Adenine derivatives as hsp90 inhibitors

Abstract

The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts and / or solvates thereof, wherein X1, X2, Y, L1, R1, R1', R2, R2', n, and A are as defined in the claims, which are useful as inhibitors of HSP90, in particular for the treatment of cancers, neurodegenerative diseases, and neurodegenerative diseases with proteins aggregates such as congenital central hypoventilation syndrome (CCHS).

Description

ADENINE DERIVATIVES AS HSP90 INHIBITORS FIELD OF INVENTION

[0001] The present invention relates to adenine derivatives, especially compounds of formula (I) as detailed hereafter, which are useful as inhibitors of HSP90, in particular for the treatment of cancers, neurodegenerative diseases, and neurodegenerative diseases with proteins aggregates such as congenital central hypoventilation syndrome (CCHS). BACKGROUND OF INVENTION

[0002] The HSP90s (Heat shock protein 90) are a ubiquitous family of ATP-dependent molecular chaperone proteins consisting of four paralogs: Hsp90α and Hsp90β in the cytosol, Grp94 in the endoplasmic reticulum, and Trap-1 in the mitochondria. Hundreds of client proteins, including growth factors, signaling kinases, transcription factors, and cell surface receptors depend on HSP90 family members for their conformational maturation, stabilization, and proper subcellular localization

[0003] HSP90s orchestrate crucial physiological processes such as cell survival, cell cycle control, hormone signaling, and apoptosis. Conversely, HSP90s, and their secreted forms, contribute to the development and progress of serious pathologies, including cancers, neurodegenerative diseases, and neurodegenerative diseases with proteins aggregates such as congenital central hypoventilation syndrome (CCHS).

[0004] As a result, HSP90 proteins have emerged as an attractive target for the development of treatments of these diseases.

[0005] Several HSP90 inhibitors have been developed and tested, such as for example Debio0932 (also referred to as CUDC-305, corresponding to 2-((6-(dimethylamino)benzo[d][1,3]dioxol-5-yl)thio)-1-(2-(neopentylamino)ethyl)-1H- imidazo[4,5-c]pyridin-4-amine). However, despite the initial promise, many of these inhibitors have exhibited limited stability, efficacy and selectivity. For example, HSP90inhibitors such as Debio0932 display an improvable metabolization profile and thus suboptimal pharmacokinetic properties.

[0006] There is thus a need for new and improved HSP90 inhibitors with good potency and selectivity, and with improved metabolization profiles.

[0007] The present invention provides such a novel class of HSP90 inhibitors that show improved CYP inhibition profiles and microsomal clearance, as detailed in the experimental part.

[0008] The novel HSP90 inhibitors of the invention have potential for the treatment of diseases or disorders in which HSP90 is implicated, such as cancers, neurodegenerative diseases, and neurodegenerative diseases with proteins aggregates such as congenital central hypoventilation syndrome (CCHS). SUMMARY

[0009] This invention thus relates to a compound of formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, wherein X1, X2, Y, L1, R1, R1’, R2, R2’, n, and A are as defined hereafter.

[0010] The invention also relates to a pharmaceutical composition comprising a compound according to the invention, or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable carrier.

[0011] The invention further relates to a compound according to the invention, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament.

[0012] The invention also relates to a compound according to the invention, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of cancers, neurodegenerative diseases, neurodegenerative diseases with proteins aggregates, infectious diseases, ROHHAD (Rapid Onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation), diabetic atherosclerosis, severe psoriasis, primary myelofibrosis, and acute pancreatitis.

[0013] In one embodiment, the cancer is selected from brain tumors, hematopoietic disorders, breast cancer, lung cancer, leukemia, lymphoma, pancreatic cancer, multiple myeloma, prostate cancer, glioma, colon cancer, gastric cancer, ovarian cancer, and any cancer with oncogene production chaperoned by HSP90.

[0014] In one embodiment, the neurodegenerative disease is selected from Alzheimer's disease, Senile dementia of the Alzheimer type, dementia of head trauma and diffuse brain damage, dementia pugilistica, frontal lobe dementia, Pick's disease, Huntington's disease, Multiple system atrophy combining dementia with ataxia and / or manifestations of Parkinson's disease, Progressive supranuclear palsy, diffuse Lewy body disease, corticodentatonigral degeneration, Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis, familial tremor, Gilles de la Tourette syndrome, cerebellar cortical degeneration, olivopontocerebellar atrophy, spinocerebellar degeneration, Shy-Drager syndrome, amyotrophic lateral sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, hereditary spastic paraplegia, neural muscular atrophy, chronic familial polyneuropathies, peroneal muscular atrophy, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, and Leber Amaurosis.

[0015] In one embodiment, the neurodegenerative disease with proteins aggregates is selected from congenital central hypoventilation syndrome (CCHS), Huntington's disease (HTT), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), synucleinopathies, and central hypoventilation syndrome (CHS).DEFINITIONS

[0016] The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims. When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

[0017] Where chemical substituents are combinations of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group recited. For example, a cycloalkylalkyl substituent is linked to the rest of the molecule through the alkyl moiety and it may by represented as follows: “–alkyl–cycloalkyl”.

[0018] In the present invention, the following terms have the following meanings:

[0019] “Alkyl”, by itself or as part of another substituent, refers to a hydrocarbyl radical of formula CnH2n+1wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Alkyl groups may be linear or branched and may be substituted as indicated herein. Non-limiting examples of alkyl groups include methyl, ethyl, propyl (n-propyl, i-propyl), butyl (n-butyl, i-butyl, s-butyl and t-butyl), pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl).

[0020] “Alkenyl” refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, still more preferably between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl (allyl), 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.

[0021] “Aminocarbonylalkyl” refers to any group –alkyl-(C=O)-NH2, wherein alkyl is as defined above.

[0022] “Cyanoalkyl” refers to any group –alkyl-CN, wherein alkyl is as defined above.

[0023] “Cyanocarbonyl” refers to a group –(C=O)-CN.

[0024] “Cycloalkyl”, by itself or as part of another substituent, refers to a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0025] “Cycloalkylalkyl”, refers to any group –alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[0026] “Halogen” or “halo” means fluoro, chloro, bromo, or iodo. Generally, halo groups of this invention are fluoro, chloro or bromo, preferably fluoro.

[0027] “Haloalkyl”, by itself or as part of another substituent, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,1,1-trifluoroethyl and the like.

[0028] “Heterocyclyl", by itself or as part of another substituent, refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3- to 7-member monocyclic, 7- to 11-member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Heterocyclic groups may in particular be 3- to 7-membered, preferably 5- or 6-membered. Heterocyclic groups may in particular be monocyclic or bicyclic, preferably monocyclic. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone). The heterocyclic group may be attached at any heteroatom orcarbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and / or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulf oxide, thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl.

[0029] “Heterocyclylalkyl”, refers to any group –alkyl-heterocyclyl, wherein alkyl and heterocyclyl are as defined above.

[0030] “Pharmaceutically acceptable” means that the component not deleterious to the subject to which it is administered and is compatible with each other component administered together.

[0031] “Pharmaceutically acceptable carrier” refers to an excipient that does not produce an adverse, allergic, or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA.

[0032] “Prodrug” as used herein means the pharmacologically acceptable derivatives of the compounds of the invention, whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the inventioninclude carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters.

[0033] “Solvate” is used herein to describe a molecular complex comprising a compound of the invention and contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol. The term “hydrate” refers to when said solvent is water.

[0034] “Administration”, or a variant thereof (e.g., “administering"), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the subject in need thereof.

[0035] “Subject” refers to a mammal, preferably a human. According to the present invention, a subject is a mammal, preferably a human, suffering from the targeted disease and / or prone to develop the targeted disease. In one embodiment, the subject is a “patient”, i.e., a mammal, preferably a human, who / which is awaiting the receipt of, or is receiving medical care or was / is / will be the object of a medical procedure or is monitored for the development of the targeted disease.

[0036] “Therapeutically effective amount” (or more simply an “effective amount”) as used herein refers to the amount of active agent or active ingredient that is aimed at, without causing significant negative or adverse side effects to the subject in need of treatment, preventing, reducing, alleviating, or slowing down (lessening) one or more of the symptoms of the targeted disease.

[0037] “Treating” or “treatment” refers to a therapeutic treatment, to a prophylactic (or preventative) treatment, or to both a therapeutic treatment and a prophylactic (or preventative) treatment, wherein the object is to prevent, reduce, alleviate, and / or slow down (lessen) one or more of the symptoms the targeted disease, in a subject in need thereof. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.DETAILED DESCRIPTION Compounds

[0038] This invention relates to a compound of formula (I)or a pharmaceutically acceptable salt and / or solvate thereof, wherein: X1is N or CH; X2is N or CH; provided that X1and X2are not both N; Y is S, SO, SO2, NH, O, or CH2; L1is a C1-4-alkyl; R1is a C1-8-alkyl; R1’is H or C1-4-alkyl; n is equal to 1 or 2. R2and R2’are each independently H, D, methyl, or halo; A is NR3R3’, OR3, or SO2R3; wherein: R3is cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, C1-4-haloalkyl, cyanoalkyl, cyanocarbonyl, aminocarbonylalkyl; wherein the cycloalkyl and heterocyclyl moieties are optionally substituted by one or more substituent selected from D, cyano, halo, hydroxyl, and C1-4-alkyl; R3’is C1-4-alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, C1-4-haloalkyl, cyanoalkyl, cyanocarbonyl, aminocarbonylalkyl; wherein the cycloalkyl and heterocyclyl moieties are optionally substituted by one or more substituent selected from D, cyano, halo, hydroxyl, and C1-4-alkyl; preferably R3’is methyl.

