4H, m), 1.36-1.28 (2H, m). 30-59: 13.69 (IH, s, NH), 10.04 (IH, s, NH), 834 (IH, d, NH, >8.8Hz), 8.26-8.16 (3H, m, CHarom), 7.81 (IH, dd, CHarom, >8.4Hz), 7.74 (IH, d,

CHarom, >92Hz), 7.66 (IH, d, CHarom, J=8.4Hz), 6.24 (IH, dd, CHarom, >9.2Hz), 30 6.10 (IH, s, CHarom), 3.82-3.76 (2H, m), 3.68-3.62 (IH, m), 3.48 (2H, t), 3.27 (4H, s),

2.43 (4H, s), 2.22 (3H, s), 1.93-1.86 (2H, m), 131-1.21 (2H, m). 30-60: 13.74 (IH, s,

NH), 10.31 (IH, s, NH), 835 (IH, d, CHarom, J=8.8Hz), 8.25 (IH, d, CHarom,

138

J=8.8Hz), 8.21 (IH, s, CHarom), 7.85 (IH, d, NH, J=72Hz), 7.81 (IH, dd, CHarom,

J=8.8Hz), 7.76 (IH, d, CHarom, J=8.0Hz), 7.66 (IH, d, CHarom, >8.8Hz), 6.67 (IH, s,

CHarom), 6.50 (IH, d, CHarom, J=8.0Hz), 3.85-3.78 (2H, m), 3.68-3.62 (IH, m), 3.48 (2H, t), 2.87 (2H, d, J=ll2Hz), 2.46-2.40 (IH, m), 220 (3H, s), 1.97-1.87 (4H, m),

l. 75-1.67 (4H, m), 1.32-1.24 (2H, m). 30-61: 13.61 (IH, s, NH), 10.32 (IH, s, NH), 8.71 (IH, d, NH, J=8.0Hz), 821 (IH, d, CHarom, >8.8Hz), 7.87 (IH, d, CHarom, J=9.2Hz), 7.80 (IH, d, CHarom, J=8.8Hz), 7.17 (IH, t, CHarom), 7.05-7.02 (2H, m, CHarom), 6.29 (IH, d, CHarom, J=9.2Hz), 6.14 (IH, s, CHarom), 4.93 (2H, s), 3.743.68 (3H, m), 3.43 (2H, t), 329 (4H, s), 2.44 ( 4H, s), 228 (3H, s), 1.90-1.84 (2H, m), 128-120 (2H, m). 30-62:13.67 (IH, si, NH), 10.59 (IH, s, NH), 823 (IH, d, CHarom, J=8.8Hz), 8.10 (IH, d, NH, J=7.6Hz), 7.92 (IH, d, CHarom, J=8.0Hz), 7.82 (IH, d, CHarom, J=8.8Hz), 7.17 (IH, t, CHarom), 7.05-7.02 (2H, m, CHarom), 6.71 (IH, s, CHarom), 6.56 (IH, d, CHarom, J=8.0Hz), 4.94 (2H, s), 3.77-3.70 (3H, m), 3.43 (2H, t),

2.87 (2H, d, J=11.2Hz), 2.45-2.40 (IH, m), 220 (3H, s), 1.98-1.91 (2H, m), 1.89-1.95 (2H, m), 1.75-1.67 (4H, m), 1.30-120 (2H, m). 30-63: 13.63 (IH, sl,NH), 1028 (IH, s, NH), 8.37 (IH, d, NH, J=8.0Hz), 824 (IH, d, CHarom, J=8.8Hz), 7.88-7.82 (2H, m, CHarom), 724-7.17 (3H, m, CHarom), 629 (IH, d, CHarom, J=92Hz), 6.14 (IH, s, CHarom), 4.87 (2H, s), 3.75-3.70 (3H, m), 3.43 (2H, t), 328 ( 4H, s), 2.45 ( 4H, s), 223 (3H, s), 1.90-1.85 (2H, m), 1.32-120 (2H, m). 30-64: 13.69 (IH, si, NH), 10.55 (IH, s, NH), 826 (IH, d, CHarom, J=8.8Hz), 8.05 (IH, d, NH, J=7.6Hz), 7.90 (IH, d, CHarom, J=8.4Hz), 7.86 (IH, d, CHarom, J=8.8Hz), 724-7.15 (3H, m, CHarom), 6.70 (IH, s, CHarom), 6.56 (IH, d, CHarom, J=8.0Hz), 4.88 (2H, s), 3.80-3.65 (3H, m), 3.43 (2H, t),

2.87 (2H, d, J=11.2Hz), 2.46-2.40 (IH, m), 220 (3H, s), 2.00-1.86 (4H, m), 1.75-1.67 (4H,m), 129-123 (2H,m). 30-65: 13.49 (IH,si, NH), 10.45 (IH, s, NH), 9.31 (IH, si, COOH), 821 (IH, d, CHarom, J=8.8Hz), 8.06 (IH, si, NH), 7.92 (IH, d, CHarom, J=8.4Hz), 7.57 (IH, d, CHarom, J=8.8Hz), 7.17-7.11 ( 2H, m, CHarom), 6.96-6.91 (IH, m, CHarom), 6.67 (IH, s, CHarom), 6.53 (IH, d, CHarom, J=8.0Hz), 4.51 (IH, d, J=13.2Hz), 420 (IH, d, J=132Hz), 3.81-3.76 (2H, m), 3.71-3.62 (IH, m), 3.56-3.41 (4H, m), 3.08 (2H, t), 2.83 (3H, s), 2.45-2.40 (IH, m), 2.07-2.00 (2H, m), 1.95-1.86 (4H, m), 1.41-129 (2H, m). 30-66:13.62 (IH, si, NH), 1022 (IH, si, NH), 8.36 (IH, d, NH, J=7.6Hz), 8.23 (IH, d, CHarom, J=8.8Hz), 7.85 (IH, d, CHarom, J=92Hz), 7.80 (IH, d, CHarom, J=8.8Hz), 7.48 (IH, s, CHarom), 7.45-7.37 ( 2H, m, CHarom), 629