[0039] In one embodiment, X1and X2are both CH or X1is N and X2is CH. In one embodiment, X1and X2are both CH. In another embodiment, X1is N and X2is CH.

[0040] In one embodiment, L1is ethyl. In one embodiment, R1is a C5-alkyl, preferably neopentyl. In one embodiment, R1’is H. In one specific embodiment, L1is ethyl, R1is neopentyl and R1’is H.

[0041] In one preferred embodiment, Y is S, SO or NH; preferably Y is S.

[0042] In one embodiment, n is equal to 1.

[0043] In one embodiment, R2and R2’are both H, both F, both D, or both methyl. In one embodiment, one of R2and R2’is F, D, or methyl and the other is H. In one embodiment, R2and R2’are both H, or both F.

[0044] In one specific embodiment, n is equal to 1, and R2and R2’are both H or both F.

[0045] In one embodiment, A is NR3R3’, OR3, or SO2R3.

[0046] In one preferred, R3is cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, or C1-4-haloalkyl. In a preferred embodiment, R3is cycloalkyl, cycloalkylalkyl, alkenyl, or C1-4-haloalkyl.

[0047] In a preferred embodiment, R3’is C1-4-alkyl; more preferably, R3’is methyl.

[0048] In one embodiment, R3is of formula (i):wherein Z is CH or N; each R4is independently H, D, cyano, halo, hydroxyl, or C1-4-alkyl; m is equal to 0, 1, 2, or 3; p is equal to 1, 2, 3, or 4; and represents the point of attachment to the rest of the compound.

[0049] In one embodiment, in formula (i), Z is CH, m is equal to 0 or 1, and p is equal to 1 or 2. In an exemplary embodiment, the moiety of formula (i) is selected from cyclobutyl and cyclopropylmethyl.

[0050] In another embodiment, R3is alkenyl; preferably R3is allyl.

[0051] In another embodiment, R3is C1-4-haloalkyl; preferably R3is difluoroethyl.

[0052] In one embodiment, R3’is methyl.

[0053] In one particular embodiment, A is NR3R3’. In one preferred embodiment, A is NR3R3’wherein R3is cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, or C1-4-haloalkyl; and R3’is C1-4-alkyl. In another preferred embodiment, A is NR3R3’wherein R3is cycloalkyl, cycloalkylalkyl, alkenyl, or C1-4-haloalkyl; and R3’is methyl. In one preferred embodiment, A is NR3R3’wherein R3is of formula (i) as defined above, alkenyl, or C1-4-haloalkyl; and R3’is methyl. In one specific embodiment, A is NR3R3’wherein R3is of formula (i) as defined above and R3’is methyl. In another specific embodiment, A is NR3R3’wherein R3is alkenyl, preferably allyl, and R3’is methyl. In another specific embodiment, A is NR3R3’wherein R3is C1-4-haloalkyl, preferably difluoroethyl, and R3’is methyl.

[0054] In one embodiment, the compounds of the invention are of formula (Ia):or a pharmaceutically acceptable salt and / or solvate thereof, wherein X1, X2, Y, L1, R1, R1’, R2, R2’, R3’, R4, n, m, and p are as defined above.

[0055] In one embodiment, the compounds of the invention are of formula (Ib):or a pharmaceutically acceptable salt and / or solvate thereof, wherein X1, X2, Y, L1, R1, R1’, R2, R2’, R3’, and n are as defined above.

[0056] According to one embodiment, the compound according to the invention is selected from those listed in Table 1: Table 1 001 2-((6- ((cyclopropylmethyl)(methyl)amino)benz o[d][1,3]dioxol-5-yl)thio)-1-(2- (neopentylamino)ethyl)-1H-imidazo[4,5- c]pyridin-4-amine 002 8-((6- ((cyclopropylmethyl)(methyl)amino)benz o[d][1,3]dioxol-5-yl)thio)-9-(2- (neopentylamino)ethyl)-9H-purin-6- amine003 8-((6- (allyl(methyl)amino)benzo[d][1,3]dioxol- 5-yl)thio)-9-(2-(neopentylamino)ethyl)- 9H-purin-6-amine 004 8-((6-(allyl(methyl)amino)-2,2- difluorobenzo[d][1,3]dioxol-5-yl)thio)-9- (2-(neopentylamino)ethyl)-9H-purin-6- amine 005 2-((6-((2,2- difluoroethyl)(methyl)amino)benzo[d][1, 3]dioxol-5-yl)thio)-1-(2- (neopentylamino)ethyl)-1H-imidazo[4,5- c]pyridin-4-amine 006 2-((6- (cyclobutyl(methyl)amino)benzo[d][1,3] dioxol-5-yl)thio)-1-(2- (neopentylamino)ethyl)-1H-imidazo[4,5- c]pyridin-4-amine and pharmaceutically acceptable salts and / or solvates thereof.

[0057] The compounds of Table 1 were named using ChemDraw® Ultra 12.0. purchased from CambridgeSoft (Cambridge, MA, USA).

[0058] All references to compounds of formula (I) include references to salts, solvates, multi-component complexes and / or liquid crystals thereof. All references to compounds of formula (I) include references to polymorphs and / or crystal habits thereof. All references to compounds of formula (I) include references to pharmaceutically acceptable prodrugs thereof.

[0059] The compounds of formula (I) and subformulae thereof may contain asymmetric centre(s) and thus may exist as different stereoisomeric forms. Accordingly, all references to compounds of formula (I) include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art.

[0060] Bonds from an asymmetric carbon in compounds are generally depicted using a solid line ( ), a solid wedge ( ), or a dotted wedge ( ).The use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included. The use of a solid line to depict bonds from an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended.

[0061] All references to compounds of formula (I) include references to isotopically-labelled compounds of formula (I), including deuterated compounds of formula (I).

[0062] The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

[0063] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, ammonium, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, bitartrate / tartrate, borate, bromide, calcium edetate, camsylate, chloride, citrate, clavulanate, cyclamate, dihydrochloride, edetate, edisylate, estolate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hibenzate, hydrochloride / chloride, hydrabamine, hydrobromide / bromide, hydroiodide / iodide, hydroxynaphthoate, isethionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, methylbromide, N-methylglucamine, methylnitrate, methylsulphate, mucate, naphthylate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate, pantothenate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, pyroglutamate, saccharate, salicylate, stearate, succinate, sulfate, subacetate, tannate, teoclate, tosylate, triethiodide, trifluoroacetate, valerate, and xinofoate salts.

[0064] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, ammonia, arginine, benzathine, N-benzylphenethylamine, calcium, choline, chloroprocaine, N,N’-dibenzylethylenediamine, diethanolamine, diethylamine, 2-(diethylamino)ethanol, diolamine, ethylenediamine, ethanolamine, glycine, 4-(2-hydroxyethyl)morpholine, lithium, lysine, magnesium, meglumine, N-methyl-glutamine, morpholine, olamine, ornithine, potassium, piperazine, procaine, sodium, tetramethylammonium hydroxide, tris(hydroxymethyl)aminomethane, tromethamine and zinc salts.

[0065] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

[0066] When the compounds of formula (I) contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g., NH), the invention also covers salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

[0067] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of these methods: (i) by reacting the compound of formula (I) with the desired acid; (ii) by reacting the compound of formula (I) with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and / or (iv) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

[0068] All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0069] Although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and / or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of formula (I) above. Process of manufacturing

[0070] The compound of invention can be synthesized by methods known in the art. Especially, the compound of invention can be synthesized by the methods detailed in the experimental part below.Pharmaceutical composition

[0071] This invention also relates to a pharmaceutical composition comprising a compound according to the invention, as described hereinabove, and at least one pharmaceutically acceptable carrier.

[0072] According to a first embodiment, the pharmaceutical composition comprises the compound according to the invention as sole therapeutic agent.

[0073] According to a second embodiment, the pharmaceutical composition further comprises at least another therapeutic agent. In one embodiment, the other therapeutic agent is selected from therapeutic agents detailed hereafter regarding combination therapy.

[0074] The pharmaceutical composition of the invention may further comprise therapeutically active compounds other than those listed herein, which are usually applied in the treatment of the targeted pathological conditions. Medical use and methods of treatment

[0075] This invention also relates to a compound according to the invention, as described hereinabove, for use as a medicament.

[0076] This invention also relates to a compound according to the invention, as described hereinabove, for use as inhibitor of HSP90.

[0077] The compounds of the invention are advantageously specific inhibitors of HSP90. In some embodiments, the compounds of the invention are selective inhibitors of HSP90 alpha with regard to HSP90 beta. In some embodiments, the compounds of the invention are selective inhibitors of HSP90 alpha with regard to the three other paralogs of HSP90 (HSP90 beta, Grp94 and Trap-1).

[0078] In some embodiments, the compounds of the invention present an improved penetration in brain compared to other HSP90 inhibitors.