139 (IH, d, CHarom, J=72Hz), 6.14 (IH, s, CHarom), 4.97 (2H, s), 3.76-3.70 (3H, m), 3.44 (2H, t), 3.28 (4H, s), 2.44 ( 4H, s), 2.23 (3H, s), l .91-1.86 (2H, m), 1.30-1.24 (2H, m). 30-67: 13.67 (IH, si, NH), 10.49 (IH, s, NH), 8.25 (IH, d, CHarom, J=8.8Hz), 8.02 (IH, d, NH, J=7.2Hz), 7.89 (IH, d, CHarom, J=8.0Hz), 7.82 (IH, d, CHarom, J=8.8Hz), 7.49 (IH, t, CHarom), 7.45-735 (2H, m, CHarom), 6.70 (IH, s, CHarom), 6.56 (IH, d, CHarom, J=8.0Hz), 4.97 (2H, s), 3.78-3.64 (3H, m), 3.44 (2H, t), 2.88 (2H, d, J=11.2Hz), 2.45-2.40 (IH, m), 2.20 (3H, s), 1.98-1.86 (4H, m), 1.76-1.66 (4H, m), 1.321.22 (2H, m). 30-68: 13.46 (IH, s, NH), 10.36 (IH, s, NH), 8.21 (IH, d, CHarom, J=8.8Hz), 8.00 (IH, d, NH, J=7.6Hz), 7.86 (IH, d, CHarom, >8.4Hz), 7.59 (IH, d, CHarom, J=8.8Hz), 7.43-733 ( 2H, m, CHarom), 7.28 ( IH, s, CHarom), 6.69 (IH, s, CHarom), 6.54 (IH, d, CHarom, J=7.6Hz), 4.58 (IH, d, J=12.8Hz), 4.30 (IH, d, J=12.8Hz), 3.78-3.75 (2H, m), 3.70-3.65 (IH, m), 3.46 (2H, t), 2.92-2.88 (2H, m), 2.452.40 (IH, m), 2.24 (3H, s), 2.05-1.95 (2H, m), 1.93-1.89 (2H, m), 1.77-1.70 (4H, m), 134-124 (2H, m). (ND: not determined).

Example 30-bls: (S)-4-(3-amlnopyrrolidln-l-yl)-N-(5-(3,5-dÎf]uorophenylthlo)-lHpyrazo!o[3,4-b ] pyrid in-3-yI)-2-(tetrahyd ro-2 H-pyran-4-y lamlno)benzamlde

876 μΐ (20 eq) of triethylamine is added to a solution of238 mg (0314 mmol) of(S)-Y(5-(3,5-dinuorophcnylthio)-l/7-pyrazolo[3,4-ô]pyridm-3-yl)-2-(2,2,2-trifluoro-N(tetrahydro-2/7-pyran-4-yl)acetamido)-4-(3-(2,2,2-trifluoroacetamido)pyrTolidin-lyl)benzamide in 6 ml of methanoL The reaction medium is stirred at 65°C for 4 hours. After retuming to room température, 8 ml of n-butanol and 260 mg (6 eq) of potassium carbonate are added. The reaction medium is stirred at 80°C for 24 hours. After retuming to room température, the solvents are evaporated, water is added and the product is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried on magnésium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (8:2 dichloromcthane/methanol as eluent) to yield 87 mg (yield=49%) of (S)-4-(3-aminopynolidin-l-yl)-JV-(5-(3,517324

140 difl uoropheny Ithio)-1 //-pyrazolo [3,4-b]pyrazine-3 -yl)-2-(tetrahydro-2W-pyran-4ylamino)benzamide in the form of a brown powder.

LCMS (El, m/z): (M+1) 566.24.

’H NMR: ÔH ppm (400 MHz, DMSO): 10.46 (IH, bs, NH), 8.60 (IH, s, CH™,), 8.50 (IH, s, CH™,), 8.26 (IH, d, NH), 7.78 (IH, d, CH,™), 7.08 (IH, t, CH™,), 6.86 (2H, d, CH.™), 5.86 (IH, dd, CH™,), 5.71 (IH, d, CH.™), 3.80-3.88 (2H, m, CH), 3.633.70 (2H, m, CH), 3.40-3.55 (5H, m, CH), 3.01-3.08 (IH, m, CH), 2.08-2.13 (IH, m, CH), 1.92-1.99 (2H, m, CHj), 1.76-1.82 (IH, m, CH), 1.30-1.41 (2H, m, CH_pymone).

Examples of method F2: réduction

Exampie 31; N-(5-(3,5-dlfluorophenethyl)-lH-pyrazolo[3,4-b]pyridin-3-y))-4-(4methylplperazin-l-yI)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide

mg of 10% Pd/C is added to 100 mg (0.175 mmol) of N-(5-((3,5dîfluorophenyl)cthynyl)-lH-pyrazolo[3,4-b]pyridîn-3-yl)-4-(4-methylpipcrazin-l-yl)-2(tetrahydro-2H-pyran-4-ylamino)benzamide in solution in a mixture of 10 ml of tetrahydrofuran and 5 ml of methanol before placing the reaction medium under an atmosphère of hydrogen. The reaction mixture is stirred for 12 hours at room température and then filtered on Celite and concentrated. 62 mg (yield=60%) ofN-(5(3,5-difluorophencthyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-l-yl)-2(tetrahydro-2H-pyran-4-ylamino)benzamide are isolated in the form of a white solid. LCMS (El, m/z): (M+1) 576.23.