[0079] This invention also relates to a compound according to the invention, as described hereinabove, for use in the treatment of a disease or disorder in which HSP90 is implicated. Examples of diseases or disorders in which HSP90 is implicated include cancers, neurodegenerative diseases, neurodegenerative diseases with proteins aggregates, infectious diseases, ROHHAD (Rapid Onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation), diabetic atherosclerosis, severe psoriasis, primary myelofibrosis, and acute pancreatitis.

[0080] In one embodiment, the invention provides a compound according to the invention, as described hereinabove, for use in the treatment of cancers, neurodegenerative diseases, neurodegenerative diseases with proteins aggregates, infectious diseases, ROHHAD, diabetic atherosclerosis, severe psoriasis, primary myelofibrosis, and acute pancreatitis.

[0081] The invention thus provides a compound according to the invention, as described hereinabove, for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer. In an embodiment the cancer is a solid cancer. In another embodiment, the cancer is a non-solid cancer.

[0082] Examples of cancers include, without being limited to, brain tumors, hematopoietic disorders, breast cancer, lung cancer, leukemia, lymphoma, pancreatic cancer, multiple myeloma, prostate cancer, glioma, colon cancer, gastric cancer, ovarian cancer, and any cancer with oncogene production chaperoned by HSP90. By “cancer with oncogene production chaperoned by HSP90” it is herein referred to cancers driven by oncogenic proteins that are HSP90 clients, wherein the oncogenic proteins are for example selected from v-Src, Lyn, Lck, Yes, Fps, Fes, Bcr-Abl, Raf-1, AKT / PKB, ErbB2, Plk-1, MET, Wee1, Cdc2, Cdc4, Cdc6, Dnmt-1, Survivin, Mutant p53, c-Myc, hTERT, MOK, MAK, MRK, DNA polymerase α, Estrogen receptor, Androgen receptor, HIF-1α, SV40 large T antigen, and SV40 small T antigen; and oncogenic translocations such as Alk-NPM, or Alk-EML4.

[0083] The present invention also provides a compound according to the invention, as described hereinabove, for use in the treatment of a neurodegenerative disease.

[0084] Examples of neurodegenerative diseases include, without being limited to, Alzheimer's disease, Senile dementia of the Alzheimer type, dementia of head trauma and diffuse brain damage, dementia pugilistica, frontal lobe dementia, Pick's disease, Huntington's disease, Multiple system atrophy combining dementia with ataxia and / or manifestations of Parkinson's disease, Progressive supranuclear palsy, diffuse Lewy body disease, corticodentatonigral degeneration, Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis, familial tremor, Gilles de la Tourette syndrome, cerebellar cortical degeneration, olivopontocerebellar atrophy, spinocerebellar degeneration, Shy-Drager syndrome, amyotrophic lateral sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, hereditary spastic paraplegia, neural muscular atrophy, chronic familial polyneuropathies, peroneal muscular atrophy, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, and Leber Amaurosis.

[0085] The present invention also provides a compound according to the invention, as described hereinabove, for use in the treatment of a neurodegenerative disease with proteins aggregates.

[0086] Examples of neurodegenerative disease with proteins aggregates include, without being limited to, congenital central hypoventilation syndrome (CCHS), Huntington's disease (HTT), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), alpha- synucleinopathies, and central hypoventilation syndrome (CHS).

[0087] In particular, the invention provides a compound according to the invention, as described hereinabove, for use in the treatment of congenital central hypoventilation syndrome (CCHS). The terms “congenital central hypoventilation syndrome”, “CCHS”, “Ondine’s curse”, “congenital failure of autonomic control”, “Haddad syndrome” and “Ondine-Hirschsprung disease” are equivalent and refer to a rare neurocristopathy characterized by absence of adequate autonomic control of respiration with decreased sensitivity to hypoxia and hypercapnia. Congenital central hypoventilation syndrome is characterized by a sleep hypoventilation associated with a dysfunction of PHOX2B CO2 / H+sensitive neurons of the retrotrapezoid nucleus / parafacial respiratory group(RTN / pFRG). The patients are thus devoid of the interoceptive alarms that normally trigger awakening in the case of life-threatening hypoxia during sleep and in more severely affected individuals, during waking periods as well. Congenital central hypoventilation syndrome is associated with a malfunction of the nerves that control involuntary body functions and abnormal development of early embryonic cells that form the spinal cord. Hypercapnia, acidosis, and hypoxemia resulting from CCHS negatively affect physiological functions and can be life-threatening.

[0088] The present invention also provides a compound according to the invention, as described hereinabove, for use in the treatment of an infectious disease.

[0089] Examples of infectious diseases include, without being limited to, viral infections such as infection by Enterovirus 71 (EV71), other virus from the picornavirus family, or COVID-19; and protozoan (Plasmodium) infections such as Malaria.

[0090] This invention also relates to the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for inhibiting HSP90.

[0091] This invention also relates to the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of a disease or disorder in which HSP90 is implicated, as defined above.

[0092] In one embodiment, the invention provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of cancers, neurodegenerative diseases, neurodegenerative diseases with proteins aggregates, infectious diseases, ROHHAD, diabetic atherosclerosis, severe psoriasis, primary myelofibrosis, and acute pancreatitis.

[0093] The invention thus provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of cancer, as defined above.

[0094] The invention also provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of a neurodegenerative disease, as defined above.

[0095] The invention also provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of a neurodegenerative disease with proteins aggregates, as defined above. Especially, the invention provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of congenital central hypoventilation syndrome (CCHS).

[0096] The invention also provides the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of an infectious disease, as defined above.

[0097] This invention also relates to a method of inhibiting HSP90 in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0098] This invention also relates to a method for the treatment of a disease or disorder in which HSP90 is implicated, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0099] This invention also relates to a method for the treatment of cancers, neurodegenerative diseases, neurodegenerative diseases with proteins aggregates, infectious diseases, ROHHAD, diabetic atherosclerosis, severe psoriasis, primary myelofibrosis, and acute pancreatitis, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0100] This invention also relates to a method for the treatment of a cancer, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0101] This invention also relates to a method for the treatment of a neurodegenerative disease, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0102] This invention also relates to a method for the treatment of a neurodegenerative disease with proteins aggregates, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove. Especially, this invention relates to a method for the treatment of congenital central hypoventilation syndrome (CCHS), in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention.

[0103] This invention also relates to a method for the treatment of an infectious disease, in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0104] According to one embodiment, the compound according to the invention is administrated to the subject as sole therapeutic agent.

[0105] According to another embodiment, the compound according to the invention is administrated to the subject in combination with at least another therapeutic agent.

[0106] According to one embodiment, the compound according to the invention is administrated to the subject in combination with at least another therapeutic agent that is beneficial for the treated disease.

[0107] In one embodiment, the other therapeutic agent may be selected from a second anti-cancer therapy, such as chemotherapy, immunotherapy, cell therapy and / or any anti- cancer agent currently in clinical use or in clinical trials.

[0108] According to one embodiment, the compound according to the invention may be administered in combination with conventional surgery, radiotherapy, or transplantation, and / or with at least another therapeutic agent as mentioned above.

[0109] Such conjoint treatments may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment. Such combination products employ the compounds of the invention within the dosage range described herein and the other therapeutic agent within its approved dosage range.

[0110] In the context of the present invention the term “combination” preferably means a combined occurrence of the compound according to the invention and an additional therapeutic agent. Therefore, the combination may occur either as one composition, comprising all the components in one and the same mixture (e.g. a pharmaceutical composition), or may occur as a kit of parts, wherein the different components form different parts of such a kit of parts. The administration of the compound according to the invention and of the additional therapeutic agent may occur either simultaneously or timely staggered, with similar or different timing of administration (i.e. similar or different numbers of administration of each component), either at the same site of administration or at different sites of administration, under similar of different dosage forms.

[0111] The compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracerebroventricular, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

[0112] The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active ingredient is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0113] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0114] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0115] The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0116] For topical use, creams, ointments, jellies, solutions, or suspensions, etc., containing the compounds of the present invention are employed.

[0117] In the treatment or prevention of HSP90-related diseases, an appropriate dosage level will generally be about 0.01 to 250 mg per kg patient body weight per day (mg / kg per day) which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 100 mg / kg per day, such as 0.1 to about 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered as a single daily dose, divided over one or more daily doses, for example on a regimen of 1 to 4 times per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. EXAMPLES

[0118] The present invention is further illustrated by the following examples. Abbreviations

[0119] The following abbreviations are used: ACN: acetonitrile, AcOH: Acetic acid, Ar: Argon, CyHex: Cyclohexane, DCM: Dichloromethane, DMF: N,N-dimethylformamide, eq: Equivalent, EtOAc or AcOEt: Ethyl acetate, EtOH: Ethanol, g: Grams, h, hr or hrs: Hour(s), L: Liters, MeOH: Methanol, mg: Milligrams, mL: Milliliters, mmol: Millimoles, mol: Moles, M: mol / L, MS: Mass spectrometry, MTBE: methyl-tert-butyl ether, PMB: para-Methoxybenzyl, RT or rt: room temperature,TEA: Triethylamine, TFA: Trifluoroacetic acid, THF: Tetrahydrofuran, TLC: Thin layer chromatography, µL: Microliters. CHEMISTRY EXAMPLES GENERAL PROCEDURES

[0120] The compounds of the invention may be synthesized using the general pathways described in Scheme 1 below.

[0121] Scheme 1: General scheme of synthesis of the compounds of the invention.SYNTHESIS OF THE COMPOUNDS OF THE INVENTION Compound 001: 2-((6-((cyclopropylmethyl)(methyl)amino)benzo[d][1,3]dioxol-5- yl)thio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine

[0122] Synthesis of intermediate (II-1)

[0123] Step 1: N2,N2-bis[(4-methoxyphenyl)methyl]-3-nitro-pyridine-2,4-diamine

[0124] To a stirred solution of 1-(4-methoxyphenyl)-N-[(4- methoxyphenyl)methyl]methanamine (4.45 g, 17.3 mmol, 1.2 eq.) and triethylamine (3.0 mL, 21.6 mmol, 1.5 eq.) in EtOH (36 mL, [C] = 0.4M) was added 2-chloro-3-nitro- pyridin-4-amine (2.50 g, 14.4 mmol) at RT and the resulting mixture was stirred at 90 °C for 8h. After cooling to RT, the mixture was concentrated under reduced pressure. The residue was partitioned between aq. sat. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give the tittle compound, 5.60 g (92% yield) as an orange oil. The crude was used directly in the next step without further purification. MS (ESI+): [M+H]+= 395.

[0125] Step 2: N2,N2-bis[(4-methoxyphenyl)methyl]pyridine-2,3,4-triamine

[0126] To a stirred solution of N2,N2-bis[(4-methoxyphenyl)methyl]-3-nitro-pyridine- 2,4-diamine (5.06 g, 12.8 mmol) in EtOH (60 mL, [C] = 0.2M) was added palladium on carbon (10% Pd / C, 546 mg, 2.57 mmol) at RT under Ar and the resulting mixture was stirred under H2 atmosphere at RT for 4h. The mixture was filtered over a pad of Celite and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (DCM / 7N in NH3 in MeOH, 90 / 10) to give the title compound, 3.53g (75% yield) as an orange oil. MS (ESI+): [M+H]+= 365.

[0127] Step 3: 4-[bis[(4-methoxyphenyl)methyl]amino]-1H-imidazo[4,5-c]pyridine-2- thiol (Intermediate II-1)

[0128] To a stirred solution of N2,N2-bis[(4-methoxyphenyl)methyl]pyridine-2,3,4- triamine (3.53 g, 9.69 mmol) in THF (48 mL, [C] = 0.2 M) was added 1,1-thiocarbonyl diimidazole (2.59 g, 14.5 mmol, 1.5 eq.) at RT and the resulting mixture was stirred at RT for 4h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (CyHex. / EtOAc, 9 / 1 to 2 / 1) to give the Intermediate II-1, 2.80g (71% yield) as a pink foam. MS (ESI+): [M+H]+= 407.

[0129] Synthesis of intermediate (III-1)

[0130] Step 1: N-(cyclopropylmethyl)-6-iodo-1,3-benzodioxol-5-amine

[0131] To a stirred solution of 6-iodo-1,3-benzodioxol-5-amine (2.0 g, 7.07 mmol) in DCM (29 mL, [C] = 0.25M) was added cyclopropanecarboxaldehyde (580 µL, 7.785 mmol, 1.1 eq.) followed by AcOH (1.2 mL, 21.2 mmol, 3 eq.) at RT and the resulting mixture was stirred at RT for 1h. Sodium triacetoxy borohydride (4.5 g, 21.2 mmol, 3 eq.) was added at 0°C and the resulting mixture was stirred at RT for 1h. Saturated aqueous NaHCO3was added under vigorous stirring. The phases were separated and the aqueous phase was extracted with DCM (2x). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (CyHex. / EtOAc (1 / 0 to 4 / 1) to afford the title compound, 1.46 g (52% yield) as a yellow oil. MS (ESI+): [M+H]+= 318.

[0132] Step 2: N-(cyclopropylmethyl)-6-iodo-N-methyl-1,3-benzodioxol-5-amine (Intermediate III-1)

[0133] To a stirred solution of N-(cyclopropylmethyl)-6-iodo-1,3-benzodioxol-5-amine (1.46 g, 3.68 mmol) in dry DMF (10 mL, [C] = 0.4M) was added NaH (60% in mineral oil, 220 mg, 5.52 mmol, 1.5 eq.) at 0 °C and the resulting mixture was stirred at RT for 30 min. Iodomethane (0.57 mL, 9.20 mmol, 2.5 eq.) was added and the resulting mixture was stirred at RT for 26h. The solution was partitioned between EtOAc and water and the layers were separated. The organic phase was washed with water (2x), brine, dried (Na2SO4), filtered and concentrated. The crude (2.5g) was purified by flash chromatography on silica gel (CyHex. / EtOAc (1 / 0 to 97 / 3) to afford the Intermediate III-1, 700 mg (57% yield) as a yellow oil. MS (ESI+): [M+H]+= 332.

[0134] Synthesis of Compound 001

[0135] Step 1: 2-[[6-[cyclopropylmethyl(methyl)amino]-1,3-benzodioxol-5- yl]sulfanyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-imidazo[4,5-c]pyridin-4-amine (Intermediate IV-1)

[0136] A microwave vial was charged with Intermediate II-1 4-[bis[(4- methoxyphenyl)methyl]amino]-1H-imidazo[4,5-c]pyridine-2-thiol (200 mg, 0.492 mmol), Intermediate III-1 N-(cyclopropylmethyl)-6-iodo-N-methyl-1,3- benzodioxol-5-amine (179 mg, 0.541 mmol, 1.1 eq.), sodium tert-butylate (118 mg, 1.23 mmol, 2.5 eq.), neocuproine (20 mg, 0.0984 mmol, 0.2 eq.) and copper(I) iodide (19 mg, 0.0984 mmol, 0.2 eq.). The vial was closed and flushed with argon for 10 min. Degassed DMF (2.5 mL, [C] = 0.2M) was added and the resulting mixture was stirred at120 °C for 17h. After cooling to RT, the mixture was diluted with EtOAc and quenched with aq. sat. NH4Cl. The layers were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue (432 mg) was purified by flash chromatography on silica gel (CyHex. / EtOAc, 4 / 1 to 3 / 1) to give the title compound Intermediate IV-1, 204 mg (68% yield) as a white solid. MS (ESI+): [M+H]+= 610.

[0137] Step 2 (A and B): 2-[[6-[cyclopropylmethyl(methyl)amino]-1,3-benzodioxol-5- yl]sulfanyl]-1-[2-(2,2-dimethylpropylamino)ethyl]-N,N-bis[(4- methoxyphenyl)methyl]imidazo[4,5-c]pyridin-4-amine[cyclopropylmethyl(methyl)amino]-1,3-benzodioxol-5-yl]sulfanyl]-N,N-bis[(4- methoxyphenyl) methyl]-1H-imidazo[4,5-c]pyridin-4-amine (200 mg, 0.328 mmol) in dry DMF (1.8 mL, 0.18M) was added caesium carbonate (267 mg, 0.82 mmol, 2.5 eq.) followed by 1,2-dibromoethane (0.14 mL, 1.64 mmol, 5.0 eq.) at RT and the resulting mixture was stirred at RT for 1.5h. The mixture was poured into water and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give the intermediate, 293 mg as a light green oil.

[0139] Step B: The intermediate was dissolved in DMF (1.64 mL, 0.17M) and neopentylamine (0.50 mL, 6.43 mmol, 13 eq.) was added at RT and the resulting mixture was stirred at RT for 7 days. The mixture was concentrated and purified by flash chromatography on silica gel (CyHex. / EtOAc, 3 / 1 to 1 / 1) to give the title compound, 150 mg (63% yield) as a colourless oil. MS (ESI+): [M+H]+= 723.

[0140] Step 3: 2-((6-((cyclopropylmethyl)(methyl)amino)benzo[d][1,3]dioxol-5- yl)thio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 001)

[0141] A solution of 2-[[6-[cyclopropylmethyl(methyl)amino]-1,3-benzodioxol-5- yl]sulfanyl]-1-[2-(2,2-dimethylpropylamino)ethyl]-N,N-bis[(4- methoxyphenyl)methyl]imidazo[4,5-c]pyridin-4-amine (150 mg, 0.197 mmol) in trifluoroacetic acid (1.5 mL) was stirred at RT for 3 days. The reaction mixture was concentrated in vacuo and the residue was diluted in H2O. Sat. aq. NaHCO3 was added and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude mixture (61 mg) was purified by prep. TLC on silica gel (DCM / MeOH, 95 / 5) to give Compound 001, 20 mg (20% yield) as a green oil. MS (ESI+): [M+H]+= 483.

[0142] The product was dissolved in MeOH (1 mL) and 0.5N HCl in MeOH (2 eq.) was added. After 5 min, the product was concentrated and dried under reduced pressure at 40 °C to give the corresponding bishydrochloride salt.Compound 002: 8-((6-((cyclopropylmethyl)(methyl)amino)benzo[d][1,3]dioxol-5- yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine

[0143] Synthesis of Compound 002

[0144] Step 1: 8-[[6-[cyclopropylmethyl(methyl)amino]-1,3-benzodioxol-5- yl]sulfanyl]-9H-purin-6-amine (Intermediate IV-2)

[0145] A microwave vial was charged with 6-amino-9H-purine-8-thiol (Intermediate II-2) (115 mg, 0.688 mmol), Intermediate III-1 N-(cyclopropylmethyl)- 6-iodo-N-methyl-1,3-benzodioxol-5-amine (239 mg, 0.722 mmol, 1.05 eq.), sodium tert- butylate (165 mg, 1.72 mmol, 2.5 eq.), neocuprine (29 mg, 0.138 mmol, 0.2 eq.) and copper(I) iodide (26 mg, 0.138 mmol, 0.2 eq.). The vial was closed and flushed with argon for 10 min. Degassed DMF (2.7 mL, [C] = 0.2M) was added and the resulting mixture was stirred at 120 °C for 20h. After cooling to RT, the mixture was diluted with EtOAc and quenched with aq. sat. NH4Cl. The layers were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (DCM / MeOH, 96 / 4) to give the title compound Intermediate IV-2, 37 mg (15% yield) as an orange oil. MS (ESI+): [M+H]+= 371.