’H NMR: δΗρρτη (400 MHz, DMSO): 13.14 (IH, bs, NH), 10.32 (IH, bs, NH), 8.40 (IH, d, CH™,), 8.22 (IH, d, NH), 7.96 (IH, d, CH,™), 7.80 (IH, d, CH™,), 7.03-6.98 (3H, m, ΟΗ,π,π,), 6.23 (IH, d, CH._rom), 6.16 (IH, bs, CH^m), 3.84-3.81 (2H, dt, CH), 3.70 (IH, m, CH), 3.52-3.46 (2H, m, CH), 3.04-2.93 (4H, m, CH), 2.59-2.69 (4H, m,

141

CH), 2.42-2.46 (4H, m, CH), 2.38 (3H, s, CHj), 1.96-1.93 (2H, m, CH), 1.40-1.33 (2H, m, CH).

The following dérivative was obtained according to the same method:

Ex.**	ArX	Ri	Rî	Yl	n	W	Ri	Compound names	Yield	Mass
31-1	.a,	Q	û N «	N	0	H	H	N-(5*(3,5-difluorophcncthyl)-1Hpyrazolo[3,4-b]pyTazin-3-yl)-4-(4methylpipcrazin-l -yl)-2-(tetrahydro2H-pyran-4-ylamino)bcnzamide	47%	577.07 (M+H)
·♦ 'H NMR, dmso-d	le, Ex. : 31-1: 13.68 (IH, si, NH), 10.11 (IH, s, NH), 8.52	[IH, s,

CHarom), 8.35 (IH, dl, NH), 7.82 (IH, d, CHarom, >9Hz), 7.05-6.97 (3H, m, CHarom), 6.27 (IH, dd, CHarom), 6.14 (IH, s, CHarom), 3.83-3.76 (2H, m), 3.74-3.64 (IH, m), 3.47 (2H, t), 3.32-3.20 (6H, m), 3.07 (2H, dd), 2.44 (4H, dd), 233 (3H, s), 1.91 10 (2H, d), 1.38-137 (2H,m).

Example 32: 5-(3,5-dinuorophenylthio)-N-(4-(4-methylpiperazin-l-yI)-2(tetrahydro-2H-pyran-4-ylamino)benzyl)-lH-pyrazoloI3,4-b]pyridin-3-amlne

100 mg (0.173 mmol) of N-(5-(3,5-difluorophenylthio)-l-H-pyrazolo[3,4-b]pyridine-3yl)-4-(4-methylpiperazine-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino)bcnzamide is added,

142 in small fractions, to a solution of I9.64mg (0.5l8mmol) of LiAlHj in 3 m! of anhydrous tetrahydrofuran under argon at 0°C. The reaction mixture is heated at 90°C for 15 hours. An additional portion of 20 mg of LiAlHj is then added and the reaction medium stirred at 90°C for 5 hours. 45 μΐ of water at 0°C is then added to the reaction 5 mixture, followed by 45 μΐ of sodium hydroxide (15% wt) and finally 120 μΐ of water.

The reaction mixture is stirred at 25°C for 1 hour and then fîltered on Dicalitc. After évaporation ofthe solvents, the crude product is purified by chromatography. 16.80 mg (17%) of 5-(3,5-difluoropheny lthio)-N-(4-(4-methy Ipiperazin-1 -yl)-2-(tetrahydro-2Hpyran-4-ylamino)benzyl)-lH-pyrazolo[3,4-b]pyridin-3-amine in the form of a yellow 10 solid is obtained.

LCMS (El, m/z): (M+1) 566.68.

’H NMR: δΗ ppm (400 MHz, DMSO): 12.57 (IH, bs, NH), 8.45 (2H, d, CH.™,), 6.977.06 (2H, m, CH^J, 6.73-6.75 (2H, m, CH.™,), 6.65 (IH, t, NH), 6.13-6.19 (2H, m, CH^_m), 4.98 (IH, d, NH), 4.30 (2H, m, CH₂), 3.73-3.77 (2H, m, CH), 3.60 (IH, m, 15 CH), 3.45-3.50 (2H, m, CH), 3.04 (4H, m, CH), 2.42 (4H, m, CH), 2.18 (3H, s, CH₃), 1.80-1.83 (2H, m, CH), 1.27-1.32 (2H, m, CH).

The following dérivatives were obtained according to the same method:

Ex**	ArX	Ri	R*	(U).	V	Υ„ΥΛΥΜΥ4	Rj	Compound naine	Yield	Mass
32- 1	A	Q ^NH	ό ♦	n=0	CH;	N,ArXC,CH,N	H	5-(3,5-difIuorophenyhhio)-N(4-(4-inethylpiperazin-1 -yl)2-(tctrahydro-2H-pyran-4ylamino)benzyl)-1Hpyrazolo(43-b]pyiazin-3amine	1%	5673

Example 33: 2-(4-aminophenyI)-N-(5-(3,5-difluorophenylthIo)-lH-pyrazolo[3,4b | pyrid 1 n-3-y l)acetamîd e

143

A solution of 152 mg (2.72 mmol) of iron and 70 mg (1.3 mmol) of ammonium chloride in 100 μί of water is added to a solution of 024g (0.544 mmol) of N-(5-(3,5difluorophenylthio)-lH-pyrazo!o[3,4-b]pyridin-3-yI)-2-(4-nitrophenyI)acetamide in 10 ml of a 2:1 ethanol/water mixture. Several drops of acetic acid are added to this mixture and it is heated at 60°C for 4 hours. After cooling and concentration of the solvents, the crude reaction product is extracted with ethyl acetate and is washed with saturated sodium bicarbonate solution. The organic phases are combined, dried on magnésium sulfate and then concentrated. The crade product is purified by silica gel chromatography (DCM/MeOH) to yield 11 mg (4%) of 2-(4-aminophenyl)-N-(5-(3,5difluorophcnylthio)-lH-pyrazolo[3,4-b]pyridin-3-yl) acetamide in the form of a brown solid.