[0146] Step 2 (A and B): 8-((6- ((cyclopropylmethyl)(methyl)amino)benzo[d][1,3]dioxol-5-yl)thio)-9-(2- (neopentylamino)ethyl)-9H-purin-6-amine (Compound 002)Step A: To a solution of Intermediate IV-2 8-[[6-[cyclopropylmethyl(methyl)amino]- 1,3-benzodioxol-5-yl]sulfanyl]-9H-purin-6-amine (37 mg, 0.10 mmol) diluted in dry DMF (1 mL, [C] = 0.1M) was added caesium carbonate (81 mg, 0.25 mmol, 2.5 eq.) followed by 1,2-dibromoethane (43 mL, 0.50 mmol, 5.0 eq.) at RT and the resulting mixture was stirred at RT for 2h. The mixture was poured into water and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give the intermediate, 46 mg as an orange oil.

[0147] Step B: The intermediate was dissolved in DMF (1 mL, [C] = 0.1M) and neopentylamine (0.18 mL, 1.5 mmol, 15 eq.) was added at RT and the resulting mixture was stirred at RT for 20h. The mixture was concentrated and purified by flash chromatography on silica gel (DCM / MeOH, 95 / 5) to give Compound 002, 20 mg (41% yield) as a light-yellow solid. MS (ESI+): [M+H]+= 484.

[0148] The product was dissolved in MeOH (1 mL) and 0.5N HCl in MeOH (2 eq.) was added. After 5 min, the product was concentrated and dried under reduced pressure at 40 °C to give the corresponding bis-hydrochloride salts. 5-yl)thio)-9-(2-

[0149] Synthesis of intermediate (III-2)

[0150] Step 1: N-allyl-6-iodo-1,3-benzodioxol-5-amine

[0151] To a solution of 6-iodo-1,3-benzodioxol-5-amine (900 mg, 3.42 mmol) in DMF (6.8 mL, [C] = 0.5M) was added potassium carbonate (709 mg, 5.13 mmol, 1.5 eq.) followed by allyl bromide (0.31 mL, 3.59 mmol, 1.05 eq.) at RT and the resulting mixture was stirred at RT for 20h. Most of the DMF was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL). The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (CyHex. / EtOAc, 1 / 0 to 4 / 1) to afford the title compound, 566 mg (52% yield) as a yellow oil. MS (ESI+): [M+H]+= 304.

[0152] Step 2: N-allyl-6-iodo-N-methyl-1,3-benzodioxol-5-amine (Intermediate III-2)

[0153] To a stirred solution of N-allyl-6-iodo-1,3-benzodioxol-5-amine (420 mg, 1.38 mmol) in dry DMF (3.9 mL, [C] = 0.4M) was added NaH (60% in mineral oil, 67 mg, 1.66 mmol, 1.2 eq.) at 0 °C and the resulting mixture was stirred at RT for 30 min. Iodomethane (0.10 mL, 1.66 mmol, 1.2 eq.) was added and the resulting mixture was stirred at RT for 20h. The solution was partitioned between EtOAc and water and the layers were separated. The organic phase was washed with water (2x), brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (CyHex. / EtOAc, 1 / 0 to 97 / 3) to afford Intermediate III-2, 383 mg (64% yield) as a yellow oil. MS (ESI+): [M+H]+= 318.

[0154] Synthesis of Compound 003

[0155] Step 1: 8-[[6-[allyl(methyl)amino]-1,3-benzodioxol-5-yl]sulfanyl]-9H-purin-6- amine (Intermediate IV-3)

[0156] A microwave vial was charged with 6-amino-9H-purine-8-thiol (Intermediate II-2) (184 mg, 1.10 mmol), Intermediate III-2 N-allyl-6-iodo-N-methyl- 1,3-benzodioxol-5-amine (384 mg, 1.21 mmol, 1.1 eq.), sodium tert-butylate (264 mg, 2.75 mmol, 2.5 eq.), neocuprine (46 mg, 0.22 mmol, 0.2 eq.) and copper(I) iodide (42 mg, 0.22 mmol, 0.2 eq.). The vial was closed and flushed with argon for 10 min. Degassed DMF (4.7 mL, [C] = 0.25M) was added and the resulting mixture was stirred at 120 °C for 20h. After cooling to RT, the mixture was diluted with EtOAc and quenched with aq. sat. NH4Cl. The layers were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (CyHex. / EtOAc, 4 / 1 to 3 / 1) to give Intermediate IV-3, 139 mg (32% yield) as an orange solid. MS (ESI+): [M+H]+= 357.

[0157] Step 2 (A and B): 8-((6-(allyl(methyl)amino)benzo[d][1,3]dioxol-5-yl)thio)-9- (2-(neopentylamino)ethyl)-9H-purin-6-amine (Compound 003)

[0158] Step A: To a solution of Intermediate IV-3 8-[[6-[allyl(methyl)amino]-1,3- benzodioxol-5-yl]sulfanyl]-9H-purin-6-amine (138 mg, 0.35 mmol) diluted in dry DMF (3.5 mL, [C] = 0.1M) was added caesium carbonate (170 mg, 0.52 mmol, 1.5 eq.) followed by 1,2-dibromoethane (0.15 mL, 1.74 mmol, 5.0 eq.) at RT and the resulting mixture was stirred at RT for 1.5h. The mixture was concentrated and purified by preparative TLC on silica gel (CyHex. / EtOAc, 2 / 3) to give the title compound, 55 mg (33% yield) as a white solid. MS (ESI+): [M+H]+= 464 / 466.

[0159] Step B: To a solution of 8-[[6-[allyl(methyl)amino]-1,3-benzodioxol-5- yl]sulfanyl]-9-(2-bromoethyl)purin-6-amine (55 mg, 0.114 mmol) dissolved in DMF (1.1 mL, [C] = 0.1M) was added neopentylamine (0.54 mL, 4.56 mmol, 40 eq.) at RT and the resulting mixture was stirred at RT for 20h. The mixture was concentrated and purified by preparative TLC on silica gel (DCM / MeOH, 95 / 5) to give Compound 003, 47 mg (86% yield) as a white solid. MS (ESI+): [M+H]+= 470.

[0160] The product was dissolved in MeOH (1 mL) and 0.5N HCl in MeOH (2 eq.) was added. After 5 min, the product was concentrated and dried under reduced pressure at 40 °C to give the corresponding bis-hydrochloride salts. Compound 004: 8-((6-(allyl(methyl)amino)-2,2-difluorobenzo[d][1,3]dioxol-5- yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine

[0161] Synthesis of intermediate (III-3)

[0162] Step 1: N-allyl-2,2-difluoro-6-iodo-1,3-benzodioxol-5-amine

[0163] To a solution of 2,2-difluoro-6-iodo-1,3-benzodioxol-5-amine (2.0g, 6.69 mmol) in DMF (8.4 mL, [C] = 0.8M) was added potassium carbonate (1.85g, 13.4 mmol, 2 eq.) followed by allyl bromide (0.87 mL, 10.0 mmol, 1.5 eq.) at RT and the resulting mixture was stirred at RT for 20h. Most of the DMF was removed under reduced pressure and theresidue was dissolved in EtOAc (50 mL). The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (CyHex. / EtOAc, 1 / 0 to 9 / 1) to afford the title compound, 1.25g (55% yield) as a colorless oil. MS (ESI+): [M+H]+= 340.

[0164] Step 2: N-allyl-2,2-difluoro-6-iodo-N-methyl-1,3-benzodioxol-5-amine (Intermediate III-3)

[0165] To a stirred solution of N-allyl-2,2-difluoro-6-iodo-1,3-benzodioxol-5-amine (500 mg, 1.40 mmol) in dry DMF (3.1 mL, [C] = 0.45M) was added NaH (60% in mineral oil, 67 mg, 1.66 mmol, 1.2 eq.) at 0 °C and the resulting mixture was stirred at r.t. for 30 min. Iodomethane (95 µL, 1.54 mmol, 1.1 eq.) was added and the resulting mixture was stirred at RT for 4h. The solution was partitioned between EtOAc and water and the layers were separated. The organic phase was washed with water (2x), brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (CyHex. / EtOAc, 1 / 0 to 9 / 1) to afford Intermediate III-3, 430 mg (87% yield) as a colorless oil. MS (ESI+): [M+H]+= 354.