LCMS (El, m/z): (M+l) 412.09.

^lH NMR: δΗ ppm (400 MHz, DMSO): 13.60 (IH, bs, NH), 10.96 (IH, bs, NH), 8.68 (IH, d, CH^), 8.55 (IH, d, CH»™,), 7.06 (IH, m, CH„_om), 6.98 (2H, d, CHJ, 6.79 (2H, m, CHarom), 6.50 (2H, m, CH^_m), 4.92 (2H, s, NH), 3.51 (2H, m, CH₂).

Examples of method F3: sulfide oxidation

Example 34:5-(3,5-difluorophenyIsulfonyl)-l H-pyrazolo[3,4-b]pyridln-3-amlne

A solutionof663 mg(1.078 mmol)ofoxone in 1.1 ml ofwater isadded to asolutionof 300 mg (1.078 mmol) of 5-(3,5-difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3-aminc in 10 ml of a 1:1 mixture of tetrahydrofuran and methanol at 0°C. The reaction mixture is stirred at room température for 16 hours. An additional portion of663 mg of oxone at 0°C is then added and the reaction medium stirred at room température for 24 hours. The solvents are evaporated and the réaction medium is diluted with sodium bicarbonate solution, extracted with ethyl acetate, dried on MgSOq and then concentrated to yield 340 mg (81%) of 5-(3,5-difluorophcnylsulfonyl)>lH-pyrazoIo[3,4bJpyridin-3-amine in the form of a yellow solid.

144

LCMS (El, m/z): (M+1 ) 311.03.

’H NMR: 5H ppm (400 MHz, DMSO): 12.72 (IH, bs, NH), 8.92 (IH, d, CH.™), 8.84 (IH, d, CH.™), 7.89-8.01 (IH, d, CH.™), 7.62-7.80 (2H, m, CH,™), 6.06 (2H, bs,

NH).

The following compounds were also obtained by this method:

Ex.**	ArX	Q	Y|, ¥4	W	Compound name	Yield	Mass MH+
34-2	ov A F	H	CH, N	H	5-(3,5dîfluorobenzy Isulfony!)-1Hpyrazolo[3,4-b]pyridin-3amine	ND	(M+l) 325.07
34-3	O-S	θ^Ό -r	N, CH	H	tert-butyl 5-(3,5dichlorophenylsulfonyl)-! Hpyrazoïo[43-b]pyridin-3ylcarbamate	ND	ND

♦♦ Ή NMR, DMSO-<U, Ex.: 33-2:12.64 (1 H, bs, NH), 8.56 (IH, d, CH.™), 8.49 (IH, d, CH.™), 7.24 (IH, ddd, CH.™), 6.94 (2H, bd, CH.™), 6.03 (2H, bs, NH), 4.80 (2H, s, CH). (ND: not determined).

Altematively, a protection step can be carried out before the oxidation reaction, followed by a deprotection step which can lead to the préparation of the corresponding sulfones or sulfoxides.

Example 34-bis: 5-(3^-dIiluorophenylsainnyl)-lH-pyrazolo[43-b]pyrazin-3-amine

145

0.55 mL of triethylamine and 22 mg of 4-dimethylaminopyridine are added under argon to a solution of 500 mg (1.790 mmol) of 5-(3,5-difluorophenylthio)-lH-pyrazolo[3,4b]pyrazin-3-amine in 10 mL of tetrahydrofiirane. The solution is stirred at 0°C and 0.915 mL of di-tert-butyl dicarbonate is added and the reaction medium is stirred ovemight An aqueous fraction is added to the reaction medium which is then extracted with ethyl acetate. The organic phases are dried on MgSÜ4 and concentrated in vacuum to give a crude product which is used in the oxidation step without further purification. The crude product obtained is dissolved in 10 mL ofa 1:1 mixture of tetrahydrofurane and methanol at 0°C and then a solution of 1.103 g (1.794 mmol) of oxone in 2 mL of water is added. The reaction medium is stirred at room température for 16 hours. An additional portion of 550 mg of oxonc is then added and the réaction medium is stirred at room température for 5 hours. The solvents are evaporated and the reaction medium is diluted with a sodium bicarbonate solution, extracted with ethyl acetate, dried on magnésium sulfate and concentrated to lead to a mixture of the corresponding sulfone and sulfoxide which are used without further purification in the deprotection step.

0.373 mL of TFA in 4 mL of anhydrous THF is added at 0°C to a solution of600 mg of the previously obtained mixture in 6 mL of dichloromethane. The mixture is stirred 1 hour at room température and an additional portion of4 équivalents ofTFA in 4 mL of THF is added. After 1 hour of stirring, this operation is repeated and the reaction medium is stirred for a total time of 3h45. The solvents are evaporated and the reaction medium is diluted with a potassium carbonate solution, extracted with ethyl acetate, dried on magnésium sulfate and concentrated to yield a 1:1 mixture of 5-(3,5difluorophcny!su!fonyl)-l H-pyrazolo[3,4-b]pyrazin-3-aminc and 5-(3,5-difluorophcnyl sulfinyl)-lH-pyrazolo[3,4-b]pyrazin-3-amine. This mixture is used in the following steps without further purification.

The following compounds were also obtained by this method:

NH₂

146

Ex.**	ArX	Yi,Y<	Compound nimes	Yield	Mass Μ1Γ
34bis-l	Φα	CH, N	5-(2,5-difluoropheny Isulfony 1)-1Hpyrazolo[43-b]pyridîn-3-amine	58% 3 steps	(M+1) 310.9
34bls-2	a A a	CH, N	5-(33-dichlorophenylsulfonyI)-l HpyTazolo[43-b]pyridin-3-amine	38% 3 steps	(M+1) 342.8
34bis-3	a a °	CH, N	5-(2,5-dichlorophcnylsulfonyl)-1Hpyrazolo[43-b]pyridin-3-amine	41% 3 steps	(M+1) 342.9
34bis-4	AA F	CH, N	5-(33-difluorobenzylsul fonyl)-1Hpyrazolo[43-b]pyridin-3-amme	58% 3 steps	(M+1) 325.0
34bis-5	F	CH, N	5-(2,5-difluorobcnzylsulfonyl)-l Hpyiazolo[43-b]pyridin-3-amine	45% 3 steps	(M+1) 325.0
34bis-6	(Jn' F	CH, N	5-(2,5-difIuorobenzy Isulfinyl)-1Hpyrazolo[43-b]pyridin-3-aminc	5% 3 steps	(M+1) 308.9
34bis-7	W	CH, N	5-(2,5-dîchlorobcnzylsulfonyl)-l Hpyrazolo[43-b]pyridin-3-amine	3% 3 steps	ND
34bis-8	a	CH, N	5-(2,5-dichlorobertzykulfinyl)-l H- pyr8Zolo[43-b]pyridin-3-aminc	18% 3 steps	ND

** *HNMR, DMSO-dô,Ex.: 34bis-1: 1231 (IH, si,NH), 8.08-8.18 (IH, m, CHarom), 8.05 (IH, d, CHarom, J=11.6Hz), 7.97 (IH, d, CHarom, J=11.6Hz), 7.87-7.93 (IH, m, CHarom), 7.64-7.76 (IH, m, CHarom), 5.81 (2H, si, NH₂). 34bls-2: 12.32 (IH, si, NH), 7.94-8.11 (5H, m, CHarom), 5.85 (2H, si, NH₂). 34bls-3: 1234 (1H, si, NH), 8.27 (IH, 5 s, CHarom), 8.12 (IH, d, CHarom, J= 11.6Hz), 8.01 (IH, d, CHarom, J=11.6Hz), 7.827.89 (IH, m, CHarom), 7.67 (IH, d, CHarom, J=11.2Hz), 5.70 (2H, si, NH₂). 34bIs-4:

12.28 (IH, si, NH), 7.89 (IH, d, CHarom, J=8.8Hz), 7.68 (IH, d, CHarom, J=8.8Hz),

147

7.21 (IH, m, CHarom), 6.91-6.97 (2H, m, CHarom), 5.87 (2H, s, NH2), 4.94 (2H, s, CH). 34bis-5: 12.28 (IH, s!, NH), 7.89 (IH, d, CHarom, J=8.8Hz), 7.68 (IH, d, CHarom, J=8.8Hz), 7.20-7.25 (2H, m, CHarom), 7.10-7.15 (IH, m, CHarom), 5.84 (2H, s, NH2), 4.87 (2H, s, CH). 34bIs-6:12.04 (IH, s, NH), 7.87 (IH, d, CHarom, J=8.8Hz), 7.40 (IH, d, CHarom, J=8.8Hz), 7.10-725 (2H, m, CHarom), 6.90-6.97 (IH, m, CHarom), 5.61 (2H, s, NH2), 4.47 (IH, d, CH, J=13.2Hz), 4.18 (IH, d, CH, J=13.2Hz). 34bls-7: 1228 (IH, s, NH), 7.89 (IH, d, CHarom, J=8.8Hz), 7.64 (IH, d, CHarom, J=8.8Hz), 7.40-7.50 (3H, m, CHarom), 5.81 (2H, s, NH2), 4.96 (2H, s, CH).

Example of method F4: déméthylation

Exampie 35: N-(5-(3,5-dinuorophenylthio)-6-hydroxy-lH-pyrazolo[3,4-b]pyridin-

3-yl)-4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamlde

443 μΐ (3 cq) of a solution of 1 M boron tribromidc in dichloromethane is added to a solution of 90 mg (0.148 mmol) of N-(5-(3,5-difluorophenylthio)-6-methoxy-lHpyrazo Io[ 3,4-b]pyridin-3 -y l)-4-(4-methylpiperazin-1 -yl)-2-(tetrahydro-2H-pyTan-4ylamino)benzamide (example 18) in 4 ml of 1,2-dichloroethane at 0°C. The réaction medium is stirred at 60°C for 3 hours and then cooled in an ice bath before adding methanol. The solvents are evaporated and the residue is redissolved in a mixture of methanol and ethyl acetate. The solid formed is filtered, redissolved in 3 ml of tetrahydrofùran and is added to 1 N soda solution. The reaction medium is stirred for 18 hours at room température. The pH of the solution is adjusted to 8-9 and the aqueous phase is extracted with ethyl acetate. The organic phase is dried on magnésium sulfate and the crude product is purified on a silica gel column (dichloromethane/methanol as eluent) to yield 21 mg (24%) of N-(5-(3,5-difluorophenylthio)-6-hydroxy-lHpyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4ylamino)benzamide in the form of a yellow powder.