[0166] Synthesis of Compound 004

[0167] Step 1: 8-[[6-[allyl(methyl)amino]-2,2-difluoro-1,3-benzodioxol-5-yl]sulfanyl]- 9H-purin-6-amine (Intermediate IV-4)

[0168] A microwave vial was charged with 6-amino-9H-purine-8-thiol (Intermediate II-2) (90 mg, 0.54 mmol), N-allyl-6-iodo-N-methyl-1,3-benzodioxol-5-amine (190 mg, 0.54 mmol, 1 eq.), sodium tert-butylate (129 mg, 1.34 mmol, 2.5 eq.), neocuprine (22 mg, 0.11 mmol, 0.2 eq.) and copper(I) iodide (20 mg, 0.11mmol, 0.2 eq.). The vial was closed and flushed with argon for 10 min. Degassed DMF (2.7 mL, [C] = 0.2M) was added and the resulting mixture was stirred at 120 °C for 20h. After cooling to RT, the mixture was diluted with EtOAc and quenched with aq. sat. NH4Cl. The layers were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (DCM / MeOH, 95 / 5) to give the title compound, 49 mg (23% yield) as an orange solid. MS (ESI+): [M+H]+= 393.

[0169] Step 2 (A and B): 8-((6-(allyl(methyl)amino)-2,2-difluorobenzo[d][1,3]dioxol- 5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine (Compound 004)

[0170] Step A: To a solution of 8-[[6-[allyl(methyl)amino]-2,2-difluoro-1,3- benzodioxol-5-yl]sulfanyl]-9H-purin-6-amine (49 mg, 0.12 mmol) diluted in dry DMF (1.2 mL, [C] = 0.1M) was added caesium carbonate (102 mg, 0.31 mmol, 2.5 eq.) followed by 1,2-dibromoethane (54 µL, 0.62 mmol, 5.0 eq.) at RT and the resulting mixture was stirred at RT for 20h. The mixture was concentrated and purified by preparative TLC on silica gel (CyHex. / EtOAc, 2 / 3) to give the title compound, 22 mg (35% yield) as a white solid. MS (ESI+): [M+H]+= 499 / 501.

[0171] Step B: To a solution of 8-[[6-[allyl(methyl)amino]-2,2-difluoro-1,3- benzodioxol-5-yl]sulfanyl]-9-(2-bromoethyl)purin-6-amine (22 mg, 44 µmol) dissolvedin DMF (0.9 mL, [C] = 0.05M) was added neopentylamine (104 µL, 0.88 mmol, 20 eq.) at RT and the resulting mixture was stirred at RT for 20h. The mixture was concentrated and purified by preparative TLC on silica gel (DCM / MeOH, 95 / 5) to give Compound 004, 19 mg (84% yield) as a white solid. MS (ESI+): [M+H]+= 506.

[0172] The product was dissolved in MeOH (1 mL) and 0.5N HCl in MeOH (2 eq.) was added. After 5 min, the product was concentrated and dried under reduced pressure at 40 °C to give the corresponding bis-hydrochloride salts. Compound 005: 2-((6-((2,2-difluoroethyl)(methyl)amino)benzo[d][1,3]dioxol-5- yl)thio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine

[0173] Synthesis of intermediate (III-4)

[0174] Step 1: 2,2-difluoro-N-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide

[0175] To a solution of compound 6-iodobenzo[d][1,3]dioxol-5-amine (2.00 g, 7.60 mmol, 1.00 eq.) in THF (20.0 mL) was added TEA (2.31 g, 22.8 mmol, 3.17 mL, 3.00 eq.) at 0°C and stirred at 25 °C for 0.5 hr. Then the mixture was added compound 2,2-difluoroacetic anhydride (1.99 g, 11.4 mmol, 1.50 eq.) at 0 °C and stirred at 25 °C for 1 hr. The reaction mixture was poured into ice water (50.0 mL) at 10 °C. The aqueous layer was extracted EtOAc (20.0 mL x 3). The combined organic layer was washed with brine (20.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1, Rf = 0.70) to give the title compound (2.10 g, 6.15 mmol, 80.9% yield, 99.9% purity) as a white solid. MS: [M+H]+= 340.0

[0176] Step 2: 2,2-difluoro-N-(6-iodobenzo[d][1,3]dioxol-5-yl)-N-methylacetamide

[0177] To a solution of 2,2-difluoro-N-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide (2.05 g, 6.01 mmol, 1.00 eq.) in DMF (20.0 mL) was added NaH (289 mg, 7.23 mmol, 60.0% purity, 1.20 eq.) at 0 °C and stirred at 25 °C for 0.5 hr. The mixture was added dropwise MeI (1.02 g, 7.21 mmol, 449 μL, 1.20 eq.) at 0°C and stirred at 25 °C for 1 hr. The reaction mixture was poured into ice saturated NH4Cl aqueous solution (100 mL) at 0 ~ 10°C and extracted with Ethyl acetate (30.0 mL x 3). The combined organic layer was washed with brine (30.0 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1to 1 / 1, Rf = 0.40) to give the title compound (1.1 g, 3.09 mmol, 51.5% yield, 99.9% purity) as a white solid. MS: [M+H]+= 356.0

[0178] Step 3: N-(2,2-difluoroethyl)-6-iodo-N-methylbenzo[d][1,3]dioxol-5-amine (Intermediate III-4)

[0179] To a solution of 2,2-difluoro-N-(6-iodobenzo[d][1,3]dioxol-5-yl)-N- methylacetamide (1.10 g, 3.10 mmol, 1.00 eq.) in THF (3.00 mL) was added BH3· . THF (1.00 M, 9.66 mL, 3.12 eq.) at 25 C. The mixture was stirred at 70°C for 2 hrs. The reaction mixture was poured into saturated NH4Cl aqueous solution (30.0 mL) at 0 ~ 10°C and extracted with Ethyl acetate (15.0 mL x 3). The combined organic layer was washed with brine (15.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1to 1 / 1, Rf = 0.60) to giveIntermediate III-4_(1.02 g, 2.86 mmol, 92.3% yield, 95.7% purity) as a yellow oil. MS: [M+H]+= 352.1

[0180] Synthesis of Compound 005

[0181] Step 1: 2-[(6-((2,2-difluoroethyl)(methyl)amino)-1,3-benzodioxol-5- yl)sulfanyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-imidazo[4,5-c]pyridin-4-amine (Intermediate IV-5)

[0182] To a solution of Intermediate II-1 (1.20 g, 2.95 mmol, 1.00 eq.) and Intermediate III-4 (1.01 g, 2.95 mmol, 1.00 eq.) in dioxane (10 mL) was added Cs2CO3 (2.40 g, 7.38 mmol, 2.50 eq.) and XantPhos Pd G3 (560 mg, 590 μmol, 0.200 eq.) at 25 °C under Ar. Then the mixture was stirred at 100°C for 2 hrs under Ar. The reaction mixture was cooled to 25 °C and poured into ice water (50.0 mL) at 10 °C. The aqueous layer was extracted EtOAc (30.0 mL x 3). The combined organic layer was washed with brine (30.0 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: UniSil 10-120 C18 70x250mm;mobile phase: [water( NH4HCO3)-ACN];gradient:50%-80% B over 20 min ) to give a crude product. Then the crude product was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1, Rf = 0.60) to give title Intermediate IV-5 (180 mg, 283 μmol, 9.58% yield, 97.4% purity) as a yellow oil. MS: [M+H]+= 620.4

[0183] Step 2 (A, B and C): 2-((6-((2,2-difluoroethyl)(methyl)amino) benzo[d][1,3]dioxol-5-yl)thio)-1-(2-(neopentylamino)ethyl)-1H-N,N-bis[(4- methoxyphenyl)methyl]imidazo[4,5-c]pyridin-4-amine

[0184] Step A: To a solution of Intermediate IV-5 (180 mg, 290 μmol, 1.00 eq.) in DMF (2.00 mL) was added Cs2CO3 (237 mg, 727 μmol, 2.50 eq.) and compound b (131 mg, 584 μmol, 2.01 eq.) at 25 °C. The mixture was stirred at 50 °C for 4 hrs. The reaction mixture was cooled to 25 °C and poured into ice water (30 mL). The aqueous layer was extracted EtOAc (15.0 mL x 3). The combined organic layers were washed with brine (15.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the resulting compound (300 mg, crude) as a yellow oil. MS: [M+H]+= 763.5

[0185] Step B: Compound resulting from step A (220 mg, 288 μmol, 1.00 eq.) in HCl / MeOH (2 M, 2.00 mL, 13.8 eq.) was stirred at 25°C for 1 hr. The reaction mixture was slowly poured into ice 20% NaHCO3(30.0 mL) at 10 °C. The aqueous layer was extracted EtOAc (15.0 mL x 3). The combined organic layers were washed with brine (15.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the corresponding deprotected compound (190 mg, crude) as a yellow oil. MS: [M+H]+= 663.4

[0186] Step C: To a solution of compound of step B (190 mg, 287 μmol, 1.00 eq.) and compound c (38.0 mg, 441 μmol, 48.8 μL, 1.54 eq.) in DCM (2.00 mL) was added NaBH(OAc)3 (152 mg, 717 μmol, 2.50 eq.) and HOAc (2.00 mg, 33.3 μmol, 1.91 μL, 0.100 eq.) at 0 °C. The mixture was stirred at 25 °C for 5 hrs. The reaction mixture was poured into ice water (30.0 mL), extracted EtOAc (15.0 mL x 3). The combined organic layer was washed with brine (15.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil (197 mg, crude). MS: [M+H]+= 733.5