LCMS (El, m/z): (M+1) 596.13.

148 'H NMR: 8H ppm (400 MHz, DMSO): 12.96 (IH, broad fiat sînglet), 12.02 (IH, broad fiat sînglet), 10.64 (IH, bs, NH), 8.46 (IH, bs), 8.09 (IH, bs), 7.72 (IH, d, CH™),

6.97-7.10 (IH, m, CH™), 6.60-6.74 (2H, m, CH™), 6.28 (IH, dd, CH™), 6.13 (IH, d, CH™), 3.80-3.90 (2H, m, CHp_>TM0„_c), 3.65-3.77 (IH, m, CH_py™one), 3.50 (2H, t,

CH_pyianoDe), 3.25-3.32 (4H, m, 2*CH₂), 2.37-2.45 (4H, m, 2*CH₂), 2.22 (3H, s, CHj),

I. 91-2.00 (2H, m, CH_pyT>n<Mie), 1.28-1.43 (2H, m, CHpy™^).

II. Biological tests ofthe compounds according to the invention • Test for measuring Inhibition of TrkA, TrkB or TrkC kinase

These kinases are produced by Millipore or Kinome Scan (DiscoverX) and are screened according to the manufacturer’s protocols.

The results are presented in the table below:

	Enzymatic inhibition at 10 nM (%)
	30	30-9	27-1	14-11	30-8
TrkA	93.8	55	97.8	97.4	99
TrkB	84	98	93	88	96.6
TrkC	64		96.8	93.4	97.3

• In vivo analgésie activity against NGF-induced hyperalgesia

Compounds of general formula (1), and particularly compound 30 hâve been tested in vivo in the mouse receiving an intraplantar injection of NGF. This treatment elicits thermal hyperalgesia (Schuligoi et al., 1998, Neuroscience Letters 252:147-149). Briefly, male mice received a 10 μΙ subeutaneous injection of NGFp (Ipg; SIGMA) into the plantar surface of the right hind paw. Following the injection, mice were retumed to their cages. Four hours after NGF injection, mice were placed on the centre of the hot plate analgesimeter (B10-HC2.00, Bioseb, France), and the latency time to the first brisk lift or lick of a hind paw or jumping will be recorded. A maximum cut-off time of 60 sec is used to prevent tissue damage. Results are given as the mean ± s.e.m. of the latency time. Test compounds were given 30 min before NGF injection.

Figure 1 shows that Compound 30 dose-dependently inhibited NGF-induced hyperalgesia, either when administered by intraperitoneal route (Figure IA) or oral

149 route (Figure IB). Complété or nearty complété reversion of NGF-induccd hyperalgesia occurred at doses of 10 mg/kg and lower (* P <0.05 vs NGF alone by ANOVA).

• In vivo analgésie activity in the formalin test in rats

The method was adapted from Wheeler-Aceto et al. (Pain, 1990,40:229-38) and Bardin et al. (2003, Pharmacology 67: 182-194). In the second phase of the test, Compound 30 inhibited paw licking by 44% vs. vchicle-treated animais (P < 0.05 by ANOVA).

• In vivo analgésie activity against acute and chronic infiammatory pain induced by Complété Freund Adjuvant (CFA)

Male Sprague-Dawley rats [Crl:OFA(SD) Charles River Lyon, France] weighing 160-180 g upon arrivai were used. Rats were first daily habituated to handling and to the test apparatus used for the von-Frey and hot-plate models one week before the induction of inflammation. On the following Monday, they were subjected to nociceptive tests for détermination of basal scores. Then, rats will be given a Ι00μ1 subcutancous injection of CFA (lmg/lml; Sigma) into the plantar surface of the right hind paw (day 0: D0). Saline was injected by the same route in the placebo group.

Then each rat was piaced on an elevated plastic mesh in a clear plastic cage and the number of spontaneous flinches (measurement of spontaneous pain) was recorded during 10 min. Mechanical allodynia was assessed using the von Frey Haïr test. Each rat was piaced on an elevated plastic mesh in a clear plastic cage and allowed to adapt to the testing environment for at least 5 min. The von Frey Haîrs (Semmes-Weinstein mono filaments, Stoelting IL, USA; 0.6, 1.4, 2,4,6,8, 10, and 15 g) was applied to the plantar surface of the injected paw from below the mesh floor for 1s in the ascending order. The threshold was determined as the lowest force that evoked a withdrawal response. The test was repeated three fîmes with an interval of 5 min between each test. The paw withdrawal score to the tactile stimulus was determined as the average of the 3 measurements. Animais received intraperitoneal or oral injections of test compounds. Compounds of general formula (I) displayed analgésie activity in this test at doses of 0.5 to 20 mg/kg, both against acute infiammatory pain (flinches) and mechanical allodynia. For instance, Compound 30 dose-dependently inhibited flinches after K

150 intraperitoneal injection (Figure 2A) and mechanicai allodynia after oral administration (Figure 2B). Compound completely or nearly completely reversed spontaneous pain from 0.16 mg/kg and mechanicai allodynia from 2.5 mg/kg.

• In vivo analgésie activity against chronic pain in a model of bone cancer pain

Bone cancer produces one of the most painful conditions that affect humans and animais. It is also the most common pain in human patients with advanced cancer and it remains difficult to treat and contributes significantly to increased morbidity and reduced quality of life. Several models of murine osteosarcoma-induced pain hâve been dcvclopcd (Pacharinsak and Bcitz, Animal models of cancer pain. Comp Med. 2008 Jun; 58:220-33.).