[0187] Step 3: 2-((6-((2,2-difluoroethyl)(methyl)amino)benzo[d][1,3]dioxol-5-yl)thio)- 1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 005)

[0188] Compound resulting from step C above (197 mg, 269 μmol, 1.00 eq.) in TFA (2.00 mL) was stirred at 50 °C for 3 hrs. The reaction mixture was slowly poured into ice 20% NaHCO3 (30.0 mL) at 10 °C, extracted with EtOAc (15.0 mL x 3). The combined organic layers were washed with brine (15.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was triturated with MTBE (2.00 mL) at 25 °C for 2 hrs, then filtered and the cake was washed with MTBE (1.00 mL x 2). The yellow solid was dissolved in ACN (2.00 mL), 1M HCl (1.00 mL) was added and stirred at 25 °C for 0.5 hr, then the mixture was diluted with water (30.0 mL) and lyophilized to give Compound 005 (45.0 mg, 83.7 μmol, 31.1% yield, 98.4% purity, HCl) as a light yellow solid. MS: [M+H]+= 493.2. 1H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 9.12 (br s, 2H), 8.60 (br s, 2H), 7.85 (J = 5.20 Hz, 1H), 7.66 (d, J = 7.20 Hz, 1H), 7.19 (s, 1H), 6.62 (s, 1H), 6.25 - 5.97 (m, 3H), 4.81 (t, J = 7.60 Hz, 2H), 3.36 - 3.26 (m, 4H), 2.83 - 2.71 (m, 2H), 2.71 (s, 3H), 1.01 (s, 9H).5-yl)thio)-1- (2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine

[0189] Synthesis of intermediate (III-5)

[0190] Step 1: N-cyclobutyl-6-iodobenzo[d][1,3]dioxol-5-amine

[0191] To a solution of 6-iodobenzo[d][1,3]dioxol-5-amine (2.00 g, 7.60 mmol, 1.00 eq.) and cyclobutanone (600 mg, 8.56 mmol, 1.13 eq.) in DCM (20 mL) was added AcOH (46 mg, 766 μmol, 43.9 μL, 1.01e-1 eq.) and NaBH(OAc)3 (4.84 g, 22.8 mmol, 3.00 eq.) at 0 °C under N2. The reaction mixture was quenched by addition to ice water 100 mL at 0 °C, and extracted with DCM (50.0 mL x 3). The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1, Rf = 0.8) to give the title compound (2.00 g, 5.68 mmol, 74.6% yield, 90.3% purity) as a yellow oil. MS: [M+H]+= 317.9

[0192] Step 2: N-cyclobutyl-6-iodo-N-methylbenzo[d][1,3]dioxol-5-amine (Intermediate III-5)

[0193] To a solution of -cyclobutyl-6-iodobenzo[d][1,3]dioxol-5-amine (1.8 g, 5.68 mmol, 1.00 eq.) and formaldehyde (936 mg, 11.53 mmol, 2.03 eq.) in DCM (18.0 mL) was added AcOH (36.0 mg, 599 μmol, 34.3 μL, 1.06e-1 eq.) and NaBH(OAc)3 (3.62 g, 17.1 mmol, 3.01 eq.) at 0 °C under N2. The mixture was stirred at 25 °C for 3 hrs. The reaction mixture was quenched by addition to ice water 100 mL at 0 °C, and extracted with DCM (50.0 mL x 3). The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to giveIntermediate III-5_ (1.80 g, 5.21 mmol, 91.7% yield, 95.8% purity) as a yellow oil which was used to the next step. MS: [M+H]+= 331.9

[0194] Synthesis of Compound 006

[0195] Step 1: 2-[(6-(cyclobutyl(methyl)amino)-1,3-benzodioxol-5-yl)sulfanyl]-N,N- bis[(4-methoxyphenyl)methyl]-1H-imidazo[4,5-c]pyridin-4-amine (Intermediate IV-6)

[0196] To a solution of Intermediate II-1 (2.00 g, 4.58 mmol, 1.00 eq.) and Intermediate III-5 (1.52 g, 4.58 mmol, 1.00 eq.) in dioxane (20.0 mL) was added Cs2CO3 (3.73 g, 11.4 mmol, 2.50 eq.) and XantPhos Pd G3 (435 mg, 458 μmol, 0.100) at 25 °C under Ar. The mixture was stirred at 100 °C for 12 hrs under Ar. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (50.0 mL × 2). The combined organic layers were washed brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 1 / 1, Rf = 0.4) to give title Intermediate IV-6 (550 mg, 891 μmol, 19.5% yield, 98.8% purity) as a red solid. MS: [M+H]+= 610.3

[0197] Step 2 (A, B and C): 2-((6-(cyclobutyl(methyl)amino)benzo[d][1,3]dioxol-5- yl)thio)-1-(2-(neopentylamino)ethyl)-1H-N,N-bis[(4-methoxyphenyl)methyl]imidazo [4,5-c]pyridin-4-amine Step A:

[0198] Step A: To a solution of Intermediate IV-6 (500 mg, 820 μmol, 1.00 eq.) and compound b (367 mg, 1.64 mmol, 2.00 eq..) in DMF (5 mL) was added Cs2CO3(667 mg, 2.05 mmol, 2.50 eq.) at 25 °C under N2. The mixture was stirred at 50 °C for 5 hrs. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50.0 mL × 2). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1, Rf = 0.4) to give the resulting compound (583 mg, 676 μmol, 82.4% yield, 87.3% purity) as a yellow oil. MS: [M+H]+= 753.3

[0199] Step B: The compound resulting from step A (550 mg, 730 μmol, 1.00 eq..) was added to HCl / MeOH (6.00 mL) (2 M) at 25 °C and stirred for 1.5 hrs under N2. The reaction mixture was diluted with water (40.0 mL) and extracted with DCM (30.0 mL × 2). The combined organic layers were washed brine (40.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the corresponding deprotected compound (390 mg, 503 μmol, 68.9% yield, 84.2% purity) as a yellow oil which was used to the next step. MS: [M+H]+= 653.3

[0200] Step C: To a solution of compound of step B (350 mg, 536 μmol, 1.00 eq.) and compound c (70.0 mg, 813 μmol, 89.9 μL, 1.52 eq.) in DCM (4.00 mL) was added NaBH(OAc)3 (341 mg, 1.61 mmol, 3.00 eq.) and AcOH (4 mg, 66.6 μmol, 3.81 μL, 1.24e-1 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was diluted with water (30.0 mL) and extracted with DCM (20.0 mL × 2). The combined organic layers were washed brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil (330 mg, 425 μmol, 79.3% yield, 93.1% purity) (which was used to the next step. MS: [M+H]+= 723.3

[0201] Step 3: 2-((6-(cyclobutyl(methyl)amino)benzo[d][1,3]dioxol-5-yl)thio)-1-(2- (neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 006)

[0202] The compound resulting from step C above (300 mg, 414.97 μmol, 1.00 eq.) was added to TFA (3 mL) at 25 °C and stirred for 12 hrs under N2. The reaction mixture was concentrated under reduced pressure to remove TFA. The residue was adjusted to pH = 9~10 by NaOH solution and extracted with EtOAc (20.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (HCl)- ACN]; gradient: 5%-35% B over 10 min) and then lyophilized to give Compound 006 (68.0 mg, 140 μmol, 33.7% yield, 99.4% purity) as a white solid. MS: [M+H]+= 483.2. 1H NMR (400 MHz, MEOD) δ 7.69 (d, J = 7.60 Hz, 1H), 7.53 (br s, 1H), 7.41 (d, J = 7.20 Hz, 1H), 7.32 (s, 1H), 6.21 (s, 2H), 4.95 – 4.89 (m, 1H), 4.85 – 4.81 (m, 2H), 4.36 – 4.20 (m, 1H), 3.62 (t, J = 7.20 Hz, 2H), 3.25 (br s, 3H), 3.06 (s, 2H), 2.61 – 2.32 (m, 2H), 2.25 – 2.09 (m, 2H), 1.86 – 1.64 (m, 2H), 1.16 (s, 9H).BIOLOGY EXAMPLES Example 1: Binding to HSP90

[0203] Purpose: The binding to HSP90 alpha and HSP90 beta of the compounds of the invention and of the reference compounds Debio0932 was evaluated by fluorescent polarization.

[0204] Material and method: Fluorescent polarization was used to evaluate compounds binding to HSP90 alpha (N-terminal, ref 50298 BPS) and beta (N-terminal, ref 50299 BPS). Binding was determined by calculating the displacement of the interaction of HSP90 isoforms with an FITC-labeled geldanamycin (first generation pan-HSP90 inhibitor). On a 96-wells plate, each compound was added by a Tecan D300E at different concentrations, ranging from 0.01 µM to 100 µM. FITC-geldanamycin and HSP90 alpha or beta was then added, and plates were analyzed using a EnVision Multimode Plate Reader.

[0205] Results: IC50 values of competitive binding were calculated based on testing of a concentration response for individual compounds and are summarized in Table 2.

[0206] Table 2 Compound HSP90alpha HSP90beta IC50 (µM) IC50 (µM) 001 0.04 0.09 002 0.12 0.15 003 0.06 0.12 004 0.45 1.9 005 0.88 0.83 006 0.6 1.15 Debio0932 0.09 0.16

[0207] Conclusion: The compounds of the invention show a binding to HSP90 isoforms alpha and beta of at least the same order as reference compound Debio0932, or even improved in some cases.Example 2: Heat shock response (HSR)

[0208] Purpose: One of the main activities of N-terminal HSP90 inhibitors such as those of the present invention is to trigger the heat shock response (HSR), mainly characterized by the up-regulation of HSP70 caused by the binding to HSP90 by the inhibitor.