We induced bone cancer pain by implanting 10 μΐ of PBS containing 2χ10⁵ NCTC 2472 osteolytic fibrosarcoma cells into the tibia of 5-6 week-old C3H/HeNCrl mice under isoflurane anesthésia. The presence of these cells induces osteolytic lésions in bone due to both an increase in the number of osteoclasts and to their activation, which leads to the destruction of bone tissue and the invasion of the adjacent soft tissue and pain related behaviours. Pain-related behaviours were evaluated both prior to and at 3, 7, 10, 14 and 17 days following tumor cell injection. The following behaviors were evaluated:

— Limb use during spontaneous ambulation on a scale of 0-4 where 0 = normal use and 4 - no use of the injected hind paw,

- Light touch-evoked pain. Light touch induced flinching were measured after the 1 min period of non noxious stimulation of the tumor injected paw with a small paint brush. The numbers of flinches were recorded over 5 min.

For drug treatment, animais were treated chronically with the test compound or saline, administered 30 min before testing by tp. route, starting on day 7 following injection of tumor cells, when pain-related behaviors were clearly présent. As an example, compound 30 at the dose of 2.5 mg/kg, significantly reduced limb use score from day 10 (Figure 3 A) and light touch-evoked flinching from day 8 (Figure 3B).

thLx

151 • Comparative experiments:

An in vitro kinase glo plus-based kinase assay (Promega) was developped in a wells assay plate format to assess the inhîbiting properties of compounds on tropomyosîn related kinases (Trk) receptors, using the soluble intracellular segment of theses receptors, containing the kinase activity (TrkA (or NTRKI; 400 ng/well;

Millipore) and TrkB (or NTRK2; 200 ng/well; Invitrogen)). The assay was performed in a final volume 50 μΙ containing 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 40 mM Mg

Acetate, 25 mM 2-glyccrophosphatc, 1 mM DTT, 2 mM Na Vanadatc, 0.01 % Triton

X-100, either 1 (TrkA) or 2.5 (TrkB) mg/ml poly EY (poly GIu-Tyr 4:1; substrate) and JO 30 (Trk A) or 40 (Trk B) μΜ ATP. Test compounds were dissolved (10 mM), and diluted in 100 % DMSO through serial dilution, with tested half log concentrations generally ranging from 1 to 30 000 nM final concentration (5% DMSO final), but these concentrations could be adapted according to compound’s potency. The reaction was started by addition of ATP, and the plates were incubated for 2 hours at 30°C. Plates 15 were removed from incubator, and 50 μί of kinase-glo plus was added to each well, followed by a 10 minute incubation at room température. The luciferase-induced luminescence, which is proportional to the ATP remaining in the well, was measured on a luminometer. Controls on each plates included wells with the kinase alone (maximal

ATP consumption, or 0% inhibition), wells without the kinase (maximal ATP signal or 20 100% inhibition), and wells with 20 μΜ staurosporinc (positive control of inhibition). A full concentration-response inhibition curve with K252a (half log concentrations from 1 to 10 000 nM) was also included on each plate. pICso values were derived from fitting the inhibition curve of ATP consumption, using the 0-100% luminescence range defined by the controls, with a sigmoidal dose-response équation: %lnhibition=10025 (100/(l+10^(X+pIC50^{r H})), where X is the fogarithm of the tested compound concentrations. Under these conditions, K252a had a pICso of 7.46 ± 0.07 on TrkA (mean ± SD; N=42; IC₅o = 30 nM), and 7.16 ± 0.18 on TrkB (N=36; IC₅o = 74 nM), these values being consistent with in vitro littérature data (Tapley et al (1992) Oncogene 7:371-381, Tan et al (2007) Mol Pharmacol 72:1440-1446).

The results obtained are presented below:

152

Structure	Compound	ICje (pM)
TrkA	TrkB
θ 0 fYVsyAn O J N Π \-N x C29H31F2N7O2S	30	0.045	0.031
θ P J] HN-\/ i HN Xji jOc^n ^===^ N N-X H H / ) X-N X C28H31F2N9O2	A	about 10	>100
o J! HN-\J HNAJ Ύ1Λ5 Q Xf^UtT'N N-\ F H H < ' r \-N X C28H3IF2N9O2	B	33	18
0 Γ0 JH HN-XJ HN-\J Fïl Jû5 Q γΑΑΑ N-*x f H H < ' x—-N X C29H32F2N8O2	C	2.1	5.8

153

Structure	Compound	ICmGiM)
TrkA	TrkB
nh2 Τι n nv i l l Γ N T H F CuHgFîNiS	D	22	35
0 F>P1 ρ^Ν Q ^n-x F H H < ? X C24H22F2N6OS	E	0.04	0.048
0 hN-A_^ Υ'ιΑγγ [j F H H CisHnFzNiOS	F	0.31	0.31

3 JAN. 2015

CablnVFc^zeirayfr SarV proMttt*

BP 50Cpfaou»tfe (Gtnrerouol

Tèl :(nTC|WW«:(OT)n2U<y

EHntllSei^etcaienaye ehotnttn.fr

Claims (15)

1. l. A compound of following general formula (I):

   R₂ ^V' R or a pharmaceutically acceptable sait or solvaté of same, a tautomer of same, or a stereoisomer or mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture, wherein:

   - Y» and Y< each represent, independently of each other, a CH group or a nitrogen atom on the condition that at least one of Yj and Y« represent a nitrogen atom,