[0209] Material and method: MCF-7 cells were treated with Debio0932 or a compound according to the invention at 10 µM, and incubated for 24 hours. Cell lysates were then prepared in RIPA buffer and each condition was analyzed by western blot analysis for HSP70 expression. GAPDH was used as a loading control. Effect of each compound on HSP70 induction was evaluated as the ratio of HSP70 signal compared to GAPDH.

[0210] Results: HSP70 levels at 10µM (i.e. ratios of HSP70 signal to GAPDH) are summarized in Table 3.

[0211] Table 3 Compound HSP70 level (10µM) 001 4.2 002 3.23 003 1.79 Debio0932 1.85

[0212] Conclusion: Treatment of the cells by a compound according to the invention led to an expression of HSP70 of at least the same order as reference compound Debio0932, or even improved in some cases, showing that the compounds of the invention trigger a strong HSR. Example 3: Metabolization – CYP inhibition profile

[0213] Purpose: Cytochrome P450 enzymes inhibition assay is used to predict drug interaction with CYP enzymes, as this interaction is predictive of the compound metabolization. In vitro inhibition of the 5 main cytochrome P450 isoforms (CYP1A2,CYP2C9, CYP2C19, CYP2D6 and CYP3A4-M) was evaluated for the compounds of the invention and for the reference compounds Debio0932 by LC-MS / MS.

[0214] Material and method: CYP isoform-specific substrates are incubated individually with human or mouse liver microsomes and a concentration range (0.05 – 50 µM) of either the tested compounds, or known CYP inhibitors used as controls. After a 10 minutes incubation at 37°C, the formation of metabolites is monitored by LC-MS / MS.

[0215] Results: IC50 values (µM) were calculated based on testing of a concentration response for individual compounds and are summarized in Table 4.

[0216] Table 4 Compound CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 001 50 50 50 50 50 002 50 50 50 50 26.1 003 50 50 50 50 5.12 004 50 50 17.8 0.24 6.1 Debio0932 45.9 4.44 0.843 3.73 16.8

[0217] Conclusion: The compounds of the invention showed an improved CYP inhibition profile (decreased inhibition), compared to the reference compound Debio0932, suggesting that they could have a more stable metabolization profile and therefore improved overall pharmacokinetic properties. Example 4: Metabolization – Liver microsome clearance

[0218] Purpose: Liver microsome clearance assay consists in calculating the time it takes for a compound to be degraded in presence of liver microsomes in order to predict its metabolization and clearing rate in a living organism. In vitro clearances of the compounds of the invention and of the reference compound Debio0932 were calculated in presence of human liver microsome by LC-MS / MS.

[0219] Material and method: Each compound was added to well containing human microsome preparation and mixed. Plates were then incubated at 37°C for different time points before adding quenching solution to stop the reaction. Plates were then sealed and shaken for 10 minutes prior to LC-MS / MS analysis.

[0220] Results: The predicted hepatic intrinsic clearance CLint(liver)(mL / min / kg) was calculated for each compound with the following formula:wherein: C0is the concentration of the tested compound at time t = 0; Ct is the concentration of the tested compound at time t (min); ke is the elimination rate constant; t is the time point of measure (min); CLint(mic)(mL / min / mg microsomes) is the in vitro intrinsic clearance, in presence of liver microsomes; CLint(liver) (mL / min / kg) is the predicted in vivo intrinsic clearance.

[0221] Results in Table 5 are expressed as a percentage of Debio0932 CLint(liver)(mL / min / kg).

[0222] Table 5 Compound CLint(liver) as a percentage of Debio 0932 Debio0932 100.00 001 48.54 002 60.63 003 55.74 004 38.78 005 77.74 006 83.80

[0223] Conclusion: The compounds of the invention showed an improved microsomal clearance profile (decreased CLint(liver)), compared to the reference compound Debio0932, suggesting that they could have a more stable metabolization profile and therefore improved overall pharmacokinetic properties.

Claims

CLAIMS 1. A compound of formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, wherein X1is N or CH; X2is N or CH; provided that X1and X2are not both N; Y is S, SO, SO2, NH, O, or CH2; L1is a C1-4-alkyl; R1is a C1-8-alkyl; R1’is H or C1-4-alkyl; n is equal to 1 or 2. R2and R2’are each independently H, D, methyl, or halo; A is NR3R3’, OR3, or SO2R3; wherein: R3is cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, C1-4-haloalkyl, cyanoalkyl, cyanocarbonyl, aminocarbonylalkyl; wherein the cycloalkyl and heterocyclyl moieties are optionally substituted by one or more substituent selected from D, cyano, halo, hydroxyl, and C1-4-alkyl; R3’is C1-4-alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, C1-4-haloalkyl, cyanoalkyl, cyanocarbonyl, aminocarbonylalkyl; wherein the cycloalkyl and heterocyclyl moieties are optionally substituted by one or more substituent selected from D, cyano, halo, hydroxyl, and C1-4- alkyl; preferably R3’is C1-4-alkyl; more preferably R3’is methyl.

2. The compound according to claim 1, wherein X1and X2are both CH or X1is N and X2is CH.

3. The compound according to claim 1 or claim 2, wherein Y is S, SO or NH, preferably Y is S.

4. The compound according to any one of claims 1 to 3, wherein n is equal to 1, and R2and R2’are both H or both F.

5. The compound according to any one of claims 1 to 4, wherein L1is ethyl, R1is neopentyl and R1’is H.

6. The compound according to any one of claims 1 to 5, wherein A is NR3R3’, wherein R3is cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, or C1-4- haloalkyl; and R3’is C1-4-alkyl; preferably wherein R3is cycloalkyl, cycloalkylalkyl, alkenyl, or C1-4-haloalkyl; and R3’is C1-4-alkyl.

7. The compound according to any one of claims 1 to 6, wherein R3is of formula (i):wherein Z is CH or N; each R4is independently H, D, cyano, halo, hydroxyl, or C1-4-alkyl; m is equal to 0, 1, 2, or 3; p is equal to 1, 2, 3, or 4; and represents the point of attachment to the rest of the compound.

8. The compound according to any one of claims 1 to 6, wherein R3is alkenyl, or C1-4-haloalkyl; preferably R3is allyl or difluoroethyl.

9. The compound according to any one of claims 1 to 8, selected from:2-((6-((cyclopropylmethyl)(methyl)amino)benzo[d][1,3]dioxol-5-yl)thio)-1-(2- (neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine; 8-((6-((cyclopropylmethyl)(methyl)amino)benzo[d][1,3]dioxol-5-yl)thio)-9-(2- (neopentylamino)ethyl)-9H-purin-6-amine; 8-((6-(allyl(methyl)amino)benzo[d][1,3]dioxol-5-yl)thio)-9-(2- (neopentylamino)ethyl)-9H-purin-6-amine; 8-((6-(allyl(methyl)amino)-2,2-difluorobenzo[d][1,3]dioxol-5-yl)thio)-9-(2- (neopentylamino)ethyl)-9H-purin-6-amine; 2-((6-((2,2-difluoroethyl)(methyl)amino)benzo[d][1,3]dioxol-5-yl)thio)-1-(2- (neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine; 2-((6-(cyclobutyl(methyl)amino)benzo[d][1,3]dioxol-5-yl)thio)-1-(2- (neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine; and pharmaceutically acceptable salt and / or solvate thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable carrier.

11. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament.

12. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of cancers, neurodegenerative diseases, neurodegenerative diseases with proteins aggregates, infectious diseases, ROHHAD (Rapid Onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation), diabetic atherosclerosis, severe psoriasis, primary myelofibrosis, and acute pancreatitis.

13. The compound for use according to claim 12, wherein the cancer is selected from brain tumors, hematopoietic disorders, breast cancer, lung cancer, leukemia, lymphoma, pancreatic cancer, multiple myeloma, prostate cancer, glioma, colon cancer, gastric cancer, ovarian cancer, and any cancer with oncogene production chaperoned by HSP90.

14. The compound for use according to claim 12, wherein the neurodegenerative disease is selected from Alzheimer's disease, Senile dementia of the Alzheimer type, dementia of head trauma and diffuse brain damage, dementia pugilistica, frontal lobe dementia, Pick's disease, Huntington's disease, Multiple system atrophy combining dementia with ataxia and / or manifestations of Parkinson's disease, Progressive supranuclear palsy, diffuse Lewy body disease, corticodentatonigral degeneration, Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis, familial tremor, Gilles de la Tourette syndrome, cerebellar cortical degeneration, olivopontocerebellar atrophy, spinocerebellar degeneration, Shy-Drager syndrome, amyotrophic lateral sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, hereditary spastic paraplegia, neural muscular atrophy, chronic familial polyneuropathies, peroneal muscular atrophy, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, and Leber Amaurosis.

15. The compound for use according to claim 12, wherein the neurodegenerative disease with proteins aggregates is selected from congenital central hypoventilation syndrome (CCHS), Huntington's disease (HTT), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), synucleinopathies, and central hypoventilation syndrome (CHS).

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