   - Y₂ represents a C-X-Ar group,

   - Ys represents a C-W group,

   - Ar represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-Ce/haloalkyl, (CiCe)haloalkoxy, (Ci-Ce)halothioalkoxy, CN, NO₂, ORn, SRn, NRbRk, CO₂R|j, CONRieRn, SO₂R|g» SOîNRiçRjo, COR₂j, NR₂₂COR₂j, NR₂4SO₂R₂j, and R₂₆NR₂₇R₂₈ and/or optionally fused to a heterocycle,

   - X represents a divalent group selected from O, S, S(O), S(O)2, NR4, SfNRt), S(O)(NR4), S(O)₂(NR4), NR4S, NR«S(O), NR<S(O)₂, CH₂, CH₂S, CH₂S(O), CH₂S(O)₂, SCH₂, S(O)CH₂, S(O)₂CH₂, ch₂ch₂, ch=ch, c=c, ch₂o, och₂, NR4CH_2j and CH₂NR4,

   - W represents an Rj, SR5, OR5 or NRsRe group,

   - U represents a CH₂ or NH group, one or more hydrogen atoms which may be replaced by a (Ci-Ce)alkyt group,

   - V represents C(O), C(S) or CH₂,

   H

   155

   - n represents 0 or l,

   - Ri represents a hydrogen atom, or an OR7 or NRiRg group,

   - R 2 represents a hydrogen atom, an optionally substituted heterocycle, NO₂, OR? or NR9R10,

   - Rj, R4, Rh to R» and R27 to R» each represent, independently of each other, a hydrogen atom or a (Cj -Ce)alkyl group,

   - R5 and Ra each represent, independently of each other, a hydrogen atom or a (CiCe)alkyl, optionally substituted aryl or optionally substituted benzyl group,

   - R7, R«, R» and Rio each represent, independently of each other, a hydrogen atom or an optionally substituted (Ci-C«)alkyl or (C3-Ci2)cycloalkyl group or an optionally substituted heterocycle, and

   - Rie represents a (Ci-Céjalkyl group, for use in the treatment or prevention of pain.
2. 2. The compound for use according to claim 1, characterized in that the pain is a nociceptive pain, an inflammatory pain, a neuropathie pain, an idîopathic pain or a psychogenic pain, preferably an inflammatory pain or neuropathie pain.
3. 3. The compound according to claim 1 or 2, wherein the pain is due to cancer, to a nerve injury or to rheumatic diseases.
4. 4. The compound for use to any onc of claims 1 to 3, characterized in that:

   - Yi=CHorN,and

   - Y₄ = N.
5. 5. The compound for use according to to any one of claims 1 to 4, characterized in that:

   - Yi represents a CH group, and

   - Y4 represents a nitrogen atom.
6. 6. The compound for use according to any one of claims 1 to 5, characterized in that X represents a divalent group selected from S, S(O), S(O)₂, NR4, CH₂, CH₂S,

   156

   CH₂S(O), CH₂S(O)₂, CH₂O, CH₂NR4, NHS(O)₂, SCH_2i S(O)CH₂, S(O)₂CH₂, S(O)₂NH,

   OCH₂, NR4CH₂, CH₂CH_2ï CH=CH, and OC; notably from S, S(0), S(Oh, NR,, CH₂,

   SCH₂, S(O)CH₂, S(O)₂CH₂, S(O)₂NH, CH₂CH₂, OC, OCH_2ï and NR,CH₂; in particular from S, S(0)₂, CH₂, SCH₂, S(O)₂CH₂, S(O)₂NH, CH₂CH₂, and OC, wherein

   5 the first atom of these groups is bound to atom Ç of chain Ç-X-Ar.
7. 7. The compound for use according to any one of claims 1 to 6, characterized in that Ar represents an aryl group, such as phenyl, optionally substituted by one or more groups selected from a haiogen atom, (Ci-Ce)a!kyl, (Ci-QOhaloalkyL, (Ci-

   10 C«)haloalkoxy, (Ci-Cejhalothioaikoxy, CN, NO₂, OR,,. SR|₂, NRbRh, CO₂Ris, and

   CONRuRn, SO₂R|g, S0₂NR|çR₂o, COR₂j, NR₂îCOR₂j or NR₂₄SO₂R₂s; or a pyndinc group.
8. 8. The compound for use according to claim 7, characterized in that Ar represents 15 a group selected from the following groups:
9. 9. The compound for use according to any onc of claims 1 to 8, characterized in

   20 that W represents an Rs, SRs, ORs or NRsR« group, with Rs and R* representing, independentiy of each other, a hydrogen atom or a (Ci-Ce)alkyl group.
10. 10. Compound for use according to any one of claims 1 to 9, characterized in that:

    - r₃=h,

    25 - U=CH₂ orNH,

    - V=C(O) or C(S), and notably C(O), and

    Ob'

    157

    - n=0 or 1, and notably 0.
11. 11. The compound for use according to any one of claims 1 to 10, characterized in that Rj represents a hydrogen atom or an NR7R3 group, with R7 representing a hydrogen atom and R* representing an optionaily substituted (C3-Ci₂)cycloalkyl group or an optionaily substituted heterocycle.
12. 12. The compound for use according to claim 11, characterized in that Ri represents one of the following groups:
13. 13. The compound for use according to any one of claims 1 to 12, characterized in that R₂ represents NO₂, NR9R10 or a heterocycle optionaily substituted by (C|-C6)alkyl or NH₂.
14. 14. The compound for use according to claim 13, characterized in that R₂ represents one of the following groups:

    —|-N N

    NH₂, NH(CH₂)₃NMe2, NMe(CH₂)₃NMe₂, NO₂, X---/ xNH₂ and
15. 15. The compound for use according to any one of claims 1 to 14, characterized in that it is selected from the following compounds: